Edited by R
L
Souhami
MD FRCP FMedSci
Emeritus Professor of Medicine, University College London, UK J Moxham MD FRCP Professor of Respiratory Medicine and Vice-Dean, Guy's King's and St Thomas' School of Medicine, King's College Hospital, London, UK
CHURCHILL LIVINGSTONE
EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2002
CHURCHILL LIVINGSTONE An imprint of Elsevier Limited © Pearson Professional Limited 1996 Assigned to Harcourt Brace and Company 1998 © 2002, Elsevier Science Limited. All rights reserved. © 2004, Elsevier Limited. All rights reserved.
Commissioning Editor: Laurence Hunter Project Development Manager: Barbara Simmons Project Manager: Nancy Arnott Designer: Erik Bigland
The right of Robert Souhami and John Moxham to be identified as editors of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without either the prior permission of the publishers or a licence permitting restricted copying in the United Kingdom issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London WIT 4LP. Permissions may be sought directly from Elsevier's Health Sciences Rights Department in Philadelphia, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail:
[email protected]. You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting 'Customer Support' and then 'Obtaining Permission First edition 1990 Second edition 1994 Third edition 1997 Fourth edition 2002 Reprinted 2004 ISBN 0-443-06464-4
British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library
Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress
Note Medical knowledge is constantly changing. As new information becomes available, changes in treatment, procedures, equipment and the use of drugs become necessary. The authors and the publishers have taken care to ensure that the information given in this text is accurate and up to date. However, readers are strongly advised to confirm that the information, especially with regard to drug usage, complies with the latest legislation and standards of practice. your source for books, journals and multimedia in the health sciences www.elsevier hea lth.com
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Preface The Fourth Edition of this textbook continues the approach, first begun fifteen years ago, to provide a comprehensive account of internal medicine that incorporates the ideas of modern medical science. The intervening years have strengthened our belief that an understanding of cellular and physiological processes makes medicine more exciting and less arbitrary. The emphasis of the book is clinical, giving a full description of the presentation, investigation and treatment of disease. We have attempted to interpret these clinical aspects by reference to the underlying mechanisms whenever possible. Modern integrated curricula demand this approach. The textbook is primarily intended for students of medicine, but we hope and anticipate that it will continue to be of value to trainee doctors and health care professionals in many fields. The Fourth Edition has been completely revised to incorporate all major developments and advances, leading to an expansion of many sections especially in the areas of infectious disease including AIDS, and cardiovascular disease. Many of the illustrations have been replaced or extended to include the most up-to-date epidemiological data. We hope that these will give the reader a sense of the way medicine is developing and where future advances in practice may lead. The most important innovation, however, affects the entire book. By linking the book to an easily-accessed internet site we
have been able to incorporate case problems, multiple choice questions and clinical images throughout the text. The illustrative case problems, some of which are in the textbook itself, are designed to allow the reader to test his or her knowledge by practical application in clinical problem solving. Knowledge and understanding can also be assessed by multiple choice questions, formerly in a companion volume but which are now located on the associated internet site. In addition the website contains 500 supplementary clinical images. This extra information, all of which is clearly cross-referenced in the text, represents for the reader an important additional compendium of knowledge, which expands the versatility of the book as a learning aid. The range and depth of specialised medical knowledge necessary for a major textbook has led us to select our authors from a wide range of medical schools. They have been chosen for their acknowledged reputation in clinical and scientific medicine. In this Fourth Edition we have again expanded the team of authors. All of us would be pleased to receive suggestions which will help the book change and develop for future editions. London 2002
RLS JM
V
Acknowledgements As in previous editions we are greatly indebted to Laurence Hunter for his help in the planning and realisation of the new edition. He has a very effective production team that have made our task much easier. Our editor Barbara Simmons has, as usual, been helpful, efficient and outstandingly courteous even in the face of occasionally rather provoking circumstances. We owe her a lot and are very grateful.
vi
The multiple choice questions and answers for the website have been developed by Dr Andrew Freedman, Dr Richard Watts and Dr Richard Evans. We are very grateful to them for their painstaking work, which has added greatly to the educational value of the book. We are also grateful to Dr Donncha O'Gradaigh for writing the rheumatology case studies.
Contributors Geoffrey J Bellingan PhD MRCP Senior Lecturer, Department of Medicine, University College London Medical School; Consultant, Department of Intensive Care Medicine, University College London Hospitals, London, UK Brian T Cooper BSC MD FRCP Consultant Gastroenterologist, City Hospital, Birmingham; Senior Clinical Lecturer in Medicine, University of Birmingham, UK John Costello MD FRCP FRCPI Consultant Physician and Clinical Director of Medicine, King's College Hospital, London, UK
Jeremy Holmes MD MRCP FRCPsych Consultant Psychotherapist, Devon Partnership Trust; Senior Lecturer, University of Exeter, Exeter, UK Cameron T C Kennedy MA MB BChir FRCP Consultant Dermatologist and Clinical Senior Lecturer, Bristol Dermatology Centre, Bristol, UK Michael E J Lean MA MD FRCP Professor of Human Nutrition, University of Glasgow; Consultant Physician, Glasgow Royal Infirmary; Non-executive Director, Health Education Board for Scotland, Glasgow, UK David C Linch BA MB BChir FRCP FRCPath FMedSci
John Cunningham MD FRCP Professor of Renal and Metabolic Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, UK J David M Edgar BSc(Hons) FRCP MRCPath Consultant Immunologist, Regional Immunology Service, The Royal Hospitals Belfast, N Ireland
Professor of Haematology, Royal Free and University College London Medical School, London, UK Richard G Long MD(Lond) FRCP (Lond) Consultant Gastroenterologist, City Hospital and Queen's Medical Centre, Nottingham; Clinical Teacher, Nottingham University Medical School, Nottingham, UK
Jeremy M Gibbs MD FRCP Consultant Neurologist and Honorary Senior Lecturer, Royal Free Hospital, London, UK
John P Monson MD FRCP Professor of Endocrinology, Department of Endocrinology, Barts and the London, Queen Mary's School of Medicine and Dentistry, London, UK
John Goldstone MD FRCA Consultant in Intensive Care Medicine and Consultant Anaesthetist, University College London Hospitals, London, UK
John Moxham MD FRCP Professor of Respiratory Medicine and Vice-Dean, Guy's King's and St Thomas' School of Medicine, King's College Hospital, London, UK
Robin A C Graham-Brown BSc MB FRCP Consultant and Honorary Senior Lecturer in Dermatology, University Hospital of Leicester NHS Trust and Leicester Royal Infirmary, Leicester, UK
John O'Grady MD FRCPI Consultant Hepatologist, King's College Hospital, London, UK
Brian Hazleman MA FRCP Consultant Rheumatologist, Addenbrooke's Hospital, Cambridge; Director Rheumatology Research Unit; Fellow, Corpus Christi College, Cambridge, UK
Peter W Overstall FRCP Consultant in Geriatric Medicine, Hereford Hospital, Hereford, UK
VII
Philip A Routledge MD FRCP FRCPE Professor of Clinical Pharmacology, University of Wales College of Medicine, Cardiff; Honorary Consultant Physician, Cardiff and Vale NHS Trust, Cardiff, UK
John Wilding DM FRCP Reader in Medicine and Honorary Consultant Physician, University of Liverpool and University Hospital Aintree, Liverpool, UK
John W Scadding MD FRCP Consultant Neurologist, The National Hospital for Neurology and Neurosurgery and Whittington Hospital, London, UK
Gareth Williams MA MD FRCP Professor of Medicine and Honorary Consultant Physician, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK
Herb F Sewell MB ChB MSC PHD FRCP FRCPath FMedSci Professor and Consultant Immunologist, University of Nottingham, Queen's Medical Centre, Nottingham, UK Martin Smith MBBS FRCA Consultant Neuroanaesthetist, Department of Neuroanaesthesia and Intensive Care, The National Hospital for Neurology and Neurosurgery, London, UK Robert L Souhami MD FRCP FMedSci Emeritus Professor of Medicine, University College London, UK L B Tan DPM FRCP FESC Consultant Cardiologist, Leeds General Infirmary, Leeds, UK J Malcolm Walker MD FRCP Consultant Cardiologist and Clinical Director of the Hatter Institute of Cardiovascular Studies, University College Hospitals, London, UK Mark H Wansbrough-Jones MSC FRCP Consultant Physician and Senior Lecturer in Infectious Diseases, St George's Hospital and Medical School, London, UK Antony P Weetman MD DSC FRCP Professor of Medicine, University of Sheffield; Honorary Consultant Physician, Sheffield Teaching Hospitals Trust, Sheffield, UK
viii
Ian G Williams BSC MRCP Senior Lecturer, Department of Sexually Transmitted Diseases, University College London Medical School, London, UK Robin M Winter FRCP FMedSci Professor of Dysmorphology and Clinical Genetics, Institute of Child Health, London, UK Stephen G Wright MB FRCP Consultant Physician, Hospital for Tropical Diseases, London; Honorary Senior Lecturer, London School of Hygiene and Tropical Medicine, London, UK
MULTIPLE CHOICE QUESTIONS Richard H Evans MRCP Specialist Registrar in Infectious Diseases and General (Internal) Medicine, University Hospital of Wales, Cardiff, UK Andrew Freedman MA MD FRCP Senior Lecturer in Infectious Diseases, University of Wales College of Medicine; Consultant Physician, University Hospital of Wales, Cardiff, UK Richard A Watts MA DM FRCP Consultant Rheumatologist Ipswich Hospital NHS Trust, Ipswich, UK
Contents 1. Therapeutics and toxicology
14. Critical care medicine
1
725
J Goldstone, G J Bellingan, M Smith
P A Routledge
2. Acute physical and environmental disorders 45
15. Gastrointestinal disease 751 R G Long, B T Cooper
J Moxham, R L Souhami
16. Liver and biliary tract disease 835 3. The genetic basis of disease
57
J O'Grady
R M Winter
17. Endocrine disease 4. Immunological disorders
79
883
A P Weetman
J D M Edgar, H F Sewell
5. Nutrition in clinical medicine
105
18. Metabolic bone disease and mineral metabolism 953 J Cunningham, J P Monson
M E J Lean
6. Cancer medicine
19. Diabetes mellitus and lipid metabolism
145
979 J Wilding, G Williams
R L Souhami
7. Ageing and disease 171 20. Renal and urinary disease 1031 J Cunningham
P W Overstall
8. Psychological medicine
205 21. Salt and water homeostasis and acidbase balance 1099
J Holmes
9. Infectious, tropical and parasitic disease 259 M H Wansbrough-Jones, S G Wright
10. Skin disease
J P Monson
22. Musculoskeletal and connective tissue disease 1119
379
B Hazleman
C T C Kennedy, RAG Graham-Brown
23. Haematological disorders 1201 11. AIDS and genitourinary disease
439
D C Linch
I G Williams
24. Neurological disease 12. Cardiovascular disease
463
1283
J W Scadding, J Gibbs
J M Walker, L B Tan
Index 13. Respiratory disease J Moxham, J Costello
1443
605 ix
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n Therapeutics andToxicology Philip A Routledge
Pharmacodynamic variability refers to differences in response to the same drug concentration at its effector site. This is sometimes related to differences in the number and/or activity of specific receptors or other effector sites (e.g. ion channels). The very young and the elderly appear to have an increased sensitivity to several drugs, particularly those affecting the central nervous system. An increased sensitivity to drugs acting on the central nervous system is also seen in patients with chronic renal and liver disease. The elderly appear also to have less adaptable homeostatic mechanisms and are therefore more prone to drug-induced postural hypotension or hypothermia. Hyperthyroid patients are more sensitive to the effects of oral anticoagulants and less sensitive to digoxin.
Causes of variability in drug response 1
Poisoning with gases and volatile solvents 33
PHARMACOKINETIC VARIABILITY
Adverse drug reactions 5
Overdose with alcohols 35
Drug interactions 7
Poisoning with corrosive agents 36
This occurs when the handling of a drug is altered in disease or in different physiological states. The causes of variability are shown in Summary 1 (p. 4).
Therapeutic drug monitoring 11 Specific drugs 12 Drug regulation and development 13
Drug overdose 15
Poisoning with insecticides, herbicides, fungicides and rodenticides 37 Poisonous plants and fungi 39 Poisonous animals 41
Diagnosis of poisoning 16 Principles of management of poisoning 18
Poisoning by metals 43
Management of specific drug overdose 23
Therapeutics is the branch of medicine that deals with the treatment and cure of disease and ill health. Medicines are the most important tool in therapeutics, and an understanding of their pharmacology in normal dose and excess dose (toxicology) is essential in ensuring their safe and effective use. Therapeutics developed as a specialty because of the need to understand the causes of biological variability in drug response in humans, particularly in disease states.
CAUSES OF VARIABILITY IN DRUG RESPONSE PHARMACODYNAMIC VARIABILITY There are three major ways in which a drug can produce pharmacological effects: • By combination with specific receptors; • By alteration of physiological enzyme processes; • By direct physical or chemical action.
Absorption Drugs are usually given by mouth and must therefore pass through the bowel wall in order to enter the bloodstream. This occurs via four different mechanisms: • Passive diffusion, which involves diffusion down a concentration gradient from the gut into the bloodstream. For this to occur the drug must dissolve in the gastrointestinal fluids, traverse the cell membrane and enter the bloodstream. The rate at which it does so depends on both the concentration gradient and the lipid solubility of the drug. This is the most important mechanism of absorption for most drugs. • Active transport, a less important mechanism by which some drugs, because of their resemblance to naturally occurring substances, use existing transport systems. Thus, levodopa is absorbed by the active process responsible for absorption of the amino acid tyrosine. • Filtration through pores, a route generally limited to molecules of molecular weight less than 100 (e.g. urea). Most drugs are too large to traverse the pores between cells. • Endocytosis, by which drugs or particles are engulfed by cells in the bowel wall. This is of relatively little importance to drug absorption. Factors affecting absorption Absorption is affected by the chemical nature and formulation of the drug, as well as the physiological characteristics of the absorption site. Thus, some drugs cannot be administered orally because they are broken down by gastrointestinal enzymes (e.g. the polypeptide insulin) or are unstable at extremes of pH (e.g. benzyl penicillin at gastric pH). Most drugs are either weak acids or weak bases and thus exist in two forms in solution - as ions or as undis-
1
sociated molecules. At the low pH encountered in the stomach, a weakly acidic drug exists mainly in its undissociated form; it is thus more lipid soluble and will tend to be more easily absorbed. Basic drugs, on the other hand, are largely ionized at low pH and exist predominantly in the undissociated form only in the alkaline medicine of the small bowel. Despite these considerations, both acidic and basic drugs tend to be absorbed predominantly in the small intestine, because they are there for longer and because the inner surface of the intestine provides a much greater absorptive area than the stomach. Formulation factors are important in determining the rate and extent of drug absorption. Most drugs consist not only of an active agent but also of diluents, granulating and binding agents, lubricants and disintegrating agents, any of which may have a marked effect on absorption. Particle size of the active constituent may also be important, and sustained- or delayed-release preparations will also delay absorption rate. Gastrointestinal motility affects the rate of absorption. Delays in gastric emptying will result in delayed drug absorption, although the extent of absorption is normally unchanged. Food has a variable effect. Some drugs (e.g. propranolol) have greater bioavailability in the presence of food because of reduced presystemic elimination, whereas others (e.g. rifampicin) are more poorly absorbed. Such factors may be important in determining the times of administration of drugs. The route of administration is also important. Alternatives to the oral route are:
2
• Intramuscular injection, either to speed the onset of effects or to enhance bioavailability when the oral route is suboptimal. Use of the intramuscular route can, however, cause local pain, and some drugs (e.g. phenytoin and diazepam) are poorly and variably absorbed when administered in this way, because of poor solubility at tissue pH. Absorption rate varies with the muscle group used and may be slow in situations of poor tissue perfusion. • Rectal administration can sometimes be used, but because the haemorrhoidal veins drain partly into the portal tract, presystemic elimination is not completely avoided. The suppository may also be variably retained or have poor and erratic absorption. • Buccal administration can completely avoid presystemic elimination and is used for drugs (e.g. glyceryl trinitrate) that are rapidly metabolized after the oral route. Unfortunately, not all such drugs can rapidly penetrate the buccal mucosa and enter the systemic circulation. • Transdermal administration is an alternative to the buccal route for drugs such as glyceryl trinitrate or the antihistamine hyoscine. The rate of absorption varies with the skin site used and the extent of absorption is limited, so that only very potent drugs (effective dose <10mg) can be usefully administered by this route. Absorption is normally rapid, but membranes are being developed to control the rate.
• Intrapulmonary route. Some drugs, and all anaesthetic gases, are administered by the intrapulmonary route. Non-gaseous compounds are difficult to introduce into the lungs. Only 10% of a drug administered by pressurized aerosol actually enters the lungs: the remainder is deposited in the buccal cavity and subsequently swallowed. Absorption of drugs is normally so efficient that it is unusual to see differences in the extent of absorption of most modern drugs, even in the presence of extensive bowel resection. However, reduced absorption may occur in severe malabsorption syndromes or in severe diarrhoea, or in severe congestive cardiac failure because of oedema of the small intestine. Differences in bowel motility may affect the rate (often more than the extent) of absorption. Gastric emptying is slow and erratic in the very young and in adults who are shocked or in pain. In such circumstances (e.g. myocardial infarction) threshold concentrations for drug effect may not be achieved rapidly, or at all, and the drug (e.g. analgesic treatment) may be more effective when given by an alternative, non-alimentary route.
Distribution If drug distribution did not occur, only those drugs with an action within the vascular compartment would provoke biological effects. Like absorption, distribution is dependent on the physicochemical characteristics of the drug as well as upon biological factors. The major physicochemical properties determining drug distribution are lipid solubility and (if the drug is a weak electrolyte) the degree of dissociation (ionization) in tissues. Highly lipid-soluble drugs are generally distributed throughout all fluid compartments and, because they can cross lipid membranes readily, can reach most organs, including the brain. Poorly lipid-soluble drugs are normally able to enter the interstitial fluid, but if they are weak electrolytes only the undissociated form can penetrate the cells, and then only to a limited extent, depending on the lipid-water partition coefficient. Biological factors determining the distribution of drugs in the body include the degree of both plasma protein binding and of uptake by tissue, either by binding or by active transport mechanisms. The blood contains approximately 180 g of protein, half of which is albumin. Albumin is thus the most abundant single protein in the plasma and, because of its structure, is able to reversibly bind many drugs by Van der Waals forces, hydrogen bonds or hydrophobic bonds. However, its binding capacity is relatively limited and it has been estimated that only 200 mg of drug of average molecular weight (300) would be bound to albumin in plasma if there were only one binding site available on each albumin molecule. For some drugs there may be more than one binding site and the binding capacity will be relatively greater. Major sites of binding are the so-called site 1 (warfarin site), which also binds the endogenous compound bilirubin, and site 2 (diazepam
1
FIG. 1.1 Relationship between the percentage of diazepam and theophylline free in plasma and plasma albumin concentration in different disorders See text for details.
FIG. 1.2 Relationship between the percentage of lidocaine (lignocaine) free in plasma and plasma AAG concentration in several disease states and in neonates
site), the site at which the endogenous amino acid tryptophan also binds. Drugs may bind to either or both of these sites and can competitively displace each other. The relationship between the serum albumin concentration and the proportion of two drugs in the free (unbound) form is shown in Figure 1.1. It can be seen that the differences in protein binding are likely to be relatively, small over the range of serum albumin concentrations seen in health. In situations of hypoalbuminaemia, however, even small further decreases in serum albumin concentration may cause marked increases in the proportion of drug free in the plasma. Another plasma protein, a,-acid glycoprotein (AAG) also binds drugs, particularly those of a basic nature. Although its plasma concentration is much lower (c. 2%) than that of albumin, its affinity for drugs is high and some drugs (e.g. lidocaine (lignocaine), erythromycin and disopyramide) may bind appreciably more to this protein than to albumin. Because of its low concentration, however, its binding capacity is relatively limited and, for several drugs, protein binding falls with increasing drug concentration. The tissues also contain proteins which combine with drugs (60% of the total exchangeable body albumin is outside the vascular compartment), whereas body fat can serve as an important reservoir for lipid-soluble agents such as thiopentone. Finally, active transport mechanisms - such as the uptake of adrenergic neuron-blocking drugs by the adrenergic neuron - may also contribute to high tissue concentrations of a drug. Extensive tissue binding tends to result in the drug having a large apparent volume of distribution (Vci), as most of the drug is outside the intravascular space. Distribution of drugs may be altered by changes in regional blood flow in disease. The volume of distribution of lidocaine (lignocaine), for example, appears to be lower in patients with cardiac failure. Protein binding also determines drug distribution. Albumin concentrations are low in the neonate, begin to decline over the age of 40, and are reduced during pregnancy. Severe hypoalbuminaemia also
occurs in nephrotic syndrome and chronic liver disease. In patients with chronic renal failure the proportion of drug in the free form is greater than would be expected from the reduction in serum albumin alone, indicating either structural changes in albumin or the presence of endogenous inhibitors of binding. AAG is reduced in neonates and in pregnancy but tends to be normal in healthy elderly individuals. It is markedly increased in patients with rheumatoid arthritis and other inflammatory diseases, including chronic renal disease, after myocardial infarction, and in cancer. As with albumin, it may be reduced in patients with nephrotic syndrome or chronic liver disease. Concomitant changes in plasma protein binding of drugs also occur, the effects depending on the relative strength of binding of the drug to these two proteins and on the disease state in question (Fig. 1.2), which may alter the amount bound to free drug. Thus the total plasma concentration of drug (free + bound), which is generally measured in clinical practice, may not always reflect the free (active) concentration. Therapeutic ranges for total drug may therefore need to be altered in diseases where plasma protein binding is affected (see Therapeutic drug monitoring).
Metabolism The liver is the main organ of drug metabolism, although some may also occur in the gastrointestinal tract, lung, blood or kidney. Metabolism is particularly important for lipid-soluble drugs, which more readily enter cells and are also prevented by their lipid solubility from being excreted unchanged by the kidney. The routes of metabolism are relatively non-specific and are shared by a variety of drugs. In most instances, more water-soluble metabolites (which are more easily excreted by the kidney) are produced. There are two groups of metabolic reaction: phase I and phase II. Phase I reactions involve the enzyme mono-oxygenase, situated in the smooth endoplasmic reticulum of cells with metabolic function, especially the liver. These are called
3
cytochrome P450 enzymes and are responsible for oxidation, reduction, hydrolysis and dealkylation of drugs with the relevant molecular structure. A given drug may be metabolized by one or more of these routes to produce more water-soluble (and thus biologically active) metabolites. Phase II reactions are conjugation reactions of more water-soluble molecules to the drug or metabolite. Conjugation with glucuronide (glucuronidation) is the commonest pathway, but conjugation can also occur with sulphate, amino acids such as glutathione, or acetylCoA (acetylation). Most of these conjugated metabolites (except for some acetylated compounds) are biologically inactive. Although most metabolic processes are controlled by environmental factors, acetylation is under genetic control: 45% of the UK population are slow acetylators and the remainder either intermediate or fast acetylators. Approximately 7% of the British population have a reduced ability to hydroxylate several drugs (e.g. debrisoquine, nortriptyline and phenformin), which may lead to an increased risk of adverse reactions to drugs metabolized by this route. Metabolism of drugs may be diminished at the extremes of age. Neonates have a reduced capacity for phase I, and most phase II reactions. Thus the effect of caffeine (a phase I pathway) is markedly reduced. Reaction of phase II pathways such as the glucuronidation of chloramphenicol, for example, may lead to grey baby syndrome in the neonate. Immaturity of these processes is greatest in the premature neonate, who is therefore at greatest risk of adverse drug reactions. In the healthy elderly, impairment of drug metabolism is only slight and tends to be overshadowed by changes in pharmacodynamic response. However, marked reductions in drug metabolism may be seen in the frail elderly. Dietary and environmental factors, such as smoking, may affect the rate of metabolism of some drugs; and chronic liver disease is often associated with an impairment of metabolism, particularly of phase I pathways. In liver disease the serum albumin concentration correlates roughly with the degree of impairment of drug metabolism (i.e. the lower the albumin the more severe the impairment). The effect of impairment of metabolism in liver disease will be greater for those drugs with extensive presystemic metabolism. The bioavailability of propranolol is much greater in patients with chronic liver disease, not because of better absorption (absorption is virtually complete in health) but because it cannot be efficiently metabolized on its first passage through the liver. This is due not only to the reduced hepatocyte metabolic activity, but also to intra- and extrahepatic shunting of blood past the liver cells and a consequent reduction in effective liver blood flow.
A MCQ1.1-1.5
4
SUMMARY 1 Pharmacokinetic causes of variability in drug response Absorption Extent of drug absorption reduced only in rare circumstances Distribution Altered in disease by changes in regional blood flow, altered plasma protein binding (e.g. hypoalbuminaemia in hepatic cirrhosis), or changes in activity of energy dependent transporter systems (e.g. P-glycoprotein) Metabolism Diminished in neonates (particular if premature) and the elderly (especially if frail). Affected by genetic factors (e.g. genetic polymorphisms), environmental factors (e.g. smoking) and liver disease Excretion Immature in neonates (particularly if premature) Impaired in renal disease and declines with advancing age over 40 years
In cardiac failure and shock, cardiac output is reduced and a disproportionately greater reduction in hepatic blood flow (normally around 1.5L/min) may result in a marked reduction in the systemic clearance of normally efficiently cleared compounds (e.g. lidocaine (lignocaine)), for which hepatic blood flow is the major determinant of delivery of drug to and clearance by the liver. In addition, the liver can be affected by the increased venous backpressure caused by failure of the right side of the heart in biventricular (congestive) cardiac failure. This results in increased size and congestion of the liver and derangement of liver function, with reduced hepatocyte clearance of several drugs. Genetic factors play a major role in determining drug response and handling, and susceptibility to adverse drug reactions. Allelic variations affecting pharmacokinetics with a frequency of at least 1% in the population are often termed genetic polymorphisms (e.g. acetylation) and are associated with a bimodal or trimodal (rather than the normal unimodal) distribution of clearance values. Some clinically important pathways of drug metabolism showing such polymorphisms are ./V-acetylation, oxidation (hydroxylation) via the cytochrome (CYP) P450 isoform, CYP2D6, succinylcholine hydrolysis (de-esterification) and thiopurine s-methylation. More are being recognized as detection techniques improve.
Excretion The vast majority of drugs must first be metabolized to more water-soluble compounds before they can be excreted in the urine. Those drugs (e.g. cimetidine, digoxin, aminoglycosides, lithium, cephalosporins, penicillins, atenolol and chlorpropamide) that are largely excreted unchanged tend to be relatively water-soluble and are not appreciably bound to plasma proteins and so can enter the glomerular filtrate. Lipid-soluble drugs may also enter the glomerular filtrate, provided they are not extensively plasma protein bound, but they then readily pass back
through the proximal tubular cells into the bloodstream by passive diffusion down a concentration gradient. Only when they have been metabolized to more water-soluble compounds will they have difficulty in passing back through the renal tubular cells and therefore be excreted in the urine. Weak electrolytes can also be actively secreted in the proximal renal tubules - weak bases sharing one mechanism and weak acids another - and there is some evidence for an active transport system promoting the excretion of digoxin in the distal renal tubule. Drugs may also be excreted in the bile, normally as conjugates and particularly if they have a high molecular weight. The drug may, however, be reabsorbed from the intestine, either directly or after deconjugation by intestinal microflora, to create an enterohepatic cycle. This may reduce the clearance of the drug and thus prolong its effect. Excretion of drugs is reduced in neonates (particularly if premature) because of a reduced glomerular filtration rate (GFR) relative to their body surface area, and also because their active renal tubular secretory mechanisms are not fully developed. These processes mature relatively rapidly and are fully functional after 6-12 months, but GFR begins to fall again over the age of 40 (the renal tubular secretory mechanisms appear to be less affected by age). Thus, the dose of digoxin or gentamicin (drugs excreted predominantly by glomerular filtration) may need to be reduced in the elderly or the very young. Renal disease is associated predominantly with a fall in GFR, with active renal tubular secretion mechanisms being less affected. Measurement of serum creatinine or creatinine clearance is therefore useful in calculating the optimum dose of drugs excreted predominantly by glomerular filtration, but it is of less value for drugs such as penicillins, which are actively secreted at the proximal renal tubule. 1
ADVERSE DRUG REACTIONS It has been estimated that approximately 5 % of all hospital admissions are because of adverse reactions to a drug; 1 in 10 patients admitted for other reasons will develop an adverse reaction to a drug while in hospital; and perhaps 1 in 1000 deaths in hospital are due to an adverse reaction to a drug, making adverse reactions between the fourth and sixth most common cause of death in the USA, for example. Adverse reactions are also common in general practice. The drug groups most commonly associated with adverse reactions are antihypertensives, anticoagulants, antirheumatics (particularly the non-steroidal antiinflammatories), cytotoxic agents, corticosteroids and digoxin. Although adverse reactions can affect all systems of the body, they are most often described in the skin and central nervous system, perhaps because detection tends to be easier. The very young (i.e. under 1 year of age) and the elderly are particularly at risk, and women appear to be at greater risk than men, although the reason for this is
unknown. Patients with a history of atopy, or who have had a drug reaction in the past, are more likely to develop further reactions, even to a drug in some other therapeutic group. The presence of disease, particularly heart failure or liver or renal disease, predisposes to a risk of adverse reactions, as may genetic factors, such as enzyme deficiencies.
1
TYPES OF ADVERSE DRUG REACTION Adverse reactions have been classified into two major types.
Type A The most common type is the dose-dependent adverse reaction (type A), which is an 'augmentation' or 'accentuation' of a known pharmacological effect of the drug not necessarily always the wanted effect. Thus, fisympathomimetic agents can cause increased tremor, a recognized pharmacological effect of the drug but one that may limit their use in bronchodilator therapy. Type A reactions account for about 75% of all adverse reactions and, because they are often insidious in onset, may go unrecognized for some time. They may therefore produce considerable morbidity, but the mortality from type A reactions is generally low. They may occur because of altered pharmacokinetic or pharmacodynamic factors and are therefore commonest in diseases (e.g. renal and liver disease) where these are most affected.
Type B The occurrence of type B reactions is not dependent on the dose given. They are unpredictable or 'bizarre' reactions to a drug that may be present only in tiny concentrations, although the severity of the reaction may be greater if a larger dose is administered rapidly (e.g. after intravenous administration). Because of their lack of predictability and their often acute onset they have a proportionally higher mortality than type A reactions, but associated morbidity is relatively low if the patient survives the initial event. Like type A reactions, type B reactions can be related to pharmacokinetic or pharmacodynamic factors. There are many ingredients in medications other than the active
SUMMARY 2 Types of adverse drug reaction (ADR) Type A Dose-dependent 'accentuation' of known pharmacological effect. Account for 75% of ADRs. Cause considerable morbidity but mortality is low. Can sometimes be treated by dose reduction rather than cessation of treatment Type B Non-dose dependent, 'bizarre' and unpredictable. Higher mortality. Type B reactions can be related to hereditary enzyme deficiencies or allergic mechanisms. Usually treated by discontinuing treatment immediately
5
compound: reactions may occur to the preservative, filler, dye, binder or solubilizing agent in the tablet or injection. Type B reactions may occur because individual subjects metabolize the drug through a novel pathway that produces a toxic metabolite. In other cases the presence of hereditary enzyme deficiencies may predispose the patient to the toxic effects of drugs or their metabolites. Thus, haemolysis caused by dapsone and other oxidizing agents is commoner in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Similarly, many agents can precipitate an attack of acute intermittent porphyria (p. 1027) in those carrying a gene for this disorder. Type B reactions are also often related to allergic mechanisms, and may involve any or all forms of antibody- or cellmediated tissue damage. Thus, anaphylaxis may occur as a result of immediate (type I) hypersensitivity associated with cell-bound IgE, after the administration of drugs such as penicillin. Cell surface (type II hypersensitivity) damage may occur as a result of the combination of methyldopa with red cell (or quinine with platelet) membranes and subsequent haemolysis or thrombocytopenia, 1 respectively. Toxic immune complexes may be formed in patients receiving gold or penicillamine, resulting in skin toxicity by a type III hypersensitivity mechanism. Cell-mediated (type IV) tissue damage is thought to be the mechanism of the relatively common (but usually mild) rash associated with ampicillin therapy 2 or the more serious erythroderma sometimes associated with drugs such as gold. 34
DIAGNOSIS AND MANAGEMENT OF ADVERSE DRUG REACTIONS Diagnosis It is rarely possible to make a diagnosis of drug-induced adverse reaction with complete certainty. Either an infective agent or the antibiotic with which the patient was being treated, for example, may cause erythema multiforme. It is therefore necessary to weigh up all circumstantial evidence carefully before making the diagnosis. This includes taking a full drug history, remembering that patients may not consider over-the-counter and herbal remedies, or even the oral contraceptive pill, as medicines or drugs. The brand names of the agents may also be important, as different pharmaceutical formulations may contain different dyes, binders, fillers, preservatives or lubricants, and reactions may occur only with certain formulations. Physical examination provides only limited information. Some physical signs may be directly attributable to drug therapy, e.g. the blue discoloration of the skin
1
Fig. 1.1
4
Case 1.1 Case 1.2
2 Fig. 1.2
3
© Fig. 1.3 6
MCQ1.6
Fig. 1.4
associated with amiodarone therapy 0 is rarely caused by disease. Similarly, an eruption occurring at a fixed site on the skin may suggest a drug-induced fixed drug eruption. 6 However, in most cases the organs affected have a limited number of responses to noxious stimuli. Biochemical tests are also of limited value, but measurement of plasma drug concentration may help to confirm the suspicion of a dose-dependent (type A) adverse reaction. In some cases measurement of metabolic phenotype may also be helpful. It is extremely rare, for example, for patients who are fast acetylators to develop drug-induced lupus erythematosus after hydralazine therapy. Probably the most helpful indication of the drug responsible for the adverse reaction is the time course relative to drug treatment, particularly the rate of resolution of symptoms on stopping a specific drug (dechallenge). Subsequent re-exposure (rechallenge) associated with a recurrence of the symptoms or signs gives the strongest evidence of causation, but it is rarely ethically justifiable unless the patient's need for the drug outweighs the potential risk of the adverse reaction.
Management The only choice with most type B reactions is to stop the suspected drug completely. With type A reactions it is sometimes possible to reduce the dose to prevent the unwanted effects while still obtaining therapeutic benefit. If an adverse reaction does occur, the patient's medical notes and prescription chart should be clearly marked with an eye-catching label to indicate the nature and date of the reaction. Any serious adverse reaction should also be reported to the Committee on Safety of Medicines using a yellow card. In addition, even minor adverse reactions to drugs that have been recently introduced (marked with an inverted black triangle in the British National Formulary) should be reported.
PREVENTION OF ADVERSE REACTIONS It must be remembered that although drugs provide enormous benefit to patients, all are potentially toxic and should be used selectively, particularly in those at greatest risk of adverse reactions, i.e. the very young, the very old and those with severe disease. The risk of developing an adverse reaction appears to increase disproportionately with increasing number of drugs prescribed concomitantly. Prescriptions should therefore be reviewed and, whenever possible, drug therapy rationalized at frequent intervals. When a drug is prescribed, the prescription should be written legibly, in block letters, and preferably using the approved name. Failure to do so may lead to errors in prescribing. In some cases the risk of adverse reactions to certain drugs is such that they should be avoided if at all possible. There are particular dangers during pregnancy or breastfeeding, when certain drugs may cause an adverse reaction in the fetus or breastfed child (Table 1.1).
TABLE 1.1 Some drugs to avoid during pregnancy or breastfeeding Pregnancy
Breastfeeding
Antibiotics
Tetracyclines Sulphonamides Aminoglycosides Chloramphenicol Trimethoprim Nitrofurantoin Quinolones
Tetracyclines Sulphonamides Isoniazid Chloramphenicol Metronidazole Nitrofurantoin Vancomycin
Antithyroids
All, including radioiodine
All, including radioiodine
Analgesics
Opiates NSAIDs
Aspirin NSAIDs (several)
Anticoagulants
Warfarin Acenocoumarol (nicoumalone)
Phenindione
Antidepressants Antihypertensives
SSRIs (several) Lithium ACE inhibitors Angiotensin receptor antagonists Thiazide, loop and potassium-sparing diuretics Hydralazine Minoxidil
Angiotensin receptor antagonists Calcium channel blocker (some)
Antineoplastics
Most
Most
Antidiabetics
Biguanides Sulphonylureas
Use with caution
Antirheumatics
Gold Penicillamine
Antiulcer drugs
Misoprostol Most proton pump inhibitors
DRUG INTERACTIONS
1
Drug interactions have been recognized for over 100 years and were described under the classic headings of antagonism, synergism or potentiation. Many of these interactions are beneficial and have been used to therapeutic advantage, but unwanted or adverse interactions also account for 10-20% of all adverse reactions to drugs. There are around 2000 potentially interacting drug pairs, but the number of clinically significant adverse interactions is much lower, largely involving drugs with a relatively low margin between safety and toxicity (i.e. a narrow 'therapeutic ratio'). Thus, they are most often described with oral anticoagulants, some antidiabetic drugs, anticonvulsants, antiarrhythmics (especially digoxin), tricyclic antidepressants, antihypertensive drugs, NSAIDs, neuroleptic drugs, lithium, anticancer/immunosuppressive agents and theophylline (Tables 1.2-1.4). The elderly, particularly if frail and suffering from multiple medical conditions, are more likely to experience an interaction and more likely to have serious adverse consequences. As with adverse reactions in general, the risk of developing an adverse interaction increases disproportionately with the number of drugs being prescribed concomitantly; the mechanisms of interaction are also similar, in that both pharmacodynamic and pharmacokinetic interactions may occur. Interactions may also take place, however, before the drugs even enter the body, and these have been termed 'pharmaceutical' interactions. 7
PHARMACEUTICAL INTERACTIONS Misoprostol Proton pump inhibitors
Antivirals
Most
Anxiolytics
Benzodiazepines Chloral derivatives
Sex hormones
Androgens, oestrogens and high-dose progestogens
Androgens, oestrogens and high-dose progestogens
Hypolipidaemics
Fibrates Statins
Fibrates
Miscellaneous
Vitamin D and its analogues Live vaccines Podophyllum resin and podophyllotoxin Tamoxifen Thrombolytics
Anthraquinone laxatives and phenolphthalein Amiodarone
NB Absence of a drug from this list does not imply safety. Further information can be obtained by consulting the manufacturer's datasheet, the British National Formulary, or by contacting the National Teratology Centre (0191-232-1525).
Interactions may occur prior to the drug entering the body when drugs are mixed together for infusion, or when a drug interacts with the infusion material itself. Guides to intravenous mixtures are available and should be consulted before compounds are given by intravenous infusion or mixed together. In general terms, it is advisable to avoid adding drugs to infusion fluids unless absolutely necessary, and certainly to avoid adding more than one drug if at all possible. Infusion fluids particularly likely to be associated with pharmaceutical incompatibilities include blood and blood products, amino acids and lipid solutions, mannitol and sodium bicarbonate.
PHARMACODYNAMIC INTERACTIONS Pharmacodynamic interaction occurs where one drug alters the response to another by interacting either at the receptor site or at a different site to enhance or diminish the primary drug effect. Partial agonists initiate a minor response but, by occupying a significant fraction of the receptors, they antagonize the action of more potent agonists. Nalorphine, for example, is a partial antagonist
7
TABLE 1.2 Some drug interactions of clinical importance resulting in increased drug effect Drug (A)
May interact with B
Effect of interaction
Mechanism of interaction
ACE inhibitors Antidepressants (tricyclic) Antihypertensive agents
NSAIDs Enzyme inhibitors Vasodilators (e.g. nitrates for angina) neuroleptics and some antidepressants NSAIDs
Hyperkalaemia, reduced renal function Increased effect of A Postural hypotension
Additive nephrotoxic effects Reduced clearance of A Combined hypotensive effects
Peptic ulceration
Enzyme inhibitors Verapamil NSAIDs (including aspirin) Enzyme inhibitors Amiodarone Diltiazem Verapamil Diuretics (loop and thiazide) ACE inhibitors Potassium supplements NSAIDs Thiazide diuretics Anticholinergic drugs (e.g. some antihistamines/tricyclic antidepressants) Enzyme inhibitors NSAIDs
Increased effect of A
Increased risk of peptic ulceration Reduced clearance of A
Increased risk of peptic ulceration Increased effect of A Increased effect of A
Corticosteroid prevents healing? Reduced clearance of A Reduced clearance of A
Increased effect of A (e.g. arrhythmias) Hyperkalaemia, impaired renal function
Diuretic-induced hypokalaemia Combined potassium-elevating effects
Increased effect of A
Reduced clearance of A
Excessive anticholinergic effects
Combined anticholinergic effects
Increased effect of A Seizures
Reduced clearance of A Pharmacodynamic interaction at CNS effector site Pharmacodynamic interaction Reduced clearance of A Reduced clearance of A
Aspirin (low-dose) Carbamazepine Corticosteroids (oral) Ciclosporin Digoxin Digoxin Diuretics (potassium-sparing) Lithium Phenothiazines and butyrophenones Phenytoin Quinolones Sildenafil (Viagra) Theophylline Warfarin
Nitrates Saquinavir Enzyme inhibitors (e.g. macrolides and 4-quinolones) See Table 1.4
Increased hypotensive effect of A Increased hypotensive effect of A Increased effect of A
TABLE 1.3 Some drug Interactions resulting in reduced drug effect Drug (A)
May interact with B
Effect of interaction
Mechanism of interaction
Antidepressants Antihypertensives (e.g. ACE inhibitors, thiazides and p-blockers) Calcium channel blockers Corticosteroids (oral) Ciclosporin Digoxin
Enzyme inducers NSAIDs
Reduced effect of A Reduced effect of A
Enzyme inducers Enzyme inducers Enzyme inducers Colestyramine (cholestyramine) Colestipol Enzyme inducers Broad spectrum antibiotics Enzyme inducers Colestyramine (cholestyramine) Colestipol Antacids Enzyme inducers Enzyme inducers Colestyramine (cholestyramine) and colestipol See Table 1.4
Reduced effect of A Reduced effect of A Reduced effect of A Reduced effect of A
Increased clearance of A Pharmacodynamic antagonism of anti hypertensive effect of A Increased clearance of A Increased clearance of A Increased clearance of A Reduced absorption of A
Reduced effect of A Reduced effect of A Reduced effect of A Reduced effect of A
ncreased clearance of A nterruption of enterohepatic recycling of A? ncreased clearance of A Reduced absorption of A
Reduced effect of A Reduced effect of A Reduced effect of A
ncreased clearance of A ncreased clearance of A Reduced absorption of A
Oral contraceptives Phenytoin Quinolone antibiotics
Theophylline Thyroxine
8
Warfarin
TABLE 1.4 Important drug interactions involving warfarin
Interacting drug
Effect of interaction on anticoagulant effect
Colestyramine (cholestyramine) Colestipol
Reduced anticoagulant effect
Impaired absorption and increased elimination of warfarin. Long-term treatment may cause impaired vitamin K absorption and enhance anticoagulant effect
Barbiturates Carbamazepine Griseofulvin Phenytoin (see also below) Primidone Rifampicin Ritabutin St John's wort
Reduced anticoagulant effect
Induction of warfarin metabolism
Amiodarone Azapropazone Chloramphenicol Cimetidine Ciprofloxacin Clarithromycin Dextropopoxyphene Erythromycin Fluconazole Itraconazole Ketoconazole Mefenamic acid Metronidazole Miconazole Nalidixic acid Norfloxacin Ofloxacin Phenylbutazone Sulfinpyrazone Sulphonamides (e.g. in co-trimoxazole)
Increased anticoagulant effect
Inhibition of warfarin metabolism
Anabolic steroids Bezafibrate Clofibrate Danazol D-thyroxine Gemfibrozil L-thyroxine Phenytoin (see also above) Salicylates/aspirin (high-dose) Stanozolol Tamoxifen
Increased anticoagulant effect
Pharmacodynamic potentiation of anticoagulant effect
NSAIDs (including aspirin at all doses) clopidogrel and ticlopidine
Increased risk of bleeding
Additive effects on coagulation and haemostasis
Oral contraceptives, oestrogens and progestogens Vitamin K (e.g. in some enteral feeds)
Reduced anticoagulant effect
Pharmacodynamic antagonism of anticoagulant effect
Probable mechanism(s)
but may add to the respiratory depression produced by opioids, whereas naloxone, despite having no opioidlike effects itself, antagonizes the pharmacological effects of most opioids. Many pharmacodynamic interactions occur when the physician forgets that a drug known to be acting at one receptor may also act at another. Thus, antihistamines, phenothiazines and tricyclic antidepressants may have muscarinic anticholinergic activity in addition to their desired pharmacological effects: administration of two or more of these agents (particularly in the elderly) may lead to pronounced anticholinergic symptoms and signs. Pharmacodynamic interaction may also occur when two drugs act at different sites, e.g. the interaction of digoxin and diuretics. Here, hypokalaemia caused by diureticinduced reduction of potassium reabsorption in the kidney may potentiate the effects of digoxin on the heart.
1
PHARMACOKINETIC INTERACTIONS Absorption Drugs may interact with each other to prevent either the rate or the extent of absorption of another compound. Drugs that increase gastric emptying (e.g. metoclopramide) will increase the rate of absorption of many other drugs, so that the peak concentration of that drug will tend to be higher. The opposite effect is achieved by agents - such as the anticholinergic compounds atropine, trihexyphenidyl (benzhexol) and propantheline - that diminish gastric emptying. These changes are likely to be more important after single-dose administration in a situation where a threshold concentration for drug effect exists, e.g. for analgesics. Under these circumstances (particularly if the rate of elimination of the drug is high), a delay in absorption may result in an inability to reach therapeutic drug concentrations. The extent of absorption of the drug may be impaired by the presence of another through the formation of chelates, ion pairs or complexes. Ion exchange resins such as colestyramine (cholestyramine) and colestipol combine with warfarin, levothyroxine (thyroxine) and digitalis glycosides to im-pair absorption. Similarly, the calcium, magnesium or aluminium ions in antacids or milk may interact with 4-quinolones such as ciprofloxacin. In most cases these interactions can be prevented by ensuring a time interval of at least 2 hours between administrations of the two compounds. In the case of warfarin and digitoxin, however, colestyramine (cholestyramine) or colestipol may also affect enterohepatic recirculation and reduce concentrations of these drugs, even if they are administered after absorption has been completed.
Distribution Drugs may compete for both plasma protein-binding sites and active transport processes in the body. The importance of plasma protein-binding displacement interactions has
9
TABLE 1.5 Some drugs causing induction of drug metabolism Barbiturates and primidone Carbamazepine Cigarette smoking* Phenytoin Rifampicin and rifabutin St John's wort * Selective induction (e.g. of theophylline metabolism).
FIG. 1.3 Factors determining the distribution of drugs in the body
been much exaggerated (Fig. 1.3). For most drugs, only the free form in plasma is available for metabolism. Thus, an increase in the percentage of free drug will result in a concomitant increase in total clearance and the rapid return of the free (biologically active) drug concentration to its original value. (The net result is a lower total drug concentration, but a larger percentage of this is in the free form.) The temporary increase in free drug concentration is only likely to be important if the drug is normally highly protein bound (e.g. >90%) and has a low apparent volume of distribution. If the displacing agent is given by a rapid intravenous injection, the temporary increase in free drug concentration of the displaced agent may also be important, but clinically significant examples of this interaction are difficult to find. At present, whenever significant clinical interactions have been shown to be associated with protein-binding displacement, other mechanisms (e.g. competition for metabolism) have been shown to be the major causes of the interaction. It is therefore possible that plasma protein-binding displacement merely reflects the physicochemical similarities of the two compounds, which leads to their competing for transport or metabolic processes. Inhibition of active transport of one drug by another can result in significant interactions. P-glycoprotein is a surface phosphoglycoprotein that functions as an energydependent efflux. It is coded by the human MDR1 (multidrug resistance) gene and is present in a wide variety of tissues, including the gut, kidney, liver, brain, testes, placenta and adrenals. Human P-glycoprotein has been shown to transport a wide range of structurally unrelated drugs such as digoxin, quinidine, ciclosporin and HIV-1 protease inhibitors. Competition for this pump between quinidine and digoxin, for example, can result in increased concen-
O MCQ 1.7-1.11
10
trations of digoxin entering the CNS and corresponding toxicity. If potent and safe inhibitors of P-glycoprotein and other similar transporters (multidrug resistance-associated proteins or MRPs) can be found, the interaction could possibly be used to therapeutic effect in overcoming the intrinsic or acquired multidrug resistance of human cancers.
Metabolism Compounds in cigarette smoke and a variety of other drugs (Table 1.5) can stimulate drug metabolism by the hepatic mono-oxygenase system. Enzyme induction is related to an increase in the amount of cytochromes present, and may therefore take 7-14 days to develop fully and a similar lag period to wear off after the inducing agent is discontinued. This time lag tends to disguise any causal relationship between the drug interaction and administration of the inducing agent. Furthermore, if the dose of the active drug has been increased to maintain adequate effects, marked increases in drug concentration and toxic effects may be seen when induction wears off. Other agents can impair the metabolism of concomitantly administered drugs, either by competing for metabolism or in a non-competitive manner (Table 1.6). Cimetidine is an interesting example in that, although not itself metabolized (it is excreted largely unchanged in the urine), it inhibits the metabolism of drugs by the liver. As the effect of enzyme inhibitors is generally direct, the lag time for this effect to occur is shorter than with enzyme inducers and the effects disappear more quickly after discontinuation. The effects also tend to be more selective than with enzyme induction. Thus, allopurinol has little effect on drugs metabolized by the mono-oxygenase pathway but, by inhibiting the enzyme xanthine oxidase, can impair the metabolism of azathioprine and 6mercaptopurine and potentiate their toxicity. If a drug has a carbon atom with four different substituents, it exists as two optical isomers or enantiomers, which are mirror images of each other. Most chemical syntheses will result in equal amounts of the two steroisomers, and this is termed a racemic mixture. One isomer may be much more potent than the other (e.g. S-warfarin is at least five times more potent than R-warfarin), or the toxicity
1
TABLE 1.6 Some drugs causing inhibition of metabolism Allopurinol Amiodarone Cimetidine Metronidazole Monoamine oxidase inhibitors Sulphonamides Macrolides (e.g. erythromycin, clarithromycin, azithromycin) Some antifungals (e.g. ketaconazole, fluconazole, itraconazole, miconazole) Some quinolones (e.g. ciprofloxacin, norfloxacin, ofloxacin, nalidixic acid) Some HIV-protease inhibitors (e.g. saquinavir, indinavir, nelfinavir, ritonavir) Some SSRIs (e.g. fluoxetine, fluvoxamine, nefazodone, paroxetine, sertraline)
of the two isomers may differ. The enantiomers may also differ in metabolic route or interact differently with other compounds. Cimetidine inhibits the metabolism of Rwarfarin, metronidazole inhibits the S enantiomer, and amiodarone inhibits the metabolism of both enantiomers.
Excretion It is unlikely that drug-induced changes in GFR will markedly alter the excretion of other drugs by the kidney. However, drugs that alter urinary pH may have a marked effect on the renal clearance of weak bases or acids, because of the effects on passive reabsorption in the proximal tubule. The administration of bicarbonate, for example, may enhance the removal of weak acids (such as phenobarbital and aspirin) by increasing the proportion of drug in the ionized form in the urine, thus preventing passive reabsorption. Similarly, acidification of the urine (using ammonium chloride) reduces tubular reabsorption of weak bases such as amphetamine, an effect that was once used in overdose to enhance renal excretion. Acidic drugs may compete with each other for the active renal tubular secretory pathway. Salicylates and thiazides may potentiate the toxicity of methotrexate in this way. No clinically important interactions involving basic drugs at this site have been reported. Quinidine and verapamil may compete with digoxin for an active tubular secretory mechanism in the distal convoluted tubule. This mechanism is now thought to be P-glycoprotein (see earlier), so that the digoxin-quinidine interaction results in reduced renal clearance of digoxin (as well as the increased CNS penetration of digoxin described earlier), thus causing increased plasma and CNS digoxin concentrations and increased risk of toxicity. P-glycoprotein may also be a factor in the excretion of some drugs into the gut via the intestinal wall and the bile, and may thus determine the apparent bioavailability of certain drugs such as ciclosporin. Like CYP450 enzymes, P-glycoprotein activity can be enhanced by enzyme induction, and this may well be an important determinant of rifampicin-induced reduction in ciclosporin bioavailability, for example (Fig. 1.4). 1
FIG. 1.4 Schematic representation of the effect of P-glycoprotein activity on the disposition and bioavailability of drugs
AVOIDANCE OF DRUG INTERACTIONS There are a number of strategies that can be adopted to decrease the risk of potential clinical problems. The number of drugs prescribed for an individual should be limited to as few as is necessary. The drug list (including over-the-counter and herbal preparations) should be reviewed on a regular basis, potentially unnecessary medicines withdrawn and the patient's progress monitored subsequently. Patients should be encouraged into a 'prescribing partnership', alerting doctors, pharmacists and other healthcare professionals to symptoms that occur when new drugs are introduced. The prescriber should be alert for the presence of medicines (e.g. particularly likely to be associated with interaction (e.g. enzyme inducers and inhibitors)) and avoid such combinations. He or she should also be prepared to check (there are excellent tables in the British National Formulary} before prescribing any new or unfamiliar drug, particularly in those already receiving drugs with a low therapeutic ratio. Clinicians should also report via the appropriate postmarketing surveillance scheme any drug-drug interactions they feel they have encountered.
THERAPEUTIC DRUG MONITORING Therapeutic drug monitoring refers to the measurement of drug concentrations in plasma to aid in optimizing drug efficacy and reducing the risk of toxicity.
11
TABLE 1.7 Drug concentration associated with optimal efficacy in most patients Usual half-life (hours) Carbamazepine Ciclosporin Digoxin Gentamicin
2-10 30-40 2-3
Lithium Phenytoin
7-20 20-60
Theophylline
4-15
Usual therapeutic plasma concentrations
Toxic concentrations
Principal route of elimination
4-1 2 mg/L 1 00-200 ^g/L 0.8-2 ng/L Trough <2mg/L Peak 4-8 mg/L 0.4-1 .0 mmol/L Plasma 10-20 mg/L Saliva 1-2 mg/L Plasma 10-20 mg/L Saliva 6-1 2 mg/L
>12mg/L >200^g/L >2 g/L Trough >2 mg/L Peak >12 mg/L >1.5mmol/L >20mg/L >2mg/L >20mg/L >12mg/L
Hepatic metabolism Hepatic metabolism Renal excretion Renal excretion
The ideal way to monitor drug therapy is, of course, to measure wanted and unwanted effects directly: where good measures of these exist (e.g. in anticoagulant therapy), measurement of plasma drug concentrations has a very limited role. There are, however, situations in which drug efficacy or toxicity is more difficult to measure and, both here and where the drug is being given prophylactically to prevent serious events (e.g. antiepileptic and antiarrhythmic drugs), therapeutic drug monitoring may have a role to play (Table 1.7). Measurement of plasma (or urine) drug concentration is also of value in detecting overdose (either deliberate or accidental) and in monitoring compliance with therapy in patients who may not be responding normally to the drug. For therapeutic drug monitoring to be of value in optimizing therapeutic benefit, the drug should work by a reversible mechanism without the development of tolerance. The possibility of accumulation of active metabolites that are not detected by the drug assay must also be considered. Procainamide, for example, is metabolized to Nacetylprocainamide, which also has antiarrhythmic activity and, ideally, should also be measured.
Renal excretion Hepatic metabolism Hepatic metabolism
tration taken just before the next dose will correlate most closely with the steady-state concentration. As it takes approximately five half-lives before steady state is achieved, sampling before this time will tend to underestimate the subsequent steady-state concentration and is only indicated if toxicity due to drug accumulation is possible. Details of sampling time, time and extent of last change in dose, and time of administration of the most recent dose should always be given on the assay request form to enable the plasma concentration to be interpreted correctly. Total drug concentrations are normally measured and these generally mirror the free plasma concentration. This may not be true in diseases where changes in plasma protein binding of drugs is likely, such as hepatic and renal disease. For some drugs (e.g. phenytoin and theophylline) the concentration in saliva may be a closer reflection of the free plasma concentration: in young children, saliva collection (stimulated by a drop of citric acid solution on the tongue) may avoid venepuncture.
SPECIFIC DRUGS
Sample collection
12
Unlike many endogenous compounds, such as creatinine, which are produced at a continuous rate, drugs are normally administered at fixed intervals and the plasma concentration will therefore vary markedly with time after administration. Early after administration the plasma concentration may be affected by the rate of gastric emptying. However, if there is extensive distribution of the drug early samples may be higher than the average, or steady-state, concentration during the dosing interval, and may not accurately reflect the concentration at the site of action of the drug. It is therefore preferable to wait at least 8 hours after administration of an oral dose of digoxin, or 12 hours after lithium, before sampling. If peak levels are important, samples should be taken 2-3 hours after a conventional tablet, or later if a sustained-release formulation has been administered, or 30-60 minutes after intramuscular injection. In most cases, however, a trough concen-
Anticonvulsants Phenytoin metabolism shows saturation rather than firstorder kinetics, so that clearance falls with increasing dose and the risk of toxicity increases. Half-life also increases with increasing dose, and so it will take longer for steady state to be achieved. Most patients tend to be given too small a dose of phenytoin, but therapeutic monitoring has reduced the tendency to prescribe a second antiepileptic drug in many patients who initially received subtherapeutic doses. Therapeutic monitoring of other anticonvulsants except carbamazepine is of limited value except in the identification of poor compliance.
Antiarrhythmics Because of their serious toxicity and the narrow margin between therapeutic and toxic doses, monitoring of several
antiarrhythmic drugs may help to reduce adverse effects and improve response. The half-life of most antiarrhythmics is short, but that of amiodarone is around 30-45 days. A loading dose is therefore necessary to achieve early therapeutic concentrations of this drug, and prolonged monitoring will help to detect the accumulation of amiodarone and its major (and possibly toxic) metabolite desethylamiodarone.
and regular monitoring of plasma concentration and renal function may be helpful in reducing the risks of nephrotoxicity.
Digoxin
The importance of drug regulation has grown with the rapid increase in the number of therapeutic agents developed over the last 50 years. Increased efficacy of new compounds is often associated with a risk of serious adverse effects.
The plasma digoxin concentration is one of the determinants of toxicity of the drug, particularly noncardiovascular toxicity, causing lassitude, depression and anorexia. Monitoring is particularly important in patients with reduced renal function (e.g. in the elderly), whose digoxin clearance is reduced, and will also help to identify poor compliance.
Theophylline Patients vary greatly in metabolic clearance of this potentially toxic bronchodilator, and dose adjustment is facilitated by the measurement of plasma theophylline concentrations.
Antibiotics The aminoglycosides (gentamicin in particular, but also amikacin, kanamycin, netilmicin and tobramycin) are the most frequently monitored antibiotics. The risk of ototoxicity can be reduced by preventing excessive plasma drug concentrations, but the nephrotoxic effects of the drugs are less closely related to the plasma concentration, so that renal function must also be carefully monitored during therapy. The antibiotic vancomycin is used systemically in the prophylaxis and treatment of endocarditis and other serious infections caused by Gram-positive cocci, including multiresistant staphylococci. Vancomycin (added to dialysis fluid) is also used in the treatment of peritoneal dialysis-associated peritonitis. After parenteral administration, vancomycin may be associated with renal damage and ototoxicity, and plasma concentrations are of help in minimizing toxicity.
Lithium Lithium is used in the treatment of hypomania, and because toxicity may develop insidiously (p. 27) therapeutic monitoring is essential.
Ciclosporin Ciclosporin is an immunosuppressant used in organ transplantation to prevent graft rejection and for the prophylaxis of graft-versus-host disease. It is also used in the treatment of severe atopic dermatitis, psoriasis and rheumatoid arthritis. It may cause renal damage,
1
DRUG REGULATION AND DEVELOPMENT
THE UNITED KINGDOM MEDICINES ACT (1968) AND THE MEDICINES FOR HUMAN USE REGULATIONS (1994) In the late 1950s thalidomide was introduced as a new hypnotic drug and was widely used in Europe, including in pregnant women. In 1961 an epidemic of appalling proportions occurred in which hundreds of the babies were born with limb abnormalities (phocomelia). The connection with thalidomide administration was soon realized and the drug was soon withdrawn. The nature of this adverse reaction and the public pressure it provoked resulted in the formation, in the UK, of the Committee on Safety of Drugs (the Dunlop Committee) in 1965, and the subsequent development of strict legislation concerning all aspects of drug manufacture, testing and selling. This legislation is contained in the United Kingdom Medicines Act (1968). In 1994, the European Union regulations were implemented in the UK by statutory instrument (the Medicines for Human Use Regulations) and the European Medicines Evaluation Agency (EMEA) was set up in London in 1995 to develop a centralized European procedure for drug evaluation. Each EU member state is required to have a national system for drug safety surveillance (pharmacovigilance) in place. In the UK this system is administered by the Medicines Control Agency (MCA), an executive agency of the
SUMMARY 3 Drug development Synthesis/isolation of new chemical entity Animal studies Pharmacological/toxicological studies Clinical trials Phase 1 Dose-finding tests in healthy volunteers (c 50) Phase 2 Tested in carefully selected patients (c 200) Phase 3 Formal, larger-scale trials (normally up to 2000) Efficacy, safety and comparison with other established therapies Phase 4 Post-marketing studies on a much larger population of patients
13
Department of Health, which is tasked to safeguard public health by ensuring that all medicines on the UK market meet appropriate standards of safety, quality and efficacy. It is advised by an independent Committee, the Committee on Safety of Medicines (CSM), which gives advice to the Licensing Authority (in this case the UK government) on whether new products (new active substances) submitted to the MCA should be granted a marketing authorization. It also helps to monitor the safety of marketed medicines.
DEVELOPING NEW DRUGS
14
Virtually all new drugs are developed within the pharmaceutical industry, because of the enormous financial investment (about £560 million for a new product in 2001) and the huge amount of work involved. Because a patent taken out on a new compound lasts for only 17 years, the 10-12 years (or longer) required for most drugs to reach the stage of a product licence erodes the patent life alarmingly. The industry therefore has to look very carefully at the likely returns on its investment over the short period that it alone can market the drug under patent. Developing drugs for less common diseases becomes commercially unattractive under these circumstances. Apart from the basic chemistry and pharmacology required to develop a new drug, a large amount of toxicological data from animal testing is also required from the pharmaceutical company to satisfy the licensing authority that the drug is unlikely to cause serious adverse reactions in humans. If it is so satisfied, the authority will grant a Clinical Trials Exemption (CTX) or Clinical Trials Certificate (CTC), both of which allow the drug to be tested in patients before an application for marketing authorization is made. In Europe, authorization for a marketing (product) licence can be sought by either a centralized or a decentralized procedure. The former process gives approval throughout Europe and is compulsory for medicinal products derived from biotechnology. The decentralized procedure (or mutual recognition procedure) applies to the majority of conventional medicines and is based upon the principle of mutual recognition by member states. The EMEA provides any arbitration between the member states before the final decision is made, normally by the European Commission. Member states can still, if they wish, give authorization for medicines to be marketed only in their own country. Clinical trials are usually divided into four phases. In phase 1 a small number of healthy volunteers (usually around 50) are given the drug for the first time. The initial doses are very low, and are titrated up to doses likely to show activity, with very careful monitoring for possible toxicity. In the UK, a CTX or CTC is not required for studies in healthy volunteers. If the results are satisfactory, around 200 or so carefully selected but clinically stable patients are given the drug to discover whether pharmacological and therapeutic effects occur in humans (phase
2). In the third phase, formal and larger-scale clinical trials are performed in order to confirm the drug's therapeutic benefit in a broader range of patients (around 2000 on average) with other concomitant conditions, to evaluate its adverse effects and compare it with alternative established therapies. At this point, assuming that the results are satisfactory, an application will be made for a product licence so that marketing and promotion of the drug can begin. It is thus unusual for more than 2500 individuals to have received the drug up to this point in time. Therefore, postmarketing surveillance is crucial to detect any rare (incidence <1 in 1000) ADRs that are unlikely to have been detected during the drug development process. Companies may institute formal (phase 4) prospective cohort studies at this stage, particularly if they wish to examine any potential drug safety issues on a much larger population of patients.
NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE (NICE) This body was set up in 1999 to assess the cost-effectiveness and clinical effectiveness of new and existing technologies, including certain drugs, and to provide patients, health professionals and the public in England and Wales with authoritative, robust and reliable guidance on current 'best practice'. When a cost-effective treatment already exists, this is used as a benchmark against which any existing or newly marketed treatment is appraised, as to whether it is a clinically effective and cost-effective use of NHS resources. Details of the appraisals can be found at http://www.nice.org.uk.
MONITORING ADVERSE DRUG REACTIONS One of the MCA/CSM's most important tools in monitoring safety of marketed medicines is the yellow card system. Set up in 1964 in the wake of the thalidomide tragedy, it now has more than 480000 reports of suspected ADRs that have been submitted on a voluntary basis by doctors, dentists, pharmacists and coroners, and (under statutory obligation) by pharmaceutical companies. If a serious reaction is suspected, or any possible reaction to a newly marketed drug (marked with an inverted triangle in the British National Formulary), a card should be sent to the Medicines Control Agency (MCA), in certain areas via the appropriate Regional Monitoring Centre. A substantial data bank is thereby accumulated and analysed regularly for associations between suspected adverse reactions and individual drugs. Data from the UK scheme and from more than 40 other countries is shared with the WHO Collaborating Centre for International Drug Monitoring in Uppsala, Sweden. Each year more than 150000 such reports are received and the cumulative database now contains over 1.4 million records, so that potential ADR
1
FIG. 1.5 Drugs involved in self-poisoning Number and percentage of admission to the Cardiff Poisons Treatment Unit in 1999 involving the seven most frequently taken drugs/drug groups. (Some patients take more than one drug).
FIG. 1.6 The relationship between age and the incidence of poisoning in children Figures are based on enquiries concerning accidental poisoning made to the National Poisons Information Service (Cardiff Centre) in 1999.
signals can be detected more sensitively. Such spontaneous reporting schemes are relatively inexpensive and extremely cost-effective. Unfortunately, less than 10% of even serious suspected ADRs are reported via these schemes, and they could be even more effective if more health professionals regularly reported their drug-safety concerns.
Whereas death from carbon monoxide poisoning predominates in adults, there are approximately 20 accidental deaths per year from all other agents, particularly tricyclic antidepressants, iron, aspirin and barbiturates in young children. The incidence of accidental poisoning in childhood is partly determined by availability.
DELIBERATE SELF-POISONING DRUG OVERDOSE Approximately 4000 people die each year of poisoning in England and Wales, a quarter of them of carbon monoxide poisoning. Approximately two-thirds of the remaining deaths occur outside hospital. Nevertheless, more than 100000 patients are admitted to hospital in England and Wales each year with poisoning, accounting for 10% of all acute admissions. The unadjusted admission rates in the USA range from 80 per 100000 in patients aged 65-74 years to 400 per 100000 in patients aged between 15 and 24 years. Toxic compounds may be ingested or inhaled either accidentally or deliberately, or may be administered accidentally or deliberately. This forms the basis for a classification of poisoning incidents, separating them into broad epidemiological categories. The major causes of admission due to poisoning are shown in Figure 1.5.
ACCIDENTAL POISONING Accidental poisoning can occur at any age but is much more likely to occur in children under 5 years of age (Fig. 1.6). Peak incidence is around 2 years, when children have become independently mobile, and boys appear to be more at risk. This contrasts with other categories of poisoning, in which women are involved more than men. Fortunately, the mortality from accidental poisoning is relatively small.
Deliberate self-poisoning is commoner in adults who, unlike children, ingest medicinal agents more readily than they do household chemicals and other non-medicinal compounds. Women are more often involved than men, and the vast majority of instances are not intended to be ultimately fatal. Generally they represent a response to an apparently insoluble personal predicament (Ch. 8), but some have a definite suicidal intent. Patients who successfully commit suicide tend to be older and may have been recently divorced or bereaved, may be living alone, suffering from a physical illness, unemployed or abusers of alcohol.
NON-ACCIDENTAL POISONING Non-accidental poisoning usually involves children and is a form of abuse. The parents of such children may have suffered child abuse or deprivation themselves, and often have marital or financial problems or difficulties in managing the child at the time of the poisoning episode.
HOMICIDAL POISONING Although often featured in novels and plays, homicidal poisoning is uncommon. When it does happen, it is often
15
caused by a close relative or friend and generally involves the use of poisons producing chronic, rather than acute, symptoms.
DIAGNOSIS OF POISONING Laboratory tests cannot identify every agent to which an individual might be exposed. A full history and clinical examination is therefore an integral part of the diagnosis. As the patient may be unwilling or unable to give a history on presentation, it is important to talk to relatives or friends, the GP or the ambulance personnel who brought the patient into hospital. Particular difficulties are encountered with the patient who is found alone and unconscious and in whom poisoning is just one of the differential diagnoses. The first priority in the unconscious patient is maintenance of the airway, ventilation and cardiovascular function. When this has been assured, the question arises as to whether the patient is poisoned. Other causes of unconsciousness are discussed in Chapter 24. In deep coma due to drug overdose the pupillary reflexes are often preserved, but the oculovestibular responses (e.g. 'doll's eye response') are absent. Focal neurological signs are rare in overdose and, unless they can be accounted for by previous pathology, these should alert the clinician to the possibility of another cause. Papilloedema due to drug overdose is rare, unless the overdose has been associated with cerebral hypoxia and oedema. If the patient shows no improvement in level of consciousness by 12 hours after admission, another pathology should be suspected.
TABLE 1,8 Physical signs suggestive of overdose or poisoning: head and neck Sign
Possible cause
Dilated pupils
Anticholinergics Tricyclic antidepressants Amphetamines Ecstasy Carbamazepine Sympathomimetics Cocaine LSD Glutethimide Methanol
Constricted pupils
Opiates Organophosphates and carbamates
Strabismus
Carbamazepine
Nystagmus
Barbiturates Carbamazepine Phenytoin Phencyclidine
Perforated nasal septum
Cocaine abuse
Acneiform rash
Solvent abuse
Erythema/burns
Corrosives Paraquat
Mouth dryness
Anticholinergics
Hypersalivation
Parasympathomimetics Organophosphates and carbamates Arsenic Strychnine Clormethiazole Clozapine
CLINICAL EXAMINATION It is sometimes possible to identify the poison by the clinical signs on examination, although it may be more difficult if the patient has taken several agents. The most helpful clinical signs are shown in Tables 1.8 and 1.9.
Mouth
Eyes Pupillary dilatation occurs in poisoning with anticholinergic drugs, such as the tricyclic antidepressants, antiparkinsonian agents, antihistamines and phenothiazines. It also occurs with agents that stimulate the sympathetic nervous system, such as amphetamines, LSD and theophyllines. Unequal pupils are occasionally seen in poisoning. Strabismus is not uncommon, particularly in carbamazepine poisoning. Papilloedema, however, is rare, except as a
1
16
result of methanol, carbon monoxide or glutethimide poisoning. Agents affecting the central nervous system (CNS), particularly phenytoin, may cause nystagmus.
Fig. 1.5
2
Fig. 1.6
Acneiform lesions around the buccal cavity may suggest solvent abuse, O and the characteristic odour of solvent or alcohol may be present on the breath. Examination of the oral cavity may reveal ulceration due to corrosion by acids or alkalis. The mouth may be abnormally dry because of anticholinergic compounds, and increased salivation may be seen in subjects who have taken agents that stimulate the parasympathetic nervous system, e.g. carbamate insecticides and anticholinesterases.
Cardiorespiratory Chest wheeze may be caused by inhalation of irritant compounds: pulmonary oedema can also be caused by these
TABLE 1.9 Physical signs suggestive of overdose or poisoning: trunk and limbs Sign
Possible cause
Bronchospasm
Irritant gases NSAIDs (rare) Arthropod envenomation Scombroid fish
Pulmonary oedema
Irritant gases Paraquat Opioid analgesics Aspirin
Tachycardia
Anticholinergics Sympathomimetics Cocaine Phencyclidine Theophylline Amphetamines Aspirin
Bradycardia
Cardiac glycosides p-Blockers Verapamil Organophosphates and carbamates
Hypertension
Sympathomimetics Amphetamines Phencyclidine MAOIs Clonidine Cocaine SSRIs (rare)
Needle tracks
Drugs of addiction
Absent bowel sounds
Anticholinergics Tricyclic antidepressants Opioids
Bladder distension
Anticholinergics Tricyclic antidepressants
Hypothermia
Phenothiazines Tricyclic antidepressants MAOIs (rare)
Hyperthermia
MAOIs Sympathomimetics Anticholinergics MAOIs SSRIs (rare) Amphetamines Ecstasy Aspirin
Hyperreflexia
Anticholinergics Sympathomimetics Opioids
Blisters
Barbiturates Carbon monoxide Opioids Tricyclic antidepressants
Extensor plantar responses
Anticholinergics Tricyclic antidepressants
agents, or by ingestion of drugs such as opioids or aspirin. There may be tachycardia with poisoning due to anticholinergics, salicylates or drugs that stimulate the sympathetic nervous system. Verapamil, (3-blockers or drugs that stimulate the parasympathetic nervous system, on the other hand, may cause bradycardia. Cardiac arrhythmias may be associated with hypoxia, but are particularly troublesome in patients who have taken tricyclic antidepressants, drugs stimulating the sympathetic nervous system, phenothiazines or quinine. Many agents can cause hypotension, but hypertension is rarer and usually associated with monoamine oxidase inhibitors or clonidine, which in overdose may act like a-adrenoceptor agonists.
1
Abdomen Absent bowel sounds or bladder enlargement suggest the possibility of anticholinergic poisoning. Rectal examination should be performed and may reveal melaena due to poisoning by iron, non-steroidal anti-inflammatories or other agents that damage the gut mucosa. The rectal temperature should be recorded using a low-reading thermometer. This may reveal hypothermia (e.g. with phenothiazine poisoning) or hyperthermia (in poisoning by salicylates, anticholinergic compounds or drugs that stimulate the sympathetic nervous system).
Skin and nails The hands, arms and legs may show needle tracks indicating drug abuse. Blisters over the bony prominences, commoner on the lower limbs, are seen in patients who have taken a barbiturate, opioid or tricyclic antidepressant overdose, 2 or are suffering from carbon monoxide poisoning (Fig. 1.7). Their presence reflects the combination of severe hypoxia and pressure, and they often occur where the patient has been lying against a hard surface. They should alert the physician to the possibility of hypoxic damage of other organs such as muscle, since there is sometimes associated rhabdomyolysis. The nails may show transverse white (Mee's) lines in poisoning with the heavy metals, arsenic and thallium (Fig. 1.8).
Neuromuscular Examination of the limbs normally reveals hypotonia and hyporeflexia in poisoning, but anticholinergic drugs, some opioids and drugs that stimulate the sympathetic nervous system may cause hypertonia, hyperreflexia and, occasionally, myoclonus. Anticholinergic compounds may also produce an extensor plantar response that is usually bilateral. Convulsions may be caused directly by a variety of compounds, including the anticholinergic agents and drugs stimulating the sympathetic nervous system, opioids, mefenamic acid and isoniazid, or may be secondary to hypoxia or hypoglycaemia associated with overdose. Dystonic reactions are much less commonly seen, and are generally
17
FIG. 1.7 Poison blister Blister on the knee of a 25-year-old male who took an overdose of the opiate drug, dextropropoxyphene. He subsequently developed signs of rhabdomyolysis.
FIG. 1.8 Mee's lines in the nails of a patient with thallium poisoning These dystrophic changes causing a white line distal to the cuticle are also seen in poisoning with arsenic.
related to poisoning with drugs with antidopaminergic activity, such as metoclopromide, the phenothiazines and butyrophenones.
The urea and electrolytes are rarely of diagnostic value. Hypokalaemia can be caused by theophylline and drugs stimulating the sympathetic nervous system, or may indicate potassium loss owing to diuretic or purgative overdose. Hyperkalaemia is sometimes seen in severe digoxin overdose. Reduction in the serum bicarbonate may indicate metabolic acidosis and should be investigated by arterial blood gas analysis. The alcohols and glycols, as well as aspirin, may cause a metabolic acidosis, often with a high anion gap (see p. 1114). The presence of both a high anion and an osmolal gap in the absence of detectable ethanol is suggestive of methanol or ethylene glycol poisoning. Profound hypoglycaemia may indicate overdose with oral hypoglycaemic agents or be secondary to overdose with alcohols, salicylates or paracetamol. Clinical judgment must be used in deciding which test will give useful diagnostic or prognostic information. It is useful to store blood for future reference.
LABORATORY INVESTIGATIONS Routine laboratory investigations are sometimes helpful in identifying the drug ingested.
Urine The urine should be examined both macroscopically and microscopically. A specimen should also be stored for possible future analysis even if this is not indicated initially. Red discoloration may be caused by rifampicin or phenindione, 1and haematuria by drugs affecting haemostasis or clotting, or by drugs causing haemolysis, such as chlorates. Drugs that contain methylene blue (e.g. some commercial analgesics) may colour the urine blue or green; a greyish discoloration may indicate poisoning with phenols or cresols. Microscopic haematuria or albuminuria may be the first sign of renal damage. Crystalluria can occur with primidone and some of the sulphonamides, and calcium oxalate crystals may be present in ethylene glycol poisoning.
Blood Brown discoloration of venous blood may indicate methaemoglobinaemia, which can be caused by oxidizing agents such as dapsone. Pink discoloration of the plasma indicates haemolysis, which may be drug induced.
O Fig. 1.7
18
Specific tests An increasing number of compounds can now be detected specifically in either urine (which tends to be more useful as it concentrates the drugs or its metabolites) or blood. Toxicological analyses are not a substitute for clinical judgment and the physician should consider whether the result would alter his or her management.
PRINCIPLES OF MANAGEMENT OF POISONING General supportive measures to prevent complications are usually more important than specific therapies to treat the particular poison, since the latter are not always available.
SUMMARY 4 Principles of management of poisoning • General supportive management, particularly of airway, breathing and circulation (ABC), is of prime importance • Identification of the cause of poisoning can be made by history and clinical and toxicological examination • Decontamination procedures should then be considered to prevent further adsorption of drug remaining in the gastrointestinal tract • Elimination of some drugs can be enhanced. Procedures can produce complications and should only be considered when clearly indicated • General supportive care. Prevention and treatment of complications remains the mainstay of management
SUPPORTIVE MANAGEMENT
• Increased capillary permeability, resulting in a reduced circulating blood volume. In hypotensive patients a central venous pressure line should be inserted. If the venous pressure is low the blood volume should be increased using a plasma expander, such as Haemaccell. If the hypotension does not respond, intravenous (i.v.) dopamine or dobutamine may restore the blood pressure: low-dose dopamine may prevent subsequent acute renal failure (see Ch. 14). Cardiac arrhythmias, which may be a direct effect of the drug or a result of hypoxia and acidosis, may also contribute to hypotension by reducing cardiac output. It is important to correct the predisposing causes if possible before considering specific antiarrhythmic therapy, as many antiarrhythmics may further reduce cardiac output. The choice of an antiarrhythmic agent is usually based on the arrhythmia rather than the specific toxin.
Maintenance of respiratory function
Prevention of complications
Maintenance of an adequate airway and respiration is the first priority in an unconscious patient, as many early deaths from poisoning are due to airway obstruction. Dentures should be removed, the tongue pulled forward and the mouth and pharynx cleared of saliva and vomitus. If the patient has no cough reflex, a cuffed endotracheal tube is necessary to protect the lungs; in other cases a short oropharyngeal tube should be inserted. The patients is then moved into a semiprone position and, if there is any suspicion of inadequate ventilation, oxygen should be administered. Assisted ventilation may be necessary. In less urgent circumstances arterial blood gas analysis is the best guide to assessing the adequacy of ventilation. Drugs that stimulate respiration (e.g. doxapram) should be used cautiously in poisoned patients as they may provoke convulsions or cardiac arrhythmias. The shock lung syndrome (acute respiratory distress syndrome, ARDS; see p. 697) may appear at about 24 hours. The patient begins to hyperventilate but remains hypoxic, and develops a respiratory and metabolic acidosis. A chest radiography may show changes similar to pulmonary oedema and, in severe cases, the lung fields may be completely obscured. Assisted ventilation using positive endexpiratory pressure (PEEP) may help to support the patient through this severe complication. The treatment of aspiration pneumonia is discussed on page 635.
Good nursing care of the unconscious patient is essential. Skin and muscle compression injuries associated with prolonged immobility and hypoxia are a particular problem. The bladder can sometimes be emptied by firm suprapubic pressure, but if it is markedly distended catheterization may be necessary, particularly when measurement of urine production is required. The level of consciousness should be measured using a scale such as the Glasgow Coma Scale (GCS) (Table 1.10). If the conscious level does not improve after 12 hours, this may indicate neurological complications of the overdose or that there is an alternative cause of the
TABLE 1.10 Assessment of consciousness (Glasgow Coma Scale) Score Eyes open
Best motor response To verbal command To painful stimulus
Maintenance of circulatory function Maintenance of circulatory function is essential. Hypotension and reduced peripheral perfusion may be caused by several mechanisms, including: • Depression of the vasomotor centre; • A direct cardiodepressant action; • Increased venous capacitance, leading to reduced venous return to the heart and a consequent fall in cardiac output;
1
Spontaneously To verbal command To pain No response
4 3 2 1
Obeys Localizes pain Flexion-withdrawal Flexion-abnormal (decorticate rigidity) Extension (decerebrate rigidity) No response
6
Orientated and converses Disorientated and converses Inappropriate words Incomprehensible sounds No response
5 4 3 2 1
5 4 3 2 1
Best verbal response
Total
3-15
19
coma. Cerebral oedema is the most life-threatening complication of overdose, and may be caused by hypoxia, hypoglycaemia, hypercapnia or hypotension. It is particularly likely to occur after cardiorespiratory arrest and may respond to dexamethasone or mannitol. Convulsions may also be secondary to hypoxia or cerebral oedema, but otherwise are generally short-lived and do not always require specific therapy. If necessary, intravenous diazepam may be used, but if the patient is vomiting, temporary intubation and mechanical ventilation may be necessary to prevent aspiration pneumonia. Gastrointestinal bleeding or paralytic ileus may be seen in patients with drug overdose. Insertion of a nasogastric tube and regular emptying of the stomach help to reveal bleeding early and prevent the aspiration pneumonia or acute gastric dilatation sometimes seen with paralytic ileus.
MEASURES TO PREVENT FURTHER DRUG ABSORPTION Emptying the stomach can sometimes reduce further absorption of the drug from the gut. Such measures are only indicated if the amount of poison taken is likely to cause serious symptoms, and are of little value if the material ingested has already left the stomach. They should therefore generally only be considered when less than 1 hour has elapsed since ingestion of the toxin, although they may sometimes still be worthwhile if the time of ingestion is unknown.
Gastric lavage Gastric lavage has been the most widely used method of emptying the stomach in adults. It is contraindicated in patients who have taken corrosive agents, unless the danger of systemic toxicity associated with a corrosive agent is greater than the risk of local damage. It is also usually contraindicated after oral ingestion of petroleum distillates, because of the risk of aspiration pneumonia. In the unconscious patient, a cuffed endotracheal tube must always be inserted first. Lavage should be carried out in the left lateral position in a bed or trolley raised at the foot. A large-bore Jaques stomach tube (external diameter
SUMMARY 5 Prevention of further drug absorption
20
• Activated charcoal prevents further absorption of many drugs, if administered sufficiently early, and is the safest and most effective method if the substance is adsorbed by charcoal • Gastric lavage may prevent absorption of the drug if performed within 1 hour of drug ingestion • Emptying the stomach by lavage should not be attempted if the airway cannot be protected • Emesis induced by syrup of ipecacuanha is no longer recommended in children or adults
TABLE 1.11 Substances not effectively adsorbed to charcoal Boric acid Cyanide Ethanol Ethylene glycol Iron salts Lithium salts Malathion Methanol Petroleum distillates Strong acids and alkalis
c 14mm) is introduced into the stomach and the contents removed. Aliquots of water warmed to body temperature are then introduced and removed until the returned fluid is clear of particles. However, gastric emptying by lavage is often relatively inefficient and may be difficult or even dangerous in some individuals (e.g. small children and patients with tricyclic antidepressant poisoning, who may become hypoxic).
Emesis There is little benefit from inducing vomiting. Although syrup of ipecacuanha produces emesis, its effect is delayed for 20-30 minutes and there is no good evidence that it reduces drug absorption significantly in poisoned patients. In addition it has side-effects (e.g. persistent vomiting) which may increase morbidity and make diagnosis more difficult. Salt and water should never be used to produce emesis, as death may occur from hypernatraemia, particularly in small children.
Oral adsorbents Activated charcoal is increasingly being used as it may reduce the absorption of many drugs. Drugs not adsorbed effectively to charcoal are listed in Table 1.11. Charcoal is most effective for agents with high-toxicity taken at low total dose, as 10 times as much charcoal as drug is required to provide optimum adsorption. The charcoal must be given soon after the overdose (normally within 1 hour) to achieve maximum efficacy. A dose of 50-100 g (lg/kg in children) can be administered orally or, in an adult, by nasogastric tube. It is of particular value in accidental poisoning in children, as these cases normally present early enough for the adsorbent to be effective.
ANTIDOTES There are direct antidotes only to about 5% of poisons, so supportive therapy remains the mainstay of treatment for
1
CASE STUDY 1.1 DOSULEPIN (DOTHIEPIN) OVERDOSE A 50-year-old man was admitted to hospital 2 hours after taking 750 mg dosulepin (dothiepin) (conventionalrelease form) and, possibly, 100 mg diazepam. He was very drowsy (Glasgow Coma Scale 9) and tachycardic (pulse 120 bpm, regular). He had dilated pupils (responding slightly to light), exaggerated limb reflexes and bilateral extensor plantar responses. His respiratory rate was 15 per minute. Bowel sounds were present but quiet, and percussion revealed a distended bladder. His blood pressure was 100/70 mmHg. His ECG confirmed sinus tachycardia but showed marked widening of the QRS complex. Questions 1. What other investigations would you ordef ? 2. What treatment would you consider? <
Discussion
Dosulepin (dothiepin) is a tricyclic antidepressant with marked anticholinergic activity in overdose. The clinical features in this patient are consistent with anticholinergic poisoning due to tricyclic antidepressants, although diazepam (a benzodiazepine tranquillizer) could also be contributing to his reduced conscious state. Tricyclic antidepressants can produce cardiac and respiratory depression, with metabolic and respiratory acidosis. Blood gases should be measured urgently and any hypoxia corrected. His temperature should also be checked to exclude hypothermia (which can be caused by a variety of drugs in overdose, including tricyclic antidepressants). Finally, urea and electrolytes should be measured. The presence of significant ECG abnormalities is an indication for intravenous sodium bicarbonate
the vast majority of patients, including those where an antidote exists. Antidotes work in several different ways: • They may speed the metabolism of a toxin, e.g. thiosulphate speeds the metabolism of cyanide by providing sulphur to form non-toxic thiocyanate, which is then excreted in the urine. • If a compound is only toxic when metabolized, antidotes may reduce the rate of metabolism. Ethanol is used in poisoning by methanol and ethylene glycol to reduce the rate of production of toxic aldehydes and acids. • For receptor-mediated toxins, an antagonist that competes for a receptor may be useful, e.g. the use of (3agonists in the treatment of (3-adrenoceptor blocking drugs overdose. • If the toxin competes with a natural substrate, an antidote may increase the natural substrate's concentration, competitively displacing the poison from the receptor site. Inhibitors of acetylcholinesterase reverse some of the features of anticholinergic poisoning in this way. • Antidotes may combine with the poison to form an inactive compound. Thus, specific antidigoxin antibody (Fab) fragments combine with digoxin to produce an inert complex, which can be excreted more rapidly via the kidney. The availability of a specific antidote does not necessarily justify its routine use. Some antidotes are toxic in their
(50mmol), even in the absence of acidosis. Further doses may be necessary, depending on clinical response. Charcoal is of limited value at this stage and may be dangerous if he cannot protect his airway, so it should not be given. Convulsions are normally controlled by diazepam. Flumazenil (a benzodiazepine antagonist) may reverse the effects of any diazepam this patient may have taken, and thus precipitate convulsions and arrhythmias. It should not be given to patients who have taken tricyclic antidepressants. Because of the large volume of distribution of tricyclic antidepressants, forced diuresis, haemodialysis and haemoperfusion are of no proven value in enhancing their elimination. If this patient were to have a cardiac arrest, there is evidence that prolonged resuscitation might be successful.
own right and should only be used if the severity of the poisoning merits their administration. In general, they are most useful early on in the course of poisoning.
ENHANCEMENT OF DRUG ELIMINATION Methods to enhance drug elimination (Table 1.12) are of limited value in the treatment of overdose and are generally only effective when the volume of distribution of the drug is relatively small. This is because drug removal can only occur from the central (intravascular) compartment, which must therefore contain a reasonable proportion of the total body burden of the compound.
Forced diuresis Forced diuresis has been used to enhance the elimination of drugs (such as aspirin) that are excreted predominantly in an unchanged form by the kidney. It acts by increasing the glomerular filtration rate and by reducing the tubular reabsorption of unchanged drug. This is dependent on renal tubular flow, and on the degree of ionization of the drug in the tubular fluid. For weak acids, alkalinization of the tubular fluid by administration of bicarbonate will result in a greater proportion of the drug existing in the
21
TABLE 1.12 Techniques used to enhance drug elimination Enteral adsorbents Activated charcoal Carbamazepine Dapsone Phenobarbitone Quinine Theophylline
Dialysis Barbitone Ethanol Ethylene glycol Isopropanol Lithium Methanol Phenobarbitone Salicylates Haemoperfusion Barbiturates Carbamazepine Glutethimide Meprobamate Phenytoin
Colestyramine (cholestyramine) Digitoxin Phenprocoumon Warfarin
ionized, poorly lipid-soluble form. It is then unable to diffuse back across the lipid membrane of the tubular cell and be reabsorbed. Conversely, acidification of the urine by administration of ammonium chloride, arginine or lysine hydrochloride will increase the ionization of some basic drugs, thereby reducing reabsorption from the tubular fluid. Owing to the risks of fluid overload and electrolyte imbalance, and its relatively limited efficacy, forced diuresis is falling out of favour and is being largely replaced by other, safer, methods of enhancement of elimination.
Dialysis Peritoneal or haemodialysis is useful to remove drugs with low plasma protein binding, poor lipid solubility and relatively low volume of distribution. It is generally reserved for cases where other methods of removal are contraindicated. This process effectively removes salicylates, phenobarbital and barbitone, methanol, isopropanol, ethylene glycol and lithium. Haemodialysis is normally the more effective of the two approaches.
Haemoperfusion Haemoperfusion involves the passage of arterial blood through an extracorporeal column of activated charcoal or ion exchange resin. This effectively removes a number of drugs where the lipid solubility or plasma protein binding reduces the efficacy of removal by dialysis techniques,
1 22
MCQ 1.12-1.14
but a low volume of distribution of the drug is still required. Haemoperfusion is therefore sometimes considered in severe poisoning with barbiturates (including the shortacting barbiturates not removed effectively by haemodialysis) and non-barbiturate hypnotics such as glutethimide, ethcholorvynol, meprobamate, methaqualone and chloral derivatives (e.g. chloral hydrate). Fortunately, these agents are now used less frequently as hypnotics. Haemoperfusion using resin columns is particularly effective in removing theophylline and, to a lesser extent, salicylates. Complications of the procedure include thrombocytopenia, bleeding and possible infection, so haemoperfusion should only be used in patients with severe poisoning who fail to improve despite supportive management and who have developed, or are at high risk of developing, complications of the overdose. Enteral removal Enteral removal is the most recent approach to the enhancement of drug elimination. It relies on the ability of some non-absorbed agents either to remove drugs that have been excreted in the bile but would have been reabsorbed in the gut, or to remove them by 'dialysis' of the splanchnic circulation. Charcoal is the most widely used enteral adsorbent, and markedly enhances the rate of removal of phenobarbitone, digitoxin, quinine, theophylline and dapsone. It is given as an initial loading dose of 50-100 g, followed by repeated doses of 50 g every 4 hours, sometimes with a single dose of a laxative at the beginning to prevent constipation. Oral colestyramine (an anion-binding resin) increases the rate of removal of digitoxin, warfarin and some other coumarin anticoagulants. This non-invasive procedure usually has no major adverse effects, although an antiemetic may be needed in patients who are vomiting as a result of the toxin (e.g. theophylline). 1 SUPPORT SERVICES It is impossible for a clinician to be familiar with all the details of the recommended current management of all toxins. As in other countries, in the UK and Eire Poisons Information Services have therefore been established in several major cities to serve their region(s) (Fig. 1.9). They also contribute to the editing of a database system (TOXBASE), accessible via the Internet, and soon via the NHS Intranet. Its role is to provide health professionals with up-to-date relevant first-line information on the management of poisoning. It can be found on the Internet at http://www.spib.axl.co.uk. TOXBASE also contains advice on holding centres for antidotes, analytical facilities for toxins, slang terms for drugs of abuse, and references on the most important aspects of toxicology. In cases where further advice is necessary, the nearest Poisons Unit in the UK can be contacted via a single national telephone number: 0870 600 6266, or, in Eire, Dublin 837 9964.
National Poisons Information Service Toxbase: http://www.spib.axl.co.uk UK national number 08706006266
SUMMARY 6 Management of benzodiazepine poisoning
1
• Benzodiazepine poisoning is common but death is rare unless other potentiating agents (e.g. alcohol) have also been taken • Flurazepam, tlunitrazepam and triazolam may cause deeper coma than the other agents • Management is generally supportive • Flumazenil, a specific short-acting benzodiazepine antagonist, has been used in the diagnosis of mixed overdose, but may precipitate benzodiazepine withdrawal in dependent individuals, convulsions in individuals with epilepsy and serious arrhythmias in patients who have also taken tricyclic antidepressants
fatal cases each year in which a benzodiazepine is the only drug identified, but they potentiate the effects of other CNS-depressant drugs such as ethanol and can thus contribute to fatal outcome.
FIG. 1.9 Areas served by the UK and Eire Poisons Information Services
On recovery from an overdose, the patient should undergo thorough psychiatric and, if necessary, social assessment (Ch. 8, p. 224). There appears to be a poor correlation between the severity of the overdose and any underlying psychiatric illness. The GP also plays an important part in supporting the patient once he or she has left hospital. Finally, voluntary services often provide useful emotional and practical support to the patient at risk, and details of these local organizations should be made available to each patient.
MANAGEMENT OF SPECIFIC DRUG OVERDOSE The drugs most commonly involved in acute poisoning are hypnotics and tranquillizers, antidepressants and analgesics.
Diagnosis The major effects are on the CNS and include drowsiness, ataxia, dysarthria and nystagmus. Coma then supervenes, although it is rarely deep unless other agents have also been ingested. Recovery is normally within 24 hours, although flurazepam and flunitrazepam may cause deeper and more prolonged coma, and clonazepam has been associated with cyclical coma. Lorazepam causes only modest CNS depression but can be associated with restlessness and hallucinations, particularly in children. Respiratory depression occurs rarely in benzodiazepine overdose, although it may occur in patients with pre-existing respiratory disease, particularly with flunitrazepam. Cardiovascular effects are also generally mild, although slight hypotension may occur. Flunitrazepam may cause more profound hypotension and a sinus bradycardia. Bullous skin lesions have been reported, but are much rarer than after barbiturate overdose. Management Management is supportive: methods to enhance elimination of the parent compound or its active metabolites are of no value. Most patients will recover with no sequelae. Antagonists of benzodiazepines (e.g. flumazenil) have been used in the diagnosis of mixed overdose, or in avoiding the need for ventilatory support in severe poisoning. However, they may precipitate benzodiazepine withdrawal (including convulsions) in benzodiazepine-dependent individuals, convulsions in those with epilepsy, and serious arrhythmias in patients who have also taken tricyclic antidepressants concomitantly. They are also short-acting, so that benzodiazepine-induced coma can recur. They are therefore seldom used.
HYPNOTICS AND TRANQUILLIZERS Barbiturates Benzodiazepines Benzodiazepines are involved in almost half of the drug overdoses in the UK. There are only a small number of
The incidence of barbiturate poisoning has declined markedly over the past 20 years, but this group of compounds is still associated with high mortality.
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SUMMARY 7 Management of barbiturate poisoning • Barbiturate poisoning is now relatively rare but has a significant mortality • Gastric lavage should be performed within 1 hour and activated charcoal left in the stomach. The airway must be protected • Bullous lesions should alert to the possibility of underlying muscle damage (rhabdomyolysis) • Repeat-dose activated charcoal enhances the elimination of phenobarbitone already absorbed, but not of other barbiturates • Charcoal haemoperfusion should be considered only in severe poisoning with barbiturates
Diagnosis In overdose the barbiturates produce an impaired level of consciousness and, in severe cases, hypotension and respiratory depression. Approximately 5% of patients have bullous lesions on the extremities, particularly over the extensor surfaces, but these are not specific to barbiturate overdose and can occur with other agents producing profound hypoxia. Barbiturates can be detected in the urine. Although their plasma concentrations can also be measured, these correlate poorly with the severity of the overdose, partly because of other confounding drugs such as alcohol, and partly because of tolerance, particularly in those taking the drug chronically. Plasma concentrations are therefore of limited value in the management of a particular case, although very high concentrations in the presence of deep coma and other complications of overdose may indicate the need to enhance the removal of the drug. Management Gastric lavage should be performed if tablets have been taken less than an hour previously, or if the time of ingestion in an unconscious patient is unknown. General supportive management is all that is required in most cases, with particular attention to respiration and cardiovascular function. However, even with these measures the mortality in deep coma (GCS 3) is about 5% and procedures to enhance drug elimination may be considered in such subjects, particularly if complications of overdose are already present. Repeated doses of activated charcoal given by mouth through a nasogastric tube can reduce the half-life of phenobarbitone from over 100 hours to less than 20 hours. This procedure is relatively non-invasive and may replace the use of haemoperfusion for phenobarbitone poisoning. Activated charcoal has not yet been shown to enhance the elimination of any of the other barbiturates, and charcoal haemoperfusion may be necessary in such cases who are deteriorating despite intensive management or who have developed serious complications (e.g. pneu-
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24
MCQ1.15
monia, hepatic or renal failure). The blisters should be treated in the same way as burns. 1
Non-barbiturate, non-benzodiazepine hypnotics These were once widely used but have now been largely replaced by benzodiazepines. Isolated overdoses of these agents still occur, however. Specific effects may be seen in addition to CNS depression. Glutethimide may cause fluctuating coma, convulsions and acute respiratory failure. Pulmonary oedema and cerebral oedema may also occur, and papilloedema may be a sign of severe overdose. Charcoal haemoperfusion is indicated in severe overdose, together with management of specific complications. Chloral hydrate and its relatives (e.g. dichloralphenazone) may cause gastrointestinal irritation, haematemesis and subsequent oesophageal stricture. Cardiac arrhythmias are a particular problem with this group of agents but generally respond well to (3-blockers. Haemodialysis may remove the active metabolite, trichlorethanol, but charcoal haemoperfusion is probably more effective and may be helpful in very seriously poisoned patients. Clomethiazole (chlormethiazole) is often used in alcoholic patients, although its value is not proven and it may be dangerous when taken in overdose together with alcohol. Increased salivation is a particular problem which may increase the risk of aspiration pneumonia, and regular oropharyngeal aspiration may be necessary. Meprobamate is still used in the treatment of anxiety, and particularly with muscle spasm. Signs of overdose are muscular incoordination and weakness and CNS depression. In severe cases pulmonary oedema may be seen. Haemodialysis may be useful in severe overdose, but haemoperfusion appears to be more effective.
ANTIDEPRESSANTS Antidepressants, particularly those in the tricyclic group, are still commonly taken in overdose and are particularly dangerous.
SUMMARY 8 Overdose of tricyclic antidepressants • Tricyclic antidepressant poisoning is common and life-threatening • Anticholinergic signs predominate in the early stages but coma may supervene • Direct cardiotoxicity may result in ventricular tachycardia or ventricular fibrillation. The ECG should me monitored until recovery • Arrhythmias and hypotension may respond to correction of acidosis, hypoxia, hypothermia and hypovolaemia. Persistent arrhythmias may respond to sodium bicarbonate, even in the absence of acidosis • Prolonged cardiopulmonary resuscitation has been reported to be successful after cardiac arrest
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CASE STUDY 1.2 BIPOLAR AFFECTIVE DISORDER A 25-year-old woman with bipolar affective disorder presented 4 hours after taking 9g (18 tablets) of paracetamol. Her parents confirmed that she had taken a package up to the bathroom and locked herself in. When she came out there were almost empty paracetamol packages, which had originally contained 20 g of paracetamol. In the emergency department she was vomiting and complained of some epigastric discomfort. She was taking carbamazepine 600 mg daily for her psychiatric condition. Examination revealed no abnormalities. She was 1.55m (5 feet 2 ins) tall and weighted 50kg (110 pounds). Her plasma paracetamol concentration at 4 hours was 150mg/L (normal treatment concentration at 4 hours is 200mg/L). Questions 1. What other investigations would you ask for? 2. What treatment (if any) 1 would you consider?
Discussion Paracetamol can damage the liver and kidney and her INR, U&Es and LFTs should be measured. In some cases the liver transaminase enzyme concentrations (AST or ALT) may rise (as early as 12 hours) before changes in the INR, and can be a useful early marker of hepatotoxicity. In this woman the y-GT and AST may already be slightly raised because of her carbamazepine therapy (this effect is seen in patients on enzyme-inducing drugs). It might also be useful to check her serum carbamazepine concentration to see whether she might have taken these in overdose. Normally, the potentially toxic dose of paracetamol is 150mg/kg or 10 g, whichever is the smaller. This patient weighs only 50kg, so any dose over 7.5 g should cause concern. In addition, carbamazepine is an enzyme inducer and may increase the risk of toxicity at any given dose. In the UK, individuals receiving enzyme-inducing drugs (carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin or St John's
Tricyclic antidepressants The tricyclic antidepressants act by blocking the uptake of noradrenaline (norepinephrine) by neurons both peripherally and in the CNS. They also have an anticholinergic effect and, in overdose, may have direct actions on the heart. Diagnosis The first signs are usually due to anticholinergic effects. Dryness of the mouth and initial stimulation of the CNS are followed by depressant effects. In severe overdose muscle hypertonia, hyperreflexia and extensor plantar responses are followed by hypotonia and hyporeflexia; generalized convulsions may also occur. Other anticholinergic features are warm dry skin, pupillary dilatation, urinary retention and, in severe cases, paralytic ileus. Depression of respiration may be associated with hypoxia and respiratory and metabolic acidosis. Hypothermia may also occur, and respiratory complications such as aspiration and ARDS (p. 697) can further compromise tissue perfusion.
wort) or at increased risk for other reasons (a regular consumer of alcohol in excess, or badly nourished and thus glutathione depleted) are treated according to the 'high-risk' line, which is half the 'normal' treatment line. The timing of the overdose relative to measurement of plasma paracetamol concentration is crucial in informing such treatment decisions. In this case the parents could confirm when the overdose occurred. However, if there is doubt about the timing of the overdose, consider treating the patient anyway. The treatment of choice in the UK is intravenous N-acetylcysteine for 16 hours. Emptying of the stomach is not indicated after 1 hour. Monitor the INR and U&Es at intervals and when the N-acetylcysteine is discontinued. Subsequent psychiatric assessment is also an important part of the treatment of this patient.
The most life-threatening complication is cardiotoxicity. Tricyclic antidepressants resemble quinidine in their action on the heart, producing a decrease in myocardial contractility, prolongation of the PR interval and widening of the QRS complex. In severe cases the T wave may disappear and the ECG may resemble ventricular tachycardia. Severe ventricular arrhythmias occur in some patients (Fig. 1.10), particularly in the early stages, and the ECG should therefore be monitored preferably even before emptying the stomach.
Management If less than an hour has elapsed, activated charcoal should be given by mouth or nasogastric tube to prevent further absorption of drug in those who have ingested more than 4mg/kg, provided the airway can be protected. A second dose of charcoal (50 g) should be considered after 2 hours in patients with features of toxicity who are able to swallow, and multiple-dose activated charcoal may be useful if a modified-release preparation has been taken. Other methods to enhance elimination of tricyclic antidepressants from the body are of little or no value because
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FIG. 1.10 Rhythm ECG in tricyclic overdose
of the large volume of distribution, with only a small proportion of the drug therefore in the blood compartment. Convulsions may be related to anoxia and will sometimes respond to adequate oxygenation, although they may require treatment with anticonvulsants such as diazepam. The anticholinesterase agent physostigmine has been used to reverse the CNS effects, but it may precipitate convulsions, ventricular tachyarrhythmias and increased salivary and bronchial secretions. It is therefore rarely used. Arrhythmias and hypotension may respond to correction of acidosis, hypoxia, hypothermia and hypovolaemia. Persistent arrhythmias may respond to bicarbonate, even in the absence of acidosis. Sodium bicarbonate (50 mmol) should be given intravenously to an adult with arrhythmias or significant ECG abnormalities. Further doses may be required depending on clinical response. Antiarrhythmic agents should be used cautiously as they may worsen already impaired myocardial contractility, but positive inotropes (e.g. dobutamine) may be necessary to correct hypotension. Prolonged cardiopulmonary resuscitation has been reported to be successful in patients with tricyclic antidepressant poisoning. 1
Monoamine oxidase inhibitors The monoamine oxidase inhibitors (MAOIs) are much less frequently taken in overdose than tricyclic antidepressants. The onset of symptoms may be delayed for up to 12 hours or more after overdose, so observation for this period at least is necessary in those who have taken a potentially toxic dose. They produce features of increased sympathetic activity, with hyperexcitability and hyperreflexia followed by coma and convulsions. Peripheral muscular effects include myoclonus and rigidity leading to hyperpyrexia and rhabdomyolysis. A sinus tachycardia is often present, but the patient may be either hypertensive or, more rarely, hypotensive. Hyperthermia, or more rarely hypothermia, has been reported. Management The agitation, convulsions and hyperthermia may respond to diazepam, and dantrolene may also be useful in controlling muscle rigidity and hyperthermia. Sympathomimetic agents (e.g. dopamine and dobutamine) should be avoided if possible, as they may lead to a severe hyper-
1MCQ1.16 2MCQ 1.17 26
tensive crisis. Severe hypertension should be treated with an a-blocker such as phentolamine.
Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants These agents appear to be safer in overdose than tricyclic antidepressants and their increasing prescription in depression is reflected in an increased use in self-poisoning. Fluoxetine, fluvoxamine, citalopram, paroxetine and sertraline are the agents available in the UK. There is sometimes a latent period of hours before features occur, and alcohol may potentiate toxicity. Drowsiness, nausea, vomiting (particularly with fluvoxamine), abdominal pain, diarrhoea and sinus tachycardia have been reported. Agitation, tremor, dizziness and sweating are also sometimes seen. Rarely, junctional bradycardia, seizures and hypertension have occurred, and influenza-like symptoms may develop after a day or two. In rare instances a condition known as serotonin syndrome has recently been described. Agitation, myoclonus and sweating, shivering tremor and hyperthermia may occur, followed in some cases by rhabdomyolysis, renal failure, disseminated intravascular coagulation and, rarely, death. This condition is similar to, although normally less severe than, neuroleptic malignant syndrome (NMS), which is sometimes seen after therapeutic doses of some antipsychotic agents. Although both syndromes present with varying degrees of mental status changes and autonomic instability, high fever and muscle rigidity predominate in NMS, whereas gastrointestinal dysfunction and myoclonus are more pronounced in the serotonin syndrome. Venlafaxine potentiates neurotransmitter activity in the central nervous system, probably by inhibiting reuptake of serotonin and noradrenaline (norepinephrine). Although probably less toxic in overdose than tricyclic antidepressants, case reports involving seizures, arrhythmias, the serotonin syndrome (alone or in combination with other drugs), rhabdomyolysis and death have been reported in overdose. Nefazodone inhibits reuptake of serotonin and also selectively blocks serotonin receptors. Nausea, vomiting and drowsiness and, on occasion, convulsions have been reported after overdose. Mirtazapine, a presynaptic a2-antagonist, increases central noradrenergic and serotonergic neurotransmission. It may cause sedation in overdose. Reboxetine is a selective inhibitor of noradrenaline (norepinephrine) reuptake. Overdose may be associated with postural hypotension, anxiety and hypertension.
Management Supportive measures are normally sufficient, although activated charcoal will reduce absorption if given in the first hour. Convulsions should be treated with intravenous diazepam if they are frequent or prolonged. Treatment for all these agents is symptomatic and supportive. Management of the serotonin syndrome is also symptomatic and supportive, although drugs with antiserotonin activity, e.g. cyproheptadine, have been advocated in severe cases.
Lithium carbonate Lithium carbonate is widely used in the prophylaxis of manic depressive psychosis. It has a low therapeutic ratio, and signs of toxicity are most often due to excessive therapeutic doses. Diagnosis Nausea, vomiting and diarrhoea are often the first signs of overdose, followed by more severe signs of toxicity, including dysarthria, ataxia, drowsiness, confusion, coma and convulsions. Renal impairment and nephrogenic diabetes insipidus may occur, and liver damage has also been reported. Cardiotoxicity may be first indicated by ECG findings of non-specific ST segment depression, T-wave inversion, atrioventricular block, and prolongation of the QRS and QT intervals. Symptoms and signs may be delayed, particularly in those who have taken a sustainedrelease preparation, so observation for at least 24 hours, with ECG monitoring and 6-12-hourly plasma lithium measurements, is recommended.
Managemenf Consider gastric lavage for non-sustained release preparations if an adult has ingested more than 4g within 1 hour. Sustained-release preparations (the majority) are unlikely to be able to be removed via a lavage tube, however, and activated charcoal does not adsorb lithium. Rehydration is important, but hypernatraemia (which may indicate nephrogenic diabetes insipidus) may require i.v. dextrose until the serum sodium and osmolality become normal. Hypokalaemia should also be corrected. Toxicity correlates relatively well with the plasma lithium level, although there are differences between those who have taken an acute overdose in the naive state and those on long-term lithium therapy. Haemodialysis should be considered in the former situation in patients with signs of severe toxicity, if the plasma concentration exceeds 7.5 mmol/L, but for those with acute-on-chronic overdose or who have chronic accumulation, plasma concentrations above 4.0 mmol/L in patients with severe toxicity indicate consideration of haemodialysis. Because of the relatively large volume of distribution of lithium, plasma concentrations may increase by up to twofold shortly after the end of the dialysis. Repeated dialyses may therefore be necessary to maintain the serum lithium level at concentrations less likely to cause toxicity. 2
ANALGESICS
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The dangers of analgesics are not widely appreciated. They are the commonest group of drugs involved in overdose in adults, and in children are associated with serious and sometimes fatal poisoning.
Salicylates Salicylate overdose is responsible for approximately 200 deaths each year in the UK. In addition to being acids themselves, salicylates also increase circulating lactic and pyruvic acid concentrations by interfering with normal carbohydrate metabolism. Stimulation of fat metabolism causes increased production of (3-hydroxybutyric and acetoacetic acids, and increased protein metabolism results in increased circulating amino acids. Impairment of reabsorption of these amino acids, by competition with the salicylate for active tubular reabsorption, produces aminoaciduria and increased fluid loss owing to the effect of this solute load. Fluid loss is worsened by the vomiting associated with salicylate overdose, and by the uncoupling of oxidative phosphorylation, which causes hyperpyrexia and increased sweating. Stimulation of the respiratory centre by salicylates causes a respiratory alkalosis, which partly offsets the metabolic acidosis but causes further bicarbonate depletion, electrolyte loss and dehydration. Diagnosis The clinical features of salicylate overdose are agitation, tinnitus and deafness, increased sweating and hyperventilation; nausea and vomiting and epigastric pain may also be present. Respiratory alkalosis may occur initially but is quickly followed, particularly in children, by a metabolic acidosis associated with increased production of lactate, pyruvate and ketones. There may be hypokalaemia and hypo- or, more rarely, hyperglycaemia. Impaired clotting factor and platelet function are sometimes seen, but bleeding is rare. Confusion and coma may occur before death. Patients older than 70 years or younger than 10 are at the greatest risk from salicylate poisoning, and CNS features, the presence of acidosis, hyperpyrexia, pulmonary oedema and salicylate levels greater than 700mg/L, as well as late presentation, are associated with increased mortality. Management Activated charcoal should be administered at the appropriate dose (50 g for an adult, 10-15 g for a child) in adults or children who have ingested more than 250mg/kg body weight of aspirin within the previous hour. Arterial blood gas measurement (in children, capillary gases or venous blood gases would be a suitable alternative) should be performed, and correction of any acid-base abnormalities and rehydration should be sufficient in mild or moderate cases of salicylate poisoning. Urea and electrolytes, international normalized ratio (INR) and blood glucose and plasma salicylate concentration should be measured, and once
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SUMMARY 9 Salicylate poisoning • Salicylate poisoning is very serious because of the derangement of acid-base and electrolyte balance (metabolic acidosis, respiratory alkalosis and dehydration) • Coma is rare except as a terminal event, and agitation and restlessness, tinnitus, deafness and hyperventilation are characteristic • The very old and young, those with metabolic acidosis, hyperpyrexia, pulmonary oedema, coma or high salicylate concentrations, and those who present late are at greatest risk of a fatal outcome. • Correction of acid-base abnormalities and dehydration is usually sufficient in mild to moderate poisoning, but haemodialysis may be necessary in severe poisoning
the serum potassium concentration is within the normal range, sodium bicarbonate may be given intravenously to enhance the urinary salicylate excretion (optimum urine pH 7.5-8.5). This entails giving 225 mL 8.4% sodium bicarbonate over 2 hours (or 1.5 L of 1.26%) if the salicylate level is greater than 500mg/L in an adult, or 1 mL/kg 8.4% bicarbonate diluted in 0.5% dextrose or saline at 23 mL/kg/h if the plasma salicylate concentration is greater than 350mg/L in a child. Potassium supplements may be necessary to achieve adequate urinary alkalinization, but if this cannot be attained without increasing the blood pH to greater than 7.5, haemodialysis is treatment of choice. It is indicated for severely poisoned patients (generally with salicylate concentrations greater than 700mg/L, although the threshold may be lower in children under 10 years or the elderly, or those with severe acidosis or impaired renal function). Pulmonary oedema may occur as a result of fluid overload or as a direct effect of the drug on capillary permeability. In the former case the pulmonary artery pressure will be raised, but not in the latter. Ventilation with positive end-expiratory pressure may be helpful. 12
Other non-steroidal anti-inflammatory drugs Salicylates form one group of non-steroidal antiinflammatory drugs (NSAIDs) but there are five other groups that can be classified according to chemical structure. These are: • The arylalkanoic acids, which include phenyl propionic acid derivatives such as ibuprofen, naphthyl propionic acid derivatives such as naproxen, and phenyl acetic acid derivatives such as fenclofenac; • The anthranilic acids, which include the fenamates (mefenamic acid and flufenamic acid);
O Case 1.3 O MCQ1.18
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QMCQ1.19
• The pyrazalone group of compounds, e.g. azapropazone and phenylbutazone; • The cyclic acetic acids, which include indomethacin, sulindac and tolmetin; • The oxicams, at present represented by piroxicam. Diagnosis The arylalkanoic acids, like all NSAIDs, cause headache, nausea and epigastric discomfort, but coma is rare. Gastrointestinal bleeding may occur and, rarely, bronchospasm. Poisoning with anthranilic acids (e.g. mefenamic acid) is more serious and severe haemorrhagic enterocolitis may occur. CNS effects are also commoner and may include convulsions. Overdose with pyrazolones can produce gastrointestinal and CNS toxicity and hepatic and renal damage. The cyclic acetic acids also produce coma, and piroxicam has been associated with coma and convulsions. Management The stomach should be emptied if appropriate. Early administration of charcoal will reduce the absorption of some of the anthranilic and cyclic acetic acids, and may also be of benefit in poisoning with other groups of NSAIDs. Although there is no definite evidence that histamine2-receptor antagonists (e.g. ranitidine) protect against gastrointestinal haemorrhage, they are often administered prophylactically. Convulsions are generally short-lived but can be treated with diazepam. Blood pressure should be measured regularly and hypotension corrected to prevent subsequent acute renal failure.
Paracetamol Paracetamol is a remarkably safe drug in therapeutic doses but in overdose may cause fatal hepatic necrosis and is responsible for approximately 200 deaths per year in the UK. The toxicity of paracetamol in overdose is related to the metabolism of the drug. Approximately 90 % of the drug is conjugated with glucuronide or sulphate in the liver and gut, with only 10% oxidized by the mixed-function oxidase system to a highly reactive intermediate compound (7V-acetylaminobezoneinonimine, or NABQI), which is normally conjugated with glutathione and subsequently excreted as a mercapturate conjugate. In overdose, more NABQI may be produced than can be detoxified, as glutathione stores in the liver become exhausted, and NABQI instead binds to macromolecules in the liver (and sometimes renal tubular) cells, causing necrosis. Patients on enzyme-inducing drugs (see Table 1.5) may produce more NABQI at any given dose of paracetamol and develop liver damage at lower plasma concentrations of paracetamol, and so they are termed 'high risk' and are given antidotal treatment at half the plasma concentrations recommended for patients in general. Other high-risk patients include those with glutathione depletion (e.g. malnourished individuals, including those with HIV, those with pre-existing liver disease and those who consume excess alcohol).
Diagnosis The clinical features are initially mild and consist of nausea, vomiting and epigastric pain. Metabolic acidosis, hypoglycaemia, hypotension and cardiac arrhythmias have been described, particularly with massive overdoses. Incipient liver damage may first be detected by measuring hepatic transaminase enzymes or the one-stage prothrombin time (INR), which may be abnormal even as early as 6-12 hours after the overdose. Liver damage may occur with as little as 12 g of paracetamol and may present clinically with right subcostal pain and tenderness, recurrence of nausea, vomiting, and then jaundice. Loin pain, haematuria and proteinuria after the first 24 hours strongly suggest incipient renal failure. Acute renal failure has also been reported, usually (but not always) in association with severe liver damage. Renal function and electrolytes should be measured daily. A/lanagemenf Activated charcoal should be considered if more than 150mg/kg or 12 g (whichever is the smaller) in total has been taken within 1 hour. The plasma paracetamol concentration should also be checked after 4 hours (earlier concentrations are uninterpretable) and, if it is greater than that on the treatment line (shown in Fig. 1.11), an antidote should be administered. Antidotal therapy should also be used without waiting for the plasma paracetamol concentration if the overdose has been taken at least 8 hours previously, as the efficacy of the antidotes declines markedly with time.
Summary 10 Acetylcysteine and methionine administration
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Acetylcysteine Dose: by intravenous infusion, in 5% glucose, initially 150mg/kg in 200 ml over 15 minutes followed by 50mg/kg in 500ml over 4 hours, then 100mg/kg in 1000mL over 16 hours. Methionine Dose: by mouth 2.5g initially, followed by three further doses of 2.5g every 4 hours.
Acetylcysteine (see Summary 10) is a glutathione precursor that is usually given intravenously in the UK because, given orally, it can exacerbate vomiting. Acetylcysteine appears to have some efficacy up to 24 hours or even longer after a large overdose. Oral methionine is also used, but is probably ineffective 8 hours or more after an overdose, and the vomiting associated with paracetamol ingestion makes it difficult to retain in the stomach. Anaphylactoid reactions have been reported in around 8% of individuals after the use of acetylcysteine, often during the initial fast infusion. The reaction is probably due to histamine release, and consists of urticaria and bronchospasm, nausea, vomiting, flushing, angioedema, tachycardia, hypotension, respiratory depression and collapse, and in severe cases renal failure and disseminated intravascular coagulation. Death has occurred in patients who have been inadvertently given an overdose (tenfold greater) of acetylcysteine, so the dose of this antidote should be checked carefully. The infusion should be stopped temporarily and an antihistamine given if necessary, with corticosteroids in addition if the reaction is severe. Nebulized salbutamol may be effective in reversing bronchospasm. Once the reaction has settled, acetylcysteine can be infused at a rate of 50mg/kg over 4 hours; further reactions are extremely rare. Blood sugar should be measured and any abnormality treated. The INR should be measured daily. An INR of 4 or more at 48 hours or >6 at 72 hours indicates the likelihood of severe liver failure, in which case the patient should be commenced on a low-protein diet and oral lactulose to help to remove nitrogenous compounds from the gut. A specialist liver unit should be contacted for advice and consideration of possible transfer for management of liver failure. Management of liver failure also includes prophylaxis against infection and peptic ulceration, and management of coagulation abnormalities. Liver transplantation has been successfully performed in some cases, but has a limited role, and patients should be identified and transferred as soon as possible. Factors associated with poor outcome are metabolic acidosis, hypoprothrombinaemia, renal failure and grade 3-4 encephalopathy. Even if acute hepatic failure does occur, the mortality is less than 50% with good supportive management (p. 854). 0
Opioids FIG. 1.11 Plasma paracetamol concentrations above which antidotal treatment is required
Opioids are used not only as narcotic analgesics but also as constituents of some cough suppressants, antidiarrhoeal
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Summary 11 Management of opiate poisoning • Opiate poisoning is a common, serious medical emergency • Naloxone reverses the effects of all opiates (except buprenorphine if given in sufficient dose, since it is a competitive antagonist) • The short half-life of naloxone necessitates repeated doses or even constant infusion in treatment of opiates with long half-lives of elimination (e.g. dihydrocodeine and methadone) • The association between intravenous opiate abuse and infection (hepatitis B and HIV should be recognized and appropriate safeguards taken)
products (e.g. diphenoxylate) and veterinary tranquillizers. The one most often involved in poisoning is dextropropoxyphene, which is combined with paracetamol in compound preparation. Opioids are being increasingly misused in society for their effects on mood, being administered intravenously as well as orally. Diagnosis Respiratory depression is the commonest cause of death in opioid overdose. The pupils are often pinpoint. Depression of the CNS eventually leads to coma and convulsions. The muscles may be hypotonic, but muscular twitching and hyperreflexia have been described. Hypotension is common, but hypertension has been described after pentazocine overdose. Non-cardiogenic pulmonary oedema may occur, particularly in methadone overdose. Management If the opiate has been taken orally activated charcoal may be of value in the first hour, or longer if the preparation is sustained release. Naloxone is a competitive antagonist that is effective in reversing the symptoms of opiate overdose with all compounds except buprenorphine (a partial agonist and not completely antagonized). It is best given intravenously (0.8-1.2 mg for an adult, and 0.01 mg/kg body weight for children), and the dose repeated if there is no response within 2 minutes. Those who have taken very large overdoses, particularly of a long-acting agent such as dihydrocodeine or methadone, may need further doses to competitively antagonize the opioid activity, and continuous intravenous infusion of naloxone, together with intensive monitoring, may be necessary. Assisted ventilation with positive end-expiratory pressure may be required if pulmonary oedema occurs. In buprenorphine poisoning naloxone may have only limited benefit and, if doxapram fails to stimulate respiration sufficiently, assisted ventilation may be necessary. Naloxone may precipitate acute opioid withdrawal, with abdominal pain, diarrhoea and piloerection, but the dan-
1MCQ1.20 2MCQ1.21 30
gers of opioid overdose are greater and life-saving treatment should not be withheld.
RECREATIONAL DRUGS In addition to opioids such as diamorphine (heroin), other drugs are being increasingly widely abused in society and may be dangerous in overdose. Amphetamines are sympathomimetic drugs of abuse. Street amphetamine usually contains up to 5% amphetamine along with inert fillers or other stimulants, but purity varies widely. Initial CNS stimulation (agitation and dilated pupils) may be followed by marked hypertonia and hyperreflexia (>39°C) and generalized convulsions. Hyperpyrexia and rhabdomyolysis may also occur. Sinus tachycardia is usual but supraventricular and ventricular arrhythmias, including ventricular tachycardia, may subsequently occur. Hypertension may be a feature and hypokalaemia may sometimes be profound. The stomach should be emptied within 1 hour and activated charcoal given. Sedation with diazepam may be necessary. Sinus tachycardia with adequate cardiac output is best left untreated, but (3-blockers may be needed. cc-Blockers or labetalol are used to manage hypertension. Diazepam is normally effective in managing convulsions, but if they are more frequent, or if vomiting is also a problem, it may be preferable to paralyse and ventilate the patient. Ventricular arrhythmias occurring in a patient who is having convulsions may respond to disopyramide. Ecstasy (3,4-methylenedioxymethamphetamine, or MDMA) is an amphetamine-like compound with a similar spectrum of toxicity. However, there is marked inter- and intraindividual variability in susceptibility, and deaths have occurred after only a single tablet in those who have previously tolerated similar or greater doses. Signs of severe toxicity include delirium, coma, convulsions, and supraventricular and ventricular arrhythmias. Hypertonia and hyperpyrexia may result in rhabdomyolysis, metabolic acidosis and acute renal failure. Hyponatraemia, disseminated intravascular coagulation, hepatocellular necrosis, adult respiratory distress syndrome and cardiovascular collapse have also been described. Death may occur from intracerebral haemorrhage. Treatment is largely symptomatic and supportive, with correction of metabolic acidosis and dantrolene (or paralysis and ventilation) for the hyperpyrexia. 1 Cocaine may be taken by the oral or intravenous route, or by inhalation. Toxicity is characterized by agitation, tachycardia, tachypnoea, sweating, delirium and hallucinations. Hypertension, hyperpyrexia, generalized convulsions, stroke, cardiac ischaemia, myocardial infarction and arrhythmias, metabolic acidosis, rhabdomyolysis and cardiorespiratory arrest may also occur. Treatment is symptomatic and supportive. Hypertension may best respond to a-blockers or combined a- and p-blockade (e.g. with labetalol). The risk of severe toxicity is particularly high
in 'body stuffers' who, on the verge of arrest, swallow the evidence, rather than in 'body packers', who are hired specifically to smuggle drugs and who have time to wrap them carefully (e.g. in a condom). Lysergic acid diethylamide (LSD) in overdose may cause acute panic attacks, delirium, hallucinations, seizures and coma, respiratory arrest and metabolic acidosis. Treatment is symptomatic and supportive, although features of psychosis may last for several days. Panic often responds to diazepam. Phenothiazines are best avoided in treating the psychosis, as they may reduce seizure threshold. y-Hydroxybutyric acid (GHB),or liquid ecstasy, is a 'psychedelic' agent that has recently become popular. It can cause coma, sinus bradycardia and hypotension in overdose, as well as respiratory depression leading to respiratory arrest. Treatment is symptomatic. The bradycardia may respond to atropine (1.2mg intravenously for an adult, 0.02mg/kg for a child). 2
ANTICONVULSANTS The incidence of psychiatric abnormalities is higher in epileptics than in the non-epileptic population. The availability of anticonvulsants to some epileptic patients results in their being taken relatively frequently in overdose. Barbiturates and primidone, which are converted into phenobarbitone and phenylethylmalonamide in the body, are described on page 23.
Phenytoin Phenytoin is one of the most widely prescribed anticonvulsants. Acute overdosage leads to ataxia, dysarthria, horizontal nystagmus, drowsiness and, in severe cases, coma. Respiratory depression is a rare but potentially serious complication, which is generally only seen after massive overdose. The stomach should be emptied within 1-2 hours of ingestion and activated charcoal will help to prevent further absorption. Because phenytoin is highly protein bound, only charcoal haemoperfusion will effectively remove the drug from the circulation. This should, however, be reserved for patients with severe overdose. Rarely, cases of permanent cerebellar damage with persistent ataxia after phenytoin overdose have been described.
Carbamazepine Carbamazepine is widely used for the treatment of generalized and partial seizures. The drug is structurally similar to tricyclic antidepressants and overdose can be associated with anticholinergic effects, including dry mouth, hyperreflexia and generalized convulsions. Nystagmus, strabismus, diplopia, ataxia, hypotension and respiratory depression have been noted, and cardiac conduction disturbances may also occur. The stomach should be emptied if appropriate, and activated charcoal administered. Repeated doses of charcoal speed the elimination of drug in
normal volunteers and may be effective in severe overdose. Effective removal of the drug by haemoperfusion has also been reported.
1
Sodium valproate Sodium valproate poisoning is associated with coma and respiratory depression. The drug is rapidly absorbed, and supportive measures form the mainstay of treatment.
CARDIOVASCULAR DRUGS Anti hy per ten si ves The major adverse effect is hypotension. With clonidine, hypotension is often associated with bradycardia, but severe hypertension caused by the drug's partial a-agonist activity is sometimes a major problem. Bradycardia often responds to atropine, and a-adrenergic blocking drugs have been used to treat the hypertension. (3-Receptor blocking agents also cause bradycardia and hypotension, and may also cause drowsiness, coma and convulsions in overdose. In hypotension atropine is used to increase cardiac output, but large doses are often required (3mg intravenously in an adult and 0.04mg/kg for a child). Glucagon is used if atropine is ineffective. An intravenous bolus of 50-150mg/kg body weight dissolved in dextrose may be effective but may need to be followed by the same dose or an intravenous infusion of 4mg/h until the patient's condition is satisfactory. Glucagon may induce vomiting and the airway needs to be protected. Pi -Agonists such as prenalterol are also effective, although large amounts may have to be given intravenously to competitively antagonize the (3-blockade. pY Agonists (e.g. salbutamol) may be necessary if bronchospasm is present, and the blood sugar should be monitored to detect and treat hypoglycaemia. Convulsions normally respond to intravenous diazepam (0.1-0.3mg/kg body weight). Calcium antagonists (especially verapamil) may also cause severe hypotension and bradycardia and conduction abnormalities and, in severe cases, asystole. If atropine is ineffective in treating the bradycardia, calcium gluconate (10-20 mL of a 10% solution in an adult) may be required. Pacing may be necessary to treat the bradyarrhythmias, and dopamine and glucagon (and, in resistant cases, insulin and dextrose) have been used to give inotropic support.
Digitalis glycosides Poisoning with the digitalis glycosides is rare but potentially very serious. Nausea, vomiting and diarrhoea are early features, but the major life-threatening complications are hypotension and cardiac conduction disturbances, with brady- and tachyarrhythmias. Hyperkalaemia is often present and mirrors roughly the severity of the overdose. This should be treated with glucose and insulin, or a sodium resonium ion exchange resin, or by haemodialysis
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SUMMARY 12 Digitalis glycoside poisoning • Cardiac glycosides may cause nausea, vomiting, diarrhoea and generalized malaise • Cardiac effects include bradycardia with PR and QRS prolongation. Sinus arrest and varying degrees of AV block may also occur • Hyperkalaemia and metabolic acidosis may occur in severe cases • Multiple doses of charcoal enhance elimination by interrupting enterohepatic recirculation • Prophylactic pacing should be considered if hyperkalaemia or heart block occur • Severe intoxication is often effectively treated with digoxin antibodies, the dose depending on the amount taken and the serum glycoside concentration
if necessary. Metabolic acidosis may also occur. Both digoxin and digitoxin have enterohepatic recirculation processes and repeated doses of activated charcoal (see p. 24 for dosage) will speed elimination. Continuous monitoring of cardiac rhythm is essential: bradycardia sometimes responds to intravenous atropine (1.2mg for an adult or 0.02mg/kg for a child), repeated as necessary until atropinization occurs. More severe bradyarrhythmias may require temporary cardiac pacing, particularly if heart block or hyperkalaemia are present. Ventricular tachyarrhythmias often respond to lignocaine, but phenytoin and intravenous (3-blockers have both been used in resistant cases. Digoxin-specific Fab antibody fragments may be necessary in the treatment of severe digoxin and digitoxin poisoning. The dose of antibody (Digibind) is about 60 times the estimated body load of digoxin or digitoxin (the amount of drug in milligrams ingested multiplied by 0.8) rounded up to the nearest 40 mg. This can be calculated from the amount taken, or the plasma concentration of the drug.
RESPIRATORY DRUGS Theophylline Theophylline is the respiratory drug most often taken in overdose. Nausea, persistent vomiting and epigastric pain may be followed by agitation, hallucinations and convulsions. Hypertonia may be associated with rhabdomyolysis. Supraventricular and ventricular arrhythmias with hypokalaemia (often profound) may follow a sinus tachycardia. Signs may be delayed for up to 12-24 hours in those who have taken a sustained-release preparation. The stomach should be emptied to prevent further absorption and charcoal (50 g) left in the stomach. The metabolic abnormalities should be treated appropriately, 1MCQ1.22 2MCQ1.23 32
but convulsions and hypertonia may respond to diazepam administered intravenously. Supraventricular and ventricular arrhythmias may respond to the use of adrenoceptor blockers (e.g. metoprolol),but the metabolic abnormalities may only respond to agents that also possess ( 2-antagonist activity (e.g. propranolol). However, (3blockers should not be used in asthmatic patients because of the risk of precipitating bronchospasm. Disopyramide or verapamil have been used successfully to treat arrhythmias in such patients. Repeated oral administration of charcoal has recently been shown to reduce markedly the half-life of elimination of theophylline. Persistent vomiting may mean that an antiemetic such ondansetron (8 mg slowly intravenously in an adult) will be necessary to allow the charcoal to be retained. Haemoperfusion is an efficient way of enhancing the removal of theophylline from the circulation. It should be considered in severely poisoned patients, particularly those with major arrhythmias, hypotension or convulsions, and if repeated-dose charcoal is not feasible. 1
Ephedrine, salbutamol and terbutaline Ephedrine, salbutamol and terbutaline are generally safer than theophylline in overdose, but can cause all the same features in severe cases. Treatment is broadly similar to that of theophylline overdose: again, -blockers must be avoided in asthmatic subjects.
DRUGS WITH ANTICHOLINERGIC ACTIVITY In addition to tricyclic antidepressants many drugs have anticholinergic activity, including some used to suppress gastrointestinal motility (e.g. propantheline), some antiparkinsonian drugs (e.g. amantidine and orphenadrine) and some antihistamines (e.g. chlorphenamine (chlorpheniramine) and promethazine). The effects of these drugs are similar to those caused by overdosage with tricyclic antidepressants, but they are less likely to cause arrhythmias. The anticholinesterase physostigmine is no longer recommended in anticholinergic poisoning because of severe adverse effects. Treatment is supportive and symptomatic.
ANTIDIABETIC DRUGS Poisoning with antidiabetic drugs and insulin produce all the features of hypoglycaemia. The management is described in Chapter 19, page 1020. Sulphonylureas (particularly those with long half-lives of elimination (e.g. chlorpropamide) are of particular concern, as hypoglycaemia may be a problem for several days and they are sometimes resistant to glucose and glucagon. Severe hypoglycaemia has therefore been treated with diazoxide, which
inhibits insulin release and raises circulating plasma catecholamines. At the dose used (5 mg/kg body weight/24 h by mouth in two or three divided doses), it rarely produces hypotension. Diazoxide may be the treatment of choice if there is a risk of hypoglycaemia over several days. Metabolic acidosis may occur after sulphonylurea poisoning, but is more common after poisoning with the biguanide metformin. ©
atrophy. Most patients recover some vision, although some are left with permanent visual field defects. The management of quinine poisoning is supportive. Stellate ganglion block has been advocated in the past but has no proven benefit. As quinine has a large volume of distribution and is predominantly metabolized by the liver, methods to enhance elimination are of limited value, but repeated dose of oral charcoal may be beneficial.
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Chloroquine ANTIBIOTICS The penicillins and cephalosporins are generally safe in overdose. Sulphonamides may cause bone marrow depression and renal damage (and haemolysis in glucose 6-phosphate dehydrogenase-deficient patients). Maintenance of a high urine output and alkalinization of the urine may prevent sulphonamide-induced renal damage, by preventing crystallization of the drug in the renal tubule. Calcium folinate may help to reverse bone marrow depression induced by sulphonamide or trimethoprim. Isoniazid can cause CNS symptoms with coma and convulsions. Pyridoxine can be used to treat or prevent both convulsions and the metabolic abnormalities: it should be given in a dose of 1 g for every gram of isoniazid ingested. Rifampicin overdose may be associated with orange discoloration of the skin (although this colour can be removed by washing). Treatment is usually supportive. Although most patients recover completely, occasional sudden deaths have been reported, presumably from cardiac arrhythmias. The antileprotic drug dapsone (also used in the treatment of dermatitis herpetiformis) is dangerous in overdose, causing methaemoglobinaemia and sometimes convulsions and coma.
ANTIMALARIALS Quinine Quinine, which is also used to treat night cramps, is the antimalarial agent most often taken in overdose and also the one most likely to cause serious toxicity. Children may take tablets belonging to a family member. Early symptoms of overdose are similar to those of aspirin, with nausea, vomiting, bowel disturbances, tinnitus and deafness. Initial respiratory stimulation may be followed by respiratory depression and respiratory arrest. Quinine can cause brady- and tachyarrhythmias, with death from ventricular fibrillation. Its effect on vision is dramatic. Visual acuity is initially impaired, and this may progress to constriction of visual fields or even complete blindness. Retinal examination reveals constriction of the arterioles initially, followed by retinal oedema and sometimes optic
Chloroquine is widely used as prophylaxis against malaria and can be purchased without prescription. Its toxicity is similar to that of quinine, and visual disturbances are also sometimes seen. As little as 5g may be fatal. Ventricular arrhythmias often occur early (within the first 3 hours) and include intraventricular conduction defects with a wide QRS, and prolongation of the QT interval. Ventricular tachycardia and fibrillation are early arrhythmias, and torsade-de-pointes sometimes occurs later. Very large doses of diazepam (2 mg/kg body weight intravenously over 30 minutes) may reduce mortality, but should be considered only when facilities for assisted respiration are available. Chloroquine is also predominantly metabolized by the liver and has a high volume of distribution; thus, none of the techniques for enhancing removal appears to be effective.
ANTICOAGULANTS The major risk of oral anticoagulant poisoning is haemorrhage: this occurs several days after the overdose because of the delayed effect of these agents. In cases of large overdose, and where the INR is raised at 36-48 hours, vitamin K (10 mg twice daily by slow intravenous injection, 250 g/kg body weight for a child) should be administered and may be necessary for up to a week. Repeated oral administration of colestyramine (cholestyramine) (4 g three times daily) may enhance the removal of warfarin and phenprocoumon, and also reduce the length of time for which vitamin K is required. Rodenticides contain only small amounts of oral anticoagulant and rarely cause toxicity.
POISONING WITH GASES AND VOLATILE SOLVENTS CARBON MONOXIDE Carbon monoxide is still the most common cause of fatal gas poisoning in the UK, despite the substitution of natural gas for coal gas in general use. Deaths occur either accidentally (often by inhalation of fumes during fires) or deliberately, from inhalation of car exhaust fumes in a confined space. Methylene chloride, which is widely used in
33
paint removers, is metabolized by the body to carbon monoxide and causes symptoms identical to those of direct carbon monoxide exposure. Diagnosis The early symptoms of chronic or acute exposure are headache, mental agitation, nausea and vomiting. The characteristic cherry-pink colour of the skin is rarely present during life, but the patient is not cyanosed, despite considerable hypoxia because of the production of carboxyhaemoglobin. Cerebral oedema and myocardial ischaemia or infarction may also occur. Management Oxygen should be given in as high a concentration as possible. There is no clear evidence that hyperbaric oxygen affects outcome, and its use should be discussed with the regional poisons unit. Patients who have been unconscious after exposure, who have a carboxyhaemoglobin concentration over 20% or who have neurological or psychiatric features, are most likely to obtain any possible benefit. Hyperbaric oxygen is not always immediately available, and transfer to such a facility should not interrupt the treatment of severely poisoned patients. Oxygen should be administered until the carboxyhaemoglobin concentration in blood falls below 15%: this may take up to 2 days. Mannitol, Ig/kg intravenously over 20 minutes, may be considered if there is evidence of cerebral oedema. Most patients who die of carbon monoxide poisoning do so before they reach hospital; those who do arrive in hospital usually survive. Unfortunately, permanent neuropsychiatric sequelae may be seen, including intellectual and personality deterioration, parkinsonism and, in rare cases, akinetic mutism. These severely affected patients often show areas of low density in the area of the globus pallidus on CT brain scans. 1
IRRITANT VAPOURS AND GASES
Carbon disulphide, hydrogen sulphide, sulphur dioxide, hydrochloric acid and ammonia are all highly irritant to the eyes and respiratory tract. Cough and chest pain may be followed by dyspnoea, bronchospasm, haemoptysis and pulmonary oedema. Management
Treatment is supportive, with bronchodilators for bronchospasm, oxygen for hypoxia and, in severe cases, assisted ventilation (with PEEP if pulmonary oedema is present). Steroids, diuretics and antibiotics have been used, but because the complications are direct effects of the gas, they
SUMMARY 13 Cyanide poisoning • Cyanide is absorbed through the skin, by inhalation or oral absorption • The clinical features are those related to severe hypoxia and metabolic acidosis • Oxygen in high dose should be given and the metabolic acidosis corrected • Dicobalt edetate is the antidote of choice if the diagnosis is certain • Sodium thiosulphate, together with sodium nitrite, is also an effective antidote
are unlikely to be of benefit. The metabolic acidosis may improve with adequate oxygenation, but if this fails sodium bicarbonate may have to be administered. Ophthalmologic advice should be sought to diagnose and treat corneal abrasions.
CYANIDE Cyanide may be inhaled in the form of hydrogen cyanide, sometimes in fumes caused by burning plastic. Symptoms appear within a few minutes, first with headache, agitation, confusion leading to coma, cardiovascular collapse and respiratory arrest. Cyanide may also be taken orally, in which case symptoms may occur much later, particularly if food in the stomach delays gastric emptying. Management Oxygen in high concentrations should be administered and assisted ventilation performed if necessary. Dicobalt edetate is the most effective antidote, but it may cause hypotension and chest pain on intravenous administration (300 mg intravenously over 1 minute), and should therefore only be used if the diagnosis is certain. It acts by forming inert complexes with cyanide, thereby preventing the cyanide-induced inhibition of cellular oxidizing enzymes. Sodium thiosulphate (25 mL of 50% solution intravenously over 10 minutes for an adult; 400mg/kg for a child) acts as a sulphur donor to allow conversion of cyanide to thiocyanate via the enzyme rhodanase. Subsequent administration of sodium nitrite (10 mL of 3% solution intravenously over 5-20 minutes for an adult; 0.13-0.33mL/kg of 3% solution for a child) converts haemoglobin to methaemoglobin, which chelates the cyanide ion. The two treatments act synergistically. They are generally used if there is doubt about the diagnosis, there is no response to dicobalt edetate, or if the latter is not immediately available.
HYDROCARBONS 1
34
MCQ1.24
Poisoning with hydrocarbons is nearly always accidental, generally from industrial or domestic exposure, but also increasingly from solvent abuse.
Aliphatic hydrocarbons The aliphatic hydrocarbons appear to be less toxic than the aromatic group. The shorter-chain aliphatic hydrocarbons are volatile, so that poisoning is usually from inhalation. High concentrations may cause asphyxia, and the butane in lighter fluid has been used to produce euphoria by solvent abusers. Coma may occur, with death from respiratory depression or ventricular fibrillation. Renal and liver damage may develop if the patient survives. Pulmonary and cerebral oedema have also been reported. Inhaled hydrocarbons may also produce myopathies, neuropathies and permanent neuropsychiatric damage, although some of these effects may be related to additives to the hydrocarbon. Ingestion of liquid aliphatic hydrocarbons can produce effects similar to the above, due either to a systemic effect or, more likely, to aspiration of the low surface tension solvents. Pyrexia, cough and hyperpnoea may be followed by basal crackles in the chest, consolidation, and collapse involving predominantly the middle and lower zones of the lung. Treatment of solvent inhalation or ingestion is generally supportive. Gastric lavage or emesis should not be performed after ingestion because of the risk of chemical pneumonitis. There is no evidence that steroids and antibiotics are effective in the pulmonary complications, but in severe cases ventilatory support may enable the patient to recover.
Chlorinated aliphatic hydrocarbons Chlorinated aliphatic hydrocarbons are widely used as solvents in industry. In addition to the effects described with other hydrocarbons, the chlorinated aliphatics are also more likely to produce hepatic and renal damage (particularly carbon tetrachloride and chloroform), haemolytic anaemia and aplastic anaemia. Methylene chloride is metabolized by the body to carbon monoxide and its systemic toxicity is that of this metabolite, although it is itself locally corrosive. It has been suggested that acetylcysteine may inhibit the metabolism of chlorinated hydrocarbons to reactive intermediate metabolites and thereby reduce hepatotoxicity if given early.
Aromatic hydrocarbons Aromatic hydrocarbons are less often involved in poisoning. Benzene is the most toxic of these agents and, in acute overdose, produces effects similar to those of the aliphatic hydrocarbons. Chronic exposure may lead to aplastic anaemia and leukaemias. Toluene and xylene are similar in structure and effects to, but less toxic than, benzene: any marrow toxicity is probably related to benzene contamination. Benzene contamination is probably also responsible for the haematological problems sometimes seen with chronic petrol inhalation.
1
FIG. 1.12 Blood concentrations after oral administration of ethyl alcohol (2 ml/kg) The concentration declines in a zero-order fashion at an average rate of 190mg/L each hour.
OVERDOSE WITH ALCOHOLS ETHANOL (ETHYL ALCOHOL) (See also ch. 24 p. 1435) Ethanol, present in alcoholic drinks, is the alcohol most often taken in overdose. It is also found as a solvent in some cosmetic and antiseptic preparations. Its major toxicity is related to its central nervous depressant effects. The loss of the gag reflex max result in aspiration of stomach contents. Alcohols inhibit gluconeogenesis and may cause profound hypoglycaemia, particularly in children. Blood ethanol concentrations give a rough guide to the severity of overdose, but may be misleading because of tolerance in chronic alcohol users. Severe intoxication with stupor and marked incoordination is generally associated with blood concentrations above 3000 mg/L. The rate of metabolism is shown in Figure 1.12. Management Because alcohol is rapidly absorbed, lavage is unlikely to be of benefit and the compound is poorly adsorbed by activated charcoal. Metabolism is saturated even at low doses. The treatment is usually symptomatic and supportive, with correction of hypotension and hypoglycaemia. Protection of the airway is paramount. Although haemodialysis will remove alcohol efficiently, it is only indicated in severe and complicated cases of poisoning. Fructose accelerates the metabolism of alcohol, but it can potentiate the metabolic acidosis already caused by the alcohol and should not be used. Intravenous dextrose may be necessary to treat hypoglycaemia. The problems of alcoholism are discussed on page 247.
METHANOL Methanol is much more toxic than ethanol and is widely used as a solvent. Methylated spirit is 5% methyl alcohol
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and 95% ethanol. The mode of toxicity is not clear, but accumulation of formaldehyde and formic acid is partly responsible. As little as 10 mL of methanol may cause serious illness. The initial features are those of mild inebriation, but 8 or more hours later the patient may develop abdominal pain and vomiting, dilated and unreactive pupils, a metabolic acidosis and, sometimes, signs of cerebral oedema. The optic disc is at first hyperaemic and then becomes oedematous; vision is progressively lost. Management The stomach should be emptied within the first hour of methanol ingestion; activated charcoal does not adsorb significant quantities. Intravenous sodium bicarbonate should be used to keep the arterial pH above 7.2, but metabolic acidosis may be resistant to treatment. Diazepam is indicated if convulsions are a problem. Ethanol competitively inhibits the metabolism of methanol to formaldehyde and formic acid, and is used in less serious poisoning. Haemodialysis may be necessary if the blood methanol concentration exceeds 500 mg/L, or if there is clinical deterioration despite other measures. Haemodialysis also removes ethanol, so that ethanol administration during this procedure has to be increased. Visual impairment is often permanent, although prompt treatment reduces its severity.
ISOPROPANOL (ISOPROPYL ALCOHOL)
Isopropanol is found in rubbing agents, sterilizing fluids and disinfectants, window cleaning fluids and some aftershave lotions. Features of poisoning resemble those of ethyl alcohol poisoning, but because some of it is metabolized to acetone, ketonuria and a characteristic smell of acetone on the breath may be observed. Management
The stomach should be emptied within an hour of ingestion, but treatment is otherwise symptomatic. Haemodialysis will remove isopropyl alcohol but is normally only indicated in severe poisoning.
overdose, but ophthalmoplegias, papilloedema and subsequent optic atrophy may also occur and the patient may become comatose and develop convulsions. After 12 hours respiratory and cardiovascular complications are seen, together with a metabolic acidosis, hypocalcaemia and hyperkalaemia. If the patient survives this phase, he or she may develop acute renal failure after approximately 24 hours. Ethylene glycol is not itself toxic but is metabolized by alcohol dehydrogenase to aldehydes, glycolates, oxalates and lactate, which are responsible for the toxic features. Management The stomach should be emptied within the first hour and arterial blood gases and serum calcium measured. Activated charcoal does not adsorb ethylene glycol. Any metabolic acidosis may respond to intravenous bicarbonate, and calcium gluconate may be necessary to treat hypocalcaemia. Ethylene glycol metabolism can be inhibited by administration of alcohol in doses sufficient to attain blood ethanol concentrations between 1000 and 2000 mg/L. In severe cases (ethylene glycol concentration >500mg/L, or clinical condition deteriorating despite other measures) haemodialysis is necessary to remove ethylene glycol metabolites. Ethanol administration may also be necessary for up to 4 days after the overdose to reduce their production. Dialysis may be required for renal failure. Fomepizole has recently been licensed for the treatment of ethylene glycol poisoning. 1 POISONING WITH CORROSIVE AGENTS
Fortunately, poisoning with corrosive agents is rare, and most incidents are accidental rather than deliberate. The majority of agents produce local tissue damage by protein denaturation, but some (e.g. paraquat) also have serious systemic toxicity. The patterns of damage with acids and alkalis are different and are therefore discussed separately.
ACIDS ETHYLENE GLYCOL
Antifreeze solutions contain ethylene glycol, a solvent that is sweet-tasting and therefore not unpleasant to drink. Death may occur after ingesting as little as 100 mL of ethylene glycol which, like alcohols, is metabolized by alcohol dehydrogenase. CNS toxicity is similar to alcohol
1
36
MCQ1.25
Acids produce severe pain on ingestion. They may cause asphyxia from epiglottal oedema and, although oesophageal damage has been described, they are more likely to cause gastric perforation, particularly in the region of the antrum. Late stricture formation is also a possibility. Lavage should not be performed unless the agents also have serious systemic toxicity. Any metabolic acidosis should be treated with intravenous bicarbonate, but weak alkalis should not be given by mouth. Endoscopy is of limited value in the acute phase and may cause perforation; in later stages, however, it may be helpful in identifying stricture formation. Corticosteroids have been used to try to prevent stricture formation, but their value is unclear.
SUMMARY 14 Acid poisoning • Acid ingestion may cause local corrosion, asphyxia due to oedema of the glottis and perforation of the stomach (less commonly of the oesophagus) • Metabolic acidosis and renal failure may also occur • Lavage should not be performed unless the agent produces severe systemic toxicity • Late stricture formation may occur but the value of corticosteroids in preventing this complication is not proven
Phenol (carbolic acid) can cause systemic toxicity as well as local corrosion, although the latter is normally less severe than with inorganic acids. The urine may be dark brown or black and the breath, urine and blood may smell strongly of carbolic. Haemolysis, renal failure, coma and convulsions, myocardial damage and metabolic acidosis may occur, and early cautious gastric lavage is indicated, provided the airway can be protected. Metabolic acidosis corrected with intravenous sodium bicarbonate and urine output and renal function carefully monitored. Cresols (methylphenols) have similar effects and treatment is therefore as for phenol poisoning. Formic acid is used in kettle descalers and destaining solutions. It too can produce a metabolic acidosis, intravascular haemolysis and renal failure, as well as local corrosion. Gastric lavage is therefore indicated early after ingestion, and any metabolic acidosis should be corrected with intravenous sodium bicarbonate. As with phenols, aspiration into the lung may cause haemorrhagic tracheobronchitis and the airway must therefore be protected during lavage.
ALKALIS Corrosion by alkalis (e.g. drain and oven cleaners) is generally more severe than by acids and is more likely to cause serious oesophageal, as well as gastric, damage. Stricture may develop weeks or months after the initial injury. Treatment is similar to that for acid ingestion; lavage should not be performed. Endoscopy by an experienced operator should be considered to assess the degree of injury and to prevent unnecessary hospitalization. The instrument should normally be passed only to the level of the first area of injury. It may also be useful in identifying alkalis in tablet form, which may adhere to the oesophagus (e.g. Clinitest tablets and some denture cleaners).
BLEACHES Most bleach contains sodium hypochlorite (up to 10%), which may produce corrosion in large or concentrated doses, and laryngeal oedema due to chlorine liberation. The stomach should be cautiously emptied within an hour if more than 300 mL has been ingested in an adult (100 mL
in a child), provided there is no evidence of oesophageal corrosion or severe gastritis. An H2-receptor blocking drug such as ranitidine should be given, and corticosteroids may be of value if laryngeal or pulmonary oedema is present. The sodium load resulting from ingestion of large amounts of bleach can cause hypernatraemia and hyperchloraemic acidosis.
1
DISINFECTANTS Although phenols and cresols (found in Jeyes fluid and some other disinfectants) have been largely replaced by dichlorometaxylenol, corrosive effects may occur after large or concentrated doses. Metabolic acidosis, coma, myocardial and renal damage and laryngeal oedema may also occur after severe overdose, and the stomach should therefore be emptied and the metabolic abnormalities corrected. Some disinfectants also contain isopropanol (discussed on p. 36).
POISONING WITH INSECTICIDES, HERBICIDES, FUNGICIDES AND RODENTICIDES INSECTICIDES The organochlorine group of insecticides (e.g. DDT) have now largely been replaced by compounds that are less persistent in the environment. These include the organophosphorus and carbamate insecticides.
Organophosphates The organophosphates act as inhibitors of cholinesterase in humans, causing symptoms of excessive cholinergic activity, with vomiting, abdominal pain, sweating, constricted pupils and hypersalivation. Muscle spasm, diarrhoea, convulsions and coma follow. Organophosphates can be absorbed from the stomach, skin or bronchial mucosa. Plasma cholinesterase activity, measured in several centres throughout the UK, is useful in the diagnosis of both organophosphate and carbamate insecticide poisoning. Severe toxicity is associated with a reduction in plasma cholinesterase activity to around 10% of normal. Treatment consists of atropine to antagonize the cholinergic (muscarinic) effects. The initial dose is 2 nig for adults and 0.02mg/kg for children, by intravenous injection. Large doses (up to 30 mg in 24 hours in an adult) may be necessary until there are signs of atropinization (dry skin, tachycardia, dilated pupils and dry mouth). Within the first 24 hours the use of an oxime (e.g. pralidoxime mesylate or P2S) will help to reactivate cholinesterase. It can be obtained from holding centres in the UK, details of which can be found on TOXBASE. The normal dose in moder-
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ate or severe poisoning is 30mg/kg by intravenous injection over 5-10 minutes. Benefit should be seen within 30 minutes, but repeated doses at 4-6-hourly intervals may be required. Alternatively, it may be given by intravenous infusion at a rate of 8mg/kg/h. Intravenous diazepam (5-10 mg for an adult; 0.02mg/kg body weight for a child) is helpful in reducing twitching and may improve survival. A clear airway must be maintained and assisted ventilation may be necessary.
the patient presents within an hour of ingestion) with care because of the corrosive effects of the toxin. Charcoal (1 g/kg body weight) is left in the stomach as an adsorbent for paraquat. Oxygen therapy should be avoided if possible as it may enhance the toxicity of these agents. Finally, haemodialysis and haemoperfusion have been tried in an attempt to remove the body burden of drug, but there is no evidence that either has any effect on mortality, particularly when the more concentrated solutions of paraquat (e.g. Gramoxone) are ingested. 2
Carbamate insecticides
Dinitro compounds
Carbamate insecticides produce similar symptoms (CNS signs are less prominent) and atropine is again the treatment of choice. However, because these compounds have a reversible effect on cholinesterase, their duration of action is much shorter and pralidoxime has not shown clear evidence of benefit in poisoning with these agents. O
Dinitro compounds (e.g. dinitro-orthocresol) are generally used in the form of washes for fruit trees. They cause yellow staining of the skin but can be absorbed subcutaneously and produce toxicity by uncoupling oxidative phosphorylation. This results in pyrexia, hyperpnoea and tachycardia, with subsequent sweating, thirst, dehydration and collapse. Treatment consists of preventing severe pyrexia and replacement of electrolytes and fluid. Pentachlorophenol acts similarly to the dinitro compounds but does not produce yellow discoloration of the skin.
HERBICIDES The five major groups of herbicides are: chlorates, triazines, bipyridilium herbicides, dinitro compounds and phenoxyacetic acids.
Chlorates The chlorates are powerful oxidizing agents that can produce haemolysis, methaemoglobinaemia, haemorrhagic gastroenteritis and, in severe cases, renal failure. Treatment consists of emptying the stomach (if appropriate) and methylene blue to reverse methaemoglobinaemia.
Triazines Triazine herbicides (e.g. simazine) appear to be relatively non-toxic, and serious human poisoning has not been reported.
Bipyridilium herbicides (paraquat) The bipyridilium herbicides, particularly paraquat, are extremely toxic. Not only can they cause local corrosion, but systemic absorption leads to renal and liver damage and later progressive pulmonary fibrosis. Diquat, which is less well absorbed from the gut, can cause similar toxicity, although pulmonary fibrosis seems to be slightly less likely to occur. Treatment consists of immediate gastric lavage (if
Phenoxyacetic acids Phenoxyacetic acids are probably the most widely used herbicides. They are relatively non-toxic unless large doses have been ingested; signs of cholinergic hyperactivity are then evident, resulting in coma and occasionally ventricular arrhythmias. Other features in severe cases include hypoglycaemia, metabolic acidosis, convulsions, hypertonia, myoclonus, rhabdomyolysis and renal failure. The stomach should be emptied if appropriate, contaminated clothing removed and the skin washed with soap and water. With 2-4-D and mecoprop urinary alkalinization may enhance their rate of removal, but haemodialysis is more efficient and should be considered in severely poisoned patients.
FUNGICIDES Organic and inorganic mercurials, organotin derivatives and dithiocarbamates are all used as fungicides in industry and horticultural practice. Organotin compounds are poorly absorbed from the gastrointestinal tract and therefore have low toxicity; dithiocarbamates are also relatively non-toxic.
Organic mercurials 1
38
MCQ 1.26, 1.27
2
MCQ1.28
Inhalation or ingestion of organic mercurials can produce severe corrosion and irritation of the respiratory tract. CNS toxicity consists of tremor, memory and psychiatric disturbances, and visual impairment that may lead to blind-
ness. The chelating agents DMSA and DMPS may reduce the systemic toxicity, but dimercaprol is contraindicated.
Inorganic mercurials Inorganic mercurial fungicides (e.g. mercuric chloride) are also predominantly corrosive. Treatment includes gastric lavage, adequate analgesia and treatment of any complications. Mercurous chloride (calomel) and mercuric oxide (the most commonly used agents) are poorly absorbed and, although corrosive, systemic toxicity is unlikely. If albuminuria occurs, however, significant absorption may have taken place and plasma mercury concentration should be measured. Treatment involves the use of the chelating agents. Although dimercaprol is licensed for this use, it has to be given by deep, painful intramuscular injection, and two orally active chelating agents, DMSA (Succimer) and DMPS (Dimaval) have also been shown to be effective. Guidance on administration should be obtained from the regional poisons centre for each individual case.
Metallic mercury Ingestion of metallic mercury is of no major consequence. However, intramuscular injection of metallic mercury may cause systemic toxicity, and intravenous injection has resulted in pulmonary embolus. Inhalation of mercury vapour may produce cough, retrosternal discomfort and breathlessness due to an acute pneumonitis, and flu-like symptoms such as lethargy, fever, aching limbs and arthralgia. High-dose corticosteroids may be useful if signs of lung damage are present. Signs of systemic poisoning may be an indication for dimercaprol, DMPS or DMSA.
cerebral oedema, coma and convulsions and ventricular fibrillation have also been reported. The chelating agents dimercaprol, DMSA and DMPS may reduce the severity of poisoning. Strychnine is sometimes used as a rodenticide, and has been found as an adulterant in some recreational drugs. It is rapidly absorbed by mouth and gastric lavage is contraindicated, as a convulsion may supervene during the procedure or be precipitated by the lavage. The clinical picture is similar to tetanus, with increase in muscle tone in the limbs and facial muscles, with severe spasms, muscle rigidity and exaggerated tendon reflexes. Twitching of muscles precedes the onset of convulsions, which may typically last between 30 seconds and 2 minutes and occur repeatedly. Convulsions may be provoked by any stimulus, including touch, pain and noise. The patient may be conscious and lucid between the convulsions. Cyanosis and death may occur during the convulsions, and most patients do not tolerate more than five convulsive episodes. The increased muscle tone can lead to hyperthermia and muscle damage (rhabdomyolysis) in severe cases. Treatment involves urgently establishing and maintaining a clear airway and ensuring adequate ventilation. This may be difficult if muscle tone is increased or convulsions are occurring, and it may be necessary to paralyse the patient before an endotracheal tube can be inserted and the patient ventilated. The patient should be kept at absolute rest and any stimuli that may precipitate further convulsions should be avoided. Sensory stimuli should be minimized by nursing in a darkened room; convulsions should be treated with diazepam. In severe cases neuromuscular blockers may be needed to paralyse the patient while ventilation is supported mechanically.
RODENTICIDES Many rodenticides contain warfarin or related coumarin anticoagulants and, unless taken in huge amounts, generally cause few symptoms. If the INR does rise, vitamin K should be administered as for warfarin overdose. Alphachloralose is a CNS stimulant that can cause coma, convulsions and rhabdomyolysis in overdose. Treatment consists of managing the complications. Fluoride salts may be associated with severe toxicity, sometimes delayed in onset, including abdominal pain and diarrhoea, with hypotension and peripheral circulatory failure. Hypocalcaemia and hypomagnesaemia cause muscle spasms, weakness, convulsions and cardiac arrhythmias including ventricular fibrillation. Coma and respiratory failure may supervene. Treatment is symptomatic and supportive. Arsenic is sometimes used as a rodenticide as well as a component of some timber (tannalizing) preservatives. Abdominal pain and vomiting precede the onset of profound (sometimes bloody) diarrhoea. Hypotension,
1
POISONOUS PLANTS AND FUNGI Although the number of plants that have been suggested to be poisonous is very great, many of these contain only small amounts of toxins and generally do not cause severe poisoning. They can be classified into those: • • • • • • • • •
producing cholinergic (nicotinic) stimulation producing cholinergic (muscarinic) stimulation with anticholinergic activity with gastrointestinal activity with effects on the heart with convulsant activity with hallucinogenic effects with dermatological effects with toxicity on other organs.
Plants with cholinergic (nicotinic) activity Alkaloids similar to nicotine are found in hemlock (coniine) and laburnum (cytisine). Nausea and vomiting
39
may be followed in severe poisoning by confusion, hallucinations, convulsions, and finally coma and respiratory arrest. Treatment for severe poisoning is as for nicotine. The stomach should be emptied and activated charcoal administered. Monitoring of fluid and electrolytes and adequate replacement therapy, together with measures to assist the respiration and cardiovascular functions, are generally only necessary in severe poisoning (rarely caused by laburnum).
Plants with cholinergic (muscarinic) activity Plants with cholinergic activity include the clitocybe and inocybe fungi. Ingestion produces increased perspiration, abdominal pain and visual disturbances. Treatment is with atropine, 1.2mg intramuscularly, repeated if necessary.
and delphinium may cause bradycardia and muscular weakness.
Plants with convulsant activity Cicuta viirosa (cowbane) and Qenanthe crocata (hemlock water dropwort) contain potent alcohols with effects similar to picrotoxin in antagonizing the CNS inhibitory effects of y-amino butyric acid. In severe cases nausea, vomiting and hypersalivation are followed by convulsions and respiratory failure. Convulsions can be controlled with either short-acting barbiturates or diazepam; respiration may require support until the effects of the toxin wear off. Strychnine is found in the seeds of the tree Strychnos nux vomica, native to India. Features and management are described under rodenticides (page 39).
Plants with hallucinogenic effects Plants with anticholinergic activity Plants with anticholinergic activity include the deadly nightshade (Atropa belladonna}, the thorn apple and henbane. In addition to atropine these plants may contain hyoscine and hyoscyamine. The symptoms are similar to those caused by drugs with anticholinergic activity (e.g. tricyclic antidepressants) and management is supportive.
Plants with gastrointestinal toxicity Oxalates present in some plants can cause local gastrointestinal irritation and painful ulceration of the mouth if chewed by children. These include the household plants dumb cane (Dieffenbachia) and some of the Monstera and philodendron species. Other plants contain irritant resins and saponins (e.g. arum, yew, bryony and Daphne mezereum), which can cause severe vomiting and diarrhoea. The beans of the Abrus species (e.g. Ricinus and Robinia) can cause delayed gastrointestinal symptoms as they contain compounds that can impair RNA synthesis. Solanum species also produce delayed gastrointestinal symptoms: these include potatoes that have been allowed to sprout, and woody and black nightshades. Treatment is supportive, with replacement of fluids and electrolyte loss.
Plants causing cardiovascular disturbances Digitalis glycosides are found not only in the foxglove but also in lily of the valley (Convallarid). Treatment is as for digitalis poisoning. The aconitine present in the monksfoot
1
40
MCQ1.29
In addition to those anticholinergic agents with hallucinogenic effects, there are several other hallucinogens in plants and fungi. These include the psilocin and psilocybin in psilocybes (magic) mushrooms, the tetrahydrocannabinol in cannabis, and the ibotinic acid and muscimol found in Amanita muscaria. Tranquillizers may be necessary if the patient is a risk to himself or to others, and adequate supervision must be given until the hallucinations subside. Table 1.13 lists various plants and their toxicities.
Plants that cause dermatological toxic ity Plants contain substances that can cause either direct chemical irritation (e.g. histamine and oxalic acid) or delayed hypersensitivity reactions (e.g. Primula obconica and the hogweeds, that can produce photoallergic dermatitis and several other species). Treatment is symptomatic.
Plants with toxic ity on other organs The lectins present in the seeds of Ricinus communis cause delayed gastrointestinal tract symptoms. Haemolytic anaemia may also occur, and haemoglobin precipitation in the renal tubules may cause acute renal failure. The principal lectin, ricin, is the most potent toxin known to man. Management is largely symptomatic and supportive. The beans of Ricinus communis are also highly allergenic and may cause anaphylaxis. Severe liver damage can also be caused by the phallotoxins and amatoxins found in Amanita phalloides and some of the other Amanita fungal species. Cooking or drying does not destroy these toxins. Vomiting, abdominal pain and diarrhoea often occur 6-12 hours after ingestion, and albuminuria, haematuria, renal failure and liver failure may occur around 1-3 days later. Treatment consists of emptying the stomach and replacing fluid loss. Specific antidotes are of unproven value, but thioctic acid and high doses of penicillin may be of value in preventing the liver and renal damage.
Blue-green algae are actually cyanobacteria, which grow as blue-green or brown rafts or sediments, usually in stagnant water, and which produce endotoxins. Their disagreeable odour usually prevents human consumption, but deaths have occurred in cattle. In humans local irritation and allergic skin reactions may occur. Consumption of contaminated water by humans may result in acute gastroenteritis, which usually resolves in 1-2 days. Occasionally a hepatitic picture or atypical pneumonia has been reported. Treatment is normally symptomatic and supportive. O
TABU 1.13 Plants and toxicity Plant or fungus
Latin name
Toxic features
Black (garden) nightshade Blue-green algae
Solarium nigrum Microcystis/Anabaena/ Aphanizomenon/ Oscillatoria Bryonia dioica Ricinus communis Clitocybe sp. Cicuta vimsa Daphne mezereum
Gastrointestinal Hepatotoxic Dermatological
Atmpa belladona Amanita phal/oides Dieffenbachia Amanita muscaria Digitalis purpurea Heracleum mantegazzianum Conium maulatum Oenanthe cmcata Hyoscamus niger Inocybe sp. Laburnum anagroides Conva/laria Psilocybes sp. Aconitum nape/lus
Anticholinergic Hepatotoxic Gastrointestinal Hallucinogenic Cardiotoxic Dermatological
Nerium oleander Thevetia peruviana Solanum tuberosum Primula obconica Philodendron Monstera deliciosa Datura stramomium Arum maculatum Solanum dulcamara
Cardiotoxic Cardiotoxic Gastrointestinal Dermatological Gastrointestinal Gastrointestinal Anticholinergic Gastrointestinal Gastrointestinal
Taxus baccata
Gastrointestinal
Bryony (white/red) Castor oil plant Clitocybe fungi Cowbane/water hemlock Daphne/mezereon/spurge olive Deadly nightshade Death cap fungus Dumbeane/Leopard lily Fly agaric Foxglove Giant hogweed Hemlock Hemlock water dropwort Henbane Inocybe fungi Laburnum/Golden rain tree Lily of the valley Magic mushrooms Monkshood/aconite/ wolfsbane Oleander (pink) Oleander (yellow) Potatoes (sprouting) Primula obconica Sweetheart vine Swiss cheese plant Thorn apple Wild arum/cuckoo pint Woody nightshade/ bittersweet Yew
Gastrointestinal Gastrointestinal Cholinergic (muscarinic) Convulsant Gastrointestinal
POISONOUS ANIMALS
1
ADDER ENVENOMATION The adder, Vipera hems, is the only indigenous poisonous snake in western Europe. Only 50% of those bitten develop signs of envenomation, which may occur either immediately, with shock, vomiting and explosive diarrhoea, or several hours later. The initial collapse may be due to activation of the kinin system; the later shock is more often due to hypovolaemia, caused by increased capillary permeability and fluid loss into the swollen limb, and direct cardiotoxicity of the venom (Fig. 1.13). Management Treatment includes reassurance, as shock may be exacerbated by the fear of impending toxicity. The limb should be kept still, but a ligature should not be used unless there is likely to be a delay of more than half an hour between the patient having been bitten and transfer to hospital. If a ligature is used, it should be tight enough to prevent
Cholinergic (nicotinic) Convulsant Anticholinergic Cholinergic (muscarinic) Cholinergic (nicotinic) Cardiotoxic Hallucinogenic Cardiotoxic
FIG. 1.13 Adder bite on the finger of a child A Note the twin puncture wounds and B subsequent oedema involving the hand and arm.
41
venous return but not to obstruct arterial inflow. If there are signs of toxicity the patient should be admitted and observed for at least a day after the bite. Pulse and blood pressure should be recorded, together with urinary output and fluid losses from diarrhoea and vomiting. Local swelling should also be noted, and the white cell count, urea and electrolytes should be measured each day. The use of antivenom should be considered if hypotension persists, ECG signs occur, the white count rises markedly to above 20000/mm3 or, in an adult, severe swelling has extended up the limb within 2 hours after the bite. Anaphylactic reactions to the antivenom occur in 1 % of patients and so antivenom should only be used when the indications described above are present. A history of asthma or allergy is a relative contraindication to its use. Antivenom is given by slow intravenous infusion and is stopped at the first signs of allergic reaction. Adrenaline (epinephrine) solution must be drawn up prior to administration of the antivenom and given intramuscularly if a reaction occurs (intravenously in the case of a severe reaction). Deaths from adder bite are extremely rare but local tissue necrosis may be severe, particularly in adults.
FISH ENVENOMATION
In the UK the only venomous fish regularly found are the Weaver fish (Trachinus vipera), which is found around the coast in the summer months, and the Lion fish (an aquarium species). Both contain heat-labile venom in their spiny dorsal fins, which causes severe local pain. Hypotension, and myocardial and respiratory depression may develop. Management Treatment is to remove any barbs and clean the wound, immersing the limb in water as hot as can be tolerated without discomfort to destroy the toxin. The wound should be examined at a later stage for signs of secondary infection.
VENOMOUS INVERTEBRATES
The Portuguese man of war (Physalia physalis) is the most poisonous jellyfish found around the coasts of the UK. Its sting contains substances capable of releasing histamine and other kinins. Local pain is common, but more serious symptoms include abdominal pain, dyspnoea, hypotension, muscular paralysis and convulsions. Most other jellyfish found around the UK are harmless, but the compass jellyfish (Chrysaora hyoscella), the lion's mane (Cyanea O MCQ1.30
42
capillata) and the sea nettle (Cyanea lamarckii) can cause a sting. Management The wound should be bathed in vinegar solution (4-6% acetic acid), and any tentacles still adherent removed with forceps, a gloved hand or adhesive tape. Treatment is otherwise symptomatic.
ARTHROPOD ENVENOMATION Wasp and bee stings contain amines, kinins, peptides and enzymes that cause local pain, erythema and swelling. Systemic effects are rare unless the stings are numerous or the subject is hypersensitive, in which case even a single sting may kill. Initial symptoms are generalized urticaria, flushing, dizziness, bronchospasm, collapse and coma. Serum sickness may occur after a week or more. Management The sting of the bee should be removed by flicking or scraping, taking care not to squeeze it and inject more venom. Severe pain may respond to local anaesthetic or aspirin. Swelling may respond to antihistamines and corticosteroids. Anaphylaxis should be treated immediately with adrenaline (epinephrine) (0.5-lmL of a 0.1% solution intramuscularly for an adult and 10|ig/kg for a child). The dose may be repeated every 10 minutes if necessary. Stings in the mouth, even in patients who are not hypersensitive, may cause severe respiratory tract obstruction. In allergic individuals, specific venoms have been used in increasing doses to produce desensitization.
POISONOUS SEAFOODS
Seafood may contain bacteria (e.g. Vibrio, Salmonella) or viruses (e.g. hepatitis A); toxicity may also occur as a result of contamination by dinoflagellates or decomposition by bacteria. Antemortem infestation by dinoflagellates of certain subtropical fish (such as groupers and snappers) may occur, but contamination usually involves shellfish, such as mussels, oysters, scallops and clams. The dinoflagellates contain neurotoxins (e.g. saxitoxin) which can cause nausea, vomiting and diarrhoea, followed by circumoral paraesthesiae, ataxia, muscular weakness and, in severe cases, respiratory paralysis. Treatment is symptomatic, with respiratory and cardiovascular support. Postmortem contamination of some oily (dark-meat) fish, such as mackerel, skipjack and tuna, sardines and pilchards, by Proteus bacteria may result in the production of histamine and other unidentified toxins that produce urticaria, flushing, abdominal pain, nausea, vomiting and diarrhoea and, in some cases, bronchospasm. This 'scombroid fish' poisoning occurs around 4 hours after ingestion,
generally lasts only a few hours and is seldom severe. Treatment is symptomatic. Prevention involves keeping the raw fish frozen or on ice to prevent decomposition by bacteria.
POISONING BY METALS IRON Although mortality from iron poisoning has fallen in recent years, it remains one of the most dangerous metals in overdose. Children are particularly sensitive to its effects. Abdominal pain, nausea and vomiting are often followed by gastrointestinal bleeding, encephalopathy, metabolic acidosis, pulmonary oedema, coma, shock, acute renal and liver failure. Doses of elemental iron of more than 150mg/kg body weight produce severe and possibly fatal toxicity. A serum iron level greater than 5mg/L (90 pmol/L) within 4 hours of the overdose is associated with an increased likelihood of severe poisoning. Coma and shock are manifestations of severe toxicity.
Management The stomach should be emptied if more than 60mg/kg has been ingested within the previous hour. Radiography of the abdomen in the first 2 hours may reveal whether or not iron tablets have been taken. Blood should be taken for urgent measurement of serum iron concentration. If coma or shock develop, desferrioxamine should be considered immediately without waiting for the serum iron result. The dose is 15mg/kg body weight/hour for 5 hours. It often causes hypotension if infused more rapidly than this, and can occasionally cause rash and anaphylactic-like reactions. Pulmonary oedema and ARDS have been reported in patients treated with more than 80 mg/kg/day for longer than 24 hours. With prompt treatment the mortality should be less than 5% in severe cases. 1
HEAVY METAL POISONING Heavy metals can cause acute or chronic symptoms,
SUMMARY 15 Iron poisoning • Children are particularly sensitive to the toxicity of iron • Abdominal pain, nausea and vomiting may be followed by gastrointestinal haemorrhage, encephalopathy and renal and hepatic failure • Severe poisoning is normally associated with plasma concentrations around 4 hours after ingestion of more than 5mg/L, with CNS signs and shock • Intravenous desferrioxamine should be given as soon as possible in severe iron poisoning
depending on the dose and duration of exposure. Acute ingestion of most heavy metals will cause gastroenteritis. Generalized convulsions may also be seen, particularly with lead poisoning, and renal failure and cardiac arrhythmias have also been recorded. Inhalation of heavy metal fumes may cause chemical pneumonitis and, in severe cases, pulmonary oedema, and a syndrome known as 'metal fume fever' may occur several hours after the inhalation of some metallic oxides. Chronic effects of heavy metal exposure are similar but milder. Chronic gastrointestinal symptoms and CNS effects occur, particularly after exposure to lead, manganese and mercury. Lead, thallium, bismuth and arsenic can also produce peripheral neuropathy, and gold, lead, cadmium and mercury may cause renal damage. Inhalation of heavy metal fumes can cause pulmonary fibrosis, particularly with beryllium, cadmium, tungsten, titanium and cobalt. An emphysematous picture has been seen with cadmium, and an asthma-like syndrome may occur as a result of sensitivity to chromium, vanadium and platinum. Nickel, chromium, cobalt, platinum and beryllium may also cause skin sensitization and subsequent dermatitis. Taking a full occupational history helps diagnosis. Clinical examination may reveal specific signs of poisoning, such as the blue line on the gums in chronic mercury poisoning or the raindrop pigmentation of the skin in arsenic poisoning. Toxicological examination of the urine, blood, or hair and nail clippings may also help, but this often has to be performed in specialized centres.
1
Management Treatment consists of preventing further exposure to the heavy metal, treatment of the complications of poisoning, and chelation therapy to enhance the elimination of the metal already absorbed. It must be remembered, however, that most chelating agents are toxic and should only be used when their benefits are likely to outweigh the risks of their use. Sodium calcium edetate is the treatment of choice for lead poisoning. It must be given by slow intravenous infusion. Dimercaprol, DMSA and DMPS are effective in severe mercury and arsenic poisoning. Finally, Prussian blue has been used successfully in the treatment of thallium poisoning.
FURTHER READING British National Formulary. British Medical Association and Royal Pharmaceutical Society of Great Britain, published biannually. An excellent reference text and practical guide to prescribing, with useful tables to prescribing in special circumstances and drug interactions. Laurence D R, Bennett P N 1997 Clinical pharmacology, 8th edn. Churchill Livingstone, Edinburgh. Highly readable, with a practical therapeutic flavour. Ritter J M, Lewis L D, Mant T G K 1998 A textbook of clinical pharmacology, 3rd edn. Edward Arnold, London. A practical guide to clinical pharmacology and drug therapy.
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2
Heat cramps
Physicaland
Environmental Disorders
Spasms of painful muscular contraction may occur with sudden rises in temperature during strenuous activities such as long-distance running, or during work in very hot environments. Muscles of the legs and arms are usually affected, typically after the exertion or heavy work is over. There is usually hyponatraemia, and severe cramps may be accompanied by a rise in creatine phosphokinase and evidence of rhabdomyolysis. Part of the pathogenesis appears to be due to replacement of fluid and salt loss by water with too low a salt content; the condition is preventable by drinking fluids containing 0.25% saline.
2
Heat exhaustion John Moxham and Robert L Souhami
Disorders due to heat and cold 45 Whole body radiation exposure 47 Disorders due to extremes of barometric pressure 49
Submersion and drowning 51 Electric shock 53 Smoke inhalation 54 Chemical warfare 54
DISORDERS DUE TO HEAT AND COLD Heat produced by metabolism is lost mainly through the skin and, to a lesser extent, through the gut, urine and breath. Inadequate heat loss leads to sweating and vasodilatation. Cold produces cutaneous vasoconstriction and shivering, which results in increased muscle metabolism and heat production. In moving from a cold to a hot climate, acclimatization occurs over a period of 1-2 weeks; this process is not well understood. There is increased sweating and the salt content of sweat diminishes. Aldosterone secretion increases, at least at first, causing a low urinary sodium with loss of potassium. A progressive rise in temperature above 38-39°C causes irritability and mental confusion. At temperatures above 40-41°C vascular, renal and hepatic damage occur.
HEAT EXCESS Three syndromes due to excess heat occur: heat cramps, heat exhaustion and heatstroke.
Heat exhaustion or heat collapse is the commonest syndrome and is especially likely to occur in individuals exposed to a hot environment for a few days. The very young and the elderly (especially those on diuretics) are particularly at risk. The syndrome is due in part to salt and water loss, and in part to a failure of circulatory adaptation to heat. When water loss predominates, there is intense thirst and weakness, agitation and confusion. Water depletion is more likely to occur in acclimatized people (whose sweat contains less salt). The plasma Na+ and Cl~ rise. With salt depletion, there are muscle cramps, headaches, vomiting and myalgia. Haemoconcentration occurs with a rise in haematocrit and blood urea. Usually, salt and water depletion occur together, and the patient has a normal temperature and appears pale and clammy. The disorder is treated by rest and oral fluids. In water depletion (where plasma sodium is elevated) this should be with water. Typically 5-8 L may be given in 24 hours by mouth or as i.v. glucose. When salt depletion is present the oral fluids should contain salt (e.g. 5L of fluid with 20 g salt).
Heatstroke Heatstroke is a serious and sudden disease which may be fatal unless treated urgently. It is caused by a failure of thermoregulation, resulting in a rapid rise in body temperature. In normal individuals it is usually due to exercise or work in a hot, humid environment. When it occurs in sedentary individuals the patient is usually elderly, often with underlying disease such as cardiac failure, diabetes (with autonomic dysfunction), obesity or alcoholism. Atropine-like drugs, p-blockers, phenothiazines and diuretics predispose to the syndrome. Heatstroke can also occur in fit men working in hot environments, and there are some clinical differences in these cases. Typically the patient develops headache, dizziness and faintness, and abdominal pain and delirium may occur. Sweating stops and the body temperature rises rapidly (and may reach 43°C). Hypotension, renal failure and
45
rhabdomyolysis may occur; the latter is especially common in heatstroke following severe exertion. In this form of heatstroke sweating may continue. On examination the skin is hot and usually dry, and the patient exhibits tachypnoea and flaccidity. Coma and shock are grave signs. The blood shows leukocytosis and respiratory alkalosis (but may be acidotic in the exertional form), the urea is raised, and hypokalaemia and hyperphosphataemia occur. Myocardial necrosis may give ST changes and even an infarction pattern on the ECG. Liver function tests are abnormal, and acute renal failure may occur. Disseminated intravascular coagulation is present in mild degree in the elderly, but may be severe in exertional heatstroke. Management Treatment is urgent. The patient must be cooled as quickly as possible. The most effective way is immersion in cold water, the skin being rubbed to increase the efficiency of cooling. An alternative is to blow cold air over dampened skin. Core temperature must be monitored using a rectal thermometer. Hypotension can be treated with small quantities of saline, taking care to avoid circulatory overload. Hypoglycaemia, if present, can be treated with glucose, and severe acidosis by sodium bicarbonate. More serious complications, such as acute renal failure and disseminated intravascular coagulation, are treated in the usual way (Chs 20 and 23). Cerebellar degeneration may occur, and coma with cortical damage is a terminal event. 1
SUMMARY 1 Clinical features of heatstroke Symptoms • Headache • Dizziness/faintness • Abdominal pain Signs • Increased body temperature • Hot, dry skin (sweating may be absent) • Tachypnoea • Flaccidity • Hypotension • Delirium -> shock/coma Results/complications • Hepatic and renal failure • Leukocytosis, alkalosis/acidosis, hypokalaemia • Rhabdomyolysis • Myocardial necrosis • Disseminated intravascular coagulation • Cerebellar degeneration • Coma, cerebral damage
as 'ecstasy'. Muscle contraction begins after the start of anaesthesia, and body temperature rises rapidly. The anaesthetic must be stopped, the patient cooled and ventilated, and i.v. dantrolene sodium given (2-10mg/kg). Acidosis should be treated. 0
HYPOTHERMIA
Neuroleptic malignant syndrome This syndrome is characterized by muscle rigidity giving rise to hyperpyrexia, tachycardia and impaired consciousness. It is an idiosyncratic reaction to drugs that block dopaminergic transmission, such as phenothiazines and butyrophenones. The increase in muscle tone develops over 12-72 hours. Death from respiratory failure may occur. Treatment is by muscle relaxants, including neuromuscular blocking agents, and ventilation if necessary. Recovery may take several days.
Significant hypothermia is an uncommon problem mainly affecting the elderly, in whom the response to cold may be defective (p. 178). Hypothermia contributes to the excess mortality in this population during winter months. It is defined as being present when the deep body temperature falls below 35°C. As the mouth temperature may fluctuate depending on the ambient air temperature, it is best to use a rectal thermometer when monitoring hypothermic patients. A low-reading thermometer is necessary. The rectal temperature is about 0.5°C higher than oral.
Malignant hyperpyrexia
Aetiology
This is an autosomal dominant disorder in which hyperpyrexia is produced by skeletal muscle contraction following anaesthetic agents such as halothane and suxemethonium and local anaesthetics. It can also occur with drugs such as amphetamines and derivatives such
Hypothermia may be due simply to an age-related impaired thermoregulatory response to a cold environment (Ch. 7, p. 178). In the majority of patients, however, there is an associated underlying pathological cause, including any cause of autonomic dysfunction (p. 178). Hypothyroidism and hypopituitarism are both associated with hypothermia, and the risk is also higher in immobile or demented patients, or in the presence of an acute illness such as bronchopneumonia. There is a clear association between phenothiazines and impairment of temperature regulation, and hypothermia may also be precipitated by sedative drugs, such as hypnotics and alcohol. Although
1
46
Case 2.1
2
MCQ2.1
3
MCQ2.2
a mild drop in body temperature is common, clinically important hypothermia is unusual. However even modest falls in body temperature may produce changes in coagulability, which may predispose to myocardial infarction. Immersion hypothermia is produced by shipwreck. Exposure to cold weather occurs in hillwalkers and climbers, especially if they have not eaten or if they drink alcohol.
Clinical features Hypothermic patients typically live alone in poor housing and have impaired mobility. A typical case would be that of an old person who gets out of bed in the middle of the night to go to the lavatory, falls, and then lies all night on the cold floor in thin nightclothes until discovered the next morning by a neighbour. The skin has a greyish look owing to a combination of vasoconstriction and cyanosis; the face may appear puffy, resembling myxoedema. The diagnosis is often first suspected during examination, when it is found that the patient's skin feels cold in normally warm areas, such as the axilla or the abdomen. There may be ataxia and slow mental response. The patient is often confused when the temperature falls below 35°C, and drowsiness and loss of consciousness occur when the temperature falls below 29-33°C. Shivering is absent below this temperature; instead, there is increased skeletal muscle tone with neck stiffness and abdominal rigidity. The heart rate is slowed and the ECG may show a prolonged PR interval and J waves (Fig. 2.1). Respirations are slow and shallow, and there may be hypoxia and hypercapnia. Hypoxia is exacerbated by a shift of the oxygen dissociation curve to the right, leading to impaired release of O2 from haemoglobin. Acute pancreatitis is often found at necropsy, but this is only rarely diagnosed in life. Impaired renal and respiratory function may lead to a raised blood urea or bicarbonate. Blood sugar levels may be raised, but do not indicate diabetes mellitus, and will fall as the temperature returns to normal. Serum asparate aminotransferase and creatine kinase may be raised due to muscle damage.
Management The lower the deep body temperature, the higher the mor-
SUMMARY 2 Clinical features of hypothermia • • • • • • • •
Contusion/impaired consciousness Cold, greyish skin Shivering absent Increased skeletal muscle tone Slow heart rate, prolonged PR interval and J waves Slow, shallow respiration, hypoxia and hypercapnia Raised blood urea or sugar levels Raised serum asparate aminotransferase and creatine kinase
2
tality (about 50% overall). This is because many hypothermic patients have a serious underlying illness. Patients with mild hypothermia (core temperature 32-35°C) should be wrapped in a space blanket and nursed in a side ward where the ambient temperature is 28-30°C. Their temperature should be allowed to rise gradually, at a rate of about 0.5°C per hour, as fast surface rewarming carries the risk of hypotension. For this reason, the patient's pulse and blood pressure must be monitored. If the blood pressure drops, the space blanket should be removed or the room temperature lowered so that the patient is temporarily cooled. Intravenous fluids are hazardous and may produce acute pulmonary oedema. A broad-spectrum antibiotic is usually given parenterally because bronchopneumonia is nearly always present, even if not clinically apparent. The ECG should be monitored, as both bradyarrhythmias and ventricular fibrillation may occur. The patient is at serious risk of developing a pressure sore and must be nursed on a suitable mattress and turned regularly. When the deep body temperature is below 32°C a more aggressive approach to resuscitation is sometimes advocated, although there is little evidence that this reduces mortality. These measures include positivepressure ventilation to correct hypoxia, measurement of central venous pressure, and active rewarming using a radiant heat cradle over the torso or warmed intravenous fluids.
Thyroid hormones should not normally be given to hypothermic patients. If there is good clinical or laboratory evidence of hypothyroidism, then triiodothyronine (5ug) may be given by slow intravenous injection every 12 hours. A particular problem is presented by patients who have become hypothermic as a result of immersion at sea. They may develop ventricular fibrillation on rescue if they exert themselves. They should therefore be kept still and rewarmed slowly. 3
WHOLE BODY RADIATION EXPOSURE
FIG. 2.1 Electrocardiogram showing J wave (arrowed) in a hypothermic patient
There are two broad types of ionizing irradiation: photons (y and X-rays) and particulate (a and |3 particles). Radiation dose is defined in a variety of ways. The energy
47
deposited in a tissue is measured in grays (Gy; IGy = 1 J/kg). Because different types of radiation have different tissue effects, a unit called the Sievert (Sv) is sometimes used, which weights the radiation dose according to the type of radiation. Particulate radiations are absorbed according to their mass and energy, but do not penetrate deeply into tissues (see also Ch. 6, p. 159). Particulate irradiation transfers more energy and is much more ionizing than Y or X-rays.
EXPOSURE Exposure to ionizing irradiation comes about in three ways: • Background irradiation. We are exposed to approximately 2-3 mSv per year from solar and geological irradiation. Cosmic rays are mostly very high-energy protons. Secondary radiations, from the upper atmosphere, are largely y-rays. Geological irradiation is largely due to radon. • Medical exposure. The therapeutic uses of ionizing irradiation are described in Chapter 6. Accidental exposure of patients or staff has been rare since the advent of stringent precautions following the radiation-induced damage to skin and eyes in the early days of therapeutic and diagnostic radiation. Exposure to whole-body radiation forms part of the treatment of leukaemia and lymphoma. The resulting bone marrow suppression is treated by allogeneic (or autologous) haemopoietic stem cell transplantation. • Military and industrial irradiation. The atomic bombs dropped on Hiroshima and Nagasaki led to numerous cases of acute leukaemia and other cancers. Fallout from nuclear tests has increased annual background radiation by 1%. Industrial exposures also occur, the most dramatic example of which has been the ingestion of radium by radium dial painters from 1916 to 1926, resulting in a great increase in risk of bone sarcoma and cancer of the air sinuses of the skull. The accident in the Chernobyl nuclear power station in 1986 resulted in many deaths due to acute radiation exposure, and an increase in background radiation over a wide geographical area.
TISSUE DAMAGE The tissue-damaging effect of ionizing irradiation is probably related mainly to damage to DNA, leading to strand
1 48
MCQ2.3
breakage and impaired reproductive integrity of the cell. At 0.1 Sv total body exposure there is a slight fall in blood lymphocyte count. At ISv there may be mild radiation sickness with slight nausea and a more profound lymphopenia, and a fall in neutrophils and platelets 2-3 weeks after exposure. Following greater degrees of whole-body exposure certain tissues are damaged acutely by relatively low doses: • Bone marrow. This can regenerate after exposure to 10 Gy, but above this dose permanent aplasia may occur. The white count and platelet count begin to fall within 10 days of exposure. • Intestine. Doses of 10 Gy or over cause severe loss of crypt cells, leading to loss of villi and extensive ulceration. The onset of nausea and vomiting is 1-2 hours after exposure, often recovering a few hours later, but above 10 Gy permanent and fatal damage to the gut occurs, with death in 4-14 days. Death is due to severe diarrhoea, consequent salt and water depletion, and severe Gram-negative sepsis. • Skin. Erythema occurs at doses below 10 Gy. At 20 Gy the skin starts to desquamate and ulcerate. • Lung. Above l0 Gy in a single fraction pneumonitis occurs, and is increasingly severe with increase in dose. Long-term changes include glomerular loss and interstitial nephritis, infertility, pulmonary fibrosis, neuronal loss and gliosis, intestinal stricture and hepatic fibrosis. After acute radiation exposure (such as at Chernobyl and Hiroshima) there is an increased risk of leukaemia at 5-10 years. The safe lower limit is not easily quantifiable but is probably below l0c Gy. Solid tumours may also occur, including bone cancer in radium dial painters, skin cancer, and lung and breast cancer. The risk of solid tumours appears to be 1 in 2000 following total body exposure of 1-2 cGy.
Clinical features After acute whole-body exposure, the clinical features depend on the received dose. Following an initial period of nausea and vomiting (sometimes with parotid swelling), the patient may be relatively well for 7-10 days and then develop a syndrome of haematological failure. There is depression of the white count and platelets, with infection, bruising and bleeding. At the same time skin reactions occur, with desquamation, alopecia and ulceration. If the whole-body dose is above 15 Gy the gastrointestinal syndrome may predominate and be the first sign of toxicity. In a patient with severe leukopenia severe diarrhoea and fluid loss are followed by septicaemia from gut bacteria. This is almost always fatal. Higher doses of whole-body radiation (25-60 Gy) cause cardiovascular collapse and shock.
Management Management is supportive. Antiemetics are given in the acute phase, and fluid losses from diarrhoea are replaced. Transfusion of blood and platelets and intensive antibiotic treatment for gut derived organisms are used during the phase of myelosuppression and infection. Haemopoietic growth factors such as GCSF may be of value. Allogeneic bone-marrow transplantation may help the minority of patients for whom there is a donor, and in whom the haematological toxicity is the major life-threatening complication. It is of no value if the major toxicity is in organs such as the lungs or gastrointestinal tract. Accidental exposure to radionuclides is treated according to the isotope. Potassium iodide is given for I31 I ingestion, and soluble phosphate for 32P overdose. Overdose with bone-localizing isotopes (caesium, radium, strontium) is treated with EDTA and large doses of oral calcium. There has been some interest in drugs that limit damage from radiation: unfortunately, these have to be given before or immediately after exposure. The best known is ethyol, which may also protect normal tissues from cytotoxic drug damage. Late effects occur 3-10 years after exposure. There is an increased risk of acute myeloid leukaemia. The risk of solid tumours is about 1 in 2000. Tumours include cancer of skin, breast and lung. This is a small increase compared to the background incidence in the population.
height. Commercial aircraft are maintained at a pressure equivalent to 2500 metres, so that no additional oxygen is needed unless a patient has severe cardiac or respiratory disease. If there is a loss of pressurization, extra oxygen is made available through masks. Acclimatization to altitude is a complex process. On rapid ascent the relative hypoxia stimulates ventilation, but this stimulus diminishes over a few weeks. This hyperventilation diminishes Paco2, with the consequent development of a respiratory alkalosis. The respiratory centre appears to adapt to a lower Paco2. The acute circulatory adaptation consists of a rise in cardiac output, a fall in renal, cardiac and cutaneous blood flow, and a rise in cerebral blood flow. These changes slowly reverse, and after several weeks cardiac output on exercise is lower than at sea level. The red cell mass increases greatly and with it the total oxygen-carrying capacity of the blood. The oxygen dissociation curve does not shift substantially (as the alkalosis shifts it to the right and the hypoxia to the left). There is an increased formation of tissue capillaries, greatly increasing tissue oxygenation. There are four recognized syndromes of altitude sickness: • • • •
2
Acute altitude sickness Acute pulmonary oedema Acute cerebral oedema Chronic altitude sickness.
Prognosis With adequate treatment, most patients will survive acute exposures up to 10 Gy. Above this dose, bone-marrow failure and the intestinal syndrome are usually fatal. 1
DISORDERS DUE TO EXTREMES OF BAROMETRIC PRESSURE
ALTITUDE SICKNESS The effects of reduced barometric pressure result from the low partial pressure of oxygen and reduced oxygencarrying capacity of the blood. Figure 2.2 shows this relationship. The barometric pressure at sea level is 100 kPa, and the partial pressure of oxygen is 21% of this, i.e. 21 kPa. At 5500 metres the barometric pressure is reduced to 50% (50kPa). The partial pressure of oxygen is, however, less than 20% of this (l0kPa) because the proportion of water vapour rises. Because of the sigmoid shape of the oxygen dissociation curve, oxygen saturation is reasonably well maintained until an altitude of 5000 metres. A precipitous fall in saturation then occurs with increasing
FIG. 2.2 Effect of altitude on alveolar Pao2 and oxygen saturation Because of the steep slope of the oxygen dissociation curve, increasing altitude above 5000 metres causes a precipitous fall in saturation. In an unacclimatized person, acute changes occur at: IT1 3000 metres (10000 feet) - slightly impaired memory and judgement, increased heart rate, abdominal cramps and nausea; [B] 3500 metres (12000 feet) - headache, nausea, diminished visual acuity, and possible pulmonary oedema; [C] 5500 metres (18000 feet) - impaired consciousness after several hours in many people; and [D] 6750 metres (22000 feet) - loss of consciousness.
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Acute altitude (mountain) sickness This syndrome occurs in unacclimatized individuals who ascend rapidly to heights in excess of 2500 metres. People who are unfit, or very young, or those who have respiratory or cardiac disease, are especially prone. The symptoms usually begin at 12-24 hours after ascent. Lightheadedness is followed by lethargy irritability and severe headache, usually occipital in position. Other symptoms include nausea and vomiting, dyspnoea with periodic respiration, and abdominal pain. Physical examination reveals little, although ataxia (shown by walking heel to toe) may be present. The cause of acute altitude sickness is unknown. It is possible that the hypoxia causes mild cerebral and brainstem oedema. This is suggested on MRI scans and by multiple petechiae in the brain in fatal cases. The syndrome is preventable by slow ascent. Individual susceptibility varies greatly and mountainous hikes and climbs should never put pressure on participants to ascend rapidly, especially if they start to feel unwell. When starting an ascent above 3000 metres a reasonable pace is 300m/day, resting for a day every 3 days. Even this may be too fast for some people. Dehydration should be avoided, and a good diet maintained. Treatment is to avoid sedatives, to take mild analgesics for headache, and if the symptoms do not abate, to descend to 1000m to await recovery. Acetazolamide can alleviate the symptoms of acute altitude sickness by acting as a respiratory stimulant, lowering the Paco2 and raising the Pao2. If ascent cannot be made slowly it may be advisable to start acetazolamide (250 mg b.d.) before ascent, and climbers should be warned of the side-effects, particularly paraesthesiae. Acute pulmonary oedema Rapid ascent to heights greater than 3000 metres may provoke the sudden onset of acute pulmonary oedema. Hypoxia is the cause, but the pathogenesis is unclear. The symptoms usually begin 5-36 hours after ascent; acute dyspnoea, haemoptysis and widespread crackles in the lungs occur. Pathologically there is acute oedema and a 'hyaline' membrane in bronchioles. Treatment is with urgent evaluation to a lower altitude, oxygen and diuretics. Nifedipine has been shown to be useful prophylactically in those who have had a previous episode of pulmonary oedema. Acute cerebral and retinal oedema Acute hypoxia increases cerebral blood flow and intracranial pressure, and can cause cerebral oedema. This is asso-
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1
Fig. 2.1
4
Fig. 2.2
2 Case 2.2 3 MCQ 2.4
ciated with headache and brain dysfunction. The patient may be incoherent, drowsy, ataxic, and progress to coma. There may be papilloedema. Deepening coma leads to death. The treatment is urgent descent to a lower altitude and oxygen. Dexamethasone (i.v.) should be given. Cerebral and pulmonary oedema often accompany each other. Many people ascending to high altitude develop asymptomatic retinal haemorrhage.1 Occasionally this may leave a permanent blind spot. Oedema of the retina is assumed to be the cause. Retinal oedema occurs in the absence of cerebral oedema. Pink optic discs and retinal haemorrhage are not in themselves a reason for urgent descent.
Chronic altitude (mountain) sickness Individuals (usually middle-aged men), who have lived for many years at altitudes above 4000 metres may develop polycythaemia and a chronic insensitivity of the respiratory centre to hypoxia. Such individuals hypoventilate and develop a raised Paco2. There is central cyanosis, with cough, headache and giddiness. Patients are cyanosed, with vascular conjunctivae and finger clubbing. There may be RV strain on ECG as a result of pulmonary hypertension. The CNS symptoms are similar to those of polycythaemia rubra vera and are due to decreased cerebral blood flow (a consequence of the raised haematocrit) and hypoxia. Not all people living at high altitude develop this syndrome, which appears in part to be an excessive response to decreased inspired Pao2. The syndrome can only be treated by permanent descent to a lower altitude.
INCREASE IN BAROMETRIC PRESSURE
An increase in barometric pressure is encountered in diving or in mining.
Breath hold diving During a breathhold dive the body directly encounters the increased pressure (1 atm for every 10 metres descent). The breathhold causes a rise in Paco2 and a fall in Pao2. The main respiratory stimulus is the raised Paco2, so that hyperventilation before diving leads to a lack of stimulus to breathe (owing to CO2 depletion). This may cause fatal loss of consciousness from hypoxia (which does not cause an irresistible urge to breathe and thus terminate the dive). As the diver surfaces, decompression lowers Pao2 and again may cause loss of consciousness.
Lung rupture, air embolism, pneumomediastinum During a breathhold dive the air in the lung is compressed and re-expands to its previous volume on ascent, with no risk of lung rupture. If a diver breathes air below the surface he must allow time for the excess air under pressure to be exhaled or the lung may rupture. Divers are taught not to ascend more rapidly than the gas they exhale. A diver breathing air may hold his/her breath while ascending rapidly, without breathing out. This often happens if the diver has accidentally lost the air supply. During the rapid ascent the lung may rupture. Lung rupture may be into the mediastinum or into the pleural space, causing pneumomediastinum and pneumothorax, respectively. The symptoms are breathlessness, cough and haemoptysis during the ascent. Air embolism may occur and cause dysphasia, paralysis, visual disturbance or convulsions. Mediastinal air may cause dysphagia and surgical emphysema in the neck. Treatment is with 100% oxygen to eliminate inert gas, and recompression.
Deep diving, decompression sickness In deep diving the gas must be delivered at the same pressure as the surrounding water. If the gas is air, the high pressure of N2 causes mental confusion below 50 metres. Helium/oxygen mixtures are better tolerated and descents as low as 700 metres can be undertaken. These mixtures must be used below 50 metres. At greater depths than 700 metres neurological disturbances occur owing to the high gas tensions. Very high oxygen concentrations in the inspired gas (even though they reduce inert gas narcosis and the risk of decompression sickness) are toxic to the lung and CNS. This toxicity is related to the level of inspired Pao2 and the duration of the dive, and must be carefully regulated. When breathing air, the nitrogen dissolved in blood (PaN2) increases and, on rapid decompression, forms bubbles, which come out of solution in small blood vessels. Ischaemia results, causing pain in joints, spinal cord injury, chest pain, cyanosis, confusion, visual defects, paralysis and fits. Minor confusion occurs with lesser degrees of compression injury. Treatment is by recompression, followed by very gradual decompression over days. Some instances of air embolization during diving occur in individuals who shunt blood from the right atrium to the left via a patent foramen ovale. About 25 % of the population have minor degrees of patency of the foramen ovale. Figure 2.3 shows the relationship between depth, duration of dive and the need for controlled ascent to the surface. QQ
REFERENCE Bennett PB. Elliott DH (eds) 1993 The physiology and medicine of diving. WB Saunders, London.
2
FIG. 2.3 Relationship between depth, duration of dive and need for controlled ascent to the surface
SUBMERSION AND DROWNING Drowning is a relatively common cause of accidental death, particularly in children, in whom only motor accidents and cancer are more common causes of death. In adolescents and adults, alcohol and drugs are frequently a contributory factor. Spinal injury is a relatively common problem, particularly after submersion following diving. There are considerable differences in the osmotic pressure of salt water (5% NaCl), fresh water (0% NaCl) and plasma (0.9% NaCl). It has been suggested that when large amounts of salt water are aspirated into the lung, water may be sucked into the alveoli from pulmonary capillary plasma, causing death from pulmonary oedema.4 When fresh water is aspirated, however, large volumes may pass into the pulmonary circulation, causing haemolysis and consequent potassium release, which may lead to cardiac arrest. In fact, in both cases death can result from acute reflex laryngospasm, causing asphyxia. The differences between submersion in fresh and salt water are probably trivial; the major factors determining survival are the duration of submersion and the severity of the consequent hypoxia.
RESUSCITATION FROM NEAR-DROWNING A patient who is nearly drowned needs urgent resuscitation. The basic techniques are the same as for any 'sudden death', but the physiology of drowning raises special issues. In both fresh- and sea-water drowning gastric aspiration must be performed once a cuffed endotracheal tube is in place. Large volumes of water tend to be swallowed during submersion, and vomiting during resuscitation is common.
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Similarly, once in hospital, ventilation with positive endexpiratory pressure is required in an attempt to reinflate atelectatic and waterlogged lungs. Acute respiratory distress syndrome (ARDS) is a complication. Hypothermia is frequently an associated problem and septicaemia is a common complication. Defibrillation for VF or VT is less effective in severe hypothermia. Patients who are breathing and coughing have a good prognosis (Table 2.1). Sea-water drowning can be associated with cardiac arrest produced by the rapid absorption of Ca2+ and Mg+ into the blood. Treatment by basic life support is frequently effective in sea-water drowning, if begun within 5 minutes. Fresh-water drowning may produce massive intravascular haemolysis, associated with ventricular fibrillation and
TULEJh Mortality following submersion Mortality (%)
Grade
Definition
1
Normal lung auscultation with coughing Abnormal auscultation, with crackles in some regions Auscultation: acute pulmonary oedema, no hypotension Acute pulmonary oedema, plus hypotension Isolated respiratory arrest Cardiopulmonary arrest
2 3 4 5 6
0 0.6 5.2 19.4 44
93
Modified from Szpilrnan
CASE STUDY 2.1 SUBMERSION AND DROWNING A 26-year-old woman went for a swim with her friend at the local pool. After she had been in the water for some time swimmers at the side of the pool noticed her thrashing around beneath the surface. The onlookers and pool staff pulled her out of the water at the shallow end. She was unconscious, not breathing, and had no detectable pulse. One of the onlookers was medically qualified. Mouth-to-mouth resuscitation and chest compression was initiated and the emergency services were called. On arrival at the scene the ambulance crew documented ventricular fibrillation on the ECG, shocked the patient and restored sinus rhythm. The patient was transferred to the local accident and emergency department. On arrival in A&E the patient was breathing and had a satisfactory blood pressure. There were no signs of external trauma. The axillary temperature was 36.0°C. There was vomitus in the mouth and the patient had obstructed breathing. The Glasgow Coma Scale was 3. The patient became greatly
O MCQ 2.5
52
agitated. Arterial blood gases, breathing supplementary high-flow oxygen, showed ^302 27.3 kPa, Faco2 9.2kPa, bicarbonate 16, pH 7.07. The patient was sedated, intubated and ventilated. She was given intravenous antibiotics and steroids. Additional history obtained from her friend revealed that the patient had been depressed for some time but was not, as far as the friend knew, taking any medication. There was no past history of attempted suicide or epilepsy. Questions 1. Wharf is the prognosA for this patient? 2. On afrival it A&E, fifhat ire the most important management issues? 3. A chest X~fay was performed; what might it show? 4. What is ydur interptetatidn of the arterial blodd gas results? For the next few days the patient was managed in the intensive care unit.
The acid-base status returned to normal. A CT brain scan showed no abnormalities. The chest X-ray initially showed bilaterial patchy air space ©pacification, but subsequently cleared (CASE FIG. 2.1.1). Gas exchange gradually improved and the patient was extubated. Moderate hypoxia persisted; the patient was treated with CPAP and transferred to the high-dependency unit. The patient became febrile, was diagnosed as having a secondary chest infection and treated with antibiotics. One week after admission the patient's jPao2 was within normal limits. The patient was alert, mobilized, and discharged 9 days after admission. She had no recollection of the events that led up to her submersion in the swimming pool. Question 5. What would you regard as being the main factor or ,„, factors that ultimately y resulted in a good outcorne for this patient?
CASE STUDY 2.1
2
CONTINUED
CASE FIG. 2.1.1 Chest X-ray. There is bilateral air space shadowing throughout the lungs, affecting the left lung more that the right Discussion Submersion and drowning is a common cause of death in young people. The most important factor determining outcome is the severity and duration of hypoxia. Clearly, cerebral and spinal trauma may also be critical in patients who, for example, dive into shallow water. Severe hypoxia causes cardiac arrhythmias, cardiopulmonary arrest, brain damage and acute lung injury. Ventricular fibrillation and
cardiopulmonary arrest indicate a poor prognosis (Table 2.1). The most important management issues are to sustain and improve tissue oxygen delivery. This patient's ventilation was inadequate and the upper airway was compromised, hence the importance of intubation and mechanical ventilation. Hypothermia is often a severe problem, but not in this particular case. The patient was treated with steroids, ostensibly to reduce lung
hyperkalaemia, which can be difficult to treat. Survival after prolonged submersion during warm weather is unusual, but survival (with normal cerebral function) has been recorded in children, even after 30 minutes' immersion, particularly in low-temperature water. Sudden death due to a combination of vagal slowing of the heart and intense peripheral vasoconstriction may occur in previously fit individuals who dive into cold water. O
FURTHER READING Szpilman D. Near drowning and drowing classification: a proposal to stratify mortality based on the analysis of 1821 cases. Chest 1997:112:660-665.
injury, but there is little evidence to support such therapy. The chest X-ray showed bilateral airspace shadowing consistent with pulmonary oedema (figure). Hypoxia causes increased pulmonary capillary permeability, alveolar flooding, and can lead to established ARDS. Many patients rescued from submersion vomit and some aspirate, and atelectasis may occur. Acute laryngospasm stops large volumes of water filling the lungs and the hypoxic lung injury is the more important lung insult. The arterial blood gas results show a severe combined respiratory and metabolic acidosis (i.e. the Paco2 is raised and the bicarbonate is reduced). This reflects reduced ventilation and inadequate oxygen delivery to all tissues. Hence the crucial importance of restoring the circulation and ventilation. With appropriate therapy the acid-base abnormalities were rapidly corrected. This patient survived and avoided hypoxic brain damage because of the prompt and effective poolside resuscitation (mouth-to-mouth resuscitation, chest compression and cardioversion). Without such rapid intervention the prognosis would have been very poor.
ELECTRIC SHOCK Injury following electric shock depends on the voltage and current. Below 100 V sudden death is less likely. Alternating current appears to be much more dangerous than direct, as it produces muscle spasm and is more likely to stop the heart. The direction of flow is also important, as flow from hand to hand or hand to foot traverses the heart. At high voltage, the body heats up as the current flows. This heating is much more severe in a small cross-sectional area (fingers) than in a large one (trunk), and burns and charring are thus found mostly in the hands. The upper limbs and trunk are less affected, and deep tissues more damaged than the superficial. The skin burns do not correlate with the level of internal injury. Burns occur at the skin, and arcing of the current may ignite clothing, causing further burns.
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Clinical features With high voltage, cardiac arrest occurs. Cardiac resuscitation is essential, as is a careful assessment for burns which may manifest themselves later. Arrhythmias may recur for up to 2 days after resuscitation. Intestinal perforation and liver and gallbladder injury may occur. There may be cerebral and spinal cord damage, and peripheral nerves may be permanently damaged. Spinal cord injury may have a delayed onset, with paraplegia or a tabes dorsalis-like syndrome. Acute muscle necrosis may result in renal failure.
Treatment After resuscitation the cardiac rhythm must be monitored for 2 days after the last rhythm disturbance. Hyperkalaemia may occur as a result of acute tissue necrosis, and may need immediate treatment with glucose and insulin or haemodialysis. Renal failure due to rhabdomyolysis must be treated. Intravenous fluids should be used to maintain urine flow, which will minimize the danger of renal failure due to massive myoglobinuria. Mannitol or a diuretic may be needed to maintain urine output. A surgical assessment must be made of burns and charring, and peripheral circulation. Debridement, fasciotomy and even amputation may be necessary. An extreme example of high-voltage injury is a lightning strike. Cardiopulmonary resuscitation is essential, as described above. Rhabdomyolysis and burns are treated in the same way as in other electric-shock injury. With effective resuscitation, over half the victims will survive.
SMOKE INHALATION
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Smoke inhalation causes anoxia, frequently exacerbated by carbon monoxide poisoning and, if plastics are burned, hydrogen cyanide poisoning. Lung and airway injury is mainly chemical rather than thermal. Initial effects are mainly on the airways, including laryngeal oedema and bronchoconstriction; severe pulmonary oedema can develop. Factors predictive of severe injury include fire in an enclosed space, black sputum, burns around the mouth, reduced consciousness, altered voice, and symptoms and signs of respiratory distress. In fires involving plastics, carboxyhaemoglobin levels generally reflect hydrogen cyanide levels. Carboxyhaemoglobin levels should be measured in all cases and levels greater than 10% indicate significant exposure; above 25% indicates severe exposure. High CO levels cause hypoxia; the true arterial oxygen saturation is not demonstrated by pulse oxymetry, and the %CO must be subtracted from the oxymeter reading to give the correct value. Treatment is supportive, including humidified oxygen, bronchodilators and mechanical ventilation in severe cases. Steroids are useful when airways obstruction is severe and persistent. Severe hydrogen
cyanide poisoning requires treatment with sodium nitrite and thiosulphate. In patients surviving smoke inhalation injury the long-term prognosis for pulmonary function is good.
PASSIVE SMOKING Breathing other people's cigarette smoke is a much less serious cause of morbidity and premature death than active smoking, but it does represent one of the most serious causes of indoor air pollution that can affect health. Respiratory symptoms such as wheezing, coughing and the development of respiratory infections are increased in the children of smoking parents. The effect is particularly noticeable in children aged under 1 year. Various international expert committees have concluded that exposure to environmental tobacco smoke increases the incidence of lung cancer in non-smokers, the observed risk being some 30% higher than expected and contributing approximately 300 cases of lung cancer annually in the UK. There is also evidence that environmental tobacco smoke can exacerbate asthma in adults.
CHEMICAL WARFARE Chemical weapons were first used on a large scale during the 1914-18 war, and although a wide range of chemicals were subsequently developed they were not used extensively until the Iran-Iraq war. Their use, but not their possession, is banned by an international treaty. The agents most readily available are nerve gases and mustard gas (see below). Other chemical agents include lewisite, hydrogen cyanide, and riot control agents such as CS gas, phosgene and chlorine. Biological weapons such as anthrax and Botulinus toxin are also potential weapons. When the use of these weapons is threatened, protection of those involved in, or close to, the conflict with respirators and protective clothing is important. Obviously, civilian populations are very vulnerable. Rescue of casualties by medical teams may expose these personnel to risk, so they should also take preventative measures. For all casualties of poisoning by chemical and similar weapons, decontamination is essential, particularly before they are transferred to areas where unprotected staff may be working. Mustard gas (sulphur mustard) is an alkylating agent (as is nitrogen mustard). It is a 'vesicant', causing skin blistering, sloughing of respiratory epithelium, ocular damage and, in a small number of cases, subsequent bone marrow depression. There is no antidote and the treatment is supportive, including careful management of the skin damage, which often takes many months to treat. Overall mortality of mustard gas exposure is only about 2%.
Nerve agents are organophosphorus compounds, closely related to insecticides. They inhibit the action of acetylcholinesterase, leading to parasympathetic overactivity and ultimately neuromuscular blockade. Clinical manifestations are meiosis, bronchoconstriction, hypersecretion and hypersalivation, rapidly progressing to general paralysis (including the respiratory muscles), convulsions and death. These events may occur in minutes, so rapid treatment is essential; this includes the use of atropine and oximes (which reactivate acetylcholinesterase). If there is a risk of nerve gases being used, pretreatment with pyridostigmine, which binds reversibly to acetylcholinesterase and thus 'protects' it from the effects of the nerve gas, is useful. Many armies now equip personnel with individual antidote packs for use in the field.
FURTHER READING
2
Howard J, Tyrer F H 1987 Textbook of occupational medicine. Churchill Livingstone, Edinburgh. A comprehensive and very readable textbook describing environmental and work hazards. Raffle P A B, Lee W R, McCallum R I, Murray R 1987 Hunter's diseases of occupations. Hodder and Stoughton, London. A traditional and comprehensive text covering the entire field of occupational medicine. Skinner D, Driscoll P Earlam R (ed) 1991 ABC of major trauma. BMV Books, London. A concise, practical account of important topics in major trauma. Ward M, Milledge J S, West J B 1994 High altitude medicine and physiology, 2nd edn. Chapman and Hall, London. An excellent book covering all medical aspects of high altitude medicine.
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3
link to form the backbone of each strand, and the bases on each strand face each other and pair by hydrogen bonding. The base pairing is specific: adenine always pairs with thymine and guanine with cytosine. The specific base pairing allows DNA molecules to be copied precisely when cells divide. A sequence of bases coding for a gene is usually divided into coding regions (exons) and non-coding regions (introns). DNA is transcribed by synthesizing a singlestrand ribonucleic acid (RNA) molecule, using one of the DNA strands as a template. The resultant messenger RNA (m-RNA) molecule is processed to splice out the noncoding regions and to modify each end, and then migrates into the cytoplasm, where it directs the synthesis of a specific protein by a process known as translation. This process involves the interaction of the m-RNA with both ribosomes in the cytoplasm and a series of molecules known as transfer RNA (t-RNA) (Fig. 3.2). t-RNA is a specialized molecule to which can be attached a specific amino acid. Each t-RNA carries a three-base coding region which pairs specifically with a corresponding sequence of three bases on the m-RNA. The sequence of three bases is known as a codon and is specific for each amino acid. The sequence of codons makes up the genetic code. There are also three codons which determine the end of a protein; these are known as stop codons. A gene may occupy a sequence of one to tens of kilobases (one kilobase = 1000 base pairs), depending on the length of the resultant protein and the number of introns in the gene. A chromosome consists of a continuous molecule of DNA coding for many thousands of genes. In a chromosome, DNA is intricately coiled and combined with proteins, including histones, which results in a compact structure that can be seen with a light microscope. Often, special stains are used which create a pattern of light and dark bands. These band patterns are specific for each chromosome, and reflect their macrostructure. Figure 3.3 demonstrates the relative size of a gene, in relation to a chromosome band and the chromosome itself.
TheGeneticBasis of Disease Robin M Winter
DMA, genes and chromosomes 57 Ways of looking at genes 58
Loci, alleles and segregation 63 Chromosomal disorders 65 Single gene disorders 69
Types of single gene mutation 60
Multifactorial disorders 72
Chromosome studies 61
Management of genetic disorders 74
Cell division 63
In the western world, chronic diseases with a substantial genetic component occur in 5-10% of the adult population. Furthermore, more than one in 50 babies has a recognizable congenital anomaly at birth, many of which will have a genetic cause. Genetic disorders and malformations account for around 30% of paediatric hospital admissions and up to 50% of deaths under the age of 15 years. The relative frequency of the different types of genetic disorders in the UK is shown in Figure 3.1. In certain populations, specific genetic disorders are of such high incidence as to represent significant public health problems, e.g. the thalassaemias in Mediterranean and oriental populations, and sickle cell anaemia and other haemoglobinopathies in Afro-Caribbean populations. The incidence of affected homozygotes with these disorders can be as high as one in 50 births in some areas.
DNA, GENES AND CHROMOSOMES The basic unit of inheritance is the gene. A gene is a length of deoxyribonucleic acid (DNA) that codes for a specific protein. The DNA molecule is a double helix, i.e. it is formed from two interwoven strands. Each strand consists of a chain of nucleotides, and each nucleotide is made up of a deoxyribose sugar and a nitrogenous base. There are four possible nitrogenous bases: adenine (A), thymine (T), guanine (G) and cytosine (C). The deoxyribose sugars
FIG. 3.1 The relative frequencies of different types of genetic disorder in the United Kingdom
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FIG. 3.2 DNA transcription and translation (After Emery A E H 1984 An introduction to recombinant DNA. John Wiley, London.) See text of details.
FIG. 3.3 The size of a gene relative to a chromosome and chromosome band, illustrated by the b-globin gene This is situated on chromosome 11 in band 11p15.5, which may contain around 4000kb. The gene itself is around 1600 base pairs long and is part of a cluster of similar genes, the (3-like globin gene cluster.
WAYS OF LOOKING AT GENES SOUTHERN BLOTTING There are three basic steps in the process of Southern blotting for the analysis of the sequences of DNA that make up genes (Fig. 3.4):
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1. Use of restriction enzymes. Restriction enzymes, which originate from bacteria, cut double-stranded DNA at
FIG. 3.4 DNA analysis S DNA is cut at specific points by restriction enzymes into different sized fragments. H These fragments are separated by electrophoresis on an agarose gel and blotted onto nitrocellulose paper (Southern blotting). Specific genes cannot be visualized at this stage, [c] A radioactive DNA probe is used to locate a specific gene. The position of the gene on the gel depends on the size of the DNA fragment in which it is contained.
specific base sequences. The distance between such restriction enzyme recognition sites may range from one to tens of kilobases, so that the genome is cut into fragments of differing sizes. 2. Electrophoresis and Southern blotting. Fragments generated using restriction enzymes can be separated by electrophoresis on an agarose gel. The fragments are then denatured (i.e. double-stranded DNA separates into single-stranded DNA) and a mirror image of the pattern of fragments is made on to nitrocellulose paper by a process known as Southern blotting. 3. Use of DNA probes. At this stage, single-stranded fragments of DNA have been separated according to size, and fixed on to the nitrocellulose filter paper. A gene probe must now be used to identify the individual gene sequences present in specific bands. A gene probe is a radioactively labelled single-stranded length of DNA whose sequence is specific for a particular gene, or length of chromosome. It is sometimes made using mRNA coding for a specific protein, by a process known as reverse transcription. The single stranded probe recognizes complementary sequences of DNA on the Southern blot, and anneals to them. Autoradiography can be used to locate the position of the gene probe, which will mark the position of all similar sequences on the Southern blot. If a gene-specific probe has been used, only a few bands will be seen on the autoradiograph, according to how many restriction enzyme recognition sites there are within the gene itself. Different
3
restriction enzymes will generate different patterns, using the same probe. The position of the various restriction enzyme cutting sites within the gene can be inferred, and a restriction map produced.
POLYMERASE CHAIN REACTION (PCR) The polymerase chain reaction (PCR) is a way of amplifying specific stretches of DNA so that further genetic analysis can be carried out on them. The revolutionary nature of the technique derives from the fact that large amounts of specific DNA sequence can be copied from only a few (or even a single) DNA molecules. At the start of the process the DNA double helix is denatured by heat to give two single strands. Two specific primers are then needed to amplify the specific sequence of interest. The primers are made up of single-stranded DNA with a specific complementary sequence to the sequences flanking the target DNA sequence (Fig. 3.5). DNA polymerase is then used to copy the target DNA, starting from the primer sequence on both of the original DNA strands. At the end of this process of DNA extension two double helices containing the target sequence will have been made. These double helices are then denatured and the process is repeated several times. At each step the number of copies of the target sequence doubles.
POLYMORPHIC MARKERS Restriction fragment length polymorphisms (RFLP) The restriction enzyme cutting sites in and around genes are variable, as a common, harmless base change may create or destroy a cutting site. Thus, in some individuals, different patterns may be seen on Southern blotting using the same restriction enzyme and the same gene probe. This is because the gene in question will be contained in fragments of different lengths according to the presence or absence of specific cutting sites. Such restriction fragment length polymorphisms (RFLPs) are extremely important because they act as genetic markers, allowing abnormal genes to be tracked through families (Fig. 3.6).
Short tandem repeat polymorphisms (STRPs) The first generation of DNA markers involved RFLPs in known genes or DNA sequences. Use of these markers required Southern blotting. More modern maps use short tandem repeat polymorphisms (STRPs), which are detectable by PCR. The genome contains many stretches of repeated di-, tri- or tetranucleotides of variable length. One of the commonest is the CA repeat. At a specific chromosomal location in an individual there may be (for
FIG. 3.5 Polymerase chain reaction
example) a (CA)10 repeat on one chromosome and a (CA)20 repeat on the other. This length difference can be detected and is the basis of a polymorphism that can be used for linkage studies. Tetranucleotide repeat sequences are easier to analyse and are the basis of the latest generation of genetic maps.
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TABLE 3.1 Molecular mechanisms of single gene mutation, illustrated by the haemoglobinopathies Abnormality of DNA
Effect
Example
Deletion of gene
Diminished or absent protein, depending on the number of genes involved
Most forms of a-thalassaemia
Point mutation (i.e. single base change)
Substitution of a single amino acid in the protein
Sickle cell anaemia, Hb E, C and many other examples Hb McKees Rocks, some forms of (3-thalassaemia Hb Constant Spring (a-chain)
Creation of a stop codon leading to a short protein chain Removal of a stop codon, leading to an elongated protein chain Alteration of splicing signal
FIG. 3.6 Restriction fragment length polymorphism (1) Shows the two alleles E and H of a gene at a specific locus. The alleles are represented by the coloured blocks on each of the two chromosomes. The arrows indicate restriction enzyme recognition sites. In allele A there is an extra site in the middle of the gene, so that when a DNA sample from this individual is cut with the restriction enzyme and a Southern blot made, three bands will be seen (2). The largest band represents allele B and the two smaller bands allele A. (3) Shows a pedigree where alleles A and B are being passed from generation to generation. Allele B causes an autosomal dominant disorder (e.g. neurofibromatosis) in this family so that the RFLP can be used to track the abnormal gene.
Some forms of a- and p-thalassaemia
Insertion or deletion of a number of nucleotides that are not a multiple of three
Frameshift mutation
Hb Cranston, Tak and Wayne Some forms of p-thalassaemia
Fusion of genes
Absence of normal product and presence of a new protein resulting from the fused genes
Lepore haemoglobins involving (3- and 8-globin chains ((3-thalassaemias)
TRINUCLEOTIDE REPEATS Single-nucleotide polymorphisms (SNPs) The most common type of polymorphism in the human genome is a single base pair change known as a singlenucleotide polymorphism (SNP). These SNPs can now be detected by oligonucleotide microarrays (so called 'gene chips'). This will allow for rapid typing of thousands of polymorphic changes in marker loci and known genes that might predispose to disease. A major project is under way to map thousands of SNPs throughout the human genome.
TYPES OF SINGLE GENE MUTATION
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At the molecular level there are many mechanisms that can give rise to a malfunctioning gene (Table 3.1). The haemoglobinopathies best illustrate the full range of molecular defects that can occur. A mechanism of mutation, only recognized in recent years, involves the expansion of trinucleotide repeats.
An unusual form of mutation consists of expansion of a CAG sequence within a gene, sometimes leading to a sequence of polyglutamine within the coded protein. This disrupts its function. Table 3.2 gives details of eight disorders caused by trinucleotide repeat mutations. For reasons unknown, they all involve abnormal neurological function. Trinucleotide repeat mutations often show the phenomenon of anticipation. This means that the severity of disease appears to increase as the gene is passed down the generations of a pedigree. The clearest example is in myotonic dystrophy, where a grandparent may just have cataracts without overt myotonia, a daughter may have the classic 'adult' form of the disease with myotonia, and her child may have the severe congenital form of the disorder with severe early hypotonia and mental retardation. The explanation for this is that the trinucleotide repeat expands (i.e. the number of repeat sequences increases) each time the gene is copied and passed on to the next generation. In fragile X syndrome premutation carriers can occur. These are males or females who have no clinical or cytogenetic abnormalities but who carry an increased number of trinucleotide repeats in the fragile X gene. When passed on by a female such a premutation can mutate to the full
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TABLE 3.2 Triplet repeat mutations and human disease Disease
Clinical features
Chromosome location
Huntington's chorea
Choreoathetosis, dementia
4p16
Spinocerebellar ataxia typel
Cerebellar ataxia
6p21
Friedreich's ataxia
Cerebellar ataxia
9q13-21
Machado-Joseph disease
Cerebellar ataxia, extra-pyramidal signs, ophthalmoplegia
14q32
Myotonic dystrophy
Myotonia, frontal balding, cataracts, diabetes, male infertility
19q13
Dentato-rubropallido luysian atrophy
• Chorea, seizures, dementia
12p12
Chromosome 1
Spinobulbar muscular atrophy (Kennedy's syndrome)
Muscular atrophy/fasciculation, gynaecomastia
Xq21
Fragile X mental retardation
Non-specific mental retardation, fragile X chromosome on cytogenetic examination
Xq28
References Mandel J-L 1993 Questions of expansion. Nature Genetics 4: 8-9 Richards R I, Sutherland G R 1992 Dynamic mutations: a new class of mutations causing human disease. Cell 70: 709-712
mutation (where the repeat is expanded) and a fully affected child can be born.
CHROMOSOME STUDIES Chromosomes are usually visualized during mitosis, at metaphase (p. 63). At this stage the DNA is coiled and condensed, and the chromosomes consist of two identical chromatids, joined together at the centromere (Fig. 3.7). The position of the centromere is specific for each chromosome. In some chromosomes (1-3) the centromere is close to the centre (metacentric); in others (13-15, 21-22) it is near one end (acrocentric), and in the remainder the centromere is somewhere in between these two extremes (submetacentric). By convention, all chromosomes are divided by the centromere into a short arm (p) and a long arm (q).
CHROMOSOME BANDING Like other cell structures, chromosomes must be stained in order to visualize them with the light microscope. Using various methods, a pattern of bands can be produced which
FIG. 3.7 Chromosome nomenclature, using chromosome 1 as an example
is specific for each chromosome. A number of staining techniques are commonly used: • G (Giemsa) banding is the most widely used technique. Light and dark bands are produced. • Q (quinacrine) banding requires a fluorescent microscope. The band patterns are similar to G-banding. Certain chromosome structures, e.g. the long arm of the Y, are particularly well stained. • R (reverse) banding produces a negative image of G-banding. • T (telomere) banding preferentially stains the telomeres (ends of the chromosomes). • C (centromere) banding stains centromeric regions.
Band nomenclature The banding pattern is specific for each chromosome, and a convention exists for labelling each band. The long and short arms are divided into regions by particularly prominent bands (landmark bands) (Fig. 3.7). Within each region, individual bands are numbered from the centromere distally, and landmark bands are included in the distal region they demarcate. Thus, in Figure 3.7 band Iq32 means band 2 in region 3 of the long arm (q) of chromosome 1.
FLUORESCENT IN SITU HYBRIDIZATION (FISH) Fluorescent in situ hybridization (FISH) is an important technique for recognizing very small deletions of chromo-
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Abnormalities in chromosome number The normal diploid number of chromosomes in humans is 46. Individuals with chromosome counts that are not multiples of the normal haploid number (23) are said to be aneuploid. A fetus can receive higher multiples of the haploid number of chromosomes to give 69 (x3) or 92 (x4) chromosomes. Such triploid or tetraploid fetuses usually miscarry early. If individuals carry one extra chromosome, they are said to be trisomic for the chromosome concerned. Very occasionally, an individual can have two extra chromosomes (double trisomy). Monosomy is the situation where one chromosome is missing. In liveborn children it is virtually only seen for the sex chromosomes, giving monosomy X (Turner's syndrome, p. 69).
Translocation, deletion and insertion
FIG. 3.8 Chromosome FISH in a patient with Williams' syndrome One probe (white arrows) identifies the two No 7 chromosomes. The other probe (elastin, black arrow) is missing from one chromosome 7 indicating a microdeletion.
some material. The technique involves preparing a DNA probe, specific for a particular gene or region of the chromosome. This probe is then labelled with a fluorescent tag. A chromosome slide is prepared and the probe is used to label the specific chromosomal region containing the gene under investigation. For a gene on the autosomes, two labelled tags should show up. If there is a deletion on one chromosome, then only one tag will be visible. FISH can detect chromosome deletions that are much smaller than those visible by conventional light microscopic techniques. Another technique involves chromosome painting. In this technique, probes derived from the whole length of a specific chromosome are labelled with a fluorescent dye (Fig. 3.8). If these probes are then used in the same way as the FISH technique, the whole chromosome is labelled with the fluorescent dye. By using different fluorescent dyes and computer image manipulation, each of the 24 chromosomes can be labelled in a different colour. Chromosome painting is useful for detecting subtle or complicated translocations of the chromosomes (see below).
TYPES OF CHROMOSOME ABNORMALITY
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Chromosome abnormalities can be divided into those involving the number of chromosomes, and those involving breakage or rearrangement.
Breakage of chromosomes can result in loss of material (deletion), exchange of material between two nonidentical chromosomes (reciprocal translocation), inversion of a segment of chromosome (pericentric inversions involve the centromere, paracentric inversions do not), and joining of the two ends of the same chromosome (to give a ring chromosome). Horizontal splitting of the centromere can result in a chromosome with identical long and short arms, an isochromosome. A translocation between the long arms of two acrocentric chromosomes, joined at the centromere, is known as a Robertsonian translocation. These possibilities are illustrated in Figure 3.9.
KARYOTYPE NOMENCLATURE The convention in karyotype nomenclature is to give the number of chromosomes first, followed by the types of sex chromosomes, followed by the types of any additional, missing or abnormal chromosomes. Thus, for example: • • • • •
46,XX - normal female 45,X - Turner's syndrome 47,XY + 21- male with trisomy 21 69,XXY - triploidy, XXY sex chromosome complement 45,X/46,XX - mosaic Turner's syndrome.
For inversions or translocations, the numbers of the chromosomes involved are given in brackets (the chromosome with the lowest number being given first). This is followed by the bands or regions involved in further brackets. Symbols are used to indicate the type of rearrangement involved. Thus, 46,XX,t(9:21) (qll :pll) karyotype means that chromosome 9 has broken at band qll and chromosome 21 has broken at band pll. The small letter t (for translocation) indicates that material has been exchanged between the two chromosomes.
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FIG. 3.9 Types of chromosome aberration ffl Two normal non-homologous chromosomes. DEI A reciprocal translocation between the two chromosomes. Note that material has been exchanged between the short arms. Q-] A pericentric inversion of the large chromosome. Breaks have occurred in the long and short arms and the middle segment of the chromosome has become inverted. [B] A deletion. The top part of the large chromosome has been lost. DEI An isochromosome. The small chromosome consists of two identical short arms due to misdivision after replication. DEI A ring chromosome. Both ends of the small chromosome have joined to form a ring.
CELL DIVISION MITOSIS Division of somatic cells is known as mitosis. This is divided into four stages (Fig. 3.10). Between cell divisions, in interphase, the chromosomes are extremely elongated and cannot be seen with the light microscope. 1. Prophase. As a preparation for cell division, the chromosomes replicate to give the classic structure with two chromatids, and they begin to condense. 2. Metaphase. The chromosomes line up at the centre of the cell. 3. Anaphase. Each chromosome separates longitudinally at the centromere, and the two chromatids pass to opposite poles of the cell. 4. Telophase. Two new daughter cells are created by the formation of a nuclear envelope around each new set of chromosomes.
FIG. 3.10 Mitosis and meiosis See text for details.
different gametes of an individual. This is brought about by two separate means: 1. Different gametes receive different combinations of maternally and paternally derived chromosomes. 2. There is an exchange of genetic material between the two members of an homologous pair of chromosomes, known as crossing over. This process results in the creation of a chromosome containing part of the maternal and part of the paternal member of an homologous pair, known as a recombinant chromosome. Without crossing over, alleles on the same chromosome would always be inherited en bloc. Crossing over takes place during the first step of meiosis (meiosis I), which is divided into prophase, metaphase, anaphase and telophase, as in mitosis. However, meiosis I differs in that homologous members of a pair of chromosomes line up and exchange genetic material during prophase, whereas at anaphase each member chromosome passes to an opposite pole without division at the centromere. Meiosis I is known as reduction division, because it results in the formation of two daughter cells containing 23 chromosomes, each of which has two chromatids that may not be identical because of crossing over. The second step, meiosis II, is similar to mitosis except that each 'parent' cell now has only 23 chromosomes (each with two chromatids), and each 'daughter' cell contains 23 chromatids at telophase. Fusion of parental gametes at fertilization restores the diploid number of chromosomes.
MEIOSIS During the production of gametes, the normal diploid complement of 46 chromosomes must be reduced to the haploid number of 23 in the gametes by the process known as meiosis. During meiosis there is the independent assortment of maternally and paternally derived genes in the
LOCI, ALLELES AND SEGREGATION The genes determining a particular trait are situated at identical points or loci on each member of a homologous pair of chromosomes. The two genes on each chromosome
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FIG. 3.11A Inheritance of alleles at autosomal loci
FIG. 3.12A Autosomal recessive inheritance with first cousin parents The boy at the bottom of the pedigree is homozygous for an abnormal gene inherited from the great-grandmother through both parents. The double line indicates consanguineous marriage.
FIG. 3.11B Inheritance of alleles at X-linked loci
at a particular locus may not be identical, and are known as alleles. If two alleles at a locus are identical, the individual is said to be homozygous at that locus; if the alleles are not identical, the individual is said to be heterozygous. The chance of a child inheriting one particular allele from a heterozygous parent is 1 in 2 (50%). For autosomal loci, if both parents are heterozygous, the chance of a child being homozygous for one particular allele is 1 in 4 (25%) (Fig. 3.11A). If a locus is on the X chromosomes, males can only carry one allele (because they only have one X chromosome). They are said to be hemizygous for a particular allele. All daughters of a male hemizygous for an abnormal gene will receive that gene; on the other hand, none of the sons will receive the abnormal gene (because a male must pass on a Y chromosome to his sons, and not an X). Each time a heterozygous female has a child, there is a 50% chance it will be a boy, and if it is a boy, a 50% chance that he will be affected. Likewise there is a 50% chance of a girl and a 50% chance she will be heterozygous (Fig. 3.11B).Q
O MCQ 3.1
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O MCQ 3.2
FIG. 3.126 Autosomal dominant inheritance Note that the disease is passed on from parent to child and that both males and females are affected. There is also transmission of the disease from father to son.
DOMINANT AND RECESSIVE INHERITANCE Disorders where it is only necessary to carry one abnormal allele in order for an individual to be affected are said to be dominant. In autosomal dominant disorders, the abnormal gene is carried on a non-sex chromosome; in X-linked disorders, the gene is carried on the X chromosome. In recessive inheritance an individual is only affected if he or she does not carry a normal allele at all. For autosomal recessive inheritance, affected individuals will be homozygous for the abnormal allele and both of the parents will be heterozygote carriers. In X-linked recessive disorders males hemizygous for the abnormal allele will be affected, whereas heterozygous females will be unaffected. Typical pedigree patterns are shown in Figures 3.12 and 3.13.2
RECENT ADVANCES THE HUMAN GENOME PROJECT
FIG. 3.13. X-linked recessive inheritance Note that half of the sons of a carrier female are affected and half of the daughters are carriers. All the daughters of an affected male are carriers and all the sons are normal, because a male passes on his one X chromosome to his daughters and his Y chromosome to his sons.
NEW MUTATION, PENETRANCE AND GENE EXPRESSION Abnormal alleles have to arise somewhere in a pedigree by the process of new mutation. Sometimes this can be inferred in a case where an affected individual for an autosomal dominant disorder has normal parents. However, many autosomal dominant disorders also display incomplete penetrance or reduced expression. This means the gene carriers sometimes show no signs, or only a few minor signs, of the condition. The two phenomena are therefore important in the context of genetic counselling. If a person has an autosomal dominant disorder but there is no family history, both parents must be examined very carefully in order to determine whether either of them carries the abnormal gene. If they do not, the chance of their having a further affected child will be small (as this would require a second, unconnected, new mutation). On the other hand, if one parent shows very minor signs of the condition the recurrence risk would be 50% for a further affected child.
GENE MAPS AND LINKAGE The presence of loci close to one another on chromosomes leads to the phenomenon of linkage. The closer together loci are on a chromosome, the lower the probability that a crossover will take place between them during meiosis. I, and the higher the probability that two alleles inherited from the parent will be passed on together to an offspring. Linkage between loci can be studied in suitable families by looking at the joint inheritance of specific traits, and an estimate can be made of the distance separating the loci. These family studies are informative for linkage but do not give information about the chromosomes on which the loci are situated. This problem is known as gene assignment and can be tackled by a number of different methods, such as somatic cell hybrids. Using these methods, a human gene map is being constructed giving information about the
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There are thought to be around 100000 genes in humans, and the total number of DNA bases in the haploid genome is around 3000000000 (3000 megabases). The ultimate goal of the human genome project is to locate every gene and to understand its function. It may not be absolutely necessary to sequence all of the 3000 megabases, as genes are known to be separated by large tracts of non-coding DNA sequences that may have no function. The first phase of the project was to create dense genetic maps of polymorphic genetic markers so that genetic diseases and traits can be located by linkage analysis. Markers are evenly spaced every megabase or so. At the same time the genome was broken up into overlapping DNA fragments (contigs) to provide a physical map. Gradually the genetic markers, known genes, and also parts of the coding sequences from expressed genes of unknown function (Expressed Sequence Tags - ESTs), are being located on contigs. This means that if researchers map a disease to a marker by linkage studies they are able to locate the marker on a physical fragment of DNA (the contig) and ask if any candidate genes are present on the same piece of DNA. If a suitable candidate is not found, the overlapping DNA fragments on either side can be examined and so on. The first draft of the entire sequence of the human genome was completed in the year 2000 and contains 90% of the entire sequence. The final sequence, with 99.99% accuracy, is expected to be completed by 2003, or perhaps earlier. The entire gene sequence of model organisms is also being examined. The fruitfly (Drosophila), an important organism in studying the mechanisms of embryonic development, has already been sequenced. Progress is being made in sequencing the genome of the mouse, which provides important models for many medical disorders. assignment of various loci and their distance from others on the same chromosome.
ICHROMOSOMALDISORDERS FREQUENCY OF CHROMOSOMAL DISORDERS About seven per 1000 babies are born with detectable chromosomal anomalies. Of these, three will have sex chromosome anomalies, 1.5 autosomal trisomies (mainly Down's syndrome) and the remaining 2.5 will have chromosomal rearrangements. Most of the latter are balanced, i.e. no genetic material is lost or gained. Of the autosomal trisomies, only trisomy 21 (Down's
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syndrome) cases are likely to survive into adulthood. The sex chromosome anomalies will frequently present with infertility or amenorrhoea. Unbalanced chromosomal rearrangements usually cause severe physical and mental handicap. However, balanced rearrangements have no effect on the carrier, although they predispose to recurrent miscarriage and children with unbalanced chromosome complements. An unbalanced karyotype means that there is duplication or deletion of some genetic material.O
TABLE 3.3 Chromosomal types of Down's syndrome Type of Down's syndrome
Chromosome complement
Comment
Standard trisomy 21
47,XX,+21 or 47,XY,+21
Approximately 95% of Down's syndrome children
Translocation Down's syndrome
e.g. 46,XY,-14,+t(14;21) 46,XX,-21,+t(21q;21q)
In about 2-3% of cases, an extra chromosome 21 is attached to another chromosome. It is essential to examine the chromosomes of the parents, as one may carry a balanced translocation
Mosaic Down's syndrome
e.g. 46,XX/47,XX,+21
Can be demonstrated in about 2-3% of cases
DOWN'S SYNDROME Between one in 700 and one in 1000 liveborn infants have Down's syndrome. The characteristic physical features are well described in paediatric texts and are present at birth, allowing immediate clinical diagnosis in most cases (Fig. 3.14). The head is foreshortened (brachycephaly) and there are usually three fontanelles. The eyes have an upward slant and crescents of skin are present covering the inner canthi (epicanthic folds). Brushfield spots are commonly seen. These are small white spots, situated around the outer third of the iris. The nasal bridge is flat and the tongue protuberant and deeply furrowed. A single transverse palmar crease is present on the hand, together with a short, incurved fifth finger (clinodactyly). A wide gap is present
between the first and second toes, often with a longitudinal plantar crease. Hypotonia and delayed development are universal. Congenital heart defects (particularly A-V canal defects) and duodenal atresia can occur. It is essential that the chromosomal type of a Down's syndrome child is obtained. There are three possibilities (Table 3.3): • In about 95% of cases there is an extra, free-lying chromosome 21. This form of Down's syndrome is associated with increased maternal age. The risk at a maternal age of 37 years is 1 in 250, at 40 years 1 in 100, and at 45 years 1 in 40. • In 2-3% of cases there is a chromosome translocation, usually involving Robertsonian translocation (p. 62). The parents of such individuals must be checked to see whether they carry a balanced translocation. • The remaining cases are mosaic. In these infants the degree of mental retardation can vary according to the proportion of abnormal cells. The recurrence risks for Down's syndrome are set out in Table 3.4.
TRISOMY 18 (EDWARDS' SYNDROME)
FIG. 3.14 Down's syndrome
1
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Case 3.1
This autosomal trisomy occurs in approximately one in 5000 live births. There is usually low birthweight, hypotonia, a prominent occiput, a small chin, a short sternum and characteristic hand and foot abnormalities. The index and little fingers of the hand overlap the middle two and the nails are small; in the feet the hallux is dorsiflexed and the lateral profile of the foot is convex, with a prominent heel (a so-called 'rocker-bottom foot', caused by a vertical talus). Analysis of the dermatoglyphic patterns of the digits reveals an increased number of arch patterns. Internal malformations are common, especially congenital heart defects (ventricular septal defects, patent ductus arteriosus) and renal abnormalities (horseshoe kidney,
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CASE STUDY 3.1 GENETIC COUNSELLING DOWN'S SYNDROME A couple is referred for genetic counselling because they have had a child with Down's syndrome. Question 1. What facts do you need to know before being able to provide accurate genetic counselling? It is crucial to know the age of the parents, particularly the mother. It would also be important to know whether there was any other family history of Down's syndrome. It is essential to know the precise karyotype of the baby. In this case, the karyotype was 46,XY,+t(14;21). This is a karyotype of a male with Down's syndrome, caused by a chromosome translocation of a chromosome 21 to a chromosome 14. Question 2. What further tests would you need to carry out before being able to counsel the parents?
Discussion Most cases of Down's syndrome have standard trisomy 21. In other words, there are 47 chromosomes, and the extra chromosome is a free-lying chromosome 21. The chances of having a baby with this form of Down's syndrome increases with the age of the mother. Recurrence risks after a baby with standard trisomy 21 are mainly related to the age of the mother, although they are slightly increased over the general population risk at any maternal age. Two to 3% of babies with Down's syndrome have a chromosome translocation. In this case it is essential to test the karyotype of the parents. In many cases both parents might have a normal karyotype, in which case the recurrence risk would be small. Nevertheless, one parent can carry a balanced chromosome translocation, as in the current case. Where the mother carries a balanced
14;21 chromosome translocation, the risks of a further baby with Down's syndrome are about 10%. In a future pregnancy an amniocentesis or chorionic villus sample (CVS) can be offered to check the chromosomes of the baby. Serum screening tests for Down's syndrome are not appropriate in this situation, as they do not provide a definitive answer as to whether the baby has Down's syndrome. The balanced translocation may also be carried by other family members. In this family, the wife's parents should be tested if possible, to see whether they carry the translocation. If one of them does, then testing should be offered to other family members, such as the wife's siblings. The other normal children of the present couple should be offered testing when they are of an age to give informed consent.
It is essential to examine the chromosome types of the parents, as one of them may be a translocation carrier. In this case, the mother had a 45,XX, +t(14;21) karyotype. This means that she was a balanced carrier for a 14;21 translocation (Case Fig. 3.1.1). Question 3. What risks would you give for a baby with Down's syndrome in a further pregnancy, and what tests could be carried out in a future pregnancy? 4. What further tests must be carried out?
CASE FIG. 3.1.1 A balanced 14;21 chromosome translocation (arrow) Note that there is only one chromosome number 21 and 45 chromosomes in all. Clinically this is a normal female.
hydronephrosis). Aplasia of the radius, facial clefts and exomphalos each occur in about 20% of cases. Prognosis is very poor, with 50% of cases dying before 2 months, 90% before 1 year and 99% before 10 years; long-term survivors are very severely retarded. Most cases are caused by an extra chromosome 18 (rather than a chromosome translo-
cation) and there is an association with increased maternal age. The risk of recurrence after a trisomic case is about 1 in 100 for a baby with a chromosomal trisomy (not necessarily trisomy 18); however, these risks might have to be modified for older mothers (see section on Down's syndrome).
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TABLE 3.4 Recurrence risks for Down's syndrome Risk to other relatives (excluding offspring of an affected patient)
Type of Down's syndrome
Risk to siblings of affected patient
Standard trisomy 21 Mother <40 years old
1%
Mother >40 years old
Maternal age risk
Translocation (Parents have normal chromosomes)
Maternal age risk
Maternal age risk
10%
Depends on chromosomes of relative Depends on chromosomes of relative Depends on chromosomes of relative
Translocation (One parent carries the translocated chromosome) Mother carries 14:21 translocation Father carries 14:21 translocation Either parent 21:21 translocation
2% 100%
1%
Mosaic
Probably similar to maternal age risk
Maternal age risk
TRISOMY 13 (PATAU'S SYNDROME) This occurs in about one in 8000 live births. There are significant craniofacial abnormalities, with punched-out scalp lesions (aplasia cutis), microphthalmia, and low-set, malformed ears. Many cases have severe bilateral cleft lip and palate and some cases have hypotelorism or cyclopia (a single central eye with a proboscis-like nose), indicating underlying holoprosencephaly of the brain (failure of midline separation of the cerebral hemispheres). In the hands and feet an extra, hypoplastic digit on the ulnar or fibular side is common (postaxial polydactyly). Brain, heart and kidney malformations are very common. Survival past the first year of life is very unusual and retardation is severe. Most cases arise by standard trisomy, but some are the result of a Robertsonian translocation involving chromosome 13. The risk of recurrence after a trisomic case is about 1 in 100 for a baby with a chromosomal trisomy (not necessarily trisomy 13); however, these risks might have to be modified for older mothers (see section on Down's syndrome).
1
68
MCQ 3.3
FIG. 3.15 Turner's syndrome (45,X) Characteristic fades, webbing of the neck, absent breast development and widely spaced nipples.
SEX CHROMOSOME ABNORMALITIES Klinefelter's syndrome Klinefelter's syndrome (47,XXY) occurs in about one in 1000 males. Adult individuals tend to have eunuchoid proportions with female fat distribution and gynaecomastia. The testes are small. Pituitary gonadotrophins are raised and androgen production is low. Affected individuals are sterile, as they produce no sperm. Androgen therapy may help to improve libido and encourage the development of male secondary sexual characteristics. Intelligence is usually normal, although mild to moderate retardation may be seen.
XYY males About one in 1500 males is XYY. Such individuals are physically normal, although they tend to be tall. Although an increased tendency to psychopathic behaviour has been reported, prospective studies have shown that the majority of affected individuals lead normal lives.
Turner's syndrome The incidence of Turner's syndrome (45,X) is one in 5000
births. Affected individuals are short, tend to have a web of skin on the lateral borders of the neck (Fig. 3.15), and may have other physical abnormalities, such as a broad chest with widely spaced nipples and an increased carrying angle at the elbows. Coarctation of the aorta can occur. The vagina and internal genitalia are normally formed, but the ovaries consist of simple streaks of fibrous tissue without ovarian follicles, so that primary amenorrhoea is the rule. Treatment consists of oestrogen replacement around puberty to promote the development of secondary sexual characteristics.
cific oncogenes (see p. 149). In other cases the precise nature of the genetic change is not known. Occasionally, an individual with a specific chromosome abnormality will be predisposed to develop particular types of cancer (see Table 6.3, p. 150). A group of single gene disorders exists that result in an increased tendency to chromosome breakage, owing to abnormalities of DNA repair after damage by agents such as ultraviolet light and radiation. These disorders, most of which are autosomal recessive, also predispose to malignancies (see Table 6.3, p. 150).
3
47,XXX females Females with a chromosome constitution 47,XXX have no physical abnormalities. However, primary and secondary amenorrhoea may occur, and average IQ is 20-30 points lower than in XX females, so that learning difficulties are more common than in the general population. Nevertheless, the majority of affected females (about 70-80%) have normal intelligence. 1
CHROMOSOME DELETIONS AND DUPLICATIONS A large proportion of individuals with chromosome abnormalities have the normal number of chromosomes but a small piece of a specific chromosome is missing or duplicated. Sometimes there may be a combination of a chromosome deletion and duplication. Any part of any chromosome can be involved. Significant chromosome deletion or duplication usually causes a combination of congenital malformations, with developmental delay. It is often difficult to predict the precise clinical picture from knowing the specific chromosome deletion or duplication, but there are a number of specific syndromes caused by particular chromosomal regions being affected. Microdeletion syndromes are also being recognized, where the deleted chromosome material must be detected by FISH (see above, page 61). Any child with a combination of malformations, or an unusual facial appearance, together with developmental delay, should have his or her chromosomes examined.
CHROMOSOME ABERRATIONS AND CANCER Cytogenetic analysis of any malignant cell will frequently reveal a non-specific chromosome abnormality. However, there are certain malignancies where a characteristic abnormality is found; in others, the development of a specific chromosome change can be of prognostic significance. In the case of Burkitt's lymphoma and chronic myeloid leukaemia, the chromosome translocations are known to bring together the loci for immunoglobulin genes and spe-
SINGLE GENE DISORDERS Sir Archibald Garrod first put forward the concept of an 'inborn error of metabolism' in 1908 after studying alkaptonuria, a familial disorder in which patients excrete large amounts of homogentisic acid. This led to the concept that an enzyme controlling a metabolic step can be missing or reduced, leading to failure of production of essential metabolites further down the metabolic chain (e.g. in albinism), or the accumulation of toxic substrates of the enzyme (e.g. in alkaptonuria and phenylketonuria) (Fig. 3.16). Today, McKusick's catalogue of genetic disorders lists over 4000 defects involving every organ system. Only a few important groups of disorders are described here.
AMINOACIDOPATHIES Defects in the metabolism of amino acids include a form of congenital hypothyroidism, albinism, disorders of the urea cycle and organic acid metabolism, as well as the disorders described below.
Phenylketonuria Phenylketonuria is an autosomal recessive disorder affecting about one in 10000 infants at birth. It is usually caused by a defect of the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. The most common clinical presentation, now rarely seen in developed countries because of screening, is vomiting in early infancy, with eczema, depigmentation of skin and hair, hypertonia, seizures, and mental retardation developing during the first years of life. Fortunately, screening at birth is now widely available, in which a drop of blood, obtained within the first few days of life, is placed on a filter paper and a bacterial inhibition assay used to measure phenylalanine levels (the Guthrie test}. Affected infants can be treated by giving an artificial diet low in phenylalanine until at least 8 years of age. If dietary control is strict the prognosis for mental development is good. Females with phenylketonuria run a very high risk of having abnormal children, unless a strict diet is reintro-
69
FIG. 3.16 Partial metabolic pathway of phenylalanine, tyrosine and related compounds showing position of 'metabolic blocks' caused by enzyme deficiencies DO Deficiency of phenylalanine hydroxylase results in an inability to metabolize phenylalanine, leading to phenylketonuria. E Tyrosinase deficiency leads to an inability to produce melanin, thus causing albinism. [3 Deficiency of homogentisic acid oxidase leads to the accumulation of homogentisic acid, and hence to alkaptonuria. OS Deficiency of any one of several enzymes at this point means that thyroxine cannot be synthesized. The result is familial hypothyroidism.
TABLE 3.5 transport disorders Disorder
Site
Metabolites affected
Clinical features
Inheritance
Intestinal disaccharidase deficiency Hypophosphataemic rickets
Small intestine
Maltose, sucrose, lactose
Autosomal recessive
Renal tubules
Phosphates
Abdominal pain and distension, diarrhoea Rickets (vitamin D-resistant)
Hartnup disease
Renal tubules
Amino acids (mono-aminomonocarboxylic group)
Red, scaly facial rash, ataxia
Autosomal recessive
Cystinuria
Renal tubules, small intestine
Cystine, ornithine, arginine, lysine
Renal stones
Autosomal recessive
Nephrogenic diabetes insipidus
Renal tubules
Insensitivity to ADH
Polyuria, polydipsia
X-linked dominant
duced throughout pregnancy. Their children do not have phenylketonuria themselves, but the abnormal metabolites cross the placenta during pregnancy and affect the developing fetus. Microcephaly, cardiac defects and mental retardation are common. Phenylketonuria is a heterogeneous disorder: the most common form results from a mutation at the phenylalanine hydroxylase locus itself. However, a rarer form caused by a defect in dihydropteridine reductase has been described. This enzyme is essential for the recycling of the cofactor tetrahydrobiopterine.
Homocystinuria Homocystinuria is an autosomal recessive disorder and affects one in 200000 infants. It is due to a defect of cystathionine (3-synthase and leads to the accumulation of homocysteine, methionine and other metabolites. Clinical 1 70
MCQ 3.4
X-linked dominant
manifestations include lens dislocation, mental retardation, osteoporosis, and thrombosis of arteries and veins. Affected individuals tend to be long and thin, making Marfan's syndrome part of the differential diagnosis. Treatment involves a low-methionine diet, and pyridoxine treatment in that proportion of patients who are vitamin B6 responsive.
Cystinosis Cystinosis, an autosomal recessive disorder, should be distinguished from cystinuria (see Table 3.5). There are abnormally high intracellular levels of free cystine, which lead to crystal deposition in the kidneys, conjunctiva, bones and leukocytes. Presentation is in childhood, with photophobia and crystalline deposits in the conjunctiva, and the effects of renal tubular malabsorption (Fanconi's syndrome). Renal failure can occur before the age of 10 years. Alkaptonuria Alkaptonuria is a rare autosomal recessive disorder caused by a defect in the enzyme homogentisic acid oxidase
(Fig. 3.16). Homogentisic acid, a byproduct of the metabolism of tyrosine and phenylalanine, cannot be metabolized and so accumulates in the body tissues and is excreted in increased quantities in the urine. Classically, the urine turns dark on standing and the sweat may be black, but these findings are not invariable. The homogentisic acid and resultant polymers also stain cartilage and other connective tissue; ochronosis is the name given to the generalized blue/grey pigmentation that results and is best seen in the cartilage of the ear and the sclerae. It can also be seen in the tendons of the hands, through the overlying skin, in older patients. The main clinical problem is arthritis, which affects the hips, knees, shoulders and spine. Onset is unusual before middle age. Radiological changes include narrowing and calcification of the intervertebral discs, together with some fusion of the vertebral bodies. Rarer complications include an increased incidence of ischaemic heart disease, calcification of the cardiac valves, and occasionally arterial aneurysms. Treatment is symptomatic.1
TABLE 3.6 Storage disorders Example
Symptoms
Glycogen storage disorders
12 types including: Von Gierke's disease (glucose-6-phosphate deficiency) Pompe disease (acid maltase deficiency)
Hepatomegaly, hypoglycaemia, muscle weakness, cardiac failure (Symptoms vary according to type)
Niemann-Pick disease Gaucher's disease Krabbe's disease Metachromatic leucodystrophy
Hepatosplenomegaly (in some), progressive neurological deterioration
Tay-Sachs disease
Progressive blindness and neurological deterioration
At least 8 types including: Hurler syndrome, Hunter syndrome, MaroteauxLamy syndrome, Morquio's syndrome, Sanfilippo's syndrome
Hepatosplenomegaly, abnormal bones (dysostosis multiplex), corneal clouding, mental deterioration
Sphingolipidoses (p. 1413)
Gangliosidoses (p. 1413)
Mucopolysaccharidoses (p. 1029)
3
The transport of metabolites across cell membranes often involves specific binding sites and transport proteins. Mutations can disrupt these mechanisms and result in a group of disorders characterized by the failure of essential metabolites to enter the appropriate body compartments. Some important disorders are outlined in Table 3.5.
STORAGE DISORDERS Macromolecules in the body are often in a perpetual state of accumulation and breakdown. Thus, if an enzyme needed to break down a macromolecule is deficient, increased accumulation occurs, leading to a variety of symptoms according to the type of molecule and the site involved. Storage material usually accumulates in the lysosomes. Several examples are given in Table 3.6.
CONNECTIVE TISSUE DISORDERS
Type
(p. 1028)
TRANSPORT DISORDERS
TABLE 3.7 Types of collagen and their functions
The main protein of connective tissue is collagen, of which there are at least four different types, each with its own functions (Table 3.7). Defects of collagen synthesis can cause a wide variety of disorders (Table 3.8). Some of these have been characterized at the molecular level, and various collagen probes are available for precise diagnosis. The specific collagen chain abnormality can sometimes be deduced from the clinical features (Table 3.8). Thus, some forms of osteogenesis imperfecta are caused by abnormalities of type I collagen, whereas type III collagen deficiency can result in a form of Ehlers-Danlos syndrome, with thin, atrophic skin and a tendency to spontaneous rupture of
TABLE 3.8 Connective tissue disorders Disorder
Clinical features
Ehlers-Danlos syndrome (At least 8 distinct forms)
Hyperextensible skin, loose joints, 'cigarette paper' scars, easy bruising, rupture of blood vessels, viscera etc.
Osteogenesis imperfecta (At least 4 distinct forms)
Multiple fractures of bones, blue sclerae, hyperextensible skin, easy bruising
Cutis laxa
Loose skin, premature aged appearance, hernias, diverticula and emphysema
(Several different forms)
Type
Function
Marfan's syndrome
I II III IV
Major collagen in skin, tendon, bones, heart valves and scar tissue Major collagen in cartilage Found mainly in blood vessels and intestine; also in skin Found mainly in basement membranes
Tall stature, span greater than height, loose joints, dislocated lens of eyes, aortic and mitral incompetence, dissection and aneurysms of the aorta
Pseudoxanthoma elasticum
Angioid streaks of retina, linear yellow raised skin lesions, vascular disease
71
CASE STUDY 3.2 LENS DISLOCATION IN A TALL BOY A 14-year-old boy was referred to the genetic clinic because dislocation of the lenses of both eyes had been diagnosed after an episode of blurred vision. He was also noted to be tall.
Marfan's syndrome. Other physical features of Marfan's syndrome are a high-arched palate, pectus excavatum 1 or carinatum, arachnodactyly (long thin fingers) 2, 3 skin striae (stretch marks), particularly over the shoulders, loins and buttocks, and loose joints. In Marfan's syndrome the lens of the eye classically dislocates upwards, whereas in homocystinuria it dislocates downwards. An echocardiogram should be carried out to look for mitral or aortic valve incompetence and dilation of the aortic root, which precedes a possible dissecting aneurysm of the aorta. Urine should be sent to look for homocystine, although a methionine loading test might be necessary where the diagnosis of homocystinuria seems likely. In the present case, span was 2 cm longer than height, which was on the 98th centile. There was a high-arched palate and significant arachnodactyly. The heart was normal. The patient's father was said to have been tall and had died suddenly at the age of 42 from a ruptured aortic aneurysm. There was no evidence of homocystine in the urine. The diagnosis of Marfan's syndrome
Questions ' What is the differential diagnosis?
What would you ask about inthe family history? What investigation would you carryout? Dislocation of the lenses associated with tall stature suggests a connective tissue disorder. The differential diagnosis lies between Marfan's syndrome and homocystinuria. In the family history, one would ask about tall stature in other family members, and heart defects or sudden death caused by ruptured aneurysms or other vascular problems. The latter would suggest Marfan's syndrome. One would also ask about parental consanguinity, which might suggest the recessive disorder of homocystinuria. In the clinical examination one would measure both height and span. A stature above the 90th centile with span greater than height suggests
blood vessels and other internal organs. Defects of the connective tissue protein elastin are thought to cause the different forms of cutis laxa. Both collagen and elastin are abnormal in pseudoxanthoma elasticum (Ch. 12, Table 12.39). Marfan's syndrome has been shown to be caused by a defect in fibrillin protein.
MULTIFACTORIAL DISORDERS Many common malformations, some diseases and many normal traits are said to have a multifactorial origin, in that both genetic and environmental factors contribute to their O Fig. 3.1 0 Fig. 3.2 3
72
Q Case 3.2 0 Fig. 3.4 6
Fig. 3.3 Fig. 3.5
therefore seemed very likely (De Paepe et al, 1996). Discussion Marfan's syndrome is an autosomal dominant condition caused by mutations in the fibrillin gene on chromosome 15. The gene can be examined to look for mutations in suspected cases, but this is technically difficult because of the size of the gene, and in many cases diagnosis relies on clinical findings. Apart from dislocation of the lens, other clinical complications include joint laxity and associated scoliosis, in addition to mitral and aortic valve incompetence and aortic root dilation leading to aneurysms. Prophylactic p-blocker therapy can be given to alleviate the risk of aneurysms. Regular follow-up is needed for cardiac, orthopaedic and ophthalmological problems. Affected individuals have a 50% chance of having similarly affected children.
Reference De Paepe A, Devereux RB, Dietz HC, Hennekam RCM, Reed E (1996) Revised diagnostic criteria for Marfan syndrome. Am J Med Genet 62: 417-426.
aetiology. Furthermore, the genetic component is thought to be due to several genes acting together - so-called polygenie inheritance. A good example is the inheritance of height. The genetic component is determined by several genes, and final height correlates between parents and children. Nevertheless, environmental factors (such as nutrition) can play an important role. The contribution of the many factors involved results in a gaussian (normal) distribution of height in the general population.
COMMON MALFORMATIONS There are many clues which suggest that a common malformation has a multifactorial origin: • After one affected family member, the risk to other firstdegree relatives is usually in the range 1-5%, depending on the condition.
TABLE 3.10 Some common disorders of multifactorial origin, with possible geneti c markers
TABLE 3.9 Recurrence risk (%) in some common multifactorial malformations Normal parent
Condition
Affected parent Risk of second Risk of third Risk of affected child affected child affected child
Cleft palate alone 2 Cleft lip ± cleft palate 4 Neural tube defect 4 Club foot 3 Dislocation of hip 6 Congenital heart disease 1-4 (varies with type) Hirschsprung's disease (long segment): Male index case 8 14 Female index case Pyloric stenosis: Male index case 3 7 Female index case
8
7
10 10 10 10
4 4 3 12
5-10
1-10
-
-
_
4 13
• The presence of additional affected family members increases the risk to subsequent offspring. • Where a condition can have varying degrees of severity (e.g. cleft lip, with or without cleft palate), risks are higher for relatives of an individual with a more severe malformation. • If there is a sex difference in incidence, risks are greater for relatives of an affected individual of the less commonly affected sex. • The risk declines rapidly as one passes from first- to second-degree relatives. It is thought that everyone inherits a liability to a particular malformation. The degree of liability can vary in different individuals and families, according to the number of adverse genes and environmental factors present. If the liability exceeds a given threshold, the malformation is manifested. Individuals from families where there is more than one affected member will, on average, have a higher liability, as will relatives of more severely affected individuals. Similarly, where a condition is less common in a particular sex, affected persons of that sex must carry a greater liability, as will their relatives. Some common multifactorial malformations with their recurrence risks are given in Table 3.9.O0O
COMMON DISEASES, GENETIC MARKERS AND DISEASE ASSOCIATION Many common diseases, e.g. the common allergies and some forms of epilepsy, have been proposed as candidates for multifactorial inheritance. As more research is carried out into these conditions, heterogeneity is recognized and subtypes are defined. Subdivision is aided by the identifi-
Disorder
Marker
Insulin-dependent diabetes mellitus
HLA haplotypes, e.g, B8, B15, DW3, DW4
Coeliac disease Ankylosing spondylitis Belter's disease Anterior uveitis Peptic ulceration Alzheimer disease
HLA-A1-B8-DW3
3
HLA-B27
Blood group 0 APoE
cation of genetic markers, which may indicate that a major contribution to the disorder is being made by a gene on a specific chromosome. These genetic markers are particular blood groups, tissue types or restriction fragment length polymorphisms (RFLPs) at specific gene loci which are found to occur more commonly in individuals with the disorder (Table 3.10). A good example of the complex interaction between environmental factors and genetic loci is provided by the various possible causes of atheroma. A proportion of patients with early-onset atherosclerosis show abnormalities of lipoproteins or lipoprotein receptors which are determined by various gene loci. In some patients a single gene defect (e.g. of the cell membrane low-density lipoprotein receptors) can strongly predispose to atheroma. In the majority of cases, however, factors such as diet, smoking and high blood pressure may play the predominant role, with minor abnormalities of the lipoproteins merely providing an extra predisposition. The genes that predispose to common disorders are now being sought using genetic linkage techniques.
Linkage disequilibrium and pleiotropy There are two possible explanations for the association of a genetic marker and a specific disease: linkage disequilibrium and pleiotropy. Linkage disequilibrium If a genetic marker (e.g. an SNP, p. 60) is extremely closely linked to a disease locus, specific marker alleles may not be separated from the disease allele by recombination over the generations and an association will be observed in random individuals. This is known as linkage disequilibrium. It should be noted that linkage disequilibrium is a special case, observed only with very close linkage. In most cases of linkage, recombination over many generations will mean that a particular marker allele will not necessarily be associated with the disease in individuals picked at random. Pleiotropy The allele at the marker locus itself may predispose an individual to develop the disease, owing to some function
73
RECENT ADVANCES IN GENE THERAPY Gene therapy, defined as the replacement of a defective gene product, has been carried out for many years, for example in the treatment of haemophilia A and insulindependent diabetes (see Table 3.12). However, recent attempts at gene therapy have involved replacing a defective gene itself, so that it functions in situ to produce the appropriate protein. This approach involves targeting normal genes to a specific tissue so that they are integrated into the genome and function under appropriate regulatory control. At present the accessibility of the affected organ or organs limits the feasibility of this form of therapy to a few diseases only. Genetic disorders affecting the bone marrow are obvious candidates because marrow can be removed and cultured and manipulated in the laboratory before being retransplanted; immunodeficiency diseases and haemoglobinopathies are therefore among the first disorders where attempts at gene therapy have been made. Other organ systems where gene therapy is being tried include the liver and the lungs. Gene therapy for neurological disorders and muscular dystrophies will be more difficult, but is being explored.
of the gene. Some of the disorders associated with specific HLA types may be examples of a pleiotropic effect. For example, a specific HLA type may predispose to infection with specific viruses, leading to some forms of insulindependent diabetes mellitus.
EEIS2 =E :ZZL IE :Z :y 32 SS22 =23 SCREENING
The treatment of many genetic disorders is often most successful if the disorder is diagnosed at an early, presymptomatic stage. In addition, the prevention of genetic disease by genetic counselling and prenatal diagnosis requires the identification of asymptomatic gene carriers. For these reasons, genetic screening programmes have been developed. Depending on the nature and frequency of the condition, screening can involve the entire population, subgroups of the population (for example particular ethnic groups), or specific families in which a genetic disorder is known to be segregating (Table 3.11).
O MCQ 3.5
74
2
Case 3.3
In order to introduce normal genes into the appropriate cells a vector must be used. Vector systems that are being tried include inactivated retroviruses, adenoviruses and liposomes (lipid vesicles containing the appropriate DNA that fuse with the host cell membrane). The Table below summarizes some of the disorders where gene therapy is being attempted. Diseases where gene therapy has been attempted or considered Genetic disorder
Target organ
Adenosine deaminase deficiency (immunodeficiency) Thalassaemia/sickle cell disease Hypercholesterolaemia Phenylketonuria Haemophilia A Cystic fibrosis Duchenne muscular dystrophy
Bone marrow Bone marrow Liver Liver Liver Lung Muscle
TREATMENT OF GENETIC DISORDERS It is still technically difficult to replace missing or defective genes; although it may be possible to isolate and replicate a gene in the laboratory, it is much more difficult to ensure that a replacement gene reaches the correct tissue, and is properly regulated. Efforts are now being made to introduce normal genes into cells to correct genetic defects (see Recent Advances box). There are also a number of treatment strategies for genetic disorders which aim to ameliorate the phenotypic effects. Many common malformations of multifactorial or chromosomal origin can be corrected surgically, and a variety of treatments have been devised for single gene disorders (Table 3.12).
GENETIC COUNSELLING Most doctors will be faced at some stage with questions about the risk of a genetic disorder in patients or their families. Straightforward situations, such as Down syndrome or neural tube defect, can be dealt with by the nonspecialist but complex problems, involving the diagnosis of rare disorders or the use of carrier detection tests and linkage studies, require a specialist opinion.O Whatever the problem, there are a number of essential steps in genetic counselling: 1. Detailed family history. A pedigree of at least three gen-
TABLE 3,11 Screening for genetic disorders Disease
Group screened
Method
Purpose
Phenylketonuria
Total population of neonates
Guthrie test
Early dietary treatment of affected homozygotes
Hypothyroidism
Total population of neonates
TSH levels from dried blood spot
Early thyroxine therapy
Cystic fibrosis
Individuals of reproductive age
Direct DMA analysis of gene mutations
Prenatal diagnosis where both parents are carriers
Sickle cell anaemia and other haemoglobinopathies
Offspring of heterozygote mothers (total population of neonates in some regions)
Haemoglobin electrophoresis
Prophylaxis and early treatment of complications Prevention by counselling and prenatal diagnosis
Tay-Sachs disease
Individuals of Ashkenazi Jewish extraction
Carrier detection by serum enzyme analysis
Prenatal diagnosis where both parents are heterozygous
Adult-onset polycystic renal disease
Relatives of affected individuals
Renal ultrasound, blood pressure, gene tracking in families using DNA probes
Early treatment of hypertension and renal failure
Multiple endocrine adenomatosis
Relatives of affected individuals
Calcitonin, urinary VMA, gene tracking in families using DNA probes
Early treatment of endocrine tumours
Familial polyposis coli
Relatives of affected individuals
Sigmoidoscopy, gene tracking in families using DNA probes, ophthalmoscopy for associated retinal lesions
Identification of gene carriers, early treatment of malignancy
Familial breast cancer
Females in families with multiple affected members
Mutation analysis of BRCA1 and BRCA2 genes
Identification of gene carriers. Prophylactic mastectomy or medical treatment
erations should be taken and details of racial background and consanguinity (i.e. whether parents have common ancestors) obtained. 2. Accurate diagnosis in affected family members. An accurate diagnosis in affected family members must be made. This should include both a pathological diagnosis (established where possible from original notes and investigations) and an assessment of any genetic subgroup of the disorder. 3. Ancillary tests. Chromosome analysis, DNA marker studies or other carrier detection tests may need to be carried out, according to the nature of the problem. 4. Risk assessment. For single gene disorders risk assessment is sometimes straightforward, providing a correct diagnosis is available. For instance, the recurrence of risk for a couple who have had one child with phenylketonuria is 1 in 4, because phenylketonuria is autosomal recessive. Difficulties arise where a disorder has different inheritance types (e.g. retinitis pigmentosa) and with X-linked disorders, where carrier detection tests may need to be applied, new mutations have to be considered and risks must be modified to allow for normal sons in the pedigree. In addition, disorders with a late age of onset (such as Huntington's chorea) or of variable expression (such as tuberous sclerosis) can present problems that may require a specialist opinion. Where linked DNA probes are used, risk assessment can become complex. If a condition is caused by a chromosomal abnormality or is multi-
factorial, empirical risks derived from follow-up studies must be used. 5. Prenatal diagnosis. The availability of prenatal diagnostic tests (Table 3.13) has to be assessed and any possible risks to the mother or fetus weighed against the risk of fetal abnormality.© 6. Communicating risks. Having marshalled all the facts, sufficient time must be set aside to discuss the risks in detail with the patient. A non-directive approach should be taken, whereby objective risks are given and discussed in detail, in the light of the severity of the condition and the availability and reliability of prenatal diagnosis. These factors may be crucial in the final decision of the parents. It is best to give the risks as a proportion (i.e. 1 in 2, 1 in 100 etc.) and to emphasize that a 1 in 20 risk of a child being affected means that 19 times out of 20 the child will not be affected. In order to put the risks into perspective, it is also worth pointing out that over 1 in 50 children are born with significant abnormalities at birth. In comparison to these background risks, a genetic risk of 1 in 20 is generally regarded as low, and those of greater than 1 in 10 as relatively high. However, the perception of an 'unacceptable' risk will depend on a large number of factors. The severity of the condition and the availability of treatment will obviously affect the willingness of a couple to have further children. For example, a 1 in 20 risk of a child with isolated cleft lip and palate will often be seen as acceptable, whereas the
3
75
TABLE 3.12 Therapy for single gene disorders*
TABLE 3.13 Techniques of prenatal diagnosis
Treatment
Procedure
Timing
Types of disorder detected
Villus biopsy
Transcervical 9-11 weeks Transabdominal 12-1 6 weeks
Cytogenetic abnormalities Enzyme defects Single gene defects (DNA probes)
Maternal ct-fetoprotein
16-1 9 weeks
a-fetoprotein Raised: neural tube defects Lowered: Down's syndrome Lowered: Edwards' syndrome (N.B. These are screening tests; diagnosis must be confirmed by further investigation)
Amniocentesis
16-20 weeks
Cytogenetic abnormalities Enzyme defects Neural tube defects Single gene defects (DNA probes)
Ultrasound
From 16 weeks
Anatomical defects Neural tube/hydrocephalus Body wall defects Limb reduction defects Hydrops Major urinary anomaly Bone dysplasias Cardiac defects Craniofacial anomalies
Fetoscopy/ cordocentesis
16-20 weeks
Fetal blood sample Clotting disorders Haemoglobinopathies Cytogenetic abnormalities Fetal skin biopsy Epidermolysis bullosa Ichthyosis Albinism Fetal liver biopsy Urea cycle enzyme defects Fetal visualization Craniofacial defects Digital defects Genital defects
Replacement therapy Replacement of deficient protein Replacement of deficient vitamin or coenzyme: Vitamin B12 Vitamin D Biotin Replacement of deficient metabolite: Cortisone Thyroxine Organ or cell replacement Kidney Bone marrow Blood transfusion Amelioration therapy Restriction of substrates in diet: Phenylalanine Methionine Galactose Drug therapy to remove harmful metabolites: Penicillamine Cholestyramine Iron chelating agents Avoidance of harmful drugs or dietary factors Preventive therapy Removal of potentially malignant tissues Removal of site of destruction of diseased cells (e.g. spleen)
Disorder
Haemophilias Diabetes
Methylmalonicacidaemia (some types) Vitamin D-resistant rickets Biotinidase deficiency Adrenogenital syndrome Congenital hypothyroidism Polycystic renal disease Immunodeficiencies Osteoporosis Thalassaemias
Phenylketonuria Homocystinuria Galactosaemia Wilson's disease Hypercholesterolaemia Thalassaemias G6PD deficiency Porphyria
Polyposis coli Spherocytosis
* After Emery & Malcolm (1995)
same risk for a child with severe, untreatable mental retardation may seem too high. 7. Sympathy and understanding. If a couple have given birth to an abnormal child, the genetic counselling clinic is often the place where considerable feelings of guilt are expressed. Alternatively, there may be an understandable tendency to blame poor medical care or environmental factors for the abnormalities. Time should be set aside to discuss all these feelings in a sympathetic and understanding manner, as they are part of the normal reaction to the birth of an abnormal child. Guilt and blame are usually the result of lack of information. Once a couple have been fully informed of the nature and causes of a child's problems, they can be helped to accept the fact that many genetic abnormalities are unavoidable.
76
Successful genetic counselling requires a combination of
communication skills, detailed genetic knowledge, and a sound clinical background in both adult and paediatric medicine, if couples are to be helped to make the most appropriate decisions about childbearing. It is this combination that makes the practice of clinical genetics so rewarding.
FURTHER READING Emery A E H, Malcolm S 1995. An introduction to recombinant DNA in medicine, 2nd edn. John Wiley, Chichester. A good introduction to the techniques and uses of DNA analysis in medicine. Rimoin D L, Connor J M, Pyeritz R E 1996. Emery and Rimoin's principles and practice of medical genetics, 3rd edn. Churchill Livingstone, Edinburgh. A comprehensive multiauthor text covering most of clinical genetics.
Harper P S 1998. Practical genetic counselling, 5th edn. Butterworth-Heinemann, Oxford. A comprehensive introduction to the problems of clinical genetics.
The UK Medical Research Council Human Gene Mapping Project Resource Centre (MRC HGMP-RC).
Lander E S, Schork N J 1994. Genetic dissection of complex traits.
This Centre exists to provide specialist resources and
Science 265: 2037-2047. An excellent review of the techniques for finding the genes involved in multifactorial inheritance. McKusick V A 1998. Mendelian inheritance in man, 12th edn. The Johns Hopkins Press, London. A catalogue of all known single gene disorders in man. . Mueller R F, Young I D 1998. Emery's elements of medical genetics, 10th edn. Churchill Livingstone, Edinburgh. An excellent
services
introduction to medical genetics.
Worldwide Web computer addresses A vast amount of free information is available through the Worldwide Web (WWW). A few useful addresses are given below:
a
URL: .. http://www.hgmp.mrc.ac.uk/
OMIM (Online Mendelian Inheritance in Man) This database is a catalogue of human genes and genetic disorders authored and edited by Dr Victor A McKusick and colleagues at Johns Hopkins and elsewhere. This is an excellent place to look for up-to-date clinical and molecular information about genetic disorders. URL: http://www3.ncbi.nlm.nih.gov/omim/
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THEIMMUNESYSTEM
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4
INNATE IMMUNITY
Immunological Disorders
The components of the innate immune system provide a constant, unchanging system of protection for the healthy individual (Table 4.1). These physical and chemical barriers are an essential contribution to good health.
David Edgar and Herb Sewell Physical barriers and phagocytes
The immune system 79
Hypersensitivity 96
Immunodeficiency
Immune-suppression 102
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INTRODUCTION This chapter describes the components of the immune system and their interactions in the defence against infection. It is only intended to provide the reader with sufficient basic scientific detail to understand the clinical disorders described. Abnormal or inappropriate immune responses cause the clinical conditions of immunodeficiency and allergy, and these are discussed with an emphasis on clinical presentation, investigation and management. The principles of autoimmunity, along with conventional and novel immunosuppressive therapies, are also discussed. Throughout, the chapter highlights how recent advances in understanding the immune response at a molecular level have had an impact on clinical practice. The human immune system has developed to combat infection by a diverse range of potential pathogenic microorganisms: bacteria, viruses, fungi, protozoa and helminths. It is a complex but effective system comprised of multiple components which have both specific and overlapping functions. The immune system is conventionally subclassified into the innate and adaptive components, the essential functions of which are: • The differentiation of self from non-self; • The recognition of foreign proteins by specific molecules (antibodies, T-cell receptors); • The recall of previous exposure to specific organisms and the production of a rapid, more effective response upon re-exposure. The last two are characteristic of adaptive immunity.
The intact skin and mucous membranes constitute a barrier to the entry of microorganisms. These agents must therefore rely on physical damage, such as injuries or insect bites, to gain access to the body. Numerous natural antimicrobial substances also exist that fatally damage microorganisms. These include unsaturated fatty acids that are secreted on to the skin, lysozyme that is secreted in tears, and others, including gastric acid. Interferons are a further family of molecules (oc,P,y) that block viral replication and promote antiviral immune responses. However, some microorganisms have developed specific attachment and penetration mechanisms to bypass these initial defences. An example is rhinoviruses, which penetrate the respiratory mucosa by first attaching to a cell surface adhesion molecule ICAM-1 (intercellular adhesion molecule-1). If microorganisms are successful in breaching the physical defences, they are usually phagocytosed and killed by polymorphonuclear leukocytes (PMN) or macrophages. Some bacteria (e.g. pneumococci) can resist phagocytosis by virtue of their capsules, whereas others (e.g. staphylococci) release toxins that destroy phagocytes. Whereas some microorganisms can survive within phagocytic cells (e.g. mycobacteria), giving rise to chronic infection, most are killed in the phagolysosomes by a combination of acid pH, oxygen metabolites (e.g. hydrogen peroxide) and various cytotoxic proteins. However, not all killing is intracellular, and macrophages or PMN can secrete toxic molecules in order to kill large targets, e.g. worms (helminths). In the case of viruses and tumours, natural killer (NK) cells also play an essential role.
TABLE 4.1 Innate and adaptive immune systems Innate Physical protection (skin, mucous membranes) Chemical protection (lysozyme, gastric acid) Interferons Phagocytes Complement
Adaptive Antibody Lymphocytes
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complement and phagocytes are recognized as primary immunodeficiency diseases (PID). In addition, individual elements of the innate system are essential in stimulating the adaptive response during antigen presentation. Although classification into innate and adaptive helps our understanding of the immune response, it is important to remember that these elements are interdependent and function as an integrated system.
ADAPTIVE IMMUNITY
FIG. 4.1 Complement activation pathways The central event in complement activation is cleavage of C3 with the subsequent formation of C5 convertase. The generation of cleavage products (indicated by blue lines) augments the inflammatory response by attracting and activating phagocytes and causing activation and degranulation of mast cells. The deposition of C3b on cellular surfaces to promote phagocytosis is known as opsonization. The terminal pathway components (C5-C9) create the membrane attack complex (MAC) which causes osmotic cell lysis.
Complement system A further line of innate defence is the complement system (Fig. 4.1), a cascade of serum proteins which, when activated in succession, mediate three important effects: • Release of small peptides that stimulate inflammation and attract phagocytes; • Deposition of the cleavage component (C3b) on microbial membranes, which promotes phagocytosis via C3b receptors on phagocytic cells; • Assembly of complement components (C5-C9) into lytic complexes which puncture cell membranes, causing osmotic death. This activation 'cascade' is triggered by numerous microbial surfaces, notably the endotoxins of Gram-negative bacteria, by C-reactive protein (CRP) and mannan-binding lectin (MBL). Through interactions with antibody, phagocytes and mast cells, the complement cascade has an important role in integrating the response to infection.
Summary
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The innate immune system is essential in the defence against infection, and deficiency can result in serious clinical consequences. The vulnerability to infection of patients with severe burns emphasizes the protective value of normal skin. As will be described later, specific defects of
The adaptive immune system differs in two important respects from the innate, with its characteristics of specificity and memory. The adaptive system responds to the environment and 'remembers' specific encounters with foreign antigens. The most important cells involved in the adaptive response are lymphocytes (B and T cells). The antigen recognition molecules on the surfaces of B and T cells (antibody and T-cell receptors) confer the specificity of the adaptive system. These molecules recognize and bind to specific antigens through amino acid sequences that are complementary in structure to the target antigen. Immunological memory is generated after the first antigen exposure (primary response) because antigen-specific lymphocytes proliferate and generate an increased pool of cells. These memory cells, responsive to the specific antigen, remain relatively inactive until the same antigen is encountered again (secondary response). Subsequent stimulation of memory cells results in a secondary immune response that is more rapid and quantitatively greater than the primary response (Fig. 4.2).
Lymphocytes Lymphocytes originate from stem cells in the bone marrow. B lymphocytes complete their maturation in the bone marrow, but T lymphocytes require passage through the thymus, where they complete their maturation and education process. Crucially, it is in the thymus that T cells learn to identify 'self proteins', and any autoaggressive T cells are either allowed to die (by apoptosis) or are rendered non-reactive (tolerant). The bone marrow and thymus are referred to as primary lymphoid organs. The secondary lymphoid organs include lymph nodes, the spleen, Peyer's patches, tonsils and adenoids. These are strategically located to encounter microorganisms entering the body through external tissues, blood, gut, and upper airway, respectively. The structure of secondary lymphoid tissue is exemplified by the lymph node, where the cortex contains mainly B lymphocytes and the paracortex T lymphocytes, whereas antibody-secreting plasma cells are found in the medulla. Peripheral blood normally contains 70-90% T cells, 5-10% B cells and approximately 1-10% natural killer (NK) cells. A characteristic of lymphocytes is their ability to 'traffic' from peripheral blood into the tissues and secondary lymphoid organs. This property allows lym-
4
FIG. 4.2 Primary and secondary antibody responses Primary and secondary antibody responses to antigen. This demonstrates the characteristics of the adaptive immune response, i.e. specificity and memory. Upon re-exposure to antigen the immune system recognizes the antigen due to immunological memory. The resulting response has a shorter lag time (lag 2) and a quantitively greater antibody response.
phocytes to encounter antigen in almost all physical locations. The lymphoid tissues of the gut, genitourinary tract, breast and lungs behave, to a certain extent, autonomously, in that particular B cells (largely IgAsecreting) and T cells recirculate selectively through them. This recirculation is mediated by the expression of specific homing receptors and is referred to as the mucosal immune system. The result is that primary antigen exposure at one mucosal site will facilitate protective immunity at other mucosal sites. B cells
The main function of B cells is antibody production. Some B cells are stimulated directly by polymeric antigens and these responses are termed T-independent (e.g. bacterial capsular polysaccharides). Most B-cell responses are however T-cell dependent. For T-dependent responses, B cells are triggered to proliferate by interaction between their surface Ig and the antigen, but they require additional signals from T-helper cells in order to differentiate into plasma cells and secrete antibody. These signals consist of non-antigen specific cytokines (particularly IL-4 and -6) and cell-cell-mediated signalling. The interaction of these cell surface molecules, e.g. gp39 (CD40 ligand, CD40L) on T cells with CD40 on B cells, is essential in facilitating effective B-cell antibody production. During T-dependent responses some proliferating B lymphocytes are retained in germinal centres instead of differentiating 'terminally' into plasma cells. These are the memory B cells. Antibodies Antibodies are a family of five major classes of molecule which have a primary role in combating microorganisms free in the blood or tissue spaces, primarily viruses in their
FIG. 4.3 Immunological molecules V = variable, D = diversity, J = joining, C = constant, HC = heavy chain, LC = light chain, VH/L = variable region of heavy/light chain, CH1(2,3) = constant region 1 (2,3) of heavy chain, CL = constant region of light chain.
extracellular stage, and many bacteria. The antibody or immunoglobulin (Ig) molecule is ideally suited to its function of promoting the removal of foreign antigens. Its basic structure is seen in antibodies of the IgG class (Fig. 4.3). The N-terminal half is composed of heavy (H) and light (L) chains and is responsible for binding to antigen (Fab portions). The C-terminal half (Fc), which consists of portions of heavy chains, determines the class of antibody and is responsible for the other biological functions of the molecule. The major role of antibody molecules is to bind to microorganisms via the Fab portion, enhancing phagocytosis, as phagocytes possess Fc receptors. This process of coating microorganisms with antibody is known as opsonization. The basic four-chain structure is preserved in all five classes of immunoglobulin, but each class has certain characteristics that subserve its specific functions. • IgG molecules are involved in the activation of complement, attachment to phagocytic cells, passage into the tissues and transport across the placenta. The four IgG subclasses (IgG1, IgG2, IgG3 and IgG4) vary somewhat in these functions. • IgM is a large molecule with a pentameric structure. It is mainly confined to the bloodstream and is very efficient at activating complement and agglutinating foreign material because of its 10 antigen-combining sites per pentameric complex. • IgA is the predominant immunoglobulin class secreted at mucosal sites. It has a dimeric structure and is protected from proteolytic damage by a special polypeptide, the secretory chain (Sc). Sc is produced by the mucosal epithelial cells and acts as a receptor-transporter, binding to and taking the antibody into external sites. IgA can
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TABLE 4.2 Immunoglobulin structure and function Class & subclass
Structure
Major functions*
Monomer Monomer Monomer Monomer
C&O
Pentamer
c
Dimer
Mucosal protection Mast cell activation Antigen binding
IgG
IgG, IgG2 IgG3 IgG4 IgM IgA
IgE IgD
Monomer Cell surface bound
c C&O 0
*C, complement activation; 0, opsonization.
therefore survive proteolytic attack in secretions of the eyes, lungs, nose, gut and urinary tract. • IgE attaches via its Fc region to receptors on mast cells. When two bound IgE molecules are cross-linked by antigen, intracellular signalling results in the release of mediators from mast cell granules which cause the clinical features of acute allergy. • IgD is found mainly on B-cell membranes and acts as an antigen receptor. Its soluble form is not thought to have a significant physiological role. The properties of the various Ig classes and subclasses are summarized in Table 4.2. Antibody genes Genes on three different chromosomes code for antibody molecules. The genes of heavy and light chains are not continuous in the germline, but consist of separate clusters of gene segments separated by non-informative regions called introns. The clusters are named according to the part of the immunoglobulin molecule that they encode (Fig. 4.3), i.e. V, variable; D, diversity (heavy chains only); J, joining; and C, constant. During the development of a B cell, the germline DNA encoding the heavy-chain genes undergoes somatic rearrangement and recombination such that a complete heavychain variable region gene, V-D-J, is assembled. After transcription, RNA is spliced to link the V-D-J segment with a C segment to encode a complete heavy chain (V-D-J-C). Once this is accomplished, the light-chain genes rearrange to encode a complete light chain (V-J-C). Heavy and light chains then link together to form a complete antibody molecule. If rearrangement is not successful, the developing B cell is aborted. Enzymes (recombinases) encoded by two genes termed RAG1 and
1 82
MCQ4.1
RAG2 largely control the recombination events in lymphocyte progenitors. Defects or mutations associated with these genes can profoundly and adversely affect the development of the immune system. After gene rearrangement, the B cell does not restore the germline configuration and daughter cells will retain this unique rearrangement, ensuring continued antigenic specificity of that clone and its entire subsequent offspring (progeny). This is the molecular basis of immunological memory, thus maintaining immunological specificity in the clonal progeny. The heavy-chain C gene can, however, change to allow class switching (e.g. IgM-IgG) during the immune response, as occurs in moving from a primary to a secondary response. During the life of a B cell, point mutations may occur within the variable regions (somatic mutation), resulting in a change of affinity of the antibody molecule. Increased affinity for antigen confers a selective advantage to any B cell. This phenomenon results in affinity maturation whereby, as an immune response progresses, antibodybinding affinity increases. The huge potential diversity (i.e. the ability of humans to respond to a multitude of different foreign antigens) of antibody binding specificity (up to 108 specificities) is thus achieved by a number of mechanisms: • Association of different heavy chains with either K or X light chains; • Association of V genes with different (D) and J genes; • Genetic joining errors; • Somatic mutation. Genetic differences between antibody molecules are known as isotypic if they occur in the constant region and as idiotypic if they reside in the hypervariable regions (the sites associated with direct binding to antigen; Fig. 4.3). The idiotype of an antibody is the portion defining the uniqueness of that variable region, and may include both the antigen-combining site and the adjacent regions. There are also allelic differences known as allotypes, mainly within the C regions, which enable the antibody molecules of different individuals to be distinguished.1
T ce//s The major effector role of T cells is the elimination of viruses, fungi and protozoa, but they also act as coordinators of the overall adaptive immune response. B and T lymphocytes are impossible to distinguish by light microscopy and therefore more sophisticated techniques are needed (e.g. flow cytometry) which can identify specific cell typespecific surface antigens (CD antigens). All T cells bear the CD3 antigen, which is associated on the cell surface with the T-cell receptor (TCR). Cytotoxic T cells (Tctx) are responsible for killing abnormal host cells (e.g. virally infected, malignantly transformed or transplanted cells) and, in addition to possessing CD3, are also positive for the surface molecule CDS. They destroy target cells by several mechanisms, including cell membrane interactions (such as that of the Fas antigen
4
FIG. 4.4 Interaction of T cell receptor and HLA molecules The T cell is 'restricted' in that CD8+ T cells only recognize antigen when it is presented in association with HLA class I molecules. CD4+ cells only recognize antigen in association with HLA class II molecules.
(CD95) with its ligand) and the release of cytotoxic substances: perforins, granzymes and other cytokines. Helper T cells (Th), in addition to expressing CDS, also express CD4. It is helpful to remember some of these more common CD numbers, as these are important in describing primary immune deficiency states and lymphoproliferative diseases.
FIG. 4.5 Antigen processing and presentation 2 = 2 -microglobulin, TAP = transporter of antigenic peptides, class 1, WV = peptide, =C = HLA class II.
= HLA
TABLE 4.3 Major HLA associations The T-cell receptor (TcR, Fig. 4.4) The T-cell receptor is a two-chain (a and , or y and 6) molecule, rather like a shortened immunoglobulin. However, it has a more complicated combining site than antibody, and recognizes linear fragments of small foreign peptides in combination with molecules of the human leukocyte antigen system (HLA). The TcR-associated CD4 or CD8 molecules determine whether the individual T cell recognizes antigen in association with class I or class II molecules. CD8-expressing T cells only recognize antigen when it is presented with HLA class I molecules, whereas CD4-expressing T cells are only stimulated by antigen in association with HLA class II molecules. The human leukocyte antigen (HLA) systems The HLA system is the major determinant of transplant rejection responses. However, its normal physiological function is mainly to control cell-cell interactions, particularly within an individual's own immune response. The HLA genes lie on the short arm of chromosome 6 and are grouped into two major sets, referred to as class I and class II. Each set contains three genetic loci that have a large number of alleles coding for HLA antigens. The genes for some complement components and cytokines also lie within the same region (the class III region), but their products are quite unrelated to class I and class II molecules. Class I molecules consist of a large oc chain, and a small P chain known as pVmicroglobulin. 2-Microglobulin is encoded on a different chromosome and shows no sequence variability. Class I antigens (i.e. alleles at the A, B and C loci) are expressed on all nucleated cells (two from
Disease
HLA-B
Ankylosing spondylitis Rheumatoid arthritis SLE Celiac disease IDDM* Hashimoto's disease
27
HLA-DR
4 3 8 8
3 3,4 5
*IDDM, insulin-dependent diabetes mellitus.
each locus on diploid cells). Class II HLA molecules are two-chain ( and ) structures both chains are encoded in the HLA locus and are polymorphic. Class II antigens (alleles at the DP, DQ and DR loci) are expressed on a more limited range of cells: classic antigen-presenting cells, B lymphocytes and activated T lymphocytes. Class I and II antigens are central to antigen presentation and the generation of an effective immune response. Knowledge of the HLA alleles expressed by an individual is clearly essential for most organ transplantation. In addition, particular HLA types are also known to be associated with certain diseases (Table 4.3). In some circumstances the HLA association is so strong as to be helpful in diagnosis, e.g. HLA B27 and ankylosing spondylitis. Antigen presentation (Fig. 4.5) Antigen-presenting cells (APC) include macrophages, dendritic cells of the spleen and lymph nodes, Langerhans' cells of the skin, and B cells. Antigenic fragments are pre-
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FIG. 4.6 CD4 + cell activation after antigen presentation The binding of cell surface receptors to their cell-bound or soluble ligands results in a series of positive (+) or negative (-) signals transmitted to the CD4 T cell nucleus. Secretion of IL-2 activates both the secreting T cell and its near neighbours. sented to T cells in specialized 'antigen-binding grooves' in HLA class I and class II molecules. Class I molecules present peptides which are endogenously synthesized, e.g. viral proteins in an infected cell, whereas class II molecules present peptides from external proteins (e.g. extracellular microorganisms) which have been engulfed and degraded to peptides by the APC. There are distinct intracellular pathways involved for class I and class II presentation. Class II molecules are synthesized within the rough endoplasmic reticulum (RER) and, bound to a second molecule called the invariant chain, are transported to the endosomal compartment. There the invariant chain is replaced by antigenic fragment and the complex is transported to the cell surface. Class I molecules are also synthesized in the RER and are initially anchored on the inner surface of this organelle. Peptide fragments generated in cytoplasmic proteasomes are transported into the RER by specialized transporter proteins TAP-1 and TAP-2 (TAP = transporter of antigenic peptides). The peptide fragments then bind to the class I molecule and this complex associates with pVmicroglobulin before being transported to the cell surface (Fig. 4.5). * In addition to TcR recognition of the HLA/antigenic fragment, the CD4 molecule binds to a non-polymorphic region of the HLA class II molecule. Several other adhesion molecule pairs (LFA1/ICAM-l, CD2/LFA-3) link together, strengthening the cellular adhesion. The interaction of a T-cell surface molecule CD28 with B7 molecules on APCs is believed to be crucial to T-cell activation, as is the secretion by the APC of IL-1.
1 MCQ 4.2
84
Th-cell activation (Fig. 4.6) CD4+ T-cell activation is dependent on a series of 'costimulatory' signals consisting of cell-cell surface binding and soluble cytokines.* The result of these 'positive signals' is the generation of gene transcription factors (such as NFAT - nuclear factor of activated T cells) which 'switch on' genes (e.g. IL-2 gene) within the T-cell nucleus. Once IL-2 is secreted, it acts on both the responding and neighbouring cells. In contrast to CD28, a molecule termed CTLA4 appears to be crucial in donwegulating the T-cell immune response. CTLA4 appears on T cells late in their activation and also binds to B7 molecules (see above), but this binding delivers a negative signal to 'switch off responding T cells. Constructs of CTLA4 have recently been used in clinical trials (phase I and II) to downregulate unwanted T-cell responses in transplantation rejection and in autoimmune disorders. The increase in understanding of the key signalling molecules involved in antigen presentation will undoubtedly result in further attempts at therapeutic manipulation. Regulation of immune responses Both T and B cells are activated by recognition of specific antigens. Effective removal of antigen is therefore an important physiological endpoint for an immune response. However, the immune system has several additional mechanisms that regulate the nature and intensity of the immune response: • Apoptosis (programmed cell death) is now recognized as an important regulatory mechanism for the disposal of immune cells which have completed their function. • Anti-idiotype antibodies are directed against the V region of the Fab portion (idiotype) of other antibody
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TABLE 4.4 The major cytokines aiid their functions Cytokine
Natural source
Functions
Potential clinical uses
TNF-a and p
Macrophages
Antitumour, antiviral, vascular damage, PMN activation, bone resorption, induces IL-1 etc.
Anti-TNF moAb used for rheumatoid arthritis, inflammatory bowel disease
Interferon-
Macrophages
Antiviral
lnterferonInterferon-y
Fibroblasts T eel Is
Antiviral Antiviral, activates macrophages, increases mycobactericidal activity
IL-2 IL-5 IL-6
T cells T cells, mast cells T cells, fibroblasts, ARC, hepatocytes T cells, monocytes Macrophages
Activates T, B and NK cells Eosinophil growth and activation B-cell growth and differentiation; induces acute-phase response Neutrophil activation and chemotaxis Granulocyte growth and maturation
Hepatitis B&C, papillomatosis, Kaposi's sarcoma, hairy cell leukemia, chronic myeloid leukaemia Multiple sclerosis Multidrug-resistant TB, lepromatous leprosy, visceral leishmaniasis, IFNyR deficiency, chronic granulomatous disease, hyper-lgE syndrome, chronic mucocutaneous candidiasis Melanoma, renal cell carcinoma Anti IL-5 moAb in phase II clinical trials for asthma
IL-8 G-CSF
IL-8 receptor antagonist in preclinical trials for airway disease Cyclical neutropenia, chemotherapy 'rescue'
After activation, however, there is a preferential commitment towards either a Thl or a Th2 pattern (Fig. 4.7). Thl cytokines are IL-2, IL-12 and IFN-y, favouring a cellular immune response, whereas Th2 cytokines, favouring an antibody response, are IL-4, IL-5, IL-6 and IL-10. There is mutual suppression between these two dominant patterns of cytokine secretion such that, once a response has become committed in either direction, this pattern will tend to be maintained. It is therefore currently believed that the 'suppression' of immune response seen in certain situations is the net result of a balance in the type of cytokines secreted in the microenvironment, rather than the function of a single cell type. This is important in understanding the influence of the immune response on the pattern of clinical diseases such as leprosy (see hypersensitivity section).1
FIG. 4.7 T cell differentiation The blue lines indicate secretion of soluble mediators, the black lines indicate suppressive activity. For explanation see text.
molecules and may block or modulate antibody function. • A specific T-suppressor cell subset has not been identified in humans. There is, however, increasing evidence, in both animals and humans, that the pattern of cytokines secreted by CD4+ T cells will preferentially induce either a predominantly cellular or an antibody response. The major cytokines, their actions and potential clinical importance are summarized in Table 4.4. Prior to activation, most CD4+ T cells are 'ThO' (i.e. they have the potential to secrete a wide range of cytokines).
IMMUNO DEFICIENCY
Immunodeficiency is classified asprnnory (where the cause is/was previously unknown) or secondary, where there is a recognized cause for the immune defect, such as cancer, infection, drug treatment, radiotherapy or malnutrition.
PRIMARY IMMUNODEFICIENCY Understanding of primary immunodeficiency has increased rapidly over recent years with the identification of specific molecular lesions in a number of these previously poorly understood conditions. Research into these conditions has increased our understanding of the cell biology of the immune response and led to new diagnostic strategies and experimental forms of gene therapy in humans.
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Primary immunodeficiency diseases (PID) are subclassified according to the individual immunological components involved, hence there are antibody, T-cell or combined deficiencies, as well as phagocytic and complement component deficiencies. The defect in each condition leads to preferential susceptibility to certain types of organisms. Typically, antibody deficiency causes susceptibility to bacterial infection: T-cell deficiency to viral and fungal infections; and some complement deficiencies to meningococcal infections. These associations are important in consideration of the initial immunological differential diagnosis.
What are the characteristics of infection in PID? If the clinical history of infection can be described as serious, persistent, unusual or recurrent (SPUR), then immunodeficiency should be part of the differential diagnosis. 'Serious' suggests a potentially life-threatening infection (meningitis or septicaemia). 'Persistent' suggests that an infection is particularly resistant to conventional therapy. Infections may be 'unusual' in terms of site (liver/ brain abscess, or osteomyelitis) or organism (Pneumocystis, Aspergillus, Mycobacteria), and these should always raise the possibility of immune deficiency. Finally, 'recurrent' infection is particularly important. The child or adult who repeatedly presents with infection deserves further investigation of his or her immune status. It is difficult to be specific about how many infections constitute a 'recurrent' problem, and this inevitably involves an assessment of both frequency and severity of infection, evidence of organ damage, impact on systemic wellbeing and normal daily activity. The '10 warning signs of immune deficiency' are by no means exhaustive, but do give practical guidance on the clinical features that should prompt investigation for PID (Table 4.5)
When to suspect the diagnosis? Patients with PID may present with a history of infection or with a family history of an affected relative. More com-
TABLE 4.5 Ten warning signs of immune deficiency
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1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
8 or more new ear infections/year 2 or more serious sinus infections/year 2 months antibiotics without effect 2 or more episodes of pneumonia within a year Failure to thrive Recurrent, deep abscesses Persistent thrush after 1 year of age Need for intravenous antibiotics 2 or more deep-seated infections (sepsis, meningitis, cellulitis) Family history of PID
monly, they may present with the long-term complications of their condition (e.g. bronchiectasis). They may also present with a combination of clinical features and laboratory abnormalities that may not initially alert the non-specialist to the underlying diagnosis (e.g. chronic ill health, autoimmune phenomena). It is very typical for patients with PID to suffer a prolonged delay before the correct diagnosis is made, despite attending many doctors. During this period of delay they suffer significant morbidity and even mortality, and it is therefore essential that there is increased awareness of these conditions to allow earlier diagnosis and treatment. The simple guidelines from the history (Table 4.5) are useful in determining the most appropriate first line of immunological investigation. It is important that investigations are used appropriately and that expert advice is available, both in the selection of tests and in the interpretation of results. The general principles guiding investigation for immune deficiency include determining both that the relevant components of the systems are present, and that they are functionally intact. It is particularly important in the investigation of children that all immunological results are compared to appropriate, age-related normal ranges. Increasingly, specific molecular tests are used to confirm diagnoses, and therefore subtler variant forms of immune deficiency are being recognized.
Primary antibody deficiency diseases X-linked agammaglobulinaemia (XLA/Bruton's type) Clinical features Affected boys usually present between 6 months and 2 years of age. There may be a family history of affected male relatives. The most common complaint is of recurrent bacterial infections (typically Streptococcus pneumoniae or Haemophilus influenzae), usually affecting the respiratory tract, which if untreated lead to bronchiectasis. Boys may present with ear or joint infection and some have a nonspecific arthropathy that responds to the introduction of immunoglobulin replacement therapy. Chronic diarrhoea and a malabsorption syndrome may occur as a result of Giardia lamblia infection. A helpful physical sign is the absence of tonsillar lymphoid tissue or lymphadenopathy. A particular long-term complication in XLA is mycoplasma or ureaplasma arthritis. This is distinct from the more frequent non-specific arthropathy and is difficult both to diagnose and to treat. XLA patients are also susceptible to enterovirus infection (polio, coxsackie or echoviruses). Oral polio vaccine is therefore contraindicated, as it may cause paralysis, and a chronic meningoencephalitis may result from coxsackie or echovirus infection. This latter complication has become rarer since the advent of intravenous immunoglobulin therapy, but it still occurs either as a generalized condition or in a more limited form, causing sensorineural deafness. The prevalence of XLA is thought to be approximately 1 in 100000 in the UK, but
with the advent of molecular testing a milder, previously undiagnosed, form is being identified. Investigation Serum IgG level is usually less than 2g/L, with serum IgA, IgM and IgE being undetectable. Measurement of IgG subclasses is not usually helpful. Isohaemagglutinins are typically absent, as are specific antibodies to previously administered vaccines. Mature B cells are not usually detectable in peripheral blood, but T-cell numbers and function are normal. Neutropenia may be a feature. In the atypical, less severe, cases immunoglobulin levels are more variable and low numbers of circulating B cells are detected (typically in young teenage or adult males). In such cases the diagnosis can be difficult and test immunization responses to protein and polysaccharide antigens (usually tetanus toxoid and pneumovax II) are very helpful. Antigen-specific antibody levels are measured before and 4 weeks after immunization. Results require expert interpretation. The underlying molecular lesion has been characterized as a defect of the intracellular tyrosine kinase 'Bruton's tyrosine kinase' (Btk), coded for at X21.3-22. This kinase is essential for normal B-cell maturation, and B-cell development is therefore arrested at the pre-B stage. Family assessment to identify carriers is possible and should be undertaken, with appropriate genetic counselling. Rare autosomal recessive cases occur. Management of antibody deficiency Replacement therapy with regular intravenous immunoglobulin (ivlg) is now the standard treatment for primary antibody deficiency. This lifelong treatment is extremely effective in controlling infection, improving quality of life and preventing end-organ damage. The usual dose is 400mg/kg, given every 3 weeks. Regular preinfusion serum IgG levels are measured and should be maintained within the physiological range (usually >8g/L). Patients contribute to their own monitoring by completing diary sheets which record their general wellbeing, frequency of infections and antibiotic requirement. Patients must be weighed regularly and appropriate increments in ivlg dose made, because growth (in children) and weight (in adults) often increases significantly after the initial diagnosis and treatment. Various ivlg preparations differ in their con-tent. Once a patient is established on a particular product, it must not be changed without clear clinical indications. The main potential side-effect of treatment is reaction to the infusions. This may be related to infusion rate, intercurrent infection, or anti-IgA antibodies in IgA-deficient patients. Transmission of viral infection is now a very small risk because of careful viral screening and new antiviral steps in the production of ivlg from pooled donor sera. Recent advances include self-administration of ivlg at home and the development of subcutaneous administration (sclg), which is of particular value in the very young. Although immunoglobulin replacement is the mainstay of
treatment for antibody deficiency, there are other aspects of therapy. When respiratory infection occurs, patients should be treated over an extended period (usually 10 days) with high-dose antibiotics, guided by antibiotic sensitivity. Patients should be encouraged to undertake regular breathing exercises to assist with expectoration of sputum, and in those with established lung damage postural drainage should be undertaken daily. Regular assessment of pulmonary function is advised; however, 'routine' use of X-ray and CT examination (e.g. at annual review) is not advised in patients with PID. Many of these conditions predispose to a range of malignant diseases, and 'non-essential' exposure to radiation should therefore be avoided.
4
Common variable immune deficiency (CVID)/ acquired hypogammaglobulinaemla Clinical features This condition usually presents in adults with established lung disease or recurrent pyogenic infections. It is very typical for there to be a diagnostic delay of many years, during which respiratory function has deteriorated. Patients with CVID are at increased risk of autoimmune phenomena, including thrombocytopenia, haemolytic anaemia, malabsorption syndromes and organ-specific autoimmune disease. They have a particular tendency to granuloma formation and may present with lymphadenopathy or hepatosplenomegaly. The finding of typical granulomata on imaging may be helpful in establishing the diagnosis. These are usually non-caseating and steroid responsive, but treatment is not necessary if lesions are asymptomatic. A further characteristic complication of CVID is nodular lymphoid hyperplasia (NLH), in which lymphoid tissue of the gut becomes hyperplastic and produces characteristic filling defects on small bowel radiology series. NLH is thought to be a prelymphomatous condition, but CVID patients without NLH also have an increased risk of malignancy, particularly of lymphoma. CVID prevalence is estimated as 2-4 :100000 in the UK, but is probably underdiagnosed. IgG subclass and specific antibody deficiencies are thought to be related conditions, and some will progress to more typical CVID. Investigation Total serum IgG level is usually less than 3g/L; the levels of IgA and IgM are more variable. The diagnosis can therefore be difficult, and test immunization as described in investigation of XLA is required. In CVID the responses are poor or absent. Measurement of IgG subclasses is not usually helpful. Peripheral blood lymphocyte subset analysis may indicate a reduction in the proportion of CD4+ T cells that also carry the CD45RA antigen. Lymphocyteproliferative responses may be reduced. Unlike XLA, a single genetic defect has not been described for CVID, but B cells from these patients do not develop normally into plasma cells. It is thought that there is an abnormality of T-cell regulation of B cells in CVID.
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Management CVID patients require immunoglobulin replacement therapy as for XLA, with the possible addition of steroids for symptomatic granulomatous disease. CVID patients who are deficient in IgA should always be prescribed an ivlg preparation that is known to be low in IgA in order to reduce the risk of infusion reactions (see below). IgA deficiency Clinical features IgA deficiency is the most common primary immune deficiency in the UK, with a prevalence of approximately 1: 600. Most people with IgA challenge are identified by chance and are asymptomatic. The challenge is therefore to identify those in whom there is a significant immune deficiency. The history is crucial because IgA deficiency is known to be associated with an increased risk of pulmonary/sinus infections, allergy, celiac disease, other autoimmune diseases and malignancy. One must therefore look carefully for any suggestive clinical features in patients presenting with incidentally identified IgA deficiency. Furthermore, IgA deficiency can be a feature of some combined immune deficiencies (e.g. ataxia-telangectasia (page 93) and Wiskott-Aldrich syndrome (page 92)), and there may be clinical features suggestive of these diseases; IgA-deficient patients may form anti-IgA antibodies, which create a high risk of transfusion reactions to IgAcontaining blood products. If immunoglobulin replacement therapy is required, a product containing the lowest possible concentration of IgA must be used. Investigation IgA deficiency is defined by a laboratory measurement of serum IgA <0.05 g/L. The automated methods used in most routine laboratories are not sufficiently sensitive to detect these levels. Therefore, a routine report of 'low' level of serum IgA does not necessarily indicate a diagnosis of IgA deficiency. Once IgA deficiency is established, however, the patient must be fully evaluated to determine whether there is a clinically significant immune deficiency. A number of these patients will have associated IgG subclass deficiency and/or a failure of antibody responses to test immunization. If a combined immune deficiency syndrome is suspected, more extensive investigations are required (see ataxia-telangectasia (p. 93) and Wiskott-Aldrich syndrome (p. 93)).
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Management It is only the minority of IgA-deficient patients who have a significant history of infection, and usually other laboratory evidence of immune deficiency (IgG subclass deficiency, failure of response to test immunization, combined immune deficiency syndromes), who require treatment. Options include prolonged high-dose antibiotics for infectious episodes, prophylactic antibiotics, and immunoglobulin replacement therapy. Very few patients without IgG subclass deficiency or failure of immunization responses require immunoglobulin replacement, which suggests that
isolated IgA deficiency, in the absence of such defects, is a relatively benign condition. IgG subclass deficiency Clinical features IgG subclass deficiency is regarded as a part of a spectrum of conditions, including CVID and IgA deficiency. In common with IgA deficiency, patients may be asymptomatic or give a typical history of recurrent bacterial infection. The simple identification of a slightly reduced level of an IgG subclass is not sufficient in itself to warrant a diagnosis of significant primary immune deficiency. IgG subclass deficiency is usually suspected when the clinical history is suggestive of antibody deficiency, but total IgG (and other immunoglobulin classes) are normal and other primary antibody deficiencies have been excluded. Full immunological assessment is essential before treatment decisions are made. Investigation IgG subclass development occurs slowly during early childhood, and it is therefore important to relate results to the correct age-related ranges. Total serum immunoglobulin levels are usually normal, or may be high if there is a compensatory rise in the level of the non-deficient subclass (usually IgG^. On investigation, T-cell numbers and function (measured by in vitro proliferation assays) are usually normal. A failure of specific antibody response to test immunization would support a diagnosis of clinically significant IgG subclass deficiency. Management Not all patients will require ivlg and a careful assessment of the clinical history and investigative results is required. As discussed under IgA deficiency, several therapeutic strategies may be introduced and monitored for evidence of clinical response. Specific antibody deficiency Clinical features These patients are particularly susceptible to pneumococcal infection, but their total serum IgG and IgG subclass levels are normal. The clinical features are otherwise typical of other antibody deficiency syndromes, except that the diagnostic delay is likely to be longer because of the subtlety of the defect. Investigation These patients fail to mount a specific antibody response to polysaccharide antigens (e.g. Pneumovax II) but respond normally to protein antigen (e.g. tetanus toxoid). By definition, they will have normal total serum immunoglobulin and IgG subclasses. Management As for IgG subclass deficiency, the appropriate therapeutic option for each individual patient is based on a combined assessment of the clinical severity of the defect and the investigative results. The typical clinical features
described will usually indicate a requirement for ivlg; however, equivocal responses to immunization do occur in some individuals who do not require specific therapy. Transient hypogammaglobulinaemia of infancy Clinical features As passively acquired maternal immunoglobulin disappears and the infant begins to produce its own immunoglobulin, there is normally a physiological low level of serum antibody levels between 3 and 6 months of life. In some infants this 'physiological nadir' is profound, prolonged, and associated with bacterial infections. There are no other specific features: this is a diagnosis of exclusion and the clinical priority is to ensure that the child does not have a primary immune deficiency, such as severe combined immune deficiency (SCID, p. 93), X-linked agammaglobulinaemia (XLA, p. 86) or very early-onset common variable immune deficiency (CVID, p. 87). Investigation Serum IgG and IgA levels will usually be below the agerelated normal ranges, but IgM levels may be normal and isohaemagglutinins should be detectable. Differentiation from primary antibody deficiency may be difficult at this stage, but it is essential that a primary immune deficiency be excluded. Close clinical and laboratory monitoring of such infants is required for evidence of emerging antibody production. A diagnosis of transient hypogammaglobulinaemia can only be made retrospectively when antibody levels have returned to normal and the baby is clinically well. Management Decisions regarding treatment depend on the severity of the clinical history. If there are only occasional minor infections, no treatment is indicated. If frequent infection is causing significant morbidity the range of therapeutic options for antibody deficiency should be considered. If immunoglobulin replacement is deemed necessary, despite diagnostic uncertainty, it is essential to observe the patient closely for signs of recovering endogenous antibody production. This may be detected by a rise in IgM or IgA levels in preinfusion testing (intravenous immunoglobulin (ivlg) products do not contain IgM or IgA). Planned withdrawal of ivlg is also possible to allow repeat immunological assessment, including test immunization. Withdrawal of ivlg must, however, be for a prolonged period before immunization, as the half-life of IgG in the circulation is approximately 3 weeks. Immune deficiency with associated hyper-IgM Aetiology This is a disorder of T-cell function which prevents IgMproducing B cells from differentiating into IgG-producing plasma cells. The molecular lesion is of the T-cell surface protein gp39 (CD40 ligand/CD40L) and the gene is located at Xq26-27. The interaction between B cells (expressing CD40) and T cells (expressing CD40L) is crucial in trig-
gering IgM-producing immunoblasts to differentiate into IgG-secreting plasma cells.
4
Clinical features As this is an X-linked condition (although autosomal recessive cases are reported), affected boys present with recurrent pyogenic infections related to their hypogammaglobulinaemia and a commonly associated neutropenia. A typical presentation is with Pneumocystis carinii pneumonia (PCP) in infancy, which is an unusual infection in antibody deficiency and the susceptibility is probably explained by an associated underlying T-cell defect. There is also increased susceptibility to cryptosporidial infection, with ascending cholangitis and chronic liver impairment. There is an increased incidence of malignancy, particularly lymphoma and a range of autoimmune diseases. Investigation Serum levels of IgG are usually less than 3g/L, but IgM levels may be up to lOg/L (normally <3g/L). Neutropenia is common, but T-cell numbers and response to mitogens are normal. The failure of CD40L expression on stimulated T-cells in vitro can help confirm the diagnosis, but mutated forms of the CD40L gene may not be identified without more sophisticated genetic analysis. Management Commencement of ivlg therapy usually results in normalization of both serum IgM and neutrophil counts. The particular susceptibility of these patients to PCP is an indication for primary/secondary prophylaxis with oral cotrimoxazole. Allogeneic bone marrow transplantation is the definitive treatment in childhood. For those (usually older) patients with established chronic liver disease (probably caused by chronic cryptosporidial infection), combined liver and bone marrow transplantation is now considered. Experience to date is too limited to give definitive statements regarding prognosis.
Complement deficiencies The complement system is represented in Figure 4.1. The clinical features of deficiency depend on which part of the activation cascade is interrupted. The major points will be described. Individual complement component deficiency Clinical features Individual complement component deficiencies are rare, and in most cases are inherited as autosomal recessive conditions. Classic pathway component deficiency (Cl, C2 and C4) may present with recurrent bacterial infection or with immune complex-mediated disorders ('lupus-like syndromes'). C2-deficient patients are especially prone to pneumococcal infection. C3 deficiency is very rare; it is associated with recurrent bacterial infection. Deficiencies of properdin (X-linked) or the terminal pathway components C5, C6, C7, C8 and C9 are associated with recurrent neisserial (meningococcal or gonococcal) infection. Any
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CASE STUDY 4.1 RECURRENT INFECTION An 11-year-old girl was referred because of a history of recurrent infection. She had been fully immunized as an infant. At the age of 4 years she had recurrent otitis media and underwent surgical insertion of tympanic membrane vents (grommets). These had required reinsertion the following year. She was well until the age of 9 years, when she presented to hospital with chest pain and pyrexia. Left basal pneumonia was diagnosed and she was treated as an inpatient. Four months later she presented with recurrent symptoms. Chest X-ray again confirmed left basal consolidation. After antibiotic treatment she was discharged and returned to school. However, her parents noted that she suffered from frequent unexplained pyrexias and persisting chest pain. Her school performance deteriorated, she complained of fatigue and withdrew from sporting activities. She had no history of allergy or family history of recurrent infection. Investigations Hb 11.5g/dL, WCC 9.2 x 109/L, IgG 4.59 g/L, IgA < 0.07 g/L, IgM 0.28 g/L. Questions 1. Give two likely explanations for her recurrent symptoms, 2. Do her preliminary investigations establish a diagnosis? 3. What further general investigations are indicated? 4. What further immunological investigations are required?
She was referred to an immunology clinic, where the details of history were confirmed and further investigation undertaken. The history was suggestive of recurrent bacterial infection and, with the suggestion of IgA deficiency, an antibody deficiency syndrome should be considered as the most likely diagnosis.
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Further investigation indicated IgA < 0.05 g/L IgG subclasses: IgGj 4.5 g/L (4.5-9.4); IgG2 0.4g/L (1.6-5.1); IgG3 0.5 g/L (0.3-1.1); IgG4 0.07g/L (0.01-1.2) Classic complement pathway (CH50): normal Nitroblue tetrazolium (NET): normal Lymphocyte phenotype: CD4+ T-cell numbers low. CD45RA expression very low on CD4 T cells Immunization responses: failure to increase specific antibody levels after immunization with tetanus toxoid and Pneumovax II CT scan of chest: no evidence of structural lung damage. A diagnosis of common variable immune deficiency was reached and treatment commenced with prophylactic ivlg (400mg/kg three times weekly) commenced. The girl made a rapid response, with a cessation of her febrile episodes, no further chest infections and a significant improvement in energy levels. Her school performance improved and she re-engaged in her competitive sporting activities. Her weight correspondingly increased, to the extent that her ivlg dose had to be carefully monitored and increased appropriately. After 9 months on hospital-based therapy she opted for a home treatment programme. She and her mother were trained in all aspects of home infusion therapy by an immunology nurse specialist, and home therapy, under the guidance and monitoring of the Regional Immunology Centre, has been successfully established. Discussion The history of recurrent infection in this case was probably not remarkable up to the age of 9 years. It is common for children to present with otitis media, but tympanic membrane vents are usually indicated for chronic secretory otitis media ('glue ear'). There may therefore be
some doubt as to the exact diagnosis at the age of 4 years. The episode of pneumonia at the age of 9 years was significant, particularly because of the recurrence 4 months after initial treatment, and the persisting pleuritic pain and recurrent fevers thereafter. It was therefore appropriate to consider a primary immune deficiency and the initial investigations by the paediatrician were abnormal. The total serum IgG was slightly below the age-related normal range, and although IgA was reported as being, 'low', the level quoted was not low enough to confirm IgA deficiency. The additional investigations undertaken at the immunology clinic confirmed that the total serum IgA was <0.05 g/L and IgG2 subclass was low. The measurement of specific antibody response to immunization confirmed a significant defect in antibody production. Tetanus toxoid is a protein antigen (T dependent), whereas Pneumovax II is polysaccharide (T independent). Thus, these two antigens test the functional integrity of both the Tdependent and the T-independent responses. A healthy response should result in a minimum fourfold (usually much greater) rise in specific antibody level. Because there were low levels of IgG and IgA, low IgG2 and a failure of normal immunization response, the diagnosis was common variable immune deficiency (CVID). The lymphocyte phenotype is not diagnostic, but the relative reduction in CD4 T cells (and the CD45RA subset in particular) is typical of CVID. The clinical presentation described is reasonably typical, with the exception that the diagnosis was made before structural lung damage had occurred. Presentation in the second and third decades of life is common, but can be at any age. Usually there is a delay of many years from the onset of infection to
4
CASE STUDY 4.1 CONTINUED diagnosis, and during this period structural lung damage occurs. Ivlg treatment is proven to prevent infection and its complications, and in this case a specialist immunology service established home therapy for
the child. Home therapy is increasingly seen as a desirable option for patients with primary immune deficiency, as it reduces the need for hospital visits that interfere with normal school or work activities.
patient presenting with a recurrence of meningococcal infection should therefore be investigated for complement deficiency. Investigation Investigation of the complement system is indicated in any patient with symptoms of recurrent bacterial (especially neisserial) infection, 'lupus-like' disorders or angioedema. Total C3 and C4 levels are readily measured, but the most useful screening tests for deficiency are the assays that test the functional integrity of the classic and alternative pathways (known as CH50 and AP50, respectively). If an abnormality is detected, further characterization is necessary to identify the individual component that is defective. Management This is dependent on the clinical presentation. For patients with recurrent bacterial infection, prophylactic antibiotics may be indicated. For those susceptible to pneumococcal and or neisserial infection, immunization with pneumococcal capsular polysaccharide and meningococcal vaccines is often advised. In some cases intramuscular penicillin is kept at home for early treatment of suspected meningococcal disease, and it is advisable for patients to wear a medical warning bracelet. For patients with prominent joint symptoms, further rheumatological assessment may be advised. C1-inhibitor deficiency Defects of the control protein C1-inhibitor (C1-INH) are inherited in an autosomal dominant manner and cause hereditary angioedema. There is a failure of the normal regulation of the classic pathway that results in uncontrolled activation of complement and kinin pathways in response to even minor trauma. Clinical features Patients present with recurrent deep tissue swelling following apparently minor trauma (typically dental treatment). This may affect any part of the body, but is of most concern when the airway is compromised. Symptoms usually begin in early adolescence, although late presentation is increasingly recognized. An interesting feature is that attacks may begin, or become more severe, after commencement of the oral contraceptive pill, hormone replacement therapy, or during pregnancy. Although inherited as an autosomal dominant trait, patients may not give a significant family history as approx-
Integrating treatment into family life also empowers the patient and emphasizes that these conditions, like many other medical conditions, can be prospectively managed, preventing illness and maintaining good health.
imately 20% of cases are caused by new mutations in the C1-inhibitor gene. As with other immune deficiencies, there is often a period of diagnostic delay during which patients will have suffered symptoms, often of a lifethreatening nature. It is typical for children with this condition to suffer recurrent abdominal pain (caused by intestinal wall swelling), rather than swelling at other sites. In one series, 30% of patients had an undiagnosed relative who had died of laryngeal oedema, 34% had had an unnecessary laparotomy and 10% had had endotracheal intubation or tracheotomy prior to diagnosis. Investigation During an acute attack there is a characteristic pattern of serum complement levels which is caused by inefficient and excessive activation of the classic complement pathway. Serum C4 and C2 are low but C3 levels are usually normal. This is a very valuable pointer to the diagnosis hereditary angioedema, and measurement of C3 and C4 in any patient with angioedema will help differentiate this from allergic angioedema. In 85% of cases there is a low level of C1-inhibitor level (usually less than 50% of the lower limit of normal) but in 15% of cases the enzyme level is normal. This latter group have 'functional Clinhibitor deficiency', the enzyme being present but nonfunctional. Management Prophylactic treatment with androgenic steroids (danazol 200-400 mg daily, stanozolol 2.5-10 mg/day - alternate-day dosage may be possible) or antifibrinolytics (tranexamic acid up to 4g/day) is usually effective. Antifibrinolytics are the preferred alternative for female patients because of the androgens' virilizing side-effects. If laryngeal oedema occurs (e.g. after dental extraction) it is life-threatening and requires emergency intravenous administration of Cl-INH concentrate (1000-1500 units i.v). Patients are advised to wear a medical warning bracelet. C1-inhibitor concentrate should also be given prior to surgical procedures, and routine dental work should only be undertaken in hospital, where laryngeal oedema can be dealt with effectively. Cellular immune deficiency Because of the central role of T cells in coordinating the immune response, isolated T-cell deficiency is rare. The following will first consider those conditions in which the T-cell defect is the major feature, and then those in which a combined defect is more prominent.
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DiGeorge's syndrome This is a rare syndrome associated with a developmental abnormality of the third and fourth pharyngeal pouches. The full syndrome consists of: • Abnormal facies with low-set ears, 'fish-shaped' mouth, hypertelorism, notched ear pinnae, micrognathia and a downward slant of the eyes;1 • Hypoparathyroidism (often presenting with neonatal hypocalcaemic tetany); • Congenital heart disease (particularly aortic arch defects: truncus arteriosus, interrupted arch or Fallot's tetralogy); • Cellular immune deficiency. Not all of these clinical features are present in every case, and the immune function usually improves with time. DiGeorge's syndrome is now recognized as one of a group of related disorders that share a common genetic lesion. This is usually a deletion at 22qll, and the group of conditions is referred to as the CATCH 22 syndrome (cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate and hypocalcaemia). Other clinical syndromes in this group include velocardiofacial syndrome, Kallman's syndrome and Schprintzen's syndrome. Not all the CATCH 22-associated conditions include immune deficiency. Investigation Diagnosis is based on the typical morphological features, associated with recurrent viral or fungal infections such as oral and perineal candidiasis and viral pneumonia. Chest X-ray may show an absent thymic shadow with an abnormal cardiac outline (Fig. 4.8). It is usual to find a reduced number of circulating T cells, but the degree of immunological deficiency is variable and is probably only significant in approximately 20% of cases identified by other criteria. Lymphocyte proliferation in response to mitogens (PHA and PMA) may be reduced. Antibody deficiency is rare. It is now possible to detect the chromosome 22qll lesion by fluorescent in-situ hybridization (FISH). However, as the range of clinical associations with 22q11 lesions is wide and the degree of immunodeficiency variable, the simple demonstration of a 22qll deletion does not necessarily imply that there is clinically important immune deficiency. Management Awareness of the features and early recognition of DiGeorge's syndrome is important, particularly as these infants may be subjected to neonatal cardiac surgery. Calcium levels must be monitored and supplemented as necessary. All blood transfusions must use X-irradiated (25 Gy/unit) blood only, and live immunizations are con-
FIG. 4.8 Di George's syndrome
Chest X-ray of a one-week-old female infant with hypocalcaemia and Fallot's tetralogy. Note the abnormal enlarged cardiac outline and absent thymic shadow consistent with her diagnosis of Di George's syndrome.
traindicated (MMR, oral polio vaccine). Antibiotic prophylaxis to prevent PCP should be considered. In our unit this is instituted if the absolute CD4 count is below 0.4 x 109/L or if there is reduced T-cell proliferation to phytohaemagglutinin (a T-cell mitogen). In cases with severe cellular immune deficiency, bone marrow transplantation is suggested. The place of fetal thymus grafting is still experimental, although there have been some recent encouraging results showing reconstitution of T cells. Other cellular deficiencies Isolated T-cell deficiencies occur but are very rare. The diagnostic approach involves recognizing a suggestive history and undertaking both quantitative and functional assessments of lymphocytes. Chronic mucocutaneous candidiasis (CMC) affects both males and females and presents with chronic candidal infection of skin and mucous membranes.2There may be an associated endocrine deficiency which may precede the immune deficiency, most commonly hypoparathyroidism or Addison's disease. There are normal T-cell responses to non-specific mitogens but a specific failure of proliferative response to Candida. NK cell deficiency is also reported; patients have an increased susceptibility to herpesviruses. Functional studies of NK cells are only performed in specialist centres.
Combined immune deficiencies Wiskott-Aldrich syndrome
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1
Fig. 4.1
2
4
Figs 4.6, 4.7
Figs 4.2, 4.3, 4.4
3
Fig. 4.5
5
6
MCQ 4.3
Figs 4.8,4.9
Clinical features This X-linked disorder presents in young boys with a typical triad of eczema, thrombocytopenia and recurrent
infection.3 Immune deficiency may be mild. There is a high frequency of malignant lymphoma in the second and third decades of life, and severe autoimmune vasculitis or glomerulonephritis may occur. If untreated, death from one of these causes is usual in the second or third decade. Investigation Platelets are small and have abnormal expression of surface glycoproteins (CD43 and gpIb). There are defects affecting the cytoskeletal proteins, including actin, and associated defects of T-cell proliferation. The molecular defect is mutation of the WASP gene at Xp11.22. Characteristically there is a failure of response to polysaccharide antigens and progressive lymphopenia. Management These patients require careful clinical and laboratory assessment to establish optimum management. Increasingly, affected males are offered bone marrow transplantation in early childhood in order to reduce the risk of long-term complications and increase life expectancy. Ataxia-telangectasia (AT) Clinical features This progressive neurological and immunological disorder presents in early childhood with neurological manifestations, including cerebellar ataxia, nystagmus and oculomotor dyspraxia. Telangiectases are typically seen on the elbows, conjunctivae and ear lobes. 4 There is a progressive, combined immune defect that is variable in its immunological features. Patients ultimately develop lymphoid leukaemia/lymphoma in the second and third decades and this, combined with progressive combined immune deficiency, is the usual cause of death. Investigation The fundamental lesion is defective DNA repair leading to increased radiosensitivity (such as is seen in other disorders, e.g. Bloom's syndrome, xeroderma pigmentosa, Nijmegen breakage syndrome). Chromosomal breaks, inversions and translocations are commonly seen at the T-cell receptor, and immunoglobulin gene complexes on chromosomes 7 and 14, respectively. The serum afetoprotein is often raised. Heterozygotes for the AT gene mutations have an increased risk of developing a number of malignancies (including breast cancer), and family members need to be aware of this. Patients with AT gradually develop immune deficiency and, after comprehensive immunological investigation at diagnosis, this is confirmed and monitored by regular review of the clinical and laboratory features. Management Careful, continuing immunological assessment is essential in these patients, and treatment is dependent on the degree of immune deficiency. Patients commonly require ivlg by late childhood. There is no corrective treatment available for the underlying chromosomal instability.
Severe combined immune deficiency (SCID) Clinical features This group of conditions has a number of causes but the clinical features are similar in most cases. By definition, both humoral and cellular responses are impaired or absent. SCID typically presents early (in the first weeks and months of life) with a history of failure to thrive (FTT), unexplained diarrhoea, and recurrent bacterial, viral or fungal infection. Unexplained lymphopenia (<2.8 x 109/L) is often present and should always prompt investigation. Total lymphocyte counts may, however, be apparently normal in B-cell-positive variants, T-cell activation deficiencies and graft-versus-host disease (GVHD). GVHD may be related to maternofetal transfusion, where normally functioning maternal lymphocytes attack the immunodeficient child. If present, GVHD occurs in the first month of life with jaundice, typical skin rash 5and diarrhoea. It may also occur as a complication of blood transfusion, and all transfusions to potentially immunodeficient individuals should be irradiated (25Gy/unit) to eradicate immunocompetent lymphocytes, the potential inducers of GVHD.
4
Investigation When SCID is suspected, immunological advice should be sought urgently, with regard to both investigation and immediate management. In general, serum immunoglobulins are low and there is a low lymphocyte count, with diminished proliferative response to mitogens. Lymphocyte subset analysis is essential and a range of other investigations is needed to exclude SCID. The molecular basis of many variants of SCID is now recognized: each has a particular pattern of abnormalities and some of the more common are summarized in Table 4.6. Molecular characterization allows greater precision in diagnosis and carrier detection. Management Early diagnosis, prevention of infection and rapid bone marrow transplantation (BMT) are all crucial to ensure ultimate survival. Delay in making the diagnosis allows complications to occur (such as disseminated CMV infection), which reduce the chance of survival. BMT can be curative and, in the UK, is currently performed at two supraregional centres. With increasing characterization of the molecular basis of immune deficiency, it is hoped that gene therapy will become a practical possibility in this group of disorders.6
Phagocytic disorders Phagocytes may be defective in numbers or function. Table 4.7 summarizes the main disorders, the commonest of which are described below. Chronic granulomatous disease (CGD) Clinical features CGD typically presents in childhood with recurrent, deep abscesses caused by catalase-positive organisms (Staphy-
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TABLE 4.6 The major features of some combined immunodeficiency syndromes Syndrome
Major immunological features
Molecular defect
Inheritance/associated features
X-linked SCID
Immunoglobulin low; T cells low, B cells normal/increased Immunoglobulin, T and B cells all low Immunoglobulin, T and B cells all low Immunoglobulin low. Progressive fall in T and B cell numbers IgG low, IgM high, T cell numbers normal Immunoglobulin normal/low, B cells normal, reduced CD4+ cells Immunoglobulin normal/low, B cells normal, reduced CD8+ cells.
IL-2 receptor y chain
(XL)
Mutation in RAG1/2 genes Stem cell defect Accumulation of lymphotoxic metabolites Mutation in CD40L gene Mutations in MHC II regulator genes TAP-2 gene mutation
(AR)
T-B- SCID Reticular dysgenesis Adenosine deaminase deficiency X-linked hyper-IgM MHC class II deficiency TAP-2 deficiency
(AR): Anaemia, granulocytopenia, thrombocytopenia (AR): Progressive onset, diagnosis may be delayed into childhood: flared ribs (XL) Neutropenia, thrombocytopenia, haemolytic anaemia, (AR) (AR) MHC class I deficiency
(XL), X-linked; (AR), autosomal recessive.
TABLE 4.7 Examples of phagocytic disorders Phagocytic defect
Clinical disorder
Numbers Adhesion
Cyclical neutropaenia Leukocyte adhesion defect (LAD-1) Schwachmann's syndrome
Chemotaxis
Intracellular killing
Chronic granulomatous disease G6PD deficiency IL-12R & IFNyR deficiency
Inheritance/associated features (AR) See text (AR) See text (AR) Anaemia, thrombocytopenia, pancreatic insufficiency, chondrodysplasia (XL/AR) See text (XL) Anaemia (AR) Susceptibility to mycobacteria and salmonella. See text
lococcus aureus, Aspergillus, Serratia, Nocardia).1 Presentation may be with osteomyelitis, unexplained granulomatous lesions, malabsorption or recurrent pneumonia. New cases have been diagnosed in adulthood. Inheritance may be X-linked or autosomal recessive. Investigation The diagnosis rests on the demonstration of a failure of the neutrophil respiratory burst. The most common screening test of neutrophil function is the nitroblue tetrazolium test (NBT) test, in which normal neutrophils reduce the yellow dye formazan into blue intracellular crystals. 2 This test
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Fig. 4.10
0 Fig. 4.11 3
Fig. 4.12
may not be abnormal in all cases, and more sensitive screening techniques have been developed. The molecular defect is a deficiency of the 91 kDa chain of cytochrome b (X-linked CGD) or the 22 kDa chain of cytochrome b, or of p47 or p67 cytoplasmic factors (autosomal recessive CGD). These proteins are all involved in the energydependent process of intracellular killing. The definitive test is to demonstrate a failure of neutrophil-mediated bacterial killing. Management Antimicrobial prophylaxis (usually with co-trimoxazole) is the mainstay of therapy. Prophylactic interferon-y (IFNy) is not useful prophylactically, but may be a useful adjunct to conventional antibiotic and surgical management of abscesses. Allogeneic bone marrow transplantation, before the development of complications of infection, is now the treatment of choice for CGD if a suitable donor can be found. Cyclical neutropenia Clinical features This condition, which may present in childhood or adult life, is characterized by recurrent abscesses, usually occurring at intervals of approximately 3 weeks, although the periodicity can vary greatly. The neutrophil count is typically <1 x 109/L at times of infection, and the diagnosis should be suspected if there is clear periodicity to the history. Alternatively, the neutrophil count may be incidentally noted as low on a blood count during acute infection. Investigation Neutrophil counts should be measured on alternate days for a 4-week period and carefully analysed for any evidence of a cyclical pattern. A cyclical pattern may also be detected for other elements, including platelets, and other leukocytes.
Management This is dictated by the clinical severity of the condition. Prophylactic antibiotics may be adequate during times of low neutrophil numbers. In more severe cases, treatment with granulocyte colony-stimulating factor is considered. Leukocyte adhesion deficiency (type 1)
heterozygous for the genetic lesion, but this is clinically expressed as a dominant susceptibility. This is in contrast to most autosomal genetic disorders, in which the normal allele dominates, so that heterozygotes only show a minor clinical abnormality. The prevalence of these conditions is not yet established.
Clinical features This is typically a disorder of infancy and childhood. Chronic/recurrent skin ulcers and periodontitis are common. There is characteristically little pus formation and an associated peripheral blood neutrophilia. There is likely to be a neonatal history of delayed separation of the cord (>10 days).
Investigation Cell surface expression of IFNyR and IL-12R is detected by flow cytometry. Specialist functional assays of lymphocyte signalling are necessary to confirm and characterize the defects. Histologically, complete IFNyR deficiency is characterized by a failure to form granulomata, whereas partial deficiency is associated with good granuloma formation.
Investigation There is defective expression of the CD18 (B chain) of the adhesion molecules LFA-1, Mac-1 and CR4. The absent expression is demonstrated on both lymphocytes and phagocytes by flow cytometry. A second variant, LAD-2, is associated with defective expression of CD15.
Management Once the diagnosis is established, appropriate antimycobacterial therapy must be commenced. Experience with adjunctive IFN-y treatment in the partial forms is increasing and discussion with specialist centres is advised.
Management Antibiotics are the mainstay of therapy. Drug choice should be guided by antibiotic sensitivities. Prophylactic therapy may be necessary, depending on the frequency of infection. Bone marrow transplantation is necessary for severely affected individuals. /nferferon-y receptor (IFNyR) deficiency Clinical features Defects in the IFNyR (and IL-12 receptor) systems have recently been identified as important susceptibility factors for mycobacterial infection. These conditions have been identified in both children and adults. They typically develop infection with poorly pathogenic mycobacteria, salmonella, or the live vaccine Bacille Calmette-Guerin (BCG). There are three types of IFNyR defect identified. Complete deficiency determines a phenotype that is characterized by severe and fatal susceptibility to either BCG or disseminated non-tuberculous mycobacterial (NTM) infection. Partial IFNyR-1 deficiency is associated with a less severe clinical defect that may allow disseminated BCG infection with tuberculoid granulomata or clinical tuberculosis. Both complete and partial IFN-y deficiencies are inherited as autosomal recessive traits. A functional defect of the IFNyR has also recently been described which is characterized clinically by susceptibility to nontuberculous mycobacteria (NTM) and variable granuloma formation.3 A notable feature of the cases described to date is that a significant number are initially misdiagnosed as suffering from Langerhans' cell histiocytosis (LCH), because of the association of fevers, lymphadenopathy, granulomatous ulcers and lytic bone lesions. The condition is caused by a premature stop codon in the intracellular signalling domain of IFNyR that reduces the mycobactericidal properties of macrophages. Inheritance of this last type is 'dominant negative'. The affected individuals are
a
SECONDARY IMMUNODEFICIENCY Secondary immunodeficiency is much more common than primary immune deficiency in clinical practice. It may occur as a result of systemic disease, including diabetes mellitus, chronic hepatic and renal failure and systemic malignancy. Autoimmune disorders may be associated with immune deficiency as a consequence of both disease and treatment. Specific infections are also associated with secondary immune deficiency. The best known of these is human immunodeficiency virus (HIV), which leads to the acquired immune deficiency syndrome (AIDS; Chapter 11). HIV causes a progressive loss of CD4+ T cells and thus disrupts both antibody and cellular responses. Several other infections are associated with immune suppression. Measles predisposes to bacterial infection partly through its disruption of phagocytic function. Epstein-Barr virus may occasionally cause hypogammaglobulinaemia. Immunosuppressive drugs are widely used in the treatment of cancer and autoimmune disease and are an important cause of secondary immunodeficiency. When using these agents it is essential to monitor treatment carefully and maintain the lowest level of immunosuppression compatible with effective treatment. Malnutrition, infection and other iatrogenic causes, including radiotherapy, are also important causes of secondary immune deficiency. The mechanisms of secondary immunosuppression are usually multifactorial: specific intervention is not usually indicated, but susceptibility to infection must be recognized in patients who are at risk. Secondary antibody deficiency may occur in lymphoproliferative disorders such as multiple myeloma and chronic lymphocytic leukaemia, or in protein-losing states such as nephrotic syndrome or intestinal lymphangectasia. In the
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lymphoproliferative disorders, where there is a failure of antibody synthesis, there is often a history of recurrent bacterial infection, and in these cases ivIg has been demonstrated to be beneficial. Interestingly, in the protein-losing states, recurrent infection is not usually a significant clinical problem, and antibody replacement therapy is the exception rather than the rule. Splenectomy is an important cause of secondary immune deficiency. These patients have a lifelong risk of suddenonset overwhelming sepsis caused by encapsulated organisms. This is related to the important role of the spleen in the immune response to polysaccharide antigens. Patients in whom Splenectomy is planned should be immunized with pneumococcal, meningococcal and Haemophilus influenzae type b vaccines. Annual flu immunization is recommended, and travel to malarial endemic areas should be avoided if possible. Patient education regarding the risks of splenectomy is very important, and they should be provided with warning cards or bracelets and advised to take penicillin early if they develop cough and fever. Prophylactic penicillin V (250 mg b.d.) should be given for the rest of the patient's life. Penicillin-allergic individuals should take erythromycin (250mg b.d.). Long-term follow-up is recommended both to monitor the need for repeat immunization and to reinforce medical advice. There are also a number of inherited syndromes, many of which are rare, associated with secondary immune deficiency.
HYPERSENSITIVITY
IMMUNOLOGICAL MECHANISMS In contrast to immunodeficiency syndromes, where the immune system is underactive, clinical disease may result from inappropriate overactivity. Overactivity of the immune system is referred to as hypersensitivity. The immunological mechanisms that cause hypersentivity were described and classified by Gell and Coombs (Table 4.8). Four types of hypersensitivity are described, each involving different immunological components. In some cases the hypersensitive response is directed at a foreign antigen (e.g. reactions to allergens, blood transfusions, transplanted organs or infectious agents) and in others it is directed at known 'self-antigens' (e.g. in autoimmune diseases). Finally, some hypersensitivity reactions appear to be directed at unknown antigens (e.g. Wegener's granulomatosis). The term hypersensitivity applies to all four types of reaction in the Gell and Coombs classification, whereas
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Fig 4.13
2
Case 4.1
TABLE 4.8 Classification of hypersensitivity reactions (Gell and Coombs classification) Type of reaction
Effector mechanism
Clinical disorders
I
IgE, mast cells
Allergic rhinitis, urticaria, angiodema
II
IgG directed at cell surface antigens
Transfusion reactions, acute graft rejection, Graves' disease, myasthenia gravis, Goodpasture's syndrome
III
Immune complexes
Cryoglobulinaemia, SLE, post streptococcal glomerulonephritis
IV
CD4+ lymphocytes,
Delayed type hypersensitivity, contact eczema, granulomatous reactions
the term allergy is used in a more restricted sense to describe type I hypersensitivity reactions. In this section, we will use the Gell and Coombs classification to illustrate and explain the important clinical conditions associated with hypersensitivity reactions. In addition to allergy and autoimmunity, the hypersensitivity mechanisms involved in the response to infectious agents can influence the clinical manifestations of disease. Furthermore, the manipulation of the immune response (e.g. in mycobacterial disease) offers new possibilities for therapeutic intervention.
Type I hypersentivity Type I hypersensitivity reactions (the major mechanism in allergy) are the result of the immune system reacting to otherwise apparently innocuous antigen (allergen). The mechanism involves: • Formation of IgE antibody specific to the inducing antigen or 'allergen'; • Binding of this antibody (via Fc receptors) to mast cells and basophils; • Cross-linking of at least two cell-bound IgE molecules; • Degranulation of mast cells, with release of preformed mediators and the generation of late-phase mediators.
Type II hypersentivity Type II hypersensitivity involves the reaction of antibody with cell surface-bound antigen. This reaction then causes downstream activation of the complement system, and attraction and activation of phagocytes and mast cells. The effect is to focus inflammatory damage at the site of antibody binding or, in the case of receptor-binding antibodies, to modulate the function of the target organ. This mechanism is especially important in organ-specific
autoimmune disease (Graves' disease, myasthenia gravis, autoimmune haemolytic anaemia, Goodpasture's syndrome), but also in blood transfusion reactions and hyper acute graft rejection.
Type III hypersensitivity Type III reactions involve the formation of soluble immune complexes that circulate in the blood and cause damage at many sites. Formation of immune complexes is part of the normal immune response, and these are normally disposed of via the complement and reticuloendothelial systems. Complexes remain in the circulation if they are produced persistently or are inadequately disposed of. Such pathological complexes become deposited, typically in the renal glomerulus, in joints and the skin, causing inflammatory reactions at these sites. The experimental model for immune complex disease is serum sickness, in which nephritis, arthritis and rash typically occur 7-10 days after the injection of foreign protein. The best examples in human disease include chronic infection (e.g. hepatitis, malaria, streptococci), systemic lupus erythematosus (SLE), inhalation of antigens (e.g. farmers lung) and cryoglobulinaemia. 1 2
Type IV hypersensitivity This is also known as delayed-type hypersensitivity (type IV hypersensitivity) because in experimental systems signs develop 12 or more hours after antigen exposure. Importantly, the major immunological effectors of type IV reactions are T cells, instead of antibody, which mediates the reaction in types I-III hypersensitivity.
CLINICAL DISEASE ASSOCIATED WITH HYPERSENSITIVITY REACTIONS Allergy Clinical allergy is becoming increasingly prevalent in western societies: it is estimated that up to 20% of the UK population is now affected by allergy. The symptoms depend mainly on the nature of the allergen and the site at which mast cell degranulation occurs. The common clinical syndromes are of seasonal or perennial rhinitis, allergic asthma, urticaria, oral allergy syndrome, angioedema and anaphylactic reactions. The term atopy is used to describe a genetic susceptibility, expressed in the clinical triad of eczema, allergic rhinitis and asthma, which are commonly associated in many patients. Diagnosis The diagnosis of allergy is often thought to be difficult, but in the majority of cases a thorough clinical history combined with relatively simple investigations will prove adequate. The history is the most important component, and
one looks for typically allergic symptoms occurring consistently after exposure to the same agent, and improvement of symptoms during periods of avoidance. Where doubt remains, further investigation by skin-prick testing and/or the detection of allergen-specific IgE (e.g. by radioallergosorbent test - RAST) is necessary. Skin-prick testing is preferred, as it is a rapid, cheap and painless form of in vivo challenge. There are, however, limitations to its use, as it should only be undertaken by trained individuals in an environment with full resuscitative facilities available. Specific IgE testing using the RAST test has the advantage of easy accessibility. Although results correlate well with skin testing for most allergens, they are not directly comparable for every allergen. RAST testing should not be used as a screening test for allergy. Its use should be guided by careful clinical assessment.
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Allergic syndromes Rhinitis Clinical features Seasonal or perennial rhinitis usually presents little diagnostic difficulty or need for specific investigation. The symptoms of a red, itchy, runny nose with associated swelling and itchy watery eyes are easily recognized. A history of seasonality and/or key triggering factors will usually indicate the offending allergen. Investigation This is required when the provoking allergen is not clear from the history, or when another cause is suspected (Table 4.9). Management The important elements in management are the avoidance of, or reduction in exposure to, the allergens and the use of nasal steroid inhalers, with or without oral antihistamines. The latter are particularly useful in young children, who may find the use of inhalers difficult. For perennial symptoms caused by house dust mite patients need to be advised on how to reduce exposure by modifications to floor coverings, bedding, and cleaning and laundering procedures. There is increasing evidence that effective control of nasal
TABLE 4.9 Differential diagnosis of rhinitis Allergic (aeroallergens) Drug induced (decongestant sprays, cocaine, antihypertensive) Vasomotor Infectious Irritant Vasculitis Hormonal (pregnancy) CSF rhinorrhoea
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allergy in asthmatic patients can improve their overall airway disease. Desensitization is returning to clinical practice for grass and house dust mite allergy, but only specialist units should undertake it.
Urticaria/angioedema Clinical features Urticarial lesions are raised red itchy weals (often described as 'like nettle stings') caused by epidermal mast cell activation. Angioedema is non-itchy, non-dependent swelling which occurs in the deep dermis. Activation of the kinin system is important in causing angioedema. It is common for both symptoms to occur in the same patient. However, when angioedema occurs in the absence of urticaria, hereditary or acquired deficiencies of Cl-esterase inhibitor (Cl-INH) should be considered. A number of specific triggers for both urticaria and angioedema may be identified (Table 4.10), but in the majority (89-90%) of cases referred to clinics no specific allergic cause is identified. If symptoms persist for more than 6 weeks, this is defined as chronic idiopathic urticaria/angioedema. The natural history is quite variable, with many patients experiencing prolonged remissions between relapses. Investigation A thorough clinical history is essential to determine the pattern of symptoms and any associated trigger factors. Screening tests for allergy are not recommended; however, the wide variety of disorders associated with combined urticaria/angioedema (Table 4.10) may justify further investigation, including thyroid function tests, full blood count, CRP and complement levels. Skin biopsy is helpful in confirming urticaria pigmentosa and urticarial vasculitis. Management If an associated medical condition is identified (e.g. hypothyroidism, infection), the urticaria should respond to management of that disorder. In other patients, if attacks are only infrequent oral short-acting antihistamines (e.g. acrivastine 8mg t.i.d.) will be adequate. In most cases, however, daily non-sedating antihistamines are necessary (e.g. fexofenadine, loratadine and cetirizine). If necessary a sedating antihistamine can be added at night (e.g. hydroxizine hydrochloride). Experience with oral disodium chromoglycate has been disappointing, with the possible exception of urticaria pigmentosa, in which it has an important role in management. H2 antagonists (cimetidine and ranitidine) are often tried for refractory cases, as is doxepin (an antidepressant with potent antihistamine effects). Urticarial vasculitis often responds to NSAID therapy. The relapsing, remitting nature of urticaria makes it difficult to be certain of the efficacy of some of these interventions,
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Fig. 4.14
TABLE 4.10 Causes of urticaria/angioedema Idiopathic Allergic (foods, drugs, hymenoptera venom, contact) Physical (pressure, heat, solar, aquagenic, vibratory) Cold induced (autosomal dominant, cryoprotein) Cholinergic (exercise or heat induced) Adrenergic (stress induced) Vasculitis (hypocomplementaemic urticarial vasculitis) Autoimmune (SLE, antibodies to lgE/FceR1/C1q) Infection (hepatitis B, Helicobacter pylori, EBV, Lyme's disease, cutaneous larva migrans, larva currens) Insect bites (papular urticaria) Drug induced (aspirin, ACE inhibitors, opiates, muscle relaxants, and radiocontrast media) Hypothyroidism Urticaria pigmentosa Systemic mastocytosis Angiodema/deafness, urticaria (Muckle-Wells syndrome) Malignancy
and it is essential that once regular therapy is commenced the dose is periodically reduced or withdrawn to determine whether continued treatment is necessary. Food allergy IgE-mediated allergy to food has been described since the 1920s but remains a source of controversy. This is probably because there are exaggerated claims made for both the prevalence and the effects of food allergy, and the diagnostic tests that are available have not been reliable. There is also confusion between food allergy (an IgE-mediated phenomenon) and food intolerance, which may have many causes. For patients in whom food allergy is suspected a double-blind placebo controlled food challenge (DBPCFC) is the only reliable investigation, but this is available in only a few specialist centres at present. Selfreporting of food allergy is common. In one large study the self-reported prevalence was 20%, but actual prevalence was only 1-2% when confirmed by DBPCFC. Food allergy is often invoked as a potential cause for complex multisystem disorders or obscure symptoms. This is unlikely to be the case, and in the absence of clear evidence of allergy patients should be encourage to eat a normal diet. IgE-mediated food allergy may cause symptoms including urticaria, angioedema, rhinitis, asthma, oral allergy syndrome, anaphylactic reactions and some gastrointestinal symptoms (chiefly acute vomiting and/or diarrhoea). Common food allergens include milk, eggs and seafood. Affected children typically become tolerant to these foods by mid-late childhood. Currently, the most important food allergy is to peanut - a relatively unknown condition until the late 1980s, the prevalence of which has increased considerably. Among the UK preschool population it is now estimated to be as high as 1:50-100. Nut allergy is different in many important respects from other food allergies:
• It appears to develop in very young children. • Reactions characteristically cause angioedema, often affecting the larynx, with airway restriction. • Anaphylactic reactions may result from exposure to even trace amounts of nut. • Indirect exposure may cause life-threatening reactions in highly sensitive individuals. • Nut allergy appears to be a lifelong problem in the majority of cases. Nut allergy is a major challenge facing the medical profession and others who look after children. Successful management requires the complete avoidance of all nut-containing foods, and teaching family, friends and school staff the symptoms and signs of allergic reactions. An emergency medication kit should be available which includes both oral antihistamines and injectable adrenaline (epinephrine) (for life-threatening reactions), and patients are encouraged to wear a medical warning bracelet. Nut allergy has now overtaken bee/wasp sting allergy as the most common cause of anaphylactic reactions occurring outside hospital.
Development of autoimmunity The occurrence of hypersensitivity reactions directed against self-antigens implies a breakdown in the body's normal tolerance mechanisms. A number of factors are implicated in the development of autoimmune reactions, including infection, drugs and chemical exposure and HLA type. The influence of the hormonal state is undoubted and is exemplified by the increased autoreactivity seen in women and the effect of hormonal change (pregnancy and lactation, hormone replacement therapy) on the clinical manifestations of disease. Several cellular and molecular mechanisms are recognized as contributing to autoreactivity. These include 'cross-reactivity', where a pathogen is sufficiently similar to self-antigen that it induces an autoimmune response, e.g. group A B-haemolytic streptococcus cross-reacts with cardiac muscle, causing acute rheumatic fever: 'Molecular mimicry', wherein a short genetic sequence of a pathogen is identical to a selfantigen, has long been postulated as a mechanism for autoimmunity. Mathematical modelling, however, suggests that molecular mimicry is likely to be so common as to be the rule rather than the exception, and thus unlikely to be important in disease aetiology. 'Provision of foreign T-cell epitopes' implies that foreign antigens containing T-cell epitopes bind to host proteins and stimulate an autoimmune response. This may be one of the mechanisms through which drug and chemical exposure causes autoimmune reactions. The important HLA disease associations have been summarized in Table 4.3. It should be remembered that T cells learn to differentiate self from non-self antigens during their maturation in the thymus; thus the occurrence of autoreactive antibodies or lymphocytes represents a breakdown in the normal mechanisms of selftolerance. One of the crucial mechanisms for eradication of self-reactive T cells is through programmed cell death
or apoptosis. Patients deficient in the Fas antigen, an essential signalling molecule in normal apoptosis, develop characteristic clinical features dominated by lymphoproliferation and autoimmunity,1 emphasizing the importance of central (thymic) deletion of autoreactive cells.
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Autoimmune diseases: classification and diagnosis Human autoimmune diseases are classified according to whether predominantly a single organ is affected (organ specific) or whether there is multiple organ involvement (non-organ specific). As with any classification system, some conditions fall between these two extremes. Table 4.11 lists some common autoimmune diseases in these two categories. Autoantibody detection is frequently requested in the investigation of suspected autoimmune disease. Autoantibodies may be primary and directly cause disease (e.g. antiglomerular basement membrane antibodies in Goodpasture's syndrome, antiacetylcholine receptor antibodies in myasthenia gravis and anti-TSH receptor antibodies in Graves' disease), but more commonly they are secondary and are formed as part of the disease process itself (e.g. antinuclear, anti-dsDNA, antismooth muscle, antimitochondrial antibodies). Detection of a secondary autoantibody does not necessarily indicate that the patient has an autoimmune disease. 'False positive' autoantibodies are associated with, for example, infection, female gender, increased age and surgical procedures. Determining the significance of autoantibody results requires careful clinical assessment. It is also important to know the exact pattern of autoantibody detected, its titre (or strength) and
TABLE 4.11 Autoimmune diseases and their associated autoantibodies Disease
Autoantibodies directed against
Hashimoto's disease Graves' disease Pernicious anaemia
Thyroid peroxidase TSH receptor Intrinsic factor Gastric parietal cells Steroid-secreting cells of adrenal cortex Islet cell Smooth muscle Acetylcholine receptor Voltage-gated calcium channel
Addison's disease Type 1 diabetes mellitus Chronic active hepatitis Myasthenia gravis Lambert-Eaton myasthenic syndrome Pemphigus Goodpasture's syndrome Sjb'gren's syndrome Primary biliary cirrhosis Systemic lupus erythematosus (SLE) Rheumatoid arthritis
Desmosomes Basement membrane Nuclear antigens (Ro/La) Mitochondria Nuclear antigens (ds DNA, Ro/La, Sm) Phospholipid IgG (rheumatoid factor-IgM class)
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CASE STUDY 4.2 ACUTE ONSET OF SWELLING A 15-year-old girl presented to her local accident and emergency department with an acute onset of swelling that affected her face. Her eyes were closed, she had swelling of the lips, but neither tongue swelling nor difficulty in breathing (Case Fig. 4.2.1). She reported eating a chocolate bar that contained peanuts 4 hours earlier, and a provisional diagnosis of nut allergy was made. She was immediately treated with i.v. chlorpheniramine and hydrocortisone. Adrenaline was not administered but she was admitted for observation and remained in hospital for 4 days, until her symptoms had completely resolved. She was discharged home with an adrenaline (epinephrine) selfadministration kit and told to read the package insert to explain its use.
Questions 1. How common is peanut allergy in the UK? 2'. Was her presentation typical of nut allergy? 3. If she did have peanut allergy was her treatment optimal?
Further history Her GP referred her for further investigation as he felt that she might have more than just nut allergy. A detailed history revealed that she had suffered recurrent swelling of her hands since the age of 4 years. She also had been investigated for intermittent abdominal pain and painful knees. She had eczema affecting her face and wrists, mild asthma and hay fever. She had previously had positive skin-prick tests to house dust mite and dog and cat dander. She was unable to wear cheap jewellery as this caused a rash. On examination she was obese, she 100
Further investigation The disparity between the low C4 and normal C3 levels prompted measurement of Cl-esterase inhibitor levels. These were normal (Clesterase inhibitor 0.52 g/L (0.28-0.5)); however, functional assessment of Cl-esterase inhibitor activity was 0% (70-140), indicating a functionally defective molecule and confirming a diagnosis of Cl inhibitor deficiency (type II).
CASE FIG. 4.2.1 Facial angioedema that is preventing the patient from opening her eyes or speaking had eczematous patches at her right wrist, marked dermographism, and respiratory examination confirmed scattered inspiratory wheeze. Investigations indicated: total IgE 731 kU/L, specific IgE to house dust mite (strongly positive), grass pollen (moderately positive), peanut (negative). Autoantibody screen negative, rheumatoid factor negative, C3 1.38g/L (0.7-1.7), C4 < 0.1 g/L (0.13-0.43), CRP 1.5mg/L (<6mg/L).
Questions 4. How does this further history affect the differential diagnosis? 5. Do the investigations rule out nut allergy? 6. What other condition(s) should be considered? 7. Do any of these have significantly different therapeutic implications?
Discussion This case demonstrates an important differential diagnosis that must be considered in anyone presenting with angioedema. Although the common causes of urticaria/angioedema are as listed in Table 4.10, Cl-esterase inhibitor deficiency (Cl-INH deficiency) typically causes angioedema but not urticaria. This presentation is typical in a number of respects of the experience with ClINH-deficient patients. She was symptomatic as a child, with some hand swelling and prominent abdominal pain. In her case this was diagnosed as abdominal migraine, but the more likely cause was Cl-INH deficiency-related abdominal pain, which is thought to be caused by angioedema affecting the bowel wall. The development of facial swelling as a teenager is also typical. Attacks commonly become more frequent and severe after puberty (and during pregnancy), the explanation for this being the relative changes in hormonal balance affecting Cl-inhibitor synthesis from the normal allele. Interestingly, however, the patient did have an atopic background with eczema and asthma, as well as a history of nickel sensitivity. On examination she also had dermographism. Thus she was demonstrating conditions characterized by types 1 and 4 hypersensitivity reactions, and this undoubtedly contributed to the initial
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CASE STUDY 4.2 CONTINUED clinical diagnosis in the A&E department of probable allergic angioedema. The importance of the complement investigations in angioedema cannot be overestimated. Cl-INH deficiency, cryoglobulinaemia or genetic deficiency of C4 usually explains the finding of very low C4 despite normal C3. Thus measurement of complement levels is an extremely useful investigation, and a normal C4 during an attack of angioedema virtually excludes the diagnosis of Cl-INH deficiency.
The treatment of acute lifethreatening angioedema in this condition is very different from that required for allergic angioedema. Life-threatening attacks commonly occur after dental work that precipitates laryngeal angioedema and respiratory obstruction. Emergency treatment consists of 1000-1500 units Cl-INH concentrate intravenously, with close clinical observation in hospital. Prophylactic therapy is also considered for patients with frequent attacks. In this
whether it is of the IgG or the IgM isotype. For example, a significant antinuclear antibody (ANA) would be of high titre (>1:80) and IgG class. If the ANA pattern was not homogeneous (e.g. speckled or nucleolar) this might indicate specific subsets of connective tissue disorders (mixed connective tissue disease, systemic lupus erythematosus, scleroderma). Once an antinuclear antibody is detected, specialist immunology laboratories will further characterize it according to which nuclear antigen is targeted (Table 4.11). Again, this is helpful in the subcategorization of connective tissue disorders and the recognition of susceptibility to specific complications (e.g. anti-Ro antibodies and neonatal congenital heart block).
Diseases associated with type IV hypersensitivity Contact eczema The most common clinical example is nickel hypersensitivity. Affected individuals develop an eczematous reaction to nickel-containing jewellery, watches, buttons etc. that are in prolonged contact with the skin. The reaction is usually confined to the area of contact. Although sometimes referred to as 'nickel allergy', IgE mechanisms are not involved in the pathogenesis of this condition. Nickel is absorbed directly through the skin and binds to selfproteins (haptenization).This stimulates CD4+ T cells, which are recruited to the area, and there is associated oedema of the epidermis. This reaction occurs over 24-48 hours and is artificially recreated during 'patch testing', which is widely used to investigate type IV hypersensitivity. Granulomatous hypersensitivity Granulomatous reactions represent the full development of type IV hypersensitivity reactions, in which antigen persists and a focus of inflammation is established. The tuberculin reaction is a modified, self-limiting form which occurs, for example, with the Mantoux and Lepromin tests.
case the patient was commenced on cyclokapron 500 mg q.i.d., in preference to androgenic steroids, because of the potential virilizing effects of the latter. She was also provided with a warning bracelet that gave details both of her diagnosis and the necessary treatment in case of an emergency. Family studies confirmed that her biological parents were not affected and that this was one of the significant minority of cases caused by a new mutation.
These involve the intradermal injection of M. tuberculosis and M. leprae extracts. The local skin reaction is characterized by an area of induration and swelling which is mediated by sensitized lymphocytes. CD4+ lymphocytes predominate and accumulate, along with macrophages around blood vessels, with a maximum infiltration at about 48 hours. This reaction is focused at the site of foreign antigen in the dermis and is self-limiting, as antigen is progressively degraded and removed. Where antigen persists, however, granulomatous features can develop. Granulomas are collections of macrophages, some of which form giant cells; others appear as epithelioid cells. A cuff of small lymphocytes surrounds these. Granulomas may develop in response to foreign antigen (Mycobacterium infections) or as part of a presumed autoimmune response (Wegener's granulomatosis, sarcoidosis or CVID). The clinical effects of granulomas depend on the underlying cause, and the number, size and location of the lesions. They may cause significant destruction and morbidity, e.g.TB in the lungs, or they may be an incidental finding, e.g. in CVID in the liver. In mycobacterial infection it is recognized that the immunoregulatory Thl/Th2 response influences the degree of granuloma formation and indeed the individual's clinical manifestation of infection. If the response is predominantly of the Thl phenotype, with activated T cells producing IFN-y and IL-2, there is marked granuloma formation and, in the case of leprosy, the clinical pattern is tuberculoid. Tuberculoid leprosy is characterized clinically by localized granulomatous lesions which may be asymptomatic and which contain few viable organisms. In lepromatous leprosy there are widespread skin lesions containing numerous bacilli but few lymphocytes. These patients have a predominant Th2 phenotypic response to the organism (Th2 cells secrete IL-4, IL-5 and IL-10) and no clear granuloma formation. Consequently, M. leprae are able to proliferate and disseminate more freely in lepromatous leprosy, and the patient suffers the systemic effects
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of the infection. Host response in the form of hypersensitivity may therefore be advantageous under certain circumstances, and modification of the response by the administration of exogenous cytokines (e.g. interferon-y) can change the pattern of disease. 1
IMMUNOSUPPRESSION The rapid development of organ transplantation has been dependent on the availability of effective immunosuppressant drugs. An ideal immunosuppressant would be antigen specific and free of side-effects, but none of the currently available drugs meets these criteria. The clinical use and relative merits of the major immunosuppressant drugs are outlined below, as are some newly emerging immunomodulatory strategies. Corticosteroids These drugs have been widely used in the treatment of autoimmune diseases, malignancy and graft rejection for many years. The immunosuppressant action is difficult to separate from other potent anti-inflammatory actions of steroids. In humans it is mediated mainly through an inhibitory action on monocytes and macrophages, with reduced phagocytic function and diminished IL-1 secretion. Although in animals there is a marked lymphocytotoxic effect, in humans this is only significant against abnormal lymphocytes, for example in lymphoproliferative disorders, and when used at very high doses. Corticosteroids are potent immunosuppressants but their major disadvantage is multiple side-effects; these include weight gain, hirsutism, hypertension, diabetes mellitus, recurrent infection, growth retardation, osteoporosis, and reduced response to physiological stress. The appropriate dose of corticosteroid is determined by the individual clinical situation. For the long-term control of autoimmune disorders an oral dose of <10mg/day prednisolone would be appropriate. In the acute management of autoimmune haemolytic anaemia, acute glomerulonephritis or immune thrombocytopenic purpura, l-2mg/kg/day is indicated. In very severe life-threatening situations, such as systemic vasculitis, pulsed high-dose regimens of l0mg/kg are used (maximum 1000mg).
CYTOTOXIC DRUGS (see Chapter 6) This group of drugs kills cells capable of self-replication and they were initially introduced in the treatment of cancer. Their introduction into the management of trans1
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MCQ 4.4
2
Case 4.2
3
MCQ 4.5
plantation and autoimmunity enabled reductions in the doses of corticosteroids required (in this situation they are often referred to as 'steroid-sparing agents'). The major complication of long-term use is myelosuppression and immunosuppression, and a long-term increase in susceptibility to malignancies. Azathioprine Azathioprine is an analogue of the cytotoxic drug 6mercaptopurine (both are thiopurines) and was originally introduced in the 1950s for renal transplant recipients. It now has a major use as a steroid-sparing agent in the management of many autoimmune disorders. Thiopurines block the synthesis of inosinic acid, the precursor of adenylic and guanylic acids, and thus impair DNA synthesis. Their major cytotoxic effect is on developing T and NK cells, and thus there is a delay before clinical onset of action. The most important side-effect is bone marrow suppression. Weekly monitoring of full blood count (FBC) is advised during induction, with 3-monthly FBC during maintenance therapy. The patient must be warned of potential susceptibility to infection, and any unexplained illness or clinical suggestion of infection requires thorough investigation and, potentially, withdrawal of treatment. The usual maintenance dose range is l-3mg/kg daily. 2 Cyclophosphamide This is one of the most widely used drugs in cancer chemotherapy and is now frequently used in combination with corticosteroids in the management of severe autoimmune conditions, especially systemic vasculitis. As an alkylating agent it acts by cross-linking DNA strands, thereby preventing normal mitosis. It is particularly toxic to B cells. Side-effects include a dose-dependent neutropenia and lymphopenia, alopecia and infertility (especially in males) and, infrequently, haemorrhagic cystitis. Cyclophosphamide is typically used in combination with prednisolone in either oral or intravenous protocols to control severe systemic vasculitis. Dosage is determined by disease severity and according to renal function, bone marrow function and the patient's age. Mycophenolate mofetil Mycophenolate mofetil is used in combination with corticosteroids and ciclosporin in the prophylaxis of renal transplant rejection. Mycophenolic acid (MPA) is the active metabolite and is rapidly produced by hydrolysis after ingestion of the drug. MPA selectively inhibits inosine monophosphate dehydrogenase (IMPDH), which prevents lymphocyte purine biosynthesis. The inhibition of IMPDH causes a depletion of guanine nucleotides, inhibition of DNA synthesis, and prevents clonal expansion of both T and B cells. Close monitoring is necessary with weekly full blood counts (FBC) for the first month of treatment, 2-weekly for the next month, and monthly for the first year of treatment. Its use is currently limited to specialist transplantation units.
Methotrexate This drug is used in maintenance treatment of childhood leukaemias and is increasingly used in the control of a number of inflammatory diseases, including rheumatoid arthritis, polymyositis, psoriasis, Reiter's syndrome and graft-versus-host disease following bone marrow transplantation. It also appears to have a role in steroiddependent asthma, although the exact mode of action in this condition is unclear. Methotrexate inhibits dihydrofolate reductase, thus preventing the conversion of folic acid to its active form, tetrahydrofolate. This prevents normal thymidine synthesis and cell division. Side-effects include bone marrow suppression, megaloblastic anaemia, pneumonitis and mucositis. Long-term drug toxicity is increased in hepatic impairment. Acute side-effects are partially reversible by the administration of folinic acid.
NON-CYTOTOXIC IMMUNOSUPPRESSION Ciclosporin This relatively recently introduced drug has revolutionized the management of post-transplantation patients and is also finding a place in the management of some autoimmune disorders. A fungal metabolite with a cyclic undecapeptide structure, it acts to selectively inhibit T-cell activation. The drug binds to cytosolic proteins, called cyclophilins, which prevent calcium-dependent activation of the IL-2 gene. IL-2 transcription is a crucial event in T-cell activation and thus cyclosporine is a relatively selective immunosuppressant. Ciclosporin does not cause myelotoxicity but does cause a dose-dependent reduction in renal function that must be carefully monitored and differentiated from renal transplant failure or rejection. Monitoring of therapeutic plasma levels is essential. Other side-effects include hirsutism, gingival hyperplasia and seizures. In common with other immunosuppressants there is an increased long-term risk of lymphoma and skin neoplasia. Tacrolimus (FK506) This macrolide is not chemically related to ciclosporin but has a similar mode of action. Its use is currently limited to hepatic and renal transplant patients, although there is evidence to suggest it will have significant clinical impact in autoimmunity. Tacrolimus binds to the cytosolic FK506binding protein (FKBP), preventing IL-2 gene activation. It has a similar range of side-effects to ciclosporin. 3
NEWER IMMUNOSUPPRESSIVE STRATEGIES In addition to the pharmacological immunosuppressive drugs, a number of new immunological therapies are emerging in clinical practice.
Plasma exchange has been available for many years and continues to be of value in the acute management of some severe autoimmune conditions, including Goodpasture's syndrome, myasthenia gravis and rhesus disease, in which autoantibodies are demonstrated to be pathogenic. Plasma exchange allows the removal of these autoantibodies acutely but has no proven role in the long-term management of these conditions. High-dose ivIg therapy (l-2g/kg) is of proven benefit in autoimmune thrombocytopenia and Kawasaki's and Guillain-Barre syndromes. Its mode of action is incompletely understood, but may involve blockade of Fc receptors, disturbance of anti-idiotypic networks, or suppression of macrophage and/or T-cell activation. This therapy has specific side-effects, including aseptic meningitis, acute haemolysis (when ivIg is uncross-matched) and acute deterioration in renal function. It should therefore only be used for conditions in which clinical benefit is proven by properly controlled studies. Monoclonal antibody (moAb) therapy has shown encouraging results in a number of areas of clinical practice. CAMPATH-1 is a humanized mouse anti-CDw52 moAb, an antigen which is present on all leukocytes. It has proved to be of particular value in the treatment of acute graft rejection and graft-versus-host disease following bone marrow transplantation. More specifically, anti-CD25 moAb (basiliximab), which prevents T-cell activation, has been introduced for the prophylaxis of acute renal rejection. Antitumour necrosis factor (anti-TNF) moAb has recently shown promising results in the control of disabling rheumatoid arthritis (RA) and in severe inflammatory bowel disease, especially Crohn's disease. TNF is believed to have a central role in the pathogenesis of these diseases. Future clinical developments in this area may follow from current preclinical studies. 'Biological immunosuppressive agents', including antibodies directed against cell surface molecules of T, B and antigen-presenting cells, are being studied in models of transplantation and autoimmunity. These models may indicate new modalities for controlling undesirable immune responses through modulation of the function of the cell surface signalling molecules. Antibodies directed against gp39 (CD40 ligand) and CD28 have been demonstrated to overcome renal allograft rejection in a primate system. Human clinical trials (phases I and II) of these agents are currently under way. Anti-LFA-1 moAb has also been used to control transplant rejection. The cell surface molecule CTLA-4, which is known to downregulate T-cell responses, also has the potential for therapeutic manipulation. CTLA-4 linked to immunoglobulin molecules (to prolong its half-life in the circulation) has been successfully used in clinical trials to treat psoriasis. In respiratory medicine, IL-8 receptor antagonists are being evaluated in airway disease, and antiIL-5 moAb is under investigation in the treatment of asthma. These experiences of 'biological immunosuppression' suggest that this will be a major area of therapeutic development in the coming years, with novel drug devel-
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opment for a wide range of disorders associated with inappropriate or excessive immune activation.
FURTHER READING Chapel H M 1994 Consensus on diagnosis and management of primary antibody deficiencies. British Medical Journal 308:581-585. Chapel H, Heaney M, Misbah S, Snowden N 1999 Essentials of clinical immunology, 4th edn. Blackwell Science, Oxford. Conley M E, Notarangelo L D, Etzioni A 1999 Diagnostic criteria for primary immunodeficiencies. Clinical Immunology 93(3):190-197.
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Janeway C A, Travers P 1997 Immunobiology - the immune system in health and disease, 3rd edn. Churchill Livingstone, Edinburgh. Primary immunodeficiency diseases. Report of an IUIS scientific group. 1999. Clinical and Experimental Immunology 118 (suppl l):l-28. Reeves W G, Todd I 1996 Lecture notes on immunology, 3rd edn. Blackwell Science, Oxford. Rosen F S, Cooper M D, Wedgewood R J P 1995 The primary immunodeficiencies. New England Journal of Medicine 333(7):431-440. Stites D P, Terr A I, Parslow T G 1997 Medical immunology, 9th edn. Appleton and Lange, Connecticut.
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Nutrition in Clinical Medicine Michael E J Lean
Food and its use 105
Overweight and obesity 128
Assessment of nutritional status 115
Nutrition support 132
Dietary intake assessment 117
Nutrition as a cofactor in disease and in therapy 136
Nutrition and feeding practices for growth 119
Food sensitivity and intolerance 140
Malnutrition 120
Nutrition in health promotion: current diet and proposals for change 141
Vitamin deficiencies and excesses 122 Trace elements 127
FOOD AND ITS USE FOOD CHOICE AND FOOD COMPOSITION There is no doubt that diet has profound influence on human health, at all ages and affecting all medical subspecialties. Defining and influencing nutritional status is, however, very complicated. Although we customarily summarize the diets of individuals and populations in terms of nutrient exposure, there are many steps in establishing this exposure, each subject to substantial variability, both within individuals over time and between population subgroups. The general scheme (Table 5.1) may seem mostly self-evident, but indicates the scope for error in research and the need for clarity of thinking. The source of variability which may affect the evaluation of the diet of an individual or a population extends well beyond those that can be established either by retrospective questionnaires (depending on memory) or by prospective food records (depending on representativeness). Most of these influences are beyond the control of individuals, and so may tend to confound efforts to change diets.
As well as variations within the population, many of the components in Table 5.1 are also subject to fluctuations over time. Meal and snack patterns have changed dramatically over the last 10-20 years, with 'grazing' now being the norm in young people. Likewise, a generation has now emerged without experience of traditional meals or home cooking, using almost exclusively pre-prepared foods eaten in 'non-meal' situations - e.g. in front of the television, or on public transport. Increasingly homes do not have conventional kitchens, and people rely on microwaves and freezers. Although daily food shopping is still usual in Mediterranean countries, where fresh foods predominate, the steady trend in UK is towards weekly shopping, and this has profound effects on the need for long-life foods and preservatives. Retailers have progressively selected smaller ranges of foods, for shelf-life, appearance and taste, but disregarding nutrient composition. The dominance of major multiples (supermarkets) has significantly reduced biodiversity and driven farmers to produce highly stylized products. The 'added-value' food processing industry is now the major profit source, such that the most heavily advertised and promoted foods are those with the poorest nutritional value. Individual food choice is very complicated, but essentially demands a mix of the known and safe with a little of something new. Over recent decades there have been progressive trends to increase the sweetness and saltiness of foods. This has created a taste expectation, such that home-prepared foods can taste unpleasant if they contain less (i.e. normal amounts) sugar or salt. On a more positive note, the quest for 'health' by consumers is becoming a major driver for food choice and for reformulation of products. Globalization and sophisticated trading and transport have introduced unfamiliar foods, but also a new layer of uniformity which makes change difficult. The influence of season has all but disappeared, to the extent that many people are suspicious of seasonal foods - even locally grown ones, such as soft fruit. The nutrient composition of foods, catalogued in food tables and databases, is drawn up from analyses of a few examples of each food. One or two (e.g. potatoes) take account of seasonal variations in composition, but not the other factors outlined above. These tables provide only a broad guide as to the nutrient composition of the foods consumed by an individual or in a particular survey. Dietary analysis is imprecise, with scope for serious error. For some foods, similar varieties can contain up to 100-fold differences in specific nutrients, e.g. flavonols in lettuces. One way to resolve this is to assess diets, and to construct dietary advice, in terms of food groups consisting of broadly interchangeable foods - bread/cereal/pasta/rice; fruit and vegetables; spreading fats and oils; meat/cheese/ eggs; sweets, cakes and confectionery. This type of grouping has some limitations, but serves to remind us that diets, and foods, are consumed in meals. The meal is the smallest unit of nutrition, and it is the 'eating episode' which provides a focus for individual planning.
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TABLE 5.1 Influences on diet composition and nutrient exposure with food choice and variability Diet composition
Source of variability
Meal and snack pattern Meal structure Cooking methods Home food storage methods Shopping and catering patterns Food choice of individuals Purchasing policies of retailers Farming methods Seasonal
Age, ethnicity, culture Culture, occupation, family Family structure, housing Housing, finance Socioeconomic, ethnic Age, gender, socioeconomic Profit-driven, convenience Profit-driven, subsidies Latitude, transport Analytical rigour
Nutrient composition of food groups Nutrient composition of specific food varieties
Plant breeding, health concerns
NUTRITION AND NUTRIENTS Nutrition is the process by which food is eaten and utilized by the body. More broadly, the principles of nutrition nutrient supply, storage, requirements, consumption and metabolism - can be applied at many levels. Nutritional balance, which incorporates all these factors, should therefore be considered at the levels of the cell, of organs, of the whole body and of populations. For all the processes that define nutritional balance, there are ranges within which balance can be achieved at a level compatible with health. Outside these ranges malfunction and disease will result from deficiencies, toxicity or competition between nutrients. Within 'normal ranges' of nutrition, research is beginning to define levels which may determine optimal long-term health, and which may differ between individuals according to genetic background. In the presence of disease, nutrient requirements, supplies and metabolism are altered. Nutritional status may be a cause, or part of a cause, of disease, and may in turn be altered by disease. This chapter is concerned with the ways in which nutrient supplies - especially energy - are utilized, and how dietary factors and deficiencies may produce specific clinical syndromes or contribute to the development of disease.
DIETARY REQUIREMENTS AND REFERENCE VALUES
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Defining the nutritional requirements of individuals, or of groups or populations, is one of the most important aims of nutritional science. Information of this kind is essential for designing food supplies, and therefore it has major economic and political implications.
Certain nutrients are essential, i.e. they are necessary components or precursors of human biological pathways, that cannot be synthesized by humans. Essential nutrients include energy (provided by carbohydrates, fat and protein, together with oxygen and water), essential amino acids and fatty acids, and vitamins and essential trace elements. Foods also contain large numbers of other biologically active compounds which can modify metabolism and function. These are not 'essential', but may have beneficial actions for current or long-term health. Finally, there are compounds in foods which are not nutrients. These include environmental contaminants and inert or non-absorbable compounds. They may still affect health through toxic or allergic mechanisms, so the quantity present in foods may be important. Living cells require a continuous balanced supply of nutrients. However, food and nutrient supply is intermittent, and the body must also accommodate periods of nutrient deprivation, whether through famine or illness. The relationship between storage and tissue requirements determines survival time during nutrient deprivation. For oxygen (with only limited local capacity for anaerobic respiration and no storage), survival is measured in minutes. For carbohydrates and water, a clinical problem may occur in hours or a few days. For most water-soluble vitamins and some minerals (e.g. zinc), nutrient status also declines in days of deprivation. In contrast, in the case of the fatsoluble vitamin B12 and iron, full stores can permit many weeks of dietary deprivation. Traditionally, dietary nutrient requirements have been established for the essential nutrients on the basis of the amount per day which is sufficient to prevent a clinical deficiency syndrome developing, with a margin between 30 and 100% to produce a recommended daily amount, or RDA. This safety margin will depend on the nature of the nutrient. Fat-soluble vitamins, which tend to accumulate in the body and can be toxic, have a lower safety margin than water-soluble vitamins, which are rapidly excreted if consumed in excess. For many nutrients, deficiency syndromes develop slowly and isolated deficiencies are rare, so it has been hard to define RDAs. The 'safe intake' is often quoted. These are intakes which are customarily consumed by apparently healthy people. However, there are variations within the range of intakes in the general population. At a cellular level, most nutrients required for normal metabolism are synthesized. In some situations - in illness when supply is limited or demand is increased - there may be a conditioned deficiency of 'non-essential' nutrients which take on the role of 'conditioned essentials'. It appears that, for some nutrients (notably the antioxidant vitamins), there are levels of intake, well above those needed to prevent deficiencies, which are associated with optimal long-term health. Higher intakes than the RDA of vitamin E, for example, appear to have some protective effect against heart disease and some cancers. The RDA for folate, sufficient to prevent folate deficiency, is insufficient to prevent neural tube defects in susceptible women. Furthermore, within the recommended or 'normal' range
a
FIG. 5.1 Dietary reference values - definitions 95% of people would be adequately nourished if they consumed the RNI, and 95% would be deficient at LRNI.
FIG. 5.2 Dietary intakes and risk of deficiency with and without adaptation The risk of clinical deficiency is reduced when there is adaptation to low intake as it falls below the LRNI.
TABLE 5,2 Criteria for defining dietary reference values of folate intakes there is an inverse correlation with plasma homocysteine, a risk factor for heart disease. For most vitamins and minerals the average intakes in western countries are well above the RDAs, but some - e.g. iron, thiamine, folate, vitamin D, vitamin E - are marginal in certain population groups In 1991, the UK Committee on Medical Aspects of Food Policy, published a new approach to dietary reference values for a total of 40 nutrients. The reference nutrient intake (RNI) is defined as 2SD (standard deviations) above the estimated average requirement (EAR), and the lower reference nutrient intake (LRNI) as 2 SD below it (Fig. 5.1). Thus 95% of people would be adequately provided for by consuming the RNI and, assuming no adaptation to low intakes, 95% would be deficient if they consumed the LRNI (Fig. 5.2). The exception to this general rule is the energy requirement. Assuming the need to maintain a constant weight, only an EAR is quoted. The evidence used included not only the classic clinical deficiency evidence, but also data on blood or tissue saturation and on nutrient-dependent enzyme function (Table 5.2). For a number of nutrients adequate scientific data are still not available, and so 'safe intakes' are quoted. The questions surrounding optimal intakes for future health are still unresolved, apart from fatty acids, which follow the recommendations for cardiovascular health. Dietary reference values (DRVs) are determined for healthy people, and assume normal status for other nutrients. The factors affecting requirements are summarized in Table 5.3.
• • • • •
Amount taken without deficiency developing Amount needed to cure deficiency Amount needed to maintain blood or tissue concentration Amount needed to maintain enzyme saturation Amounts associated with appropriate biological marker of adequacy
TABLE 5.3 Factors which affect requirements of nutrients 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Size Age Growth Sex Physical activity Pregnancy Lactation Availability from specific foods Illness Deficiencies of other nutrients
ENERGY Energy, utilized over time to produce work or build body tissues, is expressed as kcal or kJ (1 kcal = 4.18kJ). It is supplied by fat (9kcal/g), ethanol (7kcal/g), protein (4kcal/g),
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carbohydrates (3.75kcal/g) and dietary fibre (2-3kcal/g). Because energy cannot be created or destroyed, energy intake always equals energy output, plus or minus changes in energy stores. The body stores some energy as carbohydrates, in the form of glycogen (mainly in the liver), which provides a source of glucose. Total glycogen stores contain about 250 g, or 1000 kcal. The remaining energy stores are as triglycerides in adipose tissue. An average person with 20kg of adipose tissue has energy stores of 20 x 7000 = 140 000 kcal, enough to provide for 70 days' starvation at 2000 kcal/day. Carbohydrate cannot be synthesized from fatty acids. There are no specific stores of protein, but during starvation protein is metabolized from the destruction of muscle and connective tissue. This, and the glycerol from triglycerides, provides some glucose for organs dependent on glucose. Energy is necessary for the maintenance of all metabolic processes, physical activity and growth. Most dietary energy is needed to maintain oxygenation, blood supply and ionic gradients across membranes in all tissues. This is termed the basal metabolic rate (BMR). Energy expenditure can be measured by indirect calorimetry, usually in the early morning in a resting state, the subject having last eaten the previous evening. This resting energy expenditure (REE) is close to the BMR. BMR can be estimated with reasonable accuracy from the sex, age and body weight (Table 5.4). More recent 'doubly labelled water' methods measure energy expenditure in free-living adults using the different excretion rates of the stable isotopes deuterium (3H) as water, and 18O as water and CO2, to obtain an estimate of CO2 production and hence total energy expenditure (TEE). The difference between TEE and BMR measures the energy expenditure in association with feeding and from physical activity (Table 5.5). The energy requirement of an individual subject, which is equal to TEE if weight is to remain constant, depends primarily on body size and composition. Age, physical activity, environmental temperature and physiological state (whether pregnant, lactating or suffering from sys-
SUMMARY 1 Factors affecting basal metabolic rate and total energy expenditure Factors affecting basal metabolic rate • body weight • age/gender
relative proportion of lean body mass to adipose tissue recent weight change or energy imbalance
• thyroid function
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Factors affecting total energy expenditure • basal metabolic rate • physical activity and body weight (work output) • diet composition (carbohydrate, protein, fat proportions) • inflammatory conditions, altitude
TABLE 5.4 Equations for estimating basal metabolic rate (BMR) BMR (MJ/d)
Males
10-17 yr 18-29 yr 30-59 yr >60yr
BMR = 0.074 W + 2.754 BMR = 0.063 W + 2.896 BMR = 0.048 W + 3.653 BMR = 0.049 W + 2.459
SEE = 0.44 SEE = 0.64 SEE = 0.70
Females
10-17 yr 18-29 yr 30-59 yr >60yr
BMR = 0.056 W + 2.898 BMR = 0.062 W + 2.036 BMR = 0.034 W + 3.538 BMR = 0.038 W + 2.755
SEE = 0.47 SEE = 0.50 SEE = 0.47
W = body weight (kg), SEE = standard error of estimate
TABLE 5.5 Calculated physical activity level (PAL) of adults at three levels each of occupational and non-occupational activity Occupational activity Light
Non-occupational activity Non-active Moderately active Very active
Moderate
Moderate/Heavy
Male
Female
Male Female Male
1.4 1.5 1.6
1.4
1.6
1.5
1.5
1.7 1.8
1.6 1.7
1.6
1.7 1.8 1.9
Female
1.5 1.6 1.7
temic infection) are also important. BMR is determined by the size and metabolic activity of organs in a resting state, and so it has a major component from organs such as the heart, lungs, kidneys and brain. Skeletal muscle is relatively less important in determining BMR than it does in TEE. TEE has a very close relationship to body weight because the energy cost of physical activity depends closely on weight. Variations in BMR for a given weight can reflect metabolic factors such as thyroid function. Energy expenditure may be considerably increased in situations of metabolic stress, such as pyrexia and burns. The factors that control metabolism physiologically and modify it in disease include catecholamines, thyroid hormones, insulin, cortisol and cytokines (e.g. tumour necrosis factor-a). Energy requirements are highest - on a body weight basis or per unit 'lean body mass' - in infants and young children. Energy expenditure starts to fall in the 20s and declines steadily thereafter into old age, principally because of declining physical activity, with consequent reduction in muscle mass. Because the factors affecting energy requirement vary considerably between individu-
TABLE 5.6 Average daily energy expenditure In various lifestyles
a
24-hour energy expenditure in kcal (MJ) Occupation (age in years)
Men
Retired elderly (65+) Housewife (25-45) Office worker Laboratory technician (20-50) Factory worker (20-45) (heavy industry) Labourer (20-45) (heavy physical work)
2300 2500 2800 3200 3600
Women (9.5) 1900 2200 (10.4) 2100 (11.7) 2200 (13.2) 2400 (14.8)
(7.8) (9.0) (8.6) (9.0) (9.9)
TABLE 5.7 Average energy expenditure of an adult in various degrees of physical activity Degree of activity
Expenditure (kcal/min)
Minimal (e.g. sitting, slow walking) Moderate (e.g. walking, gardening) Intermediate (e.g. swimming, brisk walking) Heavy (e.g. digging, squash, running)
1 5 7 10
als, it is impossible to give an exact ideal nutrient intake, but there are clearly differences in daily energy expenditure between adults with different lifestyles (Table 5.6) and at different ages (Fig. 5.3). The energy expenditure for physical activity depends on body size, so it is convenient to express the energy costs of different activities as functions of BMR. Table 5.7 shows the energy required for various physical activities. As the total time in each 24 hours spent in strenuous activity is often rather short, significant increases in energy expenditure are difficult to sustain. Weight reduction by increasing physical activity is therefore hard to achieve. In adults the main indicator of energy balance (and often of overall nutritional status) is change in body weight. Weight varies by up to 1-2 kg from day to day in healthy adults, and is more affected by fluid balance over the short term. Weight change due to altered energy balance is usually accounted for by fat stores, at 9000kcal/kg (75% of weight change), and lean body mass, at l000kcal/kg (25%). Thus each 1kg change in adipose tissue reflects about 7000 kcal shift in energy balance. Although metabolic rate is governed principally by body weight, the alterations in metabolic rate from weight changes are relatively small: a 1kg weight change alters metabolic rate (and thus energy requirement for weight stability) by only about 15kcal/day. In children energy is required for growth, and measurements of weight gain or height gain are useful indicators
FIG. 5.3 Estimated average requirements for energy intake [A] at different ages, and B during pregnancy and lactation for women.
of dietary insufficiency. During the first few weeks of catchup growth from severe malnutrition, the energy cost of weight gain is about 5kcal/g. Thereafter, it becomes more energy expensive to lay down tissue, as fat rather than lean tissue is laid down. Energy balance can be maintained from a wide range of nutrient origins. In the UK, fat and carbohydrate each provide between 40 and 50% of dietary energy, whereas in developing countries the proportion from fat may be less than 15% and from carbohydrates more than 75%. Protein provides 10-15% of energy in most diets, in both western and developing countries.
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Dietary energy deficiency is that amount which results in negative energy balance. This results in immediate mobilization of energy stores from glycogen and fat. As underfeeding continues a greater proportion comes from protein, principally through muscle atrophy. Excess energy intake will be stored as glycogen if the limited capacity of the liver permits, or as fat in adipose tissue. Gross excess will lend to storage in tissues such as liver, impairing liver function. Minor imbalances of energy balance occur between meals and from day to day. Energy imbalances insufficient to be detected in body weight will have metabolic effects, e.g. on insulin sensitivity and serum lipoprotein.1
PROTEIN Most major human foods include protein, in an amount equivalent to 5-50% of food energy (Table 5.8). Mixed diets usually supply 10-20% of energy as protein. The requirement for dietary protein is determined by tissue growth and repair. The healthy body is efficient in the utilization of amino acids. Total body protein in an adult is about 16kg, which has accrued over 15-20 years of growth. Healthy protein is constantly being broken down and resynthesized in the process of protein turnover, but the amino acids are mostly reutilized. Losses from skin, hair and gut mucosa contribute to an absolute requirement of about 0.6g/kg/day for adults, or about 8% of dietary energy. Although humans cannot incorporate inorganic nitrogen, colonic bacteria can. It is therefore possible for some nitrogenous waste in the bowel to be rescued by bacterial amino acid synthesis and subsequent absorption. There are no body stores of protein or amino acids, but periods of low intake can be tolerated by metabolism of tissues such as muscle, gut mucosa and skin. However, atrophy of these tissues is more likely to reflect total energy deficiency, not specifically protein. The maximal protein requirement for optimal growth in infancy is about 1.5g/kg/day. This is amply provided by human milk, whose protein content is 130g/L, 7.5% energy.
SUMMARY 2 Protein requirements in health • • • •
Protein deficiency impossible with normal food provision Most dietary protein is metabolized like carbohydrate Minimum safe consumption (about 8% dietary energy) Requirements for essential amino acids virtually always met by 1 g/kg/d (= 10% dietary energy)
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MCQ 5.1
TABLE 5.8 The protein content of some foods which are often major protein sources Protein source Cassava Cooked bananas (plantains) Sweet potatoes Human milk (4.1 % fat) Rice (brown or white) Millet flour Potatoes (old, main crop) Maize (sweetcorn kernels) Wheat flour (wholemeal) Groundnuts (peanuts) Cows' milk, full fat (3.9% fat) Beans and peas Lentils
Eggs Cows' milk (skimmed) Fish (fatty) e.g. mackerel Soya (tofu) Meat (lean) (beef) Fish (white)
Proportion of energy as protein (%) 2 3 5 7 7 7 11 15 16 18 19 31 34 34 40 42 45 50 94
It is assumed that human milk contains the amino acids required for growth in optimal proportions, and this is likely to be similar for other milks, and eggs. There are nine amino acids which are not synthesized in the body, and are thus 'essential' nutrients. Others are needed in the diet to optimize utilization, although they are not technically essential. The ability to synthesize specific amino acids may be compromised during illness, such that 'conditioned essentiality' may develop, e.g. for glycine in infants. The metabolic requirement for amino acids is a separate consideration from dietary requirement. Essential amino acids thus form a small part of metabolic requirement, whereas non-essential amino acids (normally readily synthesized in the body) may be required in large amounts. To some extent alterations in colonic bacterial amino acid synthesis may modify essentiality. Because certain foods are deficient in essential amino acids (cereals, for example, are deficient in tryptophan, methionine and cysteine) an optimal amino acid balance can only be achieved by combination with other foods (such as legumes, which are rich sources of tryptophan and methionine). Thus a diet based on maize and beans is consumed by millions of healthy people all over the world. Most mixed diets contain much more protein than is required for health, and the excess is metabolized, mainly as carbohydrates, allowing the correct balance of amino acids to be extracted for protein synthesis. Protein is absorbed in the small intestine as amino acids and small
peptides, after the action of luminal peptidases such as trypsin. Isolated dietary protein deficiency is extremely rare outside famine situations. Low-protein foods such as cassava or plantains are not otherwise eaten in isolation. Even when intakes of ethanol or fat and sugar are extreme, protein requirements in western societies are usually met. There is considerable debate as to how much protein we require. The usual calculation, which has been applied to all nutritional states, is expressed as nitrogen balance - the difference between the dietary intake and the losses of nitrogen in the urine, faeces and sweat. A positive balance is achieved when intake exceeds losses, such as occurs in normal infant and child growth, or during recovery from malnutrition in adulthood. Negative balance occurs when losses exceed intake, as in systemic infection or diarrhoea, or when dietary intake is reduced. The greatest requirements for protein (relative to body weight) occur in young infants. Those less than 3 months of age require about 2.5 g protein/kg body weight/day, and the older infant (9-12 months of age) requires 1.5g protein/kg body weight/day. Children need less than infants but more than adults. Rates of protein synthesis vary with age, being highest in the newborn and declining with time (Table 5.9). Unfortunately, nitrogen balance measurements are difficult to conduct, particularly in the ill or deprived. The main problem is that they depend on having a complete 24-hour urine collection to estimate output. If urine collections are incomplete, as is very common, the results are biased towards an apparently positive nitrogen balance. Thus, improbable claims of positive nitrogen balance have even been made for subjects on very low-calorie diets and evidently losing weight. Nitrogen balance in adults to some extent changes with the customary diet. There is adaptation to low intakes, so that nitrogen balance has apparently been achieved with 0.2g/kg/day after several weeks. However, it is not certain that this is indefinitely sustainable in health. During illness, both protein synthesis and protein degradation are increased, so that total protein turnover is elevated non-specifically and irrespective of whether total body protein content changes. In general, there is net protein loss during disease, with wasting of muscle, and the losses are restored during recovery. The 'ebb and flow'
TABLE 5.9 Variation in rate of protein synthesis with age Age group
Body weight (kg)
Newborn (premature) 2.0 Infant 9.0 Young adult 70.0 Elderly 55.0
Total body protein synthesis (g/kg body weight/day) 15.0 7.0 3.0 2.0
phases of energy and protein balance after metabolic stress relate to the release of metabolically active compounds such as cytokines, and cannot be corrected by increasing the supply of amino acids or dietary protein. There is no simple biochemical test to estimate amino acid or protein status. Plasma amino acids and proteins all reflect stress non-specifically. Serum albumin falls with any stress or inflammatory condition - e.g. myocardial infarction, malignancy or infection - and is not a marker of nutritional status. Serum albumin may, however, be of some value in distinguishing disease-related cachexia from starvation. Low albumin in the presence of starvation is a worrying prognostic sign, usually indicating the presence of infection. This is the case in oedematous malnutrition (kwashiorkor).
a
CARBOHYDRATES There are three major groups of carbohydrates in the diet: sugars, starches, and the plant wall materials that comprise 'dietary fibre'. All carbohydrates are polymers of monosaccharides, with the common formula (CH2O)n. They are almost completely absorbed from the gut, either as monosaccharides in the small intestine after hydrolysis by amylases and mucosal disaccharidases, or (5-10%) as short-chain fatty acids following fermentation by large bowel bacteria. The main absorbed sugars, glucose and fructose, are ultimately metabolized in the Krebs cycle to release energy through oxidation. Each carbon atom combines with two oxygen atoms to produce H2O and CO2 and release 3.75 kcal/g. Of relevance to the management of diabetes and hyperlipidaemia is the 'glycaemic index' of foods. This is the incremental rise (i.e. subtracting this baseline value) in blood glucose over 3 hours after eating 50 g carbohydrate from a food, expressed as % of the rise after 50 g carbohydrate from bread, which is used as a standard. It is possible to predict the glycaemic index of a whole meal from those of its component parts. Low glycaemic index foods, reflecting the content of fat and dietary fibre, consistency, cooking or processing and other undefined factors, are associated with lower blood glucose and insulin (i.e. increased insulin sensitivity) and with improved serum lipoprotein profiles. • Sugars. Sucrose and its components glucose and fructose are the sugars most used as sweeteners. Lactose (glucose-galactose) is the main sugar in milk. Fructose is the sweetest. The monosaccharides glucose, fructose and galactose are readily absorbed at the jejunal surface. The disaccharides sucrose, maltose and lactose are equally well absorbed as the monosaccharide component parts, provided that there has been effective hydrolysis by the intestinal disaccharidases. Sucrose intolerance and lactose intolerance, leading to watery diarrhoea, may occur during starvation or any diarrhoeal disease, as a result of mucosal atrophy and secondary
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disaccharidase deficiency. This is a strong argument for maintaining gut function by enteral feeding in postoperative and intensive care patients. • Starches. These comprise a group of polysaccharides containing large numbers of glucose units linked together to form branched chains. They are variably hydrolysed as a result of cooking, and are then further hydrolysed within the intestine. The commonest are the dextrins amylose and amylopectin. About 90% of starch is rapidly hydrolysed and absorbed in the small intestine. The remainder (some altered by processing or cooking to become hydrolysis resistant) passes with non-starch polysaccharides to the colon. • 'Dietary fibre' - non-starch polysaccharides. Plant walls contain a range of lignins, celluloses and hemicelluloses that are not digested in the intestine, and which are variably degraded by intestinal bacteria in the colon. Dietary fibre can be measured in a variety of ways in foods, but its function in maintaining healthy colonic flora - an essential function - can be performed differently by the different subclasses, and by other compounds, such as lactose in breastfed infants. Different dietary fibres have important physiological functions in influencing the absorption of sugars and the regulation of serum lipoproteins (soluble and gum-forming fibre from vegetables, fruits, legumes and oats) and in contributing to intestinal bulk and large bowel health (cereal fibre such as bran). Dietary reference values for carbohydrate are shown in Table 5.10. 'Extrinsic' sugars are those outside intact cells in foods. Several varieties of non-sugar sweetener exist. Sorbitol is a sugar alcohol; however, its energy value is similar to that of other carbohydrates. Saccharine has no chemical or nutritional relationship to sugars and provides no energy; it is about 500 times as sweet as sucrose. Aspartame is an amino acid-based non-nutritive sweetener. EU regulations control the amounts of sweeteners that are permitted in foods. None have been shown to be hazardous to humans, but the recommended limits can be exceeded by individuals with unusually repetitive food habits, and by diabetic children who consume large amounts of highly sweetened foods. Very high consumers should vary the types of artificial sweeteners used.
FAT
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Fatty acids provide the chief store of energy in the body. They are important in the development of all cell membranes and some tissues, and are essential components of some hormones. Dietary fatty acids are mainly supplied as triglycerides. These are esters of glycerol and three fatty acids. Fatty acids are characterized by the chain length, expressed as the number of carbon atoms (short chain C2-C4, medium chain C6-C12, long chain C20-C24), and by the number and position of double bonds (one double
TABLE 5.10 Dietary reference values as percentage of total energy* Population average Saturated fatty acids cis-polyunsaturated fatty acids of which essential fatty acids
10(11)
cis-monounsaturated fatty acids frans-fatty acids Total fatty acids Total fat Non-milk extrinsic sugars Intrinsic and milk sugars and starch Total carbohydrate
12(13)
33 (35)
Non-starch polysaccharide (g/d)
18
6 (6.5) 3(3)
2(2)
30 (32.5)
10(11)
37 (39) 47 (50)
*The average percentage contribution to total energy does not total 100% because figures for protein and alcohol are excluded. Protein intakes average 15% of total energy, which is above the RNI. It is recognized that many individuals will derive some energy from alcohol, and this has been assumed to average 5%, approximating to current intakes. However the Committee on Medical Aspects of Food (COMA) allowed that some groups might not drink alcohol and that for some purposes nutrient intakes as a proportion of food energy (without alcohol) might be useful. Therefore average figurers are given as percentages both of total energy and, in parentheses, of food energy.
bond monounsaturated, two or more polyunsaturated). Most unsaturated fatty acids are cis isomers, but some, mainly synthetically hydrogenated, are trans isomers. Vegetable oils have a greater proportion of polyunsaturated fats and are more fluid than the more saturated fats from animal sources, which are often hard at room temperature (Fig. 5.4) although liquid at body temperatures. Fish oils need to remain liquid at temperatures down to freezing point, and so contain large amounts of long-chain n-3 fatty acids. Dietary fats are normally almost 100% absorbed as they pass through the small intestine, after emulsification through the action of bile salts, and de-esterification of triglyceride by pancreatic lipase. Most dietary triglyceride is absorbed as monoglyceride and free fatty acids. The triglyceride is thus reassembled by re-esterification in the mucosal cell, and secreted by the mucosal cell with the addition of a lipoprotein as chylomicron. Most reaches the circulation via the chyle and the thoracic duct. Some, particularly short-chain fatty acids, are preferentially released discretely into the portal vein. Dietary reference values are included in Table 5.9. Phospholipids - esters of glycerol with two fatty acids are important for the stability of cell membranes, and deficiency may affect satisfactory psychomotor development. Cholesterol is the most important sterol. It is the precursor of the bile acids (which are essential for mixed micelle formation in the intestinal absorption of fat) as well as of adrenal and sex hormones and vitamin D.
FIG. 5.4 Fatty acid composition of some major sources of saturated, mono, and polyunsaturated fatty acids
of carotenoids (the precursors of vitamin A found in vegetables) and other fat-soluble vitamins. The position is more serious when there is intestinal malabsorption of fat (Chapter 15), as fat-soluble micronutrients are excreted in the faeces, dissolved in the malabsorbed fat. In this situation the dietary fat requirement to maintain dietary needs is greatly increased and may need massive supplemental dosages of essential nutrients. Fats provide over twice as much energy per unit weight as protein or carbohydrate, as each carbon atom of the (CH2) chain combines with three oxygen atoms to produce CO2 and H2O, and 9cal/g. Fats are thus useful sources of energy in diets designed to increase the rate of weight gain, e.g. in malnourished children. Conversely, a reduction in the fat content of the diet is a relatively efficient way to lose weight and to maintain weight loss. The intestinal lipase inhibitor drug orlistat utilizes this principle by introducing malabsorption of 15% of dietary triglyceride. With a low-fat diet (<30% energy) this degree of malabsorption is usually asymptomatic. Long-term use permits maintenance of 12-15% weight loss in the 40% of patients who respond to this drug. These findings remind us that patients may lose weight as a result of asymptomatic fat malabsorption from conditions such as coeliac disease or chronic pancreatitis.
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ALCOHOL Lipoproteins are the chemical complexes, formed by the triglycerides, phospholipids and cholesterol with apoproteins, that circulate in the blood and which transport cholesterol and other fat-soluble compounds such as tocopherol. Lipoproteins can be separated by electrophoresis or according to density on ultracentrifugation, to demonstrate the classes (chylomicrons, VLDL, LDL, HDL) and their subtractions, which are familiar through their roles in atheroma formation. Triglycerides enter the bloodstream via the lymph, as chylomicra, and are converted in the liver muscle and adipose tissue to VLDL and LDL (see Ch. 17). The body is efficient at synthesizing triglycerides, sterols and phospholipids. Many populations whose diet provides only 15% of total energy as fat are able to lay down good stores of subcutaneous fat, reflecting the high capacity for synthesis of fatty acids from carbohydrate (lipogenesis) in liver, muscle and adipose tissue. Lipogenesis occurs whenever a meal provides more carbohydrate than can be stored immediately, but net lipogenesis is relatively unusual with the relatively low carbohydrate intakes in western diets. Most fat storage is from fat. Requirements for essential fatty acids are rather low (under 3% total energy) and deficiency is therefore uncommon. When diets are low in fat the high carbohydrate and protein content satisfies appetite more effectively. This may limit dietary intake and contribute to weight loss and the thinness of populations with lowfat diets. Low-fat diets may also limit the availability
There is no physiological requirement for dietary alcohol (ethanol). However, most adults have sufficient enzymatic capacity to absorb and metabolize much larger amounts than would have been met during evolutionary adaptation. Alcohol contributes 7kcal/g and tends not to satisfy appetite or to stimulate its own oxidation, and so energy from alcohol tends to be additive to the energy balance of the other proximate nutrients (fat, carbohydrate, protein). Alcohol has obvious immediate effects on the central nervous syndrome: it is a diuretic; in excess, alcohol alters lipoprotein metabolism to produce hypertriglyceridaemia; it inhibits folate absorption; and, in excess, supplants other energy sources, leading to multiple micronutrient deficiencies. The most important is thiamine (vitamin B1) deficiency. This constitutes the only true nutritional emergency. Without thiamine, disordered carbohydrate metabolism leads to Wernicke's encephalopathy and Korsakoffs psychosis (Chapter 24 p 1439). Alcoholics are also prone to scurvy because of neglect of their diet.
MICRONUTRIENTS There are large numbers of bioactive compounds in foods. A small number of these have been found to be essential for humans, who lack the ability to synthesize them. This is the basis for the definition of vitamins and essential trace elements. It is not known why nutrition has evolved in this
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CASE STUDY 5.1 ALCOHOLIC DIETARY DEFICIENCY A 42-year-old professional violinist is admitted following a witnessed grand mal seizure in a hotel bar following a performance. He gives a history of some weight loss, with anorexia and diarrhoea for 10 days. He is a smoker and admits to intermittent heavy drinking, including over the last months. There is no previous history of seizures, but some altered sensation in the feet for several months. A CT scan is reported as normal. A relative expresses concern over excessive and prolonged drinking since the death of his father 18 months previously, related to impaired performance and loss of employment.
Questions 1. What biochemical abnormality could explain the seizure? 2, What emergency nutritional therapy should be initiated on admission?
3. What is the cause of altered sensation in the feet? 4. What long-term management is appropriate?
Discussion The seizure threshold is lowered in alcoholics for several reasons, including head injuries, B vitamin deficiencies and cerebral atrophy, presumed to be a toxic effect of ethanol. In this case 10 days' diarrhoea is likely to have depleted magnesium status as a cause of seizures. There are no body stores of magnesium, which is plentiful in many foods, particularly cereals. Serum magnesium gives a good indication of magnesium status. Low levels block the secretion of parathyroid hormone and thus cause hypocalcaemia. Thiamine replacement should be
way. Humans have the genetic potential to synthesize ascorbic acid (in common with most other species), but the genes are not expressed. Certain micronutrients, e.g. metals such as iron, or fat-soluble vitamins, can be toxic in excess, and their absorption and transport are highly regulated. The absorption of metallic trace elements is generally low (15-30%), but can increase through adaptation to low intakes, or when requirements increase in pregnancy. Dietary reference values for mineral micronutrients are shown in Figures 5.5a and b and 5.6a and b, and 'safe intakes' for those whose true requirements are not known in Table 5.11. Deficiencies of individual vitamins result in specific biochemical and clinical responses, but vitamins are also involved in metabolism in more general ways. Folate, for example, is necessary for cell division and the transfer of
1
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MCQ5.2
started without waiting for biochemical confirmation of deficiency. Thiamine is particularly rich in cereals and grains, but not in alcoholic drinks. Peripheral neuropathy is a feature of several B vitamin deficiencies, but also of ethanol toxicity with inadequate antioxidant status, and of secondary diabetes when alcoholinduced pancreatic damage is severe. It seldom responds well to B vitamin replacement. Alcoholics are prone to multiple micronutrient deficiencies. Weight loss, often reflecting loss of lean body mass, indicates reduced total food consumption and may point to other chronic complications, e.g. tuberculosis. A multivitamin prescription is appropriate, but most preparations contain insufficient thiamine, and virtually none contain adequate folic acid. Alcoholics may benefit from greater intakes of antioxidant vitamins (C and E) than healthy people, but evidence is lacking.
methyl groups in protein synthesis; thus, a deficiency may impair tissue repair or growth, even if dietary energy and protein are adequate. Thiamine is important in carbohydrate metabolism, and lactic acidosis may occur in deficiency states and result in the brain damage of Korsakoff s psychosis. Ascorbic acid deficiency leads to scurvy, but it is also one of the hierarchy of antioxidant defences, so low vitamin C status reduces defences against free-radical damage (e.g. from smoking) without any signs of scurvy. A number of trace elements, such as zinc, are important in protein metabolism; deficiency of zinc is associated with an increased energy requirement for deposition of lean tissue. Children receiving nutrient supplements for proteinenergy malnutrition grow more slowly relative to the number of calories given, if they are not also supplemented with zinc. Severe individual micronutrient deficiencies may have recognizable clinical features, but even marginal deficiencies may affect metabolism of protein and energy, and the immune system. A variety of non-essential bioactive nutrients are relevant to human health. For example, flavonoids in fruits and vegetables are potent antioxidants, and may contribute to protection against coronary heart disease and cancers.
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FIG. 5.5 Reference nutrient intakes for consumption of minerals These amounts will be sufficient for the needs of 95% of people.
Some related flavones in legumes are oestrogenic, and may modify the risks of heart disease, osteoporosis and breast cancer. Dietary carnitine may become important in facilitating fatty acid oxidation if carnitine synthesis is impaired during illness. Caffeine and theobromine in coffee, tea and chocolate have several properties, including central nervous system stimulation and diuretic actions.1 NON-NUTRIENT DIETARY COMPONENTS Within foods there are some compounds which are either not absorbed (e.g. the fat substitute olestra) or which are absorbed but not metabolized (e.g. the sugar inulin). Occasionally the presence of such compounds leads to an important difference between the chemical analysis and the nutritional value of a food. It is important to consider the nutrient availability of foods, as well as their chemical composition. Certain plant sterols, particularly stanol esters, inhibit the absorption of dietary cholesterol, although they themselves are not absorbed. These compounds are marked for cholesterol lowering, on average by about 10%. ASSESSMENT OF NUTRITIONAL STATUS BODY COMPOSITION In weight, the composition of the body is about 16% protein, 10-25% fat in men (15-30% in women), 5% min-
TABLE 5.11 Safe intakes of micronutrients where dietary reference values cannot be defined. Nutrient Vitamins Pantothenic acid adults infants Biotin Vitamin E men women infants Vitamin K adults infants Minerals Manganese adults infants and children Molybdenum adults infants, children and adolescents Chromium adults children and adolescents Fluoride (for infants only)
Safe intake
3-7 mg/day 1.7 mg/day 10-200 jig/day above 4 mg/day above 3 mg/day 0.4mg/g polyunsaturated fatty acids 1 ug/kg/day 10 ug/day
1.4mg (26(umol)/day 16ug(0.3umol)/day 5-400 ug/day 0.5-1.5ng/kg/day 25ng(0.5nmol)/day 0.1-1 .0ug (2.20 nmol)/kg/day 0.05mg(3umol)/kg/day
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Functional measures, such as grip strength, are valuable to complement measures of muscle bulk. Given the wide ranges of normality, changes in repeated measures are more valuable (for example by showing falls, or a reduction in growth velocity in children). Estimation of body composition is a critical factor in human nutrition, both in clinical situations and when the nutritional status of populations is considered. A large number of indirect methods are available, varying in cost and complexity. The situation is complicated by the lack of any true 'gold standard', even for major components such as fat or muscle. For research purposes, estimates can be made from MRI, CT scanning or dual-energy X-ray absorptiometry (DEXA). These approaches can also characterize the physical distribution of tissues. Total body water (found only in non-fat tissues) can be accurately measured from dilution of deuterium-labelled water, and this is probably the most reliable guide to fat mass. Estimation of fat mass or lean body mass in clinical practice and epidemiology has to rely on well-conducted anthropometric measurements (skinfold measurements and waist circumference), either for static measurement or for detecting changes over time. These methods have been validated against underwater weighing (employing the principle of Archimedes) as an independent reference method. A variety of commercially promoted methods (e.g. bio-impedance) generally perform less well than simple anthropometry in estimating body composition.
Anthropometry
FIG. 5.6 Reference nutrient intakes for dietary vitamin consumption These amounts will satisfy the requirements of 95% of people.
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erals, 1% carbohydrate and the rest water (about 60%). This total body water is either in the cells (intracellular water, 35%) or in the vascular system and tissues (extracellular water, 25%). The most important static measures to assess nutrition are the height, weight, body fat content (usually expressed as percentage of body weight) and fat distribution (specifically the intra-abdominal fat mass). Lean body mass (bones, muscle, brain and other organs) is estimated by difference between weight and body fat.
The key measurements for anthropometry are height and weight, measured under standard conditions (e.g. fasting, without shoes, in light clothes and with an empty bladder). Height and weight are combined in the body mass index (BMI: weight (kg)/height2(m)) as an estimate of body build or fatness which does not depend on height. The 'normal range' for adult BMI is 18.5-25 kg/m2, with BMI <18.5 indicating chronic energy undernutrition and BMI >25 usually indicating increased medical hazards from overweight. The conventional cut-off of BMI >30kg/m2 is used for epidemiological classification of obesity. The normal range of 18.5-25 kg/m2 applies at all adult ages, although the medical hazards change. These criteria do not apply to children under 16, whose BMI is usually much lower than that of adults. Mid upper arm circumference reflects both muscle mass and subcutaneous fat and has been widely used to indicate overall nutritional status. Mid upper arm circumference below 23cm in men or 22cm in women is a guide to the possibility of chronic energy undernutrition. A variety of anthropometric approaches have been used to predict body fat (and hence, by difference, lean body mass). The simplest approach, which gives a high prediction and low error through bias, is measurement of the waist circumference at the level between the lowest ribs and the iliac crest when the patient is standing.
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TABLE 5.12 Influence of inflammation on biochemical nutritional analyses Analytes
Reference range
Minor inflammation (CRP<15mg/L)
Iron Zinc Selenium Copper Vitamin A Vitamin E Vitamin C Vitamin Eh Vitamin B2 Vitamin B6 Vitamin B12 Folate Lycopene B-carotene a-carotene Lutein
8-30umol/L 12-18n.mol/L 0.8-2.0 umol/L 11.5-23.5 umol/L 1.0-2.8 umol/L 15-40umol/L 10-115nmol/L 280-540 ng TDP/gHb <70% activation* 18-135nmol/L (PP) 188-1059 pg/mL 3.5-16.0 ng/mL 100-300 ug/L 92-312 ug/L 14-60ug/L 82-202 ng/L
Decreased by 40% Decreased by 10% Decreased by 10% Increased by 10-15% Decreased by 30-40% Negligible No data No data No data No data No data No data Decreased by -50% Decreased by -50% Decreased by -50% Minimal change
Major inflammation (CRP~ 100-200 mg/L)
Comments
Decreased by 60-90% Decreased by 40-60% Decreased by 40-60% Increased by 30% Decreased by 30% Decreased by 20-30% Minimal to >75% dec. No change No change Decreased by 40-50% No change No change Decreased by >90% Decreased by >90% Decreased by >90% Decreased by >70%
Liver uptake Liver uptake ? Redistribution ? Liver extraction Probable redistribution More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed More data needed
An approximate guide to the extent of change seen in analytes with different degrees of inflammation. The figures quoted are collated from disparate sources and the effects of diverse factors in different pathophysiologies may be important. TDP = thiamine diphosphate: * = of red cell glutathione reductase; PP = pyridoxal phosphate.
Body fat percentage (men) = (0.567 x waist in cm) + (0.101 x age in years)-31.8 Body fat percentage (women) = (0.439 x waist in cm) + (0.221 x age in years) - 9.5 Because the waist circumference incorporates a measure of the internal fat mass as well as of total body fat, it has recently found a place in health promotion to alert people to the need for weight management. Health risks start to develop when the waist circumference exceeds 80cm (32 in) in women or 94cm (37 in) in men. Cardiovascular risks are approximately tripled, and most subjects have symptoms from overweight when the waist exceeds 88cm (35 in) in women or 102cm (40in) in men. Waist circumference does not depend on height.
Biochemical nutritional assessment Biochemical measures are of relatively limited value in nutritional assessment. Blood or plasma is seldom the appropriate compartment to detect functional nutritional abnormalities, and extracellular fluid nutrient contents give only a crude (and sometimes misleading) indication of nutrient status. For some nutrients, e.g. zinc or amino acids, the plasma concentration may actually increase in starvation, reflecting tissue destruction. Abnormal plasma vitamins or trace elements are most frequently found when there is clear clinical evidence of malnutrition. An exception to this generalization is the measurement of haemo-
globin and the nutritional haematinics - transferrin iron, folate and vitamin B12 - where subclinical deficiencies are relatively common and demand treatment. Clinical biochemistry services now offer assays for vitamins (commonly vitamin A and carotenoids, B1, B2, B6, B12, folate, C, D, E) and trace elements (e.g. iron, copper, zinc, selenium). These are used mainly to confirm clinical suspicion of deficiency, and to monitor artificial feeding. Results always have to be interpreted in relation to clinical condition, and to indicators of stress or acute-phase reaction, such as C-reactive protein. Many vitamin measurements, e.g. vitamin C, are strongly influenced by inflammatory states (Table 5.12). Several proteins produced by the liver may be used in association with nutritional assessment, namely albumin, prealbumin, transferrin, retinol-binding globulin and thyroid-binding globulin. Plasma levels are of limited value on their own because they are affected more by short-term energy intake and by stress or inflammation.
DIETARY INTAKE ASSESSMENT Estimation of dietary intake, both of individuals and of groups or populations, is critically important to ensure health. It should not be considered an assessment of nutritional status but it complements nutritional status assessment. Dietary intake can be assessed in terms of eating
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pattern, foods, food groups and nutrients. All of these elements are important to different aspects of health by reference to standard recommendations or to dietary prescriptions for individuals. The dietary assessment of individuals is a specialized activity which needs to be conducted by trained dietitians.
Dietary intake of individuals The habitual eating pattern of an individual undergoes great variation from day to day. It is therefore usually inadequate to base any judgement on the eating habits of a single day, or even a small number of days. Certain foods are often consumed on only one day per week or less (e.g. fish on Fridays in some communities, carrots as the major contributor of B-carotene on Sundays, and liver as the major source of vitamin A much less frequently). The dayto-day variability of major nutrients is often of the order of 30-50%. Two dietetic approaches are used:
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• Retrospective dietary assessment This approach relies on the skill of the dietitian in establishing eating habits, depending on the memory of the subject. Retrospective approaches are sometimes used for a single 24-hour period or for a week, or through questionnaires to estimate habitual intake over a much longer period, perhaps 1 year. As a general rule, the more questions asked and the longer the interview, the more foods are remembered and a greater value is obtained for food intake. Cross-check questions should be employed in the dietary history in order to remind subjects of foods that may have been omitted (for example, asking how often milk is purchased may show a disparity from the answers to a question about the amount of milk consumed). The latter approach, which gives some indication of the nutritional quality of the diet, is usually employed to express the fat, carbohydrate and protein intake as percentage calories. Retrospective dietary assessment has a place in clinical practice when there is an interest in the consumption of individual foods, and learning about an individual's meal patterns is often more valuable than attempting to establish nutritional adequacy, which can often give misleading results. Patients currently referred for dietary intake assessment are mostly overweight or obviously undernourished. In both contexts misreporting is common. Overweight people, and those with restrained eating, systematically under-record or underreport by up to 50%. Brief questionnaires attempting to estimate the intake of individual nutrients, e.g. calcium, have been developed, but give rather poor results compared to fully quantitative methods. • Prospective dietary assessment. This approach does not rely on subjects' memories but does rely on a high degree of cooperation over several days, during which they are asked to complete a full inventory of all foods and drinks consumed, together with details of cooking methods and portion sizes, which may be weighed using food scales or again related to household measures.
The 'gold standard' for dietary intake assessment is the 7-day weighed intake. This approach is often impossible to apply to children, to busy working people, to the confused or demented, and to those who are socially deprived or have literacy problems. For this reason, dietary assessment is often problematic in sectors of the population where nutritional problems are most prevalent. Records over 3-4 days, including weekends and weekdays and appropriately adjusted to estimate 7-day intake, are often used. A dietitian compiles a list of foods consumed by the individual and then makes some assessment of the portion sizes and quantities eaten, usually by reference to simple household measures. Standard food tables (for example McCance & Widdowson's Composition of Foods) are now available on computer databases, so the foods can be identified by code number, and the nutrient composition per 100 g is then available for 40-60 nutrients. Nutrient intake data can be extracted in absolute amounts (in g or mmol per 24 hours), or in nutritional terms, expressed as % energy mg or mmol per l000kcal of food energy. It is helpful to be able to evaluate nutrient intake by meal type, in order to identify meals (e.g. lunches) which are the cause of suboptimal total diet composition.
Dietary assessment of populations and groups Several levels, of differing complexity, cost and precision, are available. The best plan is usually to use more than one approach and to check that the results corroborate each other. • Food disappearance rates. The food and agriculture organization of WHO compiles food balance sheets for each country annually. If the total food supply (commercial production, home production, importation) and the population base are known, then an estimate can be made of food consumption per head of population and therefore of nutrient consumption. Data of this kind are often incomplete, particularly with reference to home food production. A number of assumptions have to be made about the ways in which foods are used, wastage in preparation and cooking, etc. This approach gives no guide at all to the intake of individuals or of population subgroups which may be of concern. On the other hand, broad generalizations about dietary adequacy can be made, and comparisons between countries with different disease patterns. • Household food purchasing. The National Food Survey of the United Kingdom, established in 1945, set up a model which has been employed in many countries: a random selection of households is taken every year and their total food purchases surveyed for 1 week. Analysis requires a knowledge of the numbers of individuals within the household. Knowledge of the social setting may also be of value in establishing the eating patterns
of population subgroups. Assumptions still have to be made about the uses to which food purchases are put. The biggest problem in the past has been that household food surveys have not included any measure of foods purchased and eaten outside the home, or of home food production. Therefore, for a number of nutrients diet intakes are spuriously low. This applies particularly to nutrients such as fat and saturated fat, which are present in high concentrations in foods consumed as meals and snacks outside the home. • Food frequency questionnaires. A number of questionnaires have been validated to estimate the food and therefore the nutrient consumption of groups by enquiring about the frequency of consumption of a range of foods. In the computer analysis, standard portion weights are applied to enable estimation of per capita nutrient consumption. Food frequency questionnaires are not sufficiently precise to be used in the assessment of food intakes of individuals, but they are relatively cheap to use. Inevitably, they address only a limited range of major foods and will therefore tend to underestimate food intake, particularly in individuals whose range of food choices is wider. • Prospective dietary intake. Epidemiological approaches have employed the same prospective weighed intake methods used in the assessment of individuals. Although arguably the most reliable approach, this is an expensive and professionally intensive method, and problematic to more deprived sectors of the population. In clinical practice, all methods of dietary intake assessment tend to underestimate the habitual food intakes by 20-50%, particularly those who are overweight. The reason for this is uncertain and there may be selective misreporting (e.g. for high-fat foods). During the assessment period of prospective methods, overweight people tend to cut down on their usual food intake. There is also an element of self-deception and an unwillingness to reveal true eating habits. It is interesting that in many cultures high social status is associated with a denial or minimization of a number of vegetative and physical bodily functions, including food intake.
NUTRITION AND FEEDING PRACTICES FOR GROWTH Standards for child growth - compiled from subjects living in a clean environment with an abundance of food - show a considerable range in rates of gain in weight and stature. There are also differences in dietary intake in such children, which is also true in healthy adults who are not excessively over- or underweight. A man in his 30s who continues to eat the same amount of food that he ate in his late teens is likely to become overweight. In each case, the difference in nutritional status is the result of the balance between energy intake and energy expenditure.
Early infancy In the young infant nutritional requirements are particularly high in relation to body weight. Breast milk certainly provides enough energy and appropriate nutrients for at least the first 4 months, and has psychosocial and immunological advantages over artificial formula feeds. Recent evidence also points to better brain development in breastfed infants, related to essential fatty acid intake. Artificial formulae are frequently dangerous when prepared under unhygienic conditions, as in the homes of many poor families in the developing world. Cows' milk contains a dangerously high sodium content and should not be given before 1 year. Weaning should be gradual from 4-6 months: overfeeding in infancy may programme an excessive appetite.
a
Later infancy and early childhood Nutritional requirements are also high in infants over 4 months of age, when children can begin to receive solid foods in addition to breast milk. In developing countries the growth rate frequently falters at this stage, either because the energy given is not sufficient (the energy density of weaning foods in traditional societies is often low) or because of gut infection, so that food is not so well absorbed. Specific nutrient deficiencies (e.g. zinc, amino acid, folate) may also play a role. Cows' milk consumption in young children has been associated with bleeding into the bowel and anaemia, leading to the development of 'follow-on' formula feeds for use in the first year of life. There is very weak evidence that exposure to common dietary allergens in infancy may provoke allergies so foods with low allergenic potential (e.g. rice rather than wheat) are preferred.
Later childhood and adolescence Nutritional requirements for protein and energy are usually met in older children, but micronutrient deficiencies (e.g. of iron, folate and zinc), which may lead to anaemia, impaired intellectual performance and short stature, are relatively common even in western populations, and easily go unnoticed.
Pregnancy The nutritional stress of pregnancy is created by the need to produce both an infant and a placenta, plus some maternal fat stores. A 12.5kg weight gain in pregnancy would require a total of about 7000kcal (Table 5.13). There are also increased demands on maternal stores, especially of iron, zinc and folate. On the other hand, carefully conducted studies have not shown a greatly increased food intake in pregnancy. For some nutrients, e.g. calcium and iron, the efficiency of intestinal absorption is increased during pregnancy. Energy intake often falls in the first trimester, and then needs to increase to about 200kcal/day
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above non-pregnant intakes. The additional energy requirements of pregnancy are met from reduced physical activity and greater resting in the later stages. Fetal growth certainly depends on maternal nutritional status, both from starting weight and from weight gain, and may be specifically reduced by physical exertion in late pregnancy. Intriguingly, it has recently been shown that food deprivation in late pregnancy leads not only to smaller babies, but also to these offspring having smaller babies themselves. Good fetal growth is important for later, adult, health (to protect against diabetes, heart disease, stroke), and so maternal nutrition is doubly important. The Institute of Medicine recommends that, at term, women with BMI <19.8 should have gained 12.5-18 kg, those with BMI 19.8-26, 11.5-16kg, and those with BMI 26-29, 7-11.5kg. A BMI 28kg/m2 is a reasonable target at term. Table 5.13 summarizes the extra nutrient requirements of pregnancy, and suitable sources.
Lactation Babies should be exclusively breastfed for 4 months, and according to WHO recommendations breastfeeding should be continued for 12-24 months. The need to produce breast milk (up to 800kcal/day) for many months has obvious nutritional implications. Some of this can be provided from maternal stores laid down in pregnancy, but an additional 500kcal intake and extra protein are often
TABLE S.13 Summary of special nutrient requirements in pregnancy 1. Energy - an increase of 200kcal/day is required in the 3rd trimester. Aim to reach BMI 28 kg/m2 at term (2310kcal for women aged 15-18) (2140kcal for women aged 19-50) 2. Protein - an increase of 6g per day throughout pregnancy (51 g per day) Two small/moderate portions of protein-rich foods, plus milk, bread, pulses, etc. 3. Iron - 14.8mg per day required throughout adulthood. No extra routinely needed during pregnancy: absorption increases 4. Calcium - 100mg per day (19-50) 800 mg per day (15-18) No extra routinely needed during pregnancy: absorption increases Throughout life - half a pint of milk daily as a good insurance 5. Vitamin D-10ug per day Supplement. Encourage women to go outdoors Use fortified foods, e.g. margarine, and vitamin D rich foods, e.g. oily fish 6. Folic acid - supplement from before conception up to first 12 weeks (0.4 mg routinely, 4mg if previous neural tube defect) 7. Vitamin C - increase intake by 10mg to 50mg per day More fruit and fruit juice 8. Vitamin A - increase vegetables, increase intake by 100ug to 800jag
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9. Dietary fibre - to avoid constipation of pregnancy, increase by 10g/day More vegetables, wholemeal bread
recommended. Many women are able to produce adequate volumes of breast milk despite poor dietary intakes. However, when maternal nutritional status is severely decreased, there is a corresponding decrease in the volume and nutritional content of the milk. It is thus essential to improve the diet and lifestyle of women in developing countries if breastfeeding is to be promoted. When there has been substantial fat accumulation during pregnancy, as is usual in western countries and where obesity is more of a problem than undernutrition, prolonged breastfeeding (4-12 months) helps with weight loss.
MALNUTRITION MALNUTRITION IN CHILDREN The term protein-energy malnutrition (PEM) was used historically to describe a variety of clinical syndromes believed to result from a diet inadequate in both energy and protein. The term is misleading, since dietary protein deficiency is virtually never seen, and low serum proteins in malnutrition are not caused by dietary protein insufficiency. Undernutrition of energy is often accompanied by micronutrient deficiencies, electrolyte imbalance and metabolic disorders. When it occurs in the UK it is usually precipitated by a severe illness (e.g. gastrointestinal disease, surgery). In developing countries it is the result of a poor diet, often exacerbated by the added stress of infection (especially diarrhoea and measles). The term malnutrition/infection syndrome may be used to describe this situation. Classification of the severe clinical syndromes (Table 5.14) depends on the child's weight calculated as a percentage of the median international standard for a child of the same age. Milder grades of malnutrition also exist according to weight/age. Undernourished children may be further classified according to whether, or to what degree, they are short for their age (stunting); alternatively, they may be underweight and thin, i.e. a low weight/height (wasting) (see Table 5.14 and Fig. 5.7). The inference is that children who are stunted are likely to be chronically
TABLE 5.14 Classification of stunting and wasting Degree
Malnutrition (weight/age)
Stunting (height/age)
Wasting (weight/height)
Normal
Over 80%
Over 95%
Over 90%
Mild Moderate Severe
60-80%* Less than 60%*
87.5-95% 80-87.5% Less than 80%
80-90% 70-80% Less than 70%
* Defined as kwashiorkor if oedema present
FIG. 5.7 Growth chart of a severely malnourished child A Start of nutrition rehabilitation. B After discharge from nutrition rehabilitation.
infected or have been deprived of an adequate diet, usually for many months (sufficient to cause linear growth retardation). The child who is wasted but not stunted has usually lost body tissues because of a recent infection or poor diet, for example due to harvest failure.
Marasmus In marasmus (weight for age <60% without oedema), which is usually seen in older, fully weaned children, there is loss of both lean tissue and subcutaneous fat, with characteristic wrinkling of the skin. This is sometimes difficult to differentiate from dehydration. The child is usually very cachectic, and has long eyelashes and lanugo hair on the forearms despite loss of hair on the head. However, the child is generally alert and keen to eat. The plasma albumin is usually maintained, but plasma sodium and potassium levels are often low. Marasmus describes the result of dietary energy shortage, but specific nutrient deficiencies commonly coexist, as in anorexia nervosa.
Vitamin A becomes sequestered in the liver because of insufficient synthesis of the transport protein, retinolbinding protein, and patients are consequently more prone to infection. Plasma albumin is low, as are plasma sodium and potassium. The low plasma potassium indicates a reduction in the total body potassium, owing to the loss of muscle mass. The low plasma sodium, however, is misleading, as it is due to an excess of body water: the total body sodium is in fact elevated. Several factors contribute to the development of oedema. A decrease in plasma albumin decreases colloid osmotic pressure, whereas an increase in the generation of free radicals by infection (from systemic or intestinal pathogens, or toxins, such as aflatoxin) can damage the capillaries sufficiently to cause them to leak fluid into the tissues. The deleterious effects are greatest in children with impaired scavenging mechanisms for free radicals, owing to a relative excess of iron and copper but a deficiency of vitamins C, E and carotenoids.
5
Associated deficiencies Zinc deficiency is common in severe malnutrition, and may account for the skin lesions and impaired cellular immunity. Vitamin A deficiency is frequently precipitated by malnutrition, probably because of lack of synthesis of retinol-binding globulin by the liver, and anaemia often occurs as a consequence of folate and/or iron deficiency and systemic infection (especially malaria). Cellular immunity is frequently depressed, permitting infections such as tuberculosis to become rampant. Antibody production is also impaired, but to a lesser extent, so that even severely malnourished children generally produce satisfactory levels of antibodies following immunization. However, the general reduction in immunity is a key factor in the development of bacterial overgrowth syndromes in the intestine, pneumonia and septicaemia. The decreased heat production in malnutrition is often severe enough to cause hypothermia and prevents a pyrexial response to infection.
Specific organ changes Kwashiorkor The main feature of kwashiorkor, which usually affects infants at the time of weaning, is oedema, which conceals the loss of lean tissue. There is little evidence that dietary differences explain why some children develop kwashiorkor and others become marasmic; kwashiorkor is often precipitated by measles and intestinal and other infections. These children are ill and anorexic, and have very high mortality. Weight for age <60% indicates marasmic kwashiorkor. The oedema usually starts in the legs but may extend to the trunk and head. There is often an associated scaly cracking of the skin, and some children have discoloured or orange hair (caused by associated zinc deficiency). The liver is sometimes enlarged, as it becomes infiltrated with fat which cannot be removed because of inadequate production of lipoproteins (see Ch. 19).
There is atrophy of all organs, including alimentary tract mucosal atrophy, which causes hypochlorhydria and flattening of the intestinal villi with secondary malabsorption. Nearly all children are heavily colonized by intestinal parasites and bacteria. Renal function is often impaired, leading to difficulties in excreting sodium and water. Experimental studies show effects of childhood malnutrition on brain size and psychomotor development, but longitudinal studies of severely malnourished children show that the social environment is more important than nutrient deficiency in determining subsequent intellectual achievement.
Management The following principles should be followed:
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TABLE 5.15 Predicted rate of weight gain* in malnourished child weighing 7kg Total intake (kcal/day)
Excess (kcal/day)
Weight gain (g/day)
Days to gain 300 g
0
0
-
760
60
10
300
820
120 240
20 40
150
480 960
80 160
700
940 1180 1600
75 38 19
* Assuming maintenance requirements of 100kcal/kg/body weight
• The child requires resuscitation for dehydration and electrolyte restoration (in most cases using oral rehydration therapy). • Antibiotics (this is still an indication for chloramphenicol) should be given for systemic infections, together with treatment for malaria where appropriate. It is wise to assume that all children with severe malnutrition have bacterial infections, tuberculosis and intestinal infestation, even when classic signs of infection are absent. • Nutritional therapy, which depends on the introduction of special feeds providing maintenance requirements (100-150kcal/kg body weight, including 10% energy as protein, and avoiding lactose), should be accompanied by mineral mixes (especially potassium and zinc). In children with kwashiorkor, maintenance requirements are given until the oedema is cleared and then energy intakes are increased. In marasmic children the intake can be increased earlier until, ideally, about 200 kcal/kg body weight/day are given (Table 5.15).
CACHEXIA AND MALNUTRITION IN ADULTS Cachexia of dietary origin, or malnutrition in adults, is surprisingly common in medical and surgical practice. A recent survey in the UK found that 13% of admissions to general medical and surgical wards had malnutrition according to BMI criteria. Higher figures have been found using other criteria. Malnutrition was only recognized in a small proportion, and most patients lost more weight during their admission without any nutritional action being taken. Inadequate intake is the most important cause,
owing to psychological factors (such as depression, isolation or anorexia nervosa), immobility and social deprivation, pain, oral or intestinal cancer, arthritis, nausea/ vomiting, liver metastases, chemotherapy, gastrointestinal disease, fever or postoperative complications (which often cause anorexia). Nutrient intakes are often reduced drastically in those who can only take fluids. 1 Requirements may be considerably increased by sepsis. Energy expenditure increases by at least 10% for every 1°C rise in body temperature, and muscle protein is mobilized to provide amino acid precursors for the inflammatory response. Infection also increases the production of acute-phase proteins such as C-reactive protein, but levels of plasma albumin may decrease as a result of decreased synthesis by the liver and increased catabolism of circulating albumin. Any cause of malabsorption may cause a serious decrease in absorption of protein and energy. Disease of the lower small intestine and colon may cause serious leakage of endogenous protein and protein loss from blood. To produce cachexia, these factors must be chronic, or relapsing without adequate periods of remission, and often more than one factor is operating at any time. The classic causes of malnutrition in adults are cancers, tuberculosis and gastrointestinal problems, including short bowel syndrome and fistulae. Depression is another important cause, but organic disease should always be excluded. More recently AIDS and chronic obstructive airways disease (COAD) have become familiar as causes of apparently intractable cachexia. The most consistent finding is the dominance of anorexia during acute infective episodes, leading to stepwise weight loss. In HIV, as in inflammatory bowel disease, there is also a background of steady weight loss through malabsorption diarrhoea. Elevation of metabolic rate in these conditions plays only a small part in producing weight loss. The most important single manoeuvre in preventing and managing malnutrition is to have good measurements of the weight of every patient at every contact with health services (inpatient and outpatient). The diagnosis must be recorded, as it has profound medical implications, and failure to diagnose malnutrition might incur medicolegal problems. Dietetic intervention, social support and artificial feeding where necessary are much more effective if used early in the process of weight loss. Even with AIDS or COAD, effective nutritional interventions which lead to weight gain will improve muscle function, improve quality of life and reduce susceptibility to infection. Correction of malnutrition takes time, so management started in hospital must be continued after discharge. ©
VITAMIN DEFICIENCIES AND EXCESSES 1 Fig. 5.1 122
0 Case 5.1
A checklist for the methods of assessment of vitamin deficiencies is given in Table 5.16. The important food sources
SUMMARY 3 Vitamin deficiency syndromes Vitamin Syndrome A Thiamine Niacin Riboflavin Pyridoxine Folate B12
C D K
Night blindness, xeropnthalmia Wernicke's encephalopathy, Korsakoff's psychosis Pellagra Mucosal lesions Glossitis, neuropathy Megaloblastosis, villous atrophy Megaloblastosis, neuropathy Scurvy Rickets, osteomalacia Hypoprothrombinaemia
TABLE 5.16 Assessment of nutritional deficiencies: vitamins* Vitamin
Method
Comment
A
Clinical
Infections common Night blindness is a good indicator Corneal lesions are very late-stage findings
• Plasma carotenoids • Plasma retinol Thiamine
Clinical • HPLC • Erythrocyte transketolase
Sensitive indicator of liver stores but reduced in infection Neuropathy and optic atrophy are late-stage findings Specific Sensitive but rapidly altered by amount of dietary thiamine
of the various vitamins are shown in Table 5.17, and their roles in the body in Table 5.18. A table of recommended daily intake of vitamins is given in Table 5.19.
Riboflavin
Clinical • Erythrocyte gluthathione reductase
Mouth lesions are non-specific Assay related poorly to clinical state
VITAMIN A DEFICIENCY
Niacin
Clinical • Urinary n-methylnicotinamine/creatine excretion
Glossitis, stomatitis, dermatitis Sensitive. Difficult assay
Folate
• Serum folate • Erythrocyte folate
Marked changes after dietary intake Sensitive assay of body stores
B12
• Plasma vitamin level
Sensitive assay of body stores
C
Clinical • Plasma or leucocyte ascorbate (HPLC)
Specific but occur at late stage only Sensitive. Rapid response to diet, Falls non-specifically in illness
D
Clinical • Plasma alkaline phosphatase • Plasma 25hydroxycholecalciferol • Bone marrow histology
Rickets, osteomalacia Non-specific. Sensitivity may be improved by isoenzyme analysis Very specific
E
• Plasma or erythrocyte tocopherol (HPLC)
Sensitive and specific. Must be corrected for plasma LDL
K
• Prothrombin time
Non-specific, as it is influenced by hepatocellular dysfunction
Vitamin A (retinol) can be synthesized within the liver from several carotenoids (cc-carotene, B-carotene, lutein) which occur in a variety of vegetables and certain fruits. Vitamin A deficiency leads to night blindness and xerophthalmia (damage to the conjunctiva, the major cause of blindness in children). It also affects the immune system - increasing the severity of respiratory infections and diarrhoea - and the formation of epithelium in the sweat glands, lung and gut. It contributes to the high rates of child mortality in certain populations, particularly among poor communities, where dietary intakes of carotene are low and where the availability of the nutrient may be further reduced by intestinal parasites and diarrhoea, and where undernutrition suppresses the synthesis of retinol-binding protein, preventing utilization of hepatic retinol stores. Vitamin A deficiency sometimes complicates inflammatory bowel disease, coeliac disease and cirrhosis. Measles is an important contributory factor in xerophthalmia because of its direct effect on the conjunctiva, where it increases the local requirement for vitamin A to repair the damaged conjunctiva, and also by its effect on synthesis of retinol-binding protein, which normally carries vitamin A from the liver stores to the eye. Supplementation with vitamin A reduces the mortality from measles in malnourished children, even when their liver contains vitamin A (because its transport to other tissues is inhibited). Night blindness alone is easily reversible, but xerosis (the dry appearance of the conjunctiva) and Bitot's spots (heaped-up desquamated cells causing flecks on the conjunctiva) are signs that, unless treatment is started soon, the lesion may progress to irreversible corneal ulceration. In areas where dietary vitamin A intake cannot be increased by horticulture and nutrition education pro-
5
Specific
* Pyridoxine is omitted as this is not a routine assay
grammes, the administration of vitamin A capsules (100 000 IU every 4 months) will largely prevent xerophthalmia. In established xerophthalmia, retinol palmitate (100 000 IU) is given intramuscularly. Vitamin A should not, however, be given to pregnant women because of its teratogenic effect. Breastfeeding tends to prevent vitamin A deficiency.
123
TABLE 5.17 Vitamins and their important food sources
TABLE 5.18 Major roles of vitamins in the body
Vitamin
Food sources
Vitamin
Function
A
Carotenoids (esp. p-carotene), in carrots, dark green leafy vegetables, pumpkin, mango Preformed vitamin A in fish oils, liver, eggs, margarine
A
Maintenance of mucosal surfaces; production of mucus; immune system and retinal function; fat soluble
Thiamine (B1)
Thiamine (B1)
Fortified wheat flour (much of the thiamine in flour is removed by milling, but is then replaced in most flours), fortified breakfast cereals, milk, eggs, yeast extract, fruit
Metabolism of carbohydrate to provide energy; maintenance of cardiac muscle and peripheral nerves
Riboflavin (B2)
Control of intracellular oxidation; maintenance of skin, especially around the mouth
Riboflavin (B2)
Milk, cheese, eggs, fortified breakfast cereals, liver, kidney, whole grain cereals
Nicotinic acid
Utilization of energy from food; maintenance of skin, especially in light-exposed areas
Niacin
Liver, kidney, milk, cheese, eggs, beef, chicken, pork, yeast extract, instant coffee, peas, beans
Pyridoxine (B6)
Metabolism of amino acids, especially tryptophan to nicotinic acid
Pyridoxine (B6)
Liver, meat, fish, whole grain cereals, milk, peanuts
Folate
Cell multiplication, in the blood and mucosa
Folate
Liver, kidney, green leafy vegetables, peas, beans, oranges, bananas
Cobalamin (B12)
Cell multiplication, especially blood cells; control of fatty acid synthesis in myelin sheaths of nerves
Cobalamine (B12)
Liver, kidney, fish, beef, pork, lamb, eggs, cheese
Ascorbic acid (C)
Ascorbic acid (C)
Oranges, lemons, potatoes, green vegetables, fortified fruit drinks
Maintenance of connective tissue; stimulates iron absorption
D
D
Fortified milk (e.g. evaporated), fatty fish, fortified margarine, eggs, liver
Maintenance of calcium and phosphate levels in the blood; control of absorption of dietary calcium and movement of calcium between blood and bone; fat soluble
E
Vegetable oils, wholegrain cereals, eggs, margarine
E
K
Vegetables, peas, beans, liver
Contributes to antioxidant capacity of body; important in maintenance of erythrocyte membranes in neonates; fat soluble
K
Control of blood clotting; fat soluble
Thiamine deficiency
124
Thiamine is an essential factor in many glycolytic pathways and is especially important for normal function of the peripheral nervous system and the heart. Deficiency can cause a peripheral neuropathy, especially in the legs, ataxia and optic atrophy. Most cases in the UK occur in malnourished alcoholics. Such patients may develop two additional syndromes. In Wernicke's encephalopathy nuclear or supranuclear ophthalmoplegia occurs with nystagmus, pupillary abnormalities, aphasia and mental confusion. In Korsakoffs psychosis a permanent confused state, characterized by short-term memory loss and confabulation, develops (see Chapter 24, p. 1439). In beriberi, a highoutput cardiac failure develops (wet beriberi) and may accompany the peripheral neuropathy (dry beriberi). Deficiency is more common in populations which change to eating highly milled rice, as this process removes the thiamine. Curiously, Korsakoffs psychosis does not seem to occur commonly in populations prone to beriberi, suggesting that in alcoholics an additional factor may be acting. Diagnosis is usually made on clinical history and examination, but subclinical thiamine deficiency should always be suspected in alcoholics, and supplements given prior to feeding carbohydrates. If carbohydrate (e.g. dextrose infusion) is given without thiamine, then lactic acidosis can
rapidly lead to brain damage. Elevated levels of erythrocyte transketolase activity and blood pyruvate occur. Thiamine (100 mg) should be given intravenously (a multiple B vitamin parenteral infusion is appropriate), followed by repeated doses of 20 mg three times daily. Cardiac beriberi and ophthalmoplegias improve rapidly, but Korsakoffs psychosis tends to recover only partially. Many routine vitamin supplements do not contain enough thiamine to correct a deficiency. Long-term oral thiamine supplementation is a reasonable preventative strategy for alcoholics.
Niacin (nicotinic acid and nicotinamide) deficiency Nicotinic acid occurs in many plant and animal foods and can also be synthesized from tryptophan. Nicotinic acid deficiency tends to occur in those who eat a monotonous maize diet (which is low in tryptophan), such as is often supplied to refugees. The resulting deficiency syndrome is pellagra. Pellagra often starts with either a sore mouth, mild diarrhoea or confusion. The full clinical syndrome of 'dermatitis, diarrhoea and dementia' is not common, except in well-established cases. The skin lesions are initially erythe-
TABLE 5.19a Reference nutrient intakes for vitamins Males over 11 years Thiamin (mg/d) Riboflavin (mg/d) Niacin (nicotinic acid equivalent) (mg/d) Vitamin B6 (mg/d) Vitamin 812 (ug/d) Folate (ug/d) Vitamin C (mg/d) Vitamin A (ug/d)
1.0 1.2
17
Females over 11 years
Lactation (0-4 months)
0.8 1.1 14
1.4
1.2
1.5
1.5
+0.2 +0.5
+2
+0.5
200
+60
40
40
+30
700
600
+350
* no increment
TABLE 5.19b Reference nutrient intakes for minerals (SI units)
Calcium (mmol/d) Phosphorus (mmol/d) Magnesium (mmol/d) Sodium (mmol/d) Potassium (mmol/d) Chloride (mmol/d) Iron (umol/d) Zinc (umol/d) Copper (umol/d) Selenium (umol/d) Iodine (umol/d)
Females over 11 years
Lactation (0-4 months)
25
20
+14.3
25
20
+14.3
12.3
12.0 70
70 90 70 180 140
16 0.9 1.0
+2.1
90
* *
70 260**
* *
140 16 0.9 1.0
a
*
200
Males over 11 years
thus accompany general malnutrition or alcoholism and is especially liable to occur during pregnancy. The main lesions are mucosal dryness and cracking around the mouth, ears and eyelids, with the genital region also affected. Red blood cells are affected, causing a normochromic anaemia. Diagnosis is usually on clinical grounds but can be confirmed by reduced glutathione reductase activity in red blood cells. Lesions respond rapidly to riboflavin (6mg daily).
+90
+5 +0.2
*
*no increment ** 160 for females over 50 years
matous, but dry, cracked appearances then occur, especially in areas exposed to the sun, producing 'Casal's necklace' around the neck. There may be villous atrophy in the small intestine and malabsorption. If untreated, later-stage deficiency may cause severe encephalopathy and spasticity. Pellagra is rare in the UK, but may occur in malabsorption syndromes such as coeliac disease, in patients treated with isoniazid, in Hartnup's disease, in the carcinoid syndrome, in patients with very low-protein diets, or in conditions giving rise to considerable loss of protein such as the nephrotic syndrome. Deficiency responds rapidly to daily doses of nicotinic acid (500 mg).
Riboflavin (vitamin B2) deficiency Riboflavin deficiency occurs when a diet is continually deficient in legumes, pulses and animal products. It may
Pyridoxine (vitamin B6) deficiency Pyridoxine deficiency occurs in malabsorption syndromes, alcoholism and secondary to drug toxicity (especially isoniazid), but rarely as a primary deficiency disorder. Clinically, there is mental confusion, glossitis, dry skin lesions and peripheral neuropathy. Pyridoxine deficiency has rarely been associated with infantile convulsions and sideroblastic anaemia. Pyridoxine deficiency is popularly believed to be a cause of premenstrual syndrome but there is little evidence for this. Treatment of deficiency in adults is by 5-20 mg daily. Excess intake can lead to neurotoxicity.
Folate deficiency Folate deficiency occurs in those whose diet lacks fresh vegetables, or in which the vitamin is destroyed by cooking or lost through canning. It may also occur secondary to upper small bowel malabsorption, in situations of increased requirements (i.e. pregnancy or haemolytic conditions), or in patients taking anti-folate drugs (e.g. methotrexate, trimethoprim). Alcohol inhibits the absorption of folate, then aggravating the effect of poor diet in alcoholics. Clinical features, diagnosis and treatment are described in Chapter 23. As well as the megaloblastic anaemia and pancytopenia, depression has been consistently associated with folate deficiency. Folic acid supplementation 400ng/day is recommended for all women who may become pregnant, to prevent neural tube defects (spina bifida, anencephaly). This is not to treat a deficiency, but a pharmacological effect to overcome defects in folate metabolism present in a minority of women. Availability of folate from foods is lower than that of folic acid from supplements.
Vitamin B ]2 deficiency Vitamin B12 deficiency is described in Chapter 23. Dietary deficiency is rare, but can occur in strict vegans.
Vitamin C deficiency The clinical features of scurvy have been identified as part of general malnutrition for centuries, but the specific features of scurvy and its cause only became apparent after it decimated crews on long-distance sea voyages after the discovery of America. In the 18th century, Lind carried out a controlled trial, treating two cases of scurvy with oranges
125
and lemons and using mouthwashes of dilute vinegar or sea water for four other patients. Complete recovery occurred in the treated patients but none in the other patients. Today, deficiencies occur in the elderly - especially those on 'tea and toast' or 'tinned spaghetti' diets - in alcoholics and in food faddists. It may also occur in young children when requirements are high, and in smokers, as ascorbate is consumed in removing the free radicals from smoke. Low ascorbate levels are found in diabetic patients. The clinical features of tiredness, hyperkeratosis of the hair follicles, petechial haemorrhages and bleeding gums are only present in severe deficiency; bleeding gums are more usually due to poor oral hygiene than to vitamin deficiency. The classic features of infantile scurvy - irritability, pain on moving the legs, and tenderness and enlargement of costochondral epiphyses, together with megaloblastic anaemia - are now rarely seen. Diagnosis is by measurement of plasma ascorbate or leukocyte ascorbate content. Ascorbic acid is the antioxidant vitamin whose plasma concentration correlates best with diet. Low concentrations are very common in hospitalized or ill patients, and this is in part an acute-phase response. Ascorbic acid 100 mg three times per day is rapidly effective in clinical deficiency. There is limited evidence that large doses of vitamin C may reduce symptom severity in common cold but this does not point to an underlying nutritional deficiency.
Vitamin D deficiency Vitamin D deficiency occurs in those who fail to produce enough in their skin (from the precursor 7dehydrocholesterol in response to UV light), or who have inadequate dietary intake. In the UK, the high-risk group is immigrant vegetarian Asians, who tend not to expose themselves to the limited sunlight available. Although they do eat fatty fish (a good source of vitamin D), their consumption of vitamin D-fortified foods, e.g. margarine, is low, and the high phytate content (in chapatti flour) of the diet decreases its bioavailability. The result of vitamin D deficiency is rickets (in children) or osteomalacia (in adults) (see Ch. 18, p. 962). 1
Vitamin E deficiency Vitamin E deficiency can occur in low-birthweight infants and in children with malabsorption syndromes (especially cystic fibrosis). It is very rare in adults but has been reported on inadequate total parenteral nutrition, following gastroplication surgery for obesity and in abetalipoproteinaemia, as tocopheral absorption and transport depend on low-density lipoprotein (LDL). Deficiency
1
126
Fig. 5.2
2
Fig. 5.3
permits free radical damage to a number of membranes, such as red blood cells (causing haemolytic anaemia) and nerve cells (causing ataxia and peripheral neuropathy, which is usually permanent). These conditions are exacerbated if extra nutrients, such as linoleic acid and iron, are given without vitamin E. There is no consistent scientific evidence of any effect of vitamin E on athletic success, sexual potency or atheroma. The only indication for therapy is if the level of plasma tocopherol is shown to be low in an appropriate clinical setting. Plasma concentration needs to be adjusted for LDL concentration for interpretation. Deficiency can be treated by 200 mg daily doses in adults, but much larger doses (parenterally) are needed to overcome the effects of abetalipoproteinaemia.
Vitamin K deficiency This may occur in neonates because placental transfer is limited and breast milk is often deficient. It also occurs in obstructive jaundice and certain malabsorption syndromes. The result is hypothrombinaemia and bleeding, which is rapidly reversed by injections of vitamin K (phytomenadione). The prolonged prothrombin time associated with liver disease seldom responds to extra vitamin K.
Fluoride deficiency Dental enamel has a specific requirement for fluoride, whose deficiency in drinking water (under Ippm) is the main cause of dental caries in children. Where fluoride consumption is high - e.g. from tea in Ethiopia - dental caries is rare even with high sugar consumption. Fluoridecontaining toothpaste virtually abolishes the problem in areas of fluoride deficiency. To reach children who do not brush their teeth, successful strategies include fluoride normalization of water supplies to 1 ppm, or fluoridization of salt (Switzerland). Most of the UK is fluoride deficient.
VITAMIN EXCESS SYNDROMES Toxicological syndromes associated with vitamin excess (Table 5.20) are mainly found with fat-soluble vitamins (A, E, D, K) which accumulate in the body.
Vitamin A Toxicity occasionally occurs acutely in children given large doses (e.g. 200000IU) of vitamin A intramuscularly. It takes the form of irritability, and even convulsions, as a result of increased intracranial pressure. Recovery occurs within a few days. Excessive self-medication is the usual cause. Levels of vitamin A in the livers of farmed animals have risen in recent years because of feeding practices. It is quite possible to consume, in a single meal containing liver, much more than the maximum permitted of 10000IU per day for
TABLE 5.20 Main consequences of vitamin toxicity Vitamin
Symptoms of toxicity
A
Headache, convulsions, muscular stiffness, hepatomegaly, teratogenic effects Not described Not described Vasodilatation Peripheral neuropathy Not described Not described Increased urinary oxalate Hypercalcaemia, renal failure Nausea Hyperbilirubinaemia
Thiamine (B1) Riboflavin (B2) Nicotinic acid Pyridoxine (B6) Folate Cobalamine (B12) Ascorbic acid (C) D E K
a woman during pregnancy. Large doses of vitamin A are associated with an increased prevalence of craniofacial abnormalities in the infant. For this reason it is recommended that pregnant women do not eat liver, which used to be encouraged for pregnant women to provide iron and other nutrients.
Pyridoxine (vitamin B6) Pyridoxine toxicity has been occurring more frequently in recent years owing to its use - successful or otherwise - in attempts to alleviate premenstrual syndromes (depression and fluid retention). A peripheral neuropathy is likely if the daily dose exceeds 500 mg, and has been reported at lOOmg/day. Some cases have neurological abnormalities which persist even after stopping the drug.
Vitamin C Toxicity occurs among those who take enormous doses of vitamin C in the unfounded belief that it will prevent the common cold or cancer. Doses above 2g/day may cause abdominal discomfort and osmotic diarrhoea. There is increased urinary oxalate excretion - which may dispose to oxalate stones - and some evidence of damage to the intestinal epithelium.
Vitamin D Vitamin D toxicity occurred in the UK after World War II in some children given too much fortified milk. (The quantities added are now more strictly controlled.) Mild forms of vitamin D toxicity are characterized by weakness, weight loss and growth failure. Severe forms cause nephrocalcinosis, radiological changes in the epiphyses and mental retardation.
TRACE ELEMENTS
a
The clinical relevance of trace elements in health is limited, but zinc deficiency appears important. Zinc, and probably also copper, is important in protecting cell membranes against free radical damage. Zinc is a cofactor in over 100 enzymes, and there are no body stores. Absorption from the diet is about 30%, but adapts to needs in health. Deficiency is seen most clearly in the congenital disorder aerodermatitis enteropathica, which is characterized in infants after weaning by a scaly skin rash, secondary bacterial and fungal infection, diarrhoea and severe growth faltering. All are rapidly reversed by zinc therapy. Deficiencies are also seen in children with severe malnutrition, and were formerly seen in patients receiving parenteral nutrition without sufficient trace element mixes. © Selenium deficiency can cause a cardiomyopathy, although its main role is as a cofactor in the antioxidant enzyme glutathione peroxidase. The selenium content of plasma falls during stress or illness as part of the acutephase response.
Iodine deficiency Most iodine deficiency is due to low levels in the soil and water. There are many regions in the world, e.g. Nepal, Peru and Bangladesh, where iodine intakes are so low (<50-75 mg/day) that thyroid function is impaired. There is a high prevalence of cretinism in neonates in these regions, which may present as deaf-mutism, mental retardation and ataxia, with the characteristic morphological features of thickened facial appearance, stunted stature and enlarged tongue. The brain damage is irreversible if not treated early. It is now also realized that the poor intellectual performance and deafness (without any unusual morphological features) found in many children in iodine-deficient areas is due to marginal iodine deficiency. This may be partially reversible. In some areas an already limited iodine availability is made worse by the consumption of goitrogens, e.g. in certain brassicas, cassava or soya beans. The extent of the problem can be assessed by measuring the prevalence of goitre (enlargement of the thyroid gland), which is particularly common among adolescents and pregnant women. Measurements of urinary iodide and iodine/ thiocyanate levels can determine whether the problem is primary dietary iodine deficiency (low iodine) or the result of a dietary goitrogen. Richer people in goitrous areas generally obtain enough iodine by eating food (e.g. fish) brought in from other areas, but the main strategy is to iodize salt. Where this is impractical, injections of iodized oil (lipiodol) may be given, especially to women of childbearing age. A single dose (5ml) will usually last for up to 5 years. Oral doses (400 mg) of iodine preparations may provide enough to last for 2 years.
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OVERWEIGHT AND OBESITY Obesity is the accumulation of excess fat with multiple organ-specific pathology. The disease and its clinical consequences are obviously progressive, but for epidemiological purposes cut-offs of BMI 25 and 30kg/m2 are used, corresponding with the clinical hazards increasing and becoming frequent. Alternatively, waist circumference can be used as a simple indicator of total body fat, which is largely independent of weight.
Causes Obesity is due to an interaction between genetic constitution and the environment. The genetic component is clear, as is shown in studies of families and twins. The genes involved are not identified but are probably multiple, and they provide only the predisposition to more or less rapid weight gain. They may affect appetite regulation or metabolic efficiency. Together, genetic factors account for about 30% of predisposition to weight gain. The remainder comes from environmental influence - food attractiveness and availability, need for exercise etc. The fat accumulation itself can of course only come from excess energy consumption above needs over a prolonged period. 1 Obesity may be precipitated by an obvious decrease in energy expenditure due to a change in lifestyle (e.g. to a more sedentary job), or an injury or arthritis which limits mobility. However, in most obese individuals it seems that intake and expenditure problems occur together. Many people admit to eating excessively. A sympathetic request for a confidential 2-week diary of everything the patient eats may be very revealing, but most obese people underestimate their intake. Depression and psychosocial problems are common, so a brief history in the outpatient clinic will usually fail to give an accurate assessment. The metabolism of food energy has been studied in detail over the last 20 years, and the evidence gives some clues as to how some individuals are more prone to weight gain than others with a similar energy intake. • People with a high fasting respiratory quotient (RQ) (CO2 production divided by O2 utilization) are most prone to weight gain. • When volunteers are given extra calories, some put on weight faster than others. • Dieting leads to an adaptive decrease in energy expenditure, and this may vary between individuals. • Obese people have a decreased thermogenic response to stimulation by noradrenaline (norepinephrine) or food, and this persists even when they have lost weight.
1 128
Figs 5.4, 5.5
2
Fig. 5.6
There are well-described genetic obesities in experimental animals, but the mechanisms appear to be different in humans. To cause obesity there needs to be an increase in appetite without a compensatory rise in energy expenditure. The ob gene codes for a peptide hormone, leptin, which is released from adipose tissue as a long-term signal of fat storage. Leptin signals satiety via hypothalamic receptors modifying neuropeptide Y activity, and as a signal to other functions, such as the onset of puberty, and tends to downregulate energy expenditure. Overweight humans have high circulating leptin concentrations and may therefore be resistant to it, although a complete absence of leptin, usually from a very rare defect in the ob gene, results in colossal childhood obesity. Several other genetic obesities are known, such as the Prader-Willi syndrome, with a defect on chromosome 15. No common gene defect has yet been discovered in the general population of obese patients. Studies of families, twins and adoptees all point to a strong genetic influence, accounting for about 30% of variability in weight gain. Multiple genetic factors are involved, with no single common pathway controlling energy balance yet identified.
Consequences It is often overlooked that overweight people start to develop symptoms (Table 5.21) as BMI increases above 25kg/m2. Most people with BMI >30kg/m2 are chronically troubled by symptoms, including tiredness, breathlessness, sweatiness, low back pain, and hip and knee pain. Depression is a common complaint but is unlike typical endogenous depression, and is probably due in part to fatigue. Obesity is associated both with functional difficulties in simple domestic activities and with discrimination in every walk of life. This poor quality of life is only exceeded by the worse quality of life for an obese patient on a protracted diet without visible results. The metabolic effects of overweight, leading to increased risks of heart disease (hypertension and hyperlipidaemia) and cancers (related to increased adipose tissue aromatase and increased free sex hormone) are well documented. These metabolic hazards of being overweight are exaggerated in those who also have a central (appleshaped) fat distribution, with a high intra-abdominal fat
TABLE 5.21 Symptoms of overweight • • • • • • •
Tiredness Sleeping poorly Sweating Breathlessness Snoring Low back pain Hip and knee pain
• Hirsutism • Menorrhagia • Amenorrhoea • Stress incontinence • Angina • Depression • Infertility
TABLE 5.22 Medical consequences of overweight and obesity Physical symptoms
Metabolic problems
Social problems
Anaesthetic/surgical problems
Endocrine problems
Psychological problems
Tiredness Breath lessness Varicose veins Back pain Arthritis Oedema/cellulitis Sweating/intertrigo Stress incontinence
Hypertension NIDDM Hepatic steatosis Hyperlipidaemia Hypercoagulation IHD and stroke
Isolation Agoraphobia Unemployment Family/marital stress Discrimination
Sleep apnoea Chest intections Wound dehiscence Hernia Venous thrombosis
Hirsutism Oligomenorrhoea/ infertility
Low self-esteem Self-deception Cognitive disturbance Distorted body image Depression
Metromenorrhoea Oestrogen dependent cancers: breast, uterus, prostate
a
IHD, ischaemic heart disease; NIDDM, non-insulin dependent diabetes mellitus
mass shown by high waist circumference. Table 5.22 shows the range of metabolic and mechanical consequences of being overweight. They have an impact in virtually every branch of medical practice. © The extra medical costs of the overweight are estimated to account for an astonishing 2-80% of total health service budgets. For this reason the UK Government Health of the Nation White Paper made the prevention and correction of obesity one of the highest priorities for the health service in the 1990s. Most Local Health Authorities have programmes for weight management. The World Health Organization has included obesity as a worldwide epidemic needing coordinated preventive measures, as well as a disease in its own right which requires treatment to relieve distress.
Criteria for treatment The management of weight problems should address the process of weight gain. Many people say they want to lose weight: most are able to do so using a variety of approaches, but many are not prepared to adopt the permanent lifelong change in diet and lifestyle needed to prevent regain. The groups of patients who need professional (medical) weight management are those who are unable to control a weight problem using self-help methods, who are prepared to make substantial lifestyle and diet changes for relatively modest cosmetic gains, and those who should be advised on medical grounds to lose weight. People with BMI below 25kg/m 2 cannot be considered overweight, and so weight loss is usually inappropriate. A request for help from these people may indicate an underlying eating disorder, such as anorexia nervosa. There may be patients with BMI a little under 25 when some weight loss could be valuable, for example those with metabolic syndrome or non-insulin dependent diabetes. Advice on weight management should be offered to all patients whose BMI exceeds 25kg/m2, aiming first at restricting further weight gain and second at a period of weight loss, followed by a period of supervised weight maintenance. Between BMI 25 and 30, the principal aim
should be the further weight gain. Those who wish to lose weight or those who have a high risk (e.g. through family history) of developing diabetes, heart disease, hypertension or hyperlipidaemia, and those who already have these conditions, should be given advice on how to lose weight. Above BMI 30, where disease risks are high, weight loss will bring benefits in relation to metabolic and cardiovascular problems and, more importantly in older patients, from the point of view of symptoms and impairment of quality of life. With a view to health promotion for the general public the waist circumference provides more accessible criteria for treatment. Above waist 80cm (women) or 94cm (men) the risks are increasing and people should avoid further gain. Above 88cm (women) or 102cm (men) health impairment is almost universal, and professional help should be offered (Table 5.23).
WEIGHT MANAGEMENT Recognizing the aetiology of obesity, and its major medical consequences, it is vital that doctors take a leading role in advising patients about the need for and methods of weight management. The skills of several professional groups can be valuably employed, including nurses, dietitians, clinical psychologists, physiotherapists, and even commercial slimming and exercise clubs. Weight management is best conducted in the primary care and community environment, but up-to-date training should be provided for all those involved. All patients with weight problems require assessment for other related and compounding risk factors, such as smoking, blood pressure, lipids and blood glucose. Although many smokers gain some weight when they stop, this weight is usually lost over the subsequent year or so and the gain can be prevented by simple dietetic advice. The medical hazards of smoking are only equalled by weight gain equivalent to a doubling of body weight, but the combination of smoking and overweight has multiply
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TABLE 5.23a Waist watchers - Men Action level 2 Action level 1 <94cm >102cm 94-102 Increasing health High health risk Green zone risk -aim for - seek advice - no need to green zone to lose weight lose weight Prevalence (%) of Type 2 diabetes Cardiovascular risk factors Shortness of breath Poor physical functioning Chronic low back pain
0.6
1.8
26.0 10.4
47.4
4.5 64.2
17.1 10.2
31.5 17.5
19.5
21.1
4.8 14.1
TABLE 5.23b Waist watchers - women Action level 1 Action level 2 <80cm 80-88 >88cm Green zone Increasing health High health risk - no need to risk - aim for - seek advice lose weight green zone to lose weight Prevalence (%) of Type 2 diabetes Cardiovascular risk factors Shortness of breath Poor physical functioning Chronic low back pain
0.4 13.6 17.4 7.1 16.5
active effects on risks. Serum y-glutamyl transferase (y-GT) should be checked, as alcohol consumption is often an important component of weight gain in men, and it is often difficult to identify overweight drinkers. It should be remembered that y-GT will be elevated in untreated non-insulin dependent diabetes mellitus or metabolic syndrome with fatty liver. Serum TSH is useful, as subclinical hypothyroidism is common and greatly impairs ability to lose weight. Treating hypothyroidism does not automatically lead to weight loss.
Diet modification
130
A first step towards weight management is healthful balanced dietary advice. Many of the features of current health promotion dietary advice are highly appropriate to weight loss or weight maintenance. Even during slimming, patients should eat at least five portions of fruit and vegetables daily. Extra helpings, and even snacks of vegetables, can be encouraged. This will help to reduce fat intake. Fat is the nutrient with the highest energy content (kcal/g), so its major dietary origins need to be restricted, particularly full-fat milk and dairy products, processed meat products such as sausages and pies, and biscuits and baked
0.5 26.0 25.5 10.0 18.0
2.7
42.5 39.4 19.7 24.1
food. Bulky and relatively nutritious foods such as bread, potatoes and pasta can still be taken in reasonable amounts to satisfy appetite; it is the spreads or sauces that go with them that tend to contain unnecessary calories. The style of eating recommended for weight management should be continued for life. It should be explained to patients that they have a metabolic profile which will present a problem if they revert to eating a diet high in fat. Alcohol contains 7 kcal/g, so alcohol restriction is directly valuable, but alcohol consumption rapidly leads to non-compliance with diets. It is best avoided during periods of weight loss, particularly by drivers.
Eating behaviour Many patients with weight problems have a rather undisciplined eating pattern, often skipping meals such as breakfast, and even lunch, and then eating large amounts later in the day and at night. A useful management strategy is to concentrate on shopping, to advise patients not to buy what is not needed. It is helpful to plan eating patterns in advance, based on three meals a day and complete avoidance of all snacks. A breakfast which is filling and nutritious but low in calories, such as porridge, is effective.
SUMMARY 4 Practical advice for weight management • • • •
Become a non-smoker (top priority) Eat at least five portions fruit and vegetables daily Eat fish at least twice a week 20-30 minutes moderate activity daily (to breath hard or break sweat) • Avoid future weight gain (before and after loss) • Achieve weight loss 5-10 kg in 3 month stages • Feel proud to have done each of these
Porridge and 'breakfast cereals' are useful as standbys for energy-saving evening meals, and are preferable to lowcalorie commercial meal replacement products, which are often expensive and unpalatable. Individual strategies can be discussed, negotiated and used with patients. 'Rules', such as only eating off a plate, never eating with the fingers, or never eating with the television on, may be helpful.
Physical activity It is extremely difficult to lose weight simply by increasing exercise and physical activity. Each kilogram of adipose tissue (fat) contains about 7000 calories, so 7kg (a stone) contains 50000 calories. Sustainable increases in physical activity would need to be maintained for well over a year to lose this amount of weight. On the other hand, physical activity can be enormously valuable in improving quality of life and helping people to feel better, and in reducing blood lipids, blood pressure and the risks of diabetes. Increased physical activity is vital for weight maintenance to avoid regain, and it is essential to protect muscle from wasting during weight loss. Regular physical activity may help regulate appetite. The metabolic rate of a patient who has lost 7kg (one stone) will be reduced by about 120kcal/day. This can be matched by 20-30 minutes of brisk walking daily if the patient were to continue to eat the previous intake. It is useful to advise the patient to trade food at snack time for activity, even of a very limited extent. Negotiated plans should be agreed, for example to walk all journeys which are less than one mile. Organized physical activity is helpful for many patients but seldom conducted on a daily basis. For those unable to take some exercise daily, it is acceptable to undertake longer blocks of exercise less frequently (e.g. 1 hour three times a week). In addition to taking specific exercise, the avoidance of complete inactivity is important. Television watching (average 29 hours per week in the UK) relates closely to weight gain and to difficulty in slimming, even in people who take some exercise.
Drugs The main function of drug therapy for obesity is to restrict long-term weight gain below the untreated rate. Weight loss is a brief (3-6-month) phase, but no available drug can produce major weight loss alone, and a drug that did would
be dangerous. Initial weight loss is probably most efficient using a very low-calorie diet, under supervision, with drugs for the long-term maintenance phase. No drug therapy can achieve weight loss or maintenance at a lower level without dietary and physical activity changes, and so drugs should not be prescribed unless patients are achieving success with dietary and lifestyle modification as an indication of motivation. One of the main aims of using drugs for weight management is to reduce the need for drug therapy for complications of obesity, such as antihypertensive drugs or hypoglycaemic agents, lipid-lowering drugs and analgesics. These preparations are usually taken indefinitely and often in combination. There is no place in weight management per se for the use of diuretics: oedema is usually a local problem, not the result of sodium retention, and responds poorly to diuretics. Thyroxine does not produce weight loss except in large doses with dangerous cardiac side-effects, and should not be used for obesity. With recent recognition of the extent of pathology and healthcare costs attributable to obesity, there has been intense research interest in developing new drugs for weight management. Drugs may affect appetite or satiety and energy intake, or energy expenditure. Because of the physiological complexity of energy balance, no single drug is likely to have profound effects, and responsiveness varies widely between subjects. Ideally, to reduce body weight, energy intake must fall and energy expenditure must rise. Most effective agents have some effect on both sides of the energy balance equation, but pharmaceutical management will always rely on dietary restraint. The old appetite suppressant drugs, based structurally on amphetamines and sharing noradrenergic releasing activity (e.g. phentermine), have fallen out of favour, largely because of the historic association with amphetamine, despite their lacking addictive or mood-altering actions. They were never subjected to long-term clinical trials, but undoubtedly led to substantial weight loss in patients otherwise unable to achieve it. These drugs are still available in the USA and elsewhere. Sibutramine, available in most of America and Europe, has both noradrenaline and serotonin reuptake inhibition activity. Patients who respond (2 kg weight loss in 4 weeks) can expect to lose about 10 kg on average over 3-6 months, and to maintain the differences from placebo for at least 2 years. Greater weight loss, achieved by an initial period on a very low calorie diet can also be maintained. The main side effects are increase in pulse rate and in blood pressure. In patients who fail to lose weight blood pressure tends to rise, but blood pressure falls with weight loss on sibutramine, particularly in hypertensive patients. About 10% of patients do not lose weight with sibutramine. They were included in the clinical trial results, but should be identified early in a therapeutic trial in routine practice. Orlistat aids weight loss and maintenance by inhibition of intestinal lipase, leading to 30% fat malabsorption. Patients who lose 5% body weight after 3 months treat-
131
ment, together with a 30% fat diet, can expect 10-15% weight loss, maintained for 2 years. However, only 30-40% of patients are able to pass this hurdle. The main sideeffects are symptoms of fat malabsorption if patients eat too much. The drug is not absorbed. A wide variety of other weight loss agents are prescribed in other countries, or sold over the counter in pharmacies and supermarkets. For none of these is there evidence of safety or efficacy, with the possible exception of an ephedrine and caffeine combination, widely used in Europe, but not in UK.
Surgery In patients with BMI above 35kg/m2 and where metabolic or other complications are crippling or life-threatening, surgery is sometimes justified. The most widely used, operations at present are vertical banded gastroplasty and laparoscopic gastric bonding which reduce the size of the stomach to only about 50ml. Gastroplication requires the backup of a high dependency unit, but has a relatively low complication rate in experienced hands. Following operation, patients need to follow a liquid-only diet for 3 months, otherwise the staple line is likely to rupture and the surgery will be ineffective. It is a good plan to insist that all patients spend 3 months on the liquid-based diet before operation; during this time they should be expected to lose approximately 15kg in weight. Supplementation with iron and vitamins is necessary, and long-term medical nutritional and dietetic supervision is required. This form of operation usually results in a deranged eating pattern for life. For this reason psychiatric or psychological assessment and subsequent supervision should be available. Weight loss of 30-100 kg can be achieved but because regain after 2-3 years is so common gastric bypass with Roux-en-Y is becoming preferred. Long-term weight loss is more assured, but at the cost of chronic loose stools.
1 kg of fat in a week through strict dieting, but to gain the same amount temporarily from water, and this can be demoralizing.
Weight maintenance Very few patients can continue to lose weight beyond 3 months, and it is unreasonable to ask them to attempt more. Any result other than weight gain should be regarded as successful at 3 months, and then a weight maintenance programme introduced to prevent regain. This follow-on programme should include active support and lifestyle and psychological counselling for a further 3 months. Commercial and lay slimming groups may provide valuable support. Where the medical risks of weight gain are specially high (e.g. active, or family history of diabetes, hypertension, coronary heart disease), long-term medication may be considered. 1 2
NUTRITION SUPPORT Malnutrition delays wound healing and the recovery of muscle tone after an injury or operation, and may increase susceptibility to infection. Adults with a BMI below 16 have three times the postoperative mortality of betternourished patients. The striking changes in body composition from partial starvation in illness are shown in Figure 5.8. It is better to avoid malnutrition than to treat it, and it is essential to make a nutritional assessment of every patient. If the patient is already underweight, or if there is weight loss and the clinical condition gives concern, some form of nutrition support - such as dietetic supplements, enteral feeding or parenteral feeding - can be used to prevent further deterioration (Table 5.24). Every hospital should have a nutritional assessment and support policy, with a nutrition team comprising a physician and/or sur-
Expected rate of weight loss Many patients, and indeed health professionals, have unrealistic expectations during weight loss. Following a strict dietary restriction of 500 calories a day below normal maintenance, patients will lose about 0.5kg (1 Ib) per week or 7kg (1 stone) in about 3 months. More restricted diets and faster weight loss can only be achieved by a minority and for a fairly short period. More rapid weight loss may be dangerous, as it implies excessive loss of muscle or other body tissues. Weight loss of 0.5-1 kg per week should be expected and encouraged. Patients should not weigh themselves more often than every 2-4 weeks, as bathroom scales give a poor guide to body weight. It is also possible to lose
1
132
Case 5.2
2
MCQ 5.3
FIG. 5.8 Body composition of a man in health and after partial starvation
TABLE 5.24 Examples of conditions in which nutrition support may be necessary Illness associated with nausea and abdominal pain Gastrointestinal disease Malignancy Chemotherapy
Inability to eat Coma
Weakness Bulbar/pseudobulbar palsy
facing malnutrition, a formal prescription process for nutritional supplements may be as important as that for drug administration.
a
Intestinal disease
Enteral feeding Maiabsorption Inflammatory bowel disease Fistulas Thoracic duct damage Ischaemic colitis Short bowel syndrome Increased requirements Burns Sepsis Trauma
geon with special experience in clinical nutrition, a nutrition nurse/technician and a dietitian, together with strong support from the pharmacy, biochemistry and pathology laboratories.
Food and sip feed supplements Many patients find hospital food unappetizing even when they feel relatively well. In such cases, it may be possible to increase energy and nutrient intake by snacks provided by the diet kitchen between main meals. Attractive food and company can contribute greatly to maintaining nutrition; impersonal meal delivery and having to eat in bed have negative influences. If solid food is not well accepted, it is often possible to give liquid feeds for sipping but energy intake can be compromised. Semi liquid feeds can be prepared for patients with swallowing difficulties. A considerable range of commercially prepared feeds are available, presented as 200ml cartons. Some are complete feeds, containing a balance of all essential nutrients in proportion to requirements; others are incomplete, such as flavoured sugar solutions. Palatability is very variable. Sip feed supplements and enteral feeds are available in a vast range of compositions. For virtually all patients, the macronutrient contents should be similar to that of a healthy balanced diet, i.e. about 10-15% energy from protein, 50-60% from carbohydrate and 30-40% from fat. There is no clinical indication for high protein feeds: preparations with up to 40% energy as protein are available but should not be used as they suppress appetite and may lead to impaired renal function. Evidence is very limited to justify the use of 'elemental' feeds containing pre-digested peptides or oligosaccharides, or for feeds enriched with particular amino acids such as glutamate. Sip feed supplements should be served chilled and their volumes recorded accurately. They must be taken as supplements to an optimized food intake, not used as meal replacements. Patients often need a nurse to help and encourage supplement consumption. For patients
If oral intake is not satisfactory usually because of swallowing problems, a fine-bore silastic nasogastric tube may be passed. Because the enteral route should always be used when the gastrointestinal tract is intact, surgeons should also be encouraged to place a feeding nasogastric or nasojejunal tube at the time of any upper gastrointestinal surgery, or to leave a feeding jejunostomy. Even very limited enteral feeding after surgery or in the ITU nourishes the intestinal mucosa, reducing bacterial overgrowth and translocation, and permits more rapid weaning on to full enteral feeding. Enteral feeding solutions are passed down the tube at controlled rates. Small battery-operated pumps can control the exact flow rate, but they are not essential. The feed should be started in small volumes, and no more than 1000 mL given in the first 24 hours, otherwise diarrhoea may develop. The volume is then increased to the desired amount (probably a maximum of 2500mL/day). When patients are beginning to take food, the feed should be stopped for 1 hour before meals. Overnight enteral feeding may usefully supplement a limited oral intake, but care must be taken to avoid aspiration of gastric contents. A semirecumbent position is advisable. A large range of commercially available enteral feeds are available, made up from a variety of protein sources, including casein, soya and mixtures of amino acids, with glucose polymers and triglycerides added to increase the energy content. Most feeds provide about Ikcal/mL and have an osmolality of 280-420 mmol/kg. Low-lactose and cows' milk-free feeds are available. The commercial preparations have micronutrients in amounts that match dietary reference values, and so additional vitamins and minerals may be needed for patients whose micronutrient status is poor, or who have increased losses, utilization or malabsorption. Biochemical monitoring is required. Energy provision should match the metabolic rate, measured by indirect calorimetry or predicted from standard equations (Table 5.4) (BMR x 1.3 for a bedbound patient, plus 10-50% according to degree of illness or need for weight regain). It is impossible to overcome the increased metabolic rate of an ill, infected patient and to promote muscle regrowth at the same time. Protein should account for 10-15% of energy, the remainder coming in approximately equal amounts from carbohydrates and fat. The use of oligosaccharides or polydextrose may reduce the osmotic effects of glucose delivered enterally, but the evidence for using expensive peptide feeds is scanty. Enteral feeding can be performed at home; the reservoir bottles and lines should be changed every 24 hours to avoid the risk of contamination of feeds, but the silastic tubes can remain in situ for several weeks. Even so, complications of enteral feeding occasionally occur and should be anti-
133
cipated. Some patients prefer to use enteral feeding intermittently and become expert at introducing nasogastric tubes. Oesophagitis caused by the tubes is rare with modern silastic tubing, but the tube may be misplaced and a clinical check (aspiration of gastric fluid, or detection of bubbling with a stethoscope) should be carried out before feeding is commenced. When enteral feeding needs to be continued beyond a few weeks, gastrostomy feeding is usually easier and more acceptable to the patient. Percutaneous endoscopic gastrostomy is now a simple and safe procedure, increasingly used in a range of medical conditions, including pseudobulbar palsy following stroke, advanced multiple sclerosis or other neurological disorders. The most common complications of enteral feeds are diarrhoea, abdominal distension and pain, all of which relate to excessive infusion; the volume infused should then be decreased. More protracted diarrhoea can be controlled by codeine phosphate (30-60 mg t.d.s.) or imodium (2-4mg t.d.s.). Aspiration pneumonia is relatively frequent in debilitated patients (especially those with swallowing disorders) receiving enteral feeding when lying flat. Such patients should be fed sitting, if possible.
Parenteral feeding If enteral feeds cannot be given, parenteral feeding is an option; however, the dangers of infection, thrombosis and metabolic problems with this method are considerable. Enteral feeding should be commenced as soon as possible (even if very limited) to prevent mucosal atrophy. Parenteral feeds are ideal culture media for bacteria. They must be made up under sterile laminar flow conditions by specialist pharmacists (the vitamin and mineral preparations have limited stability, so feeds must be made up shortly before use). A dedicated intravenous line must be inserted under sterile conditions and only handled by trained staff. -Long-term parenteral nutrition requires a central line, as the high osmolality (often l000mmol/L) causes thrombosis in slow-flowing peripheral veins. For shorter-term feeding (up to 10-14 days), perhaps before it is ascertained that long-term parenteral nutrition will be required, peripheral veins can be used. Sterile techniques should still be used, and blood flow can be increased by a distal GTN patch. A lower glucose content allows reduced osmolality and so reduced thrombosis: a limited energy supply is often acceptable for 10-14 days for peripheral line feeding. Some commercial peripheral feeds are incomplete in terms of micronutrients, and so monitoring is important. The energy requirement for a malnourished patient receiving nutritional support is often difficult to assess. For long-term feeding, energy requirements can be estimated from standard equations published by the WHO (Table
1
134
MCQ 5.4
5.4). For ill patients and the malnourished, measurement of resting metabolic rate by indirect calorimetry is valuable, largely to avoid overfeeding, which causes a fatty liver. The amino acid content should be 10-15% of energy, and the remainder given as glucose or lipid emulsion (which permits a lower volume and lower osmolality than with glucose alone). A standard single 24-hour bag (2-3 L) containing 1500-2500 kcal is available. Parenteral feeds can be given either continuously over 24 hours, or over 12-18 hours to allow a daytime period off feeding, when the line is sealed and the patient can be mobile. Micronutrient requirements depend on clinical condition. All the essential nutrients (amino acids, fatty acids, vitamins, trace elements) are required. The matching of provision to need is more critical than with enteral feeding, because the 'buffering' influence of absorption in the gut does not apply. If the patient is malnourished and tissue growth is required, a greater than normal provision of phosphate, potassium and zinc will be needed to avoid 'refeeding syndrome' deficiencies. Because it is difficult to exclude subclinical vitamin B1 deficiency, extra thiamine should be given to patients when starting parenteral nutrition. For some, the intravenous delivery results in more rapid renal excretion, and so greater than normal dietary amounts are needed. Many patients receiving parenteral nutrition have tissue damage, and renal failure is relatively common, demanding special consideration. A number of metabolic complications may occur in patients receiving parenteral nutrition: • Hyperglycaemia is common in patients with severe surgical stress (e.g. burns and intravenous trauma) and sepsis, but plasma glucose can be controlled with carefully monitored insulin, adjusted to maintain plasma glucose 4-8mmol/L. Rebound hypoglycaemia may occur if intravenous feeding is abruptly halted. • Metabolic acidosis is rare if fructose and excessive quantities of amino acids are avoided. • Parenteral feeding, especially with lipid solutions, may cause hepatic abnormalities. The commonest reason is overfeeding, leading to fatty liver, which responds to a reduction of energy in feeds. However, most patients receiving parenteral feeding have many other potential causes for hepatic damage, and there is rarely any indication for parenteral nutrition to be stopped on account of mild biochemical changes. • Fat is metabolized more favourably than glucose by patients with sepsis. • Patients with respiratory failure should not receive large glucose loads because of their impaired ability to excrete the extra CO2 produced. • Mineral and electrolyte abnormalities occur variously according to the underlying disease processes. Fortunately, deficiencies can be made up relatively easily during preparation of the bag that contains the feeding solutions. • The stability of feed constituents is precarious, and problems have arisen with 'home-made' feeds and with
CASE STUDY 5.2 POSTOPERATIVE MALNUTRITION A 54-year-old man, height 1.75m, weight 65kg (BMI 21kg/m2) underwent a revision of a mitral valve replacement. His postoperative course was complicated by mediastinal wound infection and he had an episode of pneumonia, hypotension and acute renal failure, necessitating prolonged ventilation. During recovery the question of his nutritional status, complicated by 7 days of infection is raised at a caseconference, 10 days postoperatively, at which stage feeding had not been commenced. His weight has fallen to 60kg. Questions 1. What nutrient deficiencies are likely to be present? 2. How could management be optimized? Discussion Failure to eat for 10 days postoperatively, when metabolic rate is elevated about 50%, will have resulted in negative energy balance of about 10 (days) x 1.5 (increased metabolic rate) x 1600 (minimum daily requirement) = 24000k/cal. This would be equivalent to almost 4kg adipose tissue, but excess lean tissue is lost in infection, at about l000kcal/kg. The weight
measurement is likely to be seriously confounded by oedema, and changes in fluid balance (which may not be dependent). The patient's 'true' BMI may therefore be as low as 16kg/m2, making death from malnutrition likely. Specific deficiencies of many micronutrients are likely. Blood biochemistry is likely to be difficult to interpret owing to acute changes in protein and electrolyte balance. Deficiencies of nutrients which do not have body stores will be particularly depleted (e.g. vitamin C, B complex, magnesium, zinc, selenium). Preoperative status of thiamine, selenium may have been marginal thereby potentially impairing cardiac function. Immune function may have been impaired by a variety of nutritional factors, including a deficiency of essential fatty acids, vitamin A and zinc. Preoperative nutritional assessment and optimization should be routine. Common hazards with late, and inexperienced, nutritional support include inadequate thiamine to overcome a deficiency state, and the overprovision of energy. During illness the capacity to utilize nutrients and to synthesize body tissues is reduced, partly from cytokine action, partly from secondary nutrient deficiencies and altered nutrient essentiality. Excess energy supply
storage. Micronutrients should be added shortly before infusion. Home parenteral nutrition is occasionally necessary for patients with postsurgical short bowel syndrome and other conditions. It represents an enormous undertaking, but with family, social and medical support can be continued satisfactorily for many years. Commercial organizations exist to deliver supplies and to provide nursing and pharmacy support. In many cases total parenteral nutrition is not necessary - more limited feeding, e.g. 3 or 4 nights per week, may be sufficient. 1
Monitoring nutrition support The measurements available for monitoring support are shown in Table 5.25.
nutrition
leads to acute hepatic steatosis and impaired liver function. Measurement of metabolic rate is possible using a ventilated hood calorimeter, but it is more difficult when the patient is on a ventilator. Using estimated BMR is usually adequate. At this stage this patient requires assessment and management by a multidisciplinary Hospital Nutrition Support Team (including representation from specialist trained nursing, pharmacy, dietetic, biochemical and clinical staff). Biochemical nutritional data should be assessed at least weekly, with daily weight and assessment of state of hydration and for oedema. If the GI tract is accessible and intact, then this route is preferable to intravenous feeding. Because of mucosal atrophy after 10 days without feeding, enteral feeding will need to commence at low rates, increasing to approach energy requirement after 2-5 days. A nutritionally complete feed is required. Evidence does not support enrichment with individual amino acids. An approximate breakdown of energy 15% protein, 55% carbohydrate, 30% fat is appropriate. If increased CO2 production is clinically problematic, then higher fat, lower carbohydrate feeds might be considered.
a
TABLE 5.25 Measurements for monitoring nutrition support • Anthropometric: weight, mid-arm muscle circumference (MAC) • Minerals and electrolytes: uric acid, phosphate, sodium, potassium, zinc, magnesium, iron • Resting metabolic rate • Plasma vitamin concentrations • Nitrogen balance: corrected 24 hour urinary urea excretion • Glucose
Regular measurements of weight are necessary but are difficult to perform in the very sick without special bed balances. Changes in body weight may indicate alterations in fluid balance rather than an increase in lean body mass.
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Skinfold thicknesses and mid upper-arm circumference are valuable but affected by oedema. Plasma proteins (CRP, albumin) are useful indicators of progress in treating the underlying disease processes. Glucose should be measured regularly. Plasma phosphate and potassium levels may decrease rapidly and even precipitate cardiac arrhythmia if nutrition support is given rapidly in large quantities to a severely malnourished subject who has previously received very little dietary intake. Most modern amino acid solutions, however, have sufficient phosphate to avoid this. A low plasma sodium is often present in severely malnourished subjects. Total body sodium, however, is often high, and extra sodium should only be given with great caution. An approximate assessment of urinary nitrogen loss can be obtained by measurement of the 24-hour urinary urea excretion, corrected according to the formula: Nitrogen (g/24h) = urinary urea (mmol/L) x urine volume (L) x 0.028 x 6/5 This formula allows for the conversion of mmol of urea to g of nitrogen, and corrects for the fact that urea accounts for approximately five-sixths of total urinary nitrogen loss. Parenteral feeding solutions are ideal culture media. The previously high prevalence of infection has been reduced by the single-bag system, but a high standard of nursing and medical care of the lines is essential if sepsis is to be prevented. Different types of intravenous catheters are available - the best are those that are tunnelled subcutaneously. The feeding line must not be used for any other purpose. If other infusions are required a multilumen Hickman line may be used, keeping one lumen sterile for parenteral feeding. Hickman line insertion requires skill and experience. Complications include pneumothorax, central vein thrombosis, nerve injury, haematoma and arrhythmias. Similarly, only staff trained in the care of central venous feeding lines should be allowed to touch them, and the need for aseptic changing of sets and meticulous care of the catheter entry site should be emphasized. Feeding line infection should be suspected if fever develops, and is confirmed by cessation of fever when feeding is withheld and by a drawback blood culture (conducted under sterile conditions). Infected feeding lines can often be rescued by stopping feeding and by infusing vancomycin for 4-5 days. Central vein thrombosis can be treated by streptokinase infusion, but complete sterility must be maintained if the line is to be reused for feeding.
Refeeding syndrome
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A lesson learned from work in the developing world, and now applicable in western hospitals, is that refeeding of severely malnourished and ill patients can often precipitate rapid decline and death. The 'refeeding syndrome' relates to the dynamic changes induced by introducing nutrition support. Metabolism is reactionary to rapid shifts from
extra- to intracellular spate of potassium, magnesium, zinc and phosphate. Low plasma levels can then lead to cardiac and central nervous system problems. These shifts need to be anticipated, and clinical problems can be avoided by careful monitoring and extra provision of these nutrients during early refeeding.
NUTRITION AS A COFACTOR IN DISEASE AND IN THERAPY
Hypertension There are direct relationships between BMI, sodium intake and blood pressure. Humans evolved on very low-sodium diets. The main effect seems to be a programming effect from exposure to high sodium intake in infancy. Most patients with 'essential hypertension' are in fact obese, and the increased sodium intake is secondary to increased food intake. There is a threshold effect of additional salt in adult volunteers, with those on very high doses showing an increased blood pressure. However, there are also important cofactors, including family history, stress, obesity and potassium, calcium and magnesium intakes, which may obscure the relationship in an individual. In the UK the average daily salt intake in adults is 5-10 g, i.e. sodium intake (150-250mmol). This is more than twice the amount associated with lower rates of hypertension experimentally, and 10 times more than is required daily. Salt restriction and weight loss should always be the first steps in hypertension management. Halving sodium intake to 80-100 mmol/day has an effect similar to that of routine antihypertensive drugs (5-10mmHg) in hypertensive patients, but without the side-effects. This reduction would lower blood pressure by 25mmHg immediately for normotensive people, and would prevent a l0mmHg rise 30 years later. A weight loss of 5-10 kg will also reduce blood pressure by 3-5mmHg. Greater effects are seen during acute energy restriction, but blood pressure tends to return to pre-weight loss figures over a period of years.
Atheroma International comparisons of mortality rates from coronary heart disease (CHD) show that these are highest in populations with the highest saturated fat intakes. This is true even when the effects of obesity, hypertension, cigarette smoking, diabetes, stress and family history are allowed for. The dietary factors leading to coronary heart disease are shown in Figure 5.9. The major lipid risk factors for the development of atheroma are high levels of plasma cholesterol and lowdensity lipoproteins (LDL), and low HDL. The pattern of high triglycerides, small dense LDL and low HDL is particularly atherogenic, and is associated with insulin resistance and non-insulin dependent diabetes in the 'metabolic syndrome', characterized by a high waist circumference
Environmental factor
Metabolite or process affected
Pathophysiological change
Pathology
Disease
FIG. 5.9 Factors leading to coronary heart disease
and intra-abdominal fat accumulation. Consumption of saturated fatty acids is particularly likely to increase both LDL and cholesterol. Diets low in saturated fatty acids lower these levels. Saturated fats are prominent in butter, lard, sausages, meat pies, pastries and chocolates, whereas unsaturated fats predominate in oils or margarines prepared from olives, rape seed, maize, sunflower or soya. Not all margarines are unsaturated - those that contain coconut oil (used in many hospital canteens in the UK), for example, are highly saturated. Synthetically hydrogenated fats
contain high amounts of trans isomer fatty acids, which behave like saturated fats. Plasma cholesterol mainly indicates the production of cholesterol by the liver. Cholesterol-containing foods (such as eggs) do not necessarily increase the synthesis of cholesterol in the liver. Cholesterol absorption can be reduced 10% by plant sterols (sitosterol and sterol esters) used in non-functional foods. Dietary antioxidants (e.g. vitamins A, C, E, flavonoids in fruits and vegetables) reduce atheroma by protecting LDL from oxidation. Fibrinogen is elevated in the overweight, as are coagu-
137
lation factor VII and plasminogen activator inhibitor (PAI-1). These are all predictors of thrombosis, and other dietary factors also have an influence (e.g. dietary fat on factor VII). Certain n-3 polyunsaturated fats - such as eicosapentanoic acid, present in cod liver oil, mackerel and pilchards - tend to inhibit thrombosis and should be particularly encouraged. People who eat a lot of fish have less heart disease. Major dietary changes in the population of Finland between 1970 and 1990, increasing fruit and vegetables and fish, and reducing sodium and saturated fat, together with reduced smoking, have been accompanied by 60-70% reductions in CHD. Intentional weight reduction in overweight or obese subjects, particularly in diabetic patients, is followed by a reduced risk of mortality from CHD and an increased life expectancy.
Diabetes Insulin-dependent diabetes is not principally linked to diet in its aetiology, although prolonged breastfeeding seems to be protective. The major need in management is to provide regular meals and snacks, every 2 hours or so, to match the profile of insulin action and to avoid hypoglycaemia. Alcohol impairs glucose release from the liver and thus potentiates any risk of hypoglycaemia. Non-insulin dependent diabetes (type II) is closely linked to diet. In nearly every society, those who are overweight and whose diet is high in fat and low in soluble dietary fibre have a significantly increased risk of diabetes. The greatest risk is in those who were born small for dates and show poor growth in the first year of life. They seem specially prone to weight gain and diabetes. The major hazard in non-insulin dependent diabetes is premature heart disease and stroke. Weight loss improves the prognosis for the overweight, and physical activity probably plays a major part. For all patients with diabetes, the need to follow a low saturated fat diet, with a high fruit and vegetable intake, is even more pressing than for people without diabetes. Sugar avoidance is no longer considered necessary, but general recommendations for a healthy diet apply (Table 5.26). There is sufficient circumstantial evidence to urge high intakes of antioxidant-rich fruits and vegetables to protect against microvascular disease. There is no benefit from the use of so-called 'diabetic' foods, which exploit a vulnerable group.
The metabolic syndrome
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The 'metabolic syndrome' describes a clinical context which predisposes to premature CHD and stroke by a variety of coexisting abnormalities, including hypertension, dyslipidaemia (low HDL, high triglycerides, high small dense LDL), type 2 diabetes and hypercoagulability. The clinical syndrome is characterized by a predominantly central fat accumulation (intra-abdominally) even in those
TABLE 5.26 Summary of nutritional recommendations for people with diabetes compared with current average UK diet Approximate content of usual UK diet
Recommendations for diabetes
Energy
maintains BMI 25 kg/m2
to approach BMI 22 kg/m2
Carbohydrate (% energy) Added sucrose or fructose (g/day) Dietary fibre (g/day) Total fat (% energy) Saturated fatty acids Monounsaturated fatty acids Polyunsaturated fatty acids Protein (% energy) Salt (g/day) normotensive hypertensive So-called 'diabetic' foods
45 50-100
50-55* <25
19-25 40
>30g 30-35* <10 10-15 <10 10-15
17 11
6 12-15
10 -
None
<6 <3 None (avoid)
* Lower amounts of energy from carbohydrates and up to 35% from fat may be acceptable provided that most of the fat derives from monounsaturated fatty acids such as olive oil in 'Mediterranean-style' diets.
who are thin - with a high waist circumference. The unifying biochemical feature is probably early insulin resistance, at least in tissues other than the intra-abdominal fat mass, and there seem to be a reduced activity of PPAR (peroxisome proliferator-activated receptor-y) enzymes. The metabolic syndrome is at least partly genetic, but is precipitated by weight gain and physical inactivity, by smoking and by high alcohol consumption. Another key element is related to poor fetal and infant growth (low birthweight and size at 1 year of age). This may relate to under- or imbalanced nutrition at critical stages of fetal organ development the 'Fetal programming' hypothesis.
Cancers It is estimated that malnutrition and cachexia play a part in 70-80% of all cancer deaths, and diet contributes to 35% of all cancer development. Obesity is associated with the development of colonic cancer and also the sex hormonerelated cancers (breast, endometrium and prostate). The WHO produced a summary of dietary influences on different cancers, revealing a rather consistent pattern among major cancers of associations with dietary fat and alcohol, and with protection from fruits and vegetables. There is some suggestion that high intakes of meat perhaps burned meat containing cyclic hydrocarbons may be hazardous. It is not certain which factors in fruits
and vegetables are protective, but antioxidants probably play a part. It is possible that vitamin E supplementation may help reduce cancers. On the other hand, studies with P-carotene supplementation have actually shown increases in lung cancer in smokers, especially if they are also heavy drinkers. Vitamin tablets should therefore not be taken, or prescribed, in doses far exceeding healthy dietary intakes. It is better to promote fruits and vegetables, which also contain other bioactive compounds, such as carotenoids and flavonoids, that probably also help to protect against cancer when consumed throughout life. Advice for cancer prevention is thus essentially the same as for reduction in heart disease.
Gallstones The deposition of cholesterol to form gallstones depends on the relative concentrations of total bile salts, lecithin and cholesterol. The fine balance between these is affected by obesity and low dietary fibre intake, but the precise mechanisms of the imbalance or of the formation of gallstones are not clear. Rapid weight loss may precipitate biliary colic.
Liver disease The most important association between dietary factors and liver disease is that between alcohol and cirrhosis. However, mycotoxins may also affect the liver: aflatoxins, which are widely prevalent in cereals kept under poor storage conditions, may be a factor in causing primary liver cell cancer and may also contribute to the development of the fatty liver in kwashiorkor. Malnutrition in children does not account for the high prevalence of cirrhosis in developing countries: hepatitis B infection seems to be the major cause.
Pancreatic disease Chronic pancreatitis is frequently found in populations where malnutrition is rife. Periods of undernutrition may cause stasis of the exocrine juices within the pancreas, leading to acinar cell destruction and loss of digestive function. Pancreatic calcification often follows, with secondary diabetes. However, in western societies alcohol excess seems more important than undernutrition as a cause of chronic calcific pancreatitis.
Respiratory disease Being overweight, and particularly having a central (intraabdominal) predominance of fat, causes breathlessness, and also aggravates symptoms in patients with COPD. Sleep apnoea and hypoxia is a potentially serious consequence, with snoring as an early symptom. Weight loss is very effective. A proportion of patients with COPD and chest bellows disease become severely cachectic. The chest problem is
aggravated by wasting of the respiratory muscles, and by malnutrition-related immunosuppression. The main cause is suppression of appetite by recurrent infection exacerbations. Hypermetabolism is a lesser factor. Weight gain is extremely hard to achieve by dietetic means, but can improve respiratory function: appetite is poor, and the effort of feeding worsens hypoxia. Starvation ultimately leads to death by pneumonia in most cases, and it has been suggested that malnutrition may contribute to the development of emphysema.
5
Renal disease Patients with renal failure accumulate potassium, phosphate and nitrogenous products from protein catabolism. Traditional conservative management included a diet restricted in protein potassium (limited meat, dairy products, fruit and vegetables). Former advice to avoid fruit and vegetables is now tempered by anxieties about reduced antioxidant status, as the main cause of death is cardiac disease. A daily limit of three items of fruit and two portions of vegetables (or vice versa) is acceptable for most patients. Most patients with advanced renal diet have poor appetites and tend to undereat. The dietetic emphasis should probably be on increasing starchy carbohydrates, rather than on restricting foods. During dialysis, small molecules including vitamin C are removed, and supplements should be given afterwards. Nephrotic syndrome and proteinuric diabetic neuropathy are aggravated by high protein intakes. Restriction to about 0.8-1 g/kg/day (10% energy) is appropriate and will still allow nitrogen balance. This amount is much less than usual in UK diets.
Dental caries Fluoride is an essential nutrient, required to form healthy dental enamel. Much of the UK, particularly Scotland, has a fluoride-deficient water supply (below Ippm). Dental caries occurs when Streptococcus viridens adheres to teeth with fluoride-deficient enamel and metabolizes sugar into lactic acid. This lowers the pH acutely and erodes the enamel. Low-pH foods can be similarly damaging. All sugars can act as substrate; thus 'natural' sugars such as fructose are just as cariogenic as sucrose. The most important factor is the length of time that sugar-containing foods remain in contact with the teeth; adhesive foods and sugary drinks given in bottles to infants are particularly damaging. The low pH of many fruit drinks and colas leads to rapid enamel loss. There has been a marked decrease in dental caries among children in certain social groups in the UK over the last 20 years, but increased social division within the population reveals very high rates in deprived areas and groups. The fall in caries has been associated with an increase in the use of fluoride (in toothpaste, in drinking water or as tablets), and possibly also an increased prevalence of teeth cleaning. Perhaps paradoxically, sugar con-
139
sumption has increased over this period, although very recently low-sugar products have become more prevalent.
TABLE 5.27 Foods associated with food Intolerance* Food
% of cases
Urinary calculi
Milk
Calcium or oxalate stones are sometimes precipitated in the urinary tract as a result of increased dietary intake. Oxalate stones are those most frequently associated with dietary factors, occurring most commonly in populations with high phosphate intakes. In Thailand, for example, oxalate calculi occur most commonly in the rural populations, where the high phosphate intakes, associated with a predominantly vegetarian diet, contrast with the lower phosphate intakes of the better-off urban families. Oxalate stones may also be precipitated by dehydration in extremely hot climates, and by excessive vitamin C consumption. 1
Egg
25 22
Nuts/peanuts Fish/shellfish Wheat/flour Chocolate Artificial colours Pork/bacon Chicken Tomato Soft fruit Cheese (but not milk)
12 12
6 5 3 3 3 3 3 3
*From. Truswell AS 1986 ABC of nutrition
FOOD SENSITIVITY AND INTOLERANCE
The clinical importance of food allergy is difficult to assess as little is known of the scientific basis for hypersensitivity to food, there have been few controlled clinical trials of exclusion diets, and the mechanisms by which they work are not understood. A variety of foods have been implicated in food intolerance (Table 5.27). There has been considerable public interest in peanut allergy. Reports of food allergy can lead to needless anxiety. Parental concern can lead to poorly designed exclusion diets and nutrient deficiencies. The great majority of self-diagnosed food allergies or food intolerances turn out to be erroneous when professionally assessed. However, dramatic, even life-threatening allergies do occur. The major clinical symptoms associated with food sensitivity are shown in Table 5.28. A number of food allergies are associated with immunological reactions - usually an IgE response. A radioallergosorbent test (RAST) may detect antibodies in plasma against a specific food protein, but there is little correlation between the clinical features and the results of a variety of RAST tests. Skin tests of purified antigens may detect an urticarial response within a few minutes of intradermal inoculation, but positive skin tests do not correlate well with sensitivity reactions in other organs, such as the lungs and the gastrointestinal tract. In short, there is as yet no defined mechanism in most cases of food sensitivity, and very few laboratory tests are of any use. Management therefore depends on careful history-taking and a critical approach to elimination diets.
1
140
MCQ 5.5
TABLE 5.28 Symptoms in 100 patients with food intolerance* Symptom
Number of patients affected
Asthma Gastrointestinal Eczema Urticaria Rhinorrhoea Angioedema
58 41 37 35 31 8
* From: Truswell AS 1986 ABC of nutrition
Eczema Exacerbations of eczema are frequently associated with reactions against eggs and milk. Infantile eczema is sometimes improved by withdrawing eggs and cows' milk products; families with a strong history of eczema are advised to breastfeed as long as possible and to delay the introduction of eggs and cows' milk. Dietary manipulation in older children and adults is also worth trying but is often disappointing, and must be supervised to ensure nutritional adequacy.
Gastrointestinal symptoms The best-defined gastrointestinal hypersensitivity syndrome is to gluten in coeliac disease (see Ch. 15). Onset is sometimes precipitated by a gut infection, especially in children. Transient gluten intolerance following mucosal damage from giardiasis or rotavirus infections may occur in other patients. Secondary lactose intolerance may occur
in untreated coeliac disease through mucosal atrophy and loss of lactase. A more frequent problem is cows' milk protein intolerance. Here, mucosal damage permits access to mucosal lymphocytes, which become sensitized to the dietary protein. Subsequent exposure then produces a severe response in which lymphokines are released, damaging enterocytes. Villous atrophy occurs and malabsorption develops. There is also some evidence of exacerbation of the symptoms of ulcerative colitis by cows' milk; it is sometimes suggested (though reliable evidence is lacking) that infantile colic is caused by dietary factors transmitted in breast milk or contained in cows' milk. Early exposure to cows' milk in infancy has been related to gastrointestinal blood loss and anaemia, but the mechanism is obscure. The principal carbohydrate in milk is lactose. The expression of lactase in intestinal mucosa varies widely in adults, and in some races (particularly eastern) it is virtally absent, leading to lactose intolerance. Fermented milk products are preferred and are less liable to be malabsorbed. The very rare genetic fructose intolerance syndrome is usually identified by patients who develop symptoms after sweet foods.
Management of suspected food sensitivity If the patient suffers a reaction each time exposure to the allergen occurs, the latter should be easily identifiable. However, in the case of the general systemic symptoms described above, identification of the allergen is more difficult. There are two approaches:
5
• Exclude a suspected allergen for at least 4 weeks and then reintroduce it (this is mostly satisfactory where the condition is mild); or • Work out an elimination diet (one based on lamb, rice and pears is a classic starting point) as advised by a dietitian which ensures full nutritional adequacy. Then reintroduce a potential allergen every 2 weeks and observe the response. It is important to monitor body weight regularly and be alert to the possibility of an underlying eating disorder. Multiple food 'allergies' are less likely to have organic origins, and multiple exclusion diets can be dangerous. Restricting food choices for growing children is particularly hazardous, and needs careful supervision and counselling.
Migraine Migraines sometimes appear to be precipitated by foods such as chocolate, cheese, red wine, nitrates, cows' milk and wheat. Some of these contain amines or stimulate histamine release, which may produce an effect on cranial arteries.
NUTRITION IN HEALTH PROMOTION: CURRENT DIET AND PROPOSALS FOR CHANGE Health promotion
Respiratory tract responses Respiratory tract responses - including excessive production of tears, nasal secretions, sneezing and asthma are usually related to environmental factors, e.g. chemical sprays, cosmetics and food or plant pollens, but eggs, cows' milk and chocolate may also precipitate symptoms. Recent studies suggest that a variety of food preservatives, including tartrazine and sulphur dioxide, may also be responsible.
Urticaria and angioedema Most cases of urticaria or angio-oedema do not have dietary orgins. Acute or chronic urticaria may occur in response to eggs, nuts, fish (particularly shellfish) and cows' milk, as well as certain fruits, wine and cheese. Angioedema is a feared and potentially lethal complication.
Neurological and behavioural symptoms A range of syndromes of 'hyperactivity' in children and tiredness in adults are commonly attributed to intolerance, especially to tartrazine. Although some cases may occur, social factors are probably more important.
The promotion of good health (physical, psychological and social) incorporates an increasing emphasis on disease prevention through dietary change. Many of the major disabling illnesses and causes of premature mortality in western societies - heart disease, stroke, cancer - are progressive, not amenable to cure by drug therapy, and to a substantial extent preventable through dietary change. Two approaches are possible: • High-risk screening strategy. This approach requires a screening procedure to identify individuals at high risk, who then receive specific dietary advice and professional follow-up. The screening procedure must have very high sensitivity and must be able to reach high-risk groups, such as those in deprived areas and communities. It is dependent on high levels of professional input and therefore expensive. Such a programme must be sustained indefinitely, as there will always be new individuals entering the high-risk categories. Although this type of approach has been heavily promoted for cholesterol lowering, the principles outlined above cannot in fact be met. In particular, the sheer numbers who would require to be screened and followed up would make the system impractical (almost half the UK population has undesirably high blood lipids), and
141
the low sensitivity and specificity of cholesterol screening means that among those with low serum cholesterol the commonest cause of death is still ischaemic heart disease. The high-risk strategy approach is therefore more suited to less frequent conditions that require specific advice, such as phenylketonuria identified by a Guthrie test at birth, or the identification of women who have had a child with neural tube defect, who need high-risk folate supplementation (4mg daily) in the periconceptional period to prevent a recurrence. • Population-directed strategy. This approach does not involve screening but requires, by a combination of health education and modification of food supply, a change in the nutrient consumption of the whole population or of targeted subgroups. Examples include the abolition of marketing of high-sugar bedtime drinks for infants, as a way of reducing dental caries, and the healthy eating food and health policies designed to reduce major diseases such as ischaemic heart disease, diabetes, cancers and osteoporosis, which have been urged by many governments and umbrella organizations such as WHO. Population-directed programmes do not demand major health service inputs, although high-risk strategies may operate alongside for special groups. Because the diet of the whole population will be modified, it is essential that the changes promoted should be advantageous or safe for everybody. Given the very limited resources of health promotion agencies, effective population-directed nutritional policies must include cooperation from the food production and supply industries.
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The average dietary intakes in western countries, including the UK, have changed substantially over the last 50 years, with greatly increased intakes of foods of animal origin, and declining intakes of fruits and vegetables and starch-rich staple foods (cereals, potatoes). There is now little scientific argument in opposition to health-directed measures aimed at reducing intakes of total fat (particularly saturated fat), reducing sodium and some increase in potassium and calcium consumption, while promoting increased consumption of fruits and vegetables and, to some extent, unsaturated fats, particularly those from oilrich fish. Although the benefits to any individual from dietary change are relatively small, the burden of disease to whole populations would be reduced substantially, particularly through reductions in heart disease, stroke and diabetes, and in the prevention of obesity and osteoporosis. A comprehensive package of quantitative proposals for dietary change have been made for Scotland, a country which has a very high burden of preventable disease (Table 5.29). To some extent .this has been influenced by the observational evidence from countries such as Norway and Finland, where long-term programmes of dietary change have resulted in major reductions in heart disease, stroke and cancer. It is important to recognize that nutrient tar-
TABLE 5.29 Intermediate nutrient and dietary targets for Scotland for the year 2005 Dietary component Vegetables and fruit excluding potatoes (g/d) Carbohydrates: total % E Starch (% E) Non-starch polysaccharides (g/d) Extrinsic non-milk sugars (% E) Fatty acids (% E): Cis-monounsaturated Cis-polyunsaturated (Total) n-6 n-3 Saturated Trans Total fat (% E) Sodium consumption (mmol/d) Potassium consumption (mmol/d) Alcohol consumption* (g/d) Men Women Dietary cholesterol (mg/d)
1989-91 intake
Targets
181
>400
25.3
>40
10.5 16.3
>16 <10
12.6 6.3 5.2
<10
0.8 16.6
13 <8.8 >1.2
2.1
<11 <2
40.7
<35
163
70
62
80
34.5 11.1*
<24*
-
-
<16*
f
Current intakes relate to estimates derived from a variety of sources. % E signifies the proportion of the nutrient as a percentage of total food energy, i.e. excluding alcohol. Changes in vitamin intakes are those expected from the dietary changes; women of child-bearing age have been recommended to supplement their diet with 400 ug folic acid, * Alcohol is specified for consumers only, intakes from Adult Survey, maximum intakes proposed by Royal College of Physicians (1987).
gets can only be met if there are changes in food choices, and that these must be matched by changes in food supply. Successful intervention programmes thus require multidepartment government action over a long period. For some of the nutritional consequences of dietary change, the benefits would be seen principally in those who are currently consuming very poor diets; however, it is likely that there would be some improvement even for groups with better diets at present. Extensive studies have shown no appreciable health disadvantage in the changes proposed. In particular, the effects of cholesterol lowering, which were disputed for many years, have now been shown clearly not to be harmful. The benefits from sodium restriction had been difficult to quantify because of the variety of research addressing different groups with different levels of blood pressure and different levels of sodium intake. Large meta-analyses have clarified that a major reduction in sodium intake should be made. This would partially benefit those who already have relatively high blood pressure and would be likely to reduce the development of hypertension in younger people.
RECENT ADVANCES IN HUMAN NUTRITION Recent years have seen an important expansion of research in human nutrition, stimulated by recognition that the major sources of illness and premature mortality in the world, and specifically in highly developed Western countries, will not be amenable to cure by drug therapy. If these problems (cancers, heart disease, stroke, diabetes, osteoporosis) are to be alleviated, the answer must lie in prevention, and diet plays a major role. These are the themes that underlie the application of modern nutritional science to medicine. Most diseases develop as a result of interaction between genetic factors peculiar to the individual, and environmental exposure or conditions. Thus within human nutrition the concept of 'gene-nutrient interactions' has emerged. It is very difficult for people to change their diets, and satisfy targets to maintain good health. The science of food choice, which relates closely to food science in the context of functional foods, designer foods and therapeutic foods or diets, has become of major importance. Dietary and nutritional influences operate over a very long timespan in modifying health and disease. Longterm observational follow-up studies from cohorts of relatively young people, are already demonstrating new dietary influences on health in periodic followup surveys. A number of recent advances in human nutrition can be identified as arising from these new understandings: • Importance of fetal nutrition and development for later health: poor fetal growth predicts diabetes, hypertension, heart disease, stroke. • Folic acid supplementation in the perioconceptional period overcomes metabolic abnormalities that prevent neural tube development. • Dietary folate reduces serum homocysteine, a risk factor for CHD. • Antioxidants - vitamins C, E, carotenoids and phenolics - have the potential to be involved at several stages against development of cancers (free radical DNA damage) and coronary heart disease (protection against LDL oxidation). • Vitamin supplements given unphysiologically as tablets may have different effects from giving foods which contain these vitamins. Foods contain many other related bioactive compounds such as flavonoids, carotenoids, etc. This balance is likely to be important for health. • Specific fatty acids have different effects on plasma lipo-proteins and coronary heart disease risk. For example stearic acid, although saturated, does not elevate cholesterol. Trans-fatty acids, found mainly in synthetically hydrogenated fats such as margarine and in baked foods, elevate LDL cholesterol and are linked to heart disease prevention in the same way
as saturated fatty acids. Individuals with different apolipoprotein E subtypes respond differently to dietary fatty acids. • The human placenta can probably transfer fatty acids to the fetus and there may be specific fatty acid transfer proteins. • Immune function appears to be determined to some extent by the balance of fatty acids in the diet. New non-absorbable drugs (e.g. orlistat) or novel food products (e.g. sitosterols and sterol esters) modify fat absorption and consequent health. • The two-way interaction between nutritional status and disease may lead to 'conditioned essentiality' for specific nutrients during illness, e.g. for amino acids such as glycine or glutamine, which are not essential during health.
Some of the dietary changes required to improve health demand action principally from individuals, to select more appropriate foods and to cook and prepare them in more healthy ways. Thus an increased consumer demand for fruits and vegetables and for lower saturated fat food can be encouraged to help health promotion, and is likely to be met by increased provision from the food industry. To reach other nutrient targets, however, there will need to be greater emphasis on programmes of change within the food manufacturing and catering industries: for example, about 80% of sodium intake derives from foods that have had salt added during manufacture or processing. A programme of stepped small reductions in the salt content of common foods is likely to be acceptable and beneficial to consumers. The composition of many foods could be modified with health benefits and without impairing palatability or commercial success. Examples of effective national nutritional policies are available from countries such as Norway and Finland, where substantial changes in average diet composition over a period of 10-20 years have been accompanied by major reductions of the order of 60-70% in ischaemic heart disease and cancers before the age of 65. There are far greater effects that could be achieved by lipid lowering or other drug interventions. The three dietary components with the greatest impact are reduced saturated fat as a proportion of energy, reduced sodium consumption, and substantially increased fruit and vegetable consumption. The success of these programmes has depended on the activities of committed health professionals prepared to take on public positions and to interact with national and local governments and with the food supply industries. Responsible and well-educated media involvement, which does not seek to promote mavericks and sensationalists, has been influential. High levels of general education and minimization of social deprivation are critical for the effectiveness of health promotion.
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FURTHER READING Department of Health. Nutrition: A core curriculum for nutrition in the education of health professionals. London: HMSO, 1994. Department of Health. Nutritional aspects of the development of cancer. Report of the Working Group on Diet and Cancer of the Committee on Medical Aspects of Food and Nutrition Policy. Report on Health and Social Subjects No. 48. London: HMSO, 1998. Dietary reference values for food energy and nutrients for the United Kingdom. Report on Health and Social Subjects, 41 1991. Department of Health COMA. London: HMSO, 1991. Garrow J S Obesity and related disorders. Edinburgh: Churchill Livingstone, 1988. Holland B, Welch A. McCance and Widdowson's compositions of foods, 5th edn. Cambridge: Royal Society of Chemistry. 1991: See also supplements dated after 1991. James W P T, Garrow J S Human nutrition and dietetics, 10th edn. Edinburgh: Churchill Livingstone, 2000.
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Mann J, Truswell A S. Essentials of human nutrition. Oxford: Oxford University Press, 1998. Manual of dietetic practice, 2nd edn, Oxford: Blackwell Science, 1994. National Institutes of Health (NIH) obesity guidelines. Available online at http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm The Scottish Office Home & Health Department. The Scottish diet: Scotland's health - a challenge to us all. Report of a Working Party to the Chief Medical Officer for Scotland, 1994. Scottish Office Department of Health. Scotland's Health - A challenge to us all. Eating for health - a diet action plan for Scotland, 1996. Truswell A S ABC of nutrition, 2nd edn. London: British Medical Association, 1992. WHO Diet, nutrition and the prevention of chronic diseases. Technical Report Series 797. Geneva: World Health Organization, 1990.
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Cancer Medicine Robert L Souhami
Incidence and epidemiology 145 Aetiology 146 Tumour growth and development 149 Pathology 151 Clinical features 151 Staging and investigation 155
Supportive care in cancer management 165 New approaches to management 167 Trials of treatment 167 Care of the dying 168 Alternative therapy 168
Principles of cancer management 157
Each year in the UK there are approximately 220000 new cases of cancer. Almost one-third of the population will develop cancer during their lifetime, and of these 70% will die of the disease - 150000 deaths a year. As a cause of mortality, cancer is second only to cardiovascular disease. It is most common in the elderly: the age-specific incidence rates for men and women are shown in Figure 6.1. The frequency of cancer and the increasing complexity of management mean that every clinician must have a firm grasp of the principles of diagnosis, investigation and management. In recent years, the approach has been changing rapidly as a consequence of fundamental advances in cancer biology, the isolation of genes responsible for hereditary disposition to cancer, increasing accuracy in diagnosis and staging, and major developments in the use of radiotherapy and chemotherapy. At the same time, clinicians have developed a better awareness of the problems faced by patients who are incurable, and professional attitudes have changed in the direction of more open discussion with patients. Cancer medicine therefore demands a combination of a high degree of technical competence and a sympathetic insight into the feelings of the patients. It is this double challenge that makes it a most rewarding part of medical practice.
INCIDENCE AND EPIDEMIOLOGY Incidence means the proportion of a defined population developing a disease in a stated period of time; prevalence
is the proportion which has the condition at a single point in time. Crude incidence or prevalence rates refer to a whole population and specific rates to selected groups, for example those defined by age or sex. The age-specific incidence rates of some cancers are shown in Figures 6.2 to 6.4. It can be seen that adenocarcinomas in women have quite different age-specific incidence rates. Cancer of the breast increases rapidly in incidence before the menopause, and at a slightly slower rate thereafter (Fig. 6.2). Uterine and ovarian cancer also show an increasing incidence premenopausally, but the rate does not rise in later life. Gut cancers (Fig. 6.3), on the other hand, show no relation to the menopause but rise rapidly in incidence in old age in both sexes. The biphasic age-specific incidence of Hodgkin's disease (Fig. 6.4) contrasts markedly with the findings in adenocarcinoma. Lung cancer is at present more common in men, but the incidence in women is rising rapidly, approaching that of breast cancer. Cancer is the second main cause of death in childhood, with acute lymphoblastic leukaemia accounting for nearly half the deaths. The commonest sites of cancer in the west are the lung, skin, large bowel, prostate, stomach and rectum in men; and the breast, large bowel, skin and lung in women. The mortality rates are, however, different from incidence rates (Fig. 6.5), with skin cancer having a low mortality rate and lung cancer a very bad prognosis. However, the relative incidence of cancers is changing with time. For example, the incidence of lung cancer has been rising rapidly since the mid-1960s, especially in women, whereas that of stomach cancer has been falling for both men and women (Fig. 6.6). The rise in incidence of lung cancer is undoubtedly due to smoking, but the reason for the decline in stomach cancer is not clear. Cancer incidence varies in different countries (Table 6.1), and this variation may provide insights into aetiology. Carcinoma of the oesophagus has a high incidence in an area extending from the Caspian Sea to Central Asia and the Far East; it is also more common in the Transkei. In these areas it has an incidence 200 times that found in the UK. In Japan, gastric carcinoma is 30 times more common than it is in the UK, but pancreatic cancer is much rarer. The reasons for these variations are as yet unknown, but dietary and nutritional factors are suspected to play a part. The migration of populations has helped to determine how much of the geographical variation is genetic and how much is environmental. When Japanese people settle in the USA, the incidence of cancers in their offspring resembles that of the adopted country: the high incidence of gastric cancer falls, and the lower incidence of cancers of the breast, colon, ovary and prostate rises. These findings suggest that environmental, rather than genetic, causes account for most of the observed differences between countries.
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FIG. 6.3 Age-specific incidence of adenocarcinoma of the colon FIG. 6.1 Age-specific incidence of cancer (England)
FIG. 6.4 Age-specific incidence of Hodgkin's disease
FIG. 6.2 Age-specific incidence of carcinomas of the breast, ovary and uterus Note change in rate of increase at the time of the menopause.
AETIOLOGY Evidence suggesting aetiological factors in cancer has come from epidemiological and laboratory investigation. 1 It is probable that, for many types of neoplasm, an inter-
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MCQ 6.1
FIG. 6.5 Incidence and mortality of common cancers in men and women in England and Wales Note that whereas skin cancer is common, its mortality is low. Cancer of the lung is common and accounts for a large number of total cancer deaths.
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FIG. 6.6 Cancer of the lung and stomach A Cancer of the lung: age-standardized death rate/10000 in age group 65-74,1905-85 in the UK. B Cancer of the lung: mortality 1941-91 for different age groups. C Cancer of the stomach: change in mortality in England and Wales and in Japan, 1940-1990.
TABLE 6.1 Geographical Incidence of cancer Cancer
High incidence
Low incidence
Ratio (high Mow)
Oesophagus
Iran, Transkei, Kazakhstan Australia Mozambique Far East (China) UK Japan Europe, USA
Holland
200:1
India UK Europe Nigeria UK Japan
200:1 100:1
Skin Liver Nasopharynx Lung Stomach Breast
100:1 35:1 30:1 6:1
action of genetic and environmental factors is responsible for the development of a cancer (Fig. 6.7).
CHEMICAL CARCINOGENS
The frequency of scrotal carcinoma in chimney sweeps was noted by Sir Percivall Pott in 1775, and the high incidence of bladder cancer in dye workers in 1895. The mechanisms
of action of chemical carcinogens have been intensively studied. There are several classes of experimental carcinogens (Table 6.2) which are possible causes in humans: • Polycyclic hydrocarbons are formed from combustion of organic compounds. They are present in cigarette smoke, soot, car exhaust fumes and some foods. Dibenzanthracene was one of the first to be shown to be carcinogenic. The carcinogenic effect results from reaction with bases in DNA. • Aromatic amines and azo dyes, such as B-naphthylamine and benzidine, are metabolized to an active form. (3Naphthylamine is glucuronated in the liver. Glucuronidases in the urine liberate the carcinogen in the bladder. • Nitrosamines are formed when nitrites in food are converted to nitrates, which react with amines in food. The substances can cause stomach cancer experimentally. • Alkylating agents, such as those used in cancer management, bind to DNA. Use of these drugs in cancer treatment has been associated with the development of secondary malignancies, the most important of which is secondary leukaemia, which may also be caused by treatment with etoposide, a widely used anticancer agent.
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FIG. 6.7 The sequence of genetic events contributing to invasive cancer
TABLE 6.2 Chemical carcinogens Class
Example
Source
Polycyclic hydrocarbons Aromatic amines Azo dyes Nitrosamines Toxins Alkylating agents Chromates Asbestos
Dibenzanthracene
Smoke, cigarettes
p-Naphthylamine Dimethylaminobenzene Dimethylnitrosamine Aflatoxin Melphalan
Aniline dyes Butter yellow ?Food Aspergillus flaws Drug treatment of cancer Industrial exposure Insulation and heating installations
• Organic toxins include the best-studied example, aflatoxin, produced by the mould Aspergillus flavus growing on grain. This substance has been suggested as an aetiological agent in liver cancer in Africa. • The most important occupational carcinogen is asbestos, which causes cancer of the pleura, lung and peritoneum in workers exposed to the dust. When carcinogens act on a cell they may cause a permanent change which predisposes to cancer, a process known as initiation. Other agents can then produce transient changes which with continued exposure lead to cancer; this is known as tumour promotion. This multistage process has been shown in some experimental cancers, where mutagens act as initiators and hormones or dietary constituents act as promoters. The more prolonged the exposure to a carcinogen, the more likely the tumour is to develop. Several genetic events in sequence are necessary for the tumour to develop.
IRRADIATION
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The carcinogenic effect of ionizing irradiation was indicated by the skin cancers that developed on the hands
of early radiologists, and by the increased frequency of acute and chronic leukaemia, breast and thyroid cancer in Hiroshima during the 30 years after the atom bomb was dropped. The mechanism of carcinogenesis is probably related to the chromosomal damage caused by X-rays. It seems likely that 'background' ionizing irradiation does not contribute greatly to common cancers in humans. Therapeutic irradiation may give rise to bone and soft tissue sarcoma (after a latent period of 10 years), and possibly to lung cancer. Ultraviolet light probably plays a role in the development of skin cancers. This is seen most clearly in the autosomal recessive disorder xeroderma pigmentosum, where a defective DNA repair mechanism is associated with the early development of skin cancers on skin exposed to sunlight. Malignant melanoma and other skin cancers are uncommon in black people but are particularly frequent in fair-skinned Celts. In Australia, skin cancers are common among the non-indigenous population and increase in incidence in the north nearer the Equator.
VIRUSES Ribonucleic acid (RNA) viruses can cause a variety of cancers in animals. These viruses contain a gene which codes for the enzyme reverse transcriptase, which is produced in the infected cell and results in the cellular synthesis of DNA complementary to the viral RNA and thus to the production of more viruses. For this reason they are called retroviruses. Tumours caused by these viruses include avian erythroblastosis, rat sarcoma, feline leukaemia and murine leukaemia. The insertion of the viral genome into DNA leads to malignant transformation. A growth-factor receptor is encoded by the erythroblastosisB virus (v-erb B), and a phosphokinase by Rous' sarcoma virus (sis). RNA viruses are involved in the development of some forms of T-cell leukaemia and lymphoma (human T-cell leukaemia virus, HTLV types 1 and 2). The human immunodeficiency virus (HIV) is the cause of the acquired
immune deficiency syndrome (AIDS), in which there is a greatly increased frequency of skin sarcoma and B-cell lymphoma. These tumours are probably not caused by the virus but are a consequence of oncogenesis in patients with greatly reduced immunity. Hepatitis C is an RNA virus which is implicated in the high incidence of hepatoma in chronically infected patients. Research into RNA viruses led to the discovery that the viral oncogenes had homologues in normal cellular DNA. These cellular proto-oncogenes appear to code for products very similar to those produced by the equivalent virus. These findings have led to the search for increased expression of cellular oncogenes in human cancers, for the gene products, and for the link between carcinogenesis and oncogene activation. There is strong circumstantial evidence implicating DNA viruses in the pathogenesis of some malignant neoplasms. For example, Epstein-Barr virus (EBV) causes proliferation of normal human B lymphocytes; EBV-coded proteins are found in Burkitt's lymphoma cell lines; and African children with the lymphoma have high titres of antibody to viral antigens. Worldwide, hepatoma is one of the commonest cancers. Infection with hepatitis B virus (HBV) is associated with its development both in Africa and in Europe. Hepatoma is particularly likely to occur in chronic active hepatitis associated with HBV and hepatitis C, and in alcoholic cirrhosis where there is evidence of previous HBV infection. Cancer of the uterine cervix is increasing in frequency in young women. There is strong evidence that human papillomavirus is associated with this disease, possibly as a result of sexually transmitted infection.
GENETIC FACTORS Numerous inherited genetic abnormalities predispose to the development of malignancy (Table 6.3). These syndromes include examples of autosomal dominant and recessive inheritance, and X-linked disorders. Inherited chromosomal abnormalities may also predispose to cancer (Table 6.3). The most common is Down's syndrome (trisomy 21), where there is an increased incidence of acute leukaemia. In some cases the relationship between the genetic abnormality and the induction of cancer has become clearer. In hereditary retinoblastoma the retinoblastoma gene (Rb) acts as a growth suppressor gene. Inherited loss of this gene is followed by mutation in the other allele, which sets the scene for malignant transformation. Germline mutation, followed by loss of heterozygosity of the p53 gene, occurs in the Li-Fraumeni syndrome, in which the families of children with sarcoma show an excess of other cancers. It has become apparent that there may be an important inherited genetic component to many other common cancers. Very recently, two genes responsible for familial breast cancer have been isolated. The first, BRCA1, is prevalent in Ashkenazi
RECENT ADVANCES IN GENETIC DIAGNOSIS OF FAMILIAL CANCER, SCREENING, CANCER PREVENTION
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The cloning of two breast cancer genes that are responsible for early-onset and aggressive breast cancer, the identification of the genes responsible for hereditary colon cancer, and the likelihood that other genes are responsible for some cases of testicular, lung and prostate cancer, will lead to increasing demand for genetic testing for cancer risk. In satisfying this demand it will be necessary to provide counselling and advice to patients and their families. The identification of individuals at especially high risk may allow screening services to be directed more efficiently towards those who have extra need and in whom considerable expenditure will be fully justified. It is now feasible to consider the use of drugs which may prevent cancer developing in those at high risk. An example of such intervention is the use of tamoxifen as a preventative agent in breast cancer.
Jewish women and has an early age of onset. A wide variety of mutations have been detected. BRCA2 predisposes to both breast and ovarian cancer. In hereditary nonpolyposis colorectal cancer the syndrome arises as a result of mutation in one of a family of DNA mismatch repair genes. Acquired genetic abnormalities are frequently found in cancer cells, with mutation, transposition and deletion of genetic material. These abnormalities are sometimes consistent, such as the translocation from chromosome 22 in chronic granulocytic leukaemia, and the reciprocal translocation involving chromosome 8 in Burkitt's lymphoma. In many tumours (lung cancer, leukaemia, hepatoma) there is mutation of the p53 gene, which codes for a growth regulatory transcription factor. In colon cancer a cascade of genetic events is responsible for the transformation of polyps to invasive cancer.
TUMOUR GROWTH AND DEVELOPMENT Some tumours exhibit properties which imply that they have arisen as a result of clonal expansion caused by an oncogenic event in a single cell. Lymphomas, for example, usually show restriction to one type of surface immunoglobulin light chain; and studies in individuals who are heterozygotes for the enzyme glucose-6-phosphate dehydrogenase have shown that tumours contain only one form of the enzyme. Whether all cancer are monoclonal in origin is not known, and the development of some
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carcinomas in a polyclonal field of premalignant change remains a possibility. Even if most tumours are monoclonal, heterogeneity of structure and function arises during the course of tumour growth. Cells from a tumour are diverse with respect to resistance to damage by irradiation or cytotoxic drugs, surface antigen expression, growth rate, and expression of biochemical markers such as embryonic proteins or peptide hormones. This diversity is due to genetic instability in the cancer cells. Heterogeneity within tumours presents a formidable problem for treatment. In normal tissues, self-renewing stem cells replenish a proliferating population of cells which follow a pathway of differentiation resulting in a mature tissue (Fig. 6.8). Cell death is balanced by the formation of precursors, and the tissue is static in size or else grows and diminishes in response to such external controls as hormonal environment. In cancers the restraint on growth is disrupted, so that sustained expansion of the tumour occurs. For clinically detectable cancers, the kinetics of growth appear to be exponential and the rate of tumour volume doubling varies widely. In Burkitt's lymphoma, the doubling time of visible tumour may be as short as 1-2 days, in contrast to 100-400 days for some squamous carcinomas and adenocarcinomas. It seems unlikely that growth is exponential from the beginning of the cancer, as this would imply very long subclinical growth periods for some tumours (Fig. 6.9). Cancers are clinically apparent after about 32 doublings, and lethal after 36-38. It is possible that tumours grow more rapidly when they are very small and slow progressively as they enlarge (gompertzian growth). If true, this may have implications for therapy, as the more rapidly dividing small tumour might be more susceptible to chemotherapy. During growth, the tumour becomes vascularized and lymphatic drainage is established. Cells more than 150 um from a capillary are relatively hypoxic and resistant to radiotherapy. They are also exposed to a lower concentration of cytotoxic agents. The vascularization may be insufficient to sustain viability, and areas of necrosis and haemorrhage are frequently found in large cancers. The process of vascularization allows tumour cells to penetrate blood and lymphatic channels, and thence to metastasize to regional lymph nodes and distant sites.
Metastasis Metastasis is a remarkable process and one which is still very poorly understood. The risk of metastases increases as tumours become larger. The cells must survive tissue invasion, circulation, passage across the capillary wall, and establishment in tissues. The process of tissue penetration
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Figs 6.1, 6.2
Table 6.3 Inherited genetic abnormalities and malignancy Inherited disorder Skin disorders Neurofibromatosis (AD) Tylosis palmaris (AD) (keratosis of palms and soles) Peutz-Jeghers syndrome (AD) Immune deficiency X-linked agammaglobulinaemia (XLR) Wiskott-Aldrich syndrome (XLR) Ataxia telangiectasia (AR) X-linked lymphoproliferative syndrome (XLR) Gut disorders Polyposis coli (AD) Gardner's syndrome (AD) Hereditary non-polyposis Colotectal cancer (AD) Neurological disorders Tuberous sclerosis (AD) Retinal/cerebellar angiomatosis (von Hippel-Lindau syndrome) (AD) Other syndromes Bloom's syndrome (AR) (short stature, telangiectasia) Hemihypertrophy Fanconi's anaemia (AR) (skeletal abnormality, patchy pigmentation, mental retardation) Multiple enchondromata (S) (Oilier syndrome) Chromosomal abnormalities Down's syndrome (trisomy 21) Klinefelter's syndrome (47.XXY) Aniridia - Wilms' syndrome (11pMosaicism (45,XO/46,XY) 13q- (multiple malformations)
Cancer
Sarcoma, phaeochromocytoma, medullary carcinoma of thyroid Oesophageal cancer Intestinal and ovarian cancer
Lymphoma Lymphoma Lymphoma and stomach cancer Lymphoma
Colonic carcinoma Colonic carcinoma Duodenal carcinoma Colonic carcinoma
Glioma Hypernephroma, ependymoma, phaeochromocytoma
Leukaemia Many other cancers Wilms' tumour, hepatoblastoma Acute leukaemia
Chondrosarcoma
Acute leukaemia Breast cancer Wilms' tumour Gonadoblastoma Retinoblastoma
Hereditable component of other cancers Breast cancer BRCA1 BRCA2 Breast cancer Unknown (recessive?) gene Testicular cancer p53 mutation Sarcoma in children Breast and other cancers AD Autosomal dominant AR Autosomal recessive
XLR X-linked recessive S Sporadic
• sarcomas, which arise from mesodermal cells making up bone and connective tissue; • leukaemias and lymphomas, which arise in cells of the bone marrow and immune system.
FIG. 6.9 Diagrammatic representation of exponential and gompertzian growth
FIG. 6.8 Diagrammatic representation of cellular proliferation in a tumour A Pluripotent self-renewing stem cell. B Proliferative compartment in which cell number increases but gradually loses reproductive potential. C Mature tissue.
appears to be by secretion of enzymes known as metalloproteinases (such as collagenase). Inhibitors of tissue metalloproteinases are now in early trials as anticancer agents. The precise location of a metastasis is probably due in part to chance. Nevertheless, clinical patterns of bloodborne metastasis are apparent: gut cancers spread through the portal venous system to the liver; ovarian cancers seed into the peritoneal space; breast cancer has a predilection for bones of the axial skeleton; sarcomas characteristically spread to the lungs.
PATHOLOGY The major categories of malignant tumour are: • carcinomas, which arise from ectoderm or endodermal cells;
6
The distinction between benign and malignant neoplasms is based histologically on the cellular pleomorphism, frequent mitoses and tissue invasion that are characteristic of malignancy. The clinical manifestations of malignancy are tissue infiltration and lymphatic and bloodborne metastases. The degree of differentiation of a tumour is often an important guide to prognosis, and therefore to therapy. Poorly differentiated carcinomas have a worse prognosis than well-differentiated tumours. This is due in part to an association with a more rapid growth rate and more early and widespread metastases. About 5% of cancers present as metastases where the primary site of the tumour is unknown. The histology is usually a poorly differentiated carcinoma, often with features suggestive of adenocaicinoma, but the pathologist may find the tumour difficult to classify. The development of monoclonal antibodies has led to a greater precision in diagnosis by using immunocytochemical methods. Many anaplastic tumours can now be diagnosed as epithelial tumours, melanomas or lymphomas by using antibodies against epithelial antigens, or antigens associated with melanoma, leukocytes or T and B lymphocytes. The correct identification of lymphoma will lead to important changes in management of a patient (Fig. 6.10). Many antibodies will not bind to antigens on formalin-fixed and paraffin-embedded sections, and require fresh tissue. Other specialized investigations can be carried out on fresh tumour tissue - measurement of hormone receptor content (e.g. oestrogen and progesterone receptors) for example, which may be of importance in prognosis and in deciding treatment. Using immunocytochemical techniques, the presence of substances such as oc-fetoprotein can be detected in the tumour. The increasing complexity and versatility of histopathological diagnosis means that it is now essential for there to be close collaboration between clinician and pathologist before specimens are obtained. Ultrasound and CT scanning now allow accurate needle biopsy and aspiration cytology of hitherto inaccessible intra-abdominal and intrathoracic tumours. 1 Cytological diagnosis does have some limitations: in the diagnosis of lymphoma, for example, it may be difficult to distinguish tumour cells from normal reactive lymphocytes. For this reason, histological diagnosis is preferred, especially in situations in which there is clinical doubt about the diagnosis.
CLINICAL FEATURES Cancers cause symptoms due to the local spread of the primary tumour, and as a result of metastasis and of metabolic and remote effects of the malignancy.
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Metastatic disease in bone causes pain which is often intense and distressing. One characteristic feature of malignant bone pain is that it is often worse at night. Bone pain may occur in the absence of a pathological fracture or vertebral collapse, but becomes worse when this occurs. In the liver, metastases cause pain by stretching the capsule. Cerebral metastases give rise to raised intracranial pressure, fits, focal signs and symptoms, and mental confusion. Pulmonary spread may cause breathlessness due to large intrapulmonary tumour masses, diffuse lymphatic permeation (lymphangitis carcinomatosa) and massive pleural effusion.
SYSTEMIC SYMPTOMS Primary and metastatic cancer may cause a variety of metabolic and other disturbances which are important causes of symptoms. In general, these are produced in one of three ways:
FIG. 6.10 Section of nasopharyngeal tumour A Staining with anticytokeratin; the epithelium of normal respiratory gland stains strongly but tumour cells are negative. B Staining with antibody to the leukocyte common antigen reveals that the tumour cells are expressing the leukocyte antigen and that the tumour is a lymphoma.
SYMPTOMS DUE TO LOCAL DISEASE
152
The primary tumour is clinically silent either until it becomes a visible painless lump that the patient notices (this is a common presentation of breast cancer and Hodgkin's disease and other lymphomas), or until it impinges on surrounding tissues. Thus, carcinoma of the lung will cause increasing bronchial narrowing, with breathlessness, cough and collapse of the distal lung; colonic carcinoma may present with disturbed bowel habit and obstruction; brain tumours may cause raised intracranial pressure or focal neurological signs; cancer of the head of the pancreas will cause obstruction of the bile duct, leading to jaundice. As the primary tumour gets larger it may ulcerate and bleed. Haemoptysis is a common symptom of bronchial carcinoma, and chronic blood loss leading to iron deficiency anaemia frequently occurs with carcinoma of the colon. The tumour may infiltrate nerves and bone, leading to pain, or pain may arise from stretching of the capsule of an organ - for example pain over the liver with advanced hepatoma. Nerve entrapment frequently occurs with pelvic tumours, such as carcinoma of the cervix. Similarly, carcinoma of the bronchus occurring in the superior sulcus (Pancoast's tumour) may be accompanied by intense pain in the arm, owing to involvement of the brachial plexus.
• As a result of the tumour mass, both primary and metastatic; • As a result of secretion of hormones by the tumour (Table 6.4); • By ill-understood mechanisms which give rise to specific cutaneous, neurological and other syndromes remote from the tumour and not due to metastasis - paraneoplastic syndromes (Table 6.5). The commonest metabolic disturbance associated with advanced cancer is cachexia. This is a state of profound weight loss, muscle wasting and weakness. Many factors contribute to the state, of which anorexia is perhaps the major cause. Loss of appetite occurs early with tumours of the upper gastrointestinal tract, even before metastases have occurred. For most tumours loss of appetite is an accompaniment of advanced disease, particularly hepatic metastases. Anorexia may be made worse by treatment with radiation and cytotoxic drugs, by psychological factors such as depression, and by unrelieved pain. The tumour may promote weight loss by direct metabolic effects. For example, there may be excess lactate production by the tumour which is recycled into glucose (a process wasteful of energy), and an increased glucose consumption at a time when carbohydrate intake has declined. Some tumours may cause malabsorption (carcinoma of pancreas) or intestinal obstruction (colon cancer), which contributes to weight loss. Unlike patients who are starving, many cancer patients have a normal or high metabolic rate but the reason for this is not clear. Fever may accompany cancer and is not always due to infection, although this must always be excluded. Fever is particularly likely to occur with lymphomas, renal carcinoma, sarcomas, and any tumours that have metastasized to the liver. Both fever and anorexia may be due to cytokine production by the tumour.
6
CASE STUDY 6.1 COUGH AND BACK PAIN A 65-year-old retired warehouseman presented with a 2-month history of troublesome cough productive of clear sputum. One week previously he had had a sudden onset of midthoracic back pain while bending to clean the bath. The pain was worse on moving and on coughing. He smoked 20 cigarettes a day and for 2 years had had intermittent pain in his left calf on walking 500 yards. On examination he looked well but had back pain on undressing. BP 145/90, pulse 76 regular. Foot pulses absent except for the right posterior tibial. Both external jugular veins were distended. The heart was normal and there was no peripheral oedema. Chest expansion was symmetrically diminished, with increased anteroposterior diameter of the chest. There was an expiratory wheeze, more marked on the right. He was tender on pressure over T8, with a suggestion of angulation at this site. The rest of the examination was normal.
Questions 1. What is the probable underlying diagnosis? 2. What might be the cause of the venous distension? 3. What is the probable cause of the back pain? 4. What are the most important diagnostic investigations? 5. What should be the immediate treatment?
Discussion The patient is a cigarette smoker who has a history and signs of peripheral vascular disease in his legs. Any new
symptoms in such a patient should raise the question of whether these might be due to the development of a bronchial carcinoma. The local symptoms caused by a bronchial carcinoma depend on the site of the tumour. At the periphery of the lung it may remain silent until it invades the pleura, causing pain or an effusion, or obstructs a peripheral airway, causing breathlessness or infection. When centrally placed, tumours may obstruct an airway, causing severe breathlessness, wheeze, or an exacerbation of cough. The tumour, or associated lymph node masses, may expand in the superior mediastinum and cause superior vena cava obstruction (SVCO). Bronchial carcinoma typically metastasizes to liver, bone and brain. About 50% of cases present with symptoms or signs of metastasis. Metastasis to bone typically causes pain that may not be alleviated by rest - indeed, it is often troublesome at night. Presentation with pathological fracture may occur. One of the most important sites of bone metastasis is the cervical and thoracic vertebral column, because at this site there is a grave risk of spinal cord compression. In this case the worsening cough might equally be due to an exacerbation of the obstructive airways disease from which smokers suffer. The back pain after minor exertion raises the possibility of a vertebral collapse and therefore of metastasis to the vertebral column. Physical examination further increases the suspicion that there might be an underlying malignancy. The wheeze is more prominent on the right, suggesting a unilateral cause, and there is tenderness over
Anaemia may be due to blood loss, malabsorption, or dietary deficiency of iron or folate. The most common mechanism is a failure of release of iron (stored in macrophages) into the plasma - the anaemia of 'chronic
the spine of the eighth thoracic vertebra. The distended external jugular veins, in the absence of signs of heart failure, may indicate the early onset of SVCO. Investigations are therefore directed to establishing the diagnosis and the cause of the back pain. A chest X-ray may show appearances suggestive of a carcinoma and indicate if this is centrally placed. If a mass is present the involvement of the SVC can be further investigated by CT scan. Sputum cytology may reveal malignant cells. If negative, a bronchoscopy will be necessary provided that the clinical condition permits. A bone scan will show increased uptake in the thoracic spine if there is a vertebral metastasis, and a lateral X-ray may show vertebral collapse. The appearances will be further delineated by a thoracic CT scan. This will also give an indication of incipient pressure on the spinal cord which is the greatest threat to this patient. Routine full blood counts and biochemistry are unlikely to add to the diagnosis but will be helpful in indicating if other complications of malignancy are present, such as liver metastases or hypercalcaemia. The essential initial treatment is relief of early SVCO and treatment of the vertebral metastasis, if present. To some extent the method of treatment will depend on the histological type of lung cancer. Chemotherapy is rapidly effective in relieving SVCO if the tumour is small cell carcinoma. Other types of lung cancer will require radiotherapy treatment. The vertebral metastasis should be treated with radiotherapy, whatever the histology, especially if the CT appearances suggest that the cord may be in danger.
disease' (p. 1226). This anaemia is unresponsive to iron therapy. Chemotherapy and radiation both depress bone marrow function and contribute to anaemia. The hormonal syndromes that accompany cancer (Table
153
TABLE 6.4 Hormonal syndromes in non-endocrine cancers
TABLE 6.5 Paraneoplastic syndromes
Hormonal syndrome
Tumour
Mechanism
Syndrome
Hypercalcaemia
Squamous carcinomas Carcinoma of kidney
Parathyroid hormone related peptide
Neurological Neuropathy (usually sensory)
Hyponatraemia
Small cell lung cancer Lymphoma Pancreatic carcinoma
Ectopic ADH produced by tumour
Small cell lung cancer Bronchial and thymic carcinoids
Ectopic ACTH produced by tumour
Gynaecomastia
Teratoma Hepatoma Large cell bronchial cancer
Excess oestrogen activity
Hyperpigmentation
Small cell lung cancer
Ectopic MSH produced by tumour
Cushing's syndrome
Cerebellar degeneration Eaton-Lambert syndrome Musculoskeletal Clubbing Hypertrophic pulmonary osteoarthropathy Dermatomyositis
Polyarthritis Haematological Multiple venous thrombosis
6.4) are important because they are a cause of symptoms which are frequently treatable. In many patients hypercalcaemia is due to bone destruction by metastases, but some cancers produce hypercalcaemia by a hormonal mechanism. In these cases the calcium level falls if the tumour is removed. The tumour elaborates a peptide (parathormone-related peptide) and other factors (such as growth factors) which can mobilize bone calcium. Hypercalcaemia associated with cancer can be very severe, requiring urgent management (see Ch. 18). Hyponatraemia, caused by the production of antidiuretic hormone (ADH) by the tumour, is a frequent accompaniment of small cell lung cancer. Malaise, fatigue leading to fits, and coma may result. The condition can be reversed by demeclocycline and water restriction (Ch. 21). Adrenocorticotrophic hormone (ACTH)-like peptides may also be produced by small cell lung cancer. In this disease the high levels of ectopic ACTH produce profound metabolic disturbances, with proximal muscle weakness, hyperglycaemia and hypokalaemic alkalosis. These symptoms can be reversed by management of the tumour. The paraneoplastic syndromes (Table 6.5) can cause diagnostic difficulty in two ways. First, the syndromes must be distinguished from other diseases causing a similar clinical picture. For example, the peripheral neuropathy accompanying cancer may be clinically indistinguishable from other causes. Second, the underlying carcinoma may not always be clinically apparent. Tumours such as carcinoma of the ovary or pancreas may be associated with multiple migratory venous thromboses at a time when the primary disease is not detectable. The diversity of symptoms caused by primary and
0 Case 6.1
154
O Fig. 6.8
0 Figs 6.3-6.6
Q Fig. 6.7
Erythrocytosis
Disseminated intravascular coagulation
Associated tumours
Small cell lung cancer Cancers of breast and ovary Small cell lung cancer Small cell lung cancer
Carcinoma of the lung (particularly squamous cell) Lung cancer Oesophageal cancer Other cancers Adenocarcinomas of breast, gut and ovary
Pancreatic cancer Other adenocarcinomas Renal carcinoma Hepatoma Cerebellar haemangioblastoma Uterine cancer Mucinous adenocarcinomas
metastatic cancer, together with the hormonal, metabolic and paraneoplastic syndromes that accompany many malignant tumours, mean that a diagnosis of cancer must be considered in any unexplained illness, particularly in a middle-aged or elderly patient.
METASTASIS FROM AN UNKNOWN PRIMARY SITE From 2 to 5% of patients with cancer present with a metastasis, in lymph nodes, bone, liver, brain or lung, the primary site not being clinically apparent. Usually the histological appearances are of adenocarcinoma or poorly differentiated cancer. This common clinical problem is a considerable test of medical skill, because the patient is understandable extremely anxious and it is probable that only limited treatment will be available if the primary is discovered. The site may suggest the source of the metastasis. Lymph node metastasis in the head and neck will suggest a head and neck or lung cancer. Metastases in the liver commonly arise from the gut. An axillary node containing adenocarcinoma 1 may be due to a primary in the breast. Detailed histological analysis may be necessary to rule out important and curable cancers such as germ cell tumours or poorly differentiated lymphomas. Investigation is directed towards discovering a treatable primary source, for example in breast or prostate, where hormone therapy
may be effective. Multiple invasive investigations seldom produce information that will affect management. In 20% of cases the primary site is never discovered. Empirical treatment with chemotherapy may be given, but the risk of toxicity is considerable and the response rates are poor.
STAGING AND INVESTIGATION Once a diagnosis of cancer has been established, further investigation is usually needed to establish the degree of spread of the primary tumour and to determine whether metastasis has occurred. It has been known for many years that the prognosis of a patient depends, among other things, on the size of the tumour and the presence of metastases. Our ability to locate the tumour and distant metastases accurately has improved immeasurably in recent years with the introduction of radionuclide and ultrasound scanning, CT scanning and magnetic resonance (MR) imaging. These techniques have shown that in many patients the cancer is metastatic at the time of presentation. This realization has led to a greater emphasis on systemic treatments such as hormone therapy and chemotherapy and, in some cases (e.g. breast cancer), a tendency towards less radical surgical procedures for the primary tumour. The determination of the degree of spread at presentation is generally known as staging. The international acceptance of staging systems has meant that, in treatment trials, comparable groups of patients can be treated allowing a comparison between different methods.
TNM CLASSIFICATION
A generally accepted system which is applicable to some (but not all) cancers is the TNM (Tumour, Nodes, Metastases) classification. 0 The T component defines certain characteristics of the primary tumour, such as its size, site or depth of invasion; the defining criteria will be different with each type of cancer. N refers to the presence or absence of involved nodes; the degree of node involvement may be designated as NO (no involved nodes) and Nl, N2, N3 etc. as more nodes are involved. If no metastases are present the designation is MO, and Ml if they are detected. Clearly, the TNM stage assigned to a tumour will depend on the thoroughness of the clinical and radiological investigation, and this will change as new techniques are invented and perfected. The TNM stages can be grouped into categories which have prognostic significance. These categories or 'stage groups' have been of great value in the design of treatment trials. The TNM stages and related stage groupings for carcinoma of the kidney are shown in Table 6.6 and the prognosis related to the stage grouping in Figure 6.11.
TABLE 6.6 Renal carcinoma TNM staging and stage
grouping Stage
Definition
T1 T2 T3 T4
T stage Small tumour surrounded by normal kidney Large tumour with kidney deformity Perinephric infiltration or renal vein extension Invasion of local structures (e.g. abdominal wall)
NO N1 N2 N3
N stage No nodes involved Ipsilateral nodes involved Contralateral nodes involved Fixed nodes
M1
M stage No distant metastases Distant metastases
Stage I Stage II Stage III Stage IV
T1 T2 T3 T4
M0
6
Stage grouping NO NO NO-2 NO-3
MO MO MO M1
The stage grouping refers to the worst prognostic feature of the case: e.g. a T1 N1 tumour would be stage III
The TNM system is not applicable to some tumours and is of limited value in others; it is clearly inappropriate, for example, in acute leukaemias, and prognostic factors in these diseases are based on other criteria (see Ch. 23). Nevertheless, staging classification is possible and useful in diseases such as chronic lymphatic leukaemia and myeloma. The criteria have nothing to do with a TNM system, but are related to tumour mass. In lung cancer the TNM system is useful and widely used in squamous carcinoma, but is of considerably less value in small cell carcinoma. In this disease, a rough categorization is made into limited disease (confined to one hemithorax) and extensive disease (spread beyond one hemithorax, including metastases). There is a clear difference in prognosis in these two categories (Fig. 6.12).
STAGING INVESTIGATION Much information can be obtained from a chest X-ray. © As techniques are developed, the sensitivity (ability to detect an abnormality if it is present) and specificity (ability to distinguish a metastasis from other pathologies) of the investigations changes. At present, radionuclide bone scanning is the most sensitive method of detection of bone metastases (Fig. 6.13A). 4 CT scanners are better than,
155
FIG. 6.12 Prognosis of small cell carcinoma of the lung related to the disease extent at presentation
Limited disease = disease confined to one hemithorax. Extensive disease = more widespread local extent or metastasis.
CT has proved of value in detecting lymph node enlargement in the thorax and the abdomen. Unfortunately, nodes can be replaced by secondary tumour and yet not be enlarged. Lymphography - in which contrast material is injected into lymphatics in the dorsum of the feet can show filling defects in normal size nodes, as well as node enlargement. For tumours that spread transperitoneally, such as carcinoma of the ovary, laparoscopy (peritoneoscopy) is the most sensitive method of detecting spread of tumour if a laparotomy is not carried out. Although invasive, this procedure can also be used to obtain liver biopsy material under direct vision.
TUMOUR MARKERS 4
FIG. 6.11
A Carcinoma of the left kidney. T = degree of local spread; N = involvement of adjacent lymph nodes; M = metastasis to bone or other sites. B Prognosis according to stage grouping.
or at least equal to, ultrasound scanning in the detection of hepatic metastases (Fig. 6.13B), 1 but ultrasound is much cheaper and can be repeated regularly to assess response. CT is the best method of detecting pulmonary metastases and is able to demonstrate metastases of 2-3 mm in size (Fig. 6.13C). MRI is superior to CT in detecting deepseated brain tumours, especially in the brainstem and spinal cord, and is the preferred method for showing brain metastases (Fig. 6.13D). 2 MRI is of great value in demonstrating cord compression (Fig. 6.13E) 0 and the soft tissue extent of tumours such as sarcomas (Fig. 6.13F).
156
1
Fig. 6.9
4
MCQ 6.2
0 0
Fig. 6.10
0 Fig. 6.11
Figs 6.9-6.11
Tumours may secrete substances into the blood which can be used both diagnostically (to detect the presence of disease) and in therapy, to monitor the effects of treatment. A variety of biochemical disturbances may be induced in the body by a tumour, such as the rise in alkaline phosphatase caused by liver or bone metastases, but these are crude and insensitive guides to the effect of treatment. The markers in common clinical use (Table 6.7) are oncofetal antigens, placental products, isoenzymes, ectopic hormones and some cellular antigens, usually derived from the cell membrane. Ideally, the tumour marker should always be produced by the cancer in question. In choriocarcinoma, human chorionic gonadotrophin (hCG) is produced in over 95% of cases; and 75% of germ cell tumours secrete either oc-fetoprotein (AFP), hCG or both. Carcinoembryonic antigen (CEA) (a glycoprotein produced by colonic mucosa) is found in the serum in 65% of cases of colorectal cancer. With some markers, e.g. hCG, AFP and placental alkaline phosphatase (PLAP), the serum level of the marker is a reasonably accurate and sensitive reflection
6
FIG. 6.13 Scanning 0 5] Isotope bone scan showing multiple areas of increased uptake in a patient with bone metastases from lung cancer. B Ultrasound scan of liver showing several metastases (arrowed) in a patient with colorectal cancer. C CT scan of thorax showing a solitary subpleural metastasis in the left lung. D MR scan of the brain showing a left-sided frontal metastasis with some associated oedema. The patient had non-small cell lung cancer. E MR scan of the thoracic vertebrae. A large paravertebral mass is invading the left lateral T9 vertebra. The tumour passes through the intervertebral foramen and is displacing the spinal cord to the right. This was a round cell sarcoma of the chest wall. F MR scan showing a large intraosseous tumour arising in the right tibia. The associated soft tissue mass is clearly shown. This was an osteosarcoma.
of the tumour mass in an individual patient, and can therefore be used as a guide to therapy. Prostate-specific antigen (PSA) is a sensitive marker of early prostate cancer which is now widely used in screening. This has led to considerable controversy over the treatment of early, screen-detected, prostate cancer. The antigen is a serine protease produced at low levels in non-malignant prostate disease. The serum marker may be a valuable guide to tumour recurrence and, in most cases of germ cell tumours (such as teratoma of the testis), is a more sensitive indicator of tumour recurrence than any other technique. There is, of course, little value in knowing when relapse is occurring if there is no effective treatment. However, in the case of early-stage germ cell tumours, the markers have allowed a policy of observation following initial surgery, as highly effective chemotherapy is available for relapse. An example of the use of tumour markers is shown in Figure 6.14.
The tumour marker may be produced in other conditions: for example, serum AFP is raised in early pregnancy, and CEA may be present in inflammatory bowel disease. AFP is produced in the fetal liver, in the malignant yolksac cells in teratoma, and in hepatoma. It has a plasma halflife of 5-7 days. hCG is produced by the placenta and by choriocarcinoma, and by the trophoblastic elements in teratoma. The plasma half-life is 30 hours.
PRINCIPLES OF CANCER MANAGEMENT Surgery and radiotherapy are the principal methods of treating the primary tumour. For many early-stage cancers - e.g. in cancer of the breast, squamous cancer of the lung, and cancers of the ovary, kidney, testis and gastrointestinal tract - surgery alone has a good chance of cure. Unfortu-
157
FIG. 6.14 Tumour markers in management of testicular cancer A Both hCG and AFP markers are elevated before orchidectomy but fall following operation (hCG more rapidly because of its short half-life). B No evidence of recurrence, followed by a rise in marker levels. C Combination chemotherapy for recurrence is followed by a fall in levels to normal. D, E A further rise in marker levels is treated more intensively and the patient is disease-free at 3 years F.
TABLE 6.7 Tumour markers present in blood Marker Oncofetal antigens oc-fetoprotein
Tumour
Carcinoembryonic antigen Pancreatic oncofetal antigen
Germ cell tumours of ovary and testis Hepatoma Gastrointestinal cancer Pancreatic carcinoma
Placental products Human chorionic gonadotrophin Placental lactogen Placental alkaline phosphatase
Choriocarcinoma Teratoma Choriocarcinoma Seminoma
Isoenzymes Alkaline phosphatase Lactic dehydrogenase Neuron specific enolase
Osteosarcoma Neuroblastoma, many cancers Small cell carcinoma of lung
Ectopic hormones (see Table 6.4) Other cellular antigens (defined by antisera) Ca 125 (aglycoprotein) Ca 19-9 (a carbohydrate) Prostate-specific antigen (pSA)
158
Ovarian cancer (also breast, pancreas and gut) Pancreatic cancer (also gut) Prostate cancer
nately, many patients cannot be cured surgically, either because the tumour is so advanced locally as to make resection impossible, or because investigation has revealed metastases. Advances in radiotherapy technique and the recent developments in combination cytotoxic chemotherapy have meant that, for many patients, a combined approach
to management is needed to achieve the best results. This involves close collaboration between surgeon, radiotherapist and medical oncologist. Before treatment begins, it is essential to decide whether there is a possibility of cure or whether the intention should be palliative. Many factors will influence this decision, including the degree of spread of the tumour locally, the presence of distant metastases, and the patient's age and state of health. It may be very difficult to decide on the best policy if the chances of cure are relatively small and the toxicity of treatment considerable. In a young patient the aim of cure would probably overcome doubts about toxicity, but this might not be the case in the elderly. If the clinical evidence makes it quite clear that there is no hope of cure, then investigations should only be performed if they will alter management. Investigation, as previously outlined, will be necessary in all other patients to determine the degree of spread of the disease before deciding on the treatment plan. The principles of surgical management of cancer are beyond the scope of this chapter, but it is important for all physicians to have an understanding of the basis of management using radiotherapy, chemotherapy and hormone therapy.
RADIOTHERAPY Most radiotherapy treatment involves the use of electromagnetic waves with very high energy and short wavelength - gamma rays and X-rays. Some modern radiotherapy machines use 60Co as a source, which decays to a more stable form with a half-life of 5.3 years. The process of decay (with loss of a neutron) is accompanied by emission of gamma rays with a high energy (1.2MeV). X-rays were first produced by Roentgen, who heated an electrode in a sealed vacuum tube. The electrode produced electrons which bombarded a target, resulting in the emission of
TABLE 6.8 Relative radiosensitivity of tumours
Depth/cm FIG. 6.15 Tissue penetration of different types and energies of radiation
electromagnetic waves which were designated 'X-rays' and whose nature was the same as that of gamma rays. By increasing the voltage, X-rays of shorter wavelength and higher energy are produced which have greater tissuepenetrating power than those produced from low-voltage machines (Fig. 6.15). Modern machines accelerate the electrons almost to the speed of light, resulting in a high-energy beam. These machines (linear accelerators) have become standard equipment in most departments. They provide a sharper beam than that obtained from 60Co sources and greater depth doses. When the target is moved out of the path of the electrons, the high-energy electron beam can be used for the treatment of superficial tumours. The tissue-penetrating power of high-energy X-rays and gamma rays means that normal tissues will be irradiated as well as the tumour. With lower voltage X-rays, the penetrating power is less and more energy is deposited in superficial tissues, especially bone. With electrons, the radiation decays rapidly in tissue, the depth of penetration depending on the energy of the beam (Fig. 6.15). The important site of radiation damage is nuclear DNA. The damage appears to be induced indirectly. The radiation first produces highly reactive radicals, which in turn damage the DNA, impairing the reproductive integrity of the cell. The damaging effects of radiation are less marked in cells which are hypoxic. Some areas of tumour may not be well vascularized and these cells are relatively radioresistant. The mechanisms of resistance are not well understood. The amount of cell death following exposure to irradiation is also proportional to the dose administered. At low doses the damage is sublethal. Nevertheless, radiation administered as a few large fractions may not be as effective as multiple-fraction regimens using smaller daily doses. The latter technique may be more effective because it allows the tumour to shrink and become less hypoxic, may be easier to tolerate, and allows normal tissues to recover at a faster rate than the tumour. In treating tumours, multiple fractions are usually employed and the total dose administered depends on what is known of the radiosensitivity of the neoplasm (Table 6.8). The total dose
Highly radiosensitive Lymphomas Ewing's sarcoma Seminoma Wilms' tumour Myeloma
Relatively resistant Squamous cell lung cancer Hypernephroma Bladder carcinoma Rectal carcinoma Soft tissue sarcoma (adults) Cervical carcinoma
Moderately radiosensitive Breast cancer Small cell lung cancer Ovarian cancer Medulloblastoma Basal cell carcinoma Teratoma
Very resistant Melanoma Osteosarcoma Pancreatic carcinoma
received by the tumour is measured in grays (1 Gy = 1 J/kg) orrad (100 rad = 1Gy). The planning of the radiation field is often a highly complex procedure that has been greatly facilitated in recent years by the use of CT scanning and simulators, which allow the fields to be constructed with precision. In planning the fields, the radiotherapist must therefore consider the localization of the tumour, its probable inherent radiosensitivity, the tolerance of the normal tissues in the path of the beam, and the need to include draining lymph nodes in the treatment. Multiple fields may be necessary to achieve the desired dose in the tumour without damaging normal tissues. The fields may be open (or direct}. Here, the radiation beam is applied directly, usually at rightangles to the skin. Alternatively, if several fields are used, the field may be wedged. These wedges, inserted into the beam, alter the dose distribution so that the tumour dose is homogeneous and problems of irradiation of normal tissue where fields overlap are minimized. An example of a multiple field is shown in Figure 6.16. The treatment area is immobilized and, for some tumours, such as head and neck cancers, moulds and shells are used to ensure accurate and reproducible positioning. The radiation source is mounted in a gantry which moves isocentrically about the patient. Radiotherapy may also be given by placing a sealed source containing a radioactive isotope inside a body cavity or in tissues. This is known as brachytherapy. Examples of such isotopes are 137Cs, which is widely used as an intracavity source of radiation in treating carcinoma of the cervix, and iridium wires, which may be placed in breast tissue to provide interstitial irradiation when radical radiotherapy is used following conservative surgery for breast cancer. Unsealed sources of radioactivity may be taken by mouth, e.g. 131I in the treatment of thyroid cancer, or given intravenously, e.g. 32P in the treatment of polycythaemia rubra vera.
6
159
TABU 6.9 Complications of radiotherapy Complication
FIG. 6.16 Radiation planning for carcinoma of bladder The relationship of the three beams to the tumour and the dose levels (% of maximum) achieved within the tumour and surrounding normal tissue are shown.
The complications of radiotherapy depend on the radiation sensitivity of normal tissues in the path of the beam, and may be immediate or delayed. A summary of some of these is given in Table 6.9.
SYSTEMIC TREATMENTS In the last 40 years there has been a dramatic increase in interest in the use of drugs to kill cancer cells. So many cancers are either disseminated at diagnosis or too advanced locally to resect, that a systemic approach to treatment offers the only chance of remission or cure. The two treatments in general use are cytotoxic chemotherapy and hormone therapy.
Cytotoxic chemotherapy The earliest compounds to be introduced were nitrogen mustards, which were shown to be cytotoxic to lymphoid tissue and then to have activity against lymphomas in humans. In 1948, Farber demonstrated remissions of leukaemia using the antifolate aminopterin, and this led to the development of a wide variety of antipurines and antipyrimidines. Antitumour antibiotics were first developed in 1940 (actinomycin A), with a significant step forward in 1963 with the isolation of anthracyclines. The platinum drugs were introduced in the 1970s and proved to have great activity in germ cell tumours. The epipodophyllotoxins were also introduced at that time. Recently the taxoids have been introduced. There are now about 35 cytotoxic drugs of proven value in routine use, and the
1
160
MCQ 6.3
Tissue
Immediate
Delayed
Skin
Erythema, desquamation
Oral cavity Gut Bone Kidney
Mucosal ulceration Nausea, diarrhoea Bone necrosis Acute nephritis
CNS
Radiation myelitis and encephalitis
Eye
Conjunctivitis
Gonads Bone marrow
Sterility Leukopenia
Fibrosis Telangiectasia Squamous carcinoma Loss of saliva Fibrosis and stricture Loss of bone growth in children Chronic nephritis Hypertension Demyelination Possible alteration of personality and intellect Dry eye Cataract formation Sterility Suppression of haemopoiesis in area irradiated
RECENT ADVANCES IN NEW METHODS OF ADMINISTERING RADIOTHERAPY The advent of CT scanning has meant that precise three-dimensional images of the tumour can now be obtained. The radiation can now be channeled with considerable accuracy using new methods of directing the beam ('beam's eye view'). A further development has come from the knowledge that repopulation of tumours with new cells occurs rapidly. This has led to the development of hyperfractionated schedules of radiation, in which two or more treatments are given each day. This, and conventional fractionation, may now be given at the same time as cytotoxic chemotherapy in an attempt to improve local control and to prevent interruption of systemic treatment. These complex procedures are likely to play an increasing part in modern cancer management.
increasing complexity of medical treatment of cancer has led to the development of medical oncology as an important specialty in cancer management. Mechanisms of action Cytotoxic drugs produce their effect mainly by damaging the capacity of the cell to divide, and also by interfering with synthesis of essential proteins. For many of these agents the most important toxicity concerns DNA, with impairment of DNA synthesis, reaction with the DNA helix or damage to DNA repair mechanisms. During cell division there is a phase (G1) which precedes the phase of DNA synthesis (S). Following the S phase
SUMMARY 1 Common chemotherapeutic agents Alkylating agents Nitrogen mustard Melphalan Cyclophosphamide Ifostamide Busulphan Chlorambucil Nitrosoureas Cisplatin
Plant alkaloids Vinca alkaloids Epipodophyllotoxins Taxoids Antibiotics Anthracyclines Doxorubicin Daunorubicin Bleomycin
Anti-metabolites Methotrexate 5-fluorouracil 6-mercaptopurine 6-thioguanine Cytosine arabinoside
there is a postsynthetic phase (G2), which is followed by mitosis (M). The daughter cells then either enter into the cycle of division or remain in a non-reproductive stage (Go). Because of their action on DNA, most cytotoxic drugs exert their maximum effect on replicating rather than resting cells. If, after damage to DNA (e.g. by alkylation), the cell does not divide, there will be time for DNA repair mechanisms to excise the attached alkyl groups and to repair strand breaks. Rapidly proliferating cells are thus more susceptible to cytotoxic damage, but this is not the only determinant of susceptibility since, as with radiation, different tissues and tumours show inherent differences in susceptibility, the biochemical basis of which is poorly understood. Alkylating agents are very reactive compounds which exert their effect by linkage of the alkyl group to DNA bases, particularly guanine. If the drug is bifunctional (having two alkyl groups), inter- and intrastrand crosslinks will form. Nitrogen mustard, phenylalanine nitrogen mustard (melphalan), cyclophosphamide, busulphan and chlorambucil are commonly used alkylating agents. Cyclophosphamide itself is inactive but is metabolized by the liver to 4-hydroxycyclophosphamide, which is transported to the tissue and there releases the active alkylating compounds. Nitrosoureas and cisplatin probably act mainly as alkylating agents. Methotrexate inhibits dihydrofolate reductase, thus preventing the formation of tetrahydrofolate, which is necessary for thymidine synthesis. Other antimetabolites include 5-fluorouracil (5FU), which also blocks thymidine formation; 6-mercaptopurine (6MP), which interferes with purine nucleotide biosynthesis; and 6-thioguanine, which has a similar mechanism of action to 6MP. Several plant alkaloids have anticancer activity. The vinca alkaloids interfere with the formation of the mitotic spindle by blocking the assembly of tubulin. The taxoids interfere with disassembly of the microtubules that constitute the mitotic spindle. The epipodophyllotoxins damage
DNA through topoisomerase II. This enzyme normally allows the unwinding of DNA during DNA replication. Anthracycline antibiotics intercalate between DNA bases, as does actinomycin, which has the additional action of interfering with RNA synthesis. Bleomycin causes DNA strand breaks.
6
Testing a new drug When a new drug has shown activity in the laboratory, it is tested in patients with cancer. At first, it is given in gradually increasing doses to patients with advanced drugresistant cancer. These trials are called phase I studies: the aim is to monitor toxicity and to study metabolism and distribution of the drug, as well as to note any activity. In phase II studies, patients with a wide range of tumours are then treated in order to determine the spectrum of activity of the drug. Later, phase HI studies are performed in which the drug is tested, usually in previously untreated patients, either alone or in combination with other drugs, and often as part of a randomized comparison. Combination chemotherapy In recent years it has become standard practice to use cytotoxic drugs in combination. The aim is to produce a variety of different biochemical lesions in the tumour, if possible without increasing toxicity. It quickly became apparent that quadruple therapy in, for example, advanced Hodgkin's disease, produced a far higher complete response rate (disappearance of all symptoms and signs of the tumour) than did single-agent therapy. Furthermore, many of these complete responses were sustained, about 40% of patients being disease free between 5 and 10 years later. This had not been observed with single-agent therapy. Similar results were reported with non-Hodgkin's lymphoma and, later, with testicular teratoma, Ewing's sarcoma and other childhood tumours. In the common tumours of adults (such as cancer of the breast and small cell lung cancer), an increased response rate is also obtained with drugs in combination, but most of these responses are partial (>50% reduction in size) and not sustained for long. Most of the regimens used today have been derived empirically by oncologists with knowledge and experience. There are, however, some general principles governing selection of the drugs (Table 6.10). Using these general principles, combination chemotherapy has been introduced into the treatment of many cancers and forms the mainstay of management in an important minority of uncommon tumours. Unfortunately, most of the common adult cancers are only moderately sensitive to these drugs, and some are very resistant (Table 6.11). Cancer is a disease of the elderly and many patients are not fit enough to risk the toxicity of chemotherapy, especially if the intention is to palliate rather than cure. Complications of chemotherapy 1 There are both immediate and long-term complications of chemotherapy. Many patients greatly fear chemotherapy
161
TABLE 6.10 General principles governing the selection of drugs used in combination therapy • The drugs are known to be effective when used as single agents. • Where possible, drugs with differing modes of action are combined. • The major toxicity of each drug should be as different as possible from that of other agents. • Pulsed intermittent treatment is used to allow recovery of the gut and bone marrow. • If possible each drug should be used in its optimum dose and schedule, although in practice some reduction in dose is nearly always necessary. • There should be no known synergistic toxicity.
as they have often been told lurid stories about toxicity. However, with many regimens toxicity is very mild. The drugs are not equally toxic and it is incorrect for inexperienced physicians to give patients the impression that they are. Immediate The most troublesome immediate side-effects of some chemotherapy regimens are nausea and vomiting, mucosal ulceration, bone marrow depression and alopecia. Nausea and vomiting are probably initiated by a centre in the medulla. Intravenous alkylating agents tend to produce nausea at 12-18 hours, and cisplatin and doxorubicin typically produce nausea about 6 hours after administration. Many other drugs produce very little nausea. Nausea is often accompanied by vomiting, and the symptoms usually last 12-24 hours. These symptoms can be very troublesome but are tolerated by the majority of patients. Skilled, meticulous and flexible use of antiemetics is essential. 5HT3 antagonists have been a big advance in controlling nausea and vomiting, and are now the mainstay of antiemetic treatment. The most widely used agents are ondansetron and granisetron. These are the antiemetics of first choice for chemotherapy which regularly produces troublesome vomiting,
SUMMARY 2 Complications of chemotherapy Long-term Impairment of fertility Secondary cancers Pulmonary fibrosis Cardiomyopathy Nerve damage Loss of hearing Renal impairment
Immediate Nausea and vomiting Mucosal ulceration Bone marrow depression Immune suppression (opportunistic infection) Alopecia
1
162
Case 6.2
2
Figs 6.12-6.15
3
MCQ 6.4
TABLE 6.11 Relative chemosensitivity of tumours Highly sensitive tumours (which may be cured by chemotherapy) Teratoma of testis Hodgkin's disease High grade non-Hodgkin's lymphoma Wilms' tumour Embryonal rhabdomyosarcoma Choriocarcinoma Acute lymphoblastic leukaemia in children Ewing's sarcoma Moderately sensitive tumours (in which chemotherapy may sometimes contribute to cure and often palliates) Small cell carcinoma of lung Breast carcinoma Low grade non-Hodgkin's lymphoma Acute myeloid leukaemia Ovarian cancer Myeloma Relatively insensitive tumours (in which chemotherapy may sometimes produce palliation) Gastric carcinoma Bladder carcinoma Squamous carcinoma of head and neck Soft tissue sarcoma Cervical carcinoma Resistant tumours Melanoma Squamous carcinoma of lung Large bowel cancer
such as cisplatin (Table 6.12). Piperazine phenothiazines (e.g. prochlorperazine) are of some help when given in full dose, but aliphatic phenothiazines (e.g. chlorpromazine) have less antiemetic effect. Metoclopramide is of some value, and its effect may be increased by giving it in high dosage. Benzodiazepines enable the patient to sleep during the period of maximum nausea. Mucosal ulceration in the mouth and gut is a complication of chemotherapy which is particularly likely to occur following methotrexate and anthracyclines. It is dose related, but some individuals are especially susceptible and the dose may then need to be lower than usual. Alopecia is very common with many drugs especially doxorubicin and cyclophosphamide, and is caused by damage to the proliferating cells of the hair follicle. Although the hair regrows when treatment is finally stopped, many patients find this a distressing side-effect. With anthracycline the hair loss can be minimized by scalp cooling during drug administration. The patient must be warned of the likelihood of hair loss, and a wig ordered if desired. Bone marrow depression results in acute leukopenia
TABLE 6.12 Commonly used antiemetic agents Drug
Usual dose
Side-effects
5HT3 antagonists Ondansetron Granisetron
0.15mg/kg 3mg i.v.
Constipation, headache Constipation, headache
12.5mg i.m. or as suppository
Drowsiness Dyskinesia
Benzodiazepine Lorazepam
1-2 mg p.o, or i.v.
Sedation, dizziness, hypotension
Steroids Dexamethasone
6-8 mg i.v.
Restlessness
Phenothiazines Prochlorperazine
10mg p.o. or i.v., Metoclopramide or 1-2mg/kg i.v. (5HT3 and dopamine antagonist)
Dyskinesias, diarrhoea
and thrombocytopenia and the slower onset of anaemia (because of the greater lifespan of red cells). The nadir of the leukocyte count often comes at 7-9 days after intravenous chemotherapy, and it is at this time that the patient is most susceptible to serious infection. 1 Increasingly, oncologists are adjusting the dosage in each cycle of very myelosuppressive regimens according to nadir counts, even though this involves an extra blood count between visits. Patients must be forewarned of their susceptibility to infection and bleeding, so that they can report symptoms promptly. The commonest infections are of the respiratory and gastrointestinal tracts. Immune suppression is cumulative. Patients become increasingly susceptible to opportunistic infection. These are typically pulmonary (aspergillosis, Pneumocystis), oral and oesophageal Candida, and herpes zoster 2 and simplex, which can be severe, confluent and disseminated. Long-term The long-term sequelae of cancer chemotherapy are now becoming better defined as more children and adults are surviving previously incurable cancers. One in 1000 adults now has been cured of cancer in childhood or adolescence. Although complications may be an inevitable risk of regimens that are potentially curative, they are a reminder of the risks attached to increasing the intensity of treatment. Cytotoxic drugs impair fertility in adults. In men, complete and irreversible loss of fertility occurs with many regimens, particularly those that include an alkylating agent or procarbazine. Prepubertal boys do not become infertile, but Leydig cell function may be impaired and testosterone levels may fall. It is important to inform adolescent boys and men of this risk and to arrange sperm storage before chemotherapy begins. Curiously, in Hodgkin's disease, where there is greatest experience of
this problem, patients are often subfertile even before chemotherapy begins. For women, the problem is more complex. Amenorrhoea is common during chemotherapy, especially if an alkylating agent is used. Menstruation will usually return when treatment is finished, although subfertility is common. Chemotherapy may, however, induce the onset of menopause; this is more likely to occur in older women who are nearer the natural menopause. Even in younger women the period of reproductive life may be reduced. It is essential to discuss this potential problem. In both sexes, patients who are receiving chemotherapy should be advised of possible short-term teratogenic effects and to use a contraceptive during treatment. Second cancers are increasingly recognized as a longterm consequence of chemotherapy, particularly in ovarian cancer or Hodgkin's disease. In both cases the risk is especially of acute myelomonocytic leukaemia. Second cancers are also more common in patients receiving immunosuppressive therapy with cytotoxic drugs, and in these patients there is an increased incidence of brain lymphoma, cervical carcinoma and skin cancer. Pulmonary fibrosis is a complication of treatment with busulfan (e.g. for chronic myeloid leukaemia), and acute pneumonitis leading to fibrosis is a dose-related complication of bleomycin. Other cytotoxic agents rarely produce lung damage, although pulmonary fibrosis is a long-term complication of cyclophosphamide and nitrosourea treatment. Anthracyclines such as doxorubicin cause a cardiomyopathy, the risk being dose related. Above a total dose of 400mg/m2 of doxorubicin about 50% of patients will have measurable impairment of cardiac function, but only 5% will develop cardiac symptoms. Established cardiomyopathy leads to cardiac failure, which is irreversible on stopping the drug. Vinca alkaloids cause damage to peripheral and autonomic nerves. The earliest symptoms are of tingling paraesthesiae. There is loss of tendon reflexes and, later, sensory loss and motor weakness. Autonomic neuropathy produces ileus and postural hypotension. Vincristine and vindesine are particularly likely to produce neuropathy, and vinblastine less so. The neuropathy is usually reversible, is totaldose related and is more common and severe in the elderly. Cisplatin may cause irreversible loss of hearing, particularly of high frequencies, and peripheral neuropathy. Renal impairment is also common and irreversible. These toxic effects are a reminder that the treatment of cancer with cytotoxic drugs is a matter requiring skill and judgement if the benefits are not to be outweighed by the disadvantages. Nevertheless, the improvement in prognosis in some cancers as a result of cytotoxic drug treatment fully justifies the acute and long-term risks involved.
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Hormone therapy3 The growth of many normal tissues is under hormonal regulation, and the cancers that arise in them often retain
163
sensitivity to changes in the hormone environment. Hormone therapy is an essential part of management of cancers of the prostate, breast and endometrium. In these cases, the steroid hormone binds to a hormone-binding molecule (receptor) in the cytoplasm and the receptor/ hormone complex is transported to the nucleus, where it modifies the activity of DNA. There is an increase in RNA polymerase activity, resulting in increasing production of cytoplasmic proteins followed by cell division (Fig. 6.17). In some cases the hormone provokes the increased synthesis of receptors for other hormones; oestrogen, for example, increases the synthesis of progesterone receptor in breast epithelium. Response to hormone therapy is strongly associated with the presence of cytoplasmic hormone receptors. In advanced breast cancer, the presence of oestrogen receptors is associated with a 60% response to hormone therapy but only a 5% response if the cancer contains very low levels of receptor. Response is also strongly associated with the presence of progesterone receptors. The following general approaches are taken in hormonesensitive tumours. Blocking the action of circulating hormones In breast cancer, the use of tamoxifen has been a major advance. It appears to exert most of its effect by binding to the oestrogen receptor, thereby preventing the activity of circulating oestradiol. Paradoxically, the drug is effective in postmenopausal women whose tumours are receptor positive, but in whom circulating levels of oestrogen are likely to be low. A direct growth-regulatory effect of the drug may be responsible. Reduction in concentration of circulating hormones Until recently, this was the mainstay of hormone therapy and was usually accomplished surgically. In breast cancer, oophorectomy was performed, or in premenopausal
164
women a radiation menopause induced. In those who showed an initial response but then relapsed, further responses could be obtained by adrenalectomy, which prevented sex hormone synthesis in the adrenal, and by hypophysectomy which produced a similar effect. The advent of aromatase inhibitors has led to a decline in frequency of these operations. Androstanedione is converted in peripheral tissues (and in the breast itself) to oestradiol by enzymes known as aromatases, and several powerful aromatase inhibitors can now be used to prevent oestradiol formation. In prostate cancer, luteinizing hormone-releasing hormone (LHRH) agonists cause a spurt of LH release followed by a profound fall, which reduces plasma testosterone levels to those seen after castration. Prostate cancer is usually very sensitive to a fall in testosterone levels. LHRH agonists are therefore a widely used medical alternative to orchidectomy.
Addition of hormones The hormonal environment can be altered by the administration of hormones which are judged to provide an unfavourable environment for the tumour. Stilboestrol has for many years been used to produce regression in carcinoma of the prostate, and androgens, glucocorticoids and progestogens may all slow the growth of the tumour in breast cancer. Progesterone derivatives will also produce regression in about 20% of carcinomas of the endometrium. In advanced breast cancer, endocrine therapy has the great advantage of low toxicity and low cost compared to chemotherapy. Tumour responses are often more complete and more durable than those achieved with cytotoxic drugs. On the other hand, the proportion of responding patients is lower (30% with endocrine therapy, 60% with chemotherapy). For these reasons, many physicians prefer to start treatment with hormone manipulation, moving to chemotherapy when the disease becomes unresponsive and progresses.
FIG. 6.17 The mechanism of oestrogen action on cell growth Tamoxifen acts by binding to the oestrogen receptor and blocking its action.
Adjuvant chemotherapy and hormone therapy There are many situations in which a cancer has been removed surgically or treated with radiotherapy, but the risk of local or systemic recurrence is high. Examples include breast cancer, where there is involvement of axillary nodes; gastric and other cancers, where the regional nodes are involved; or Ewing's sarcoma of bone, where the tumour is highly sensitive to radiotherapy but the risk of metastasis is very great. In these situations, advances have been made by the use of cytotoxic drugs or hormones in an attempt to delay or prevent recurrence. Even if these treatments are not very effective against advanced cancer (of the stomach or breast), they may be more so when the residual tumour mass is small, when the penetration of the drugs may be better and the degree of cell kill may lead to cure rather than temporary tumour regression. Many large-scale trials have been undertaken to assess the value of adjuvant cytotoxic or endocrine therapy. For the results to be accepted with confidence, there must be both sufficient numbers of patients in the study, and prospective randomization of the allocation of the treatment policy. (The difficulties involved in these trials are discussed below.) In patients with stage II breast cancer, both adjuvant endocrine therapy (using tamoxifen) and cytotoxic therapy (using drug combinations such as cyclophosphamide, methotrexate and 5-fluorouracil) have been shown to give a survival advantage of about 7% at 5 years and 10% at 10 years (Fig. 6.18). A follow-up overview of all randomized trials now shows that patients with stage I disease also benefit from chemotherapy if they are premenopausal, and from hormone therapy after the menopause. Adjuvant drug therapy after surgery or irradiation has become an essential part of management in most childhood tumours (rhabdomyosarcoma, Wilms' tumour, osteosarcoma, Ewing's sarcoma), and in a number of adult tumours, such as breast cancer, ovarian cancer, and in Duke's C colon cancer. There are many other tumours (gliomas, gastric carcinoma, operable lung cancer) in which adjuvant chemotherapy has not yet been adequately evaluated. As the survival benefit is likely to be small, it will only be demonstrated in very large-scale trials, which are still to be undertaken or in patients data-based metaanalyses. Even a 5 % improvement in survival in colorectal cancer is worthwhile, as the disease affects 1 million people a year in eastern and western Europe.
SUPPORTIVE CARE IN CANCER MANAGEMENT Patients with cancer need supportive care for both the psychological impact of the disease and the physical effects of the tumour and its management. Even if there is no
6
FIG. 6.16 Radiation planning for carcinoma of bladder The relationship of the three beams to the tumour and the dose levels (% of
prospect of cure, the patients' quality of life can be greatly improved by the attitude of the medical staff and by meticulous attention to the management of pain, anaemia, infection, nausea and anorexia.
Psychological support The last 20 years have seen an increasing readiness on the part of doctors to discuss the diagnosis of cancer with their patients and to explain the principles of management. Indeed, the complexities of modern cancer management make it difficult to withhold the facts of the diagnosis, even if it were desirable to do so. Nevertheless, the manner in which the diagnosis is explained and the words used are of great importance, and must be carefully judged in each case. Cancer is the only word that conveys the nature of the complaint accurately; other words used are often misinterpreted by patients as implying a less, or even more, serious condition. The problem is that in the mind of many patients cancer is invariably fatal. Explanation of the diagnosis must therefore be accompanied by an unhurried and easily comprehended account of management and the possibilities of cure. It is nearly always wrong to offer no hope of either cure or a period of normal life. Usually, the physician will need to talk to the patient on several occasions, as their understanding of the problems may be incomplete at the beginning. Time taken in unhurried, private conversation is always well spent and greatly appreciated. One of the advantages of having specialized oncology units in hospitals is that all members of the medical team - nurses, doctors, social workers and counsellors - become familiar with the problems that are associated with malignant disease and skilful in dealing with them. It is important that all members of this team know what has been said to the patient in the way of explanation, in order to avoid conflicting advice. A relapse of the disease or the appearance of a new symptom will often cause a slump in morale and confidence which will require more explanation and reassurance. The emotional demands of this aspect of cancer
165
medicine are considerable, and are one reason why some doctors have been reluctant to spend time in discussion with their patients. Nevertheless, the patient will need the help and support of the doctor at these difficult times. It is an essential aspect of cancer medicine and one of the most rewarding.
PAIN RELIEF This is a very important aspect of management, particularly in patients with widespread disease who are terminally ill. No single analgesic will suit all patients all of the time. A patient will need to change from one to another, depending on the severity of pain. A brief classification of some of the most useful analgesics is given in Table 6.13. When using opiates, the dosage should be adjusted to the patient's requirements. A wide range of dosages is encountered. Long-acting morphine and heroin are especially useful and should be given regularly, rather than 'as required'. The constipating effects of opiates can be partly relieved by regular laxatives. If pain is at a particular site, it may be possible to give relief by local measures, such as radiotherapy to a bone metastasis, a nerve block or a coeliac plexus block. The advice of colleagues specializing in these forms of pain relief is often helpful, and the procedures may allow a reduction in dosage of opiate.
Nutritional support
166
Patients lose weight because of the local effects of the tumour (especially if this is in the alimentary tract), metastases, and as a result of treatment. Successful treatment of the primary tumour (e.g. by surgery) will be accompanied by a return of appetite and weight gain. During radical treatment with surgery, radiotherapy and intensive chemotherapy, weight loss is common. Calorie supplements can be given both in the form of oral supplements and intravenously to patients undergoing cancer treatment. However, the value of nutritional support is difficult to demonstrate. It is usual practice to consider total parenteral (intravenous) nutrition in patients undergoing exceptionally intensive treatment, such as high-dose chemotherapy or total-body irradiation with bone marrow transplantation, or during the intensive phases of chemotherapy for acute leukaemia, where there is prolonged hypoplasia. At these times, mucosal ulceration, nausea and diarrhoea make it difficult to feed the patient by mouth, and nasogastric tubes may produce monilial infection or exacerbate acid reflux and oesophagitis. Parenteral nutrition is also used for patients undergoing extensive surgery, particularly gut resection. The aim is to maintain the patient's weight and nutritional status so that recovery is more rapid, allowing further treatment with chemotherapy or irradiation to begin as soon as possible. There is no evidence that additional enteral or parenteral feeding is of value in the management of advanced
TABLE 6.13 Useful analgesics Drugs Mild analgesics Aspirin Paracetamol Indole derivatives (e.g. indomethacin) Propionic acid derivatives (e.g. ibuprofen)
Duration of action (hours)
4-6 2-4 6-8 4-6
Moderate analgesics Codeine (and dihydrocodeine) Pentazocine Dipipanone Oxycodone
4-6 3-4 6 8
Strong analgesics Morphine sulphate Diamorphine Dextromoramide Pethidine Methadone
4-6 (up to 12 with sustained-release forms) 4-6 4-6 3 12-30
cancer where cure is impossible. It is, however, important to encourage the patient to eat by giving food that appeals (often in the form of smaller, more frequent meals), by controlling nausea with drugs such as metoclopramide, and by the careful use of corticosteroids which improve wellbeing and stimulate the patient's appetite.
Tumour lysis syndrome In some very sensitive untreated cancers, chemotherapy may produce massive tumour breakdown when treatment is first given. This process may be accompanied by severe metabolic disturbances, which constitute the tumour lysis syndrome. The syndrome is usually associated with the early phases of treatment of lymphoma and leukaemia in children and, less frequently, in other chemosensitive childhood tumours. In adults the syndrome is infrequent but may occur with treatment of lymphoma, especially if there is impairment of renal function (such as ureteric obstruction by lymph nodes), which diminishes renal excretion of the tumour products. Tissue destruction releases large amounts of urate, phosphate and potassium. The urate may be deposited in the renal tubule, causing reversible renal failure, which in turn diminishes further urate excretion. Severe hyperuricaemia and renal failure may necessitate dialysis. This complication can be largely avoided by using the xanthine oxidase inhibitor allopurinol (100-200 mg 8-hourly) before and during the early phase of treatment, and by establishing and maintaining a diuresis during the first 24-48 hours.
Hyperkalaemia may be severe, particularly if renal failure occurs, and may need treatment with glucose and insulin (see Ch. 21). Hyperphosphataemia can be partly prevented by hydration and diuresis before and during the initial treatment.
NEW APPROACHES TO MANAGEMENT Progress in cancer treatment is slow, and results usually improve after many small refinements in therapy, rather than by sudden steps forward. Since the late 1970s only modest progress has been made, and the search for new drugs and new approaches continues.
Haemopoietic growth factors (see also Ch. 23) The production of haemopoietic growth factors by recombinant technology has allowed their use in chemotherapy to reduce the period in which the white count is low. Proven advantages are a modest reduction in the period of neutropenia and somewhat diminished antibiotic use. It is possible that the intensity of chemotherapy may be increased by avoiding dose reductions. It has yet to be proved that the routine use of growth factors increases the cure rate of cancer by allowing increasing dose of chemotherapy. They are used if the dose of a curative treatment would otherwise have to be reduced but can be maintained if growth factors are given. Granulocyte colony-stimulating factor (GCSF) is most widely used. It is given for 7-10 days subcutaneously following chemotherapy. It may cause fever and bone pain. It is expensive and should only be given if there is a clear indication, and not if treatment is palliative.
High-dose therapy Allogeneic (from one individual to another) bone marrow transplantation was introduced for the treatment of acute myeloblastic leukaemia in the early 1970s. Allogeneic marrow was infused after an attempt had been made to eradicate the leukaemia by total-body irradiation and high-dose cyclophosphamide. The results (Ch. 23) showed that the leukaemia might be eradicated. This finding led to the consideration of total-body irradiation in the management of other disorders, such as lymphomas and myeloma. More recently, attempts have been made to eradicate leukaemia, lymphoma and some solid tumours with very high-dose chemotherapy (rather than total-body irradiation) using autologous (taken from, and reinfused into, the same individual) bone marrow, harvested just before treatment, as a means of preventing life-threatening myelosuppression. These approaches are based on the assumption that increasing doses of chemotherapy will eradicate residual disease when multiple conventional doses will fail.
This approach has been revolutionized in the last few years by the finding that the haemopoietic progenitor cells appear in large numbers in the peripheral blood following chemotherapy and the use of haemopoietic growth factors. These cells can be 'harvested' by a leukopheresis machine and used, instead of bone marrow, to reconstitute the blood count following high-dose treatment. This is called a peripheral blood stem cell (PBSC) transplant. High-dose therapy and PBSC transplant has now become a safe and much cheaper treatment allowing further exploration of the value of high-dose therapy.
6
Monoclonal antibodies to cell surface antigens Many tumours express oncofetal or differentiation antigens not usually found in the normal tissue from which the cancer is derived. An example are the antigens found on the surface of both acute lymphoblastic leukaemia cells, lymphomas and normal lymphatic progenitor cells. The development of monoclonal antibodies of defined specificity has resulted in the production of monoclonal reagents, which bind preferentially to antigens on the surface of some tumour cells (and to those normal cells that express the antigen). Cytotoxic drugs, radioactive isotopes, and enzymes capable of converting an inactive cytotoxic agent to an active one, can be attached to such antibodies with the aim of selectively destroying the tumour. There are considerable difficulties with this approach: heterogeneity of antigen expression within the tumour; variable uptake and distribution of antibody in normal and malignant tissue; and the production of antibodies by the patient against the foreign (usually mouse) protein. Nevertheless, there are interesting future possibilities for therapy and tumour localization using this approach.
TRIALS OF TREATMENT Many cancers have a long and unpredictable natural history: cancer of the breast, for example, is associated with an excess mortality for over 25 years after diagnosis. If survival is the endpoint of treatment, assessment of therapy in this disease will mean prolonged periods of observation. In small cell lung cancer or acute myeloblastic leukaemia, on the other hand, a majority of patients are dead within 2 years, and relapse in those who survive is less frequent beyond that point. Treatment trials will therefore give answers quickly. In assessment of therapy of a cancer (such as breast cancer), there may be more than one endpoint to be considered: does the treatment give effective local control: does the treatment influence the onset of metastasis; is the proportion of survivors at 5 and 10 years or longer increased? Comparison of a treatment with historical controls is very unreliable, as diagnostic and staging criteria are changing constantly and selection of cases is thereby
167
altered. Randomized prospective studies are now regarded as the only reliable way of making a comparison between two treatments. Such studies must include sufficient numbers of patients to allow the questions to be answered with confidence statistically. The studies require careful documentation and prolonged observation of the patient groups. The treatments being compared must be justifiable ethically and the design of the study capable of giving a clear answer to the central question. These considerations mean that treatment trials in cancer are complex and usually demand collaboration between many different centres: even, in the case of rare tumours, between different countries. To detect a 5 % difference in survival with confidence may require many hundreds or even thousands of patients in a study. Nevertheless, a 5% difference in long-term survival in breast cancer, if achieved by a non-toxic hormonal means, would mean 1000 lives saved a year in the UK alone - more than the number of patients cured of Hodgkin's disease. However, a 5% difference achieved by means of toxic chemotherapy might be regarded with less enthusiasm. At present, because progress in cancer management is slow and achieved only by small improvements, large-scale clinical trials are the only reliable way of validating new treatments.
CARE OF THE DYING
168
Many patients with cancer die from their disease; it is the responsibility of the oncologist to be sure that aggressive management of the tumour is not thoughtlessly continued beyond the point at which cure is possible. This does not mean that treatment is discontinued, but that the aim of management becomes palliative rather than curative. In skilled hands palliative treatment can often give the patient a period of happy life free from distressing symptoms. Palliation may require radiotherapy, e.g. for painful bone metastases or bronchial obstruction; chemotherapy at low dose to suppress constitutional symptoms in lymphoma; aspiration of ascites or pleural effusion; or surgical pinning of a bone weakened by metastasis. There is more to palliative management than pain relief. Nevertheless, relief of pain, control of nausea and treatment of depression become increasingly important as the disease progresses. The most important component of management at this stage is the psychological support of the patient and his or her family. Support comes from the nature of the relationship that the patient has established with the medical team throughout the illness. Extra help may be needed from domiciliary nursing teams, which are increasingly providing expert and readily available advice on symptom control to patients in their own homes. Many patients prefer to remain at home in the last few weeks of life, and the family doctor and specialist nurses can often make this possible. Alternatively, the patient's wishes or family circumstances may make admission to a hospital or hospice necessary.
The nursing practices and the approach to symptom control that have been developed in hospices are now being incorporated into hospital practice. In some hospitals, nurse specialists have been appointed to advise on these aspects of management. The gradual awareness of death produces many different reactions. The patient may become angry and direct this at the medical or nursing staff. Feelings of apathy, hopelessness and fatigue are common, and depression may be severe enough to need treatment with antidepressants. The support of relatives and friends is essential. Meticulous attention to detail and a willingness to take time to talk to the patient are just as important at this stage in management as during the early stages when the intention may have been curative. Even though active management of the cancer has finally failed, this does not mean it was not worthwhile, nor is it a reflection on the abilities of the medical or nursing staff. The fact of treatment failure leads some doctors to avoid seeing their patients at this stage. This is bad practice and increases the patient's feeling of isolation and helplessness. Many non-medical agencies are able to help the patient and his or her family. Patients with religious beliefs may gain great comfort from their clergyman and other members of their local religious community. Counselling and support groups have been set up in many towns to provide help during the illness and to the bereaved relatives afterwards.
ALTERNATIVE THERAPY A multitude of unorthodox approaches to management of cancer have been offered to patients over the years. These usually have echoes of current medical practice. Serotherapy was used after antitoxins were introduced for infectious disease; tooth extraction was practised, based on the interwar notions that dental sepsis was responsible for chronic inflammation. Nowadays, psychological ideas are translated into visualization therapy, and concern over pollution and diet are transmuted into strict vegetarian or fatfree diets. The uncritical assumption that answers will be found in nature has led to a wide range of herbal remedies, some of which (e.g. laetrile) are somewhat dangerous. As with many chronic diseases, the practitioners of homeopathy and faith healing offer their remedies. Most of these approaches share certain recognizable characteristics. These include a tendency to borrow the jargon of medicine without its science; a belief that all tumours can be treated by the same or similar remedies; a tacit or explicit assumption that there exists a medical conspiracy to conceal the truth about the remedy in question; and a complete failure to adopt any of the proven methods of validation of the results of treatment. What these approaches offer distressed and anxious patients is a feeling that they can themselves do something to combat their disease, a glimmer of hope that they might
be cured, and relief from the side-effects of conventional treatment if this is abandoned. These benefits are often a reflection of inadequacy in the relationship of the patient and doctor, rather than a clearly held view by the patient and family. The damaging aspects of these approaches are that they may induce the patient to abandon a worthwhile treatment, weaken the relationship between doctor and patient, and impose unpleasant constraints on the patient's life, such as rigid dietary control. These disadvantages should be discussed with the patient and, if patients are thinking of abandoning a potentially curative treatment, every attempt should be made to persuade them not to do so. Nevertheless, the doctor's role in management is to offer help, advice and expertise; the patient has the right to choose what to do. In many cases no great harm will be
done, and an experienced doctor will make it clear that the patient is welcome to continue under his or her care now and in the future.
6
FURTHER READING DeVita V T, Hellam S, Rosenberg S 1997 Cancer: principles and practice of oncology, 3rd edn. Lippincott, Philadelphia. A comprehensive cancer textbook. Souhami R L, Tannock I, Hohenberger P, Horiot J C 2001 Oxford textbook of oncology, 2nd edn. Blackwell, Oxford. A comprehensive textbook of oncology. Souhami R L, Tobias J S 1997 Cancer and its management, 2nd edn. Blackwell, Oxford. A medium-sized text covering most aspects of cancer treatment.
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7 Ageing and Disease Peter W Overstall
Theories of ageing 172
Altered reactions to disease 189
Sociological aspects 173
Clinical approach 191
Special features of disease in old age 174
Investigation in the elderly 193
Autonomic dysfunction 178
Assessment of fitness for operation 196
Nutrition and ageing 179
Prescribing for the elderly 197
Balance and falls 180
Cholesterol lowering in stroke 200
Urinary incontinence 185 Faecal incontinence 187 Sleep and insomnia 187
Rehabilitation 201 Community care and long-stay care 202
Sexual function 189
Most ill health in developed countries now occurs in elderly persons. Not only are the elderly more prone to illness, but the proportion of elderly people has increased considerably in the last 100 years. The response of an individual to growing old depends more upon the previous pattern of life than upon anything in the ageing process itself, so that one of the features of old age is increased differences between individuals.
LIFE EXPECTANCY Life expectancy is the average observed years of life from birth, or from any stated age. Since 1900, life expectancy at birth in the UK has increased from 49 to 75 years for men and from 52 to 80 years for women (Fig. 7.1). This is mainly the result of reductions in infant mortality from the major
1 MCQ 7.1
infectious diseases. Tuberculosis, acute rheumatic fever, smallpox, diphtheria, tetanus and poliomyelitis now account for less than 2% of the ill health they caused in 1900. These changes are largely due to improvements in nutrition and to public health measures which have reduced water- and food-borne diseases. The influence of immunization and treatment on mortality is comparatively much smaller. Life expectancy may also deteriorate sharply. In the former Soviet Union and eastern bloc countries male life expectancy has fallen since 1980 from 62 to 58 years. This has been blamed on the disruption caused by the transition to market economies and the resulting poverty, unemployment, homelessness, excessive drinking and smoking. Life expectancy in sub-Saharan Africa has also fallen since the 1980s because of HIV/AIDS. Much interest was aroused by early studies in industrialized countries which suggested that there was a connection between income inequality and life expectancy, implying that income inequality is bad for the whole population. It has now been shown that there is no association at the population level, although household income has a powerful effect on mortality. In the UK life expectancy at birth for daughters of semiskilled and unskilled manual workers is 3 years less than for those born to professional and managerial classes. For their brothers there is a 5-year class divide.
CHANGES IN THE ELDERLY POPULATION The age structure of a population is affected by infant mortality and by fertility rates, late-age mortality and migration. Demographic ageing, i.e. a shift towards a larger proportion of elderly people in the population, began in Europe in the early 20th century, as a result of falling fertility. This change has already occurred in the UK, so that during the 1990s there was very little overall change in the population aged 60 years and over, but a rapid expansion of the over-85s. After 2001, the cohort of the post-1945 'baby boom' reaches retirement and there will then be a further rise. The proportion of elderly in the population will not increase thereafter unless there are further substantial falls in both fertility and late-age mortality. Fertility rates are declining worldwide and we can anticipate the most rapid changes in age structure of the population to be in the developing world (Fig. 7.2). Note the narrowing of the base of the pyramids during the 21st century due to lower fertility rates. The population pyramids in Europe and the western Pacific are starting to invert. Already over 60% of older people live in developing countries, and by 2020 this will reach 70%. Absolute numbers of elderly in the world will increase from 385 million now to 1.5 billion in 2050. Most of this increase will occur between 2025 and 2050, as children bom in the 1960s reach the oldest population cohorts. 1
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FIG. 7.1 Life expectancy at birth (both sexes) in WHO regions (weighted by population)
SUMMARY 1 Epidemiology of ageing • In the UK, the increase in life expectancy at birth seen in the early part of the 20th century was due largely to a decrease in infant mortality. • The rising percentage of elderly in the population is due to falling fertility and lower mortality rates, particularly in the very old. • During the 1990s there was a pause in the overall growth of the elderly population in the UK, but the over 85s increased by onethird. • Developing countries face a growing number of elderly in the first half of the 21st century.
FURTHER READING ON LIFE EXPECTANCY Mackenbach JP 2002 Income inequality and population health. BMJ 324: 1-2. FIG. 7.2 Population pyramids of WHO regions
THEORIES OF AGEING
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Ageing is a complex process resulting from intrinsic and extrinsic damage to the organism at a rate dependent on each particular individual's genetic background and environment. The resulting disability is not fixed or inevitable. For example, high-tone deafness and high blood pressure are common in elderly Britons, but are absent among
elderly persons in the Easter Islands. Osteoporosis is common in western Europe and the USA but rare in China. Thus descriptions of physical decline are too variable to be useful for defining ageing. A better approach, which allows populations to be compared and so highlights differences in environmental or intrinsic ageing factors, is to define ageing
as a process which brings about an ever-increasing age-specific mortality (i.e. the older the individual becomes the more likely he or she is to die). In the UK mortality is at its lowest around puberty, and ageing can be said to begin at this point, rising progressively throughout adult life. There is general agreement that ageing is at least partly genetically determined. Each animal species has a specific lifespan: the maximum recorded longevity of Marion's tortoise, for example, is over 152 years, for man 122 years, and for golden hamsters 2 or 3 years. In species of Drosophila, the Fl hybrid has a greater longevity than either parental strain. Female sex also generally confers increased longevity in a number of different species. Individuals whose parents live to the age of 75 years or more live longer than those whose parents died before the age of 60, and siblings of centenarians have a four times greater chance than average of surviving to their early 90s. The mean difference in longevity in dizygotic twins is twice that of monozygotes. Current theory sees the ageing process as non-adaptive, with ageing evolving as a late by-product of processes that benefit the individual during its earlier, more fecund lifespan. With limited energy resources, an organism has to strike the right balance between investing in bodily maintenance and repair, and producing and rearing its young. Oxidative metabolism plays a key role in cellular ageing. Over the years free radicals cause increasing damage to enzymes, structural proteins, and nuclear and mitochondrial DNA. Mitochondria are the main intracellular source of free radicals, and with increasing age more free radicals are generated while at the same time antioxidant production declines. This suggests that defective mitochondria are central to the process of ageing. The only proven way to delay ageing in higher animals is to eat a low-calorie diet. A 50% calorie diet restriction increases the lifespan of mice from 38 to 56 months. Whether humans would show a similar gain is unknown, but restricting calories by onethird results in lower blood pressure, cholesterol, glucose and white blood cell counts.
FURTHER READING ON THEORIES OF AGEING Kirkwood T 1999 Time of our lives: the science of human ageing. London: Orion Publishing.
SOCIOLOGICAL ASPECTS Retirement age is an administrative measure without relation to the capacity of individuals. Most people at retirement can expect good health for several years, and for developed countries the World Health Organization has introduced a new demographic indicator of 'life expectancy without incapacity'. At age 65 this is estimated to be between 8 and 11 years for men, and between 9 and 12 years for women. People in developed countries are main-
taining better health in later life than ever before, and severe disability in older people is declining at 1.5% per annum. For example, it is anticipated that in the USA the number of severely disabled elderly will halve between 2000 and 2050. The notion that the older you get the sicker you get has been challenged by the finding that centenarians appear to have lived most of their lives in good health, with a relatively rapid terminal decline. This suggests that the older you get the healthier you have been, and promises a potential reduction in morbidity and disability as people approach the limits of their lifespan. None the less, medical costs are four times greater in the first decade of retirement than during working life, and by the second decade of retirement they are nine times as great. The top diagnostic categories for healthcare costs for the over-70s are dementia, stroke, musculoskeletal disorders and falls.
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ATTITUDES TO THE ELDERLY In Europe the falling birth rate, increased longevity and trend to early retirement has reduced the workerpensioner ratio. In 1901 4.7% of British citizens were aged 65 or over; today this figure is 15.6%. This striking change had occurred by the 1980s (since when it has levelled off) and was not accompanied by undue economic strain or intergenerational strife, despite concerns in the 1960s and 1970s about 'dependency ratios' (the ratio of non-working people to those of working age). Discrimination against elderly people springs from three main impulses: a fear of death and dying, a social belief that falsely associates success with productivity, and misconceptions about the inevitability of senility. There is, in fact, little or no sign of a significant decline in happiness or life satisfaction with age. Over 80% of elderly people maintain independent house-holds, three-quarters of those over 85 can wash all over unaided, 95% can go to the toilet alone, and only 5% of people over 75 have significant dementia. It is true that institutionalization rates for the very old have increased considerably in the last 30 years owing to a decline in the amount of family support available to the elderly. Women aged between 45 and 60 have carried the brunt of community care, and since 1900, when there were 83 women in this age group for every 100 people over 65, there are now only 45. None the less, families do still care for their elderly relatives and indeed provide far more support than is available from health or social services. Family support ratios compare the relative sizes of older and younger generations and indicate the availability of family support for the elderly (Fig. 7.3).
RETIREMENT Retirement is now a well established part of life in developed countries and is starting to appear in developing countries among government employees and urban
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FIG. 7.3 Parent support ratio in WHO regions (weighted by population) The increase in the parent support ratio (population aged over 80 divided by the population aged 50-64) is most marked in developed countries, particularly Japan (increase in ratio from 8 to 41 between 1975 and 2025).
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workers (Fig. 7.4). Most people no longer see it as a traumatic event marked by major losses to the individual, but instead prepare for it as a normal and expected part of the life-cycle and welcome it as a time of opportunity and increased leisure. The rate of early retirement is, therefore, rising. Since 1975 there has been a decline in the UK of about one-third in the number of men aged 60-64 in fulltime employment. Of course, not all of these early retirements are voluntary, and there has been a noticeable trend for businesses in economic difficulties to make their older rather than their younger workers redundant. The period of active retirement, in which many take up part-time or voluntary work, ends when the person becomes disabled by declining physical or mental health. The difference between these two stages of old age depends on functional capacity, not on chronological age. Some people do find that retirement produces troublesome stresses. The most frequent problem is adjustment to a lower level of income. Some suffer from a loss of selfesteem, others fear the onset of ill health, or are distressed by their idleness. Most of these problems fade as the new pattern of activity is taken up, and serious depression is not a particular feature of retirement. Claims of large numbers of super-centenarians living in certain geographical regions - such as Vilcabamba in Ecuador, Hunza in Pakistan and Abkhasia in Georgia have been shown to be exaggerated. However, it is true that the inhabitants of each of the above areas are relatively long-lived, and in each case the esteem and merit enjoyed by a person increases with age. There is no retirement age
FIG. 7.4 Percentage of the population aged 65 years and over that is economically active worldwide The developed countries have still to find a satisfactory role for their unemployed elderly.
and old people continue to play an active role in the economic and social life of their communities.
FURTHER READING ON SOCIOLOGICAL ASPECTS Grundy E 1996 Age, 'dependency' and intergenerational relationships. Rev Clin Gerontol 6:303-304.
SPECIAL FEATURES OF DISEASE IN OLD AGE Measurement of physiological functions in healthy young adults gives fairly uniform results, with a narrow range between the upper and lower limits of normal. From about 30 years of age, a functional decline in performance can be detected in most organs and body systems (Fig. 7.5). However, the organs and systems age differentially, so that the variation both within and between individuals increases with age. The chronological age of an old person may therefore bear little relation to his or her functional age (Fig. 7.6), and the response of an old person to the stress of illness will be more unpredictable than that of a young adult. Degenerative changes occur throughout the body with increasing age, but these may become sufficiently marked to constitute a pathological process. The distinction between this and normal physiological ageing is often difficult to make, and there is increasing recognition that so-called normal ageing is the result of occult pathology. These changes have an important bearing on the management of the patient, as will be seen in the examples that follow.
TABLE 7.1 Good practice guidelines in osteoporosis 1. Frail housebound elderly should be prescribed calcium and vitamin D, assessed and managed for falls risk and considered for hip protectors.
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2. Patients with osteoporosis risk factors should have their bone mineral density measured (DXA at the hip). If their T-score is above -1 they can be reassured. If between -1 and -2.5 they should be given lifestyle advice and osteoporosis treatment if there is a history of a previous fracture. If the T-score is below -2.5 they should have lifestyle advice and osteoporosis treatment.
30
40 Age (years)
3. Patients with a previous fragility fracture should have routine investigations (blood count, ESR, bone and liver function tests, serum creatinine, serum TSH) and, because they are at high risk for a further fracture, should be started on osteoporosis treatment and given lifestyle advice.
FIG. 7.5 Age decrements in physiological functions in males A Fasting blood glucose; B resting cardiac index; C maximum breathing capacity; [6] maximum work rate.
cause of visual impairment is age-related macular degeneration. This is untreatable, but about 80% of patients can improve their reading performance with simple magnifying devices and brighter illumination.
THE AGEING EAR
FIG. 7.6 The relation between resting cardiac output and age in men without circulatory disorders Note that several men over the age of 70 have values similar to men in their 30s.
Impaired hearing increases with age and can contribute to poor health, social isolation, depression and (probably) paranoid psychosis. About 30% of the elderly regard themselves as having a hearing impairment, but audiometric testing reveals a much higher prevalence (60%) in those aged over 70. Presbyacusis is age-related loss of high-frequency hearing, but this cannot be reliably distinguished from the effect of ototoxic drugs, diuretics or vascular disorders. Some of the hearing loss usually regarded as an inevitable part of old age may be due to our noisy environment.
OSTEOPOROSIS (See Table 7.1)
THE AGEING EYE The force required to focus the eye increases considerably at about 40 years of age and, by 45 or 50, accommodation will be so poor that for most persons small print can be read only at arm's length (presbyopia). This is a result of both a reduction in elasticity of the lens capsule and a thickening of the lens, which prevents it adapting its shape to focus on near objects. Opacities and general yellowing of the lens, together with an age-related meiosis, cut down the amount of light entering the eye and reduce visual aculity. A loss of cells in all regions of the visual pathway affects perception and contrast sensitivity. About 20% of those aged 75 and over have a visual acuity of less than 6/12. With continuing advances in the management of cataracts, glaucoma and diabetic retinopathy the main
Postmenopausal (type 1) osteoporosis results from accelerated bone loss due to oestrogen deficiency. There is mainly a loss of trabecular bone, typically resulting in fractures of vertebral bodies and the distal forearm in women in their 60s and 70s. Senile (type 2) osteoporosis is a slower, age-related bone loss that occurs in both sexes. There is cortical as well as trabecular bone loss, which typically results in femoral neck fractures in men and women in their 70s and 80s. These fractures are a serious threat to older people and are associated with a 20% increased risk of either death or institutional care over the following year. Secondary causes of osteoporosis include endocrine (thyrotoxicosis, hypogonadism, hyperadrenocorticism) and gastrointestinal (malabsorption, primary biliary cirrhosis) disorders, rheumatoid arthritis, malignancy, hypertension, and drugs such as corticosteroids and heparin. Other risk
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factors include a strong family history, inactivity, excessive alcohol and smoking. Unfortunately, clinical risk factor profiles correlate poorly with both bone density and fracture risk, and the most useful way of assessing increased osteoporosis risk is to measure bone density by dual energy X-ray absorptiometry. Ultrasound assessment of the skeleton is a promising alternative method. The predictive value of bone density is similar to that of blood pressure in determining the risk of stroke. The relative risk of fracture increases two to three times for each standard deviation decrease in bone density. Definite indications for bone density measurements include fracture after minimal trauma in previously fit individuals, past history of early menopause (<45 years) in women up to the age of 70 years, underlying secondary causes of osteoporosis and apparent osteopenia on X-ray. There is currently no evidence to indicate that routine population screening is valuable, and instead a case-finding strategy is used. Bone density measurements are not needed in patients at greatest risk, such as those over 80 years who are frail and housebound or institutionalized, those with a previous fragility fracture and patients taking prolonged oral steroid therapy (>7.5 mg prednisolone/day), as they should be treated regardless of their bone density. Prevention of osteoporosis depends on achieving the maximum peak bone mass (regular weight-bearing exercise and dietary calcium intake of 1000-1500 mg/day, between the ages of 15 and 25) and reducing the rate of bone loss by encouraging elderly people to keep exercising, maintain a daily calcium intake of 1000 mg, avoid falls (see p. 175), stop smoking and moderate alcohol intake. These are all worthwhile interventions at the population level. For the individual postmenopausal patient at risk, particularly if she has climacteric symptoms such as hot flushes, the single most effective intervention is hormone replacement therapy (HRT). The greatest benefit is gained by starting treatment soon after the menopause. For current users of HRT there is a 65% reduction in hip fracture risk but 5 years after stopping HRT most of the benefit is lost. For optimal protection HRT should be continued for long periods. Long-term use increases the risk of breast cancer; for women aged 50-70 the risk of developing breast cancer increases from 51 cases per 1000 women to 57. HRT reduces the risk of coronary artery disease but the benefit is not as great as early studies suggested. The risks of developing Alzheimer's disease appears to be reduced. Raloxifene is an alternative to HRT for the postmenopausal patient without climacteric symptoms, which can be exacerbated by raloxifene. It appears to be associated with a lower incidence of breast cancer and does not cause
1
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MCQ 7.2
2
Fig. 7.1
endometrial bleeding, but, like HRT, it can cause deep vein thrombosis. For the elderly patient HRT is rarely indicated and bisphosphonates or calcium and vitamin D are used instead. The best evidence for efficacy in reducing spinal, non-vertebral and hip fractures is for alendronate and risedronate. Calcitonin has proven efficacy for preventing spinal fractures and is also effective in relieving the pain associated with vertebral fractures. Calcium and vitamin D have proven efficacy in preventing non-vertebral and hip fractures, and it has been argued that these supplements should routinely be prescribed for frail housebound elderly persons. Corticosteroid treatment doubles the risk of fractures of the hip and distal radius and quadruples the risk of vertebral fracture. All patients over 65 years taking prednisolone 7.5 mg a day or more should have treatment to prevent osteoporosis: the first choice is a bisphosphonate1212.
FURTHER READING ON OSTEOPOROSIS Royal College of Physicians, 2000. Osteoporosis: clinical guidelines for prevention and treatment. RCP, London.
DEMENTIA AND NORMAL AGEING Cross-sectional and longitudinal studies consistently demonstrate a decline in cognitive function with increasing age. A decline in cognitive ability is not confined to old age, and tests that measure the ability to solve novel problems rapidly (fluid intelligence) show a fall in performance by the late third and early fourth decades. Age-related changes in cognitive function appear to be related to a general decline in the speed at which information is processed. Thus, highly practised skills, such as vocabulary test scores, alter very little with age, but timed novel problem solving, reaction time tests and the ability to learn new material decline with increasing age. Ill health undoubtedly affects cognitive performance, particularly cardiovascular disease. Congestive cardiac failure doubles the risk of cognitive impairment, and systolic hypertension in middle age increases the likelihood in old age of developing white matter hyperintensities (on MRI) and dementia. Other predictors of cognitive decline are increasing age, 'old age forgetfulness', low educational status, lack of social and physical activities and possession of the ApoE-4 allele. The major cause of intellectual loss in old age is Alzheimer's disease (AD), followed by vascular dementia and Lewy body dementia. There is increasing recognition that vascular risk factors are important predictors of AD as well as of vascular dementia. Severe atherosclerosis carries a threefold risk of developing AD, and the Syst-Eur study showed that treating systolic hypertension halves the likelihood of developing dementia. AD is a distinct entity rather than a mere exaggeration of normal ageing, and prevention strategies
17
pathological decrements in SUMMARY 2 Normal vs physiological performance in old age Normal age-related functional decline
pathological process
Impaired sight (presbyopia)
Cataracts, macular degeneration
Impaired hearing (presbyacusis)
Effects of ototoxic drugs, diuretics or vascular disorders
Bone loss
'Accelerated' osteoporosis
Decline in intellectual function
White matter lesions due to hypertension; Alzheimer's disease
Impaired glucose tolerance
Diabetes
Minor gait slowing and balance impairment (increased sway)
Parkinson's, Alzheimer's or cerebrovascular disease; dementia; vestibular lesions; cervical spondylosis; visual problems
Altered sleep pattern
Insomnia due to nocturia (due to detrusor instability); pain, depression, etc.
need to concentrate on 'cognitive impairment, not dementia' in people aged 65 and over. This has twice the prevalence of all types of dementia combined and is associated with functional disability and the need for institutional care, yet little is known of its natural history.
IMPAIRMENT OF BIOCHEMICAL HOMEOSTASIS Most normal old people can, under resting conditions, maintain their internal environment at levels similar to those in the young. When stressed, however, it is apparent that homeostatic mechanisms in the elderly are impaired. Blood glucose control and osmoregulation are two good examples of this.
The control of blood glucose The average fasting blood glucose level increases only slightly with advancing age. When a glucose load is imposed, however, the rise in maximum blood glucose levels is clearly greater, and the return to resting levels slower, in old people (Fig. 7.7). The upward drift of blood glucose with age produces diagnostic difficulties. If criteria used to diagnose diabetes in young populations were applied to the elderly, there would be a considerable increase in the number of those diagnosed as diabetic from the glucose tolerance test. Thus, elderly patients with an impaired glucose tolerance test (i.e. a 2-hour post-glucose blood sugar of 7-llmmol/L) should probably not be regarded as diabetic if they are asymptomatic, but they do carry a
Minutes FIG. 7.7 Mean blood sugar levels after a 50 g oral glucose load in a cross-sectional population study Known diabetics have been excluded.
higher risk of developing frank diabetes. Recent American Diabetic Association (ADA) criteria propose the use of fasting blood sugar, with 6.1-6.9 mmol/L indicating impairment and 7.0 mmol/L as the new diagnostic cut-off (instead of the WHO fasting criterion of 7.8 mmol/L). The fasting ADA criteria are less predictive than the WHO criteria of cardiovascular risk in the elderly, and for older adults a fasting glucose cut-off of 7.8mmol/L is preferable.
Osmoregulation On average, young adults maintain their blood osmolality in the range 280-295 mmol/kg. Although resting plasma osmolality is unchanged in the elderly, the osmoregulatory response to 24-hour water deprivation is impaired, even in good health. Despite developing higher plasma osmolality and sodium concentrations in response to dehydration, elderly subjects do not respond with appropriate thirst and water intake. They do not drink sufficient water to replenish their body water deficit and return plasma sodium levels to normal. Not only is there reduced thirst and water intake following dehydration, but the old person's kidneys are less able to retain water, due to reduced renal responsiveness to arginine vasopressin (AVP). These changes can predispose even healthy old people to fluid and electrolyte disturbances when there is excessive salt and water loss. They are also at risk of overhydration and hyponatraemia because they are unable to excrete excess water, mainly because of a decline in glomerular filtration rate with age. Particular care is needed with intravenous infusion to avoid overhydration and hyponatraemia. Postoperative patients are at high risk, especially if they have been taking a thiazide diuretic and as a result have mild hyponatraemia. Surgical stress causes inappropriate ADH secretion, which increases the hypona-
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traemia. Sympathetic blockade resulting from spinal anaesthesia lowers the blood pressure, and if in an attempt to counteract this large volumes of i.v. 5% dextrose/saline are given, serious hyponatraemia ensues, which carries a 20% risk of brain damage or death. Hypotonic fluids must not be given to elderly postoperative patients.
FURTHER READING ON SPECIAL FEATURES OF DISEASE IN OLD AGE Mosekilde L 1998 Aging of bone. Rev Clin Gerontol 8:281-296. O'Neill P A 1997 Aging homeostasis. Rev Clin Gerontol 7:199-211. Sorlie P, Gordan T, Kannel W B 1980 Body build and mortality: the Framingham Study. JAMA 243:1828-1831. Staessen J A, Fagard R,Tuijs L et al 1997 for the Systolic Hypertension in Europe (Syst-Eur) trial investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 350:757-764.
AUTONOMIC DYSFUNCTION This results from a number of factors: a reduction in nerve density and neurotransmitter concentrations in the autonomic nerves; reduced responsiveness of effector organs, such as blood vessels and stretch receptors in arterial walls; and a decline in cellular p-adrenergic sensitivity. Dysfunction may follow central lesions such as cerebrovascular disease, Parkinson's disease, Shy-Drager syndrome, Wernicke's encephalopathy (due to thiamine deficiency associated with alcoholism) and Alzheimer's disease. Peripheral autonomic neuropathy may occur in diabetes mellitus, chronic alcoholism and malignancy. Autonomic dysfunction may also be caused by drugs such as phenothiazines, tricyclic antidepressants and haloperidol. The important clinical consequences are orthostatic hypotension (Table 7.2), bowel and bladder disturbances, impotence and impaired thermoregulation.
AGEING AND THERMOREGULATION
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Under normal circumstances the body core temperature is about 37°C with, in temperate climates, a skin temperature of 33°C, giving a core-skin temperature gradient of 4°C. Thermoregulatory responses are impaired in old age due to disordered autonomic function. This usually passes unnoticed, but in times of environmental stress the old person is less able to maintain a constant deep body temperature. Surveys of old people living at home in winter show that only 0.5% had frank hypothermia (deep body temperature less than 35°C) but that 10% had a deep body temperature below 35.5°C. The latter had impaired
TABLE 7.2 Orthostatic hypotension • Fall in systolic blood pressure of at least 20mmHg or a fall of 10 mmHg or more in diastolic pressure on standing • Prevalence in elderly between 10 and 24% • Age-related aetiology Impaired baroreceptor response Failure of cerebral autoregulation Increased arterial and arteriolar rigidity Autonomic dysfunction • Cardiovascular causes Low cardiac output (e.g. heart failure) Restricted cardiac output (e.g. aortic stenosis) Absolute hypovolaemia (e.g. blood loss) Relative hypovolaemia (e.g. venous pooling) • Drug causes Centrally acting (e.g. L-dopa, MAOIs, sedatives) Vasodilators (e.g. nitrates, alcohol) Diuretics, calcium channel blockers • Symptoms Typically these consist of faintness, giddiness and blurring of vision, and are precipitated by standing and exacerbated by exertion or a heavy meal. However, if there is a lesion of the parasympathetic system these symptoms may be absent, so that despite a fall in blood pressure on standing there is no warning giddiness. The patient remains upright and experiences symptoms such as profound weakness, falls, confusion and pallor • Management Raise head of bed 15-20°, leg and abdominal compression, 9afludrocortisone 0.1 mg daily initially, increasing by 0.4mg each week. Other drug treatments include mididrone, dihydroergotamine, indomethacin, domperidone (in Parkinson's disease) and octreotide (for postprandial hypotension)
thermoregulation, as shown by a core-skin temperature gradient only half that of normal individuals. The elderly may also suffer impairment of thermal perception. Young persons can detect temperature differences as small as 0.8°C, but old people only perceive differences of 2-5°C. Furthermore, the elderly shiver less efficiently in response to cooling, with little more than half the metabolic heat production seen in young subjects. Old people are thus not only less able to maintain their deep body temperature when subjected to cold stress, but may also be less aware of cold conditions and therefore fail to take the appropriate steps. This may explain why some old people can tolerate cold living conditions without discomfort. Although most British homes now have central heating, hypothermic patients are less likely than controls to have the heating on at the time of collapse. Typically, hypothermia occurring indoors results from a collapse due to illness, when the patient is alone, lightly clothed and not in bed. These conditions cause progressive core cooling. About 80% of the variation in mortality rates throughout the year is associated with changes in temperature
a
FIG. 7.8 Observed and expected deaths in the UK during the cold winter of 1984/5 Note the rise in death rate during the winter months and the excess deaths during the two exceptionally cold periods in early 1985.
FIG. 7.9 Relation of obesity to mortality found in the Framingham study The obesity index is the ratio of the subject's weight to a reference weight obtained from height and frame charts compiled by large insurance studies. Note that the lowest mortality occurs at an obesity index rather above 1.0.
FURTHER READING ON AUTONOMIC DYSFUNCTION (Fig. 7.8). For every degree change in the average winter temperature, the number of annual winter deaths rises or falls by about 8000. Thus, in the UK in the mild winter of 1983/4, about 30000 more elderly people died than during the summer months (a 14% increase). In the cold winter of 1984/5 this figure rose to 46000 (an increase of 20%). However, the majority of these 'excess' deaths are not directly due to hypothermia, but to coronary and cerebral thrombosis resulting from haemoconcentration and hypertension after cold exposure. Over the last 20 years there has been a decline in this excess winter mortality. About half of this decline is the result of non-seasonal factors, such as improved general medical care. The rest is due to improvements in home heating and greater car ownership, which reduces outdoor exposure to cold. The diagnosis and treatment of hypothermia are discussed in Chapter 2, p. 46. The elderly are also less able to cope with excessive heat, and the mortality rate during heatwaves rises with increasing age. In Chicago during the benign summers of 1992, 1993 and 1994 the heat-related mortality was 1, 3 and 9, respectively, but during the exceptionally hot summer of 1995 it rose to 515, with 162 deaths on a single day in July. It has been estimated that on the hottest day of a heatwave there are six extra deaths per 100000 population. There is much unrecognized heat illness and large variations in the mortality rates, as there are no international or even national agreements on the definition of heat-related death. Various criteria have been introduced, such as a core body temperature above 40.6°C at the time of death. Most models of global warming predict an increase in the frequency and intensity of heatwaves. The impact is likely to be greatest in mid-latitude cities with infrequent but extreme heatwaves, so that in cities such as Shanghai and New York there will be several thousand extra heat-related deaths annually by the middle of the 21st century.
Collin K J 1997 Aging, disease and the autonomic nervous system. Rev Clin Gerontol 7:119-126.
NUTRITION AND AGEING At retirement age in developed countries the average person is more likely to be obese than undernourished, but subsequently body weight and nutrient intake fall and, for the very elderly, the main concern is undernutrition. Moderate overweight is not associated with a high mortality in old age (Fig. 7.9), but low body weight is associated with a higher mortality in both fit old people and those admitted to hospital. Nutritional surveys have shown a marked decrease in energy requirements and nutrient intake with increasing age. However, this is due mainly to physical illness and reduced physical activity, which reduce appetite and energy expenditure. With increasing age there is a gradual decline in metabolism at rest, but this is relatively unimportant. For healthy active persons over 60 years of age the energy and nutrient requirements are similar to those of a 30-year-old. Longitudinal studies have shown that nutrient intakes are maintained in old people who remain in good health. Housebound elderly women consume 15% less carbohydrate and 46% less vitamin C than do active age-matched controls.
NUTRITIONAL DEFICIENCIES A survey of old people living at home found that 3% were suffering from malnutrition, including protein-calorie malnutrition, iron deficiency and specific vitamin deficiencies.
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supplement of 800 IU vitamin D and calcium reduces fracture rates and should be widely prescribed to at-risk patients. 1
TABLE 7.3 Risk factors for malnutrition Unexpected weight change of more than 3 kg Physical disability Lack of sunlight Gastrectomy Mental confusion Chewing or swallowing difficulties Fewer than eight main meals, hot or cold, in a week Absence of fruit or vegetables in diet Food wastage Alcoholism Poverty (receiving financial support from state) Depression or loneliness
BALANCE AND FALLS
In most cases this was the result of some underlying medical problem and was only rarely due primarily to economic or social factors (see Table 7.3). Social factors are, however, likely to be important in cases of subclinical malnutrition. For example, 31% of those living alone had leukocyte ascorbic acid levels below 7.0ug/108wbc, compared to 8% of those living with a spouse. Scurvy remains rare even in the most isolated patients. Almost 10% of acute hospital admissions are seriously malnourished and this is associated with a slower rate of recovery, longer hospital stay and increased treatment costs. Patients should be weighed on admission and questioned about their diet. Megaloblastic anaemia due to a folate-poor diet is rare in old people in the UK. However, low serum folate levels are found in about 8% of elderly hospital patients, and often in patients with physical or mental disorders that interfere with shopping and cooking. Osteomalacia may contribute significantly to the skeletal rarefaction seen in old age (although this is more commonly due to osteoporosis). There are many causes of osteomalacia, but two of the most important are reduced vitamin D intake and low exposure to sunlight - two factors often present together in the elderly. More than half of elderly admissions to a general medical ward have 25-OHD concentrations below 37.5nmol/L and nearly a quarter of these have a level below 20nmol/L indicating severe deficiency. The current UK recommended intake of vitamin D for people aged 65 years and over is 400IU (10 ug) daily, and this is not easily achieved without fortified foods or adequate levels of sunlight. A daily
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0 Case 7.1 3
4
Fig. 7.3
0 Fig. 7.4 6
0 Fig. 7.5
Fig. 7.2 MCQ 7.3
During normal quiet standing balance is maintained when the centre of gravity is kept within the support base provided by the feet. Maintenance of this upright position is associated with body sway, mainly in the anteriorposterior (AP) direction, and this sway may be measured either as degrees of angular movement or, using force platforms, as changes in the pressure over the soles of the feet. Threats to balance are detected principally by vision, lower limb cutaneous sensation and proprioception, and to a lesser extent by the vestibular system. Following a pertubation sensory information is centrally processed and corrective responses, such as muscle stiffening and cocontraction, or protective responses, where one or more steps are taken or an arm is thrown out to catch hold of an external support, are triggered. Disease in any part of this system will impair balance. Loss of a single sensory input is rarely completely disabling because of good overall reserve, but closing the eyes always causes an increase in postural sway and it appears that peripheral vision in particular is necessary for normal balance.
CHANGES IN BALANCE IN OLD AGE Both AP sway velocity and area increase in normal elderly subjects (Fig. 7.10), (i.e. those who report that their balance is normal and who are functionally independent). Further increases in AP sway correlate with spontaneous falls, but a better predictor of falls is increased mediolateral sway. Age-related changes occur in all parts of the postural control system. There is reduced visual acuity, contrast sensitivity, depth perception and dark adaptation. There is decreased cutaneous sensitivity in the feet and proprioceptor loss in the ankles and apophyseal joints in the cervical spine. In the vestibular system there is loss of labyrinthine hair cells and vestibular ganglion cells. Centrally there is an age-related loss of neurons, resulting in slowing of information processing and depletion of neurotransmitters such as dopamine in the basal ganglia. The older person has to pay much more attention to their balance, and loss of concentration contributes significantly to the risk of falling. On the motor side there is an agerelated reduction in muscle strength due to decreases in the size and number of muscle fibres and motor neurons. Loss of strength of the ankle dorsiflexors and knee extensors (i.e. quadriceps) is particularly associated with an increased risk ofgn f There has been a long-running debate on what constitutes normal gait in old age and the cause of senile gait
TABLE 7.4 Risk factors for falls
a
More than one previous fall Lower limb disability (including muscle weakness) © Impaired balance or gait Use of sedative drugs Use of more than four drugs Cognitive impairment (mini mental state examination score <26/30) Impaired activities of daily living 0 Visual deficit
FIG. 7.10 Postural sway (measured as movement in the anterior-posterior plane with the subject standing) increases with age At all ages, women sway significantly more than men. 1 unit = 3.5° of angular movement.
disorder. There are undoubtedly some elderly people who maintain a normal gait even in extreme old age. However, gait laboratory studies show subtle changes even in carefully screened healthy elderly subjects. Gait slowing is due to a decreased stride length and cadence (steps per minute) remains unaltered. Stance time and double support time increase and there is a less vigorous push-off. Whether this represents an early degeneration of the balance control system or an adaptation to make the gait safer is unclear. However, it is now apparent that the senile gait disorder, which is characterized by caution and shorter and more frequent strides and is said to occur in about 20% of the elderly, is not due to age but to underlying neurodegenerative syndromes and subclinical cerebrovascular disease. These patients have a twofold increased risk of cardiovascular death, compared to age-matched subjects with a normal gait. 4 FALLS Although falls are the leading cause of death from injury in people over the age of 75, serious injury only occurs in about 5 % of falls in community-living elderly, and a much more common consequence is loss of confidence, a reluctance to go out of doors and reduced quality of life. Thirty per cent of people over the age of 65 give a history of having had a fall in the previous year, and 50% of fallers do so repeatedly. Incidence rates in nursing homes and hospitals are nearly three times the community rate and the likelihood of an injury is more than doubled. Falls increase with age and fall rates in women are twice those in men. The more risk factors a person has (Table 7.4) the more likely they are to fall. Over 1 year 65-100% of people with three risk factors will fall, compared to 8-12% for those with none. The typical frequent faller usually has multiple defects affecting the postural control system.
Clinical or subclinical disease is a far more important cause of falls than environmental factors such as trailing wires and loose rugs. It is therefore no surprise to find that falls, incontinence and functional dependence all share the same risk factors. Increased fall rates in women probably reflect greater muscle weakness and possibly lower levels of fitness: for example, over 50% of women over the age of 55 are unable to walk at 3 miles per hour on the level, and the average healthy 80-year-old woman has to make a maximum quadriceps contraction to rise from a low armless chair or the lavatory. 7
HISTORY AND EXAMINATION It is important to spend time with the patient (and ideally a reliable witness) getting a precise account of the circumstances surrounding the fall. Was it a simple trip or accident, which carries a relatively good prognosis? Or was it a more ominous spontaneous fall (' I don't know what happened, I just went down') (Table 7.5). Some may say that they felt dizzy (particularly if prompted by the doctor). However, only very rarely does the patient experience true vertigo (a sensation of the surroundings or the inside of the head spinning round). They do not so much feel dizzy as unsteady when standing or walking, and are frightened that they are going to fall over. Some of these patients suffer drop attacks. These are falls which occur without warning: the patient suddenly crumples to the ground and there are no neurological sequelae. As with other spontaneous falls their aetiology is multifactorial, although sometimes a specific cause will be found, such as reflex-mediated syncope, normal-pressure hydrocephalus or Meniere's disease. Specific causes of falls such as these are less common than widespread postural defects (e.g. cerebrovascular disease and a diabetic peripheral neuropathy), which result either in spontaneous falls or a fall following a trivial pertubation because of slowing or even loss of the normal corrective responses. These patients are usually older and more frail, their gait and balance are noticeably impaired and their general health poor. Their mortality is about five times that of non-fallers.
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TABLE 7.5 Causes of spontaneous falling
TABLE 7.6 Causes of syncope
Patient usually impaired in more than one of the systems concerned with balance control:
Pathophysiology of syncope is complex in older patients. Orthostatic hypotension, carotid sinus hypersensitivity and vasovagal syncope overlap in 30% of elderly with syncope.
• • • • • •
Vision, e.g. impaired depth perception Impaired cutaneous sensation (e.g. peripheral neuropathy) Impaired proprioception, e.g. cervical spondylosis, peripheral neuropathy Vestibular lesions, e.g. Meniere's disease Impaired central coordination, e.g. cerebrovascular disease Unstable support base, e.g. turning quickly, walking downstairs or arising from a chair
If balance is already impaired, falls are precipitated by: • Acute illness, e.g. chest infection, worsening of heart failure • Drugs, e.g. tranquillizers • Occult ill health, e.g. anaemia, hyponatraemia
Reflex mediated (neurovascular instability) Vasovagal Carotid sinus hypersensitivity Orthostatic hypotension Situational syncope (cough, micturition, etc) Cardiac Arrhythmias Obstruction (aortic stenosis, pericardial effusion etc) Neurological Vertebrobasilar insufficiency Subclavian steel syndrome
Rare
Points to note in the history are: • Circumstances of the fall; • If the fall occurred soon after standing up (raising the possibility of orthostatic hypotension) • Loss of consciousness (can the patient remember hitting the floor?). There are only two common causes syncope (Table 7.6) and epilepsy; • Syncope accounts for up to 6% of medical admissions and 20% of elderly patients presenting to A & E with unexplained falls, such as drop attacks. Patients will sometimes deny loss of consciousness, despite unequivocal evidence that it occurred; • Vasovagal syncope may be preceded by the classic symptoms of lightheadedness, sweating and nausea, but in the 'malignant' variety there is no warning, the patient falls unexpectedly, the attack is prolonged with slow recovery and injury, and convulsions and incontinence are common; • Palpitations before the fall, a sense of dizziness or faintness and dimming of vision are important pointers to syncope; • Loss of consciousness, dizziness and faintness are not features of transient ischaemic attacks. These depend for their diagnosis on focal neurological signs (e.g. motor or sensory loss, dysphasia); • The patient's drugs will need to be checked. Sedatives or hypnotics frequently slow the patient down and may precipitate a fall. B-Blockers, certain calcium channel blockers and diuretics may cause orthostatic hypotension or vasovagal syncope; • Acute or chronic medical problems
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182
Fig. 7.6
SUMMARY 3 Typical features in patients with recurrent falls • • • • •
Have several risk factors, especially lower limb muscle weakness Significantly impaired gait and balance Difficulty in accounting for how they fell Show fear of falling Generally have multiple defects both in the sensory systems concerned with balance control (vision, proprioceptors and the vestibular system) and in central coordination centres
• Mental state should be assessed if there is a suspicion of dementia or depression; • A history of tinnitus, deafness or vertigo should be sought. If present, this may indicate a vestibular lesion, either peripheral (e.g. Meniere's disease) or central (vascular disease in the brainstem or cerebellum). • A sudden onset of severe vertigo suggests a posterior circulation stroke. Episodic vertigo lasting less than 1 minute and provoked by rapid positional change is probably benign positional vertigo, which is confirmed by a positive Hallpike test (for description see p. 183); In the general examination: • The lying and standing blood pressure should be measured (a drop in systolic pressure of more than 20mmHg indicates postural hypotension). • Carefully examine the heart. • The range of neck movements should be assessed. • Watch the patient rise from a chair, walk several paces and return. • Normal old people should not have a positive Romberg test (i.e. closing the eyes when standing should not markedly impair balance). • Check for impaired righting reflexes by tapping the
RECENT ADVANCES IN THE PREVENTION OF FALLS 1. Intervention studies have demonstrated significant reductions in falls. Because falls' are multifactorial broad-based interventions are best. Programmes such as the following reduce the risk of falling by 30%: • Review and adjust drugs • Balance and gait training • Muscle strengthening exercises • Practise transfer skills from bed/chair/toilet • Make home safer. 2. Assessment and appropriate treatment and referral of patients attending an A & E department lowers the risk of recurrent falls, reduces fracture rate by 50% and decreases the odds of hospital admission. 3. The Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT) programme demonstrated that exercise alone could produce a 25% reduction in falls. In particular, Tai Chi appeared beneficial and led to a 47% reduction in falls incidence in elderly women. A home visit by a physiotherapist and the prescription of 30 minutes of strength and balance retraining exercises and an outdoor walk three times a week reduces fall rate and remains effective for at least 2 years. 4. Hip protector pads reduce the risk of hip fracture. They are indicated for frail at-risk patients who are sufficiently well motivated to wear them. 5. Patients with parkinsonism can be taught how to manoeuvre more safely in the home and to walk with a normal stride length using markers on the floor or attentional strategies.
patient lightly on the sternum or giving the shoulders a tug from behind. Be ready to catch them if they fall. • In severe cases there will be manifest anxiety and fear of falling, with the patient reluctant to move without clutching on to furniture or onlookers for support. • Check muscle strength (especially quadriceps), lower limb joints, vision, neurological function (especially lower limb peripheral nerves). In addition to routine investigations: • A 24-hour ambulatory ECG should be obtained for patients suspected of having episodes of cardiac syncope due to an arrhythmia. • Patients with a normal 24-hour tape, but who have symptoms suggesting vasovagal syncope or carotid sinus syncope, require head-up tilt testing and carotid sinus massage (a positive response produces asystole exceeding 3 seconds, a decrease in systolic blood pressure exceeding 50mmHg, or a combination of the two). 1 • An EEG is occasionally helpful, although the diagnosis of epilepsy is essentially clinical (see Ch. 24 p. 1321).
Early morning falls in patients taking a long-acting hypoglycaemic drug (e.g. chlorpropamide) raise the possibility of hypoglycaemia. Patients suspected of having a vestibular lesion can have this accurately localized only by specialist examinations, which include electronystagmography and caloric tests. The Hallpike manoeuvre can be carried out in the clinic and tests for the presence of positional vertigo. The nystagmus of benign positional vertigo occurs after a latent period of 2-20 seconds when the head is reclined and turned to the affected side. To carry out the test the patient is seated at the top end of a flat examination couch and warned that they will experience vertigo. The examiner holds the patient's head firmly and turned 45° to the left or the right; the patient is then carried rapidly backwards until the head is dependent. The patient is asked to keep his eyes open all the time and look at the examiner's nose. The nystagmus of benign positional vertigo is rotatory (torsional) and is directed towards the affected ear when it is undermost (i.e. when the left ear is affected the nystagmus is to the left when the head is hanging to the left.) The nystagmus lasts for up to a minute and coincides with a sense of vertigo, which may be severe. When the patient sits up the nystagmus may reappear beating to the opposite side. With repeat testing the symptoms and signs adapt and fatigue. Central types of positional nystagmus may also be recognized by this test. In contrast to benign positional vertigo the central type of nystagmus appears after no latent period, it persists for longer than a minute, it does not fatigue, vertigo is usually absent, and the direction is variable. The patient's vision, both with and without spectacles, should be noted (depth perception, low contrast, etc.). Low-contrast visual acuity and contrast sensitivity (the detection of large visual stimuli under low-contrast conditions) are better predictors of falls than impaired high-contrast visual acuity.
a
MANAGEMENT Many patients with recurrent falls have multiple postural defects and their balance is precarious. All require a multidisciplinary assessment. Sometimes a minor illness such as a chest infection or a newly prescribed sedative drug can simply prove too much for a frail patient. Identification of precipitating factors enables the patient to be appropriately advised. Culprit drugs should be withdrawn in patients with syncope. Vasovagal syncope may be treated with B-blockers, SSRIs or pacing. Cardioinhibitory carotid sinus syndrome usually needs a permanent pacemaker. Cervical spondylosis should be treated with neck exercises, not a cervical collar, which often makes the patient feel more unsteady. Faulty spectacles should be replaced and everything possible done to improve the patient's vision, including better illumination in the home.
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CASE STUDY 7.1
FALLS AND 'FY T
An 83-year-old woman, who looks after her 90-year-old husband, gives a 2-year history of increasing difficulty with walking. When standing or walking she feels unsteady, as if she might fall, but there is no sense of vertigo. She goes out for a walk every day with her daughter, who lives nearby, but lacks confidence and does not go out of doors on her own. She has had several spontaneous falls, sometimes going over backwards. She says that her walking has become difficult and that her legs feel 'as if they are in concrete', but they are not painful. Sometimes when she starts walking her legs will not move - 'they seem to be nailed to the floor' - but after a few seconds she is able to get going. She finds a similar problem when she turns: her legs lag behind her upper body, with the feet seemingly stuck to the floor, and she has fallen over twice as a result. She also describes 'funny turns'. These occur about once a week without warning. She has an unpleasant sick feeling in her stomach that rises rapidly to her head. Her daughter says that during these episodes her mother looks vacant. Her eyes are open, but she does not respond to questioning and sometimes makes a funny grunting noise. The episodes last just a minute or two, but she often feels unwell for some hours afterwards. The daughter has also noticed that her mother's
memory has deteriorated. On direct questioning the patient admits to urinary urge incontinence and daytime frequency, sometimes having to pass urine every hour. At night she gets up two or three times. There is no dysuria.
Questions 1, What gait abnormality has the patient described? 2. What is the cause of her 'funny turns'? 3, What is the likeliest explanation for her urinary incontinence?
The patient's description of her feet sticking to the ground when she tries to walk or turn is known as freezing. It is a feature (in order of frequency) of progressive supranuclear palsy, arteriosclerotic parkinsonism, normal pressure hydrocephalus and idiopathic Parkinson's disease. It is rare in multisystem atrophy and very rare in drug-induced parkinsonism. The commonest type of freezing is start hesitation (sometimes called gait ignition failure), but it can also be observed in speech, the eyelids, in handwriting and in tasks such as shaving. Her 'funny turns' are typical of complex partial fits (elderly patients
Peripheral vestibular lesions may be improved with cinnarizine (15 mg t.d.s.) or betahistine (8mg t.d.s.), but these drugs may have troublesome sedative effects. Central vestibular lesions are rarely helped by drugs and these should therefore be avoided if this diagnosis is definitely made. Phenothiazines should not be prescribed for vague complaints of dizziness, because of the risk of drug induced parkinsonism. Benign positional vertigo can be treated by a physiotherapist with the Epley manoeuvre or Cooksey1
184
Case 7.2
0 Figs 7.8-7.9
0 Fig. 7.7
do not have petit mal). There is a steep rise in the incidence of fits in old age and the commonest cause is cerebrovascular disease. She has described urge incontinence and frequency, and the likeliest explanation for this is detrusor instability. Examination of the patient The patient scored 24/30 on the minimental state examination, confirming mild cognitive impairment. She was unable to stand unsupported with her feet together, even with her eyes open. When asked to walk there was start hesitation before she got into her stride. She walked with a broadbased, short-paced gait. Her posture was upright and she swung both arms normally. There was no tremor and tone in her arms was normal. In her legs tone was increased and there was also bradykinesia, shown by marked slowness and frequent hesitations when asked to rapidly tap her heel on the ground. Reflexes were brisk in her legs, but plantars were flexor. The rest of the examination, including PV and PR, was normal. Is this idiopathic Parkinson's disease? Probably not. Despite having three of the four cardinal signs (rigidity, bradykinesia and gait disturbance) the signs are all confined to the legs and this strongly suggests arteriosclerotic parkinsonism
Cawthorne exercises. The Epley manoeuvre is based on the premise that debris moving in the endolymph of the posterior semicircular canal stimulates the hair cells and causes vertigo. The manoeuvre aims to direct the debris out of the canal into the utricle. About 80% of patients experience immediate relief of vertigo and nystagmus after a single session. Cooksey-Cawthorne exercises are suitable for any patient with chronic dizziness. They are performed twice a day and help the patient to develop tolerance to the vertigo and increase confidence. The patient's chair should be at the right height (the seat level with the top of the knee) so that getting out of it is not difficult. A walking frame may initially help both mobility and confidence, but should be removed once the
7
CASE STUDY 7.1 CONTINUED (sometimes known as lower-half parkinsonism). Further support for this diagnosis and against idiopathic Parkinson's disease is the symmetry of the findings, the initial presentation with a gait abnormality, normal arm swing and upright posture, the early appearance of cognitive impairment and the absence of tremor. Management Patients with arteriosclerotic parkinsonism (unlike idiopathic Parkinson's disease) only rarely improve with levodopa. Treatment was started with co-careldopa 12.5/50 one tablet b.d., and gradually increased until she was taking the equivalent of 400 mg levodopa a day. The drug made her feel sick and
shaky and there was no improvement in her walking, and so it was stopped. Gait, mobility and confidence improved with physiotherapy. After an MSU was checked to exclude a urinary tract infection she was started on bladder retraining; after 6 weeks she was no longer incontinent and was managing to hold for 2-3 hours between voids during the day. A CT brain scan confirmed small vessel disease. (Case Fig. 7.1.1) She was checked for vascular risk factors and started on 75 mg aspirin daily. Although hypertension is associated with small vessel disease there is no evidence that lowering blood pressure or taking aspirin slows the rate of progression of the disease.
patient's walking is better. Balance and muscle strengthening exercises and measures to improve confidence and wellbeing are of proven benefit. If the falls have been such as to warrant hospital admission, then follow-up for a few weeks in a day hospital is helpful. In case of another fall, the patient should be taught how to get up off the floor 3 and advised of the various alarm systems that can be installed in the home. An occupational therapist should also visit the home and correct obvious environmental hazards and teach the patient safe transfers. Preventing fractures is important. Patients should be assessed for osteoporosis and treated accordingly (see p. 175). FURTHER READING ON BALANCE AND FALLS AGS/BGS/AAOS Panel on Falls Prevention 2001 Guidelines for the prevention of falls in older patients. J Am Geriatr Soc 49:664-672. Campbell A J, Robertson M C, Gardner M M 1999 Falls prevention over 2 years: a randomised controlled trial in women 80 years and older. Age Ageing 28:513-518. Close J, Ellis M, Hooper R et al 1999 Prevention of falls in the elderly trial (PROFET): a randomised controlled trial. Lancet 353:93-97. Davies A J, Kenny R A 1999 Syncope in older patients. Rev Clin Gerontol 9:117-126. Lempert T, Gresty M A, Bronstein A M 1995 Benign positional vertigo: recognition and treatment. BMJ 311:489-491. Maki B E, Mcllroy W E 1996 Postural control in the older adult. Clin Geriatr Med 12:635-658. Nutt J G, Marden C D, Thompson P D 1993 Human walking and higher level gait disorders, particularly in the elderly. Neurology 43:268-279.
CASE FIG. 7.1.1 CT of the head showing leukaraiosis. This is a radiological diagnosis indicating periventricular white matter hypodensity. It is commonly caused by small vessel disease and is associated with gait disturbance, falls and dementia it may also be seen in normal elderly people.
Province M, Hadley E, Hornbrook M et al 1995 For the FICSIT Group. The effects of exercise on falls in elderly patients. A preplanned meta analysis of the FICSIT trials. J Am Med Assoc 273:1341-1347
URINARY INCONTINENCE Although this is more common in the elderly, the causes and management are similar to those in the young (see Ch. 20). The major difference is that elderly patients are more likely to suffer in silence or even to deny the problem. Doctors must be proactive and should routinely ask at-risk patients whether they have 'any bladder problems'. After a pertinent general assessment (diuretics, mental state, mobility, etc.), examination to exclude prolapse, pelvic mass and prostatic carcinoma and urine tests for infection, blood, glucose and protein, the patient is referred to the continence nurse specialist for initial management. Age has little effect on prognosis and the majority of patients can expect to become dry following treatment.
DETRUSOR INSTABILITY The majority of patients are incontinent because of idiopathic detrusor instability. The cortical centre for this willed control over the hindbrain-sacral reflex lies in the frontal premotor area. In old age these tracts are vulnerable to cerebrovascular disease and Alzheimer's disease. An early sign of detrusor instability in old age is nocturia,
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TABLE 7,7 Principles of bladder retraining 1. 2. 3. 4. 5. 6.
Explanation of condition Establish baseline micturition pattern using chart Select appropriate time for patient to wait between urinations, e.g. 1-2 hours Provide patient with a suitable pad to wear in case of incontinence Gradually extend interval as patient improves Concomitant relaxation therapy for stressed or anxious patients
which may progress to overactive symptoms of urgency, urge incontinence and daytime frequency. Stress incontinence is usually due to urethral sphincter weakness, but similar stress leakage may be seen in patients with detrusor instability and is due to cough or sneeze raising intraabdominal pressure and triggering an unstable contraction. A cystometrogram is needed to distinguish between the two causes, and patients with genuine stress incontinence can expect good results from pelvic floor exercises and surgery. Whether the detrusor instability is idiopathic or due to cortical damage (e.g. from a stroke), the response to bladder retraining is good provided that the patient can comprehend the instructions and is well motivated. About 80% of patients will be dry after 6 weeks' treatment. Bladder retraining (see Table 7.7) depends on asking the patient to urinate only after a certain fixed time, the underlying assumption being that 'holding' in this way strengthens cortical inhibition over the sacral reflex. If patients are struggling with retraining they may benefit from the addition of tolterodine m/r 2mg o.d. or oxybutyrin m/r 5-30 mg o.d. The modified release formulation is less likely to cause dryness of the mouth. If despite these measures patients continue to wet the bed or have very troublesome nocturnal polyuria, they can be helped by desmopressin tablets 0.1-0.2 mg at bedtime. This reduces urinary output in patients with a high nocturnal diuresis (>0.9mL/min) and is ideal for occasional use, such as a stay in a hotel. Up to 3 weeks treatment is safe; over longer periods blood pressure and serum sodium must be monitored. 12
VOIDING DIFFICULTIES These increase with age and also occur in women. Typical symptoms, such as hesitancy, poor stream, straining to void and a feeling of incomplete bladder emptying, do not reliably distinguish bladder outlet obstruction from detrusor hypocontractility, which may be idiopathic or sec-
1
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Case 7.3
2
ondary to, say, a cauda equina or peripheral nerve lesion. Neurological and rectal examination and pressure-flow studies are required for an accurate diagnosis. Hypocontractility causing a large residual urine volume carries the risk of recurrent urinary tract infections, and is managed initially by advising the patient how to empty the bladder completely and, if necessary, with prophylactic antibiotics. Long-term management is with intermittent self-catheterization. Patients with benign prostatic obstruction have a choice of treatments: watchful waiting if symptoms are causing little trouble, drugs if symptoms are troublesome and surgery is declined (a-blocker or a 5-a-reductase inhibitor), TURP, or alternatives such as laser prostatectomy or thermotherapy.
POSTOPERATIVE URINARY RETENTION This may happen to any elderly man following surgery. It is commonly assumed to be due to prostatic outflow obstruction, but is much more likely to result from a combination of postoperative pain, preoperative opiates, anticholinergic anaesthetic agents, a bladder overdistended with intravenous fluids, and lying immobilized in bed. If the patient does not respond to an oc-blocker, such as alfuzosin 2.5mg b.d. (beware hypotension and give the first dose at bedtime), then the bladder should be emptied with intermittent catheterization until normal detrusor activity returns.
CATHETERS A permanent indwelling catheter is the last resort for urinary incontinence, but is not necessarily a bad solution. Some patients are very relieved to be clean, dry and comfortable for the first time in years. The gauge should be 14 or 16 Ch and the retaining balloon should contain no more than 5 mL of water to reduce the risk of provoking unstable contractions, which will cause urine to leak out around the catheter. If leakage persists tolterodine or oxybutyrin b.d. should be tried; if this is unsuccessful the best solution is to change to a suprapubic catheter. Catheters always become infected within 2 weeks of insertion. This is rarely a problem if drainage is satisfactory and fluid intake is l-1.5L/day. Catheter specimens of urine should only be sent for culture if there is an unexplained deterioration in the patient's condition or symptoms of system infection. Bladder washouts and prophylactic antibiotics are ineffective (see Table 7.8).
FURTHER READING ON URINARY INCONTINENCE Fig. 7.10
Incontinence. Causes, management and provision of services. London: Royal College of Physicians, 1995.
TABLE 7.8 Good practice guidelines: Urinary incontinence
FAECAL LOADING
Summary of recommendations from Good Practice in Continence Services (Dept. of Health 2000) and US Department of Health and Human Services: Clinical Practice Guidelines: Urinary Incontinence in Adults (1996). The strength of evidence supporting each recommendation is based on the following criteria: A Scientific evidence from properly designed and implemented controlled trials providing statistical results that consistently support the guideline statement; B Supported by scientific evidence from properly designed and implemented clinical series; C Supported by expert opinion.
This is the commonest cause of faecal soiling. Rectal sensation is impaired, probably aggravated by chronic rectal distension, and the patient often leaks before experiencing a call to stool. Problems result not only from a large hard stool in the rectum, but also from a mass of soft stool, which is not readily recognized. The rectum and lower colon should be cleared either with repeated enemas, which are uncomfortable and time-consuming, or a kinder alternative such as oral polyethylene glycol (Movicol). To clear faecal impaction, eight sachets in a litre of water are taken over at least 6 hours on 3 consecutive days. Bran must be used with caution, as it may make the stool consistency too soft and can actually cause faecal incontinence.
In primary and secondary care • All patients require initial assessment, to include a review of symptoms, examination of abdomen and perineum (including pelvic floor contraction) to identify prolapse and excoriation, and rectal examination to exclude faecal impaction and urinalysis (grade B). • Detrusor instability should be treated with bladder training (grade A).and, if necessary, anticholinergic drugs (grade A). Symptoms of stress incontinence are reduced by pelvic floor muscle exercises (grade A). • There is no evidence that oestrogen supplementation improves incontinence in postmenopausal women (grade B). • Colposuspension and sling procedure are more effective than anterior colporrhaphy or needle suspension (grade B). • Appropriate continence aids such as pads need to be provided (grade C). • Existing medications (e.g. diuretics) need to be reviewed (grade C). • Refer immediately to a urologist patients with acute retention of urine, renal impairment, carcinoma of the prostate, haematuria or recurrent infection (grade C). • Refer immediately to a gynaecologist patients with a pelvic mass, vaginal bleeding or a history of previous gynaecological surgery (grade C). • If, after initial assessment and 6 weeks of bladder retraining or pelvic floor exercises patients are not improving, they should be referred for specialist review (grade C).
SLEEP AND INSOMNIA Insomnia is a common complaint in the elderly and there is great pressure on doctors to prescribe hypnotics. The elderly receive more hypnotics than any other age group. It is often assumed that hypnotics are both harmless and effective, but for the elderly neither assumption is true. Elderly patients taking hypnotics regularly rate the quality of their sleep as worse than those not on hypnotics, and more than one in 10 persons aged 70 or over taking nitrazepam (10 mg) at night have troublesome daytime sedation, with confusion unsteadiness and an increased risk of falling. Any patient complaining of insomnia - but particularly an elderly one - needs careful assessment and not just a prescription for a hypnotic.
TABLE 7.9 Causes of faecal incontinence
NORMAL SLEEP
• Secondary to colorectal disease, e.g. infective diarrhoea, carcinoma of the rectum • Idiopathic weakness of the anal sphincter and pelvic floor muscles • Faecal loading • Neurological causes, e.g. dementia, impaired consciousness and rectal instability
A person falling asleep 'descends' rapidly through progressively deeper stages of sleep. Slow-wave sleep - which occupies about 20% of the night in the young - is reduced to only 5% by 70 years of age, and stage four is almost completely absent (Fig. 7.11). The elderly wake more frequently and take longer to fall asleep, so that even for the normal old person sleep becomes increasingly fragmented. Rapid sleep onset is promoted by dilatation of the blood vessels of the hands and feet, which increases distal heat loss. A hot water bottle at the feet rapidly induces vasodilatation and the resulting heat loss is most effective when the ambient temperature is cool. Difficulty falling asleep in old age may reflect an inability to vasodilate owing to impaired autonomic responses. Thus, the doctor needs to decide whether an elderly patient's complaint of insomnia is an unrealistic expectation of what constitutes a good night's sleep. Less physical activity and daytime naps will further reduce the ability to sleep well at night.
FAECAL INCONTINENCE Faecal incontinence is distressing for both patient and carer and is a major reason for care breaking down in the home. The prevalence in the community is less than 1%, rising to 10% in residential homes and 25-30% in nursing homes or on long-stay wards. The causes are given in Table 7.9.
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TABLE 7.10 Advice to patients with insomnia • • • • • •
Avoid daytime naps. Avoid caffeine or alcohol at bedtime (a hot milky drink is better). Ensure that the bed is warm and comfortable. Only go to bed when tired. Do not read or watch television in bed. If not asleep in 20 minutes get out of bed and sit in another room until feeling tired again. • Get up at the same time every morning.
A similar effect can be seen after hypnotics are withdrawn, when the patient complains of anxiety, tension and insomnia. If these withdrawal effects are not understood by the doctor and patient then a hypnotic may be needlessly represcribed.
CHOOSING A HYPNOTIC
FIG. 7.11 Typical hypnograms for young adults and elderly people The elderly wake more frequently and have less deep sleep.
SUMMARY 4 Causes of insomnia • • • • • •
Age-related changes in sleep pattern Nocturia (probably due to detrusor instability) Pain Anxiety and depression Drug induced, e.g. alcohol, withdrawal from hypnotics Specific problems, e.g. sleep apnoea, myoclonus
CAUSES OF INSOMNIA
188
Insomnia may be age related, as discussed above. Nocturia is another common reason for an old person waking up; the condition may be caused by heart failure, renal failure or diabetes, but is most likely due to detrusor instability (especially if associated with some urgency). Pain is also an important cause of insomnia, and the akinetic parkinsonian patient who cannot turn over in bed will find that sleep is disturbed. Anxiety and depression commonly cause sleep disturbances, and are best managed by psychiatric treatment directed at the primary condition. Insomnia may be drug induced. The most familiar example is alcohol which, if taken in the evening, will quickly induce sleep but because of its rapid metabolism results in rebound insomnia with awakening later the same night.
Hypnotics should only be used when insomnia is impairing the patient's daytime performance, and after advice on non-pharmacological measures (see Table 7.10). There should be a clear indication, such as a recent bereavement or impending major surgery, and the prescription should be limited to 7 or 10 days wherever possible. The drug should have a rapid onset of action, particularly if the patient's main complaint is difficulty in falling asleep. There should be no daytime sedation, although this may occur because of the accumulation of long-acting hypnotics and their active metabolites, or because of an age-related alteration in sensitivity to the drug.
Benzodiazepines Diazepam has a half-life in hours approximately equivalent to the person's age, but the constant clearance rate means that its average steady-state plasma level is unaffected by ageing. However, the half-life of its major active metabolite, desmethyldiazepam, is prolonged as a result of reduced plasma clearance. The dose necessary to produce sedation is therefore inversely correlated with age, owing partly to an increased sensitivity to the drug in old age and also to accumulation of the active metabolite. Diazepam (2 mg or 5 mg) may be a suitable hypnotic for anxious old people where a daytime anxiolytic effect is required. Daytime drowsiness, confusion and falls, however, may be a problem. Nitrazepam also produces more sedation in the elderly, probably as a result of increased receptor sensitivity (as the pharmacokinetics remain unaltered). The unwanted daytime sedation is largely dose dependent (Fig. 7.12); 2.5 mg is the maximum dose that should be given to an old person.
Morgan K 2001 Mental health factors in late life insomnia. Rev Clin Gerontol 11:71-81.
7
SEXUAL FUNCTION
FIG. 7.12 Relationship of daily dose (5.0-9.9mg/day and 10.0 or more mg/day) to the frequency of unwanted daytime CNS depression attributed to nitrazepam, with the population stratified according to age
Temazepam has a half-life of only 5-10 hours in young people but may be as long as 30 hours in the elderly. Accumulation therefore occurs and, after a week of continuous dosing at 20mg each night subjects show a significant slowing of reaction times. The effect is likely to be dose related; 10 mg at night rarely causes serious problems. Lormetazepam has a good pharmacokinetic profile for use in the elderly. Although the elimination half-life is prolonged to about 14 hours in elderly subjects, accumulation does not occur and there is no impairment of daytime performance with a nightly dose of either 0.5 mg or 1.0 mg.
Other hypnotics Zopiclone, a cyclopyrrolone, has a half-life of about 8 hours in the elderly; it does not accumulate over 7 days' treatment and psychomotor performance is unimpaired. Treatment should start with 3.75mg. Clomethiazole (chlormethiazole) is valuable in the elderly. Its pharmaco-kinetics are unaltered by age and its short plasma half-life of 3-4 hours prevents accumulation. It is metabolized by the liver, and should be used with caution in patients with cirrhosis of the liver or in alcoholics. One capsule (192mg of chlormethiazole base) may be sufficient but two capsules is still safe. Restless and confused patients are often best sedated with haloperidol (0.5-3mg nocte). Long-term use carries a risk of extrapyramidal side-effects and should be avoided in parkinsonian patients.
In western society sexuality among adolescents and young adults is openly studied and discussed. No such liberal attitude exists towards sex in old age and, unfortunately, the stereotype of the sexless old persists. Although sexual activity does decline with advancing age, much of this is due to ill health or the death of the marriage partner. Old age itself causes very little impairment of sexual enjoyment: 81% of married men and women aged 70-79 are sexually active and find it enjoyable. Overall, it would appear that continued sexual activity in old age depends on the frequency and enjoyment it afforded in middle age, the availability of a suitable partner and (particularly in men) continuing good health. The main physical changes in women result from a lack of oestrogen, which may cause vaginal and clitoral soreness, with reduced lubrication and painful intercourse. Length of orgasm may be reduced but many postmenopausal women report increased desire and arousability. Male fertility is usually maintained into extreme old age, although the volume of prostatic secretions reduces, it takes longer to achieve an erection, orgasm is briefer and the following refractory period is longer. Many doctors are reluctant to discuss sexual practice with their elderly patients and thereby lose the opportunity for helpful counselling. Vaginitis due to oestrogen deficiency responds to topical oestrogen cream and lack of lubrication is helped by over-the-counter products such as K-Y jelly or Senselle. Complaints of impotence in the male should prompt a thorough physical examination, including a blood sugar estimation. Sildenafil is generally safe and effective, but is contraindicated in patients taking nitrates. Many drugs interfere with sexual function and the elderly should be warned about this when they are prescribed. Propranolol and thiazide diuretics may produce impotence. All of the phenothiazines may cause impotence; thioridazine may also cause lack of ejaculation. Haloperidol is free of these problems. Sexuality - or the lack of it - in old age should not be seen in isolation. The need for affection, tenderness and caressing may be more important than intercourse, and counselling as to what is normal and appropriate may dispel fears of inadequacy or embarrassment.
ALTERED REACTIONS TO DISEASE FURTHER READING ON SLEEP AND INSOMNIA Espie C A 1993 Practical management of insomnia: behavioural and cognitive techniques. Br Med J 306:509-511.
In the elderly acute illness frequently presents in a non-specific way, such as with confusion, falls and incontinence.
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TABLE 7.11 Differential diagnosis of confusion and dementia Differential diagnosis Acute confusional state
Dementia
Onset Clouding of consciousness
Abrupt Yes
Course
Fluctuates, lucid intervals during day. Worse at night Yes (may be intermittent)
Gradual, months or years No (but there may be drowsiness due to sedation) Stable over course of day
Disorientation and cognitive impairment Alertness Hallucinations Duration
Increased or impaired Yes (common) Hours or days
After treatment of any underlying cause, management of the confused patient relies mainly on the correct environment, and sedation should be kept to a minimum. The patient is best looked after in a side-ward so as to avoid disturbing other patients. A relative or nurse should stay with the patient at all times to reassure, comfort and explain what is happening. The light should be kept on in the room at night. Sedation is best avoided but may be needed if the patient is very restless, e.g. haloperidol 1-3 mg q.d.s. by mouth, or 2.5-5mg i.m. (NB the oral and i.m. doses are not equivalent).
Yes
Usually normal Yes (uncommon) Steadily progressive
N.B, None of the clinical features of the acute confusional state is reliable and a confident diagnosis depends on the history.
CONFUSIONAL STATES A toxic confusional state is the ageing brain's response to a number of insults: the stress of a physical illness, a variety of powerful drugs, and alterations in the old person's familiar environment. It tends to occur more commonly in those whose mental state is already impaired, for example by Alzheimer's disease, or who have communication difficulties because of defective hearing and vision. Typically, the onset is abrupt over hours or days. This and the clouding of consciousness are the main points of differentiation from dementia (see Table 7.11). Typically, the acutely confused patient is drowsy; it is difficult to get their attention and there are fluctuations in the level of consciousness. The patient's agitation and confusion are usually worse at night. About 15% of elderly patients admitted to acute medical wards are delirious. One-third die within a month; of the survivors, 80% will have recovered mentally within a month.
Investigations
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Management
Proper assessment and diagnosis are essential, and require a careful history from a reliable witness. Physical illness, coexisting dementia, recent emotional stress, alcohol abuse, drugs (especially benzodiazepines, antidepressants, antiparkinsonian drugs, analgesics, NSAIDs and steroids), or head injury are important precipitating factors. In hospital, surgery is an important cause of confusional states. Physical examination should concentrate on identifying possible causes. The commonest are cardiac failure, Gram-negative septicaemia and pneumonia.
ABSENCE OF PAIN For reasons not clearly understood, pain due to illness or trauma, which would be expected in a younger individual, is often minimal or absent in the elderly. Thus, myocardial infarction is commonly pain free and the patient presents instead with dyspnoea or non-specific illness. Similarly, abdominal pathology such as gastric ulcers or mesenteric thrombosis may be silent; however, acute appendicitis often has a fulminating course in older patients, with the rapid development of gangrene and peritonitis. Even a fracture of the neck of femur may cause the patient only slight discomfort, evidenced by a disinclination to walk.
MULTIPLE PATHOLOGICAL PROCESSES The explanation of all symptoms, signs and abnormal investigations by one diagnosis is seldom possible in older patients, the usual pattern being one of multiple disorders. Thus, a momentary cardiac arrhythmia which may produce only a slight feeling of dizziness or palpitations in a young person may cause loss of consciousness or even a stroke with hemiplegia in an old patient. Similarly, a chest infection may precipitate heart failure because the cardiac reserve is already impaired by ischaemic heart disease. Common conditions such as obesity, osteoarthritis, diverticular disease, hypertension, diabetes, dementia and presbyacusis may all be present in a single individual, and the aim then is to decide which are causing important functional disability.
UNREPORTED ILLNESS The early identification of disease or disordered function allows treatment to be initiated or social support organized before things have gone too far. Studies in general practice show that an elderly person has, on average, at least three disabilities, and for every one known to the GP there is another that is not. Typically, cardiac, chest and neurological disabilities are known to the GP, but incontinence,
difficulty in walking, painful feet, dementia and depression often go unreported.
FURTHER READING ON ALTERED REACTION TO DISEASE Treloar A 1998 Delirium: prevalence, prognosis and management. Rev Clin Gerontol 8:241-249.
CLINICAL APPROACH When assessing an elderly patient it is generally more useful to think in terms of functional ability than to emphasize the underlying pathology. For example, the distinction between rheumatoid and osteoarthritis in a patient with arthritis of the knees may be largely academic: the fact that the patient has poor mobility is much more important. Emphasis is placed on physiotherapy, walking exercises and possibly surgery to improve mobility and independence.
HISTORY A full history remains the primary investigation. In a confused patient it is necessary to obtain additional information from a relative, community nurse, or someone who knows the patient well. The tempo with which the symptoms have developed is particularly important. Forget fulness gradually increasing over 2 or 3 years suggests Alzheimer's disease (AD), whereas a sudden onset of confusion over a day or two indicates a toxic confusional state and requires a search for underlying physical problems, such as an infection or myocardial infarct. A sudden onset of headaches or a recent change in bowel habit is never normal in old age, whereas gradually failing hearing and vision may be. The history must include a full list of the patient's medications, including details of dose and frequency; details of their functional ability (shopping, cooking, cleaning and personal toilet); and social circumstances. The main carer at home should be identified, as well as additional support that might be provided by family, neighbours and social services.
ASSESSMENT The chances of successfully discharging an elderly, frail person, if his or her homelessness, anxiety and impaired psychological state are ignored, are remote. Seeing the patient as a whole is thus not only good for the patient, it
is essential if limited health service resources are to be used effectively. Recent legislation and guidance place a responsibility on local authorities, health authorities and health providers to work together to assess, plan and meet the needs of people leaving hospital. An overall view of the patient includes assessment of medical, functional, social and psychological status, and usually brings together the professional views from several disciplines. The doctor attends to the physical and mental diagnosis and appropriate treatments. The nurse notes to what extent the patient can wash and feed him or herself or use the lavatory, and also particular problems such as incontinence, pressure sores or nocturnal confusion. The physiotherapist is concerned with whether the patient can get in and out of bed, rise from a chair, balance and walk; and as the patient improves, the occupational therapist assesses how well they can dress, bathe, cook and care for themselves. Discharge planning begins as soon as possible after admission. The social worker or discharge liaison nurse enquires into the patient's social background to find out what circumstances are like at home - whether they are already receiving support from relatives, neighbours, community nurse or social services, and whether this support will be continued or need to be increased once the patient returns home. Whether the patient's needs are simple or complex the social worker, together with the rest of the multidisciplinary team, draws up a care plan before discharge and later reviews this plan as an essential part of the care management process. The aim is to ensure that patients are speedily and effectively treated and returned to their own home in a planned and thoughtful manner, so that the gains resulting from treatment are likely to be maintained. A similar process of assessment can be initiated by family doctors using community staff, for patients living at home.
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PHYSICAL EXAMINATION An extensive and detailed examination of every system can exhaust a frail patient. However, with practice, the
SUMMARY 5 Assessment of an elderly patient • Main stress is on functional disability, rather than underlying pathology. • Overall view essential: Medical status - manner of onset of symptoms is important. Full drug history required. Functional ability - washing, cooking, shopping etc. Psychological status - depression, anxiety, confusion etc. Social circumstances - support available at home from family and friends. • Involves a multidisciplinary team of doctors, nurses, occupational and physiotherapists and social workers.
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examination can be thorough, informative and quick if the doctor concentrates on identifying disabilities and assessing loss of function.
General appearance The examination should begin with an observation of the patient's general appearance and clothes, noting any signs of self-neglect. Facial pallor is frequently present and so is a poor indicator of anaemia. Pupil size is often small, with reduced response, and upward gaze is often limited. Angular stomatitis - if not due to ill-fitting dentures - suggests multivitamin deficiency or iron deficiency anaemia, but a black hairy tongue or sublingual varicosities are of no significance.
Skin changes Loose, dry, scaly skin is a common finding, as is senile purpura owing to increased capillary fragility on the dorsum of the hands and extensor surface of the arms. Sunexposed skin should be searched for basal cell carcinomas or actinic keratoses, which are potentially malignant. The incidence of both conditions increases with years of exposure to the sun, and both are common in the elderly. Intertrigo - sore, inflamed patches of skin under the breasts or in the abdominal folds of obese patients - is often the result of poor personal hygiene. A keratinized transverse crease across the abdomen is the consequence of long-standing kyphosis, following osteoporotic spinal wedging. The breasts should be examined for lumps.
of unwanted drug effects (see p. 199). Systolic murmurs usually of the ejection type and present at the left sternal edge and aortic area - are found in up to 60% of the elderly. They are commonly associated with significant disease such as cardiac failure, ischaemic heart disease, arrhythmias and hypertension, and should not therefore be regarded as always benign.
Feet
Bowels and bladder
The ankles and feet should be inspected for signs of peripheral vascular disease (especially in diabetics), oedema and the need for chiropody. 1
A rectal examination is essential: carcinoma of the rectum or prostate is common in the elderly, and there may be loading of the rectum with faeces - a common cause of faecal incontinence. The presence of urinary incontinence should be noted and, particularly in bedridden patients, the pressure areas inspected for sores.
Cardiovascular Abnormalities of cardiac rhythm are frequently present: occasional ectopic beats occur in about one-sixth of elderly persons, but any other arrhythmia should be regarded as abnormal and investigated by electrocardiography. Systolic and diastolic blood pressure increases with age, although there is little change over the age of 65; values up to 160/90 can be regarded as normal. Overviews confirm that treating systolic or diastolic levels above this reduces total mortality as well as coronary and stroke mortality and morbidity in persons up to the age of 85 years (Fig. 7.13), but the value of treatment needs to be set against the risk
FIG. 7.13 Distribution by age of deaths from stroke in England and Wales The single most important risk factor for stroke is hypertension. Lowering the diastolic pressure at any level by 7mmHg halves the relative risk of stroke.
Eyesight and hearing The patient should be asked whether their vision is satisfactory; if it is not, it should be tested with eye charts (Fig. 7.14). Hearing is probably adequate if the patient can hear a normal conversational voice. Examination of the eardrums for wax should be routine, particularly where a hearing aid is worn, as the earpiece may compress wax into a hard, impenetrable lump.
Neurological changes 1
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Fig. 7.11
Ankle jerks are absent in about 10% of elderly patients. Superficial abdominal reflexes are also often absent, but the presence of extensor-plantar responses is always pathological.
ing the benefits and risks of investigation and treatment. For example, a patient may be having repeated falls associated with loss of consciousness which do not bother them unduly but cause the relatives great stress and anxiety, because they dare not leave them alone in the house. Tilt table testing could be used to detect whether the falls are due to cardioinhibitory carotid sinus hypersensitivity. If they are, then a pacemaker can be safely inserted - even in the very elderly - with the potential for a considerable improvement in quality of life.
7
FIG. 7.14 Causes of visual impairment and blindness in the elderly
Vibration sense in the lower limbs is reduced, and may be absent at the ankles, in up to a half of patients over 75. However, joint position sense is usually normal. Appreciation of pain, temperature and light touch is very variable, but at least one of these sensations is impaired in about a quarter of the elderly. Both the glabellar tap, and primitive reflexes such as the pout reflex (tap the upper lip and the lips pout), grasp reflex and palmomental reflex (the palm is scratched and the chin wrinkles on the same side), can often be elicited in the elderly, particularly in those who have dementia.
Gait and balance Healthy old people show very little change in gait. There may be slight slowing, but a speed greater than 1m per second is still maintained. Nearly a fifth of the very elderly have a normal gait. A variety of pathologies, especially cerebrovascular disease, produce the senile (or cautious) gait typified by a normal to mildly widened base, shortened stride, slowing of walking and en bloc turns. There is mild disequilibrium in response to a light tap on the chest or a flick on the shoulders from behind, and difficulty in balancing on one foot (see section on falls).
WILL THE INVESTIGATION INFLUENCE MANAGEMENT? Before ordering an investigation it is necessary to consider whether the result is likely to usefully influence management. For example, a severely demented patient with an abdominal mass and positive faecal occult bloods could have the presumptive diagnosis of carcinoma of the colon confirmed by a barium enema. However, if surgery is not being considered (because of the patient's poor general condition and inability to cope with a colostomy), there is little point in the barium enema. On the other hand, if the same patient is found to be unable to walk following a fall, the hips should certainly be X-rayed. Repair of a fractured neck of femur will not only relieve the patient's pain: it is also much easier to nurse an ambulant patient than one who is bedridden.
WILL THE DIAGNOSIS AFFECT PROGNOSIS? It is important to consider whether the investigation will establish a diagnosis which significantly affects prognosis. A very frail patient with severe dyspepsia can be treated easily with an H2 antagonist. But if symptoms persist it may be important for the patient and relatives to know if the diagnosis is peptic ulceration or carcinoma of the stomach.
INVESTIGATION IN THE ELDERLY Potentially remediable conditions cannot be ignored simply because the patient is elderly, but it is not good medicine to order invasive, uncomfortable and possibly expensive tests when the potential benefit to the patient is minimal.
OVERALL STATE OF HEALTH Does the patient have the physical and mental capacity to benefit from a proposed treatment? If surgery is an option, would the patient be fit for operation? If the patient is debilitated and being looked after by family at home, then the views of these relatives must be included when assess-
ROUTINE SCREENING Most patients seen in clinic or admitted to hospital will have a full blood count, ESR (or viscosity), urea and electrolytes, glucose and TSH. Urine should be analysed for protein, glucose and blood. All of these tests can usefully detect treatable disease where the clinical diagnosis is unsuspected or doubtful. This is particularly true of thyroid disease, which is found on screening in about 4% of elderly inpatients in whom the classic symptoms and signs of hypoor hyperthyroidism may be absent. The interpretation of thyroid function tests can be difficult in the elderly because of the effects of severe systemic illness, which cause a reduction in circulating T3 often accompanied by a rise in reverse T3. As the illness becomes more severe T4 levels
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fall, partly due to interference with binding to plasma proteins. TSH immunoradiometric assays can accurately measure the subnormal range and are now widely used as the single first line test of thyroid function. Although TSH measurements are usually reliable, in very severe illness this may not be true with subnormal levels being seen during the acute stage and sometimes a rebound to slightly above the normal range during recovery. A number of drugs can interfere with thyroid function, both lithium and amiodarone commonly cause goitre and either hypothyroidism or hyperthyroidism. In the case of amiodarone the total and free T4 levels are raised and cannot be used to diagnose thyrotoxicosis. A routine chest X-ray is usually taken, as about 5% of patients over 65 admitted to hospital are found to have an unexpected lesion on chest X-ray (such as a tumour, cardiomegaly or TB). It is particularly valuable in patients presenting with falls, immobility, incontinence or deteriorating mental function; nearly a quarter of these have cardiopulmonary disease without classic features. An electrocardiogram is not routine, but is required for patients with cardiopulmonary disease, strokes (quite commonly associated with a myocardial infarct) and falls (which might be caused by a cardiac arrhythmia).
In addition to the routine blood tests, the patient should have the serum B12 level checked and a VDRL test to exclude syphilis. Although it cannot positively diagnose dementia or Alzheimer's disease, a CT scan is a valuable screening test as it can identify multiple infarctions, spaceoccupying lesions and hydrocephalus. However, only 2% of all demented patients could expect an improvement in their mental state from treatment following a CT scan. Thus, CT is only indicated in patients with mild to moderate dementia (i.e. a mini mental state examination score of 10-26/30) of less than 1 year who are fit enough for surgery if a remediable lesion is found. 1
INVESTIGATION OF DEMENTIA
INVESTIGATION OF GASTROINTESTINAL LESIONS
The main concern in the investigation of dementia is not to miss a cause for which there is specific treatment. Although rare among elderly patients referred to a geriatrician or general physician, such reversible dementias are
In the investigation of upper gastrointestinal lesions, both barium meal and endoscopy give accurate results. However, endoscopy has the advantage of providing a tissue diagnosis where a tumour is suspected, and tends to be
relatively common among referrals to specialist neurological centres. Conditions which may respond to treatment include: • • • • • • • •
depression and other psychiatric disorders normal pressure (communicating) hydrocephalus resectable tumours subdural haematoma toxic drug effects thyroid disease pernicious anaemia syphilis.
RECENT ADVANCES IN THE CARE OF THE ELDERLY 1. Comprehensive geriatric assessment with immediate and ongoing specialist multidisciplinary interventions improves functional status and reduces the length of the initial hospital stay and the likelihood of subsequent readmissions. It also reduces the rate of immediate nursing home admissions and delays permanent nursing home placement. 2. Older adults who adopt or maintain a lifestyle with increased moderate daily physical activity derive considerable health benefits. The range of activities of daily living is increased, walking speed and balance improve, and there is a reduced risk of morbidity, institutionalization and mortality. Even social and productive activities involving little or no physical exertion improve survival.
1
194
MCQ 7.4
2
Fig. 7.12
3. The benefit of thrombolysis following myocardial infarction increases with age and is most cost effective in patients 75 years and older. The development of left ventricular failure is a more important determinant of outlook than age. 4. A daily supplement of 200 mg of vitamin E improves T-cell-mediated immune response in healthy elderly people. Vitamin E may also delay the progress of Alzheimer's disease and reduce cardiovascular events. Randomized controlled trials on the use of vitamin E have given conflicting results and its use as a regular dietary supplement is not currently recommended. 5. Hypertension as a risk factor for coronary artery disease, stroke and heart failure has a greater impact on elderly than on middle-aged patients.
RECENT ADVANCES IN THE CARE OF THE ELDERLY (CONTINUED) Lowering blood pressure, particularly systolic pressure, has a marked effect on reducing the incidence of stroke. Isolated systolic pressure greater than 140 mmHg or a diastolic greater than 85 mmHg should be treated, in patients up to the age of 80. No trial has looked specifically at those aged 80 and over, although the Hypertension in the Very Elderly Trial is underway. A meta-analysis of other trials which included very elderly subjects suggests that antihypertensive treatment reduces stroke, cardiovascular events and heart failure, but does not reduce mortality or major coronary events. At present no firm clinical guidelines can be given, but patients over the age of 80 should stay on existing treatment. Treatment decisions in newly diagnosed patients should be based on biological rather than chronological age. Treatment should begin with a low-dose thiazide, calcium antagonist or ACE inhibitor. 6. Non-rheumatic atrial fibrillation is associated with a fivefold increase in the risk of stroke or transient ischaemic attacks. Its prevalence increases with age to 11% in those aged over 75. The absolute annual risk of stroke in patients with atrial fibrillation is about 5% and this is increased in the presence of other stroke risk factors (see below). For primary prevention warfarin prevents 31 strokes for every 1000 patients treated per year, but at a cost of three haemorrhages. In secondary prevention warfarin prevents 80 strokes for every 1000 patients treated per year but at a cost of 21 major haemorrhages. Aspirin is less effective than warfarin in the secondary prevention of strokes in patients with atrial fibrillation, and prevents 40 strokes per 1000 patients treated each year at a cost of seven haemorrhages. Patients with non-rheumatic atrial fibrillation should be considered for warfarin if they are aged 65-75 and have one stroke risk factor, and over the age of 75 if they have two risk factors. Patients with no risk factors should be given aspirin. Paroxysmal atrial fibrillation carries the same risk of stroke as continuous atrial fibrillation, and patients should be considered for warfarin if they have one or more risk factors present. For patients on warfarin the INR should be kept around 2.0 to minimize the risk of bleeding. Aspirin or
better tolerated by a frail elderly patient. It is the investigation of choice but may need to be preceded by a barium swallow (to check if a pharyngeal pouch is present) when investigating dysphagia. For lower bowel disorders the first steps are usually rectal examination, sigmoidoscopy, stool culture, examination of the stool for occult blood and, finally, barium enema and possibly colonoscopy. Colonoscopy is the investigation
7
warfarin is best begun within a few days of the stroke, provided that a CT scan has excluded haemorrhage. If the cerebral infarct is very large there is a risk of haemorrhagic transformation and warfarin should not be started for 14 days. Contraindications to warfarin include cerebral haemorrhage, active peptic ulceration, uncontrolled hypertension, falls, moderate to severe cerebral periventricular small vessel disease and concerns over compliance. It is particularly important for elderly patients taking these drugs to have annual review to reassess the risk-benefit ratio. Treatment with aspirin is simpler and safer than warfarin and should always be considered for patients in atrial fibrillation when warfarin is difficult to control or is contraindicated.
Stroke risk factors • Previous stroke, transient ischaemic attack, myocardial infarct or peripheral arterial thromboembolism • Hypertension • Ischaemic heart disease • Recent heart failure • Diabetes mellitus • Thyrotoxicosis • Echocardiographic abnormalities, e.g. impaired left ventricular function, enlarged left atrium, enlarged left ventricle, intracavity thrombus. 7. Advances in surgical techniques have meant that major cardiac and vascular surgery is now routinely carried out on elderly patients. Thrombolysis and angioplasty allow successful treatment of peripheral ischaemia, and carotid endarterectomy should now be considered for a patient of any age who has a stenosis of greater than 70% and is either having transient ischaemic attacks or has made a good recovery from a cerebral infarct. Patients over the age of 70 years undergoing aortic valve replacement have a survival rate of 95% at 1 year and 75% at 5 years, which is no different from age- and sex-matched controls from the general population. Even in octogenarians undergoing aortic valve replacement the 5-year survival is 65%. By comparison aortic balloon valvuloplasty results are poor. 0
of choice for colonic adenoma, carcinoma or angiodysplasia, as it is more sensitive than barium enema and often better tolerated. Treatment of non-metastatic colonic malignancies gives a good prognosis; vigorous investigation of fit and active elderly patients is therefore justified. In the frailer patient, however, more caution is necessary before ordering a barium enema. Both the preparation (laxatives and sodium citrate enema) and the barium
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enema itself are uncomfortable and difficult procedures for elderly patients to undergo. Ultrasound scans have the advantages of being non-invasive, quick and relatively cheap, and are particularly useful for investigating jaundice, abdominal masses, pancreatic tumours and possible liver metastasis. In some centres CT scanning of the colon is now established as an alternative to barium enema in frail patients. Investigation of faecal incontinence is described on page 187.
INVESTIGATION OF BACTERIURIA
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A routine midstream urine (MSU) test in elderly patients admitted to hospital will show significant bacteriuria (bacterial count of more than 100000 organisms per mL) in 20-30% of men and women. Provided the patient is asymptomatic this bacteriuria is best ignored, as it is not associated with excess morbidity or mortality. A better guide to infection is pyuria, and in the presence of lower urinary tract symptoms even a sterile pyuria may be relevant. This is most conveniently detected by the finding of leukocytes on urine dipstick (e.g. Multistix 8 SG), with an MSU being sent for culture and sensitivity if dipstick testing is positive. The cardinal feature of a urinary tract infection is dysuria, but there is increasing recognition that some patients with urinary incontinence have no dysuria yet have a low-grade infection indicated by pyuria, and when this is treated with antibiotics the symptoms improve. Similarly, some patients complain of suprapubic or perineal pain during bladder filling, which may not be attributed to infection if the MSU fails to show a significant bacteriuria (i.e. more than 105 organisms per mL). However, it is possible that this criterion is inappropriate in these patients and bacterial counts of 102 per mL may be relevant. Urine should also be cultured for Chlamydia trachomatis, Trichomonas vaginalis and yeast. In summary, patients with a significant pyuria (positive urine dipstick or more than 10 leukocytes per highpowered film) who have lower urinary tract symptoms should be given a course of an appropriate antibiotic, such as trimethoprim or nitrofurantoin. Some patients require several weeks' treatment before the urine is clear. Patients with recurrent urinary tract infections associated with lower urinary tract symptoms should be considered for continuous low-dose antibiotic prophylaxis. A number of different regimens have been used, but all appear equally effective. Patients with recurrent urinary tract infections should have their postmicturition residual urine checked. If this is increased it is usually the result of detrusor hypocontractility or bladder outflow obstruction, and patients need to be advised on the importance of emptying the bladder completely as a chronic residual urine increases the risk of further infection. Surgery or intermittent self-catheterization may be needed. A group of patients often difficult to manage are those with recurrent episodes of suprapubic or perineal pain
during bladder filling, which is relieved by emptying and associated with frequency and urgency, but no actual urinary incontinence. Repeat urine testing is always unremarkable and antibiotics do not relieve symptoms. These patients usually have idiopathic detrusor hypersensitivity and some improve with bladder retraining. Patients with severe pain or with red cells in their urine should undergo cystoscopy to exclude interstitial cystitis or bladder cancer.
FURTHER READING ON INVESTIGATIONS IN THE ELDERLY Kafetz K 1998 Blood tests in elderly people and their interpretation. Rev Clin Gerontol. 8:305-318.
ASSESSMENT OF FITNESS FOR OPERATION Advanced age is no longer a contraindication to surgery as over the last 40 years the surgical mortality rate for patients over 80 has fallen from 25% to about 5%. In those over 90 mortality is around 10%. This compares with less than 2% for younger patients. This increased risk is only justified if surgery offers a reasonable prospect for improving the quality of the patient's life, or preventing loss of function. Average life expectancy for a 70-year-old male is 11 years and for a female 14 years, and many patients feel that this potential outweighs high surgical risks. Surgery for the relief of severe pain or complete bowel obstruction would probably be indicated even in the most severely disabled patient. However, a patient would need to be relatively fit and active before removal of a non-obstructive malignant bowel tumour, repair of an aortic aneurysm or a coronary artery bypass would be considered. Ageism should not be allowed to cloud the issue and each patient requires careful individual assessment. This is especially true of cancer in old age, which is less extensively investigated and receives less treatment than in younger patients, a difference not wholly explained by appropriate adjustment for comorbidity or frailty. Patients should always have a specialist opinion, as chemotherapy and radiotherapy protocols can be modified in less fit patients. The 1999 report of the National Confidential Enquiry into Perioperative Deaths highlighted the need for senior surgeons, anaesthetists and physicians to be closely involved in the care of elderly patients who have poor physical status and a high operative risk. Patients needing an urgent operation should be given a high surgical priority. The increased surgical mortality in the elderly is due to several factors, which are shown in Table 7.12. The mortality risk must be weighed against the likely final outcome of surgery. Total hip replacement has trans-
TABLE 7.12 Selecting patients for surgery or intensive care Chronological age alone is a poor indicator of outcome: • Good results in the elderly reflect good selection criteria • Consider the patient's previous health, level of physical independence, exercise tolerance and mental state • Patients' and families' views must be considered; they may be much less enthusiastic than the doctor about major surgery Increased mortality is associated with: • The presence of unsuspected heart disease • Reduced pulmonary and cardiac reserve (making a postoperative chest infection or myocardial infarct more likely) • Greater susceptibility to anaesthetic drugs • Greater risk of developing pressure sores postoperatively
is practicable). Many patients will have a minor ECG abnormality which provides a useful baseline measurement for comparing postoperative changes. Preoperative ECG abnormalities do not reliably predict postoperative cardiovascular complications, which can be expected in about one-fifth of elderly patients and consist mainly of heart failure with some cases of myocardial infarction. Cardiovascular disease is the major cause of increased mortality following general surgery in the elderly. Impaired mental function and poor motivation are also barriers to postoperative rehabilitation. If concentration and short-term memory are poor the patient may be unable to grasp the physiotherapist's instructions; episodes of mental confusion and agitation may also occur.
7
FURTHER READING ON SURGERY formed the lives of many old people and is now a routine operation. However, if chronic lung disease or an old stroke has reduced the patient's exercise tolerance to a few yards, the operation is unlikely to be worthwhile unless for the relief of severe pain. Before surgery, heart failure and diabetes should be controlled, dehydration and electrolyte disturbance corrected, and severe anaemia remedied by blood transfusion. A routine preoperative ECG is worthwhile. Its major use is in detecting a recent myocardial infarct, which would mean postponement of surgery for 6 months (if this
Seymour D G 1999 The ageing surgical patient - an update. Rev Clin Gerontol 9:221-233.
PRESCRIBING FOR THE ELDERLY A general rule when prescribing drugs for the elderly is 'not too many and not too much'. Although the elderly make up only 18% of the total population, they receive almost half of all prescriptions issued.
CASE STUDY 7.2 SURGERY IN OLDER PATIENTS A 90-year-old woman was admitted to hospital for rehabilitation following an accidental fall at home. She had a past history of left ventricular failure due to ischaemic heart disease, which was well controlled with drugs. She also suffered chronic osteoarthritis of her hips and 2 years previously she underwent an elective total hip replacement on the left. She lived alone in a house with downstairs bed and toilet. She was fairly independent and mobile around the house with the help of a walking frame. She had home care visits five times a week. She was taking furosemide (frusemide) 40mg o.d., captopril 25 mg b.d., diclofenac 50mg t.d.s., aspirin 75 mg o.d. and co-codamol 2 tablets q.d.s. She weighed 47.6kg.
A few days after admission she had an episode of haematemesis and melaena. Although frail she was alert and haemodynamically stable. Pulse 90 per minute, BP 140/100. Abdominal examination was normal, haemoglobin 8.8g, serum albumin 27 g. The rest of her blood results, chest X-ray and ECG were normal.
Question
1. How would you manage this patient?
She needs a blood transfusion (2 units were given) and an urgent oesophagogastroduodenoscopy (OGD). This showed a duodenal ulcer with a deformed pylorus. CLO
test was negative. The aspirin and diclofenac were stopped and she was given omeprazole 20 mg daily. Over the next few days she made good progress and was eating and drinking well, but she then had a second episode of haematemesis and melaena. Haemoglobin was 10.4 g. The omeprazole was increased to 40 mg daily. Three days later the nurses reported faecal vomiting. The abdomen was distended and tender, but bowel sounds were normal and the rectum was empty. Plain abdominal X-rays showed only gaseous distension with no signs of obstruction. She was treated with intravenous fluids, given nil by mouth, and had a phosphate enema. The nausea and vomiting persisted intermittently for the next few days. 197
CASE STUDY 7.2 CONTINUED A barium enema showed only diverticular disease of the colon. She was referred to the surgeons, who recommended the continuation of conservative management as she was considered unfit for surgical intervention.
Question 2. Do you think that this was the right decision?
The view of the physicians at the time was that this patient should have had surgery. Prior to admission she had been in relatively good health. Her heart failure was well controlled and she had successfully undergone a total hip replacement. All of these factors would point to a relatively good prognosis. The 1999 report of the National Confidential Enquiry into Perioperative Deaths stressed the importance of a team of senior surgeons, anaesthetists and physicians being closely involved in the care of elderly patients who have poor physical status and high operative risk. Furthermore, the experience of the surgeon and anaesthetist need to be matched to the physical status of the elderly patients as well as to the technical demands of the procedure. Following the decision not to operate the patient continued to have
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nausea and vomiting and steadily deteriorated. Four weeks after the second episode of haematemesis her haemoglobin had dropped to 8.6g and her weight was now 38kg. She declined a repeat OGD and a barium meal showed complete pyloric obstruction. Again she was referred to the surgeons, who remained very reluctant to operate. The opinion of the anaesthetist was sought and he felt that surgery might be considered under epidural anaesthesia. Despite her general frailty the patient was fully alert, and after the available options and surgical risks were explained to her she opted for surgery. She was transferred to the intensive therapy unit where total parenteral nutrition was given for 3 days; by this stage her weight was 32 kg. She then underwent gastrojejunostomy under epidural anaesthesia, which was successful. She had an uneventful postoperative recovery. Three days later nasogastric tube feeding was started and 2 days after that she was swallowing liquids. After another 10 days she was able to start rehabilitation, and 2 months following surgery, by which time she weighed 38 kg, she successfully returned home. Discussion This patient had haematemesis and melaena as a result of peptic ulcer disease, presumably secondary to her intake of non-steroidal anti-
About 75% of those over the age of 65 and living at home are taking some kind of medication, with 15% receiving four drugs or more. However, multiple prescriptions increase the risk of drug interactions and adverse effects, and compliance is likely to be poor. Over 90% of people in residential and nursing homes receive prescribed medicines: many of these are unnecessary. Adverse reactions are two or three times more common in the elderly than in those under the age of 60. This is due primarily to slower rates of inactivation and excretion but also, with some drugs, to increased sensitivity
inflammatory drugs. She developed gastric outlet obstruction due to a deformed pylorus. Conservative management was initially adopted, but without success. Despite the high surgical risk this patient survived, but with hindsight it is apparent that the surgical risk would have been considerably less had the operation been carried out electively 2 or even 3 weeks previously. Emergency surgery for whatever reason in older people increases the surgical risk. Mortality in patients over the age of 70 undergoing emergency surgery is 20%, compared to 1.9% in patients undergoing elective operations. Postoperative complications and morbidity are also higher. Over the last few years surgery has become much safer owing to improvements in anaesthesia and surgical expertise. Age is generally a poor predictor of surgical morbidity or mortality, and certainly a much poorer predictor of outcome than severity of illness. Careful preoperative assessment of a patient's co-morbidities is more important than age in determining risk. This patient's major preoperative risk was associated with her poor nutritional status: weight loss of more than 20% or a serum albumin less than 35 g/L increases mortality. Giving preoperative total parenteral nutrition for severely malnourished patients probably reduces morbidity and mortality, although the evidence is inconclusive.
of the target organ. Thus, many drugs need to be given in lower dosage.
ALTERED PHARMACOKINETICS Drug absorption Changes in gastrointestinal function with increasing age include a rise in gastric pH, decreased gastric emptying time, decreased splanchnic blood flow, and loss of small
bowel mucosal surface area. Although these changes are theoretically rate-limiting for drug absorption, none appears to be important for passively absorbed drugs.
young patients. The drug plasma concentration may have to be measured.
Distribution
ALTERED PHARMACODYNAMICS
There are a number of theoretically important changes that affect drug distribution in the elderly: • A decrease in lean body mass and total body water reduces the distribution of water-soluble drugs. • Increase in body fat results in an increased volume of distribution of lipid-soluble drugs such as lidocaine (lignocaine), chlordiazepoxide and diazepam. • The small decrease in plasma albumin that occurs in the elderly will reduce drug binding and may thus result in an increased distribution of the drug. As it is the unbound fraction that is clinically active, there may be an increased pharmacological effect. This may be important in sick or malnourished patients, who have a greater reduction in plasma albumin concentration. • Conversely, if the drug binds predominantly to a1-acid glycoprotein (e.g. lidocaine (lignocaine) and disopyramide) then protein binding is likely to be normal, or even slightly increased, in the elderly.
Metabolism There is a reduced rate of hepatic metabolism with increasing age. This reduces presystemic metabolism and causes a marked increase in the bioavailability of drugs metabolized by the liver, such as propranolol, labetalol, lidocaine (lignocaine), clomethiazole (chlormethiazole) and verapamil. In the case of propranolol the age differences in plasma concentrations are large, with the mean concentration in the elderly being about twice that found in the young. However, because of reduced sensitivity, the dosage need not be lowered. Age-related effects on drug metabolism are variable, so that even some extensively metabolized drugs, e.g. warfarin or diazepam, may show no change in clearance.
Excretion Advancing age is accompanied by a reduction in both glomerular filtration rate and tubular function. At 60 years of age renal function is about half that at age 30, and will be further impaired by dehydration, cardiac failure and urinary retention, as well as by diseases such as diabetic nephropathy. Normal elderly people may have significant reductions in glomerular filtration rate and tubular function yet have a normal blood urea and serum creatinine. For drugs excreted by glomerular filtration the rate of excretion correlates with glomerular filtration rate. Some of these drugs, e.g. digoxin, gentamicin, lithium, cimetidine and chlorpropamide, have a low therapeutic index and their dosage therefore needs to be carefully chosen in the elderly. In general, a lower dose will be needed than in
7
The most clinically important result of altered pharmacodynamics occurs with drugs acting on the central nervous system. Sedatives and tranquillizers are more likely to produce drowsiness and hangover effects in the elderly. Although nitrazepam and diazepam have similar plasma concentrations in both young and old, psychological testing shows that the elderly make more mistakes and have longer reaction times for 36 hours after a single dose. They also show increased sensitivity to anaesthetic agents such as halothane. A reduced sensitivity to adrenergic agonists is seen in the elderly heart. Sensitivity to propranolol also decreases, so that despite the higher plasma propranolol concentrations seen in elderly subjects the degree of B-blockade is reduced. The dose of warfarin needed to produce anticoagulation in the elderly is reduced, but this is not due to an agerelated rise in plasma warfarin concentration. Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, and this inhibitory effect is greater in the elderly, resulting in an increased sensitivity.
ADVERSE REACTIONS Whenever a reduction in drug elimination or increase in receptor sensitivity occurs, there is the likelihood of an excessive drug effect and hence an adverse reaction. The risk of these adverse reactions increases with age (Fig. 7.15A). About 3% of all admissions to geriatric units in the UK are due solely to unwanted drug effects; in a further 8% of cases an adverse reaction is a contributory cause. Two-thirds of all reactions are caused by two groups of drugs: • Cardiovascular drugs: diuretics, digoxin and hypotensive drugs • Drugs acting on the central nervous system: antiparkinsonian drugs, antidepressants, hypnotics and tranquilizers. Although more than 70% of patients taking cardiovascular drugs make a full recovery from the adverse reaction, only 46% recover from the ill effects of antiparkinsonian drugs. The risk of an adverse reaction increases with the number of drugs taken (Fig. 7.15B). Elderly people are more likely to have multiple diseases than the young, and the likelihood of polypharmacy is therefore high. Not only is the patient apt to be muddled by a large number of drugs and inadvertently take the wrong dose, but drug
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FIG. 7.15 Adverse drug reactions A The increase in adverse drug reactions with age; B Prevalence of adverse reactions related to number of prescribed drugs. The risk in a patient taking only one drug is about 11%, but is 27% if six drugs are taken.
interactions lead directly to an increased adverse reaction rate. This is particularly likely to occur when drugs with a low therapeutic index, e.g. anticoagulants, antidepressants, anticonvulsants and antihypertensives, are used in combination. There are a number of important causes of adverse drug reaction in the elderly other than altered pharmacokinetics and pharmacodynamics. Inadequate clinical assessment is perhaps the most common. Dependent leg oedema, for example, is more often due to immobility than to congestive cardiac failure, and a diuretic is thus not an appropriate treatment. Similarly, old people who complain of dizziness are often expressing a sensation of unsteadiness and fear of falling, rather than true vertigo. Prochlorperazine - an effective vestibular sedative - is frequently prescribed in this situation but is quite useless and also carries a serious risk of parkinsonian side-effects. Loneliness and social problems often present as minor aches and pains, unhappiness and insomnia. Although both difficult and time-consuming, it is far better to deal with the underlying problems than simply to issue a number of drug prescriptions.
COMPLIANCE There is no evidence that the elderly are less compliant than the young, but they do make more medication errors. These occur in up to three-quarters of old people taking
1
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MCQ 7.5
2
Fig. 7.13
drugs, but only about a quarter are potentially serious, usually because of underdosage. Medication errors are more commonly made by patients over the age of 75 who are living alone and are confused. Poor visual acuity often prevents an old person from reading the instructions correctly, and impaired manual dexterity may make it difficult or even impossible to unscrew the cap on the bottle (particularly if it is one of the child-resistant types). Compliance can be improved, and errors in medication reduced, by careful counselling and an explanation of when and how to take the drug. After a single lesson in inhaler technique up to 30% of elderly patients are still unable to use a metered dose inhaler. Further instruction may be needed, or patients can be given a breath-activated device or a large-volume spacer, which they find easier to use and thus prefer. Written instructions or a calendar pack can be helpful. Dosette boxes (devices which organize a week's supply of tablets) can be useful for patients who are motivated to take their drugs but are absentminded. They can be prepared by the pharmacy or by a carer. 1
CHOLESTEROL LOWERING IN STROKE Total and low-density lipoprotein (LDL) peak at around age 65 in males and 75 in females, and thereafter decline. There is probably also a decline in high-density lipoprotein (HDL) after age 65. Thus cholesterol levels measured in old age do not necessarily reflect lifetime levels. There is an inverse relationship between serum cholesterol and haemorrhagic stroke, and a direct relationship with ischaemic stroke. In general the association between cholesterol and stroke is considerably weaker than those reported for blood pressure, diabetes and atrial fibrillation. Systematic reviews indicate that for people with known CHD and cholesterol levels in the mid to elevated range statins significantly reduce stroke risk by approximately 32%. This is probably greater than the relative stroke risk reduction achieved with aspirin therapy (approximately 25%) and compares with the 40% resulting from antihypertensive treatment. The number needed to treat to prevent one stroke over 5 years using statins in patients with CHD is approximately 80-150, compared with 40-70 for treating elderly hypertensives. The best advice at present is that patients up to the age of 75 years with known CHD and total cholesterol >5 mmol/L will benefit from a statin to reduce the risk of a first stroke, and also to reduce the risk of further CHD events. Patients up to the age of 70 with cholesterol >5 mmol/L and no history of CHD, but at high cardiovascular risk, benefit from a statin because of reduced CHD risk. The cardiovascular risk can be assessed using various tables
RECENT ADVANCES IN STROKE REHABILITATION
RECENT ADVANCES IN DYSPHAGIA AFTER STROKE
• The accuracy and completeness of clinical notetaking is improved by using a clerking proforma. Although there is no reliable evidence it is likely that improved assessment leads to improved outcome. Certainly audit is facilitated and, where the process being audited is of proven effectiveness (e.g. the use of aspirin as secondary prevention of ischaemic stroke), it is reasonable to assume that improved performance (i.e. ensuring that all ischaemic stroke patients leave hospital taking aspirin) will lead to improved outcome. • An overview of controlled trials confirms that stroke units reduce early mortality by 28%, disability (measured as an 'activities of daily living' score) is significantly reduced and there is a substantial reduction in the odds of being dead or requiring institutional care 1 year after a stroke. 2 • The characteristics of a stroke unit are: coordinated multidisciplinary rehabilitation with involvement of carers; a specialist interest in stroke disease and rehabilitation; and training and education programmes for both staff and carers. • There is early evidence to suggest that, after discharge from hospital, stroke patients have better outcomes if physiotherapy is continued in their own homes rather than at geriatric day hospitals.
Patients should be routinely tested by asking them to sip some water and observing any tendency to choke, make a gargling sound when asked to say 'aah' or have a 'wet voice'. The gag reflex is unreliable. Patients with dysphagia should take nothing by mouth, be given intravenous fluid, and be assessed by a speech and language therapist. After 48 hours many clinicians start tube feeding, but there is no evidence that early feeding increases the proportion of patients surviving without severe disability, or indeed whether a nasogastric tube or percutaneous endoscopic/gastrostomy (PEG) is preferable. There is an indication from a small trial that a PEG is better tolerated and produces a greater improvement in nutritional state, but the evidence is not strong and there is considerable uncertainty regarding when tube feeding should begin, which is the best method, and, for patients who are able to swallow, whether nutritional supplements by mouth improve stroke outcome. A large international trial (FOOD) is under way to try to resolve these issues.
(e.g. Sheffield table or the New Zealand guidelines) that predict risk based as the ratio of total: HDL cholesterol, age, sex and the presence of hypertension, smoking and diabetes. • Patients who have had a non-haemorrhagic stroke or TIA are at high risk of a myocardial infarction, and a statin is justifiable for the secondary prevention of CHD if total cholesterol is >5mmol/L up to the age of 75.
REHABILITATION The aim of the rehabilitation team is to help restore maximum capability within the limits of the elderly patient's needs and disability.
PRINCIPLES OF REHABILITATION When setting a realistic rehabilitation goal it is important to consider the patient's needs. For a very elderly and frail
amputee wheelchair independence may be perfectly satisfactory, but this would not be acceptable for a fit 65-yearold amputee who is a keen golfer. Although rehabilitation is a core activity of geriatricians it has suffered in recent years as services have had to focus on the increasing number of acute admissions. As a result, rehabilitation goals are often set merely at achieving independence in activities of daily living (ADL), so that patients can be discharged from hospital as quickly as possible, but goals directed towards quality of life, such as driving the car or using public transport, may be just as important to the patient. Rehabilitation does not stop once the patient leaves hospital, and there is increasing interest in the role of rehabilitation as a means to prevent hospital readmission. Programmes of chronic disease management agreed between primary care and the relevant specialist teams improve outcomes and are cost effective. Hospital admissions can be reduced for patients with chronic obstructive pulmonary disease by comprehensive pulmonary rehabilitation (coordinating medical treatment, nutrition and exercise) and for heart failure by nurse-led monitoring and advice. For patients with Parkinson's disease home-based rehabilitation can be particularly effective. Patients can be taught to break up long movement sequences into separate steps and do only one movement in the sequence at a time. They can be advised to avoid doing two things at once, such as carrying a tray of drinks when walking, and to consciously think about each movement before starting to do it. Movement around the home can be improved by the occupational therapist providing visual cues, which are par-
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ticularly useful in overcoming freezing episodes. Cue cards can be placed around the house with instructions such as 'go' or 'step', and strips of adhesive tape on the floor, particularly in confined spaces such as bathrooms or kitchens, can encourage more normal walking patterns. For patients who have had falls it might seem obvious that a home visit by an occupational therapist should concentrate on removing environmental hazards. However, apart from correcting obvious dangers (such as a broken light bulb at the top of the stairs) most studies on environmental manipulation have shown little benefit in the form of reduced rate of falls. However, what the occupational therapist can do is to teach the patient how to cope safely with various everyday activities and to help them regain their confidence. There is some evidence that this type of intervention reduces the risk of falling not only in the home, but outside it as well. The principles of rehabilitation in the elderly are essentially the same as for young patients, but some special features of old age should be noted. Multiple pathology is likely to be present, so that the speed with which a stroke patient can be mobilized is often hampered by shortness of breath due to chronic lung or heart disease. The mental barriers to recovery may also be greater, whether due to dementia or to the increased feelings of passivity and dependence sometimes shown by older people. There may be difficult social problems owing to lack of family support or poor housing. Rehabilitation is concerned with helping the patient to learn to do things for him or herself, and there may be times when it is better to let a stroke patient struggle to feed himself rather than to always rely on feeding by a carer. Patients enjoy exercising their painfully regained skills and it is essential to regain independence before leaving hospital and returning home.
THE MULTIDISCIPLINARY TEAM
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The most effective approach to rehabilitation is through a multidisciplinary team, with each member contributing their special skills and working together with the patient and family towards an agreed goal. The team meets regularly to discuss the patient's progress and review future plans. With a good team the patient is undergoing rehabilitation all the time and not just during the half an hour a day spent with the physiotherapist or occupational therapist. Although elderly patients can be successfully rehabilitated on a busy general medical ward, there are definite advantages to grouping them together in one ward: the nurses develop greater expertise, the pace of treatment can be better geared to the patients' needs, and it is easier to create an atmosphere of 24-hour-a-day rehabilitation. Correct positioning of a stroke patient is something all nurses and doctors should be aware of (Fig. 7.16). Before discharge, the occupational therapist will take
FIG. 7.16 Positioning the stroke patient A Incorrect; B Correct. The forearm on the affected side should be supported and should point straight forwards with wrist and fingers extended and thumb abducted. The arm must not be allowed to hang from the shoulder in internal rotation. Choosing a suitable chair - with unrestricted view and with arm rests - is important3, C Transferring the stroke patient to a chair. Note the support given to the affected arm.
the patient on a home visit to see how well they cope in familiar surroundings. This also allows assessment of the need for a specific aid, e.g. a grab handle on the wall next to the lavatory, and the opportunity to have it fitted before the patient arrives home. The social worker not only organizes the care package at home or arranges funding for patients going into residential or nursing homes, but also plays a valuable role in providing support and advice. Increasing disability and loss of independence can cause considerable distress to both patient and family, which can be helped by skilled counselling.
FURTHER READING ON REHABILITATION Department of Health 2001 National Service Framework for Older People. Standard 5: Stroke, www.doh.gov.uk/nsf/olderpeople.htm Young J, Brown A, Forster A, Clare J 1999 An overview of rehabilitation for older people. Rev Clin Gerontol 9:183-196.
COMMUNITY CARE AND LONG-STAY CARE The demand for community and long-stay care rises rapidly with age. Of those aged 65-74 only 1 % are living in institutional care and only 6% are receiving visits from a home help. For those aged 85 and over the figures rise to 26% and 36%. In the UK the principal demographic change in recent years has been a one-third rise in the number of those aged 85 and over. The escalating cost of caring for this frail and dependent section of the population (Fig. 7.17) has caused governments of all industrialized countries to think hard about how this need might be met. In the UK the NHS and Community Care Act of
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FIG. 7.17 Resources required to keep pace with demographic change Demographic change has the most marked effect on spending on long-term care C 1991 = £8 billion: this includes nursing and residential homes as well as NHS long-stay beds. A Hospital and community health services expenditure 1991 = £16 billion B General practitioners and prescription medicine expenditure 1991 =£5.5 billion.
1990 (implemented 1993) coordinates domiciliary, day care and respite services so that the old person can live in their own home for as long as possible; when this becomes no longer feasible they are cared for in private residential or nursing homes. The cost of this is borne by the individual until capital has dwindled to a threshold level (currently £18500), when the bill is then picked up by the local authority. Local social services departments and health authorities have to agree joint policies for providing both residential and nursing home care and arrangements for discharge from hospital to the community. An old person living at home in need of support has a care worker who identifies his or her needs and plans a package of care. This may involve home carers, district nurse, bathing attendant and 'meals on wheels'. Respite care to give the carers a break may be arranged in either a residential or nursing home or the local community hospital. Day care is available at local authority centres, where the needs are mainly social, or at the geriatric day hospital if the needs are medical. Patients in hospital may not be sent home until there is an agreed discharge plan based on a multidisciplinary assessment. If this assessment, whether carried out in hospital or in the community, determines that the patient is no longer able to cope at home then a decision will be made whether to admit them to a residential or nursing home (paid for as outlined above). Patients with complex conditions or multiple problems who need continuing weekly assessments by the geriatric medical team are cared for free of charge in an NHS long-stay hospital bed. These patients now make up only a tiny minority and the
FIG. 7.18 Vicious circle
NHS withdrawal from the long-stay sector has raised important issues about standards of medical care in private institutions. The Community Care Act has brought improvements in the form of a better coordinated, patient-orientated service, but the time patients spend in hospital waiting for transfer to institutional care has increased because of funding difficulties, and there are continuing uncertainties about the eligibility criteria for an NHS long-stay bed. Increasing acute hospital admissions and a declining number of available beds are putting unprecedented pressure on acute medical services. An important response has been to try to find ways of preventing inappropriate admissions of elderly patients to district general hospitals and to speed up the discharge of those whose investigations and treatment is completed. Initiatives include improved community rehabilitation services; hospital at home; rapid response teams to provide short-term support for patients sent home from A & E departments; and increasing use of community hospitals. This range of services is now described as intermediate care. Despite these developments, community services have not been expanded sufficiently to cope with the increased demand resulting from hospital bed closures. Elderly people are being discharged from hospital 'quicker and sicker', and this has two predictable results. The increased demand on social services departments from a few people with a high level of personal care needs means that very many people who require less intense service packages receive no service at all. Secondly, the pressure for earlier hospital discharge results in
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insufficient rehabilitation, creating a vicious circle (Fig. 7.18). This will only by broken by joint working between the NHS and social service departments to develop better services. It should not be forgotten that in the UK, as in other countries, the unpaid support provided by relatives, friends and neighbours easily outweighs that provided by statutory services. Advising and helping these carers is an important part of the doctor's role. It is also important to remember that the quality of care in long-stay institutions, private or NHS, is crucially dependent on the visiting doctor's vigilance and enthusiasm. This applies not only to ensuring that high-quality nursing standards are maintained, but that the environment for the patients is made homely, pleasant and comfortable. The emphasis should be on educating patients to do as much for themselves as possible, and physiotherapy and occupa-
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tional therapy may be entirely appropriate for certain patients.
FURTHER READING ON COMMUNITY CARE AND LONG-STAY CARE Black D, Bowman C 1997 Community institutional care for frail elderly people - time to structure professional responsibility. Br Med J 315:441-442. Department of Health 2001 National Service Framework for Older People. Standard 3: Intermediate care. www.doh.gov.uk/nsf/olderpeople.htm Nikolaus T, Specht-Leible N, Bach M et al 1999 A randomised trial of comprehensive geriatric assessment and home intervention in the care of hospitalised patients. Age Ageing 28:543-550. The Coming of Age - improving care services for older people. London: Audit Commission, 1997.
8
Psychological Medicine Jeremy Holmes
Classification and overview 205
Hysteria 235
The causes of psychiatric illness 210
Histrionic personality and related conditions 238
The psychiatric examination 211
Eating disorders 239
Treatments in psychological medicine 212 Anxiety 212
Drug dependence 243 Alcoholism 247
Loss, grief and bereavement 217
Mental handicap or learning difficulties 252
Depression 218
Psychiatry and the law 253
Suicide and parasuicide 223
Mental health legislation 253
Mania and hypomania 226
Medicine and the emotions 255
Schizophrenia 228
Sex and medicine 256
Paranoid states 231
Death and dying 257
psychiatry are psychology and psychoanalysis, child development and sociology. Neurochemistry and neuroimaging, and the new genetics and neo-Darwinism, are making increasingly important contributions to the subject. The central meeting ground for medicine and psychiatry is the doctor-patient relationship. All patients, whatever their illness, have feelings and fears that the doctor needs to understand and know how to handle. The meaning to the patient of a particular symptom - chest pain, for example, whether due to angina or to anxiety in a 40-yearold man whose father died suddenly of a heart attack in middle age - needs to be understood, in order to appreciate its impact on the patient, as well as diagnosed and investigated. Psychiatry is concerned with meaning as well as explanation, and with methods of communication with the patient, as well as the technology of treatment. Despite the inseparability of psyche and soma, many doctors find psychiatry difficult and confusing. This is partly because the subject is inherently complex and multifaceted, but also because psychiatry involves the doctor's own feelings and attitudes in a way that can often be avoided in other branches of medicine. In approaching psychiatry, doctors have to learn to deal not just with the patient, but also with themselves.
CLASSIFICATION AND OVERVIEW A simple classification of psychiatric illness is summarized in Table 8.1. Some aspects of psychiatry of old age are also considered in Chapter 7.
Somatoform disorders 233
MINDS AND BRAINS
Psychiatric disease constitutes a large proportion of disability and illness in society (Fig. 8.1 and Summary 1). The World Health Organization has identified depression as the main cause of disability throughout the world; suicide is one of the commonest cause of death in young people, especially males, in developed countries. Somatization disorders are among the most frequent cause of consultation in general practice. Throughout the western world, most of the large mental hospitals have now closed and acute psychiatric illness is treated in general hospital units and the community, alongside the other medical disciplines. The boundary between general medicine and psychiatry is much less rigid: patients and their illnesses are no longer seen by physicians purely as scientific puzzles to be solved: psychological aspects of physical illness are, through liaison psychiatry, now recognized to be of great importance. Medical science is, in turn, making an increasingly important impact on psychiatric knowledge and practice. The basic disciplines underlying
An eminent neurologist once stated that 'psychiatry is neurology without physical signs'. This would be true if psychiatry were simply concerned with the brain and its disorders; the problem of psychiatric diagnosis and classification would then be no different from that of any other system of the body. A significant part of psychiatry is indeed concerned with diseases of the brain - the organic psychoses, such as confusional states, for example, or the affective symptoms (i.e. disorder of mood) caused by adrenal disorders. The 19th century discovery that the psychosis known as general paralysis of the insane (GPI) was caused by syphilis stimulated one of the founding fathers of psychiatry, Emil Kraepelin, to search for other physical causes of insanity, with the expectation that all mental illness would soon be found to be caused by diseases of the brain. Psychiatry continues, rightly, to try to understand the structural and biochemical correlates of psychiatric disorders, but the Kraeplinian project can never be fully realized, partly because brain research is difficult and at a rather primitive stage, but also because psychiatry is concerned with minds as well as brains.
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TABLE 8.1 Classification of psychiatric disorders Organic syndromes Delirium Dementia Intoxication and withdrawal syndromes Functional psychoses Schizophrenia Manic-depressive psychosis Paranoid states Neuroses Anxiety Phobias Depression Obsessive-compulsive neurosis Somatoform disorders Conversion Somatization Hypochondriasis
Others Addictions Alcohol Drugs Eating disorders Sexual dysfunction and deviation Personality disorders (Axis II in DSM) (see p. 180) A. Paranoid Schizoid B. Antisocial (psychopathic) Histrionic Borderline C. Avoidant Dependent Obsessive-compulsive
Prevalence Prevalence of psychiatric ill health in the community Prevalence of psychiatric disorder in general practice Prevalence of psychiatric disorder among schoolchildren Psychiatric referral rate from general practice Psychiatric beds as a proportion of all NHS beds Major disorders Severe depression Suicide attempts Suicide Chronic mental illness Severe mental handicap
SUMMARY 1 The prevalence of psychiatric morbidity among adults aged 16-64, living in private households, in Great Britain • 14% of adults have a neurotic health problem. Women are far more likely to suffer this type of problem than men. • The most common neurotic symptoms are fatigue (27%), sleep problems (25%), irritability (22%), and worry (20%). • The most prevalent neurotic disorder is mixed anxiety and depressive disorder (7.7%), followed by generalized anxiety disorder (3.1%). The prevalence of all neurotic disorders is higher among women than men. • Functional psychosis has a prevalence of 0.4%. • The overall rates of alcohol and drug dependence are 4.7% and 2.2%, respectively. Men are three times more likely than women to have alcohol dependence and twice as likely to be drug dependent. Alcohol and drug dependence are most prevalent among young adults, particularly young men aged 16-24.
Mind has three main properties: • The ability to experience emotions • Intentionality (i.e. having desires and goals) • Self-awareness.
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Although psychiatric diagnosis approaches the mind as if it were an organ, this is often merely an analogy. When we speak of psychiatric illness we may be speaking about a brain disease, e.g. GPI, Alzheimer's disease or (possibly) some forms of schizophrenia, in the same way we speak of pneumonia as a disease of the lungs. On the other hand, although conditions such as personality disorders or agoraphobia are in some ways like illnesses, they also differ in many important respects because they affect the mind. They are best seen as disorders, rather than diseases. This important distinction between mind and brain may
Neurotic disorders Social pathology Chronic alcoholism (identified cases) Chronic alcohol ism (unidentified cases) Juvenile delinquency Problem families One-parent families with children under 15 FIG. 8.1 Epidemiology of psychiatric disorders A Prevalence of, and provision for, psychiatric ill health in the community. B Cases per annum of various psychiatric disorders in a typical British general practice population of 2500.
help to explain the discomfort some feel when confronted with the essentially rather simple issue of psychiatric diagnosis. The categories of mental illness are few and not difficult to memorize. The main problem is philosophical, rather than one of classification. A number of other difficulties may also be encountered on first approaching psychiatry. First, psychiatric diagnoses tend to be at a rather general level. They are symptomatic/syndromic rather than pathological/specific. The diagnosis of anxiety neurosis or schizophrenia is analogous to that of 'heart failure' rather than 'mitral stenosis'. Secondly, with the exception of the organic psychoses, the underlying pathology of psychiatric disorders is usually complex and multifactorial. This follows from the nature of mental phenomena. Just as there is usually no simple reason why an individual chooses medicine as a career, so
there is rarely a single 'cause' of depression. There may be many explanations for a particular symptom or problem. A third difficulty encountered in psychiatric diagnosis is that of deciding what is normal or abnormal, which is sometimes more a political or ethical question than a technical one. The doctor's own standards and feelings are involved in assessing a psychiatric patient. This also leads to two errors commonly made by newcomers to psychiatry: either the student identifies the patient with himself, and so decides there is nothing much wrong, or he identifies himself with the patient and worries that he must be psychiatrically ill! (Note that throughout this chapter 'he' is used to mean 'he or she'.) Two systems of classification are widely used in psychiatry: ICD (International Classification of Diseases), which is favoured in Europe, and DSM (Diagnostic and Statistical Manual), which has been developed in the USA by the American Psychiatric Association. The latter is interesting in that it is a multiaxial classification: Axis I diagnoses classify the psychiatric disorder; Axis II classifies any personality disorder that may or may not accompany the psychiatric illness; and Axis III allows for the diagnosis of any concomitant physical disorder.
FURTHER READING ON MINDS AND BRAINS Fulford K W 1989 Moral theory and medical practice. Cambridge University Press, Cambridge Kendell R 1975 The concept of disease and its implications for psychiatry. Br J Psychiatry 127: 305-315
PSYCHOSIS AND NEUROSIS The distinction between psychosis and neurosis has been and remains fundamental to psychiatric thinking, although neither is easily defined on its own, and some classifications have attempted to do away with the rather vague and blanket term neurosis. The difference turns on four main issues: • • • •
Relationship to reality Severity Relationship to normality Insight.
Relationship to reality The essence of psychosis is that the patient loses contact with everyday reality. This may happen as a result of either hallucinations or delusions, or both. Delusions and hallucinations are not a feature of neurosis. The neurotic's feelings and beliefs about himself may be distorted, but perception and understanding of the external world remains intact.
SUMMARY 2 The distinction between psychosis and neurosis Feature Relationship to reality
Psychosis Loss of contact with reality Delusions and/or hallucinations
Neurosis Perception of external reality intact Problem is with the self
Severity
More severe, more global disturbance
Areas of normal function remain
Relationship to normality
Clear distinction between normal and psychotic experience
Represents extremes of normal difficulties
Insight
Usually lacking
Present
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Hallucinations A hallucination is a false perception. The patient undergoes a sensory experience in the absence of an external stimulus, for example hearing a voice when there is nobody there. For this to be diagnostic of psychosis it should be clear-cut; hearing an 'inner voice', which the person recognizes as really part of himself, is not a hallucination. An illusion should be distinguished from a hallucination in that it is an elaboration of a real percept, e.g. 'seeing faces in the fire', and is of less, if any, pathological significance. In hallucination, any of the five senses may be involved in the patient's altered perception of reality. Hearing Auditory hallucinations are probably the commonest type of hallucination, found especially in paranoid states, in schizophrenia, and occasionally in psychotic depression. Sight Contrary to popular belief, schizophrenic patients rarely 'see things': visual hallucinations occur most commonly in drug and alcohol withdrawal states, temporal lobe epilepsy and hysterical psychosis. Smell and taste Olfactory hallucinations are usually a sign of organic disease, e.g. temporal lobe seizures. Touch Tactile hallucinations are rare, but can occur in schizophrenia and drug withdrawal. Hallucinations are not always a sign of pathology. After bereavement, visual or auditory hallucinations of the lost loved one are common. Delusions A delusion is a fixed and firmly held false belief. The patient's perceptions are unaltered, but his interpretation of them is, and is at variance with common experience. The patient sees people chatting at a bus-stop and is convinced
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they are talking about him, saying he is homosexual or a spy, for example. These beliefs may be well concealed and not evident in superficial conversation. We normally assume that our thoughts are private, that individuals are autonomous, that the non-human world is indifferent to our existence, that we are not in any special danger, and that we are not of any particular importance or interest to strangers. The deluded patient (e.g. in schizophrenia) has experiences that conflict with these everyday beliefs. The patient may feel that his thoughts can be interfered with from outside, or that his movements can be controlled by others; he may believe there is some special significance in the number plate of a passing car, that he is in great danger from hostile forces, or that television programmes or public events are caused by, or directed at, himself.
SUMMARY 3 Classification of psychosis Organic Acute (delirium) Chronic (dementia)
Functional Manic-depressive psychosis Schizophrenia
oneself and one's emotions and motives without denial or self-deception. Although insight in this second sense may be desirable, it bears no relationship to the presence or absence of illness. It is possible to be perfectly healthy and yet to lack self-knowledge, or to be profoundly insightful yet mentally ill.
THE PSYCHOSES Severity In general, psychotic disorders are more severe, more disabling and produce greater overall disturbance of mental functioning than neuroses. There are exceptions to this. An obsessional neurosis, for example one in which the individual may spend many hours a day engaged in complicated washing or dressing rituals, can be incapacitating.
Relationship to normality In psychosis there is a clear departure from normality. In contrast, minor neurotic symptoms, e.g. depression, anxiety, obsessional symptoms and hysteria, are common in normal people. The neurotic population is best seen as an extreme end of a normal distribution curve in which quantitative, but not qualitative, change has taken place.
Insight
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It is commonly stated that the difference between neurosis and psychosis is that the psychotic 'lacks insight'. The psychotic patient attributes his symptoms to reality rather than illness, and cannot be persuaded out of these delusions or hallucinations; the neurotic, on the other hand, can usually see that his view of the world might be mistaken. However, although it is undoubtedly true that the psychotic lacks insight, there are several reasons for giving less prominence to insight than is customary. First, if the psychotic is identified on the basis of a loss of touch with reality, then he will, by definition, lack insight. If the patient knew that his delusions or hallucinations were false, he would not be deluded or hallucinating. Secondly, the patient often tacitly accepts that he is ill by coming for help, despite the apparent illogicality of complaining to a doctor about a delusion. Thirdly, the word 'insight' has two distinct meanings in psychiatry: one, given above, refers to the patient's relationship to reality and his illness; another more literal meaning refers to the ability to look into
Psychoses may be divided by their features and causes into two main groups: organic and functional (or, more accurately, 'of unknown origin'). In organic psychosis there is established biochemical, infective or structural brain disease. In functional psychosis no such disease process can be demonstrated. Organic psychoses can be divided into acute organic psychoses (also known.as acute confusional states, delirium or 'acute brain syndrome') and chronic organic psychoses (also known as dementia and 'chronic brain syndrome') (see also Ch. 24).
Functional psychosis vs. acute organic psychosis It is essential to be able to distinguish functional psychoses from acute confusional states, as the former require psychiatric, the latter medical, treatment. The key difference is the state of consciousness. In functional psychosis consciousness is clear and the patient fully orientated: it is possible to complete a complicated crossword puzzle while suffering from paranoid schizophrenia. In organic psychosis, however, there is almost always some disturbance of consciousness; this is usually variable ('fluctuating level of consciousness') and is often worse at night. Some causes of acute organic psychosis are given in Table 8.2.
Functional psychosis One hundred years ago, Kraepelin divided the functional psychoses into two main groups: manic-depressive psychosis, and schizophrenia (or, as he called it, 'dementia praecox'). Manic-depressive psychosis is primarily a disorder of mood. The patient becomes psychotically depressed or elated ('unipolar manic depression') or experiences episodes of both ('bipolar manic depression'). There are usually periods of normality between episodes of illness. Schizophrenia is primarily a disorder of thinking, and on the whole it produces, a more severe and more general disturbance of mental functioning. The prognosis is less good than for manic depression.
TABLE 8.2 Some causes of acute organic psychosis Cause
Examples
Systemic infection Metabolic disturbance Vitamin deficiency
Malaria, HIV, pneumonia (especially in the elderly) Electrolyte imbalance, renal failure, liver failure Thiamine deficiency (Wernicke-Korsakoff syndrome in alcoholics, and beriberi) Hypoglycaemia, hypothyroidism, steroid administration Anticonvulsants, hypnotics, antidepressants, LSD, amphetamines CVA, subarachnoid haemorrhage, tumour, cerebral abscess DTs, benzodiazepine withdrawal
Endocrine Drug intoxication Intracerebral Withdrawal syndrome
cal health than those who are mentally untroubled. Childhood adversity, for example, is strongly associated with poor physical health in adult life. This link was orginally conceptualized by Freud in terms of 'hysterical conversion disorders' - i.e. the 'conversion' of mental distress into bodily symptoms. The basic themes of hysteria were denial, dissociation, displacement and dependency. The patient denies a painful conflict and thus avoids anxiety or depression, but at a price: she (many hysterical patients are female) dissociates herself from her feelings and displaces the latter into her body instead. Psychic pain is thereby converted into physical symptomatology, and the patient becomes dependent on doctors and others. Although the possibly perjorative and aetiologically loaded term 'hysteria' has been replaced with the more neutral 'somatization' the underlying themes remain.
THE NEUROSES
Obsessive-compulsive neurosis
Unlike psychosis, in neurosis the patient experiences no alteration of external reality. Instead, he is troubled by, and tries to avoid, some unacceptable aspect of himself or of his internal reality. There are four main patterns of neurosis:
Here the patient deals with anxiety - often aroused by fear of his own feelings of aggression, sexuality or wish for power or independence - by an attempt at control. A ritual action or a repetitive thought is repeated over and over again in the magical hope that this will keep some imagined danger at bay. The patient knows it is absurd (thus has insight and is not psychotic), tries to resist, but still has, say, to wash in a particular way every morning in order to feel safe to start the day.
• • • •
Anxiety neurosis and phobia Depressive neurosis Hysteria and somatization Obsessive-compulsive neurosis.
Anxiety neurosis and phobia Anxiety is an almost universal feature of all psychiatric illness. It is the psychic equivalent of pain. Anxiety is normally a response to external threat or unpredictability in the environment. In anxiety neurosis, rather than being alerted and mobilized into action by anxiety, the patient is paralysed or overwhelmed by it. Where anxiety is experienced only in specific situations, the patient is said to suffer from a phobia. In phobic disorders the patient attempts to master anxiety by avoidance (e.g. an agoraphobic patient avoids public places).
Depressive neurosis If anxiety is the psychic equivalent of pain, depression is the equivalent of disability (although anxiety can also of course be disabling, and depression intensely painful). In depression, the patient has lost not a limb or a function but a relationship. It is usually a person who is lost, but the 'lost object' can also be a job or a house, or the patient's own self-esteem. Depression can be seen as an attempt to avoid painful reality by withdrawal.
Hysteria Body and mind are inseparable. There is good evidence that patients with psychiatric disorders have worse physi-
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PERSONALITY DISORDER Individuals are recognizable not just by their appearance but by their personality which, despite ageing and change, remains relatively constant through time. Personalities can be classified dimensionally or categorically. A dimensional approach is exemplified by Hans Eysenk who, following his intellectual opponent Jung, devised a method for assessing personalities along the dimensions of extrovert (outgoing, gregarious, stimulusseeking) and introvert (inner-directed, shy, stimulusavoiding). The problem of differentiating between normal and abnormal personality is even more difficult than in neurosis. There are undoubtedly individuals whose personalities are very unusual, at least in the statistical sense, but they are not necessarily abnormal. An alternative approach to the classification of personality uses psychiatric categories to describe different types of individual. Someone suffering from schizoid personality, for example, is withdrawn and aloof, preoccupied with material objects or intellectual pursuits rather than people, lacking in close emotional contact, and is defensive and easily hurt. These features may only be a personality trait, and may even be advantageous: many creative people have schizoid tendencies. However, when taken to extremes they become a personality disorder. Here, the individual is so handicapped by
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SUMMARY 4 Classification of personality Dimensional approaches e.g. extrovert/introvert DSM categorization A. Paranoid Schizoid
B. Antisocial (psychopathic) Borderline Histrionic
C. Avoidant Dependent Obsessive-compulsive
his personality that he seeks, or is brought for, help, e.g. someone with a schizoid personality who suffers from severe social isolation. Unlike psychosis and neurosis, a personality disorder is not an illness. Its features date back to childhood or adolescence, and so there is no premorbid period of normality. However, personality disorder often coexists with, and may predispose to, psychiatric illness (this is an example of 'comorbidity'). Personality disorders are conveniently grouped into three main types. Group A have some of the features of schizophrenia and paranoia, but without any overt signs of psychosis. They may, however, predispose to a psychotic illness, and eventually develop into one. Thus someone with a paranoid personality may, in later life, develop pamphrenia. In group B, sometimes described as 'dramatic', patients experience social difficulties that often bring them into conflict with authority. Many of the patients who present to casualty departments after episodes of deliberate self-harm (see below) suffer from borderline personality disorder, characterized by unstable relationships, substance abuse, chronic feelings of emptiness, and difficulty in regulating emotions. For histrionic personality disorder, see page 238, and for antisocial personality disorder, page 253. Group C are neurotic personalities typified by anxiety, avoidance of threat or challenge, and dependent relationships. An example is that of obsessional personality disorder. Here the individual is meticulous, controlled, orderly and rigid, and may find the sloppiness of others unbearable. Such characteristics may be advantageous in certain circumstances, e.g. the armed forces or the operating theatre, but may also bring the individual into conflict with others when flexibility is needed, e.g. under stress and in intimate relationships.
THE CAUSES OF PSYCHIATRIC ILLNESS
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The complexity of the interactions underlying psychiatric illness can be confusing. A causal model of the type 'one pathogen-one disease' rarely applies in psychiatry. There are three main types of causal factor in psychiatric illness: genetic/biochemical, developmental, and social. All play at least some role in most psychiatric disturbances, and part of the art of psychiatry lies in assigning the appropriate weight to each factor and identifying which may be
FIG. 8.2 The origins of psychiatric disorder
the most important (Fig. 8.2). Most psychiatric illnesses are genuinely 'multifactorial' in origin. This is not surprising, considering the complexity of brain development and the numerous branching pathways that development can take. The eventual outcome in terms of mental health will depend on genetic inheritance, childhood environment, resistance or vulnerability factors, adverse and healthpromoting experiences, and accidental factors such as loss and trauma. Eliciting this personal narrative or life story is central to psychiatric history taking and provides an essential backdrop to understanding current psychiatric disorder.
Genetic/biochemical ('organic') Occasionally a single genetic defect can determine a psychiatric illness, e.g. the psychiatric manifestations of Huntington's chorea. However, although genetic inheritance may, as in schizophrenia, be a necessary organic cause of illness, it is rarely sufficient. Biochemical, viral, immunological and nutritional factors may well be important in a number of psychiatric illnesses, although few have so far been convincingly demonstrated as a unique cause.
Developmental ('infrapsychic') Each individual is a product of, and in a sense contains and continues, his past. Psychological development, especially that shaped by early childhood experience and family relationships, plays a crucial part in determining personality and ways of reacting to stress in later life.
Social ('interpersonal') Many psychiatric illnesses are triggered by recent social events, such as bereavement, divorce or unemployment. The patient's social and family situation can play a major role in both initiating his illness and helping or hindering his capacity to recover. The quality of family relationships is itself influenced by the personality, which is in turn a product of both genetic and developmental factors.
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THE PSYCHIATRIC EXAMINATION The psychiatric examination, although similar to the medical examination insofar as it is a systematic gathering and ordering of facts and observations, is unique in a number of important ways. First, it consists of a detailed account of a person's biography and current circumstances. Second, in gathering the history the interviewer uses a much more open style than is usual in the closed-question 'checklist' approach of conventional history-taking. The 'facts' of psychiatry are often feelings, and these are often most effectively elicited by open questions such as 'How do you feel about...?' or 'What was the worst moment .. .?' Third, the interviewer's own reactions and thoughts, rather than being put aside, should be recognized as relevant data to be noted and recorded. The interviewer should maintain a non-judgemental, balanced, compassionate but neutral position. The interviewer should also be gentle but firm and should not avoid eliciting material (e.g. sexual or traumatic) that may be painful for the patient simply because of his own scruples or anxiety. The psychiatric history, which may have to be supplemented by interviewing close friends or relations, should include the following: • Reason for referral. Did the patient ask for help, was he encouraged to seek it, and if so by whom, or was he brought unwittingly or unwillingly to the doctor? Why now? • History of present complaint. A detailed account, as far as possible in the patient's own words, of what he experiences as 'wrong', unusual or bizarre, or would like to change in his life. • Previous psychiatric and medical history.
SUMMARY 5 Psychiatric history and examination History • Reason for referral • History of present complaint • Previous psychiatric history • Previous medical history • Drugs and alcohol • Family history - genogram • Personal history • Personality Examination • General appearance and behaviour • Speech - form and content • Mood • Abnormal beliefs • Abnormal experiences • Cognitive state • Insight • Interviewer's responses
FIG. 8.3 A genogram
Drug and alcohol history. Family history. A detailed description of the patient's 'family of origin' and 'family of procreation' (if they have one) can conveniently be recorded in the form of a family tree or 'genogram' (Fig. 8.3). Personal history. Detailed biography, starting at birth, recording all significant memories and events, including early separations, family atmosphere, school experiences and achievements, work history, psychosexual and marital history. Personality. A person's likes and dislikes, interests, attitudes and aptitudes should be recorded to establish a premorbid stage against which to evaluate the present condition.
MENTAL STATE EXAMINATION This is a systematic compilation of the abnormal phenomena observed and elicited by the interviewer or complained about by the patient. • General appearance and behaviour. How is the patient dressed? How does the patient relate to the interviewer - is he relaxed and friendly, or suspicious and taciturn? Does the patient sit immobile in the chair, or is he fidgety and restless?
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• Speech. Is the speech normal in form and content, slowed down, or accelerated? Does it follow a logical progression or does it jump from idea to idea ('flight of ideas'); or is there evidence of a disorder of the logical progression of thoughts ('thought disorder')? • Mood. Is the mood normal, depressed or elated? Is the person troubled by feelings of guilt and unworthiness and suicidal thoughts, or is the patient grandiose and overexcited? Is the patient anxious or agitated? • Abnormal beliefs (delusions). Does the patient feel he is being spied on, talked about or got at? Are his thoughts or actions being interfered with? • Abnormal experiences (hallucinations). Has the patient had any bizarre or unusual sensations? Is he hearing noises or voices when no-one is around? • Cognitive assessment (for mini-mental state examination, see p. 1288). What is the general level of intelligence? Is there evidence of impairment of consciousness, immediate memory or recall? Is the patient fully oriented in time, place and person? • Insight. What is the patient's self-appraisal and theory about what is happening to him? • Response of the interviewer. How does the patient make the interviewer feel? Sympathetic? Angry? Irritated? Bored?
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The examination should be concluded by a formulation containing the salient points of the history and mental state, with a differential diagnosis and some ideas about possible aetiological and precipitating factors. Risk assessment should be considered in each case, with a specific discussion about suicidality ('How suicidal do you feel at the moment', or 'How would you rate your suicidality on a scale of 0-10?'), and consideration of risk to others, based on past history of violence, if any. Example of a psychiatric formulation: 'Mr A is a 22-yearold unemployed man currently living in a bedsit. For the past few months he has become increasingly withdrawn and self-neglectful, and caused worry to his landlord, whom he has accused of spying on him. He has been smoking cannabis on a daily basis since leaving school at the age of 16. He has few friends, and has only held down casual jobs for short periods. In his background his maternal uncle suffered from schizophrenia; his parents split up when he was 8, he has lost contact with his father and does not get on with his stepfather, whom his mother married 2 years ago. On mental state examination he appears mildly depressed and shows evidence of paranoid delusions of being watched, and occasionally hears a voice warning him that he is in danger. There may be some suicide risk, but there is no history of any violence to others. The differential diagnosis includes schizophrenia, cannabis psychosis, depressive disorder, and insidious organic brain disease. A degree of maternal neglect (his delusion could reflect a psychotic expression of his feeling of being unnoticed), lack of a positive male role-model, low self-esteem and underachievement may all contribute to the underlying dynamic of his developing illness'.
FURTHER READING ON THE PSYCHIATRIC EXAMINATION Leff J, Isaacs A 1990 Psychiatric examination in clinical practice. Blackwell, Oxford Sims A 1995 Symptoms in the mind, 2nd edn. WB Saunders, London
TREATMENTS IN PSYCHOLOGICAL MEDICINE Psychiatric treatments are of three types: • physical - psychotropic drugs - ECT • social - housing - day centres • psychological - see Table 8.3
ANXIETY Anxiety, like pain, is an unpleasant necessity. A person unable to feel anxious would be severely incapacitated. Arousal, which may be experienced subjectively as anxiety, leads to an adaptive response to threat: fight or flight.
AROUSAL AND ANXIETY There are three main components of the arousal response: • Psychophysiological • Psychological • Interpersonal.
The psychophysiological component This is mediated by the autonomic nervous system and is accompanied by increased adrenaline (epinephrine),nora-
SUMMARY 6 Manifestations of anxiety Physical Tachycardia Tightness/pain in chest Difficulty in breathing Headache Paraesthesia Muscular pains Muscular weakness Dizziness Difficulty in swallowing Abdominal discomfort Diarrhoea Frequency of micturition
Psychological Irritability Inability to memorize Inability to concentrate Fear of impending death Fear of madness (depersonalization and derealization)
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TABLE 8.3 Choosing a psychological therapy Principal recommendations
Evidence
• Psychological therapy should be routinely considered as an option when assessing mental health problems (B)
Psychological therapy shows benefits over no treatment for a wide range of mental health difficulties.
• Patients who are adjusting to life events, illnesses, disabilities or losses may benefit from brief therapies such as counselling. (B)
There is evidence of counselling effectiveness in mixed anxiety/depression, most effective when used with specified client groups, e.g. postnatal mothers, bereaved groups.
• Post-traumatic stress symptoms may be helped by psychological therapy, with most evidence for cognitive behavioural methods. Routine debriefing following traumatic events is not recommended. (A)
CBT has been found helpful. Some evidence of efficacy has been shown for other forms of psychological therapy. Single session debriefing appears to be unhelpful in preventing later disorders.
• Depression may be treated effectively with cognitive behavioural therapy (CBT) or interpersonal therapy (IPT). A number of other brief structured therapies for depression may be of benefit, such as psychodynamic therapy. (A)
CBT & IPT effectively reduce symptoms of depression. Benefit has also been found for other forms of psychological therapy.
• Anxiety disorders with marked symptomatic anxiety (panic disorder, agoraphobia, social phobia, obsessive-compulsive disorders, generalized anxiety disorders) are likely to benefit from cognitive behaviour therapy. (A)
CBT effectively reduces symptoms of panic and anxiety. Behaviour therapy and cognitive therapy both appear effective in treatment of obsessional problems.
• Psychological intervention should be considered for somatic complaints with a psychological component with most evidence for CBT in the treatment of chronic pain and chronic fatigue. (C)
Psychological therapies have benefit in range of somatic complaints including gastrointestional and gynaecological problems. CBT found more effective than control in improving functioning in chronic fatigue and chronic pain.
• Eating disorders can be treated with psychological therapy. Best evidence in bulimia nervosa is for CBT, IPT and family therapy for teenagers. Treatment usually includes psychoeducational methods. There is little strong evidence on the best therapy type for anorexia. (B)
Efficacy of CBT and IPT in bulimia has been established. Individual therapies have shown some benefit in anorexia, with little to distinguish treatment types. Early onset of anorexia may indicate family therapy, and later onset, broadly based individual therapy.
• Structured psychological therapies delivered by skilled practitioners can contribute to the longer-term treatment of personality disorders, (C)
Meta-analysis found a number of therapy approaches, both individual, group and milieu show some success, including dialectical behaviour therapy, psychoanalytic day hospital programme and therapeutic communities.
The recommendations are weighted as follows: A. Based on a consistent finding in a majority of studies in high quality systematic reviews or evidence from high quality studies. B. Based on at least one high quality trial, a weak or inconsistent finding in high quality reviews or a consistent finding in reviews that 'high quality'. C. Based on evidence from individual studies that do not meet all the criteria of 'high quality'. D. Based on evidence from structured expert consensus.
drenaline (norepinephrine) and corticosteroid secretion. These result in tachycardia, piloerection, sweating and pupillary dilatation; and subjective manifestations of autonomic activity, including paraesthesiae, giddiness, 'butterflies in the stomach', breathing difficulties, a sensation of painful pressure in the chest, and muscular tension, especially around the head and neck. These symptoms may be mistakenly attributed by both patients and doctors to organic illness.
The psychological component There is a continuum of arousal responses to threat, from alertness and readiness, through mild fear to severe anxiety and incapacitating panic. Effective action depends on an optimal state of arousal: little can be achieved when an individual is either barely aroused or in a state of panic. Examination nerves, if not too great, improve results. During a panic attack the patient experiences a sense of threat, or even of impending death. Chronic anxiety states
not meet all the criteria of
SUMMARY 7 Aetiology of anxiety syndromes Past Genetic factors (predisposition) Faulty learning (as a child) Early childhood relationships (Attachment theory)
Present External threat Relationships to attachment figures Internal conflict
may produce irritability, lack of concentration and a subjective sense of failing memory. Anxious patients fail to habituate to stimuli and so remain chronically overaroused; this can result in extreme sensitivity to sudden noises or movements. In extreme anxiety a state of detachment may supervene in which anxiety suddenly disappears, to be replaced by a feeling of being outside of oneself (depersonalization) and cut off from one's surroundings, which appear unreal and distant (derealizatiori). These
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TABLE 8.4 Classification of anxiety syndromes Primary anxiety Generalized Situational Agoraphobia Social phobia Hypochondriasis Specific (e.g. spiders) Panic attacks (hyperventilation syndrome)
Secondary anxiety Psychiatric illness, e.g. depression Organic illness, e.g. thyrotoxicosis Alcohol-related withdrawal symptoms Benzodiazepine-related withdrawal symptoms
experiences may be misinterpreted by the patient as signs of 'going mad'.
The interpersonal component A frightened individual 'regresses' (see p. 217) and, childlike, clings to those he loves and on whom he depends. This is part of 'attachment behaviour' and, like anxiety, is adaptive: species survival depends on secure bonding. The dependency and excessive demands on others that so often accompany anxiety states (and which can be trying to both relatives and doctors) can be understood as part of the attachment response to threat.
anxiety syndromes because in a phobia the patient avoids the feared situation and is thus restricted by the underlying anxiety. Situational anxiety syndromes include: • Specific phobias, e.g. snake or spider phobia, or fear of heights. These have a good prognosis, are found in otherwise healthy individuals, and respond well to behavioural treatment (p. 215). • Agoraphobia is named after the Greek agora, or meeting place. In agoraphobia the patient is frightened to leave home unaccompanied, avoids public places such as supermarkets and department stores, and cannot travel on public transport, especially underground railways and aeroplanes (claustrophobia is usually part of agoraphobia). The patient is usually female and may be very dependent on her mother, daughter or husband. The prognosis is less good than with specific phobias, but behavioural therapy is usually helpful. Agoraphobic symptoms may develop as part of a depressive illness (p. 218). • Social phobia, i.e. fear of meeting people in social situations, e.g. parties, canteens. This affects mainly young people and is an extreme form of normal 'shyness'. Patients can be helped by social skills training in groups with fellow sufferers in which they 'role-play' the feared situations. • Hypochondriasis, a morbid fear of illness, leading to a frequent need for reassurance by family, friends and doctors.
ANXIETY SYNDROMES Anxiety may be a primary diagnosis, or secondary to another psychiatric or physical illness. It is a non-specific symptom which occurs in a wide range of psychiatric syndromes, including benzodiazepine withdrawal, depression, alcoholism and schizophrenia. It can also be an important manifestation of organic illness, particularly thyrotoxicosis, paroxysmal tachycardia, carcinoid syndrome, hypoglycaemic attacks, phaeochromocytoma and temporal lobe seizures.
CLASSIFICATION Primary anxiety syndromes may be classified as shown in Table 8.4.
Generalized anxiety Individuals who experience anxiety symptoms, either chronically or intermittently, without a clear stimulus or an obvious focus of fear, suffer so-called 'free-floating' anxiety.
Situational anxiety 214
In situational anxiety there is an identifiable precipitant to which the anxiety is related. Phobias are closely related to
Panic attacks (hyperventilation syndrome) These may be part of a specific syndrome, e.g. agoraphobia, or may occur on their own. They frequently present to physicians as medical emergencies and are usually selflimiting. The patient presents in a state of terror, overbreathing, complaining of chest pain, and often feeling he is dying. The diagnosis can be established by provoking these symptoms with voluntary overbreathing, which are then relieved by rebreathing from a paper bag. Tetany may be a feature. Organic causes (e.g. hyperthyroidism) must be eliminated and a positive psychiatric history should be established (i.e. a history of recent stress/conflict, or a background of chronic difficulty).
Aetiology There is no single cause of anxiety syndrome. Individuals vary in their tendency to become over-aroused: genetic factors may play a part in this. Anxiety may also arise from faulty learning. A child who senses his mother's tension in social situations may become socially phobic himself. Repeated avoidance of a feared stimulus then exaggerates the threat associated with it, as there is no opportunity for mastery through repeated exposure. Attachment theory explains how early childhood relationships may predispose to anxiety in later life. In order
to survive, a developing child must bond to an attachment figure (usually the mother). If the mother is consistently present, reliable in her handling and 'good enough' in her emotional responsiveness, then a bond of secure attachment, or 'secure base', will develop. This enables the child to engage in exploratory behaviour, to deal with new situations without becoming overanxious, and so gradually to separate, safe in the knowledge that the mother is available if necessary. The child builds up an internal image of a good parent, which provides a sense of security. If, on the other hand, the early relationship with the parent is disrupted - by separation or by inconsistent handling, for example - the child may develop a bond of anxious attachment. Rather than being able to explore and become autonomous, the child clings to the mother, at first physically and later emotionally, showing signs of distress when separation is threatened. This childhood experience then acts as a template for separations in later life. Faced with threat, the anxious individual clings to attachment figures • spouse, parent, child or doctor. The following factors should be considered in cases of anxiety: • The nature of the current external threat. This may be obvious, such as major illness in the patient or a close relative. The 'threat' may, on the other hand, appear as trivial and 'normal' as an adolescent leaving home, or a family holiday. For an anxiously attached individual these can be major hurdles. • The relationship to attachment figures, past and present. A pattern of anxious attachment in childhood now repeated in relationship to spouse or children is often found. • 'Internal threat'. Anxious patients often experience an inner conflict between their need for dependency and their feelings about those on whom they depend. The patient is threatened not so much by external circumstances as by himself. A patient who feels angry, for example with an unfaithful spouse, but is unable to express this because of fear of separation and loss, may develop anxiety symptoms. He fears to bite the hand that feeds. The patient is frightened by his own inner impulses: sexual or aggressive feelings, or the wish for independence and autonomy. Anger in particular often coexists with anxiety; the angry individual is often a frightened one, and vice versa.
SUMMARY 8 Management of anxiety syndromes • Exploratory psychotherapy • Cognitive-behavioural psychotherapy
• Psychotropic drugs
Exploration and resolution of underlying conflict. Non-directive. Aims to change patients' behaviour directly through desensitization, and/or to, challenge their underlying assumptions. Antidepressants, minor tranquillizers, B-blockers.
MANAGEMENT
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Michael Balint, a psychoanalyst who pioneered the use of psychotherapeutic methods in medicine, wrote 'the doctor is a drug: the question is in what dose, and with what frequency it should be prescribed'. The two drugs most commonly prescribed for anxiety are tranquillizers and, via supportive psychotherapy, 'doctor'. Both can be effective in the short term, but can in the long term produce the complication of dependence, and may even exacerbate the symptoms of anxiety.
Exploratory psychotherapy Normal individuals who become anxious are usually relieved of their fears by reassurance, and the ability to reassure is thus an important part of a doctor's skill. Reassurance in neurotic individuals is often ineffective, however, because it deals only with the surface fear and not with the underlying conflict. A man who develops repeated attacks of pain, in which he is convinced that he is about to die of a heart attack, can be reassured that his ECG is normal and that he is a fit man, and be discharged. Yet a few days later he may develop another attack and present again to the doctor. The underlying fear, and the root cause of his anxiety, of which he may be unaware or unconscious, may be that his mother, on whom he is very dependent and who has recently had an illness, will die and that he will be left alone. Only when this fear is exposed and when he has learned to accept the dependent part of his himself, will his panic attacks cease. This kind of exploration is helpful in the evaluation of most cases of anxiety. In some cases it may need to be followed by longer-term psychotherapy. If the patient can learn to resolve his inner conflicts through his relationship with a doctor or therapist, and so move from a position of anxious attachment to one of secure attachment, he will be relieved of the symptoms.
Cognitive-behavioural psychotherapy (CBT) In exploratory psychotherapy the doctor aims to be understanding but is non-directive. In behavioural psychotherapy, on the other hand, the doctor aims to change the patient's behaviour directly. A phobic patient associates the feared stimulus (e.g. a spider or a department store) with unpleasant feelings. The therapy aims to desensitize the patient by gradual exposure to the feared stimulus, often in the reassuring presence of the therapist. An important feature of behavioural treatment for anxiety is relaxation training. Here the patient learns to control anxiety through muscular relaxation and deep breathing, sometimes with the aid of tape-recorded instructions. Physiological measures of arousal - galvanic skin response and pulse rate - may provide objective evidence of anxiety
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TABLE 8.5 Side-effects of benzodiazepines Tolerance Drowsiness Incoodination, ataxia Emotional blunting Anger and irritability Diminished sexual response (women) Withdrawal syndrome: insomnia anxiety depression (may be profound) irritability muscular pains and twitching perceptual distortion fits
reduction. When self-administered, this is known as autogenie training. Behavioural therapy, as its name implies, works directly with how the patient behaves and acts in the world. The focus in cognitive therapy is on the patient's thoughts, which may themselves be as anxiety-provoking as real-life situations. Indeed, one of the basic principles of CBT is Epictetus' dictum: 'Men are troubled not so much by things as by their thoughts about things'. In cognitive therapy the patient's underlying assumptions and view of the world are challenged: for example, someone with fear of flying is asked to consider rationally the probabilities of an aircraft crashing and to compare them with accident rates for road and rail travel. Their tendencies to catastrophize (i.e. fear the worst) and dichotomize (divide the world into black and white, good and bad) are pointed out, and alternative strategies suggested.
Psychotropic drugs When anxiety is a manifestation of depressive illness, the treatment of depression with antidepressants (many of which are sedative) also relieves the anxiety. Short-term (up to 10 days) prescription of minor tranquillizers such as benzodiazepines is occasionally justified for the relief of stress-related anxiety. Longer-term prescription of tranquillizers should be avoided because of the likelihood of habituation and physiological dependence. B-Receptorblocking drugs relieve the peripheral symptoms of anxiety and may also occasionally be useful. Side-effects of benzodiazepines are common (Table 8.5) (see also p. 23).
DEFENCE MECHANISMS
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Life is beset with threats. A variety of social and psychological defence mechanisms exist that keep anxiety within manageable limits. Many of these can be observed on
SUMMARY 9 Defence mechanisms against anxiety Denial Dissociation or conversion Splitting Projection
Idealization Regression Obsessional defence Intellectualization
hospital wards, where both patients and staff face the daily threat of illness and death and yet usually manage to remain cheerful and efficient.
Denial 'Everything's wonderful'. One way of dealing with fear or pain is simply to pretend it does not exist. Men are particularly prone to this in everyday life, but false cheerfulness (sometimes known as manic denial) may conceal unvoiced fears or sadness.
Dissociation or conversion 'I'm not worried about anything, doctor, it's just that I keep getting this pain ...'. Akin to denial is dissociation, in which a fear is displaced or converted into a bodily symptom. Patients who have inexplicable and elusive pains, in addition to established physical disease, may well be harbouring unspoken fears and conflicts.
Splitting 'You're wonderful, doctor, not like those terrible doctors at the other hospital.' As Trojans should fear Greeks bearing gifts, so doctors should beware the patient who heaps excessive praise (as opposed to expressing genuine gratitude). The patient may be dealing with anxiety by splitting his world into good and bad, and clinging to the good in the vain hope of absolute security. As with the Trojans, the tables may suddenly turn and we may be seen as bad, and they good. Patients can sometimes split ward staff in this way; physicians and nurses must learn to take both praise and condemnation with equanimity.
Projection 'It's the psychiatrists who are mad, not me'. Closely linked to splitting is projection, in which unwanted feelings are attributed instead to a convenient other.
Idealization 'The doctors here are the best in the world'. The defence of idealization is closely linked to splitting and projection. It is probably best seen as an example of
positive transference, in which past childhood feelings towards one's parents are, under the threat of illness, transferred on to current medical attendants.
Regression
SUMMARY 10 Mourning responses • • • •
Denial Numbness Searching Guilt
8 • Anger • Detachment • Acceptance
'Nurse ... nurse ...'. The sick, like children, are tucked up in bed, fed, pampered and waited on. This sometimes helps the physiology of recovery, but can also lead to helpless behaviour on the part of the patient, who may deal with the fear associated with illness by becoming more and more childlike, regressed and demanding.
Obsessional defences 'I always have my bowels open at such-and-such o'clock, doctor.'
MOURNING The mourning response is divided for convenience into a number of stages, which can be summarized as denial, despair and detachment, but emotional reality does not conform to any such neat sequence. Grief is characterized by surges and cycles of often confused feelings, rather than an orderly progression of recognizable stages.
Denial
The 'malade-d-petit-papief - the patient who presents with a written list of symptoms - is a familiar figure in medical folklore. The obsessional defence is an attempt to deal with fear by control. This may produce feelings of irritation and discomfort in the doctor that mirror the patient's feelings. This is an example of how the doctor's subjective response to the patient (technically known as countertransference} can be a useful guide to what the patient is feeling.
The initial reaction, especially to sudden bereavement, may be denial: 'Oh no .. .'. This attempt to resist the reality of death may persist long after the bereaved have consciously and rationally accepted their loss; they find themselves talking to their lost loved one, or may 'hear' or 'see' them in one of the hallucinatory experiences that not uncommonly occur after bereavement.
Intellectualization
Another early response to bereavement is a complete absence of feeling. The bereaved person may appear to be coping very well because of this emotional shutdown which, like the analgesia of a soldier injured in battle, enables him to get through the initial phase of loss. When this is prolonged, however, it produces chronic impoverishment of emotional life.
'Just a few more tests should clinch the diagnosis.' This defence applies more to doctors than to their patients. Incurable illness and death are inescapable reminders of the limitations of medicine. The feelings of inadequacy and sadness that this creates may be defended against by a preoccupation with diagnostic precision and excessive investigation and treatment.
FURTHER READING ON ANXIETY Holmes J 1993 John Bowlby and attachment theory. Routledge, London Marks I 1987 Fears and phobias. Oxford University Press, Oxford
LOSS, GRIEF AND BEREAVEMENT
Numbness
Searching Part of the 'work' of grief involves a mental combingthrough of the events that led up to the loss of the loved one. This phase is often accompanied by intense anxiety and restlessness. Searching, a form of separation anxiety, may lead to apparently aimless wandering, or visits to familiar spots associated with the lost one. The bereaved person appears to be struggling to negate the reality of the loss, or to rewrite history with a different, happy ending. Acceptance of loss only occurs when this impossible task has been attempted countless times.
Guilt Man is not an island, and human beings are inevitably vulnerable to loss. The mourning response - a patterned sequence of psychophysiological reactions to the loss of a loved one - is as deeply embedded in our psyche as are the phases of inflammation in our pathophysiology. Common to both are the experience of pain, immobility and gradual recovery.
Pangs of guilt or self-blame are a very common feature of bereavement. Survivors blame themselves, often quite irrationally, for the loss of their beloved. 'If only', they say, T had phoned the doctor earlier/not gone on holiday/been kinder...'. This response can be seen as an example of omnipotence, a relic of childish thinking which attempts to deny human vulnerability to fate and fortune.
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Anger Anger and guilt go together in bereavement. Outbursts of anger towards medical staff or close relatives often occur after a death, and should be met by acknowledgement of the underlying pain rather than with retaliation.
Detachment As mourning proceeds, so the grieving individual begins to separate himself from the loss and develop new interests and attachments. Pangs of grief recur, particularly at times of stress and on special dates such as birthdays, Christmas, and anniversaries of loss.
one. Feelings of guilt (associated perhaps with past fantasy wishes that the person would die) are more intense in such cases. 'Symbiotic' relationships, such as those involving unmarried daughters living with their mothers, are also often difficult to recover from when they are severed. Personality of the survivor. Dependent, insecure or depression-prone individuals are more vulnerable to prolonged grief, as are those with difficulty in expressing feelings. The latter may in part account for the greater vulnerability of men to lasting problems after bereavement. Social circumstances of the survivor. A lack of close family, friends, religious beliefs or employment all make recovery from loss more difficult.
Acceptance When mourning is 'successful' and circumstances favourable, the bereaved individual may come to accept that death and loss are part of life and may sometimes even be enriched by the experience. More usually, scars remain, and many bereaved people continue to struggle with feelings of meaninglessness and diminished vitality for many years.
Physiological changes Psychological reactions to loss are accompanied by physiological changes, including disturbance of corticosteroid metabolism and depression of T-lymphocyte response. Death from 'a broken heart' is a reality: mortality rates, mainly from coronary artery disease, are higher in widowers and widows than in their non-bereaved counterparts.
DELAYED OR PATHOLOGICAL MOURNING Return to near-normality after a major loss generally takes from 1 to 3 years. However, chronic states of depression, numbness, anger, anxiety and hopelessness can continue for much longer following a bereavement. The patient becomes stuck in one of the phases of mourning and is unable to progress towards detachment and acceptance. The likelihood of pathological grief depends on four main factors: • Type of death. A sudden, untimely (of a child, for example) or horrifying death is especially hard to accept (see Recent Advances in Post-traumatic Stress Disorder). • Nature of the relationship. An ambivalent relationship (one in which love and hate coexist) is more likely to lead to pathological mourning than a straightforward
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MCQ 8.1
MANAGEMENT About one-third of bereaved persons may be in need of professional support or intervention. Support groups, such as those for widows (in the UK, CRUSE) or for parents whose children have died (the Compassionate Friends), can be very helpful. Psychotherapy may be necessary in order to recapture and work through buried feelings associated with the loss. Sometimes this is systematized as guided mourning, in which the sufferer is encouraged to think about the lost one, talk about the details of his or her death, look at photographs of him or her, visit the grave, and so face and accept loss with diminished denial.
FURTHER READING ON LOSS, GRIEF AND BEREAVEMENT Garland C (ed) 1999 Understanding trauma: a psychoanalytical approach. Butterworths, London Parkes C M 1988 Bereavement: studies of grief in adult life, 2nd edn. Penguin, London
DEPRESSION The complaint of 'depression' can refer to a number of different feelings and reactions - anger, boredom, frustration,
SUMMARY 11 Features of depressive illness (as opposed to unhappiness) • • • • •
Sustained lowering of mood Severe Definite onset Low self-esteem Physiological changes: disturbance of sleep, appetite, weight, libido • Sometimes atypical features brought to the surface by depressive illness: pain, obsessional thoughts, violence
RECENT ADVANCES IN POST-TRAUMATIC STRESS DISORDER (PTSD) The word trauma comes from the Greek 'to pierce'. It is now known that trauma, whether individual or in mass disasters, pierces not just the body but also the psyche of those affected, either directly, or as witnesses or relatives. Also, the recognition that as many as 60% of psychiatric inpatients, whatever their diagnosis, may have been sexually abused in childhood suggests that many psychiatric disorders have PTSD as at least a component of their aetiology. These people, after diagnosed as 'personality disordered', are sometimes referred to as suffering from 'complex PTSN'. In the USA the lifetime prevalence of traumatic events - accidents, suicide, homicide or sexual assault is estimated to be around 70%. Of those so exposed, 20-40% will develop post-traumatic stress disorder. Diagnostic criteria include feelings of intense fear, horror and hopelessness at the time of the traumatic event; intrusive imagery ('flashbacks') in waking consciousness and dreams; avoidance behaviour, e.g. being unable to pass the spot where an accident occurred, or to read accounts of similar events; hyperarousal phenomena, such as disturbed sleep, increased reactivity to noise, muscular tension, poor concentration; and significant interference with normal coping behaviour; all of these lasting for more than one month after the event.
Risk factors include the nature of the trauma itself: the more horrific and violent, the greater the likelihood of PTSD; denial of emotional difficulty on the part of the sufferer; a previous history of trauma, especially in childhood; and dismissal of the severity of the symptoms by significant others such as family and doctors. Comorbidity (i.e. the coexistence of other diagnoses) is common, especially affective disorder. Neurobiology of PTSD. It is now known that prolonged exposure to high cortisol levels (as occurs in clinical stress) produces shrinkage of the hippocampus and that PTSD is associated with neuro-anatomical changes, especially in the non-dominant hemisphere. Management includes: (a) 'debriefing' - a detailed 'action replay' of the traumatic event and the sufferer's reactions, although there is some evidence to suggest that this may have a reinforcing effect and so should be used judiciously; (b) cognitive-behavioural treatment directed at intervening in the intrusive thought-avoidance cycle: the subject is systematically asked to recall the painful events until they can look squarely at them without undue anxiety; and (c) long-term psychotherapy if the trauma has reawakened previous childhood trauma such as sexual abuse; (d) in some cases antidepressant medication can be helpful.
anxiety, hopelessness and helplessness - as well as the specific psychophysiological state that psychiatry recognizes as 'depressive illness' and which is sometimes colloquially referred to as 'clinical depression'.
table, and takes no pleasure in anything. He feels he has no future and that it is pointless or impossible to make plans. Thoughts of suicide almost invariably present, although the patient may try to resist these by saying I would not have the courage'. • Low self-esteem. The patient feels worthless, inadequate, unwanted and useless. He feels intense guilt and plagues himself with thoughts of past failures and mistakes. He can only see himself in a negative light and emphasizes his weaknesses and faults. • Physiological changes. The most important of these is sleep disturbance. Anorexia, weight loss, loss of libido, constipation, retardation (slowing of thought and movement) or occasional agitation are also all important features, especially in severe or psychotic depression. • 'Atypical' features. Sometimes a depressed patient may present atypically, with physical symptoms such as unexplained pain, obsessional thoughts, agoraphobia, criminal behaviour (such as shoplifting) or episodes of anger and violence. These may have been brought to the surface by a depressive illness. In a so-called 'smiling' or 'masked' depression, the patient conceals severe depressive feelings behind a cheerful facade.
DEPRESSIVE ILLNESS Clinical features Clinical depression can be distinguished from both 'ordinary' depression or sadness (transient depressive moods) and depressive personality by three main features: • Depressive illness is a sustained depression of mood lasting for weeks or months. • The seventy of the depression is great enough to interfere with normal functioning. • The depression has a definite onset, with a distinct change from normal to depressive thinking. Depressive illness involves an alteration of many different aspects of mind, body and behaviour. It is nearly twice as common in women as in men. The features of depression may be summarized under four main headings: • Depressed mood. The patient feels weepy and miserable, 'low in spirits', anxious, lacking in concentration and irri-
Although the presentation of depressive illness can vary greatly, there are two common clinical pictures (Table 8.6). 1
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TABLE 8.6 Clinical features of neurotic and psychotic depression Clinical features
Psychotic
Neurotic
Severity of depression Delusions/hallucinations Sleep disturbance
More severe Yes Early morning wakening Yes, prominent
Less severe No Difficulty in getting off to sleep Yes/No
Worse on wakening and a.m. Yes Yes
No, or worse p.m.
Yes No
Sometimes
No
Yes
Yes
Yes
No
'Vegetative features', e.g. weight loss, constipation Diurnal mood variation 'Reactive', i.e. precipitated by loss Genetic factors, e.g. family history of manic-depressive psychosis Dexamethasone suppression test abnormal Response to tricyclic antidepressants Response to ECT
Neurotic depression Here the patient, despite depressive feelings, remains in contact with reality: 'I know it is stupid, but I feel as though I have let everybody down'. The patient might be a woman in her 30s with several small children, living in poor housing and with a husband who drinks and who is having an affair which she has just discovered. She is tearful, has lost weight and cannot fall asleep at night. She feels she is not coping with her job or housework, and no longer enjoys company or television.
Psychotic depression
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Depressive psychosis is a part of manic-depressive psychosis, an affective psychosis. The depth of the depression is here much greater than in neurotic depression. The ratio of women to men affected is more equal. The patient becomes immobilized in both thought and action. He wakes very early in the morning and may have diurnal mood variation, feeling at his worst in the morning and improving slightly towards the evening. Depressive delusions develop, the patient becoming convinced that he has, for example, brought ruin on his family, that he is evil or ugly or radioactive. Depressive hallucinations may occur: the patient may hear a voice telling him that he is evil, or he may feel that his insides are rotting and complain that he smells. Endocrine disturbance may occur in psychotic depression, with disruption of the pituitary-adrenal axis. In some cases the normal diurnal variation of cortisol output is abolished, providing the basis of the dexamethasone suppression test, in which dexamethasone is administered but fails to reduce urinary steroid levels.
SUMMARY 12 Factors contributing to depression • Loss • Genetic • Biochemical, e.g. reduced catecholamine levels at postsynaptic nerve endings • Social, e.g. lack of close relationships, unemployment, lack of good childhood experiences to build self-esteem, learned helplessness
DIFFERENTIAL DIAGNOSIS OF DEPRESSION The differential diagnosis of depression includes: • Organic illness, especially hypothyroidism • Drug administration, especially steroids and some antihypertensive drugs • Alcohol-induced depression, where depression is secondary to alcoholism (or drug addiction), and withdrawal of the intoxicant results in lifting of depressive symptoms • Anxiety states, as anxiety is a common feature of depression. When they coexist, treatment of the depression usually (but not always) removes the anxiety • Other psychoses, especially schizophrenia.
THE CAUSES OF DEPRESSION Depression is often divided into: • Reactive depression, whose symptoms correspond with neurotic depression and which is said to be a response to external events; • Endogenous depression, where the symptoms are psychotic in character and where there is no clear environmental precipitant. The distinction is misleading. Psychotic depression is usually also 'reactive' in the sense that it is triggered by a painful event in the patient's life; and neurotic depression can be 'endogenous' in the sense that genetic and personality factors influence the likelihood of an individual developing depression in response to misfortune. Loss Loss plays a central role in the origins of depression and is the link connecting grief with depression. The grieving person is in pain not just because of the loss of an external relationship, but because he has lost a part of himself. His internal world as well as his external world has been impoverished. The similarity between the clinical features of grief and those of depression are striking. In grief, an external loss dominates the picture; in depression, it is an internal feeling of loss. In 70% of depressions there has been a preceding external loss or stress: a bereavement (delayed grief is best seen as a special case of depression),
loss of job, break-up of a relationship, a child leaving home or a theft, for example. It is when this then leads to a feeling of internal loss - of optimism, vitality and (especially) of self-esteem - that a depression occurs. Whether or not a particular individual reacts to loss by developing depression depends on a number of interrelated factors, genetic, social, developmental and psychological.
Genetic/biochemical make-up Twin studies have shown that genetic factors play an important part in manic-depressive psychosis. Changes in neurotransmitter biochemistry in depression are important: current views emphasize a reduction of catecholamine levels at postsynaptic nerve endings. Antidepressant drugs may work by preventing the breakdown of cerebral amines (monoamine oxidase inhibitors), or reducing their reuptake (tricylic drugs) at central nerve endings. Similarly selective serotonin reuptake inhibitors (SSRIs) increase the concentration of serotonergic neurotransmitters in the synaptic cleft.
Current social situation The presence of a close confiding relationship, usually with a spouse, protects individuals from developing depression after the experience of loss. Employment is another protective factor; the unemployed are thus doubly vulnerable to depression, the loss of a job being a precipitant and lack of a job being a vulnerability factor. Women with three or more children under 15 and long-term social and financial difficulties are more vulnerable to depression following loss.
Early childhood experience Women who have lost their mothers before the age of 11 - whether through death, separation (for example, due to illness) or divorce - are especially vulnerable to depression in later life. A reservoir of good experiences in childhood is needed for an individual to develop a lasting sense of self-esteem. This provides a child with a good and secure internal world which can withstand the inevitable separations and losses of later life, and enables them to respond to such situations with appropriate sadness rather than by developing depression.
Psychological factors Recent studies of depression have focused on the vicious circle of depressive thinking and its accompanying negative assumptions about the self and the world. The depressed individual has developed learned helplessness, feeling that nothing he can do will make any difference to the situation. Actions and experiences that might make the individual feel better are avoided, and he continues to view himself in a negative light. His depression thus becomes a self-fulfilling prophecy. Depression produces and may be produced by patterns of dysfunctional thought, such
SUMMARY 13 Management of depression Psychological treatment Exploratory therapy Cognitive-behavioural therapy Family/marital therapy
8
Physical treatment Anti-depressants ECT
as dichotomous thinking (seeing everything as black or white), catastrophization (making a drama out of every crisis - inability to buffer and cope with minor setbacks), and a cascade of negative thoughts about the self that are triggered by everyday events, minor losses or difficulties. These serve to reinforce a basic view of the world characterized by hopelessness about the future, helplessness in the present, and guilt and remorse about the past.
Management Mild depression This is best dealt with by psychotherapy, which may take one of three main forms. Exploratory and psychodynamic psychotherapy Here, the patient is encouraged to express depressive feelings, to vent anger and despair and - through the relationship with the therapist (who may be a GP, social worker, psychotherapist or physician) - to experience the responsive empathy and containment that was lacking in childhood and so to recognize and recapture some of the good experiences the depression has blotted out. As self-esteem improves, so the patient can begin to tackle some of his current difficulties, which in a depressed state seem overwhelming. Cognitive-behavioural therapy (CBT) and interpersonal therapy (IPT) Controlled trials have shown that CBT is as effective as antidepressants in the treatment of mild-to-moderate depression. CBT counteracts learned helplessness and negative depressive thinking by challenging the erroneous assumptions on which they are based (e.g. if I phone my boyfriend and he is out, it does not mean that he does not love me, merely that he is working late), and by considering positive features of the self. The patient is encouraged to set himself small, easily accomplished tasks and to feel pleased if he succeeds. IPT is similarly focused and time limited. It explicitly adopts a medical model, seeing depression as an illness over which the patient has little control. IPT homes in on one of four underlying factors that contribute to depression: 'role transitions', e.g. depression associated with retirement, or becoming a mother, or divorce and so becoming single; grief and bereavement linking depression with unworked-through losses; interpersonal conflict, usually with partners; and social skills deficits: here depression is linked with lack of personal effectiveness and competence, and therapy is specifically designed to improve communication and social flexibility.
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Family and marital therapy Here the aim is to improve the marital relationship, which can then provide a bulwark against depression in response to loss. Partners often unwittingly contribute to the maintenance of a depressed state, perhaps by being overconcerned and 'helpful' and so reinforcing the sufferer's sense of their own helplessness and loss of role. The safe expression of anger can strengthen a relationship and reverse the inward turning of anger that is so common in depression. Moderate depression A combination of antidepressant drugs and psychotherapy can be more effective than either alone in treating moderate depression. Both depressed mood and biological symptoms improve with drugs; low self-esteem and social difficulties improve with psychotherapy. Antidepressants are always indicated when sleeplessness and guilt are prominent features. Tricyclic antidepressants (TCA) such as amitriptyline (75-200 mg/day) take 10-14 days to produce their full effect. Side-effects include parasympathomimetic symptoms of dry mouth and urinary retention, constipation, blurred vision and 'muzziness'; and cardiac arrhythmias can occur. Dosulepin (dothiepin) and lofepramine have fewer side-effects. Imipramine and clomipramine are less sedative. Tricyclics should be avoided in patients with prostatism or a history of heart disease. Mianserin, a tetracyclic, has fewer side-effects but can produce haematological reactions and is possibly also less effective in its antidepressant action. If mianserin is used, a blood count should be carried out every 4 weeks. Selective serotonin re uptake inhibitors (SSRIs) such asfluoxetine,fluvoxamine, sertraline and citralopine have fewer antimuscarinic side-effects and low cardiotoxicity, and are therefore preferable, especially when the suicide risk is strong. They may, however, cause nausea and vomiting. Venlafaxine has mixed SSRI and TCA properties and is another popular antidepressant. Monoamine oxidase inhibitors (MAOIs) such as phenelzine (15-90 mg daily) are still occasionally useful as second-line drugs, especially when phobic symptoms are present, but dietary restrictions (e.g. no cheese or yeast-extract) are needed because of harmful (hypertensive) interactions with tyramine-containing substances. Moclobemide is a newer MAOI that can be taken without any major dietary restrictions. Severe depression Depressed patients who are severely incapacitated, psychotic or actively suicidal require hospital admission. Antidepressants, which may have to be given in large doses (up to 250mg of amitriptyline or equivalent daily), are the first line of treatment.
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ECT Despite debate about its mode of action and efficacy, and despite popular prejudice, controlled trials of electroconvulsive therapy (ECT) have shown it to be an effective and rapid treatment for depressive delusions and hallucinations (Fig. 8.4); it is also free from side-effects, apart
FIG. 8.4 Effect of ECT on severity of depression
from the dangers of the anaesthetic and some short-term memory impairment. ECT is a first-line treatment in depressive stupor or where the patient is refusing food and drink. When the patient refuses consent, in the UK it can only be given after Section 3 of the 1983 Mental Health Act has been applied and a second, independent, psychiatric opinion obtained, although in a life-threatening situation one application of ECT may be given pending the second opinion. ECT produces a rapid improvement in severe depression and is especially effective in elderly patients, in whom tricyclics may produce confusion and cardiac arrhythmias. The basis of ECT is the delivery of a convulsion or fit, and its effectiveness depends on an adequate fit of around 25 seconds. A 'course' of ECT, given twice or thrice weekly, should deliver a total of around 250 seconds of fit if relapse is to be avoided. ECT can be given to both hemispheres (bilateral) or to the non-dominant one (unilateral), depending on the position of the electrodes. Unilateral ECT produces less memory impairment but may also be less effective. ECT is very effective in the short run but, unless supported by psychological and pharmacological therapies, relapse is also common. Chronic or recurrent depression Most depressive illness has a tendency to remit, but relapse is common. Prolonged treatment with tricyclics has a prophylactic effect, as does 'maintenance' psychotherapy. Relapse of depressive psychosis may in some cases be prevented by prophylactic lithium carbonate. Chronic depressive states are rare but disabling, and prolonged attendance at a supportive day hospital may be required.
FURTHER READING ON DEPRESSION Brown G, Harris T 1978 The social origins of depression. Tavistock, London
TABLE 8.7 Clinical profiles of suicide and parasiticide Suicide
Parasuicide
Central theme
Despair, depression
Anger, frustration
Epidemiology
Increase in men aged 15-25, 1985-1999
Increase in all groups 1985-1999
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Commoner in women aged Age, sex, class Commoner in age range 25-34; commoner in men 18-35 and in social than women; no class classes IV and V preference; recent increase in death by suicide in young men Social circumstances
Isolated, e.g. unemployed, retired, divorced, children left home, few friends or religious/social groups
Disturbed but not isolated, e.g. teenager unhappy with parents or boyfriends
Method and build-up
Planned. Usually leaves a note; method often violent, e.g. hanging, shooting, drowning
Impulsive. Commonest method is swallowing pills. Cutting (usually wrists) a more disturbed subgroup
Alcohol
May play a part - 'Dutch courage'
Attempt very commonly associated with alcohol/ drugs, i.e. reduced impulse control
Illness
90% of suicide case are mentally ill, usually with depressive illness. Physical illness also common
Only about 30% are mentally ill. Some have personality disorder. Majority normal or with 'minor affective illness'
Outcome
Not all 'succeed'. Survivors need hospital admission for treatment of mental illness
Not all survive, but most do. About 5% repeat. May benefit from counselling or psychotherapy
FIG. 8.5 Death rates for suicide and undetermined injury in England 1969-91
Lee A 1999 (ed) Affective and non-pychotic disorders. Gaskell, London Scott J 1995 Psychological treatments for depression. Br J Psychiatry 167: 289-292
SUICIDE AND PARASUICIDE Suicide appears to be an integral part of human psychology. There are few individuals lucky and happy enough never to have had even a fleeting thought of suicide at some point in their lives. There has been a worrying increase in suicides in young men (Fig. 8.5). 'Parasuicide', a syndrome of deliberate self-harm, appears to be a relatively recent phenomenon and has reached epidemic proportions over the past 25 years. It is the commonest cause of hospital admission for women under 65, and the second commonest for men. Many cases of deliberate self-harm go unreported; probably only about one-third reach hospital.
Clinical profiles The clinical profiles of suicide and parasuicide are, on the whole, distinct (Table 8.7). A person who commits suicide could be a male with a previous history of depression and alcoholism, recently divorced or made redundant, living alone and with few close friends or relations. He deliberately tells the neighbours and milkman that he is going away for the weekend, and then takes a bottle of aspirin or shoots himself. A parasuicidal person might be a woman in her late teens living with her mother and stepfather, and getting on badly with her boyfriend. After a row with him, in which both have been drinking, she goes home, swallows some of her mother's sleeping tablets, and is then noticed to be drowsy. When challenged about what has happened, she immediately 'confesses' and is rushed to hospital.
The central theme of suicide is despair and depression; in parasuicide it is anger and frustration. Although there are important differences there are also psychological similarities. Both involve a physical attack on self, on the body. In both cases the patient feels a combination of personal inadequacy and anger towards friends and family. This anger is directed inward, but there is often a wish to punish or harm those to whom the patient feels close. This is done indirectly via the suicide or suicide attempt. It is often said that parasuicide cases 'do not really mean it'. This is only partially true, and can sometimes be used by staff as justification for adopting a punitive attitude. It is best to assume that both suicide cases and parasuicide cases want both to die, and not to die. The relative proportion of the two feelings varies greatly, but both feel both. A third point of overlap follows from this. Not all suicide cases succeed and, conversely, it is possible in parasuicide to die by mistake. Patients who have made major suicide attempts may recover and, with the help of drugs, psy-
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FIG. 8.7 Primary diagnosis of suicides (England and Wales Suicide Inquiry cases), 1996-2000 FIG. 8.6 Age and sex profile of general population suicides (England and Wales), 1996-2000
chotherapy and time, regain the will to live. In the majority of parasuicide cases the attempt resolves the difficult social situation that prompted it, and so is not repeated. In a minority - about 5% - the attempts are repeated, and a proportion of these will eventually 'succeed'. Parasuicide repeaters are more likely to have a personality disorder, to be addicted to drugs or alcohol, or to have been in trouble with the law. (See Figs 8.6 and 8.7.) 1
Management of 'failed suicide' The causes of suicide are essentially the causes of depressive illness, and the management of attempted suicide is that of prevention, and particularly the early detection, of depression. About half of successful suicide cases have contacted a helping agency - a counselling organization, a GP, social worker or priest - in the month before they kill themselves. It is important to ask troubled, unhappy or depressed patients about suicidal feelings. Fleeting suicidal thoughts - 'I would like to sleep' or 'I would like to be dead but would never have the courage to do anything' - are less worrying than a definite suicide plan. Talking about suicidal thoughts may in itself be a relief. Suicidal patients with symptoms of depressive illness should be admitted to a psychiatric unit. Patients who are managed as outpatients need to be seen frequently while they are in a suicidal state.
1
224
MCQ 8.2
Antidepressants can be prescribed, but only in small amounts, as hoarding of tablets can be a danger. Although the prevention of suicide remains the ideal, this is difficult to achieve in practice. Counselling organizations such as the Samaritans seem not to have had a major impact on overall suicide rates, but the incidence of suicide in the UK has fallen slightly over the past 30 years compared with the rest of Europe. Suicide is a reminder of the limitations of psychiatric and social care. When a patient who is receiving treatment commits suicide, it is especially stressful for the doctors and nurses involved, as it always is for the patient's family. Feelings of guilt and anger are inevitable. Suicide, like any death, is a reminder that doctors are not omnipotent. In dealing with suicide or the threat of it, it should be remembered that, ultimately, a person determined or ill enough can always find a way to end his life.
DELIBERATE SELF-HARM Causes The causes of attempted suicide cannot be found solely within the individual. Social factors that need to be considered in understanding the increase in parasuicide rates include: • Complex family structures without clear rules or roles, such as unsupported one-parent families; adolescents who want freedom but lack the emotional or financial resources to leave home; families with step-parents; • Drugs being a socially acceptable means of dealing with distress: the commonest tablets taken in parasuicide are mild analgesics and minor tranquillizers;
8
CASE STUDY 8.1 SUICIDE OF A 20-YEAR-OLD ART STUDENT A 20-year old art student was brought by her friends to the psychiatric ward in a highly aroused state. She had not slept for several days, was dishevelled, could not sit still, and was talking 'nineteen to the dozen'. She was convinced that she was a direct descendant of van Gogh and that her paintings were worth several million pounds. She came from a loving family but one in which there was a very high incidence of mental illness. Her mother suffered from alcoholism, her half-sister had committed suicide, and her father, a very successful businessman, had marked mood swings. A diagnosis of hypomania was made. She was treated with haloperidol and started on lithium carbonate. After 2 weeks in hospital she was well enough to return home, but not to resume her studies. She was followed in outpatients and offered fortnightly supportive psychotherapy in addition to her continuing drug therapy. She found the side-effects of the neuroleptic drugs troublesome, and often 'forgot' to take her haloperidol. Her mood continued to be somewhat elated, and she worried her parents by mixing with what they saw as a 'wrong' crowd, many of whom had also suffered psychiatric illnesses or abused drugs. She suffered an episode of depression when an exboyfriend killed himself while drunk, and had once more to be admitted to hospital for a brief period. Two years after her original admission she felt well enough to resume her studies at art college. Things seemed to be progressing well, and she reduced her contact with psychiatric services to a
3-4-monthly outpatient attendance. She wanted to come off all her drugs, and was only persuaded to continue with lithium with some difficulty. Then one weekend, apparently without warning, she was found dead in her flat having taken an overdose of aspirin. On reconstructing the preceding history it appeared that she had taken no lithium for several weeks prior to her tragic death. Lithium levels were supposedly checked by the student health service every 3 months, but she had failed her most recent appointment.
Questions 1. What was the diagnosis? 2. Could her suicide have been prevented?
Discussion She showed many of the features of manic-depressive psychosis, bipolar type. There was a strong family history of mood disorder. She showed features of hypomania on first admission, which responded to neuroleptics and a mood stabilizer. Later she developed depressive symptoms in response to a painful life event. The mortality rate from suicide in manic-depressive illness is around 10%, and there is some evidence that taking a mood stabilizer such as lithium reduces mortality. There was an administrative and ethical conflict between the patient's reasonable desire to lead as normal a life as possible and the fact that she was
An epidemic factor. Deliberate self-harm is often behaviour learned from friends, fellow patients, relatives or television.
Management The medical management (p. 23) of the parasuicide patient takes initial precedence over the social and psychiatric
suffering from a potentially lethal psychiatric illness. Insisting on regular contact with medical/psychiatric services - her GP, community psychiatric nurse or consultant psychiatrist - might well have meant that her deteriorating mental state and poor drug compliance would have been picked up. Even better would have been attendance at a 'lithium clinic' run as part of a mental health service. Ongoing psychotherapy could also have identified the recurrence of her depressive symptoms and her irrational view of herself as useless and a burden to everybody, which was revealed in her suicide note. But all of this is to be wise after the event. She appeared to be doing well, and there is a limit to the extent to which treatment can be imposed on someone who feels and seems to be functioning well. Her case illustrates one of the most poignant dilemmas of psychiatry. Severe mental illness affects young people and has a mortality comparable to that of diseases such as leukaemia. She survived for nearly 5 years after diagnosis, a result which would be considered quite good in physical medicine but can lead to a very pessimistic appraisal of psychiatric treatments. All this had to be discussed in the case review, which occurs whenever there is a suicide among patients known to psychiatric units - open meetings in which staff can express their feelings without fear of censure, and work through the inevitable emotions of guilt, failure, anger and despair that suicide can evoke.
assessment. Medical staff often feel angry with overdose patients compared to those whose illness is not selfinflicted and, like alcoholics and drug addicts, such patients may become scapegoats. Their irresponsibility affronts the overworked nurses and doctors, who are often similar in age and maturity to the patient. In addition, medical staff work in a stressful and hierarchical situation in which they can at times feel angry or frustrated, and these emotions
225
can be displaced into a punitive attitude towards parasuicide patients. This can be avoided if ward procedures give time for discussion of these patients and the feelings they arouse.
History A careful history must be taken from the overdose patient, who should be kept in hospital until alert and cooperative enough for this to be possible. The presence of depressive illness and suicidal rather than parasuicidal features must be identified. The risk of a repeat attempt has to be assessed (Table 8.8). Social isolation, marked sleep disturbance preceding the attempt, strong feelings of guilt or unworthiness, evidence of preplanning, inability to look to the future and previous psychiatric history - especially if there are drug or alcohol problems - all point to serious disturbance and should lead to referral to a psychiatrist. A detailed account of the attempt itself and of events surrounding it should be taken. It is often unhelpful to ask the patient 'why' he harmed himself. If the patient knew, he might not have had to do so. In attempted suicide one often finds an acting-out of feelings, rather than the capacity to contain or verbalize them. The patient will find it much easier to answer questions about 'what happened,
TABLE 8.8 Deliberate self-harm: assessment of severity of disturbance. Ideally, all eases should be referred for psychiatric assessment, Psychiatric referral is essential if any of the following are present Circumstance of the attempt Evidence of preplanning (e.g. suicide note, use of car exhaust) Violent method used (e.g. attempted hanging) Social circumstances of patient Alone Away from home Personal history of patient Recent loss (e.g. bereavement, divorce/separation, unemployment) Physical illness Previous attempts Alcohol or drug addiction History of depressive illness Family history of patient Suicide Depressive illness Mental state examination Sleep disturbance, low mood before attempt Low self-esteem, hopelessness Psychotic features (e.g. 1 deserve to die')
226
Future No relatives or other support Unresolved crisis Continued determined suicidal intent
and how'. This provides an 'action replay' of the attempt, which will contain the clues to the question of 'why'. Most commonly the patient feels angry but is unable to express this directly, usually for fear of rejection by a partner, spouse or parent on whom he feels dependent. As in depression, he dare not bite the hand that feeds, and so attacks himself instead. It can be useful to ask the patient who he thinks would have been most distressed if he had died. Later, it is often helpful to discuss alternative strategies with the patient, to examine what he could have done in the same situation other than attempt suicide. Followup counselling after discharge, either as an individual or in a family, by a social worker, psychiatrist or psychotherapist, may be offered, although less than half of patients accept such help. However, even without follow-up the prognosis of parasuicide, in the absence of depressive illness or personality disorder, is fairly good.
FURTHER READING ON SUICIDE AND PARASUICIDE Hawton K 1987 Assessment of suicidal risk. Br J Psychiatry 150: 145-153. Hawton K, Catalan J 1987 Attempted suicide: a practical guide to its nature and management. Oxford University Press, Oxford Owens et al 1999 Assessment of deliberate self-harm in adults. In: Lee A., ed. Affective and non-psychotic disorders. Gaskell, London.
MANIA AND HYPOMANIA Clinical features In depression, mood is abnormally lowered. In mania, or its milder form hypomania, it is abnormally elevated. In unipolar manic-depressive psychosis the patient may have recurrent depressive or recurrent manic episodes. If both manic and depressive episodes occur, the patient has bipolar manic-depressive psychosis. There are three main groups of symptoms in mania and hypomania: • Psychological symptoms. The patient feels elated, cheerful and expansive, and his thoughts are speeded up. He may develop grandiose delusions of wealth, potency and fame. He is full of optimistic (and unrealistic) plans for the future. • Physical symptoms. The patient is restless, sleeps little, eats voraciously or not at all, often loses weight, has poor concentration, and tries to do several things at once. • Behavioural symptoms. The patient often spends large amounts of money, dresses flamboyantly and may behave in an outrageous, disinhibited and promiscuous manner. Outbursts of irritability and aggression are common. Speech is rapid, may be incoherent, and flits from subject to subject (known as flight of ideas). The patient is often humorous in an irreverent and infectious way.
CASE STUDY 8.2 A 32-YEAR-OLD WOMAN WHO HAS TAKEN AN OVERDOSE A 30-year-old married woman was sent to A&E by the emergency GP service having been found by her husband in a comatose state with a bottle of Prozac beside her and smelling of alcohol. She was admitted to the medical ward, given a fluid diuresis, and made a full physical recovery within 12 hours. The duty psychiatric team was then called to evaluate her. She said that she had been feeling low for several weeks, with poor sleep and reduced appetite. She had had a difficult year, since her mother had been killed in a car accident, and her 9-year-old son had been diagnosed as suffering from hyperactivity attention deficit disorder and excluded from his school. Her husband, a builder, had been unemployed because of a bad back, and on the day of the overdose they had received a final demand for a gas bill which she could not pay. This felt like the final straw - she felt she could not cope, her husband was out at the pub with his friends, and her son would be better off without her. She and her husband had been getting on badly, with lots of rows, she had no libido and they had not had sex for several months. She had a history of puerperal depression after the birth of her son, and had taken a minor overdose in her teens following a row with her boyfriend. She was an only child. Her parents had separated when she was 13. She had stayed with her mother who soon remarried, but the patient had not got on with her stepfather. She saw her father infrequently and felt awkward with him. On examination she was a bedraggled, miserable-looking person, appearing older than her 30 years. She was overweight. History-taking was difficult and she made little eye
contact. Her speech was normal in form but slightly slowed. She was subjectively and objectively depressed. She felt guilty towards her family, feeling she had let them down and that she was in some way responsible for her son's problems. She had no delusions or hallucinations. Cognition was normal and she was of average intelligence. The interviewer felt a mixture of pity and irritation towards the patient. She said that she no longer felt suicidal, but was unable to visualize how things would be different if she returned home. On being offered admission to a psychiatric ward, she refused.
Questions 1. What is the diagnosis? 2. How serious is the risk of further self-harm or suicide? 3. Should she be compulsorily admitted to hospital?
Discussion The diagnosis of depressive illness is fairly clear in this case. She gives a history of low mood, poor appetite, loss of libido and difficulty in sleeping over several weeks, culminating in an overdose of tablets with suicidal intent. She felt guilty, unattractive and useless. This was not a purely situational episode of deliberate selfharm, although there was an impulsive element to it, and there was no evidence of preplanning and she had not written a suicide note. The depression was of moderate severity, but there were no psychotic features. She claimed that her suicidal feelings had resolved, but was unable to give
8
a convincing account of how things could change in her life. Her home support was problematic. There was a definite, but not extreme, continuing suicide risk. Compulsory admission is a grave step, especially in the absence of psychotic features, but to let her go home might be to court disaster. During these deliberations her husband appeared on the ward. He was interviewed and revealed himself to be a reasonable man, desperately worried about his wife and shocked by her suicide attempt. He admitted that he too had felt depressed and had tended to resort to alcohol and avoid his home problems by going to the pub with his friends. He was strongly opposed to compulsory admission and said that he would guarantee to keep a close eye on his wife. Compulsory admission requires the consent of the nearest relative, unless that power is taken away by applying to a local magistrate - an extreme measure. A further attempt to persuade the patient to stay in hospital was made, and she reluctantly agree to stay voluntarily. While on the ward she was started on a more sedative antidepressant, sertraline, joined a self-esteem and assertiveness group, and she and her husband attended marital therapy sessions, in which her anger about the way in which she felt he had abandoned her was clearly expressed. He accepted the legitimacy of this and apologized. She could link this with her feelings about her father, who had abandoned her after her parents' divorce, and began to see that, despite his faults, her husband was a loyal and loving man. Her suicidal feelings lifted, she began to sleep better and was discharged from hospital, although therapy continued.
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Hypomania frequently coexists with depressive symptoms: the patient laughs and cries almost simultaneously. This is known as a mixed affective state. Hypomanic episodes may, like depression, be triggered by a painful rejection or loss. This has led to the concept of manic defence, whereby the patient escapes into mania as a way of avoiding unhappy or sad feelings.
Management A hypomanic patient can cause havoc to both himself and his family. Hospital admission is often indicated but may be hard to achieve voluntarily, as the patient denies illness, often claiming to have never felt better, or to have discovered the secret of life. Immediate management is with tranquillizers such as chlorpromazine (100-600 mg daily) or haloperidol (15-60mg daily). Subsequent relapses may be prevented by prophylactic lithium carbonate (800-1600 mg daily). Lithium also has a mild immediate antimanic effect. Blood levels should be monitored regularly and be in the range 0.8-1.5mmol/L. Lithium may produce hypothyroidism and renal damage, leading to nephrogenic diabetes insipidus, and thyroid and renal function should be monitored. Other side-effects include abdominal pain, fine tremor, subjective memory impairment, thirst and lowered zest for life. Patients should be encouraged to keep up fluid intake in hot weather. Anticonvulsants such as carbamazepine (400-1600 mg daily) can be used as second-line antimanic prophylactics if lithium is ineffective or cannot be tolerated.
SCHIZOPHRENIA Just under 1 % of the population develop schizophrenia at some point in their lives, a statistic that appears to hold true for all cultures and countries. Chronic major mental illness in people under 65 is due mainly to schizophrenia. Until the move towards community care began, about half of all hospital beds in the UK were in mental hospitals and the majority of these (for the under-65s) were occupied by patients with a schizophrenic illness. As the number of hospital beds has fallen, a significant proportion of the vagrants living in large inner-city hostels and prison recidivists are found to be suffering from schizophrenia.
Aetiology Schizophrenia is the core disorder in adult psychiatry. Much debate has raged about the nature of schizophrenia, or even whether it is a valid clinical entity. It is probable
1
228
MCQ 8.3
Chances of developing schizophrenia (%) Relationship Parent: one Parents: both Sibs (neither parent schizophrenic) Sibs (one parent schizophrenic) Children Half sibs Uncles and aunts Nephews and nieces Grandchildren First cousins Fraternal twins Identical twins FIG. 8.8 Lifetime expectation of schizophrenia in relatives of schizophrenics
that schizophrenia is not a single disease but a group of related conditions. Both genetic and environmental factors are important in the aetiology of schizophrenia. It is best seen as a developmental disorder of the brain to which genetic and perinatal factors (birth trauma or maternal viral infection) contribute, but manifesting itself in late adolescence when brain maturation is finally completed. Pathogenic environments contribute to relapse in schizophrenia, but their role in aetiology is uncertain. It is possible that abnormal brain development may result from unstimulating or traumatic environments. • Twin and adoption studies have demonstrated the role of heredity in schizophrenia (Fig. 8.8). The concordance rate for identical twins is about 50%, that for nonidentical twins around 15%. • The efficacy of antipsychotic drugs such as chlorpromazine, with its inevitable parkinsonian side-effects, suggests a disturbance of midbrain dopaminergic pathways in schizophrenia (the 'dopamine' hypothesis). There is convincing evidence of increased D2 activity in patients with positive symptoms of schizophrenia. Dopamine abnormality may be the end result of other metabolic aberrations. It seems likely that serotonin (5HT) is also involved, perhaps by increasing D2 levels. Also glutamate, an excitatory neurotransmitter, may behave abnormally, leading to underactivity of Nmethyl-D-aspartate, which in turn may stimulate abnormal dopamine and 5HT activity. • A subgroup of patients show ventricular abnormalities on CT scan. There is slight ventricular enlargement, a reduction in the normal asymmetry between the cerebral hemispheres and, particularly in males, a reduction in cortical grey matter, especially in the temporal lobes. It has been suggested that structural abnormalities are more common in patients who lack a family history of the illness, suggesting that non-genetic organic factors, perhaps associated with perinatal brain injury, may be important in some cases.
SUMMARY 14 Schneider's first-rank symptoms
TABLE 8.9 Relapse rate for schizophrenia
• Delusional perception • Auditory hallucinations Audible thoughts (thought echo) Voices arguing or discussing ('third person') Voices commenting on the patient's actions • Thought disorder Thought withdrawal Thought insertion Thought broadcasting • Passivity experiences: delusions of control 'Made' feelings (includes somatic hallucinations) 'Made' actions Somatic passivity (body invaded from outside)
A. At 9 months
• Family and social factors have also been shown to be important, although not pathognomonic. In established schizophrenia the relapse rate is high when the patient is living in an over-involved family where there is a negatively charged emotional atmosphere (high 'expressed emotion', or 'EE') (Table 8.9). • Schizophrenic patients have a high state of psychophysiological arousal, possibly related to family stress. This may reflect limbic system dysfunction and lead to a difficulty in processing sensory stimuli.
8
Relapse rate 50% 12%
High EE homes Low EE homes B. In high EE homes Face-to-face contact
Maintenance therapy
Relapse rate
High High Low Low
No Yes No Yes
92% 53% 42% 15%
Delusions In schizophrenia these include the feeling that one's thoughts originate from outside ('thought insertion'), that they are being interfered with, removed ('thought block' and 'thought withdrawal') or transmitted to outsiders as though on a loudspeaker ('thought broadcasting'). 'Passivity feelings' are the feeling that one's thoughts or actions are 'made' from outside.
Delusional perception Clinical features Schizophrenia usually starts in young adulthood (the exception being paraphrenia, a form of paranoid schizophrenia affecting the elderly). There is a slight preponderance of men. The features of the illness can be divided into two parts: the effects on mental processes, and the effects on social functioning.
Mental disturbance There is a general disturbance of mental functioning in schizophrenia. The normal progression of logical thought is disrupted ('thought disorder'). The privacy of the self is breached. Certain patterns of disorganization of thinking are characteristic of schizophrenia, and are known as Schneider's first-rank symptoms.
Hallucinations These are usually auditory. Characteristic of schizophrenia are 'third-person' hallucinations, in which more than one person is heard discussing the patient and referring to him as 'he', 'she' or 'it'. Voices commenting on a person's actions like a 'running commentary' are also characteristic, as are voices that echo the patient's thoughts. Tactile or 'kinaesthetic' hallucinations, for example electric-shock feelings in the limbs, are rare but pathognomonic.
In delusional perception, a neutral stimulus (e.g. a car number plate or a traffic light) suddenly acquires special and often frightening significance for the patient. 1
SUMMARY 15 Management of schizophrenia • First attack: admit to hospital or day hospital for assessment, confirm diagnosis, establish contact and initiate treatment. • Treat symptoms with neuroleptics. Chlorpromazine 100mgt.d.s. by mouth Trifluoperazine 5mg t.d.s. by mouth Risperidone 2-4 mg b.d. by mouth Examples of Olanzapine 5-10 mg b.d. by mouth moderate moderatedoses doses Flupentixol ('Depixol') 40 mg 2-weekly Fluphenazine ('Modecate') 25 mg 2-weekly Treat side-effects as necessary with antiparkinsonian agents, e.g. Kemadrin 5 mg t.d.s. • Assign 'community key worker' as part of community care programme who will offer supportive psychotherapy and coordinate care package. • Assess family situation: offer psychoeducational programme to lower 'EE' if indicated. • Rehabilitation: attend day hospital, day centre, sheltered workshop, live-in hostel, sheltered housing. • Where resistant to medication consider newer neuroleptics: clozapine and risperidone.
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Social deterioration The second main feature of schizophrenia is social deterioration. This is known as a negative feature of the illness, as opposed to the positive features of thought disorder, delusions and hallucinations. The patient may withdraw from social contact, give up his job, shun his friends and family, and spend many hours in isolation.
Differential diagnosis
Antipsychotic drugs These are of two main types: the so-called 'typical' antipsychotics, and the newer 'atypicals', orginally developed in the search for drugs with fewer extrapyrimidal side-effects (EPSs), which are rapidly becoming standard treatments. 'Typicals' can be divided into three main groups. All are potent D2 receptor antagonists.
An important subtype of schizophrenia is paranoid schizophrenia, characterized by paranoid delusions. Here the onset is later (around 30-40 years of age), social deterioration is much less marked, and the personality is relatively well preserved. Schizoaffective disorder has features of both schizophrenia and an affective illness, e.g. first-rank symptoms plus considerable depression. Its diagnosis is intermediate between that of the two 'parent' disorders. Not all madness is schizophrenia. The differential diagnosis includes:
• A group characterized by profound sedative effects and moderate antimuscarinic and extrapyramidal effects, e.g. chlorpromazine (50-1000 mg daily); • Moderate sedative effects, marked antimuscarinic effects, but fewer extrapyramidal effects, e.g. thioridazine (25250 mg daily), often used as a sedative in the elderly; • Fewer sedative and antimuscarinic effects but more pronounced extrapyramidal effects, e.g. trifluoperazine (2-30 mg daily); haloperidol (2-80 mg daily); flupentixol (2-100 mg daily).
• Organic psychosis, such as acute confusional states and drug- and alcohol-related psychosis; • Manic or depressive psychosis (in which auditory hallucinations occur but are more often 'second-person', in which voices speak directly to the patient); • Hysteria; • Stress-induced or 'psychogenic' psychosis; • Severe personality disorder.
Atypical' antipsychotics tend to have strong 5HT2a receptor antagonist activity. They include:
Prognosis The course of schizophrenia is very variable. About 30% of patients have only one episode. A good prognosis is more likely if the psychosis has an acute onset, a clear precipitant, florid symptoms, marked mood change in addition to disturbance of thinking, and good previous social adjustment and personality. At the other end of the scale, about 15% remain severely disabled and will still be in institutional care after a year. In these patients the negative features of schizophrenia (withdrawal and inertia) may predominate. In the middle group, representing the majority of patients, the illness has a fluctuating course but relapse and some residual disability are likely to occur.
Management Acute schizophrenic symptoms respond well to antipsychotic medication. There is some evidence that prompt treatment is associated with a good prognosis. The patient will normally be admitted to a psychiatric unit and treated initially with 100-1000 mg daily of chlorpromazine or its
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equivalent. The longer-term management of schizophrenia is difficult. It involves both prevention of relapse and management of chronic disability.
MCQ 8.4
• Clozapine. This has serotonergic and dopaminergic properties and is effective against positive and negative symptoms of schizophrenia which have failed to respond to typicals. Its main drawback is that it causes agranulocytosis in 3% of subjects, and weekly blood count monitoring is necessary. Excessive salivation and sedation can also be problematic. • Risperidone. Also effective against positive symptoms, but can cause agitation and insomnia. • Olanzapine and quetiapine (an anagram of quiet-apine!, subtly drawing attention to its sedative properties) are also effective drugs and generally well tolerated, although they can cause alarming weight gain. A wide range of side-effects and idiosyncratic reactions may be produced with the antipsychotic drugs (Table 8.10). Perhaps the most serious of these is the rare but potentially fatal neuroleptic malignant syndrome, characterized by hyperthermia, confusion, muscular rigidity and autonomic disequilibrium (tachycardia, labile blood pressure, sweating). The patient should be admitted immediately to a medical unit; all antipsychotics should be discontinued and bromocriptine and dantroline given. Psychosocial interventions Analytical psychotherapy is generally not favoured in schizophrenia, and indeed the emotional arousal it may evoke can cause deterioration. There are, however, a number of 'psychosocial interventions' that significantly improve the wellbeing of patients with this disease. These comprise: • Family intervention. Because high 'EE' is associated with relapse, measures to reduce EE, either in families or in the hostels where some patients with schizophrenia live,
TABLE 8.10 Side-effects and toxic effects of antipsychotic drugs (e.g. chlorpromazine, flupentixol) Type of effect
Examples
Autonomic (antimuscarinic)
Blurred vision Dry mouth Constipation Precipitation of glaucoma Postural hypotension Inhibition of ejaculation Urinary hesitancy Akinesia (Parkinson-like) Acute dystonia Tardive dyskinesia (involuntary repetitive movements) Akathisia (motor restlessness) Weight gain Galactorrhoea and amenorrhoea Gynaecomastia Agranulocytosis Cholestatic jaundice Skin rashes
Extrapyramidal
Endocrine effects
Hypersensitivity reactions
Neuroleptic malignant syndrome Provocation of epileptic fits Hypothermia (especially in the elderly) Skin photosensitivity
will be valuable. A programme of 'psychoeducation' for families teaches them about the nature of the disorder and, via family group therapy or regular therapy sessions with families, works to reduce the emotional tension and foster a more benign atmosphere. Long-term supportive psychotherapy. Therapy in schizophrenia has to be long-term: perceptible change may take 4 years or more. A stable consistent therapeutic relationship with a psychiatrist or community key worker is needed and often bears fruit. Cognitive-behavioural therapy (see Recent Advances box). 1
Management of chronic disability Chronic mentally ill patients are severely handicapped. Their prospects of employment are poor, they may have little or no family support, and their capacity to care for and occupy themselves may be very limited. They are sometimes also shunned or made scapegoats by society, which tends to fear and despise madness. For at least 150 years these problems were dealt with by removing patients from society and locking them away in mental hospitals, thereby reinforcing the helplessness and isolation produced by the illness. Because of this, and also because mental hospitals are expensive to run and often sited on valuable land, government policy in the UK has now shifted away from the mental hospitals and towards community care. Patients are supposed to be cared for within the local community, in a network of hostels, sheltered houses, day hospitals and day centres, and community mental health centres. These are run by a locally based team of professionals, the 'multidisciplinary team' including community psychiatric nurses (CPNs), social workers and general practitioners, as well as psychiatrists. However, although this pattern of care is desirable for many patients, and is already a reality for some, it is not necessarily suitable for all patients, some of whom continue to need highly staffed or secure facilities on an intermittent or continuous basis. The care programme approach aims - through ensuring that every patient has an identified key worker, a definite 'care programme' and regular reviews with all concerned - to prevent patients from drifting away from services and thus to prevent the relapse that is likely to ensue when continuity of care is lost.
8
FURTHER READING ON SCHIZOPHRENIA Drug and Therapeutics Bulletin 1996 Drug treatment of patients with schizophrenia. Drug Ther Bull 33:81-86 Kane J, McGlashan T 1995 Treatment of schizophrenia. Lancet 346:820-825 Lewis S, Buchanan R 1998 Schizophrenia. Health Press, Oxford
PARANOID STATES Long-term maintenance on medication (which in the case of 'typicals' can sometimes be given in the form of a weekly or fortnightly injection because of problems of compliance) prevents relapse in schizophrenia. Phenothiazines can, however, have unpleasant and serious side-effects, especially a feeling of tiredness and extrapyramidal syndromes of stiffness and involuntary movements (Table 8.9). Antiparkinsonian drugs such as orphenadrine (100 mg t.d.s.) or Kemadrin (5 mg t.d.s.) should be given to counteract these. Reducing family tension has also been shown to prevent relapse. This can be achieved by family counselling sessions and by physical separation of the patient from an over-involved family through the provision of hostel accommodation and/or attendance at a day centre.
Paranoia means literally 'to be beside oneself, or 'out of one's mind'. In psychiatry, it refers to a psychosis whose
SUMMARY 16 Conditions resulting in paranoid states • • • • • •
Organic psychosis Manic-depressive psychosis Paranoid schizophrenia Paranoid psychosis Paranoid personality Paranoia in the elderly
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RECENT ADVANCES IN THE PHYSHOSOCIAL MANAGEMENT OF SCHIZOPHRENIA Schizophrenia remains psychiatry's greatest challenge. Although the essential nature of the schizophrenias remains as elusive as ever, the past few years have seen, for the first time for two decades, significant psychotherapeutic advances. There is evidence that the longer the time between the onset of symptoms and beginning treatment, the worse the prognosis. This has led to much current interest in the notion of 'early intervention' in schizophrenia - trying to pick up the prodromal stages of the illness and initiating treatment, both psychosocial and pharmacological, as early as possible.
Psychosocial treatment of schizophrenia Exciting results have recently been claimed for cognitive-behavioural treatment in schizophrenia. Contrary to earlier views, it seems that patients can develop some control and mastery over their symptoms, especially abnormal beliefs and auditory hallucinations. Patients can, for example, distract themselves from voices by concentrating on external tasks, by playing music on 'Walkman' headphones, or even by 'bargaining' with the voices so that they confine 'their' attentions to particular times of the day. With the help of a therapist, or even a self-help 'voices' group, patients can also be encouraged to test the validity of delusions, e.g. 'if I go into that shop I will be killed', and on the basis of the 'results' of these 'tests', modify their beliefs. Early studies of these approaches are encouraging in producing, for some patients at least, reduced symptoms, improved
central theme is a feeling of persecution and fear of being attacked. Paranoid states are common in general medical and hospital settings. A postoperative patient may suddenly rip out an intravenous cannula and attack one of the nurses. A patient may refuse all drugs, convinced that the staff are torturers dressed up as doctors and nurses. The conditions resulting in paranoid states are as follows: • Organic psychosis. This is by far the commonest cause in hospital settings. Paranoid delusions are frequently found in patients with acute confusional states. Any of the causes of organic psychosis (p. 208) may be responsible, with steroid-induced psychosis, alcohol withdrawal syndrome and amphetamine psychosis being particu-
1
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Case 8.1
social functioning and compliance, and reduced drug dosages.
Compliance therapy A major problem in schizophrenia is drug noncompliance. Borrowing on the techniques of 'motivational interviewing' developed for addiction, researchers have shown that compliance can be dramatically improved if the clinician provides much greater information about the drugs, and attends closely to patients' feelings about side-effects and the stigma associated with taking long-term antipsychotic medication. A simple useful intervention appears to be to compare the schizophrenia sufferer's need for medication with the diabetic's need for insulin. From this perspective schizophrenia becomes a disability to be lived with, rather than a disease which is either denied or devastating. Assertive outreach programmes aim to tackle non-compliance by treating the patient in his or her home environment and by offering intensive therapeutic nursing, family and practical help at a time of maximum stress.
Early intervention The prognosis in schizophrenia is worse the longer the gap between the onset of symptoms and starting therapy. Early intervention programmes aim to identify and treat young schizophrenia sufferers using a combination of destigmatization, drug therapy, combating concomitant substance misuse ('dual diagnosis') and psychosocial intervention.
larly common. Alcoholism may also produce a chronic paranoid state in which auditory hallucinations predominate (p. 251). Manic-depressive psychosis. Feelings of being disliked and shunned are common in depression, and may assume psychotic proportions if the patient feels he is so wicked that he is deservedly in danger of attack. Paranoid ideas can occur in mania, but elation and overactivity are usually more prominent features. Paranoid schizophrenia (see p. 229). Paranoid psychosis. Sometimes the patient develops paranoid delusions and hallucinations without the full range of features of schizophrenia. There is often a sexual content to the psychosis. The patient may, for example, become convinced that his spouse is having an affair (morbid jealousy, or Othello syndrome). The feeling that workmates or strangers are accusing the patient of homosexuality is often a prominent feature of paranoid psychosis. Paranoid personality. People with paranoid personalities have a tendency to mistrust and blame others, and so
frequently become involved in complaints and battles with authority. The patient is often sensitive, isolated, insecure and quick to take offence, and misinterprets the behaviour of others as hostile. When his fragile self-esteem is threatened by illness or rejection, he may develop a paranoid psychosis. • Paranoia in the elderly. Elderly patients may develop a paranoid psychosis (paraphrenid) with schizophrenic features. Deafness, social isolation and previous paranoid personality are important predisposing factors. Common to all the different forms of paranoia are isolation, insecurity, mistrust and misperception. In some cases the defence of projection seems to be operating. Here an inner state of persecution is transferred on to the external world, presumably as a defensive manoeuvre designed to reduce inner mental tension. Thus a cancer patient may develop a paranoid state in which he denies there is anything physically wrong, but refuses to leave hospital on the grounds that he is in danger of being attacked. Here the 'hostility' felt from the cancer within is attributed to the outside world instead. Paranoid states can be treated symptomatically with phenothiazines (see p. 230), but the underlying cause itself should be treated whenever possible.
SOMATOFORM DISORDERS Somatoform disorders are conditions in which (a) physical symptoms are present for which no organic or physiological basis can be found, and (b) where there are demonstrable underlying psychological factors or conflicts, i.e. the physical symptoms are manifestations of underlying psychological distress or disease.
Terminology and definitions There are several terms commonly used to describe physical disorder in which psychological mechanisms may be important. The outmoded but still widely used term psychosomatic illness refers to conditions in which there is definite structural physical illness (e.g. bowel inflammation in ulcerative colitis) but whose precipitant or maintaining factors are thought to be in part psychological. The term functional is sometimes used to describe symptoms produced by changes in organ function in the absence of structural change. Functional illness may or may not be psychological in origin. Functional bowel disease (irritable bowel syndrome, see p. 817), for example, may result from faulty diet or disturbance of the autonomic system (potentially stress related) or both. Controlled trials suggest that chronic intractable irritable bowel syndrome responds well to psychotherapy. The term psycho genie usually implies that the symptoms are entirely psychological in origin. Many of the ill-defined
conditions seen in general practice and medical outpatient clinics could be labelled psychogenic, although this term may obscure the fact that physical factors (e.g. muscular tension) are also important. The concept of hysteria (p. 235) has a long history and has become differentiated from the more non-specific psychogenic symptoms. Hysteria is divided into two types:
8
• Conversion disorders. These are psychogenic illnesses often simulating neurological disorders - based on unconscious mechanisms, in which mental conflict is avoided both by 'converting' anxiety into physical symptoms (hence conversion hysteria) and by dissociation (i.e. a split between the mental self and the physical self). • Somatization disorders. These are polysymptomatic disorders in which the patient experiences multiple unexplained symptoms without physical disease and in the context of a disturbed personality. 1 In psychosomatic illness psychological factors aggravate, prolong or cause relapses in an illness whose basis is physical (just as a poor ward atmosphere has been shown to delay postoperative wound healing). Psychogenic symptoms are often based on circular patterns in which, for example, emotional conflict produces muscular tension, which results in pain, which leads to greater emotional stress, or anxiety (e.g. fear that the pain may be due to cancer), which results in more muscular tension and so on. Chronic fatigue syndrome (CFS, see p. 236) can be thought of as a somatoform disorder; some however would classify it as a psychosomatic illness, in which psychological factors exacerbate an organic illness, albeit one whose pathology is currently unknown.
MIND-BODY MODELS There are two extreme but widely held views on the nature of psychosomatic illness. The first, corresponding to the philosophical position of materialism, holds that all phenomena are physical in origin and denies the existence of the mind. For the materialist there are no psychogenic conditions, only illness whose physical cause has yet to be determined. The second, idealist, view holds that psychosomatic illness is mental in origin. There are problems with both these models. The materialist might point to the numbers of patients labelled as hysterical who have subsequently died of carcinoma or multiple sclerosis; but the existence of mind is undeniable. The idealist, on the other hand, tends to confuse the symbolic meaning of an illness with its cause, claiming, for example, that a man who developed oesophageal cancer did so because he could not swallow his wife's infidelity. A classic error of this type was the pre-1956 theory of Down's syndrome. This held that Down's syndrome was caused by physical or mental trauma in pregnancy, as mothers of Down's syndrome babies regularly reported such traumatic incidents. Only when the chromosomal abnormality
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responsible was found was it realized that the trauma theory was a retrospective rationalization rather than a causal explanation. In reality, the relationship between mind and body is far more complicated than either the pure materialist or the idealist model allows. The interesting questions concern the interactions between the mental and the physical, just as many important problems in genetics involve interactions between heredity and environment. For example, there is good evidence that psychological adversity in childhood - neglect or abuse - is associated with poor physical health in adult life. The mechanisms by which this is mediated remain to be elucidated. To some extent they may result from excessive alcohol and drug abuse, and smoking, which are associated with both psychological stress and poor physical health. The effects of stress via the hormonal system on immune mechanisms may also play a part. Thus the 'Descartian' split between mind and body is beginning to be seriously challenged. It has been cogently argued that we 'think with our bodies': that the body is more than just a metaphor for much emotional experience (we speak of 'gut feelings' and 'emotional pain'), but that we use bodily sensations to help us choose between different equally rational courses of action. Body and mind, reason and emotion are ultimately inseparable.
more likely to develop coronary artery disease than those with more placid temperaments. This is particularly true where aggression plays a large part in the 'type A' makeup. Similarly, the prognosis of breast cancer may depend in part on personality: women who are emotionally inhibited appear to have, on average, a less good prognosis than those more able to express anger and sadness. The intervening variables that link the psychological to the physical are largely unknown. Autonomic and corticosteroid responses to stress play their part, as do changes in the immune system (especially T lymphocytes), but the precise pathways and links remain to be elucidated. Current evidence does not support the view that psychosomatic diseases are primarily psychological in origin, nor that any specific relationship exists between personality type and a particular disease or target organ.
Experimental evidence
Development of the body image
There is evidence that painful events in a person's life can precipitate physical illness. The link between stress and myocardial infarction, for example, is well documented (Fig. 8.9). Bowel disease, such as ulcerative colitis or even appendicitis, may also be triggered by a preceding painful or stressful life event. Personality plays an important part in determining the impact of such events. Individuals with 'type A personality' (competitive, driving) are, other factors being equal,
In adult life mind and body are separate realms. The body is experienced as an object among other objects in the world, but is also, for its 'owner', the source of knowledge and sensation and the means by which contact and communication with others is possible. The mind, though experienced as a separate domain, is indissolubly connected to the body. As Freud pointed out, it only takes a toothache to feel that 'the molar hole contains my soul'. The adult state in which the self comfortably inhabits both mind and body, experiencing each as separate and yet connected, is a complex product of health, maturation and culture. The infant is born in a state of psychosomatic unity: pain for a young child is both mental and physical. In adult life physical illness may produce regression to a childlike state. Childhood experiences may play a crucial part in determining later relationships between mind and body. In early childhood, the parents' love and care for the child and his body sow the seed of healthy self-love in later life. A girl who was 'meant' to be a boy may have to struggle with the effects of her parents' disappointment for years to come. Later, the adolescent has to learn to accept his or her body and sexuality. Self-acceptance is an essential precondition of loving others. When this process is disturbed, some individuals may, when anxious, ask their doctor for an examination, complaining that there is something wrong with their body or even asking for it to be changed by plastic surgery. The patient is looking for the acceptance and care he feels he missed from his parents. If external relationships fail, the patient may turn for interest and gratification to his
FIG. 8.9 Experience of potentially stressful life events by myocardial infarction patients in the 12 weeks before Ml occurred
PSYCHOLOGICAL APPROACHES TO SOMATOFORM DISORDERS Psychiatric understanding of psychosomatic and psychogenie illness can be considered under two headings: the development of the body image, and repression and the unconscious.
own body, and this too can lead to development of, and preoccupation with, psychogenic physical symptoms.
Repression and the unconscious Repression is the active removal from consciousness of painful or disturbing thoughts, feelings or memories. The mind's eye is blinded to problems and conflicts. The difficulties and the feelings they evoke remain, however, even though the patient is unconscious of them. They may then manifest themselves in physical symptoms, by the process of displacement. Thus a 20-year-old student presented with a hysterical hemiplegia and unexplained fits. She described her family life as happy and uneventful. In the course of therapy it emerged that her father had had a disabling stroke when she was 10, and that a fellow student had attempted to rape her a few weeks before her hemiplegia presented. She had 'forgotten' both of these painful events, but the neurological aspect of her presenting symptoms were reminiscent of her father's disability, suggesting that at some level they were still active in her mind, albeit at an unconscious level. The trauma of the rape re-evoked the shock, terror and vulnerability she had experienced when her father became ill.
'MINOR' PSYCHIATRIC ILLNESS Minor psychiatric illnesses are hard to classify and often go undetected, hiding behind and contributing to physical symptoms (Tables 8.11 and 8.12). In these illnesses a somatic 'facade' conceals difficulty in adjustment to social stress ('adjustment disorders'), symptoms of anxiety and/ or depression, or personality difficulties. Once these are explored and the patient reassured, the physical symptoms may be relieved. In considering patients with somatization disorders, a number of psychosocial factors should be explored: • Stress factors, especially recent losses, such as bereavement, unemployment, children leaving home, financial difficulties, divorce and termination of pregnancy; • Social support, relationship with partner (including sexual relationship), parents, children and friends, housing conditions; • Personality: how the person has reacted to stress in the past, previous stressful or painful experiences, especially in childhood, and whether the patient is able to respond with appropriate anger or sadness; • Alcoholism, drug abuse and eating disorders, which frequently present indirectly via physical symptoms.
FURTHER READING ON SOMATOFORM DISORDERS Goldberg D, Huxley P 1980 Mental illness in the community - the pathway to psychiatric care. Tavistock, London Lloyd G 1991 Textbook of general hospital psychiatry. Churchill Livingstone, Edinburgh
TABLE 8.11 Characteristics typical of doctors who frequently detect psychological problems • • • • • • •
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Show empathy Sensitive to emotional cues Use appropriate psychiatric questions and probes Tend to ask for clarification of the patient's complaints Make early eye-contact with the patient Do not bury themselves in notes Good at dealing with interruptions and garrulous patients
TABLE 8.12 Psychiatric illness in general practice: how much goes undetected? Category
All patients
Probability of detection by GP
Physical illness without psychiatric disorder Physical illness and unrelated psychiatric disorder Physical illness with secondary psychiatric disorder
67%
not available
8%
19%
1%
74%
19% 13.5%
47% 33%
5.5%
85%
5%
95%
Somatization Physical illness with symptoms exacerbated or caused by psychiatric disorder Somatized psychiatric illness (no diagnosable physical illness) Psychiatric disorders presenting with psychological symptoms
Smith G 1999 Managing somatoform disorders. In: Lee A (ed) Affective and non-psychotic disorders. Gaskell, London Wilson A, Hickie I, Lloyd P 1994 A treatment of chronic fatigue syndrome: science and speculation. Am J Med 96:544-550
HYSTERIA The essential features of hysteria are: (a) physical symptoms, (b) absence of organic pathology, and (c) psychological conflict.
Classification and clinical features There are three main patterns of hysteria: monosymptomatic, polysymptomatic and epidemic. Monosymptomatic hysteria (conversion disorder) Typically there is gross loss of neurological function. This may involve: • the limbs, e.g. paralysis, anaesthesia or dystonia
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RECENT ADVANCES IN CHRONIC FATIGUE SYNDROME (CFS) Patients suffering from feelings of chronic physical exhaustion frequently present to physicians and sometimes to psychiatrists. Although there may be nothing new in this - such patients were formerly seen as suffering from 'neurasthenia' - much recent effort has been devoted to the clarification of diagnostic criteria, the search for possible causes, and developing structured treatment approaches. The criteria for CFS include disabling physical fatigue which is unexplained by primary physical or psychiatric diagnoses, myalgia, depression and poor concentration, all lasting for more than 6 months. CFS subsumes other diagnostic labels such as Royal Free disease, postviral syndrome and, where there is or has been definite evidence of infection, postinfectious fatigue syndrome. There is no generally accepted theory about causation. Enteroviruses have been implicated, and increased litres of anti-Coxsackie B IgM are reported; muscle fibre damage is found in some cases; some have claimed deficiency of intracellular magnesium. In contrast to the metabolic explanations, psychiatric intervention shows much promise. Fifty per cent of CFS sufferers meet the criteria for major depression. Whether this is cause or
consequence is unclear: one study found that 100% of patients who lacked evidence of infection were depressed, suggesting that 'CFS' represents a number of disorders of differing aetiology. Management includes:
• the higher functions, e.g. hysterical fits, hysterical blindness, fugue states (in which the patient has complete memory loss), or even hysterical psychosis (where the patient develops a short-lived and dramatic psychosis in response to external stress).
with monosymptomatic hysteria, their prognosis is poor and is related to general personality difficulties rather than a specific conflict.
The pattern of dysfunction follows the patient's 'idea' of how the body works, rather than anatomy. Similarly, in hysterical psychosis the patient behaves in the way he thinks a madman ought to behave, rather than demonstrating the specific symptoms of schizophrenia. A neurologist can usually determine the integrity of the nervous system, either by subtle physical examination (extensor activity in apparently paralysed limbs) or by investigation (intact visual evoked potentials in hysterical blindness). The patient may also exhibit the belle indifference described by Janet, i.e. an apparent lack of anxiety in the face of a crippling disorder. Psychophysiological measures of arousal show that hysterical patients are in fact often highly aroused, despite the absence of manifest anxiety.
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Polysymptomatic hysteria (Briquet's syndrome, somatizotion disorder) Patients suffering from polysymptomatic hysteria (usually women in their 30s) develop a wide variety of physical complaints with no organic basis over a number of years. These often involve pain in the abdomen, back and pelvis. Such patients have often been extensively investigated by physicians and frequently admitted to hospital. Their medical notes are thick but inconclusive. Unlike patients
• A sensitive and tactful approach in which the patient is engaged and supported via the adoption of a psychosomatic approach (see main text) which does not attempt to deny the reality of the symptoms or to undermine directly the patient's belief system about his illness; • Psychotherapy directed to helping the patient to adjust to the losses (e.g. of job, mobility, social life) that result from CFS; • Cognitive-behavioural therapy aimed at reattribution of symptoms (e.g. 'I am tired because I am unused to exercise, rather than because my muscles are irremediably damaged'); • Anxiety management to reduce tension and panic; a programme of graded exercise • if depression is a prominent feature; prescription of antidepressants.
Epidemic hysteria This rare and self-limiting condition occurs in schools and other situations where young people are in close proximity. Fainting, nausea and paraesthesia brought on by overbreathing are common presentations. The condition is sometimes wrongly assumed to have an infective cause.
Diagnosis Hysteria is not an easy diagnosis to make. A proportion of patients diagnosed as hysterical turn out to have genuine organic disease: multiple sclerosis or occult cancer, for example. Others may develop another psychiatric condi-
SUMMARY 17 Psychological mechanisms in hysteria • • • • • • •
Dissociation Denial Primary gain - elimination of mental pain Secondary gain - attention, care Identification Illness behaviour Unconscious avoidance of conflict
tion, such as a depressive illness or even schizophrenia. However, it is important to recognize and diagnose hysteria when it does occur, so as to spare the patient unnecessary investigation. Hysteria and organic illness can also, and often do, coexist; establishing one diagnosis should not prevent the search for another.
SUMMARY 18 Management in hysteria • • • • • •
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'Psychosomatic' attitude on part of doctor Exploration of conflict Behavioural approaches (Antidepressants) Abreaction Long-term psychotherapy
Meaning and aetiology The manifestations of hysteria are often dramatic, and therein lies a clue to its nature. Most people, especially as children, have the capacity to act a role. This involves an internal splitting, or dissociation, between the actor and his part. The actor is not really Hamlet, yet becomes Hamlet as he acts the role. The hysteric is not paralysed and yet, psychologically, can become so. According to Freud, the symptoms in hysteria have a meaning which can be understood in terms of the patient's life. Psychological theories of hysteria also highlight several other important aspects of the illness: • Defence. Hysteria is a defence against the anxiety created by conflict. A young man from an academically minded family was facing exams which he feared he would fail; he became paralysed. • Unconscious behaviour. Although a conflict is often obvious to others, the patient is unconscious of it. • Personal gain. There are two kinds of gain for patients in being ill. The primary gain is the fact that they are unaware of their conflict and thus do not experience anxiety. The secondary gain is the care and attention they get from family, friends and relatives. This is only possible if the family to some extent go along with it, or allow the patient to manipulate them. Here they may be meeting their own needs, e.g. the husband who only feels potent when he has a sick wife to look after. 'Manipulation' is a normal process in childhood, and hysteria always has childlike aspects. The child who does not want to go to school develops a tummy-ache; his mother lets him stay at home with her. A similar process is at work in hysteria. The child is not consciously making himself ill or malingering (as, for example, is the soldier who deliberately shoots himself in the foot to avoid going to battle): there really is a pain, even if it clears up quickly once the danger of having to go to school has passed. • Identification. A common finding in the histories of hysterical patients is that there has been a close relative who has suffered illness, often serious. The young man who became paralysed because he feared his exams had had a younger brother who had died with cerebral palsy, and on whom his parents had lavished all their care and attention. The patient often has such a model of illness and its accompanying behaviour which influences him. Sociologists speak of 'illness behaviour' to describe the socially sanctioned behaviour that accompanies illness and which is not strictly related to the pathophysiology of the disease. Sick people are allowed to retire tem-
porarily from work and spend time in bed; they receive flowers, cards and gifts from relatives and are treated with special consideration; they are allowed to be childish and demanding. Their medical attendants also adopt a particular role, usually one of reassurance, benevolence and quasi-omniscience. One of the rules of illness behaviour, however, seems to be that the patient should recover, or at least attempt to recover. When this does not happen there may be a sudden switch: the previously privileged patient may be seen as manipulative, attention-seeking and deviant, and be shunned or covertly punished by irate relatives and medical attendants. In hysteria this often results in a worsening of the symptoms.
Management It is tempting to try to argue a hysterical patient out of his illness. Occasionally this can be helpful, but more often it entrenches the patient more deeply in his symptoms and an escalating battle between doctor and patient may then ensue. There is, moreover, a sense in which the patient is right: he is ill, but psychologically, not physically. There is something wrong, namely a psychological conflict, albeit one of which the patient is unconscious. A more helpful approach is therefore to adopt a psychosomatic attitude. This involves explaining to the patient that stress can cause illness, that he may have a psychological conflict, and that there may be a connection between this and the physical problem, both of which are real. The patient who has committed himself to a physical illness should be offered appropriate physical treatments (e.g. physiotherapy, massage) and should not be deprived of it out of spite. When recovery does take place the temptation to say T told you so' should be resisted. Instead, the patient needs a face-saving formula: the paralysed person must be allowed to put his crutch down gradually, inadvertently even, not have it knocked from under him. The psychological principles of treatment are: • Exploration of conflict. With allowance for face-saving, this is perhaps the most helpful strategy. If the conflict is removed (e.g. the time for exams past) the symptoms will usually remit. • Cognitive-behavioural approaches. These are often useful. They (a) aim to avoid reinforcement of the symp-
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toms, e.g. by suggesting to ward staff or relatives that they respond positively to any signs of movement in the paralysed patient, but as far as possible ignore (nonpunitively) helpless behaviour; (b) are directed towards helping the patient overcome his cognitive responses (e.g. of panic and catastrophe) towards the imagined illness. The latter is sometimes known as 'reattribution therapy' - the patient learns how he wrongly attributes normal bodily sensations to illness, and that this may be influenced by emotion, especially anxiety. Drugs. Where hysteria is secondary to a depressive illness antidepressants should be prescribed. In general, however, drug treatment should be avoided in hysteria, as the patient is often very suggestible and tends to develop dramatic reactions and side-effects. Hysterical amnesia can sometimes be approached by abreaction, in which painful experiences are 'relived' with the help of an intravenous injection of a sedative drug such as diazepam. Psychotherapy. Some patients will benefit from longterm psychotherapy.
HISTRIONIC PERSONALITY AND RELATED CONDITIONS There are a number of conditions that are related to hysteria but which take the form of a lifelong personality disorder rather than an illness. These conditions share with hysteria the capacity for dissociation and the use of illness for manipulation of those around them.
HISTRIONIC PERSONALITY A patient with histrionic personality (usually female) finds it difficult to form close attachments, and when she does they are highly dependent. Her emotions are often superficial and rarely satisfying. She may be very alluring and attractive to men, but finds it difficult to enjoy sex herself. She carries with her an atmosphere of drama: her life is often a series of emotional or practical crises. Her feelings
SUMMARY 19 Conditions related to histrionic personality
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Multiple personality
Aspects of the self entirely dissociated from one another, with lives of their own
Factitious illness
Self-inflicted illness
Fictitious illness Patient travels from hospital to hospital (Munchausen's syndrome) with fictitious illnesses. Pseudologia phantastica.
are dramatized and exaggerated; her headaches are always 'migraines', her diarrhoea 'dysentery' and her pains invariably 'excruciating'. She uses her crises to coerce those around her (including doctors and nurses), and sometimes has a husband whom she abuses and yet clings to, and who appears to submit willingly to all her demands. As a child she may have felt emotionally neglected and insignificant, helpless and dependent. The anger and manipulation that manifest themselves in adult life can be seen as a continuation of this, an attempt, through the coercive power of illness, to keep attached to her those whom she feels may otherwise ignore or abandon her. Patients with histrionic personality sometimes develop the physical symptoms of hysteria.
MULTIPLE PERSONALITY The adult personality is made up of a number of elements: • Some come from identifications based on parents ('he has his father's temper and his mother's charm'). • Some represent different aspects of the self: the caring self, the aggressive self, the childish part of the self, and so on. • Some can be defined in terms of relationships: in a marriage a partner may be expected to be a spouse, lover, parent, colleague and friend. Eric Berne has summarized the different aspects of the self as 'parent', 'adult' and 'child', all of whom coexist within one person. In the mature personality there is a blending together of the different aspects into a coherent whole, so that a person is all of a piece, although minor discontinuities and splits in the personality are common. The fascinating but rare clinical condition of multiple personality, in which several quite separate personalities appear to inhabit the same individual (fictionalized in such works as DrJekyll and Mr Hyde and The Three Faces of Eve), is an extreme example of this everyday splitting. In multiple personality the different personalities have lives of their own which are entirely dissociated from one another; the good self is totally unaware of the bad self and would be horrified by its activities. This enables, say, a prudish aspect of the self to live alongside the sexual side without being aware of it, thereby avoiding anxiety or guilt. Patients with multiple personality can occasionally be helped towards integration with psychotherapy.
FACTITIOUS ILLNESS Patients with unexplained symptoms are sometimes found - often after lengthy investigation - to have caused their own illness. A patient with unexplained and extensively investigated 'haemoptysis' was found to be venepuncturing herself, swallowing blood and then spitting into a sputum pot; a person with unexplained intestinal bleeding
may be inserting foreign bodies into the rectum; hypoglycaemic attack can be produced by insulin injections in non-diabetics; dermatitis artefacta (p. 436) is yet another example of such factitious illness. Occasionally such behaviour is due to psychosis, but more often it is a manifestation of a personality disorder. These patients are often very 'nice'; they may be nurses or members of the other caring professions. They are often on good, even intimate, terms with medical staff. They may induce incomprehension, abhorrence and anger once they are discovered. Factitious illness is best seen as an extreme example of histrionic personality disorder. The patient has split off an angry, destructive, defiant part of herself which acts semiautonomously and of which the 'good' self may be partially unaware. The principles of management of hysteria may be applied in these cases. A full history will reveal underlying conflicts, and the patient can then be told, in as gentle and unconfrontational a way as possible, that these conflicts may be responsible for her symptoms and that she may thus be playing a part in causing her own illness. Although the patient may become angry, the results of such an approach are rarely disastrous. The patient will often be relieved and even begin to accept psychological help.
FICTITIOUS ILLNESS: MUNCHAUSEN'S SYNDROME Baron von Munchausen was an 18th-century fictional character who travelled extensively and told fantastic stories. His name is now used to describe a group of patients with characteristic features: • Patients often experience recurrent unexplained symptoms, especially abdominal or chest pain, which are often thought to be due to renal colic, myocardial infarction or intestinal obstruction. The patient may be given opiates and have had several inconclusive laparotomies, which reveal themselves as multiple abdominal scars. • These patients travel from hospital to hospital, usually discharging themselves after a brief admission, and using a variety of assumed names. • They give dramatic accounts of their lives, for example stories of heroic wartime feats or tragic losses, none of which can be corroborated and none of which quite add up. These stories are sometimes labelled pseudologia phantastica, Munchausen patients may be seen as the male counterparts of factitious illness patients. They are hard if not impossible to manage or help, but awareness of the diagnosis will avoid unnecessary or dangerous investigations. Most doctors have had at least one experience of being hoodwinked in this way, and this may be a necessary learning experience. The doctor must be friendly but firm in refusing to treat these patients as though they are ill. The patient usually disappears, but may occasionally accept social help and often become highly dependent on medical services.
SUMMARY 20 Factors contributing to anorexia nervosa • • • •
8
Contradictory social attitudes towards eating and thinness Enmeshed, i.e. mutually overdependent, families Fear of loss of control of eating and of sexuality Fear of separation
EATING DISORDERS Eating is not just about physiology: food has great psychological and sociological significance. Morality starts with the child's discovery of what is good and bad to eat, and a mother's self-evaluation may continue to depend on how well she feels she feeds her family. Birth, the reaching of adulthood, marriage and death are all marked by a meal. In addition, there are two factors, specific to many highly industrialized western societies, that are of especial relevance to eating disorders: the role of the food industry, with its large marketing system; and the emphasis on a slim body image as a mark of vitality and attractiveness. Eating disorders are increasingly common, especially among women (Fig. 8.10). Although the overall incidence of anorexia nervosa is only 1 per 100000 population, 1% of 16-18-year-olds are affected; 2% of women attending a family planning clinic suffer from bulimia nervosa; and the prevalence among dance students is 20%.
ANOREXIA NERVOSA Aetiology and pathogenesis No single cause of anorexia nervosa has been found. A number of factors appear to be involved: • Social pressures towards both eating and thinness, though contradictory, are important.
FIG. 8.10 Epidemiology of anorexia nervosa Social class distribution of anorexic patients (father's occupation) compared with that for general population.
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CASE STUDY 8.3 A 30-YEAR-OLD WOMAN WITH AN EATING DISORDER AND A WEIGHT OF 30 KG A 30-year-old woman was admitted to a psychiatric unit weighing 30 kg. Her body mass index (weight in kilogrammes divided by height in metres, squared) was, at 13, near the lower limit considered to be compatible with life. She was brought in by her husband, who had been increasingly worried about her but up to this point had been unable to persuade her to accept help. She had had eating disorder symptoms since at least the age of 15, when she had left home to live with her boyfriend, who eventually become her husband. She was terrified of excess weight and weighed herself several times a day. She ate little more than a crispbread and a slice of cucumber daily. She had never had regular periods, although, unusually for someone with anorexia nervosa, had managed to get pregnant with the help of ovulationassisted fertility treatment. She was closely involved with her mother, to whom she presented an 'everything is normal' front, while seeing her almost every day. She was very worried about her parents' marriage, which she saw as in great jeopardy. She was treated with a refeeding schedule, with which she was surprisingly compliant, until she weighted 45 kg, and then was discharged from hospital. Her outpatient care consisted of a combination of individual psychotherapy and family therapy. Her individual therapy concentrated on looking at all the ways in which she pretended to herself and others that she was eating when in fact she was avoiding food. It used an 'addiction' model and suggested that she was addicted to not eating in the way that an alcoholic is addicted to alcohol - using it as a refuge whenever she felt stressed or confused. Therapy also looked at her
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image of herself as a woman, and at how frightened she was about becoming 'like' her mother, whom she saw as being trapped in a loveless marriage, constantly at her father's beck and call. The family therapy sessions tried to help extricate her from the parent-child relationship she had established with her husband and to foster a more equal partnership, in which she took charge of her own eating, rather than either deceiving him or relying on him to prompt her to eat. There were no further admissions, but her weight hovered just under 7 stone for many years, and she said that the idea of being 7 stone terrified her. Over the years she made many life changes. She left her husband and formed a new partnership, which was more emotionally open and caring, although not without its problems. Her new partner was more able to help her to eat at times when she was in the grip of her anorexic symptoms. Her parents' marriage also broke up, and she become much less involved with her mother.
Questions
1. Could intervention have started earlier? 2. What is the long-term prognosis of anorexia nervosa?
Discussion It is notoriously difficult to engage people suffering from anorexia nervosa in treatment. Teenage sufferers are often taken unwillingly to the doctor by worried parents. It is always important for the doctor usually a family doctor in the first instance - to interview the patient on her own and to make determined
attempts to establish rapport, a process which may take several interviews. There is a danger that the doctor will be pulled into identification either with the worried and exasperated parents, in which case he may become heavy handed and insensitive, or with the patient, when he may minimize the seriousness of the situation and fail to be appropriately firm and challenging. Anorexia is 'delusional' in the sense that such patients are convinced that they are fat, despite every rational argument to the contrary. There has been much debate about the ethics of admitting people with anorexia compulsorily to hospital. The current consensus is that the thinner the patient the less rational they are, and that in lifethreatening situations the use of the Mental Health Act is justified. On the other hand, it is essential to help the patient move towards taking responsibility for her own illness, and a Section may militate against that. Many patients put on weight while in hospital but immediately revert to dangerous weight loss once they are back home. Anorexia nervosa is a very varied illness, with many different trajectories, making it difficult to generalize about prognosis. In general, the shorter the interval between onset of illness and treatment, the better the prognosis. Most studies suggest a 60-70% recovery rate within 5 years. The longer the period of illness the greater the mortality. Different studies have shown lifetime mortality of between 5 and 10%. Partial recovery is probably the best that can be hoped for in a chronic form of the illness such as that suffered by the patient described, whose symptoms had lasted for more than 15 years.
• The fear of losing control, both of eating and of sexuality, and a feeling of inadequacy and of not being a separate person are characteristic of the anorexic's inner world. Anorexia is an attempt by the individual to remain in complete control by regulating her food intake and her weight, and thereby putting her sexuality into reverse. • Family function in anorexia is often abnormal. The families (where food is frequently a central theme) tend to be 'enmeshed', i.e. mutually overdependent. This causes little difficulty in early childhood, but with the advent of adolescence the family may be threatened by the possibility of autonomy and separation. • Endocrine abnormalities occur in anorexia nervosa. Hypothalamic function is disturbed, with reduced luteinizing hormone (LH) and gonadotrophic hormone output, but this is more probably a consequence rather than a cause of weight loss. Low levels of plasma thyroxine and plasma TSH are also common. There may be alkalosis if there is surreptitious vomiting.
Clinical features
overweight, which may appal the girl, who then begins to pursue thinness. Her thoughts are dominated by food and how to avoid it. She absents herself from family meals, although she may pride herself on providing food for others, while secretly despising and envying those who eat normally or, as she sees it, gluttonously. As long as she is thin she will be happy. To be thin is to be good; to be fat, bad. She may augment her efforts at dieting by taking laxatives, amphetamines or diuretics, and by self-induced vomiting. Battles about food may develop with her parents. Denial of weight loss (p. 216) is an important feature: she may conceal her emaciation within voluminous and floppy clothes. She is physically overactive as part of her secret plan for weight loss. Sometimes, deliberately excessive exercise may be a major factor in the weight loss. She complains of a feeling of 'fullness' in her stomach which prevents her from eating. She will be emotionally and socially, but not intellectually, less mature than her peer-group. Physical examination will reveal thinness, scanty secondary sex characteristics, possibly peripheral cyanosis, a soft downy covering of the face and body (lanugo hair), hypotension and bradycardia.
8
Four features are characteristic of anorexia nervosa.
Differential diagnosis • The most important is phobic avoidance of normal weight. The patient is terrified by the idea of her normal weight. • With this goes a distortion of body image, known as overperception. By asking women to choose a silhouette that they feel represents their shape, it can be shown that it is normal for women aged 15-30 to perceive themselves as up to 50% fatter than they really are. Patients with anorexia nervosa see themselves as at least 100% bigger than they are: an emaciated girl of 35kg may be disgusted by what she perceives as her gross obesity. • The consequence of phobic avoidance and overperception is relentless dieting, especially the renunciation of carbohydrates. • Amenorrhoea is an essential diagnostic feature. In males (10% of all anorexics) there is disturbance of sexual function, usually with loss of libido. Anorexia nervosa usually starts in early or midadolescence. There is frequently an initial period of mild
SUMMARY 21 Features of anorexia nervosa • • • • • • • • • •
Phobic avoidance of normal weight Lanugo hair Hypotension Relentless dieting Denial, concealment Self-induced vomiting, laxatives Overperception of body image Excessive exercise Enmeshed families Amenorrhoea
The clinical picture may be one of two types: • In typical anorexia the only obvious psychological abnormality is the difficulty in eating. Here, the main differential diagnoses are organic causes of weight loss in a young woman, for example malabsorption syndrome, thyrotoxicosis or occult neoplasm. • An atypical picture also occurs. Here the woman is often older (in her 20s) and her anorexic symptoms coexist with other psychiatric features, such as depressive symptoms of misery and withdrawal; obsessional symptoms centring, for example, on cleanliness; and personality difficulties.
Management A patient weighing less than 35 kg should be admitted to hospital. A behavioural regimen in which the patient agrees on a target weight and is rewarded with privileges (watching television, being allowed visitors) in return for weight gain is usually effective in the short term. Occasionally a small dose of a phenothiazine (e.g. chlorpromazine 50 mg b.d.) is helpful. However, the patient will often lose weight again once she is discharged, unless psychotherapy is also started. Psychotherapy is the treatment of choice for outpatients. Mild anorexia can respond to simple counselling. In more severe cases family therapy is the best treatment for those under 17, whereas for older patients (especially if they have left home) individual psychotherapy is the preferred treatment. In each case, the aims of therapy are: • to maintain normal weight (body mass index 18-25) and a regular eating pattern. Some patients use therapy as a diversion from this central task;
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to help both patient and family to move away from the area of food as a focus for all conflicts and difficulties; to help the patient accept herself as she is, in both her body and her feelings, i.e. to cope with the problems in living from which the eating disorder may have been a diversion as well as a cause.
SUMMARY 22 Treatment of bulimia nervosa • Keep a diary of everything eaten and all episodes of vomiting • Re-establish dietary control; eat three meals per day even if bingeing • Identify triggers to bingeing (anger, loneliness) • Challenge erroneous assumptions, e.g. 'If I eat a chocolate bar will become grossly obese and no-one will love me'
Prognosis Twenty-five per cent of anorexic patients recover spontaneously; 25% make a full recovery with medical intervention; about 25% continue to experience some difficulties with eating but can lead a normal life; and 25% remain quite severely handicapped. About 5-10% die of the condition. Poor prognosis is associated with later onset, 'atypical features' (see above), marked body image disturbance and self-induced vomiting. Recovery is accompanied by a reversal of the hormonal abnormalities and the onset of normal menstruation. 1
BULIMIA NERVOSA Bulimia nervosa is a syndrome of 'binge eating' (bulimia: to stuff oneself with food) and self-induced vomiting in the presence of normal weight. There is an overlap here with anorexia nervosa, where binge-vomit cycles can also occur, but in anorexia the patient is always abnormally thin and also amenorrhoeic. The usual age of presentation in bulimia also tends to be older, with patients (usually women) in the 20-30 age range, rather than the teens. The bulimic is frightened of becoming fat, but can accept her normal weight. She is terrified by her greed and tries to avoid its consequences by making herself sick. She normally feels deeply ashamed about this. She lives in a state of dietary chaos, in which she is determined to fast, succeeds for a while, then succumbs to hunger and starts eating. She binges, then feels guilty, makes herself sick and then starves; and so the cycle starts again. The physical consequences of bingeing and vomiting include erosion of dental enamel from exposure to gastric acid, Mallory-Weiss oesophageal tears, and even oesophageal rupture. Repeated vomiting causes hypokalaemia, which may in turn produce tetany, paraesthesiae, ileus, cardiac arrhythmias and epileptic fits. Bulimia is more common than anorexia: the prevalence rate in Europe and North America is 1-2%, compared to 0.5-1% for anorexia; 20% of women attending a family planning clinic admitted to bingeing, and 2% had the full syndrome. Like anorexia, bulimia may exist either on
1
242
MCQ 8.5
2
MCQ 8.6
its own, or as part of a general disturbance of personality, and be associated with alcoholism, deliberate self-harm or shoplifting, all of which make the prognosis less good. Treatment of bulimia nervosa is usually successful and involves helping the woman to re-establish a regular eating pattern, and to feel less guilty. The bulimic often feels a great relief when dietary control is re-established, unlike the anorexic, who feels threatened at the idea of giving up her own control. In addition to a cognitive-behavioural approach, exploration of the conflicts underlying the bulimia (such as marital difficulties or feelings of anger which the patient is unable to express) is also necessary. A proportion of bulimics have experienced sexual abuse in childhood, and this too needs psychotherapeutic exploration.
OBESITY Obesity in itself is not a psychiatric problem, but morbid obesity can be experienced as a severe handicap, comparable to amputation or disfigurement. Respiratory, endocrine and cardiovascular complications are common and serious, and gross obesity should, like anorexia nervosa, be considered a life-threatening condition. Obese people feel ostracized and experience self-disgust. They long to be 'normal' and may become depressed by unsuccessful efforts at dieting. There are often marital and family difficulties which are both a cause and a consequence of their obesity. The prognosis for weight loss, either by dieting or surgery (e.g. intestinal bypass) is not good. Psychotherapy can be a precursor to weight reduction if it helps the patient to accept himself as he is. The patient may then find it easier to diet, being less inclined to resort to the comfort of food whenever an emotional upset occurs.
FURTHER READING ON EATING DISORDERS Fairburn G C, Wilson G (eds) 1992 Binge eating. Guilford, New York. Schmidt U, Treasure J 1992 Getting better bit(e) by bit(e). Laurence Erlbaum, Hove Tiller J, Schmidt U, Treasure J 1993 Treatment of bulimia nervosa. Int Rev Psychiatry 5:75-86.
by doctors) and 'bad' ones (self-administered by addicts). This distinction does not take account of the fact that almost all drugs, even when medically prescribed, have harmful effects and can be misused: analgesics and tranquillizers are the best examples of this. Conversely, opiates can be of great benefit in the treatment of severe pain. Current definitions of drug dependence are based on the interaction between the individual and the drug, leading to a compulsion to take it:
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• In order to experience its psychic effects, and/or • To avoid the unpleasant effects of its withdrawal (abstinence syndrome). There is no single cause of drug addiction. The prevalence of addiction is determined by:
FIG. 8.11 New and former addicts notified to the Home Office
• The availability of the drug. The greater the availability, the greater prevalence of addiction. In Hong Kong, where heroin is widely available, 8-10% of the adult male population is addicted. • The accessibility of the drug. This explains the relative commonness of drug addiction among doctors and nurses, and in inner-city and coastal areas. • The susceptibility of individuals to addiction or misuse. Management of drug addiction is equally multifaceted and involves a combination of physical, psychological and social rehabilitation.
DRUG DEPENDENCE Addiction to illicit drugs, especially opiates, is a source of widespread medical and social concern (Table 8.13) 2. There are several reasons for this. First, there has been an epidemic increase in opiate abuse over the past 50 years. In 1936 there were about 500 known addicts in the UK (of whom one-quarter were doctors); by the mid-1970s this figure had risen to 6000; and in 1988, following the introduction to the UK of cheap heroin, the number of known addicts was estimated to be at least 50000 (Fig. 8.11), of whom 9000 were registered with the Home Office. By the year 2000 this figure had reached 20000. Secondly, the impact of opiate addiction has profound medical and social consequences. Within 5 years of diagnosis 10% of addicts will have died from drug-related causes, including AIDS, hepatitis B and overdose. Thirdly, 'drug addiction' is a microcosm of a much wider social problem. Finally, there is increasing concern about the way that substance abuse complicates and worsens the prognosis of many psychiatric illnesses. For example, schizophrenia may be accompanied by, and sometimes be difficult to distinguish from, cannabis, heroin and/or amfetamine abuse, leading to a so-called 'dual diagnosis'.
Nature and causes of drug dependence In the past, definitions of drug abuse have concentrated on a contrast between the harmful and the beneficial effects of drugs, thus dividing drugs into 'good' ones (prescribed
OPIATE ADDICTION Causes The most important cause of opiate addiction is availability. Susceptible individuals expose themselves to the drug, either because they inhabit a subculture in which drug taking is prevalent, or because they are psychologically vulnerable owing to family difficulties, depression or boredom. The pharmacological features of opiates - tolerance and withdrawal syndrome - ensure the establishment of a habit, and social as well as physiological factors then maintain the addiction and make rehabilitation difficult.
Biochemical factors The discovery in 1977 of the encephalin neurotransmitters was a major advance in the understanding of opiate addiction. Endorphins are naturally occurring, opiate-like substances which mediate pain and other sensations in the midbrain. It is possible that individuals susceptible to addiction may genetically be deficient in endorphins and so 'opiate hungry'. Both opiates and endorphins reduce the amount and effects of other cerebral neurotransmitters, such as acetylcholine. This has led to the 'supersensitivity' theory of withdrawal syndrome, which postulates that addicted individuals have reduced amounts of transmitter reaching postsynaptic receptors. Stopping the drug then
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TABLE 8.13 Addictions: Prevalence data Substance use is one of the major social and health problems facing society Illicit drugs • 23% of those aged 14-15 have taken an illegal drug in last year, 13% in last month, 29% of those aged 16-24 in last year, 14% in last month. • Known heroin addicts have increased from about 5000 in 1980 to about 50000 now, with growth continuing at about 20% per year. • The number of seriously problematic drug misusers in UK is estimated to be between 100000 and 200 000. • Amfetamine seizures have increased from about 3000 in 1987 to about 18000 in 1997. Cocaine use is also increasing rapidly. Alcohol • 41% of men aged 18-24 drink above recommended levels, but recent increase highest among young women (currently 25%). • Alcohol use increasing rapidly among schoolchildren - currently 5-10% 14-15-year-olds drinking more than recommended adult levels. • 51% of rough sleepers are alcohol dependent. • More elderly people are drinking above recommended limits - from 1984 to 1996 increase from 12% to 18% of men, and 3%-7% of women. Smoking • By 13 years, 19% smoking cigarettes daily. 29% of 16-19-year-olds are current smokers, 39% of 20-24-year-olds and 28% of all adults. Mortality • Between 1000 and 3000 drug misusers died as a result of overdose in 1998 in England and Wales (uncertainty relates to problems with current databases). Compared to the general population, mortality rates are higher among addicts (SMR = 7) • Injecting drug users have a mortality 12-22 times greater than their peers. Compared to the general population, suicide rates are high among addicts (SMR for males = 4.4; SMR for females = 11.3). • 25% of road accident fatalities have blood alcohol above 80mg%, 30% of pedestrians sustaining injuries. Illicit drugs are found in blood of 15-20% of drivers involved in fatal road accidents. • 40000 alcohol-related deaths per annum. • 120000 smoking related deaths per year in England and Wales. This accounts for 20% of deaths at all ages, and 25% of deaths between 25 and 35. Psychological and physical morbidity • 62% long-term injectors are positive for hepatitis C, and 52% for hepatitis B. About 80% of those positive for HCV will develop long-term infection, and 5% of those positive for HBV. About 20% of those with chronic infection will develop cirrhosis or liver cancer. Between 152000 and 228000 drug users in the UK are currently infected with HCV. • 10000 individuals seek help for their own or someone else's drinking problems each day. • 30-40% of hospital in-patients drink alcohol excessively. Alcohol is associated with heart disease, liver cirrhosis, cancer, neurological and gastro-intestinal problems. • 30-40% of substance misusers also have a psychiatric diagnosis. 60% of parasuicides are alcohol related. In a health district of 250000, 3000 problem drinkers will also have severe mental health problems. • Alcohol is strongly related to high-risk sexual practice, unwanted pregnancy and sexually transmitted disease. • Domestic violence, accidents and social disharmony: 30% of divorces, 40% of domestic violence, 20% of child abuse cases and 30% of domestic accidents are associated with alcohol misuse. Crime • 32% of proceeds of acquisitive crime is spent on heroin or cocaine. • The costs of drug-related crimes to the criminal justice system is at least £1 billion per year. Approximately 30% of prisoners are problem drinkers. 30-60% prisoners claim to have offended under influence of alcohol. 60% of those arrested test positive for drugs, 20% for opiates. Costs • The costs to industry of excessive alcohol consumption are estimated at £2330 million per year, as a result of unemployment, premature death and sickness absence. • Smoking costs the NHS approximately £1500 million per year. For a typical health authority this means £14 million per year, broken down as GP visits £2.5 m, prescriptions £1.5m, in-patient stays £3.2m, day-care £1.9m and outpatient visits £4.9m. Cost-effective treatments require proper training and specialist support • Many studies have shown that the treatment of opiate users saves much more money than it costs. • In North American studies it is estimated that for every $10000 invested in alcohol treatment, $30000 is saved by the managed care provider. • Smoking cessation interventions cost between $212 and $873 per life year gained, compared with £17000 as the median cost per life year gained of 310 common medical interventions.
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results in a sudden increase in transmitter and stimulation of the already supersensitive receptor.
Psychological factors Drugs can be administered ('dropped') by injection ('fixing'), either subcutaneously ('skin-pop') or intravenously ('mainline'); or by smoking ('chasing the dragon'). All these methods are powerful reinforcers in the pavlovian sense:
TABLE 8.14 History and examination of suspected opiate abuser History Previous contact with a prescribing doctor or clinic History of recent use (doses, frequency, legal, illegal) Assessment of demands or requests Assessment of withdrawal symptoms Current legal problems
• Primary reinforcement from both the pleasure ('buzz') and the removal of withdrawal symptoms; • Secondary reinforcement from the associated rituals of administration, e.g. filling the needle; • Social reinforcement from fellow addicts.
Examination Injection sites: needle marks, tracks, bruises, thrombosed veins, abscesses, skin ulcers Arterial spasm or gangrene (caused by, e.g. dipipanone, cyclizine) Jaundice from hepatitis Emaciation
Psychiatric factors
Investigation Urine for drug assays Liver function tests Hepatitis serology HIV test (with consent)
Opiate addiction is more likely to be a cause than a consequence of psychiatric illness. 'Loners' may well be suffering from anxiety and depressive symptoms which they are trying vainly to treat with opiate drugs. Hospitalized addicts (as opposed to the generality of addicts) tend to be suffering from personality disorder and to have difficulty in forming close relationships. Addicts are caught in a vicious circle in which their primary relationship comes to be with the drug, which is felt to be more accessible, reliable and instantly gratifying than a person. There is some evidence that family discord and alcoholism are more common in the childhood histories of addicts than in controls. The anxiety associated with the early stages of opiate withdrawal may mirror early childhood experiences of separation from desired, but inaccessible, parents.
Social factors There is no particular social class preponderance for opiate addiction.
Presentation Addiction to opium and its derivatives, morphine and heroin (diacetyl morphine), can be considered as a model of drug addiction in general. The physical signs that should arouse suspicion of opiate abuse are listed in Table 8.14. Addicts present to doctors in one of four ways: • With infective complications of self-administered injections, e.g. septic abscess at injection site or septicaemia, infectious hepatitis or manifestations of HIV; • With confusion or unconsciousness due to drug overdose, either deliberate or accidental; • Wanting, or apparently wanting, help with their habit; • With a withdrawal syndrome. This consists of a craving for the drug together with physiological features, which include rhinorrhoea, lacrimation, yawning, perspiration, irritability, gooseflesh, nausea, diarrhoea, cramps,
8
muscle pains, tachycardia, flushing and involuntary movements. It is not life-threatening and the symptoms begin to recede about 72 hours after last taking the drug.
Management Legal requirements In the UK, any doctor attending a patient who is known or suspected to be addicted to opiates is required to inform the Home Office Drug Branch. Only specially licensed doctors are permitted to prescribe morphine and diamorphine (heroin) for the maintenance of addiction. Other opiates, such as methadone, may be prescribed by any doctor for the management of withdrawal syndrome, but this should be done only with great constraint and in an emergency. General management Drug abusers may not be open about their habit, which should be suspected in unexplained cases of psychosis, sepsis, serum hepatitis or HIV infection. Scapegoating should be avoided, and drug users should be treated with the same concern and courtesy as any other patient. At the same time, caution should be exercised: addicts may steal prescription pads and syringes, and exaggerate their drug needs in order to obtain drugs, which are then sold. In an initial interview a urine screen should be carried out to confirm that the patient is a user, and blood should also be tested for hepatitis serology and HIV (the latter normally with the patient's consent). Whenever possible, the patient should then be referred for specialist help. Occasionally
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TABLE 8.15 A typical detoxification schedule for opiate addiction 10-day detoxification (volume kept at 25 ml)
28-day detoxification (volume kept at 25 ml)
Methadone 25 mg/day - 2 days 15mg/day-2days 8 mg/day - 2 days 4 mg/day - 2 days 2 mg/day - 2 days
Methadone 30 mg/day - 4 days 25 mg/day - 3 days 20 mg/day - 4 days 13 mg/day-3 days 10 mg/day-4 days 6 mg/day - 3 days 3 mg/day - 7 days
TABLE 8.16 Characteristics of methadone linctus which justify its use as a treatment • • • • •
Non-injectable Not attractive to users looking for buzz Low street retail value Controlled drug - able to be prescribed on daily collection Long half-life for established users, hence reliable urine testing and stabilizes drug-taking experience • If it does 'leak' from the drug service to the streets it is likely only to be used by established users for whom it is a safer preparation. Some of these will use purchased methadone for detoxification • As a linctus', consumption can be supervised if necessary
(e.g. in a casualty department at a weekend) withdrawal symptoms have to be treated and a dose of methadone given equivalent to the average daily intake which the doctor calculates is being used. The usual dose is between 20 and 70 mg of methadone. Typical detoxification schedules are given in Table 8.15. Where heroin intake is low, diphenoxylate and clomethiazole (chlormethiazole) can be used. Prescriptions should be on a daily basis for not more than 2 days. A clear management policy should be instituted and explained to the patient. Treatment of medical complications of addiction The main medical complications of addiction are septicaemia (p. 273), hepatitis (p. 846), endocarditis (p. 574) and HIV infection (Ch. 11).
Rehabilitation In the UK, all regions have drug clinics to which the addict should be referred. Here, the patient may be offered an oral methadone maintenance programme (Table 8.16) in the hope - not always realized - of reducing the use of illicit drugs. An attempt is made to form a rapport with the user. After establishing a baseline habit, some addicts will be gradually withdrawn from the drug over a 10-week period, either as an outpatient or, more rapidly, as an inpatient. Others will be stabilized on a maintenance methadone programme as a way of facilitating a period of stability in their life which reduces the need for crime and enables them to form a relationship with the drug clinic team. Withdrawal is an essential, but by no means sufficient, aspect of treatment. Addicts exposed to enforced abstinence, e.g. in prison, almost always relapse when released. Psychotherapeutic and social help is also needed if the addict is to remain drug-free.
FIG. 8.12 Changing patterns of consumption of non-opiate drugs in the UK A Prescriptions for sedatives/tranquillizers and hypnotics, 1974-1985. B Current benzodiazepine use and dependence in the UK. In one year, (A) 9-10 million people use benzodiazepines. (B) Of these, 3.2-3.5 million use them for more than 4 months and are at risk of dependence. (C) Of these, 0.64-1 million are likely to suffer withdrawal problems.
Benzodiazepines ADDICTION TO NON-OPIATES
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Dependence on non-opiate drugs has become a major health problem in recent years. The changing pattern of dependence is shown in Figure 8.12.
Benzodiazepines have now replaced barbiturates both in popularity and as a cause for widespread addiction. Although the three million annual prescriptions cause less mortality than barbiturates (as they do not produce respiratory depression), they are an important source of mor-
TABLE 8.1? Symptoms of benzodiazepine withdrawal • • • • • • • •
Insomnia Anxiety Depression Outbursts of anger Muscular pains Tremor Headache Nausea, weight loss, anorexia
• Sweating • Tiredness • Perceptual abnormalities Visual disturbance Depersonalization Vertigo • Fits • Psychosis
bidity (see p. 216). There is an increased incidence of road traffic accidents in benzodiazepine takers. A withdrawal syndrome occurs in patients who have taken more than 20 mg daily over 6 weeks (Table 8.17). The symptoms of minor affective disorder (often self-limited), for which benzodiazepines are initially prescribed, may also then become part of a withdrawal syndrome, which can be mistaken for the original illness and lead to further prescriptions. Like barbiturates, benzodiazepines are best withdrawn in a slowly reducing dosage over several weeks. Antidepressants or even ECT (see earlier) may be needed to treat the depression associated with withdrawal.
Barbiturates Barbiturate addicts now comprise a small number of older patients (mostly women) who are relics of the barbiturate era, and a number of young multiple-drug users for whom barbiturates are one of a number of drugs in their repertoire. The effects of barbiturates are similar to those of alcohol, i.e. intoxication, ataxia and depression of consciousness. Respiratory depression due to overdose is a frequent cause of death. A withdrawal syndrome occurs in which convulsions are common. This should be controlled by pentobarbital (short-acting) 4-6-hourly. Withdrawal should be carried out slowly over several weeks.
Stimulants Amfetamines do not appear to cause physiological dependence, but produce a psychosis which is clinically very similar to paranoid schizophrenia. Symptoms abate within 2 weeks of withdrawal. Diagnosis is by urine screening. Treatment is by neuroleptics such as phenothiazines. Withdrawal from amphetamines often leads to a severe state of depression. Ecstasy, a synthetic amfetamine derivative, is widely used, especially at 'rave parties'. Fits, hyperpyrexia, renal failure and death may follow. Tactile hallucinations ('formication') are a feature of cocaine intoxication, which otherwise produces effects similar to amfetamines.
Removing the hydrochloride molecule from cocaine produces 'crack', which can be smoked rather than snorted. Crack is said to be the most powerful stimulant of all and produces profound depression and anxiety, and concomitant craving, following withdrawal.
8
Hallucinogens Hallucinogenic drugs such as LSD (lysergic acid diethylamide) and 'magic mushrooms' produce a toxic psychosis characterized by vivid hallucinations and delusions. Prolonged psychosis may be precipitated by LSD in susceptible individuals. 'Flashbacks' may occur for several months after an LSD 'trip'.
Cannabis Cannabis, like alcohol, appears to have few harmful effects if taken in moderation. Ten per cent of all young people have tried cannabis at some time, and 25% of students use it at least once a week. In some cultures and subcultures (e.g. Rastafarians) regular cannabis use, especially among males, is the rule. The active principle is tetrahydrocannabinol (THC), which is sometimes used as an antiemetic in terminal care. As with LSD, excessive use (or occasional use in susceptible subjects) produces a psychosis, and a withdrawal syndrome may occur. It has been suggested that regular use of cannabis may produce a state of apathy or amotivational syndrome.
Solvent abuse Inhalation of solvents such as toluene and acetone (used as vehicles for glue and other agents) produces a temporary state of euphoria. Glue-sniffing is common in certain youth subcultures. It is dangerous: an appreciable mortality has been recorded from direct cerebral damage, as well as asphyxia from the use of polythene bags to concentrate the vapour. Morbidity includes hepatitis, renal damage, cardiac arrhythmias, polyneuropathy and aplastic anaemia.
Drug screening Urine can be analysed for benzodiazepines, cannabis, amfetamines and opiates (but not LSD), and this is a useful test in cases of psychosis where drug abuse may be a possible cause.
ALCOHOLISM Alcohol is a major cause of medical and psychiatric morbidity in the UK (Table 8.18; see Table 8.13) and worldwide. In the UK, a 200% increase in alcohol consumption since 1950 (Fig. 8.13) has been accompanied by a 25-fold increase in admissions for alcoholism to psychi-
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TABLE 8.18 Alcohol consumption and alcoholism in the United Kingdom (population 55 million) Alcohol consumption
Estimated numbers
Regular drinkers Heavy drinkers Problem drinkers Addicted drinkers
36m 2m 700000 200000
TABLE 8.19 Criteria of alcohol dependence • • • • •
More than 80 g of alcohol consumed daily Tolerance: blood alcohol levels greater than 150mg/100mL Withdrawal symptoms Continued drinking in spite of psychological, social, and physical problems Abnormal blood tests, e.g. macrocytic anaemia and raised y-GT
Definitions Some criteria for alcohol dependence are given in Table 8.19. Two important patterns of alcoholism require definition: problem drinking and alcohol dependence. Problem drinking The WHO defines alcoholism as drinking that causes emotional, social or physical damage to the individual. Problem drinkers may suffer from all three, e.g. anxiety or depression related to alcohol; divorce, unemployment or financial difficulties; and gastritis or physical trauma associated with drinking. Alcohol dependence The essential feature of alcohol dependence is the development of a withdrawal syndrome when the drug is removed. The dependent alcoholic will drink, usually early in the day, in order to stave off withdrawal symptoms such as nausea, tremor, sweating or agitation. Other features of alcohol dependence include: • Narrowing of the drinking repertoire. The ordinary drinker's consumption varies from day to day. The dependent alcoholic has a daily drinking routine that must be followed. • Predominance of drinking over other activities. For the alcoholic, drink, even if it is clearly damaging their life, comes first. • Tolerance. The capacity of the dependent individual to drink large quantities of alcohol is an expression of physiological tolerance.
FIG. 8.13 Trends in alcohol consumption and expenditure in the United Kingdom A Alcohol consumption 1910-1990. 00 Consumer expenditure on alcohol, 1965-1990.
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atric hospitals. About 20% of admissions to medical wards are due to alcohol or alcohol-related diseases. Forty per cent of male attenders at hospital casualty departments have drink-related problems (p. 861). In 2000 40% of UK students drank above safe limits and 25% of the general population drank above safe limits.
Presentation: the hidden alcoholic Alcoholics have to be very ill or very brave to complain of their condition directly. Only about 10% of alcoholics in the community are in contact with psychiatric services, and about half are known to other agencies such as GPs, social services or parish priests. The remainder are unknown and untreated. Doctors need a high index of suspicion if they are to diagnose these hidden alcoholics correctly. The following factors should alert the examining doctor: • Unexplained gastrointestinal complaints • Complaints of anxiety and depression or panic attacks without obvious external precipitants
SUMMARY 23 Some presentations of undeclared alcohol abuse (should raise Index of suspicion') Psychological Memory lapses Depression Anxiety Outbursts of unprovoked anger Suicide attempts Morbid jealousy Paranoia Acute confusional state (DTs) Unpredictability
Physical Gastrointestinal symptoms Dyspepsia Pain Nausea Haematemesis Neurological symptoms Tremor Paraesthesia Muscular weakness Unexplained fits
Social Marital difficulties Problems at work Accidents at home or on the roads Delinquency, crime Violence
TABLE 8.20 The CAGE questions* • • • •
Have you ever felt you ought to Cut down on your drinking? Have people Annoyed you by criticizing your drinking? Have you ever felt bad or Guilty about your drinking? Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (Eye-opener)?
'Positive answers to two or more of these suggests a drinking problem.
Table 8.21 Factors associated with risk of alcoholism Factor
Examples of occupations affected
Availability of alcohol
Workers in the drink trade, caterers, business executives Coal miners, seamen, medical students, journalists Company directors, lawyers, GPs Commercial travellers, seamen, oil-rig workers, service personnel Coal miners, doctors, military personnel, actors Doctors, the unemployed Doctors, workers in the drink trade
Social pressure to drink
• • • • • •
Social difficulties, e.g. marital disruption, absenteeism Unexplained accidents Smelling of alcohol at unexpected times Single males over 40, socially isolated females Certain occupations, e.g. publicans, journalists, doctors Unexplained macrocytosis, or elevated liver enzyme values.
Where alcoholism is suspected, a detailed alcohol history should be taken. Vague questions such as 'How much do you drink?' are unlikely to be informative, but positive answers to two or more of the CAGE questions (Table 8.20) suggest a drinking problem. A detailed account of a typical 'drinking day' is required. Alcohol intake is measured in units. One unit equals half-a-pint of beer, a quarter-of-a-pint of strong lager, one 'short' or one glass of wine. Regular intake of six units or more per day puts men at risk of alcohol dependence. Women need half as much (i.e. three units per day) for half as long (e.g. as little as 2 years) for dependency to occur. The patient should be asked when he last had a day without a drink; about the longest period without a drink in the preceding 5 years; about withdrawal symptoms; and about blackouts. A 'drink diary', in which the patient records his drinking behaviour for a week, can be a useful aid to history taking. Raised serum y-glutamyl transpeptidase (y-GT) and increased mean corpuscular volume (MCV) are useful supportive evidence of abnormal drinking and are also helpful in monitoring progress. A blood alcohol concentration may confirm suspicions of recent excessive intake.
Aetiology Mutually interacting genetic, psychological and cultural factors underlie alcoholism. Adoption studies show that adopted children of alcoholics are four times as likely to develop alcoholism as are adopted children of nonalcoholics. The biochemical mediator of an inherited
8
Freedom from supervision Separation from normal social or sexual relationships Strains, stresses, and hazards High or low income Collusion by colleagues
tendency to alcoholism is unknown; however, active alcohol dehydrogenase leading to higher (and unpleasant) acetaldehyde levels has been postulated as protective against alcoholism. Psychological factors operate in two ways in alcoholism: • Imitation learning. An individual's tendency to drink follows that of his subculture, parents and peer group (Table 8.21). • Alleviation of unpleasant feelings. Alcohol reduces unpleasant feelings such as social anxiety and guilt. Each time an individual drinks, the experience of reduction of unpleasant mood ('drowning your sorrows') is reinforced. Family disruption is a common experience in the history of alcoholics. The true aetiology should be distinguished from the reasons for drinking offered by the patient, as the alcoholic's explanation of why he drinks is often a rationalization. The alcohol addict drinks because of his physiological state of addiction.
Physical complications The physical complications of alcoholism (see Chs 12,16, 24) include liver disease (Ch. 16), neurological syndromes (Ch. 24) (including peripheral neuropathy, cerebellar
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CASE STUDY 8.4 A 50-YEAR-OLD FARMER WITH CONFUSION A 50-year-old separated farmer was brought to A&E by his neighbour because he had been acting strangely for 2 days and was saying things that did not make sense. He was unable to give a clear history, but it seemed that he had separated from his wife 6 months previously and had been living on the farm on his own, although she continued to visit by day to help with the farm work. He had a new girlfriend but she lived in a different part of the county and he felt he could not afford the petrol to visit her. He had no previous psychiatric history and denied illicit drug taking, but was a smoker and admitted to heavy drinking over the past few months. He had been eating poorly. His farm had been in the family since the 14th century, but times had been hard recently and he had had to diversify into holiday letting, and had sold his milk quota. On examination he was a well-built man with obvious signs of weight loss. He was dishevelled and confused. His speech was normal in form but rambling. He did not appear depressed. He believed that he was being spied on by some unknown power, and that his thoughts could be extracted from his brain. His level of attention and orientation seemed to fluctuate, but on systematic examination he was generally orientated although he got the date wrong. Physical examination was essentially normal, apart from the evidence of weight loss and slight generalized tremor and sweatiness. He was admitted to the psychiatric ward for further observation but almost at once appeared to fall and injured the back of his head, with extensive bleeding. He remained unconscious for several minutes. The emergency crash team was called, but his vital signs were normal and consciousness returned. He was very confused, complained of headache,
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and on examination, although his pupils reacted equally to light there was weakness of elevation of the eyes, which was hard to evaluate as his cooperation with examination was poor. He became more lucid as the day went on, and was able to explain that he had been drinking a bottle or more of vodka a day for several months, but that he had decided to stop drinking some 5 days before admission, and confirmed that he had eaten little for several weeks. Later he had a grand mat fit.
Questions 1. What is differential diagnosis in this man's case? 2. What further investigations are needed? 3. What treatment, if any, should be instituted?
Discussion There are several diagnostic possibilities here. 1. The combination of delusional ideas with fluctuating consciousness makes this likely to be a confusional state ('acute brain syndrome') rather than a functional psychosis such as late-onset schizophrenia ('paraphrenia'), although at this stage no possibilities should be ruled out. 2. A first presentation of a psychotic illness in a 50-yearold man, accompanied by weight loss with a history of smoking, who then develops fits, should arouse the suspicion of organic pathology, such as a cerebral secondary tumour from a bronchial primary, or possibly cerebral non-metastatic manifestations of lung cancer.
3. The head injury was confusing: was his confusional state the result of the head injury and a possible subdural haematoma, or was some intracerebral pathology causing fits? 4. The history of heavy drinking, poor diet, sudden cessation of alcohol intake and possible eye muscle dysfunction makes alcohol withdrawal syndrome ('DTs') or even Wernicke's encephalopathy a distinct possibility - alcohol problems are common and 'common things commonly occur'. An emergency CT scan could help decide whether there was any intracerebral pathology - a haematoma or a tumour - although this investigation is difficult in such a restless and confused subject. Chest X-ray would eliminate the possibility of a lung primary. Liver function tests and haematology would help clarify whether there was any evidence of alcohol-related damage. Interviewing informants such as his ex-wife or girlfriend would help confirm and clarify the history - a good history is worth a thousand investigations in psychiatry. In the absence of any positive evidence of intracerebral pathology a presumptive diagnosis of DTs with possible Wernicke's encephalopathy was made. His confusional state coming on 5 days after stopping drinking, 'rum fits', and eye movement disorder were consistent with this diagnosis. He was given injections of parenterovite and started on a 'detox regimen' of reducing doses of carbamazepine, starting with 400 mg q.d.s. and reducing to 200 mg daily over a 5-day period. He made a good recovery and returned to his farm, determined to decide between his wife and girlfriend, to employ a neighbour to provide him with regular meals, and to abstain from alcohol.
degeneration, myopathy and convulsions), cardiomyopathy, pulmonary tuberculosis, anaemia, hypoglycaemia and pancreatitis. Children of alcoholic mothers may be born with a syndrome of low birthweight and developmental retardation known as the fetal alcohol syndrome.
Psychiatric complications There are three levels of severity at which psychiatric complications of alcoholism occur. In the initial stages the patient may present with minor psychiatric symptoms of panic attacks, anxiety, depressions or sexual difficulties. If withdrawn suddenly from the drug, the alcoholic addict is at risk for delirium tremens and sometimes alcoholic hallucinosis. Prolonged and severe alcohol addiction leads to alcohol-related dementia, including Korsakoff's psychosis (Ch. 24). Delirium tremens (DTs) is discussed on page 1438. Alcoholic hallucinosis Alcoholics may experience auditory hallucinations, usually derogatory or persecutory, in the presence of clear consciousness (consciousness is always clouded in DTs). These usually stop when drinking ceases but occasionally persist, suggesting coexisting schizophrenia. Morbid jealousy Alcohol is a frequent cause of a syndrome of morbid jealousy, in which an individual (usually male) becomes convinced that his spouse is unfaithful. Wernicke-Korsakoff syndrome (q.v.) and alcoholic brain damage are discussed in Chapter 24.
Management The outcome of treatment for alcoholism (Table 8.22) depends less on the nature of the treatment than on the social situation and personality of the patient. Addicts with a stable family and employment and a good personality do best. The impulsive or psychopathic drinker lacking home, family or job has a very poor prognosis for sobriety. The aim of treatment should almost always be abstinence. Any doctor who attempts to help alcoholics must be prepared for disappointment, as relapses ('slips') are common. A combination of limit-setting and acceptance is needed in all of the following treatment approaches.
TABLE 8.22 Outcome of treatment for alcoholism Outcome
1 year (%)
2 year (%)
Improved Still drinking Dead Lost to follow-up
35 45 1
25
19
21
51 3
Psychotherapy A supportive relationship, with either a spouse, a peer (e.g. through Alcoholics Anonymous) or a professional helper, is probably essential. Formal psychotherapy or social help should be conditional on sobriety, on the principle that whatever an alcoholic's problems (and they will be many), drink makes them worse. Wherever possible, the spouse and family should be included in any psychotherapy programme.
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Inpatient treatment Brief admission for 'drying-out', or longer admission to a therapeutic community with group therapy, can help maintenance of sobriety. Patients who need admission are by definition more disturbed, and the long-term prognosis is therefore often poor. Drug treatment Disulfiram (Antabuse) reacts with alcohol to produce acetaldehyde, producing unpleasant feelings of flushing and nausea. Some patients find it helpful to have this internal 'chemical fence' to discourage drinking. Alcoholics anonymous Alcoholics Anonymous (AA), started in the 1930s by an alcoholic doctor ('Bob'), is a worldwide self-help organization for alcoholics run by ex-alcoholics. It offers a structured personal and group psychotherapy programme aimed at sobriety. An important feature of AA is that it provides a social life that is not based on pubs or drinking. A parallel organization, Al-Anon, offers support to the families of alcoholics. 'Shop-front'/'dry house' programmes The 'skid-row' alcoholic has usually lost everything - job, home, family, possessions, friends - through drinking, and special facilities are needed for this group of patients (about 10% of alcoholics). These include non-threatening 'drop-in' day centres, after-care hostels and long-term medical and social support.
Prevention There is a direct relationship between per capita consumption and the price and availability of alcohol. As the real cost of alcohol has fallen steadily in the UK over the past decade, so per capita consumption and hence alcoholism rates have risen accordingly (Fig. 8.11). Internationally, there is a direct correlation between the price of alcohol and the incidence of cirrhosis and other indices of severe alcoholism. Governments, through pricing policies and licensing laws, can have a direct effect on alcoholism rates. Well-funded education programmes are also needed to alert the public to the dangers of alcohol.
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FURTHER READING ON ALCOHOLISM AND DRUG ABUSE Chick J 2000 Treatment of alcohol dependence. In: Gelder M, Lopez-Ibor J, Andreason N (eds) New Oxford textbook of psychiatry. Oxford University Press, Oxford Ghodse A 1997 Drugs and addictive behaviour. Blackwell, Oxford Heather N, Robertson I 1997 Problem drinking. Oxford University Press, Oxford Royal College of Psychiatrists and Royal College of Physicians 2000 Drugs: dilemmas and choices. Gaskell, London
MENTAL HANDICAP OR LEARNING DIFFICULTIES Mental handicap can be defined as the arrested or incomplete development of the cognitive (i.e. intellectual) part of the mind. Such a broad definition covers a wide range of individuals: • Severely mentally handicapped, who lack speech, are unable to learn, cannot dress or feed themselves, may be incontinent, and may have stereotyped movements such as rocking or thumb-sucking. The majority are looked after in institutions. • Moderately mentally handicapped, who have a considerable handicap (e.g. very restricted speech) but are able to live in sheltered accommodation in the community. • Mildly mentally handicapped, who have the capacity to learn and to live normal, if somewhat restricted, lives. Their primary problems are social and educational rather than medical. Most can live independently in the community.
MENTAL ILLNESS AND MENTAL HANDICAP It is only recently that mental illness and mental handicap have been properly distinguished. It is now understood that the majority of mentally handicapped people are not psychiatrically ill, and that they should be cared for by the social, rather than medical, services. Nevertheless, the mentally handicapped are particularly vulnerable to mental illness because of both their physical handicap and their emotional and social immaturity. They can develop the full range of mental illnesses, including schizophrenia, manic depression, anxiety states and hysteria. Distress is likely to be expressed behaviourally, for example through withdrawal, temper tantrums, compulsive masturbation or lawbreaking (e.g. shoplifting or self-exposure), rather than verbally.
• A single gene disorder, e.g. untreated phenylketonuria, tuberous sclerosis, mucopolysaccharidoses, untreated galactosaemia and Tay-Sachs disease; • Chromosomal, e.g. Down's syndrome, fragile-X mental retardation, deletion and duplication syndromes; • Traumatic, e.g. birth injury or anoxia. Here, the mental handicap is usually associated with spasticity; • Infective, e.g. maternal toxoplasmosis, cytomegalovirus and rubella; bacterial and viral meningitis. All may cause severe mental handicap; • Other causes include rhesus incompatibility, lead poisoning, and maternal drugs such as anticonvulsants or alcohol. Mild mental handicap usually lacks a specific inherited or environmental cause. It is thought to be a result of polygenie inheritance, often coupled with an impoverished environment.
AUTISM AND ASPERGER'S SYNDROME Autism is one of the most serious of the development disorders. It is characterized by 'autistic aloneness', in which the child is unable to make warm relationships; speech and language disorder, in which conversation as opposed to monologue may be deficient; an obsessive desire for sameness; and bizarre mannerisms. IQ is usually impaired, although the child often has artistic or musical abilities. The aetiology is unknown but is thought to be genetic, and possibly also due to perinatal minor brain injury. There is no known treatment that alters the condition, although individual psychotherapy has been claimed to have achieved remarkable results in some cases. The management usually consists of support for the family and special educational arrangements for the child. As in autism, in Asperger's syndrome there are marked impairments in social interaction, but the development of language and curiosity about the environment is normal. Sufferers usually show intense circumscribed interests or restricted repetitive stereotyped patterns of behaviour. The abnormalities persist into adult life, and most Asperger sufferers are 'loners', who are able to work but rarely able to sustain intimate relationships.
Management The principles of management of adult mental handicap are shown in Table 8.23.
Prevention CAUSES OF MENTAL HANDICAP 252
Moderate and severe mental handicap usually has a distinct cause. This may be:
Primary prevention is exemplified by rubella inoculation and the provision of lead-free paint. Secondary prevention is made possible by genetic counselling and by prenatal diagnosis and screening (see Ch. 3, p. 74).
TABLE 8.23 Principles of management of adult mental handicap • Accurate diagnosis • Treatment of coexisting mental and physical illness • Provision of training facilities, day centres, sheltered workshops and social clubs • Residential provision, e.g. hostels for those whose relatives cannot cope or are not available • Provision of emotional support for carers who, for example, worry about what will happen when they are no longer able to care for their mentally handicapped dependant
FURTHER READING ON MENTAL HANDICAP OR LEARNING DIFFICULTIES Bouras N 1994 Mental health in mental retardation. Cambridge University Press, Cambridge Matson J, Mulick J (eds) 1991 Handbook of retardation. Pergamon, Oxford
PSYCHIATRY AND THE LAW Mental illness may be associated with crime in one of three ways: • Psychosis. The most famous example of a crime being the result of a psychosis is the 19th century McNaughten case, in which a man who had tried to shoot the American President was acquitted 'by reason of insanity'. • Neurotic disorder. Depression, for example, may make a criminal act such as shoplifting more likely ('diminished responsibility'). • Psychopathic personality.
ANTISOCIAL PERSONALITY DISORDER People with an antisocial personality disorder may be described as those with persistent social difficulties (often, but not always, involving law-breaking) in the absence of a psychosis or neurosis. Their crimes, if they do occur, may be as trivial as repeatedly breaking shop windows, or they may be serious, such as murder. In the 19th century these individuals were classified as 'morally insane'; they were not deluded or hallucinated, but they appeared not to know right from wrong, or to be aware of the consequences of their actions. The term antisocial personality disorder is now used in order to avoid the derogatory connotations of 'psychopath'. The concept implies: • A persistent abnormality of interpersonal functioning, extending backwards to a childhood which was often disrupted and poor ('depraved because deprived');
• A major problem of social adjustment; • The absence of another psychiatric disorder.
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An antisocial individual has trouble not just in relation to himself or to immediate family (although this usually does happen), but also to institutions such as the law, school, the armed services, employment and marriage. He is both dependent on institutions and unable to coexist peaceably with them. There is often associated alcohol and/or drug abuse. The dividing line between normal and abnormal is harder to draw in this than any other psychiatric category and it is not a diagnosis that should be applied lightly. It is also important not to make such patients scapegoats. Antisocial individuals sometimes benefit from psychotherapy (providing firm limits are set), and from help with the social consequences of their disorder, such as homelessness and unemployment.
Dangerousness and risk assessment Psychiatrists are often called upon to assess the dangerousness of an individual so that decisions can be made about whether he should be allowed to live freely in the community. Assessment of dangerousness, which cannot be an exact science and will always to some extent be dependent on clinical judgement, rests on two main criteria: • Past behaviour. Violent or law-breaking behaviour in the past is the most reliable predictor of future trouble. A very careful history, taken in an atmosphere of trust, is essential if this is to be reliably assessed. • Psychological understanding of the causes of specific episodes of violence. Unless caused by organic factors such as epilepsy, violence rarely, if ever, emerges out of the blue. There are always antecedents and triggers that can be identified and which constitute a psychological explanation for the violent episode. These can best be elucidated by reconstructing a detailed 'action replay' of the events leading up to the episode. Thus many people resort to violence when they feel cornered, threatened, or are made to feel inadequate. Substance abuse often plays a major part in lowering thresholds to violence. Risk can be reduced if these factors are known, and steps can be taken to avoid them; conversely, situations likely to increase the likelihood of violence can be identified.
MENTAL HEALTH LEGISLATION Psychotic patients lack insight and may occasionally be dangerous, either to themselves or to others. In the UK, until the 1930s nearly all psychiatric inpatients were legally detained in hospital. Today, less than 10% of patients are detained on a 'Section'. Although compulsory admission is sometimes necessary for the protection of the patient and the public, this power is open to misuse or even abuse. The
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CASE STUDY 8.5 APPLICATION OF THE MENTAL HEALTH ACT TO A 45-YEAR-OLD MAN WITH HYPOMANIA A 45-year-old man was brought by his son to the accident and emergency department at 11.30 at night. The history was that since losing his job recently he had not slept for several days, had run up huge debts on his credit cards, and had become irritable and aggressive, so much so that his wife had temporarily moved out of the family home. He was complaining of a headache and his son, who was at his wits' end, had persuaded him to come to the hospital to have it investigated. On assessment there was no previous history of formal psychiatric disorder, although he had been prone to mild episodes of depression and withdrawal. Physical examination revealed no abnormality. He was restless, spoke rapidly without sticking to the subject, and was hard to interrupt. He appeared to have no insight into his situation and repeatedly demanded to leave. The provisional diagnosis was hypomania. The junior psychiatrist was worried about him, and felt that he needed further psychiatric assessment. Not surprisingly, he refused the offer of informal admission to hospital. Arrangements were therefore made for him to have a formal mental health assessment. This involved assembling a consultant psychiatrist (who was approved under Section 12 of the 1983 Mental Health Act), a mental health-approved social worker and his GP. During this time the patient was insisting on leaving, but with the help of psychiatric nurses he was distracted enough to stay. Eventually the assessment team arrived, he was duly put on a Section
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for assessment and admitted, with much protest, to the psychiatric ward, with a diagnosis of hypomanic disorder.
Questions 1. Under what powers can patients be held in hospital against their will? 2. What safeguards are there for both patient and doctor in this situation? The law requires that a strict procedure be followed if someone is to be deprived of their liberty under the Mental Health Act. There is often a period prior to bringing that procedure into play in which the patient may need to be restrained. The legal safeguard here is 'common law', i.e. the right (and duty) of a citizen to protect an individual from causing harm either to others or to himself. In this instance the patient was clearly in danger of harming others or himself. His aggression had resulted in his wife having been physically hurt; equally, he was likely to provoke others to hurt him; his financial profligacy (a typical symptom in hypomania) was also self-injurious. His headache was unexplained, and he needed investigation and overall assessment as well as restraint. Following the mental health assessment he could be given appropriate treatment - in this case tranquillizing drugs such as haloperidol - and if he refused to take them forcible administration was
United Kingdom Mental Health Act of 1983 (currently under review) aimed to provide safeguards against such abuse, and the Sections of the Act of particular relevance to general physicians are described below. In all cases it is a duty of the hospital administration to inform the patient of his Section, and a statutory right of the patient to appeal against compulsory detention.
permissible (although this is rarely necessary). The assessment procedure could begin in a safe environment. The 'Sectioning' procedure involves a clear reading to the patient of his 'rights' including the right of appeal against the Section, to be heard by independent experts in as short a time as possible. In this case the full mental health assessment team had to be brought together. However, had the patient already been formally admitted to hospital the junior psychiatrist would have had the right to impose a 'Section 5.2' on the patient, giving the staff the powers to hold him against his will for up to 72 hours, until a formal assessment could be mounted. Thus the combination of the 'common law' provision, with rights of appeal, gives both doctor and patient some safeguards. The Section 2 imposed on the patient was in fact lifted some 2 weeks later as his clinical condition improved, his insight returned, and he could begin to see that he needed help. Had this not happened, the Section 2 would have expired by the end of 28 days, and were he to have needed further restraint a 'Section 3' treatment order would have been needed. The rules of appeal apply equally to this procedure. The Mental Health Act is currently under review in the UK. It is likely that any decisions about detention for longer than 28 days will be taken out of the immediate hands of clinicians altogether, and referred to a mental health panel comprising an independent psychiatrist, a lawyer and a lay member.
Admission for assessment (Section 2) The patient may be detained for up to 28 days if (a) he is suffering from mental disorder which warrants assessment; or (b) he is a danger to himself or others. The application for such assessment must be made by a social worker or the patient's nearest relative. There has also to be a medical
recommendation from two medical practitioners. One of these must be a doctor officially approved as having special psychiatric experience ('Section 12' doctor, often a consultant psychiatrist); the other should, if possible, have known the patient previously (and is thus usually the patient's GP). In an emergency the patient may be detained for up to 72 hours (Section 4) on the basis of only one medical recommendation, which need not necessarily be by a psychiatrist.
detained patients can still be treated without their consent (e.g. given ECT or phenothiazine drugs), but a second opinion must first be obtained from a doctor appointed by the Mental Health Commission. Patients may not undergo psychosurgery (a brain operation occasionally undertaken in cases of depression or phobic anxiety) if they do not consent to it. Even if they do, a doctor and two nonmedical appointees of the Mental Health Commission must scrutinize the case to ensure that consent has been validly given.
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Admission for treatment (Section 3) The patient may be detained for up to 6 months. The conditions of the application and recommendation are therefore more stringent, and the rights of appeal greater than under Section 2. The patient must have a defined mental disorder, be thought likely to improve, and be unable to be cared for within the community. Section 3 can be extended for a further 6 months, with the approval of an independent tribunal.
Emergency detention of patients already in hospital (Section 5) An informal patient may be held in hospital for up to 72 hours on the recommendation of the doctor in charge of his treatment without a Section 2 or 3 being instituted. Under Section 5(4), a psychiatric nurse can detain an informal patient already being treated for mental illness for up to 6 hours. Under Section 5(2) a patient in a general hospital who is being treated by a non-psychiatrist can be detained, under the report of the doctor in charge of the case (the 'responsible medical officer' RMO), for up to 72 hours. A psychiatrist should see the patient as soon as possible to decide whether further detention is needed. Section 5(2) cannot be renewed.
Powers of the courts (Sections 36, 37, 38) Under these Sections, mentally ill offenders can be compulsorily admitted to psychiatric units for assessment and treatment, rather than going to prison.
Place of Safety Order (Section 136) Police officers have the power to remove to a place of safety any person whom they find in a public place who appears to be suffering from mental disorder and who is in immediate need of care and control for his own sake or that of others. Once removed, the patient must be medically examined and assessed. The place of safety is often a police station, but may also be a hospital A&E department.
Consent to treatment (Sections 57, 58) An important feature of the Act is a tightening of the procedure surrounding consent to treatment. Compulsorily
FURTHER READING ON MENTAL HEALTH LEGISLATION Faulk M 1994 Basic forensic psychiatry, 2nd edn. Blackwell, Oxford Gunn J, Taylor P 1993 Forensic psychiatry: clinical, ethical and legal issues. Butterworth-Heinemann, Oxford
MEDICINE AND THE EMOTIONS There are two basic types of mental activity. One is pictorial, non-rational and emotional, and concerns the biological fundamentals of birth, attachment, sex, separation and death, as well as art and creativity; the second is rational, verbal and logical and concerns the achievement of specific goals and the solving of particular problems. Freud called these the primary and secondary processes. Non-rational thinking is primary because it precedes rational thinking developmentally: infants and young children think in feelings and pictures. The secondary processes are only gradually acquired. In healthy adult life both coexist. Much of waking life is dominated by secondary processes, but in dreams, daydreams and instinctual activity the primary processes take over. In mental illness the balance of primary and secondary processes may be disturbed: the psychotic, for example, is dominated by primary processes, whereas the patient with obsessional neurosis is trying to apply the false logic of secondary processes to his emotions. Modern medicine is based on scientific rationality. This means that at times doctors may find it difficult to comprehend the emotional reactions of the patient to illness, death or sexuality. For the doctor, the patient who needs a routine hernia operation presents a technical problem to be solved; the patient, however, may at some level be wondering whether he will survive the operation and, if so, whether his sex life will continue. Medical training is predominantly a training in rationality, in learning to set feelings aside. In order to understand the 'irrational' anxieties that trouble patients the doctor has to remain in touch with and respect the primary processes. The following sections on sex, and on death and dying, highlight some of these issues.
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SEX AND MEDICINE Sex matters for three main reasons: identity, attachment and continuity. Sexual abuse in childhood threatens all three and is an important underlying cause of psychiatric disturbance.
Identity Gender is fundamental. When a baby is born the mother asks 'Is it alright?', then 'Is it a girl or a boy?'. Gender is integral to a sense of identity, and this can be threatened by illness at any of the stages of development. Hypospadism, hirsutism, hernia, delayed puberty, amenorrhoea, infertility, hysterectomy, prostatectomy, diabetes-related impotence are just a few of the many medical conditions that may threaten the sense of identity that is rooted in gender and sexual functioning.
Attachment Human attachment occurs through the body. Even when communication is at a distance, hands are, needed to write a letter, a voice to speak on the telephone. Sexual bonding is a powerful and rewarding form of attachment. The adolescent worries whether his or her body is 'good', 'big' or attractive enough to find a partner. Where sexuality is threatened by illness and disability, the patient fears that the basis of his or her attachment may be undermined: 'Who will want me i f . . . I have a colostomy ... a mastectomy ... am impotent... ?' Psychogenic symptoms such as lower abdominal discomfort, pruritus or back pain may both arise from and lead to sexual difficulties. Such symptoms may draw attention to an underlying sexual anxiety, and at the same time provide the patient with the care and attention that he fears may be lost through sexual failure. Occasionally, guilt about masturbation may be based on the misconception that it is 'wrong' or harmful, and this too may lead to psychogenic symptoms.
Continuity Psychologically, sex and reproduction may serve as an insurance against the fear of extinction. The idea of personal death is more acceptable if there is family continuity, or if an individual feels he has contributed something: that children, memories, ideas or objects will live on in the next generation. Threat to this sense of continuity can lead to feelings of anxiety or depression.
1
256
MCQ 8.7
TABLE 8.24 Common anxieties about sex Adolescence Masturbation Homosexuality Genital inadequacy Young adults Impotence Anorgasmia Infertility Lack of libido
Middle-aged Extramarital affairs Sex and illness Any age Incest Fetishism Non-consummation of marriage
Taking a sexual history Sex, at least in theory, is no longer a taboo subject, but in practice both doctor and patient are likely to feel anxious about some aspects of their sexuality. It is important that the doctor feels reasonably comfortable when asking about a patient's sexual life. All human beings have a sexual life - in the sense of thoughts, fantasies and feelings about sex - regardless of whether or not they are celibate. The doctor needs to be sensitive to the common anxieties about sex and to be aware of those that may apply to a particular patient's age and situation (Table 8.24).
SEXUAL AND MARITAL DIFFICULTIES Divorce and family disruption are becoming increasingly common. More than one in three marriages in the UK now ends in divorce; in the USA the figure is one in two. There is good evidence that in general marital disharmony and divorce are psychologically damaging for children, who are more likely to have emotional disorders in adult life and to underachieve academically than their counterparts from stable families. Nevertheless, single mothers and even same-sex parents are capable of providing a loving and nurturing environment for their children. Partly in response to this, there is now great interest in marital and family therapy. The commonly encountered sexual difficulties are impotence, premature ejaculation and delayed ejaculation for men, and vaginismus and lack of sexual enjoyment (including anorgasmia) for women. Both sexes may suffer diminished libido. Transient difficulties are common; it is only when they are persistent and cause distress that they constitute a problem. Sexual problems may be primary, i.e. present from the onset of sexual life, or secondary, i.e. developing after a period of satisfactory sexual functioning.
Erectile dysfunction This can be defined as the inability to achieve an erection sufficient for satisfactory sexual intercourse.
Aetiology Contrary to popular belief, as many as 50% of cases of impotence are organic in origin. Where impotence is psychologically based, it arises out of anxiety. This may be in the context of an episode of anxiety/depression, or as a manifestation of personality disorder. Organic causes include: • Endocrine causes, such as hypopituitarism and hypogonadism • Diabetes. At least 30% of diabetic men experience impotence by the age of 50 • Vascular disease, such as Buerger's disease • Alcoholism • Drug induced, e.g. diuretics, p-blockers and neuroleptics.
•
•
•
Treatment • If psychogenic, the Masters and Johnson approach outlined below is normally effective. • The underlying cause should be treated whenever possible. • Symptomatic treatment: - Intracavernosal injections of papaverine, papaverine plus an a-blocker such as phentolamine, or alprostadil (prostaglandin E2) can be self-administered and are effective in up to 70% of cases. The main danger is priapism, and erections lasting more than 4 hours should be treated as an emergency, with venous aspiration together with a vasoconstrictor. The drug Viagra is a significant advance over these cumbersome measures. In the presence of sexual desire and stimulation it produces good erections that have a more 'natural' quality. - Mechanical aids such as a vacuum condom are also useful in some cases. The Masters and Johnson approach Current thinking about sexual dysfunction has been greatly influenced by the work of Masters and Johnson, who studied the physiology of sexual response and introduced a new classification and treatment for sexual difficulties. General principles of the Masters and Johnson approach include the following: • Treatment is in couples. Sexual difficulties are often complementary (e.g. premature ejaculation and an-
SUMMARY 24 The Masters and Johnson approach • • • • • •
Treatment in couples Physical examination/history-taking (to reassure they are 'normal') Instruction in sexual arousal Instruction initially not to make love (to dispel anxiety) Graded exercises based on 'sensate focus' Psychotherapy if necessary
•
•
orgasmia), even though one member may present as the person with the problem. The non-presenting partner is given the role of co-therapist. Physical examination and careful history-taking of both partners are required both to rule out organic causes of sexual dysfunction and to reassure the patients that they are 'normal'. There is more to sex than penetration. Sexual arousal, especially in women, depends on a series of steps, arid a man may need to learn that foreplay cannot usually be omitted if his partner is to be fully aroused. Anxiety is seen as a central element in sexual dysfunction. Anxiety is antagonistic to sexual arousal, and a vicious circle can arise in which the patient fears they will fail (for example to maintain erection, not to ejaculate prematurely, or to have an orgasm), which makes them 'try' harder, which makes them less able to relax and respond to sexual stimuli and thus more, rather than less, likely to 'fail'. The aim of treatment is to break this circle. Paradoxically, the couple are initially instructed not to make love, in order to prevent performance anxiety. They are given a series of graded exercises based on sensate focus or stroking, in which they learn to give and receive pleasure. Initially this is non-genital, but later moves on to 'genital sensate focus', i.e. mutual masturbation. It is ironic that whereas masturbation was viewed (wrongly) by 19th century psychiatry as a major cause of insanity, it is now considered important that both sexes are able to masturbate without guilt. Psychological factors in sexual dysfunction may also need treatment, through either individual or marital therapy. Unexpressed anger is a common cause of sexual disharmony: a couple who cannot row may also not be able to make love. Fear of loss of control, ignorance or guilt may also affect sexual pleasure.
8
The results of the Masters and Johnson approach are generally good, with 60-70% improvement rates reported in well-motivated couples. 1
FURTHER READING ON SEX AND MEDICINE Hawton K 1985 Sex therapy: a practical guide. Oxford University Press, Oxford Hawton K 1995 Treatment of sexual dysfunction by sex therapy and other approaches. Br J Psychiatry 167:307-314
DEATH AND DYING Death is an integral part of medicine, but doctors and other medical staff often feel confused by the psychological and ethical questions it poses. Should a terminally ill patient be kept alive as long as possible, or allowed to die in peace? Should every patient with a fatal illness be told of his diagnosis, and if so how should they be told? Can a dying
257
patient be helped to come to terms with death, and how can this happen? What are the psychological reactions in the relatives of dying patients, and what support do they need? These questions are problematic not only because of a lack of training and technique, but also because death is an intrinsically difficult subject which all but the exceptionally compassionate find hard to face. Patients and doctors alike deny the reality of death in order to carry on with life.
REACTIONS IN THE PATIENT The response of the patient to the knowledge that he has a terminal illness can be compared to a bereavement reaction. The patient enters a state of grief for the loss of his own life. The initial reaction is usually one of numbness and shock, a struggle between denial and acceptance. The patient attempts to fight off what is happening and cannot believe it is true, that it is happening to him. This is often followed by a period of severe anxiety, in which the patient becomes dependent on visitors, family and medical staff, and finds it very hard to be alone. A period of sadness and weeping is inevitable. Anger is also a normal feature of this phase, and the patient may become difficult, complaining, ungrateful and demanding. With time, however, the patient gradually becomes calmer, and during this phase the opportunity to talk may be very helpful. This series of reactions may be compressed into a few hours or spread over months, and, as with bereavement, does not follow a neat, orderly course.
TALKING TO DYING PATIENTS Breaking bad news and talking to dying patients is an art that can be learned through watching others, and through discussion of the feelings and difficulties it arouses. The patient can often be helped if staff and family recognize the subsequent reactions for what they are and then let the patient talk about his anger, panic and sadness. When this has happened the patient may feel better.
258
SUMMARY 25 Emotional reactions in terminally
ill patients • • • • • •
Numbness and shock Struggle between denial and acceptance Severe anxiety Sadness and weeping Anger Eventual calmness
The issue of 'to tell or not' is a false alternative. Some patients want to know their diagnosis in great detail; others would rather not know. It is unnecessary and inappropriate to confront all patients with the stark reality of their illness. On the other hand, far more patients than are officially 'told' want to know their diagnosis or know it already. The patient needs space and time in which to discuss his feelings and ask questions. Gentle probing may be needed to help the patient make use of this opportunity.
REACTIONS IN THE FAMILY Like the patient, families also go through an anticipatory grief reaction when a loved one is dying. The death of a child or adolescent is especially painful and unsupportable. Spouses of dying patients are particularly vulnerable. They may, for example, feel angry with their husband or wife for being ill, and feel very guilty about having such unvoiced thoughts. The stress of death may lead to tense and angry outbursts, either within the family or outside it at medical staff. Doctors and nurses should be prepared for this. Family counselling can help with these grief reactions and help to make death and bereavement, when they come, more bearable.
FURTHER READING ON DEATH AND DYING Holland J, Rowland J (eds) 1990 Handbook of psycho-oncology. Oxford University Press, Oxford
9 Infectious, Tropical
and
Parasitic Disease Mark H Wansbrough-Jones and Stephen G Wright
The relationship between humans and microorganisms 259 Principles of diagnosis and management 261 Antimicrobial agents 262 Infection in the immunocompromised patient 269
Rickettsia 305 BACTERIAL INFECTIONS 307 Gram-positive cocci 308 Gram-negative cocci 310 Gram-positive bacilli 311 Gram-negative bacilli 315
Control of infection 271
Mycobacteria 325
Syndromes of infection 273
Spirochaetes 329
VIRUS INFECTIONS 283
Actinomycoses 330
Enveloped double-stranded DNA viruses 283
Madura foot 331
Enveloped single-stranded DNA viruses 289 Non-enveloped double-stranded DNA viruses 290 Enveloped single-stranded RNA viruses 290 Non-enveloped single-stranded RNA viruses 302 Non-enveloped double-stranded RNA viruses 303 CHLAMYDIAL, MYCOPLASMA AND RICKETTSIAL INFECTIONS 303
Nocardioses 331 SYSTEMIC MYCOSES 332 PROTOZOAL INFECTIONS 335 Protozoal infection of the gut 335 Genital tract protozoa 342 Free-living protozoa causing human disease 342 Non-pathogenic gut protozoa 343
the upper hand, particularly over children. Worldwide, infectious gastroenteritis is the most common cause of death in children under the age of 1 year. The causative organisms are similar in underdeveloped and western countries, but in the former there is more frequent exposure from water supplies, methods of food preparation and poor standards of hygiene, including sewage disposal. The outcome is worse because of the severity of dehydration. Table 9.1 shows how the frequency of some infections varies in different areas of the world. The figures illustrate differences attributable to climate (malaria), standards of hygiene (typhoid) and immunization (poliomyelitis, measles and diphtheria). The mortality associated with these diseases is also higher in underdeveloped countries because of a poor nutritional state at the onset of illness and limited access to medical facilities. The pattern of infections is constantly changing. Infectious diseases become less important as a cause of death as the standard of living improves. England in 1860 was much the same as parts of Africa and southeast Asia today with respect to some infectious diseases (Table 9.2). Improvements in standard of living and immunization account for the change in many of these diseases, but sometimes the pathogen itself changes in virulence. Scarlet fever (scarlatina) is no longer the feared disease it was 50 years ago because erythrogenic toxin-producing streptococci have become less virulent. Changes in microorganisms may produce little change in the clinical disease but are of no less significance. The type of meningococcus most commonly incriminated in bacterial meningitis in the UK has for many years been group B, but recently there has been a resurgence of group C infections. Meningococcal vaccine will protect against group A or C infection, but group B meningococci are poor immunogens. Similar antigenic variation occurs repeatedly in influenza virus. Most of the changes in the pattern of infections are gradual. New infections are extremely rare but can have an enormous impact; an example is human immunodeficiency virus (HIV), the cause of the acquired immune deficiency syndrome (AIDS). All of the infections encountered in temperate and developed areas of the world will be found in tropical regions. Certain infections are exclusive to the tropics because of climate, and the presence of animal reservoirs and insect vectors.
Tissue and blood protozoa 343 HELMINTH INFECTIONS 358 Nematodes 359
Chlamydia 303
Trematodes 370
Mycoplasmas 305
Cestodes 375
The relationship between humans and microorganisms is usually one of balanced conflict. In the first months of life encounters with microorganisms are both a threat and a stimulus to the development of complex immune responses. In many parts of the world microorganisms appear to have
THE RELATIONSHIP BETWEEN HUMANS AND MICROORGANISMS Microorganisms that can cause disease in humans are widely distributed in nature, and humans are colonized by vast numbers of organisms. Whether a particular organism causes disease is determined by its natural distribution, its pathogenicity, and the state of the host defence systems. With common pathogens it is likely that immunity will develop early. The age at which this occurs can influence the outcome of infection. At extremes of age the immune
259
TABLE 9.1 Cases of infection reported to WHO from different geographical regions and countries Region or country Americas (all) USA* Europe
Malaria (1993) 984000 1217
50000
Poliomyelitis (1995)
Measles (1994/5)
Typhoid (1980/1)
Diphtheria (1994/5)
0
22988
42160
0 202
286
324
73729 23594
75203
245379
28418
1420 3791
7810
708
0 49483
312
Africa
2590000
643 411
S.E. Asia
3077000
2269
106773
329980
674000
226
110776
145
614
0
7763
265
13
E. Mediterranean
W. Pacific England and Wales
292000
1992
(Data supplied by Communicable Diseases Surveillance Centre, Colindale.) All figures are to nearest 100. *AII figures for USA are for 1995. AII figures for England and Wales are 1995 (except malaria - 1993)
TABLE 9.2 Deaths from infection in England in 1800 fall age groups) Cause
Number
Measles Scarlatina (scarlet fever) Smallpox Diphtheria Typhus Whooping cough Cholera Tuberculosis
9557 9 681 2749 5212 13012 8553 327 58564
system is either immature or in decline, and the patient is highly vulnerable. Paradoxically, during childhood many viral infections are silent or mild, but the same infection in an adult may be severe and complicated. This may reflect a difference in the vigour with which inflammatory responses are generated.
PATHOGENICITY
260
Microbial pathogenicity - that is, the potential of a microorganism to cause disease - is determined by its ability to enter the host and colonise, to penetrate tissues, to evade host defences and to damage tissues. The virulence of an organism is its degree of pathogenicity. An organism is described as highly virulent if a small number of microbes can cause severe disease. Skin is an effective barrier to most organisms and they usually enter either through a breach or via more delicate mucosal surfaces, such as those of the oropharynx and respiratory tract. Attachment to the cell membrane is essential for viruses, and bacterial colonization is also often facilitated by a specific attachment mechanism. Examples are Vibrio cholerae or Escherichia coll in the intestine, and
E. coli in the urinary tract. In each case a determinant on the bacterial surface interacts with a specific receptor on epithelial cells. Some pathogenic organisms cause disease at the site of colonization by producing toxins (V. cholerae),but most traverse the epithelium and their further success depends on their ability to avoid host defences. In the first encounter between human and organism innate immunity is the only defence. In the case of bacteria this centres on phagocytosis, and some bacteria are equipped with capsules that confer resistance to phagocytosis. Interferons play a major part in first-line resistance to viruses, but viruses differ both in their ability to stimulate interferon production and in their susceptibility to its effects. The mechanisms of disease provoked by bacteria are complex, but a distinction can be made between effects caused by exotoxins (tetanus or diphtheria toxins, for example) and those resulting from release of bacterial components such as endotoxins.
SUSCEPTIBILITY TO INFECTION
The effects of even virulent microbes are curtailed by an immune response. Infections therefore typically result from a small number of identifiable situations: • First encounter with a virulent organism, in sufficient numbers, entering by an appropriate route; • Breach of normal anatomical barriers, e.g. by surgery, injury or indwelling lines; • Impairment of innate immune responses; • Impairment of adaptive immune responses. When anatomical barriers are breached by surgery, tissues that are usually sterile are exposed to normal microbial flora at the adjacent site. Similarly, accidental injury often results in exposure to environmental organisms, such as Clostridium tetani present in the soil. Impairment of immune responses leads to susceptibility to infection by organisms of low pathogenicity as well as
9
FIG. 9.1 Incubation periods and periods of communicability of common infectious diseases
to virulent organisms. Infection by organisms of low pathogenicity is called opportunistic. Patients with impaired immunity may therefore present with frequent infections, infection caused by opportunist microorganisms, unusually severe disease caused by infection, or repeated infection by the same organism.
• Incubation period: time from contact with microorganisms to onset of symptoms (Fig. 9.1) • Prodromal illness: minor symptoms preceding the definitive illness • Overt disease • Resolution (convalescence).
This approach will often lead to a simple management plan. It may also be necessary to establish the source in the community. In some cases the doctor has a legal obligation to notify the disease (see Control of infection, p. 271).
This pattern is often influenced by the immune state of the patient and may be altered by drug therapy. Some symptoms, such as sore throat and fever, are more commonly associated with infection than with other disease processes. The pattern of fever may be helpful, but patients may say that they have had a fever when they have not measured their temperature. They may mean aching in the limbs, sweatiness feeling hot or cold, shivery, or true rigors. Of these, a rigor is a good indicator. This is a sensation of coldness accompanied by shivering (associated with a rise in temperature) followed by a hot sensation and marked sweating. Although no one symptom is specifically associated with infection there are many symptom complexes that are highly suggestive of an infective aetiology. For example, although headache has many causes, the combination of headaches with fever, photophobia and vomiting strongly suggests infection of the meninges (meningitis).
Is the disease caused by infection and, if so, where is the site of infection?
Examination The findings on examination may be helpful in three ways:
A careful history and examination will provide important indicators that the patient is suffering from infection.
• Some infections are associated with signs that are specific or which suggest only a short list of differential diagnoses. Examples are the rash of chickenpox or measles, neck stiffness caused by acute meningitis, or the characteristic cough of whooping cough. • More commonly a combination of signs is highly suggestive of an infection. For example, exudative tonsillitis, generalized lymphadenopathy and splenomegaly together suggest infectious mononucleosis; fever, relative bradycardia, splenomegaly and rose spots suggest typhoid. • Physical signs may indicate the site of infection. Consolidation in the lungs suggests pneumonia; loin tenderness is associated with pyelonephritis; inflammation,
PRINCIPLES OF DIAGNOSIS AND MANAGEMENT The principles guiding the clinician in the diagnosis and treatment of an infective illness can be considered by asking some simple questions: • Is the disease caused by infection and, if so, where is the site of infection? • What is the microorganism responsible? • Which drugs can eliminate the organism, and will treatment benefit the patient?
History Three aspects of the history are likely to be helpful: • Pattern of the illness • History of contact with patients with a similar illness, or types of behaviour that confer a risk of infection • History of travel to places where particular infections are known to be common. Illnesses caused by infection tend to have a form that is reproduced in most individuals and which is characterized by the following features:
261
volume of fluid permits. The yield will be higher and a Gram stain can be performed. • Think of culture before allowing a tissue specimen to be immersed in fixative such as formalin. • Ensure that specimens for culture are transported to the laboratory without delay. Microorganisms must be nurtured, and all too often they die waiting for transport, or are overgrown by contaminant organisms. Specimens for viral or fungal culture often require special collection techniques and the laboratory should be consulted before obtaining the specimen.
Which drugs can eliminate the organism from the infected site, and wifl treatment benefit the patient?
FIG. 9.2 111ln white cell scan in a paracolic abscess At 24 hours after the intravenous injection the activity is localised, indicating the accumulation represents an enclosed abscess rather than inflamed bowel. (Reproduced by kind permission of Dr Seth Saverymuttu.)
swelling and fluctuance beneath the skin suggest an abscess.
What is the microorganism responsible? A careful history and examination may point to a diagnosis of infection and can be specific for a particular infection. More frequently, infection is strongly suspected but the site and the organism responsible are unknown. Imaging techniques are often helpful in finding the site of infection, e.g. ultrasound or CT scanning can demonstrate an abscess in soft tissues. Gallium or technetium (99mTc) leukocyte scans frequently demonstrate a soft tissue abscess. In the latter technique the patient's leukocytes are labelled with 99mTc and reinjected (Fig. 9.2). Labelled leukocytes enter sites of acute inflammation, such as an abscess, surgical wounds and the bowel wall of patients with inflammatory bowel disease. Before appropriate treatment can be started the right samples must be collected and sent to the laboratory. The laboratory can give most help if the correct samples are taken and are accompanied by a brief summary of the patient's illness. The drug history is particularly important, as antibiotic in the sample may inhibit the growth of bacteria in vitro. There are simple rules for the collection of samples:
262
• Avoid contamination of the sample with irrelevant organisms by careful cleansing, e.g. cleanse skin with antiseptic before taking blood for culture, and wear gloves during venepuncture. • When infected fluid is to be cultured (e.g. pus) send a fluid sample in a sterile bottle rather than a swab, if the
Some guidelines for the choice of antimicrobial drugs are given on page 263. Whether treatment is to be started immediately or after the results of laboratory tests are available depends on the severity of the disease and the likely consequences of delay. There is virtue in waiting until the precise diagnosis is known if the clinical situation permits, and this applies particularly when antibiotics have been given before admission to hospital. Acute meningitis and septicaemia are obvious exceptions because the patient may die before a final result is available, but even then it is desirable that the correct specimens are obtained before treatment is started. Valuable preliminary information can be obtained by Gram staining and microscopy of specimens such as sputum or pus. Direct testing for microbial antigens may increase in importance for disease caused by a limited range of organisms, such as acute meningitis. Treatment is not always beneficial to the patient, even when an antimicrobial drug with appropriate activity can be delivered to the site of infection in adequate concentration. Faecal excretion of salmonellae may be prolonged by treatment with some antibiotics.
ANTIMICROBIAL AGENTS The choice of antimicrobial drugs is central to the management of infection. General measures should not be neglected: these include use of analgesics, attention to nutrition and hydration, and cleaning, debridement or drainage of infected areas. The term 'antimicrobial agent' can be applied to any substance that is active against microorganisms. Strictly, an antibiotic is a substance produced by a microorganism which inhibits the growth of another. In this chapter 'antibiotic' will be used (inaccurately) to refer to antibacterial drugs, whether synthetic or naturally produced. In this section the dose of antimicrobial is not normally given, as this often depends on the nature of the particular infection being treated, and the reader should refer to sections on the management of specific diseases. Only the more severe side-effects are noted here.
edge of antibiotics, including the known sensitivity of particular organisms to them. The latter are not constant, and so treatment is often started on the basis of an intelligent guess and modified later according to laboratory results. Bacterial sensitivity is tested using discs impregnated with antibiotic and measuring the size of the ring of inhibition on culture plates. Other factors are also important in the choice of antibiotic, such as absorption and penetration to the site of infection. Whenever possible the antibiotic chosen should have a spectrum of antibacterial activity limited to a few organisms, as the broader the spectrum the greater the chance of side-effects owing to disturbance of the normal microbial flora. The choice between a bactericidal and a bacteriostatic drug is not usually critical but it may be important when the organisms are fairly inaccessible, as in infective endocarditis, or when host defences are impaired (see Table 9.6). Combinations of antibiotics are used for one of three purposes:
Choice of appropriate drugs The selection of a suitable antimicrobial agent is fairly straightforward when the microorganism responsible is known (Table 9.3), but often this is not the case and a sensible guess has to be made as to the organisms responsible. In the case of a urinary tract infection in a previously healthy young woman, for example, faecal organisms such as E. coli would be the most likely pathogens, and this would guide initial therapy. The information required to make an appropriate choice can be summarized as follows: • • • • •
Probable organism(s) Probable antimicrobial sensitivities of the organisms Ability of the chosen drugs to reach the site of infection History of allergy to drugs Interaction of these drugs with any other drugs the patient is taking • Side-effects of the chosen drug • Cost of the drug.
• To obtain a spectrum of antibacterial activity that could not be achieved with a single agent (e.g. treatment of septicaemia when the causative organism is not known); • To take advantage of synergy between drugs (e.g. during the initial treatment of infective endocarditis); • To prevent the emergence of resistant organisms (e.g. treatment of tuberculosis).
An example of the process of decision is shown in Figure 9.3. This logical sequence assumes a considerable knowl-
TABLE 9.3 Common sensitivities of some bacteria to antibiotics Bacteria
1st choice
2nd choice
Streptococci (except anaerobic) Staphylococci Neisseria meningitidis Neisseria gonorrhoeae Gram-positive bacilli Escherichia coli (urinary tract) Pseudomonas aeruginosa
Penicillin
Erythromycin
Flucloxacillin Penicillin Azithromycin Penicillin Trimethoprim
Erythromycin Cefotaxime Penicillin
H. influenzae (respiratory infection) Gram-negative (septicaemia)
Route of administration The ideal drug would give adequate serum levels after oral administration, whatever the state of the patient. However, an ill patient often cannot swallow tablets and absorption from the gut may be unreliable. The choice between intravenous (i.v.) and intramuscular (i.m.) administration is determined by the form in which the drug is available and its pharmacokinetics, the discomfort of intramuscular administration, and practical issues such as accessibility of veins and other drugs being administered. Topical antibiotic treatment is sometimes useful in the eye (p. 304), on the skin (Ch. 10) or in the respiratory tract (e.g. in cystic fibrosis, see p. 651), but the development of resistance is a problem.
Amoxicillin
Piperacillin and gentamicin (usually requires a combination) Co-amoxiclav
Ceftazidime and gentamicin
Cefotaxime
Ciprofloxacin Piperacillin and gentamicin
Erythromycin
Duration of treatment The aim of treatment with antibiotics is to eliminate infec-
Antibiotic
Probability of sensitivity
Penicillin
>95%
+ +When meninges inflamed (iv administration)
Allergy
Low
Cefotaxime
>95%
+ + (iv administration only)
Allergy in 10% of penicillin-allergic subjects
High
1st choice in Western world if penicillin allergy
Chloramphenicol
>95%
+ + +(Oral or iv administration)
Very rare marrow aplasia
Low
1st choice in Third World country
Penetration
9
Toxic effects
FIG. 9.3 Choice of antibiotic in a patient with acute pneumococcal meningitis
Cost
Decision 1st choice if no allergy
263
tion, when this is achievable, or to reduce the number of organisms to a point at which host immunity can do the rest. Surprisingly little is known about the duration of treatment needed to achieve these aims in most infections, and there is considerable unsupported dogma regarding the importance of completing a prescribed course of antibiotics. The usual argument for finishing a course of treatment is that early discontinuation encourages the emergence of resistance. However, resistance rarely arises during treatment except when the bacterial population already contains resistant mutants, as in streptomycin therapy for tuberculosis. It is most likely to occur in chronic and heavy infections (e.g. Pseudomonas aeruginosa infection in cystic fibrosis), and with particular antibioticbacterial groupings, such as quinolones or fucidic acid in staphylococcal infections, cephalosporins in some Gram-negative infections, and rifampicin in infections by many bacterial species. There is good evidence about the duration necessary for treatment of tuberculosis, urinary tract infection, gonorrhoea and infective endocarditis, but virtually none about upper and lower respiratory tract infections, which account for 75% of community prescriptions. Opinions vary considerably about the appropriate time to treat in most other infections, and often the only advice available is to be guided by the clinical response.
MECHANISM OF ACTION OF ANTIBIOTICS
TABLE 9.4 Examples of major pathogens which have developed new resistance patterns
Antibiotics act in one of the following ways:
Organism
Resistance to
• Inhibition of bacterial cell wall synthesis (penicillins and cephalosporins); • Inhibition of particular aspects of bacterial cell function: protein synthesis (aminoglycosides, chloramphenicol, tetracyclines, macrolides, clindamycin); DNA replication (rifampicin, quinalones); microbial enzymes (sulphonamides, trimethoprim, isoniazid).
Enterococcus Strep, pneumonias N. gonorrhoeas Staph. aureus
Ampicillin/gentamicin Penicillin Penicillin Methicillin (flucloxacillin)
Resistance to antibiotics There are two major ways in which resistance occurs: • The bacterium produces an enzyme which inactivates the antibiotic. The best-known example is B-lactamase, which alters the B-lactam ring of penicillins and cephalosporins (Fig. 9.4). Aminoglycosides and chloramphenicol are other drugs broken down by bacterial enzymes. • The bacterium may alter such that the antibiotic is rendered ineffective. This occurs either by a change in the permeability of the bacterial cell wall or by an alteration at the target site of the antibiotic.
264
FIG. 9.4 Structure of B-lactam ring
Resistance tends to emerge by natural selection in a population of bacteria exposed to antibiotic. This may be acquired by mutation (leading to a single base alteration), but more often it is the result of incorporation of new
genetic material into the bacterial nucleus or the transfer of genetic material from other organisms in the form of extrachromosomal DNA as plasmids (episomes) and transposons. There is an increasing problem with emergence of resistance among bacteria (Table 9.4) which is largely related to the use of antibiotics acting as a selection pressure. In hospitals methicillin-resistant Staphylococcus aureus (MRSA) colonize the skin of patients admitted with other problems and can be difficult to clear. For the majority of patients these organisms are harmless, but they can cause deep infection in certain, groups, such as orthopaedic and cardiac surgery patients, and there is controversy about whether hospitals should isolate all colonized patients and attempt to clear their skin of infection, or just take steps to protect high-risk groups. On a wider scale, antibiotics introduced in poor communities for the treatment of common conditions become useless after a few years because resistance develops.
This has happened when trimethoprim was given for the treatment of dysentery in the past, and it is an emerging problem with antibiotics used to treat gonorrhoea and Strep. pneumoniae infections. It is most likely to happen when antibiotics are given in inadequate doses in a random manner, which happens when they are available over the counter. Antibiotic policies have been devised to avoid the problem but they are most easily applied in hospitals, and even there they are not wholly successful. So far pharmaceutical companies have been able to produce new compounds to keep ahead of the problem, but it is important that we learn more about the ways in which resistance emerges if it is to be controlled.
ANTIBIOTICS IN COMMON USE B-Lactams
These are the most commonly used antibiotics and have in common the B-lactam ring (Fig. 9.4). There are two major groups, the penicillins and cephalosporins. Penicillins Benzyl penicillin or penicillin G is a highly potent bactericidal natural penicillin which was the forerunner of all the other penicillins. Long-acting forms, procaine and benzathine penicillins, allow longer intervals between doses. Its disadvantages are that it can only be given parenterally, it has little activity against Gram-negative organisms, and many staphylococci are resistant to it. Semisynthetic and synthetic penicillins have been developed to circumvent these problems. Doses are now usually expressed in mg (600mg = 106 units = 1 megaunit). Standard adult dose: 300 mg 6-hourly; high dose 600 mg 4-hourly. Phenoxymethyl penicillin is a natural penicillin which is acid resistant and can therefore be taken by mouth for the treatment of minor infections with streptococci which are highly sensitive. Absorption is variable, and so it should not be used for more serious infections. Standard adult dose: 500 mg qds. Broad-spectrum penicillins, such as ampicillin and amoxicillin, have useful activity against Gram-negative organisms, excluding Pseudomonas species. They are well absorbed from the intestine. Standard adult doses: amoxicillin 250 mg tds; ampicillin 0.25-lgqds. B-Lactamase-resistant penicillins, such as flucloxacillin and methicillin, are used mainly to treat penicillinaseproducing staphylococci. Standard adult dose: flucloxacillin 250 mg qds. Co-amoxiclav is a combination of amoxicillin and the B-lactamase inhibitor clavulanic acid, which makes the amoxicillin active against resistant strains of Staph. aureus, H. influenzae, E. coli and many Bacteroides and Klebsiella species. Standard adult dose: 375 mg (containing amoxicillin 250 mg) tds. Antipseudomonal penicillins: the ureidopenicillins (azlocillin and piperacillin) are distinguished by their activity against Pseudomonas species and have a broader
spectrum of activity against Gram-negative organisms. Standard adult doses: azlocillin 2 g 8-hourly; piperacillin 150mg/kg/day in divided doses, up to 16g daily in severe infections. Toxicity. The most common problem is hypersensitivity causing rash and anaphylaxis (see p. 96). This is an allergic reaction which develops 10-14 days after first exposure, but much sooner on re-exposure. Its severity varies from mild to fatal according to the reactivity of the patient, the dose of drug and the route of administration. There is crossreactivity between penicillins, and to some extent with cephalosporins. Ampicillin is particularly likely to cause rash in patients with infectious mononucleosis.
9
Cephalosporins Cephalosporins have a similar structure and mode of action to penicillins but modifications to their structure have produced a range of drugs with a broader spectrum of activity. Examples are cefaclor, which has a broad spectrum of activity, including some against staphylococci, and can be taken orally (standard adult dose: 250 mg tds); cefotaxime, a parenteral drug with a very broad spectrum excluding Pseudomonas (standard adult dose: 1g 12hourly, or up to 4 g 8-hourly); and ceftazidime, similar to cefotaxime but including Pseudomonas activity (standard adult dose: 1 g 8-hourly, or up to 2g 8-hourly). Ceftriaxone has a similar spectrum of activity to cefotaxime but is unusual in that it is given only once a day (standard adult dose: 1 g daily, or up to 4g daily; doses above 1 g given in several sites). These drugs are expensive and their use should be part of a defined antibiotic policy. Their sideeffects are similar to those of penicillins. Other B-lactams Imipenem is a carbapenem which differs from other (3lactams in its remarkable spectrum of antibacterial activity and resistance to hydrolysis by most B-lactamases and other enzymes. It is administered in combination with cilastatin, which inhibits its renal metabolism by inhibiting a kidney enzyme (standard adult dose: 500mg 12-hourly, up to 750mg 12-hourly). CNS side-effects such as convulsions and confusion limit its usefulness, and meropenem is less likely to cause such toxicity (standard adult dose: 500mg 8-hourly, up to 1 g 8-hourly). These are reserve drugs, only prescribed when conventional drugs have failed. Aztreonam is a monolactam with a spectrum of activity limited to some aerobic Gram-negative bacteria (standard adult dose: 2g 12-hourly). Macrolides Erythromycin is an extremely useful drug with a macrolide structure. It can often be used as an alternative to penicillin when the patient is allergic. In addition it is active against Haemophilus influenzae, Mycoplasma, Legionella, Bordetella pertussis and Campylobacter (standard adult dose: 250mgqds). Newer macrolides such as clarithro-
265
mycin and azithromycin are less likely to cause gastrointestinal side-effects and can be given in shorter courses than erythromycin (standard adult doses: clarithromycin 250 mg bd; azithromycin 500 mg daily for 3 days, or as a single 1g dose treatment for genital chlamydial infection). Chloramphenicol Chloramphenicol is a cheap drug, well absorbed and distributed, with useful activity against Gram-positive and negative cocci and H. influenzae. Its major drawback is the very rare but usually fatal induction of marrow aplasia. It is also difficult to use safely in babies. Standard adult dose 50mg/kg/day in four doses. Tetracyclines Tetracyclines were widely used to treat exacerbations of chronic bronchitis until resistance became common. Now their main use is for the treatment of chlamydial infection, but they are also active against Mycoplasma, Brucella, rickettsiae, Coxiella and Borrelia. They should not be used in pregnant women and children under 9 years old because they cause staining of teeth and sometimes dental hypoplasia. Doxycycline is less prone to cause diarrhoea than other tetracyclines but occasionally causes oesophageal ulceration. Standard adult dose: 200mg on day 1, then l00mg daily. Aminoglycosides Aminoglycosides such as gentamicin, amikacin and tobramycin are used in serious Gram-negative infections. They are ototoxic and nephrotoxic. Blood levels have to be monitored carefully, especially when there is renal impairment, as they are excreted purely by the kidneys. Peak blood levels are measured 15 minutes after intravenous or 1 hour after intramuscular administration, and trough levels immediately before the next dose. Standard adult doses: gentamicin 2-5mg/kg/day in two doses; amikacin 15mg/kg/day in two doses; tobramycin 3 mg/kg/day in three doses. Sulphonamides and trimethoprim Sulphonamides were the first synthetic antimicrobial drugs, but their use is now limited by the development of resistance and by the frequency of troublesome sideeffects such as nausea, rash (Stevens-Johnson syndrome at worst) and bone marrow toxicity. Sulfamethoxazole is still widely used in combination with trimethoprim (cotrimoxazole; standard adult dose 960mg bd, but see p. 344 for treatment of Pneumocystis carinii infection) because they were thought to be synergistic, but it now seems that trimethoprim alone is just as effective in the treatment of
1
266
MCQ 9.1
Gram-negative urinary infection. Trimethoprim can cause thrombocytopenia and megaloblastic anaemia. Standard adult dose 200mgbd. Clindamycin Clindamycin is a lincosamide with activity against Grampositive organisms, including resistant staphylococci, but also against anaerobic organisms. It achieves good penetration into bone and can be used to treat osteomyelitis. Common side-effects include rash and diarrhoea, rarely with pseudomembranous colitis. Standard adult dose 300mgqds. Metroindazole Metronidazole is an excellent drug for the treatment of anaerobic infection. It is cheap when administered orally or rectally, and the more expensive intravenous preparation is rarely indicated. It is also the first choice in treatment of Giardia lamblia, amoebic disease and Trichomonas vaginalis. Serious side-effects are rare, but nausea and abdominal pain are common. Standard adult dose 400mgtds. Sodium fusidate Sodium fusidate is highly bactericidal against staphylococci, including penicillin-resistant ones, but resistance develops during treatment unless another drug is given concurrently. It is reserved for treatment of serious infections such as septicaemia and osteomyelitis. It is necessary to monitor for hepatotoxicity. Standard adult dose 500 mg tds. Vancomycin Vancomycin is reserved for serious penicillin-resistant staphylococcal infection or for the treatment of pseudomembranous colitis. Serum levels must be monitored, as it is ototoxic and nephrotoxic. Standard adult dose 1g infused over 100 minutes 12-hourly, or 125mgqds orally for pseudomembranous colitis. Teicoplanin is a similar drug which is slightly less toxic. Standard adult dose 400 mg 12-hourly for three doses, then reduce to 200400 mg daily. Quinolones Nalidixic acid has been used exclusively in the treatment of urinary infection by Gram-negative organisms, as adequate levels are only found in the urine. Standard adult dose 1 g qds. Resistance to this group of drugs is rare, as they are not susceptible to plasmid-mediated resistance. The newer generation. of 4-fluoroquinolones includes ciprofloxacin, which is well absorbed from the intestine and widely distributed. Standard adult dose 500 mg bd. This group contains the only orally administered drugs active against Pseudomonas, and they have become increasingly important in the management of gut infections and severe systemic infections, including typhoid. Major toxicity is uncommon.
Rifampicin Rifampicin, a synthetic derivative of rifamycin, is central to the treatment of tuberculosis but is also very active against staphylococci, streptococci and E. coli. Its major toxicity is to the liver. Standard adult dose 300 mg bd, but see p. 645 for the treatment of tuberculosis. Quinuprastin/dalfoprastin Quinuprastin/dalfoprastin is a new streptogramin recently licensed in the UK and the USA which is active only against Gram-positive bacteria, including methicillinresistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium (but not E. faecalis) and penicillin/ macrolide-resistant pneumococci, and its use should be restricted to treatment of such infections. Administration is recommended through a central venous catheter, as peripheral lines tend to develop complications. Linezolid Linezolid, a new oxazolidinone antibiotic is active against Gram-positive bacteria which are resistant to other antibiotics. It can be given orally or intravenously (600 mg every 12 hours by either route). 1
ANTIFUNGAL DRUGS Most fungal infections of the skin are treated with topical preparations, but cuticular infection requires prolonged systemic therapy. Visceral infections also require systemic therapy. Amphotericin B and nystatin Amphotericin B and nystatin are polyene antibiotics produced by Streptomyces species. They exert a fungistatic effect by binding to sterols in the fungal cell membrane, causing leakage of cell components. Amphotericin B acts synergistically with the unrelated compound flucytosine, probably by increasing permeability to flucytosine. Amphotericin B can be administered intravenously, after which there is wide tissue distribution but poor penetration to brain and meninges. The plasma half-life is 24 hours and it is excreted very slowly in the urine, 40% of the infused dose appearing in the urine during the following week. Amphotericin B has a broad spectrum of activity and is used against the agents of candidiasis, aspergillosis, histoplasmosis, blastomycosis, coccidioidomycosis, cryptococcosis and some organisms causing mucormycosis. Minor symptoms following infusion are common, and a wide variety of symptoms may be unpleasant enough to require suppression with analgesics, antiemetics etc. More serious side-effects occur when there is impairment of renal function, which is exacerbated by the resultant rise in plasma drug levels. Renal and haematopoietic toxicity are the main problems. Therapy has to be interrupted to allow a fall in plasma level. It is given in a dose of 0.25 mg/kg body weight
intravenously over 6 hours, increasing to 0.8 mg/kg according to tolerance. Treatment is withdrawn intermittently as required to maintain the plasma level at l-1.5mg/L. A less toxic liposomal form of amphotericin B is expensive and its use is limited to febrile neutropenic patients and to those unable to tolerate the native form. Standard adult dose of liposomal amphotericin: Img over 10 minutes test dose, then 3 mg/kg/day in one dose. Neither amphotericin B nor nystatin is absorbed from the intestine but they are useful as topical or mucosal preparations, particularly for treatment of Candida infections. Nystatin is available as a suspension or pastilles for oral infection, cream and pessaries for vaginal infection, and cream or ointment for skin infections.
9
Flucytosine Flucytosine is a synthetic fluorinated pyrimidine which enters fungal cells and inhibits metabolism by interfering with DNA and RNA synthesis. It can be given in combination with amphotericin B for treatment of systemic fungal infections, but is rarely used now. Standard adult dose 200 mg/kg/day in four doses, each infusion over 20-40 minutes. Imidazoles Ketoconazole, miconazole and clotrimazole are imidazole drugs. Most are available only topically and have activity against dermatophytes and Candida. Imidazoles have no place in the treatment of systemic fungal infections. The mode of action is not fully understood, but imidazoles interfere with synthesis of sterols and other fungal membrane lipids, resulting in defective cell wall synthesis. In vitro they enhance killing of Candida by leukocytes. Ketoconazole is an oral preparation which is useful for treatment of severe mucosal infections, such as oesophageal candidiasis which is not responsive to topical treatment. The major toxicity is drug-induced hepatitis, which can progress to irreversible hepatic failure. Standard adult dose 200 mg daily. Triazoles Triazoles are a new group of antifungal agents, including fluconazole and itraconazole, which are useful as oral agents for treating systemic mycoses. Both are effective in treating oesophageal candidiasis using very short courses, e.g. a single dose of fluconazole 150 mg. Prolonged treatment in patients with immunodeficiency often results in emergence of resistant strains of Candida, but at present cross-resistance between itraconazole and fluconazole is uncommon. Fluconazole (but not itraconazole) penetrates into the CSF and is useful for treatment of cryptococcal meningitis (dose 400mg, then 200mg i.v. daily). Sideeffects are rare but there is a small risk of hepatotoxicity. Standard adult dose of itraconazole: 100 mg daily. Griseofulvin and terbinafine Griseofulvin, produced by Penicillium griseofulvum, is
267
absorbed from the gastrointestinal tract and deposited in keratin, where it inhibits the growth of dermatophytes. It is relatively non-toxic and can be used in extensive dermatophyte infections which are unresponsive to topical treatment. It is particularly useful for nail and scalp infections (p. 389), but has to be given for weeks or months. Serious side-effects, such as bone marrow and neurological disorders, have been reported occasionally after griseofulvin use. Standard adult dose: 500mg daily. Terbinafine, an allylamine, can also be used for these infections and may be effective after shorter courses. Standard adult dose: 250 mg daily. 1
ANTIVIRAL TREATMENT Considerable progress has been made in synthesizing agents which specifically inhibit an essential step in virus replication without causing host toxicity. This has been achieved: • By using an agent which is activated by the virus, thus localizing its action within infected cells; • By using an agent which inhibits virus metabolism specifically. Usually this is achieved when the agent inhibits a viral enzyme. Drugs have been developed which are active against herpes viruses, human immunodeficiency virus, hepatitis B and C, influenza viruses, enteroviruses, respiratory syncytial virus, and some viruses which cause viral haemorrhagic fever.
Drugs active against herpes group viruses Aciclovir, the most widely used agent currently available, produces its specific effects using both of these mechanisms. It is inactive until phosphorylated to a triphosphate by viral thymidine kinase in infected cells. In this form it produces its main antiviral action by inhibiting viral DNA polymerase, essential for synthesis of viral DNA. Aciclovir triphosphate is a more powerful inhibitor of viral than of host DNA polymerases. Aciclovir seems to be a safe drug but is expensive. Its use is restricted to situations in which it is clearly beneficial (Table 9.5). Newer drugs such as famciclovir and valaciclovir are similar in their spectrum of activity and toxicity but differ in absorption, so that famciclovir can be given less often than aciclovir, and valaciclovir achieves a higher serum concentration than aciclovir after oral administration. During acute viral infections much of the inflammation is caused by the host response in the later part of the illness, 1
268
MCQ 9.2
TABLE 9.5 Treatment of herpes virus infections with aciclovir Virus
Infection
Route
Herpes simplex virus
Encephalitis Neonatal infection Primary genital infection Keratoconjunctivitis Prophylaxis: bone marrow transplantation Shingles in immuncompromised patients Chickenpox in immunocompromised children Chickenpox in neonates Chickenpox in adults Possible Chickenpox pneumonia
IV IV 0 T 0 IV IV IV IV 10
Varicella zoster
IV = intravenous; 0 = oral; T = topical
and antiviral treatment must be started early to be effective. Antiviral treatment does not affect virus integrated into the host genome, and treatment of the primary herpes simplex infection does not influence subsequent viral reactivation. Ganciclovir, an antiviral drug licensed for treatment of cytomegalovirus (CMV) infection, is activated by phosphorylation in a similar way to aciclovir, but depends on human cellular enzymes for this process (Fig. 9.5). Because phosphorylation occurs in infected and normal cells, toxicity is greater than that of aciclovir and it causes bone marrow suppression. Foscarnet, a phosphonate, also inhibits CMV DNA polymerase and has a different toxicity from ganciclovir.
Antiretroviral drugs There are three main classes of antiretroviral drugs: nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase, and a third class that inhibit HIV protease. At least three drugs are used in combination to limit the development of resistance and, once started, treatment is normally maintained for life (see Ch. 11).
Ribavirin (tribavirin) Ribavirin is another nucleoside analogue that is active against a wide spectrum of DNA and RNA viruses, but its clinical use is confined to treatment of severe respiratory syncytial virus infection causing bronchiolitis, some of the viral haemorrhagic fevers such as Lassa fever, and hepatitis C virus infection in combination with interferon-a. For RSV infection it is given by inhalation.
Interferons Interferon-a, which is produced by T lymphocytes, has been shown to inhibit replication of hepatitis B and hepatitis C viruses, possibly by inhibiting virus assembly. It has many side-effects, including flu-like syndrome early in
9
FIG. 9.5 Mechanisms of action of ganciclovir Virus replication in host cells induces the enzymes (guanosine kinase and phosphorylase). Because the same enzymes are involved in phosphorylation of ganciclovir, infected cells have higher concentrations of ganciclovir triphosphate. This is the activated form, which blocks viral replication,
therapy, lethargy throughout treatment, bone marrow toxicity and depression, and is only effective in a small proportion of patients, but it is the only substance known to have any influence on these infections at present.
FURTHER READING ON ANTIMICROBIAL AGENTS
TABLE 9.6 Some microorganisms causing infection in immunocompromised patients Type
Microorganism
Remarks
Deficiency
Bacteria
Gram-positive, e.g. Pneumococcus Gram-negative, e.g. H. influenzae Mycobacteria, e.g. avium intracellulare
Encapsulated
Ab/Neut/S
Encapsulated
CMI
Both tuberculous and non-tuberculous Reactivation
CMI
Encephalitis Virulent Septicaemia/ pneumonia Mucosal Systemic Meningitis Pneumonia Cerebral Gut Gut Systemic Systemic
Ab Ab/CMI Ab/Neut
Lambert H P, O'Grady F, Finch R, Greenwood D 1996 Antibiotic and chemotherapy, 7th edn. Edinburgh: Churchill Livingstone.
INFECTION IN THE IMMUNOCOMPROMISED PATIENT An immunocompromised patient is defined as one in whom any part of the innate or adaptive immune response is defective. Defects of the immune system are physiological (neonates and the aged), and either primary or secondary. Primary immune deficiency diseases are rare and an account is given in Chapter 4. Secondary immune deficiency is more common and of increasing importance. Causes of secondary immune deficiency are: • Malignant disease and its treatment; • Drug-induced chronic immune suppression, e.g. in organ transplantation or chronic inflammatory diseases, such as systemic lupus erythematosus (SLE); • Infection: the most severe infection is HIV (Ch. 11), but many other viruses cause a milder deficiency of cellmediated immunity (CMI); • Splenectomy; • Chronic diseases, e.g. chronic renal failure, malnutrition, protein deficiency, diabetes mellitus. These conditions cause varying combinations of neutropenia and impairment of humoral and cellular immunity. Deficiencies of antibody or neutrophils are associated with infection by encapsulated bacteria, yeasts and fungi. Defi-
Viruses
Yeasts Fungi Protozoa
Helminths
Herpes, e.g. herpes simplex virus, varicella zoster virus, cytomegalovirus Echo Live vaccines, e.g. measles Candida Aspergilius Cryptococcus Pneumocystis Toxoplasma Cryptosporidium Giardia lamblia Malaria Strongyloides
CMI
CMI CMI CMI CMI/Ab CMI CMI CMI/Ab Ab/S CMI
Ab = antibody; Neut = neutrophil; CMI = cell-mediated immunity; S = post-splenectomy
cient CMI causes infection by a wider range of pathogens, including Gram-positive and -negative bacteria, viruses, yeasts, fungi, protozoans and helminths (Table 9.6). In all these situations immunization with live viral vaccines is dangerous, as the attenuated organism may behave as a pathogen. The pattern of infection in immunocompromised
269
SUMMARY 1 Management of the neutropenic patient with fever
TABLE 9.7 Organisms causing pneumonia in immunocompromised patients
• Take samples for culture: blood, urine, stool, i.v. line tip, etc. as appropriate • Start treatment after taking samples, guided by any previous culture results • Examples of empirical treatment regimens: - gentamicin plus piperacillin or ceftazidime - If no response within 48 hours, switch to - vancomycin If no response, or recurrence, particularly if previous antibiotic courses given - amphotericin B or fluconazole for Candida septicaemia • If chest X-ray shows pulmonary infiltrates, add erythromycin initially for atypical pneumonia. Consider a wide range of organisms (including M. tuberculosis) and viruses (e.g. CMV) if there is no response to antibiotics
Bacteria Gram-positive, e.g. Strep. pneumoniae Gram-negative, e.g. H. influenzae, Klebsiella pneumoniae Viruses Cytomegalovirus, herpes simplex, varicella zoster Measles (giant cell pneumonia) Protozoa Pneumocystis carinii Fungi/yeasts Candida Aspergillus
NOSOCOMIAL INFECTION patients is unusual in several respects. Bacterial infections in splenectomized patients are sudden in onset and rapidly progressive, fulminant pneumococcal septicaemia being the most common. Cellular immune deficiency causes viral infection to be more severe, prolonged and widely disseminated than is usual. Fever in the neutropenic patient (see Summary 1) During periods of neutropenia the onset of fever should be taken to indicate serious infection unless there is an obvious alternative explanation. 'Blind' treatment with antibiotics is started immediately after the collection of specimens, including blood cultures. Blood cultures are negative in over half of such fever episodes, but the choice of antibiotics is guided by positive results in which Gram-negative bacteria, including Pseudomonas species, predominate, and a combination of a broad-spectrum penicillin with activity against Pseudomonas (e.g. piperacillin) and gentamicin is often used (p. 265). New pulmonary infiltrates on chest radiograph New pulmonary infiltrates may be due to infection with a wide range of possible pathogens (Table 9.7). Sputum induction, bronchoscopy and lavage, and transbronchial biopsy may provide diagnostic information. Invasive procedures have a risk in neutropenic and thrombocytopenic patients.
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Reactivation of herpes viruses Patients with impaired CMI may suffer severe herpes virus infection. Shingles (varicella zoster) in patients with Hodgkin's disease tends to involve more than one dermatome, and there may be dissemination of virus causing widespread chickenpox lesions on the skin and occasionally in viscera. Within affected dermatomes lesions are dense and heal slowly. Reactivation of herpes simplex virus (HSV) may cause extensive perioral ulceration and occasionally visceral dissemination. CMV reactivation causes pneumonia in renal transplant recipients.
Hospital patients may be particularly susceptible to infection and hospital bacteria are often resistant to common antibiotics. Susceptibility is increased in postoperative patients, patients with bums, patients on ventilators, in malnourished patients, and in disease states that compromise immunity specifically. Hospital-acquired infections are known as nosocomial and are a particular problem on intensive treatment units. Nosocomial infection is an increasing problem and the resistance pattern of bacteria is constantly changing. The most important factors influencing the likelihood of cross-infection are the use of handwashing, the ratio of nurses to patients, the number of visits from doctors and the space between patients. The bacteria associated with particular situations can sometimes be predicted, e.g. staphylococci and streptococci are common causes of surgical wound infections, and Pseudomonas frequently infects burns. In ventilated patients difficulties arise in deciding whether bacteria such as Pseudomonas are merely colonizing the respiratory mucosa or whether they are pathogenic. Antibiotic treatment of colonising organisms is undesirable since the local flora then change to more resistant organisms. With increasing use of antibiotics there has been a resurgence of outbreaks of nosocomial infection with methicillin (and flucloxacillin)-resistant Staphylococcus aureus (MRSA). MRSA colonize the skin and nose of normal or diseased subjects, but they are particularly persistent in patients with any form of skin lesion. In most cases MRSA do not cause disease, but occasionally vulnerable patients can develop septicaemia or local suppuration which necessitates the use of vancomycin. Because MRSA spreads rapidly from person to person it is important to isolate infected patients from other vulnerable patients, and to screen staff for carriage. Colonized subjects are treated with topical antiseptic preparations and, in the case of staff, removed from work until repeated swabs are clear. Vancomycin-resistant staphylococci have been isolated and the increasing use of this antibiotic has led to a problem with resistant enterococci. There is some evidence
that antibiotic cycling in intensive care units - that is, changing the first-choice antibiotics every few months limits the rate of increase in resistance among common nosocomial bacteria. For example, resistance to gentamicin in enterobacteriaceae such as Klebsiella pneumoniae and Serratia marcescens increases when gentamicin is used, but decreases when amikacin is substituted. However, there is no consensus on the best policy at present. The use of antibiotics must be controlled both in hospitals and in the community. Most hospitals have antibiotic control policies which recommend the antibiotic to be used in a particular situation and restrict the administration of some drugs to special situations. Policies for antibiotic prophylaxis before surgery need to be reviewed regularly to keep ahead of the development of bacterial resistance.
CONTROL OF INFECTION Containment of outbreaks of infection is required when susceptible subjects may develop a serious illness if they become infected. It is not always desirable to contain infection. Chickenpox, a mild disease in normal children, is usually severe in adults and so outbreaks among schoolchildren should not be controlled. In a hospital where non-immune patients are liable to develop severe manifestations, however, it is important to prevent crossinfection to non-immune individuals (about 10% of the adult population). Isolation of patients in single rooms greatly facilitates control of infection. Other measures are determined by the mode of transmission and the degree of infectivity of the organism. Transmission is by: • Respiratory secretions (e.g. measles, pulmonary tuberculosis) • Excretions and secretions (e.g. gastroenteritis, hepatitis A, typhoid) • Skin contact and fomites (e.g. MRSA). Respiratory transmission can be prevented by having the patient and/or the attendants wear appropriate masks. Organisms transmitted in respiratory secretions usually infect others through the upper or lower respiratory tract, and gowning and handwashing are of minor importance. When excretions and secretions are infectious the most important containment measure is handwashing. When close contact is necessary with a highly infectious patient, such as a patient excreting Shigella in the faeces, gowns and gloves are worn. Special arrangements are needed for the disposal of excreta, contaminated dressings and contaminated clothing and bedding. When microorganisms are found in significant number on the skin, in fomites and in dust around the patient, as when MRSA colonize patients in hospital, additional precautions must be taken, including the use of overshoes together with gowns and gloves.
TABLE 9.8 Notifiable diseases under the Public Health (Infectious Disease) Regulations 1988 (UK, October 1988) Acute encephalitis Acute poliomyelitis Anthrax Cholera Diphtheria Dysentery (amoebic or bacillary) Food poisoning Leptospirosis Malaria Measles Meningitis meningococcal pneumococcal Haemophilus influenzae viral other specified unspecified Meningococcal septicaemia (without meningitis) Mumps
9
Ophthalmia neonatorum Paratyphoid fever Plague Rabies Relapsing fever Rubella Scarlet fever Smallpox Tetanus Tuberculosis Typhoid fever Typhus fever Viral haemorrhagic fever Viral hepatitis Hepatitis A Hepatitis B Hepatitis C other Whooping cough Yellow fever
AIDS is not a statutorily notifiable disease but doctors are urged to participate in a voluntary confidential reporting scheme Source: PHS Communicable Disease Surveillance Centre
In many countries some infections are notifiable (Table 9.8), that is, the medical attendant is obliged by law to report the case to the authority that controls the area in which the patient lives so that steps can be taken to trace contacts. Notification also allows surveillance of the incidence of these infections. Most patients have ceased to be an infectious risk by the time they are discharged from hospital, but intestinal pathogens often remain in the stools for several weeks. Carriers of such pathogens are advised to avoid handling food for others, to wash hands regularly and to avoid towel sharing. Following notification, stool samples will be checked by the local authority until they are pathogen free.
IMMUNIZATION Active immunization Active immunization is the administration of antigen to induce a protective immune response in the host. Antigens used include crude preparations of killed organisms, extracellular products of organisms, and live attenuated organisms. The aim is to induce an optimal response at the site where infection normally occurs, but it has proved difficult to achieve this at mucosal surfaces. Currently, oral poliomyelitis vaccine is the most successful intestinal vaccine because the attenuated virus induces a prolonged and renewable response in the gut. Oral vaccines have been developed against typhoid and shigel-
271
Contraindications to immunization
TABLE 9.9 UK immunization schedule (2001) Age
Immunization
Type of vaccine
Route
2 months
Diphtheria Tetanus Pertussis Polio H. influenzae type b Meningococcus type C As above Measles, mumps, Rubella (MMR)* Diphtheria Tetanus Polio MMR BCG Tetanus Polio Diphtheria Rubella
Toxoid Toxoid Killed Live attenuated Capsular antigens Conjugate vaccine As above Live attenuated
IM or SC IM or SC IM or SC 0 IM or SC IM As above IM
As above
As above
Live attenuated
ID
As above
As above
3 and 4 months 12-18 months 5 years
10-14 years School-leaving Adults
Diphtheria Polio Tetanus Hepatitis B Influenza
For seronegative women For non-immunized " Selected groups
IM
*MMR introduced into UK in October 1988 Detained in UK until MMR established IM = intramuscular; SC - subcutaneous; 0 = oral; ID = intradermal
losis but they are less effective. Oral cholera vaccine has been developed using the adjuvant properties of cholera toxin B subunit, and tests in Bangladesh have yielded promising results. In contrast, the cholera vaccines available using heat-killed organisms are ineffective. A similar local immune system operates in the respiratory tract and further studies may help to develop local vaccines against respiratory pathogens. The immunization schedule in the UK in 2001 is shown in Table 9.9. Mumps vaccine was introduced as part of the routine childhood immunization schedule in 1988. The policy of immunizing only females against rubella has also been changed, as there is still a notable incidence of congenital rubella. BCG (bacille Calmette-Guerin) immunization for protection against tuberculosis is more important in children of racial groups with a high incidence of the disease, and it may be given to neonates who are at risk of developing meningitis. In North America the incidence of tuberculosis was not high enough to justify its routine use. In contrast, BCG vaccination of neonates is a common practice in the tropics.
1
272
MCQ 9.3
• Live vaccines should not be given to anyone with untreated malignant disease or with any form of immunodeficiency, including those receiving immunosuppressive therapy, or to pregnant women. • Live vaccines should not be given within 3 weeks of another injected live vaccine. • Coincidental severe febrile illness may limit the response to immunization. Immunization should therefore be postponed, but not forgotten. • Significant documented allergy to any component of the vaccine may be a contraindication to its use. • Rubella vaccine should not be given in pregnancy, and pregnancy should be avoided for 1 month after immunization against rubella. 1
Passive immunization Passive immunization is the administration of antibody preparations to prevent or ameliorate infection. Pooled human immunoglobulin is the crudest form, and was commonly used to protect travellers against hepatitis A virus infection. More defined preparations of hyperimmune globulin contain high levels of antibodies to particular organisms, usually viruses, which are not present in sufficient concentration in pooled human immunoglobulin to provide protection. Examples are hepatitis B immunoglobulin given following needle-stick injuries, varicella zoster immunoglobulin used in neonates born to mothers who have recently developed chickenpox (p. 284), and tetanus immunoglobulin used for patients at risk of developing tetanus. Most current antibody preparations are derived from human serum. Passively administered antibody has a short half-life, giving protection for only a few weeks. Treatment has to be given soon after exposure to be effective.
PREVENTIVE MEASURES FOR OVERSEAS TRAVEL OR RESIDENCE The question that is most commonly asked prior to overseas travel to or residence in the tropics or subtropics is 'what vaccines are needed?' In fact, the main disease threats do not come from vaccine-preventable conditions, but from trauma, alcohol-related illness, sun exposure, unprotected sexual contacts and infectious diarrhoeal disease. Malaria is the main threat that is amenable to preventive measures.
Protection of skin The skin must be protected against biting insects. This is important not only for the prevention of malaria, but also for protection against viral, rickettsial, protozoal and filarial diseases transmitted by insect vectors. Exposure to ticks occurs mainly in rural bush areas and
so appropriate clothing and footwear is needed to prevent ticks getting on to the skin. Evening and night hours are times for maximum frequency of biting by many insects, and at these times the skin should be covered as much as possible wearing shirts with long sleeves and long trousers or skirts. Insect repellent (diethyltoluamide (DEET)containing compounds with formulations designed to have a long retention time on the skin) is applied to exposed areas, including the forearms, lower legs, ankles and feet, and face and neck. Elasticated wrist and ankle bands can be impregnated with DEET and worn for the same purpose. Mosquito nets should be used in malarial areas if doors and windows are not screened. Impregnation of bed nets and curtains with permethrin enhances protection through its residual insecticidal action. It is also useful to spray bedrooms with insecticide last thing at night. Schistosomiasis is acquired by contact between skin and slow-flowing or still water containing cercariae. Swimming and paddling in fresh water are best avoided in endemic areas.
Protection against malaria Measures to prevent mosquito bites (see above) and chemoprophylaxis against malaria are the sole means of preventing malaria in the traveller. The traveller must be told that there is no vaccine against malaria and that none of the vaccines received prior to travel is of any benefit in this regard. Details of chemoprophylaxis against malaria are given in Table 9.36, p. 352.
Immunization for travellers or overseas residents A range of vaccines is available and the commonly used ones are listed in Table 9.10. Poliomyelitis is still common in many areas of the world, and so adequate vaccination should be assured in all travellers. Meningococcal vaccine is most often recommended for backpackers in subSaharan Africa. It is occasionally a requirement for travel to specified countries, e.g. Saudi Arabia for the Hajj pilgrimage. Yellow fever vaccination is essential for those visiting tropical Africa, the Caribbean and South America. Oral poliomyelitis and yellow fever vaccines should be given either together or separated by an interval of 3 weeks. Active hepatitis A vaccination is available and is usually used in preference to passive immunization, although it is more expensive. Hepatitis B vaccination is particularly recommended for those at particular risk, i.e. healthcare and hospital laboratory workers, although increasingly backpacking travellers are having this vaccine. Pre-exposure rabies vaccination is needed by those who may have any contact with animals, but again increasing numbers of tourists undertaking overland travels are having pre-exposure vaccination. The intradermal route allows more economical use of the vaccine. Tetanus vaccination is needed for any who may be at particular risk of trauma, e.g. military personnel, construction workers etc.
TABLE 9.10 Immunization for travellers to the tropics
9
Isolated visit to main tourist areas Typhoid Polio Hepatitis A Yellow fever (for some locations) Extensive travel (backpacking, trekking, gap-year students) Typhoid
Polio Hepatitis A & B Rabies Meningococcal disease A & C (sub-Saharan Africa) Yellow fever (West Africa, Central & South America, Trinidad) Frequent visitor (business or holiday) or resident Typhoid Hepatitis A & B Rabies Yellow fever (West Africa, Central & South America, Trinidad) Meningococcal disease A & C Note: these groupings of vaccines are guidelines only and need modification for individuals in relation to their potential exposure during proposed travels. Although on a risk/cost analysis some of these recommendations may seem excessive, they give the traveller coverage for vaccine-preventable conditions endemic in many areas. All travellers should be up to date with childhood vaccines.
Typhoid vaccination is a sensible precaution for many areas, but those vaccinated should be told that having the vaccine does not mean that they are 100% protected and can be careless about sources of water and food. Although the whole-cell killed vaccine has the greatest efficacy it also has the greatest incidence of side-effects and is not now obtainable. The choice lies between two vaccines: (a) the Ty21a oral vaccine containing the epimerase-deficient strain of S. typhi, which has the appeal of stimulating an immune response at the site of entry of the natural pathogen, and (b) the vaccine based on the Vi antigen of S. typhi. Cholera vaccination is not effective.
Protection of the gut Gastrointestinal infection is the most common affliction faced by the traveller. Boiled water used to make tea and coffee or left to cool in a covered, clean container is safe to drink. Bottled drinks are safe. Water from the tap or water used to make ice cubes may not be safe. Tincture of iodine (2%) can be used to sterilize water, adding 0.5mL per litre and allowing it to stand for 30 minutes. Iodine is more potent than chlorine-based sterilizing tablets.
SYNDROMES OF INFECTION SEPTICAEMIA Septicaemia is uncontrolled bacterial infection in the blood. Unlike septicaemia, transient bacteraemia is fairly common
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in normal subjects. Septicaemia is a much more serious condition which is likely to lead to death if untreated.
Aetiology A wide range of bacteria can cause septicaemia, but they can be divided into those that do so as part of a primary infection by a single organism acquired in the community, and those that cause septicaemia as a complication of another process, such as abdominal sepsis following surgery, when there is often a mixed infection. Community-acquired infections are usually recognized as part of a specific illness, as when Strep, pneumoniae septicaemia complicates pneumonia, meningococcaemia with meningitis, or E. coli septicaemia with pyelonephritis. The other kind of septicaemia is usually seen in hospitals, often in a debilitated patient, and the likely bacteria can often be predicted from the clinical situation.
Pathogenesis Whole bacteria and substances released by bacterial lysis trigger a complex series of events. A major component is endotoxin, the lipopolysaccharide component of Gramnegative bacterial cell walls, of which lipid A is thought to be responsible for most of the toxic effects. Lipid A can activate complement and Hageman factor and can cause the release of cytokines, including tumour necrosis factor. Important pathological consequences ensuing from activation of the potent inflammatory pathways are hypotension, increased vascular permeability and consumptive coagulopathy. Less attention has been paid to the effects of Grampositive organisms, but activation of inflammatory processes can certainly be triggered by cell membrane components of these organisms. An example is alternate pathway complement activation (Fig. 4.1, p. 80) by teichoic acid found in Staph. aureus membranes.
negative septicaemia, but also occurs with Gram-positive septicaemia. For this reason the general term septicaemic shock is usually used. Prolonged hypotension leads to acute renal failure, and disseminated intravascular coagulation causes bleeding. Acute respiratory distress syndrome (p. 697) frequently complicates hospital-acquired septicaemia. The diagnosis is based on clinical assessment, but blood cultures, urine cultures, wound swab and any aspirate from an infected site should be obtained at the time the patient is seen, so that antibiotic treatment can be started without undue delay. The antibiotic regimen can be changed if necessary when culture results are available and the response to treatment has been assessed. Blood cultures should be taken whether the patient is febrile or not.
Management Treatment is urgent because of the high mortality. Antibiotics and circulatory support are the mainstays of management. The use of plasma expanders and selective vasoactive drugs is discussed on page 731.
Antibiotics The initial choice of antibiotics is based on a logical guess at the bacteria responsible (p. 263). As few antibiotics as possible are given to achieve the necessary cover. At present a common choice is a combination of a broadspectrum penicillin, such as ampicillin, with an aminoglycoside such as gentamicin. One problem is that many patients are in incipient renal failure, which enhances the toxicity of gentamicin. Newer drugs, such as cefotaxime and piperacillin, are active against Gram-positive and Gramnegative bacteria and lack the toxicity of gentamicin, but they are more expensive. If anaerobic septicaemia is suspected metronidazole is often used, and for hospitalacquired staphylococcal infection a B-lactamase-resistant penicillin, such as flucloxacillin, is added. Pseudomonas infections are treated with a combination of drugs, e.g. azlocillin and gentamicin. 1
Clinical features and diagnosis The manifestations depend on the age of the patient, the illness being more featureless and more lethal at extremes of age. Signs are usually non-specific, but there are signs in the skin suggestive of the diagnosis, such as purpuric lesions associated with meningococcaemia and pustular lesions in staphylococcal septicaemia. Usually there is a rapid deterioration in the patient's condition, including a change in mental state. Fever is often present, with tachycardia and a bounding pulse, but as the condition progresses the patient becomes hypothermic with a rapid thready pulse and peripheral vasoconstriction. The latter situation is often considered to be typical of Gram1 274
MCQ 9.4
PYREXIA OF UNKNOWN ORIGIN When a patient has an elevated body temperature for a period of longer than 3 weeks without a cause being found the diagnostic problem is called pyrexia (or fever) of unknown origin (PUO). A febrile patient may lose the normal diurnal variation in body temperature or may sometimes have an exaggerated diurnal pattern, with a rise during the night causing drenching night sweats (common in tuberculosis and lymphoma) followed by a rapid fall. Many patterns of fever are described but they are rarely helpful in diagnosis.
Causes of PUO The most common causes of PUO vary according to the
age of the patient, and published incidences vary with the type of institution at which the problem is studied. Infection is usually the most common cause in children, whereas infection and neoplastic disease are equally important in adults. Connective tissue disease can present with fever at any age: Still's disease and SLE are commoner causes in children and young adults, and polymyalgia and giant cell arteritis more frequent in the elderly. Infection Most bacterial infections cause an illness which is clinically manifest within 3 weeks, but there are some exceptions. Bacterial endocarditis can cause low-grade illness, particularly in the elderly. Most cases can be diagnosed by blood culture, but occasionally blood cultures are repeatedly negative. Infection in the biliary tract may be associated with only minor clinical signs and little abnormality of liver function tests. Intracellular bacteria, such as Brucella and some Salmonella species, can cause recurrent septicaemia, but this can usually be diagnosed by blood culture. Deep-seated abscess is a possible cause of PUO, and modern imaging techniques are helpful in locating the collection (p. 262). Tuberculosis is still a major cause of PUO in developing countries and in some temperate countries such as the UK. Often the granulomatous lesions of tuberculosis are too small to cause pulmonary radiological abnormalities, and the site of infection is often outside the lungs. In recent years tuberculosis has become a common feature of HIV infection. Viral infections rarely cause PUO (within the definition), with the important exception of HIV. The history should therefore enquire into sexual practices, intravenous drug abuse and transfusions. Fungal infections rarely cause PUO without a predisposing cause, but they may do so as a complication of immunosuppressive disease or therapy. An exception is histoplasmosis.
Neoplasia Lymphomas frequently produce a prolonged period of fever before any other manifestation emerges. Leukaemias can also cause PUO, but this is sometimes caused by a complicating infection. Many occult solid tumours can present as PUO, among them hypernephroma, pancreatic carcinoma, intestinal tumours, bronchial carcinoma, ovarian tumours and sarcomas. Fever is particularly likely when there are hepatic metastases. Atrial myxoma is a rare benign tumour (p. 582) which occasionally produces an illness similar to bacterial endocarditis. Connective tissue (autoimmune) disease Most diseases in the category of connective tissue disease can present with PUO before the characteristic disease pattern emerges. SLE, rheumatoid arthritis and Still's disease (including the adult form), polyarteritis nodosa, temporal arteritis and polymyalgia rheumatica should be considered depending on the clinical setting.
Miscellaneous Granulomatous conditions. Granulomatous conditions include sarcoidosis, granulomatous hepatitis and Wegener's granulomatosis. Sarcoidosis often lacks overt signs in the early phase of the disease and should be considered, particularly in ethnic groups with a high prevalence, such as West Indians. Factitious. One of the most odd forms of human behaviour is the habitual feigning, or the deliberate inducement, of illness. Factitious fever is caused in two ways:
9
• In the first the fever disappears when the temperature is measured by someone other than the patient, with the patient under continuous observation. The patient is either saying that fever exists when it does not, or is manipulating the thermometer. • In the other, more serious form the patient induces true fever by self-injury or self-infection. The methods used are diverse, but faeces are the usual source of organisms and infection is induced by rubbing or injecting organisms into the skin or blood. Suspicion is aroused when mixed and varying organisms which could be faecal are found in an unexpected site, or when infection persists despite treatment that would normally be effective. The condition is more common in young females than in males, and the deceit may be helped by some medical knowledge. There are sometimes personal problems, which suggest that this behaviour is a plea for attention or help. When suspicion grows that fever is factitious it is wise to avoid directly confronting the patient with the possibility. Usually it will be denied, and sometimes confrontation can precipitate a psychiatric crisis, even resulting in suicide. It is preferable to attempt to solve the associated problems if they can be identified and to create a situation in which it is difficult for the patient to continue to provoke sepsis, e.g. by removing intravenous catheters or covering inflamed sites. The patient should be made to realize that the manoeuvres are understood, if possible without a direct accusation. The best efforts to resolve factitious fever often fail, and patients either return intermittently or present themselves to another medical team. Bowel disease. Inflammatory bowel disease is usually associated with incriminating symptoms such as weight loss and diarrhoea, but these may be slow to emerge. Whipple's disease, caused by the periodic acid-Schiff-positive Grampositive bacterium now known as Tropheryma whippelii, usually presents with polyarthralgia and diarrhoea in middle-aged men, but initially there may be only PUO and abdominal pain (see p. 792). Intestinal lymphoma may also present with the latter symptoms. Drug reaction. Once thought of, drug reaction is a straightforward cause of PUO. The possibility that the fever is caused by a drug is tested by withdrawal. Multiple pulmonary emboli. When frequent small embolic events occur, pyrexia may be the sole manifestion before the pulmonary circulation is greatly compromised.
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SUMMARY 2 Causes of pyrexia of unknown origin in UK Frequency is given in parentheses • • • • •
Infection (30%) Neoplasia (25%) Connective tissue (autoimmune) disease (20%) Miscellaneous (12%) Undiagnosed (13%)
Other causes. Other occasional causes of PUO are alcoholic hepatitis, familial Mediterranean fever and occult haematoma. There are some young women whose normal evening temperature runs above the normal range by up to 0.5°C. This usually comes to light after an infection with slow recovery. Once it is established that there is no underlying pathology the patient can be reassured. Tropical causes are discussed below.
Diagnosis A careful history and examination of the patient is essential, and it is important to return to the patient repeatedly to go over parts of the history and to look for emergent physical signs. Simple screening tests which may need to be repeated at intervals include full blood count, ESR and CRP, routine biochemistry of blood and urine, cultures of blood, urine and other relevant samples, and chest radiograph. Additional investigations are guided by the clinical findings. There are two approaches. One is to perform tests which are more or less specific for particular diseases, e.g. exclude autoantibodies in autoimmunity or antibodies to particular pathogens. The other is to investigate a particular site which seems to be generating symptoms or signs. The latter is more often helpful, and it is in this area that advances in imaging techniques change the methods for diagnosing PUO. Ultrasound is particularly useful for abdominal examination, both in the detection of solid tissue abnormalities, such as tumours of the kidney or pancreas, lymph node enlargement or infiltration of the liver, and in locating collections of pus (subphrenic, perinephric, intrahepatic etc.). CT scanning supplements, and is in some situations superior to, ultrasound, for example when intestinal gas limits the views on abdominal ultrasound. MR scanning is often more sensitive than CT and is clearly superior for detecting lesions in soft tissue and bone. CT scanning and ultrasound are used to guide the needle during tissue biopsy. The use of 99mTc-labelled leukocytes is described on page 262.
MCQ 9.5
276
Even if no localized lesion has been found by imaging techniques, certain biopsy procedures are sometimes rewarding. If the liver enzyme tests are abnormal percutaneous liver biopsy should be considered, as diffuse granulomatous or infiltrative diseases such as sarcoidosis or lymphoma may be detected. Marrow aspiration and biopsy may reveal cryptic tuberculosis, or lymphomatous or carcinomatous infiltration. The marrow and liver biopsy should be cultured for Mycobacterium tuberculosis, bacteria including Brucella fungi and, where relevant, leishmania. Patience and persistence are essential in managing PUO. Neoplasia is the major cause of death among PUO patients, and so the exclusion of treatable neoplastic disease such as lymphoma is a priority. In some cases there is evidence to support a diagnosis of bacterial infection although the infection cannot be defined, and it may be justified to give blind antibiotic treatment. This should be aimed at the type of infection suspected. For example, a Staph. aureus osteomyelitis would require two antibiotics, such as flucloxacillin and fucidic acid, whereas an appendix abscess could be treated with ampicillin, gentamicin and metronidazole to cover E. coli, enterocci and anaerobic bacteria. In other circumstances a therapeutic trial of treatment for M. tuberculosis may be required. In most studies about one-fifth of cases remain unsolved despite the best efforts. 1
The approach to the patient with fever from or in the tropics Febrile illness is common in the tropics, or after travel to the tropics. The causes encompass infectious and noninfectious causes. Infections include those peculiar to tropical regions and those common worldwide (such as urinary tract infection, pneumonia) (Table 9.11). Clinical features A detailed history is essential. This should include accurate recording of the dates of travel, duration of stay and countries visited, with information on the places involved (cities, rural areas, beach resorts etc.) and the reasons for travel. Information about sexual contact during travel is also important. The history should also include details of vaccination prior to travel and malaria prophylaxis,
TABLE 9.11 Leading causes of imported fever (Hospital for Tropical Diseases) Malaria P. fdlciparum P. vivax P. ovale Viral (presumed) Dengue (proven) Bacterial gut infections
42% 57% 9% 4% 25% 6% 5%
9
TABLE 9.12 Incubation periods for some tropical diseases Type of organism
Short (less than 2 weeks)
Intermediate (2-6 weeks)
Long (more than 6 weeks)
Viruses
Arbovirus infections (e.g. Dengue) Marburg virus disease
Poliomyelitis Hepatitis A virus Arenavirus infection Ebola virus infection Lassa fever virus infection Haemorrhagic fever with renal syndrome
Hepatitis B Non-A, non-B hepalitis Rabies HIV
Q fever
Rickettsia Bacteria
Typhoid
Typhoid Brucellosis Leptospirosis Relapsing fever Lymphogranuloma venereum
Protozoa
Trypanosoma cruzi infection
Malaria Toxoplasmosis Trypanosoma rhodesiense infection
Helminths
with some assessment of the regularity of taking prophylaxis. The chronology of events should be recorded, particularly noting the interval between the end of the patient's travels and the onset of illness where this has occurred after leaving the tropics. This gives an idea of the incubation period of the disease (Table 9.12). Physical examination should pay attention to the presence of skin lesions, oral lesions, jaundice, adenopathy, hepatosplenomegaly, and involvement of the nervous system. After initial assessment it is vital to reassess the patient at frequent intervals, looking for the appearance of diagnostic symptoms and signs. Antimalarial chemoprophylaxis should be discontinued while investigation is proceeding as it may suppress parasitaemia and prevent diagnosis of malaria.
Visceral leishmaniasis Trypanosoma gambiense infection
Schistosomiasis (Katayama syndrome)
SUMMARY 3 Causes of imported fever Malaria Dengue Other arboviral infections Tuberculosis AIDS related infections Typhoid Rickettsial infections Amoebic liver abscess Visceral leishmaniasis Viral haemorrhagic fevers* * While numbers of cases of VHF are very low it is essential to consider this group of conditions in any patient who has visited an endemic area, is febrile and has a low platelet count. See risk assessment, p. 298.
Investigations The investigations performed will depend on the clinical diagnosis or the differential diagnosis. • Blood films should be examined daily for malaria parasites in any febrile patient who has been to a malarial area until either a diagnosis is made or the fever resolves. Blood films may also be examined for trypanosomes in a patient who has been in rural east or west Africa. A full blood count is useful for looking for leukocytosis (suggesting bacterial infections), leukopenia (typhoid, viral infections), pancytopenia (visceral leishmaniasis) or eosinophilia (helminthiasis: schistosomiasis, fascioliasis, visceral larva migrans, clonorchiasis, Bancroftian filariasis). • A Mantoux test should be done early on. • Blood cultures should be taken and, if brucellosis is a possibility, kept under observation for up to 6 weeks, as the organism grows slowly.
• Serological tests that may be useful include those for syphilis, leptospirosis, rickettsial diseases, brucellosis, amoebiasis, leishmaniasis, trypanosomiasis, toxoplasmosis, filariasis and schistosomiasis. They should be used selectively in relation to the clinical presentation and the exposure. A serum sample should be taken on admission and saved, and a second sample taken 10 days later. This pair of sera can then be used to look for a change (usually a rise) in titre. • Imaging procedures should include a chest X-ray and the scanning procedures mentioned under PUO are used as clinically indicated. • Liver and marrow biopsy (see PUO above) are also performed where there is a clinical indication, with samples cultured for routine organisms, brucella, fungi and parasites, in addition to histological examination of sections and microscopy of smears for tubercle bacilli and leish-
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mania. Bone marrow culture may yield S. typhi in a patient who has previously taken antibiotics.
Management Ideally treatment will follow from the specific microbiological diagnosis of the cause of fever. Occasionally it is necessary to treat the patient for a disease suspected clinically but not proven by available laboratory tests. This may be treatment for malaria, or typhoid or rickettsial infection, or tuberculosis in fevers of longer duration. 1 12
GASTROENTERITIS Gastroenteritis is defined as an acute disease with diarrhoea and/or vomiting and a variable degree of systemic illness. 'Food poisoning' is a term used to describe a selflimiting form of gastroenteritis caused by eating contaminated food.
Aetiology A large variety of microorganisms can cause gastroenteritis (Table 9.13) but in over half of all cases the causative organism cannot be identified. Salmonellae and Campylobacter species are among the most frequent causes. In children the spectrum of organisms is slightly different and rotavirus is the most frequently recognized agent.
Epidemiology Gastroenteritis is a common infection in all parts of the world, occurring sporadically or in epidemics. Epidemics occur when a common source of food or drink is contaminated with micro-organisms and when infection spreads from person to person by the faecal-oral route. For example, Salmonella enteritidis frequently colonize the gut of chickens bred in battery conditions and may infect the oviduct and eggs of hens in batteries. During evisceration in the factory the meat is contaminated and the salmonellae survive freezing and thawing. If such chickens are not thoroughly cooked, salmonellae are ingested and colonize the intestine. During the last few years there have been outbreaks of diarrhoea due to E. coli O:157, which in patients of all ages can go on to cause a haemolytic uraemic syndrome with a significant mortality. This has occurred in retail food outlets where both cooked and uncooked meats are on sale, with the opportunity to contaminate cooked meats with E. coli O:157 from uncooked meat. Some forms of gastroenteritis show striking seasonal variations in frequency but these are usually significant only in temperate areas. Rotavirus is the most common
1
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Case 9.1
2
MCQ 9.6
TABLE 9.13 Common causes of gastroenteritis Cause
Clinical presentation
Invasive bacteria Shigella species Salmonella species Campylobacter jejuni
Dysentery Diarrhoea, vomiting Diarrhoea predominantly
Toxin-producing bacteria Enteroxin E.coli(ETEC) Vibrio cholerae
Secretory diarrhoea Secretory diarrhoea
Neurotoxin Staphylococcus Bacillus cereus Clostridium botulinum
Vomiting (short incubation) Vomiting (short incubation) Vomiting, diarrhoea, neurological
Cytotoxin Clostridium difficile
Bloody diarrhoea, haemolytic uraemic syndrome Watery diarrhoea
Tissue-damaging viruses Rotavirus Norwalk virus Adenovirus Enterovirus
Infantile diarrhoea Winter vomiting Diarrhoea, vomiting Diarrhoea, vomiting
Protozoa Cryptosporidium Entamoeba histolytica Giardia lamblia Cyclospora cayetanensis
Diarrhoea Dysentery Chronic diarrhoea Diarrhoea
E. coli 0:157
cause of infantile diarrhoea worldwide. In Britain and the USA its peak incidence is in 2 or 3 months during the winter, but in tropical climates there is little seasonal variation. Outbreaks of food poisoning caused by Salmonella, Campylobacter or toxin-producing Staph. aureus are more common in summer.
Pathogenesis Organisms must evade the host defences and colonize the intestine before they can cause disease. Gastric acid is an important defence, and patients with a partial gastrectomy are susceptible to intestinal infection. Some bacteria have on their surface determinants that bind to epithelial receptors. Examples are Vibrio cholerae and some strains of E. coli. The known mechanisms by which microorganisms cause diarrhoea can be divided into two groups: toxin secretion and mucosal damage. These are not mutually exclusive, and for many organisms the precise mechanism is unknown. Toxin secretion Three different mechanisms are recognized by which toxins can cause intestinal pathology. Cholera is a good example of small intestinal toxin-mediated secretory diarrhoea (see
9
CASE STUDY 9.1 ACUTE INFECTIVE DIARRHOEA A 21-year-old female student was travelling in rural Nepal staying in guest houses. Overnight she developed fever, chills and generalized body aches and pains. The next day she was anorexic and developed acute watery diarrhoea, but after 12 hours started to get severe griping abdominal pains which were particularly severe in the left lower quadrant. The character of the diarrhoea changed to the passage of frequent small volume stools, with exacerbation of pain. After 12 hours the stools became uniformly bloodstained. She also described the sensation of wanting to empty the rectum with extreme pain in the anus and relatively little blood-stained material coming out (tenesmus). She was wakened from sleep numerous times in the first 24 hours of the illness and sought medical attention at a local hospital. On examination she looked unwell. Pulse 110 regular, BP 90/60, temperature 38.4°C. There
Questions 1. What is the differential diagnosis? 2. What investigations should be performed? 3. What are the main points of management?
was tenderness over the left lower quadrant of the abdomen. She passed a small amount of blood stained watery stool shortly after admission. Comment This history is suggestive of acute invasive bacterial infection of the gut. It is typical of shigellosis, with the initial fever, followed by acute watery diarrhoea and then dysenteric diarrhoea, passing small volumes of stool with pain and tenesmus. However, the distinction between shigellosis, Campylobacter infection and salmonellosis is clinically unreliable. The marked systemic upset initially would be against giardiasis, cyclospora (first described as a cause of diarrhoea in Asia among western travellers in Nepal), cryptosporidium, toxigenic E. coli and cholera. Amoebic dysentery begins more insidiously and is gradually progressive. Investigations must include examination of the stool for amoebic trophozoites, and culture for Shigella and Salmonella. The finding of amoebic cysts in her stool is irrelevant, as motile trophozoites with ingested red cells would be evident in faecal smears in invasive amoebiasis. Microscopy of the stool would have shown large number of pus cells, which do support a diagnosis of invasive bacterial infection.
p. 322), and enterotoxigenic strains of E. coli secrete a heatlabile enterotoxin which acts in a similar way. In staphylococcal food poisoning neurotoxin-secreting staphylococci multiply in food, and the toxin causes vomiting and diarrhoea within hours of ingestion. Staphylococci are not detected in the stools of patients with this type of food poisoning. Bacillus cereus, which contaminates reheated rice, causes vomiting by a similar mechanism. Cytotoxins, such as verotoxin produced by E. coli O:157 and toxin B of Clostridium difficile, cause tissue damage. Mucosal damage Shigellae invade the colonic mucosa and cause local inflammation, and so the faeces contain blood and inflammatory cells. Impairment of water absorption from the colon and exudation of protein-rich fluid through the
Since amoebic cysts were seen in a faecal smear, she was treated with metronidazole as well as norfloxacin for shigellosis. She was also given intravenous fluids as she could not initially tolerate ORS, but within 36 hours of starting treatment the fever regressed and the diarrhoea started to improve, though after finishing 7 days' treatment with both drugs bowel actions remained abnormal both in frequency and the consistency of the stools. No more blood was seen for the remainder of her stay in Nepal or after her return to the UK. The management was appropriate, though one could argue that there were sufficient clues to suggest that norfloxacin alone would have been enough. With marked systemic upset and dysenteric stools there are clear indications to give antibiotics. Rehydration by the oral route was first attempted, with recourse to intravenous fluids when that failed. The persisting abnormalities of bowel habit after effective treatment are an indication of postinfective intestinal irritability, but it is essential to ensure that there is no persisting infection, such as giardiasis, and that there is no possibility of non-specific inflammatory bowel disease which, some reports indicate, may be precipitated by acute gastrointestinal infection.
inflamed and ulcerated mucosa are the cause of fluid stools. Salmonellae, Campylobacter and rotavirus are also invasive and cause tissue damage, but the precise mechanisms are not understood. Damage to the brush border of the enterocytes causes temporary disaccharidase deficiency, which may prolong the diarrhoea even after the pathogen has been eliminated.
Clinical features Most episodes of gastroenteritis are mild and self-limiting. The incubation period is usually short, ranging from a few hours with staphylococcal food poisoning up to 5 days with Campylobacter infection. Vomiting, diarrhoea and cramping abdominal pains are typical features. Large volume stools suggest a small bowel diarrhoea. The stools are fluid
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without blood or pus in toxin-mediated disease (e.g. cholera), but when invasion and mucosal damage occur in Salmonella, Shigella and Campylobacter infections blood and mucus may be seen in the stool. The appearance of the stools is an unreliable guide to the type of organism. The major consequence of gastroenteritis is dehydration with electrolyte imbalance. Babies are more vulnerable and can rapidly become severely dehydrated. It is essential that the clinician can make a reasonably accurate assessment of the degree of dehydration and Table 9.14 gives some guidelines. Fever and signs of systemic illness suggest invasive pathogens. Some invasive organisms can cause septicaemia (e.g. Salmonella typhimurium), and some shigellae produce neurotoxins which enter the circulation in the absence of septicaemia and, on reaching the central nervous system (CNS), cause headache and meningism. The illness is usually over within 7 days, but symptoms are liable to persist for longer with shigellae and Campylobacter. Persistent diarrhoea suggests Giardia infection, especially if steatorrhoea is present. Although amoebiasis is commonly thought of as a cause of acute watery diarrhoea in the tropics it is in fact relatively uncommon, causing only 6% of cases in a large study from Bangladesh. Usually the diarrhoea has an insidious onset and gets worse gradually, though all ranges of severity are possible, from the passage of a little bloodstained mucus with stools to a severe illness every bit as bad as ulcerative colitis.
Diagnosis The diagnosis is usually clear, but problems arise when there is vomiting in the absence of diarrhoea; when abdominal pains are accompanied by localized tenderness, suggesting pelvic inflammatory disease or appendicitis; and when blood in the stools is taken to indicate inflammatory bowel disease. A positive diagnosis is established by identification of the organism in stools by microscopy, antigen assay (for rotavirus) or culture.
Management The management of diarrhoea is concerned mainly with the management of dehydration. After an assessment of the degree of dehydration using the criteria set out in Table 9.14, a plan of management is determined. Where there is no dehydration (<5% body weight lost) oral fluids are given freely and normal feeding is encouraged. When there is some dehydration (5-10% body weight lost) the deficit should be replaced using oral dehydration solution (ORS; Table 9.15) 80ml/kg over 4 hours. In addition to ORS, water and other non-electrolyte fluids should be 1
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MCQ 9.7
TABLE 9.14 Assessment of dehydration A No dehydration
B Some dehydration
C Severe dehydration
Condition
Alert
Eyes
Normal
Restless*/ irritable* Sunken
Tears Mouth and tongue Thirst Drinks Skin turgor
Present Moist
Absent Dry
Lethargic*, unconscious* Very sunken and dry Absent Very dry
None Normally Normal
Thirsty* Eagerly* Reduced*
Drinks poorly* Not able to drink* Markedly reduced*
Features in bold with * are key signs. If 2 signs from column C including 1 key sign are present then severe dehydration is present; if 2 signs from column B including 1 key sign are present, there is some dehydration. (After A Manual for the Treatment of Diarrhoea, World Health Organisation 1990.)
TABLE 9.15 Composition of oral rehydration solution (WHO formulation) Sodium chloride Trisodium citrate, dihydrate Potassium chloride Sucrose Made up to 1 litre with clean water
3.5 g/L 2.9 g/L 1.5 g/L 40 g/L
given to provide water for insensible losses. After each bowel action an additional 400 mL of ORS should be given to replace continuing losses. Oral rehydration solution very effectively replaces lost fluid despite the presence of an enterotoxin-mediated secretory process in the gut, but it does nothing to reduce the volume of diarrhoeal stools produced. The use of rice flour as the source of glucose in cereal-based ORS solutions not only replaces lost fluid but also reduces the volume of faecal effluent. It has the further advantage of being widely available in areas of the world where infectious diarrhoeal diseases are common, but preparing cereal-based ORS requires heating the solution to make a palatable gruel. When there is severe dehydration (>10% body weight lost) intravenous access should be established immediately and Ringer's lactate (or normal saline if that is not available) infused at 30mL/kg over 30 minutes, and then 70mL/kg over 2 hours. Thereafter, continuing losses should be replaced orally if the patient is able to drink, or intravenously if not. In all patients with diarrhoea it is essential that their progress is assessed every hour, so that if symptoms and signs are deteriorating on an ORS regimen they can be
switched to intravenous fluids. Vomiting may prevent successful ORS therapy, but first the administration of frequent small volumes of fluid by mouth should be tried. When initial rehydration has been achieved, continuing faecal losses should be replaced by ORS, 400 mL after each bowel action, and feeding begun as soon as the patient wants to eat. Bowel sedatives have little place in the management of intestinal infections and they may be harmful, precipitating toxic dilatation in elderly and young patients in infections with the invasive bacterial pathogens. Antibiotics are normally not required, but they are needed when there is profuse watery diarrhoea, marked systemic upset and obviously dysenteric (bloodstained) diarrhoea. Empirical treatment with ciprofloxacin 500 mg twice daily for 5 days is usually given. In addition, the following situations merit antibiotic treatment: • • • • • • • •
Septicaemic Salmonella infection (ciprofloxacin) Severe shigellosis (ciprofloxacin) Severe Campylobacter infection (erythromycin) Yersinia (doxycycline) V. cholerae (doxycycline) Entamoeba histolytica (tinidazole, metronidazole) Giardia lamblia (tinidazole, metronidazole) Cyclospora cayetanensis (co-trimoxazole).
Problems associated with use of antibiotics are exacerbation of diarrhoea, prolonged carriage of some organisms (e.g. salmonellae) and development of resistance to multiple antibiotics (e.g. shigellae). There is evidence to suggest that antibiotic treatment in E.coli O:157 infection may increase the risk of renal complications by promoting toxin release. 1
FURTHER READING ON GASTROENTERITIS A manual for the treatment of diarrhoea 1990. Geneva: World Health Organization Programme for the Control of Diarrhoeal Diseases.
ACUTE UPPER RESPIRATORY INFECTION
TABLE 9.16 Causes of upper respiratory infection Disease
Causative organism
Common cold and pharyngitis
Rhinovirus Coronavirus Influenza virus Parainfluenza virus Respiratory syncytial virus Adenovirus Unknown
Pharyngitis/tonsillitis
As above, plus: Epstein-Barr virus B-haemolytic streptococcus group A Mycoplasma pneumoniae Mixed anaerobes and spirochaetes* Corynebacterium diphtheriae* Neisseria gonorrhoeae*
Stomatitis
Candida albicans Herpes simplex virus Coxsackie A and other enteroviruses Mixed anaerobic bacteria
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*Less common
treatment of choice for streptococcal pharyngitis, with erythromycin for penicillin-allergic subjects. Ampicillin and related drugs should be avoided, as they often cause a rash in patients with infectious mononucleosis. Upper respiratory infections are frequently complicated by otitis media in children and, less often, by sinusitis in adults or children. These are usually caused by secondary bacterial infection, and it is therefore important to recognize them and treat with antibiotics. Common bacterial causes of otitis media include Strep. pneumoniae, H. influenzae (mainly untypable), group A B-haemolytic streptococci and Branhamella catarrhalis. Many H. influenzae are now resistant to amoxicillin, and co-amoxyclav can be used instead. The bacteria that cause acute sinusitis are similar to those incriminated in otitis media, but anaerobes, Gramnegatives and Staph. aureus should also be considered. Upper respiratory anaerobic bacteria are usually penicillin sensitive, in contrast to those found in the large bowel.
Common cold and pharyngitis The common cold has an incidence of 1-4 episodes per person per year. Large gaps remain in our knowledge of pathogenesis, although it is clear that many viruses can cause the same clinical entity. There is considerable overlap between organisms causing colds and those causing pharyngitis (Table 9.16). Pharyngitis is more important, as it is often part of a more systemic illness. The majority of episodes of pharyngitis are caused by viruses. Antibiotic treatment should be reserved for culture-proven cases of streptococcal pharyngitis. In the developed world, group A streptococcal pharyngitis is now rarely complicated by rheumatic fever or glomerulonephritis. Penicillin, as a single i.m. dose or orally for a minimum of 10 days, is the
Acute stomatitis In contrast to pharyngitis, the microbial cause of acute stomatitis can often be diagnosed from the appearance of lesions in and around the mouth. Candida is a common pathogen, particularly in debilitated patients, patients receiving broad-spectrum antibiotics and patients with HIV infection. White plaques occur on an erythematous background. The distribution is wide, including the buccal mucosa. Ulcers are usually superficial and not easily confused with primary herpes simplex infection. The latter is often associated with perioral clusters of vesicles. Severely painful ulceration of the mouth and lips in a young immunocompetent patient is usually due either to
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Stevens-Johnson syndrome or to primary herpes simplex infection. Coxsackie virus infection may cause small, scattered vesicles and ulcers, but they are more sparse than those of herpes simplex and less painful. Noninfective causes of ulcers must also be considered, such as aphthous ulcers and, rarely, Behget's disease (p. 1153). Infections in the subcutaneous tissue spaces of the
CASE STUDY 9.2
CHRONIC FATIGUE
A 34-year-old female nursery school teacher in a stable relationship complained of recurrent episodes of sore throat, the most recent of which was 2 months ago. She had had difficulty throwing off 'flu and other infections for 3 years and felt tired all the time. She had pains in the neck and the 'glands' in her neck were going up and down. Her muscles ached during and after exertion and she became fatigued sooner than she would have expected. She denied depression and had no problems at work. There were no abnormalities on examination and, in particular, no lymphadenopathy but minimal tenderness in the anterior cervical region. Muscle power was normal and there was no convincing muscle tenderness. Her affect was normal but she was clearly tired of her symptoms, sometimes sighing while describing them, and she was anxious about an underlying persistent disease of a 'weak immune system'. Questions
1. What is the differential diagnosis? 2. What further investigations would you perform? 3. What would be your approach to management? Discussion
The GP had checked her full blood count repeatedly so we know that she did not have neutropenia or lymphopenia. Examination of the pharynx showed normal tonsils but it would be helpful to see her during an episode of sore throat to exclude 282
face and neck often originate from periodontal infection. Ludwig's angina is an anaerobic bacterial infection of the submandibular and sublingual spaces which causes firm swelling of the tissues below the chin. These may press inwards and compromise the airway. There is accompanying fever and tachycardia and the patient requires urgent antibiotic treatment, usually with penicillin and metronidazole.
recurrent tonsillitis. Persistent pharyngeal infection with group A Phaemolytic streptococcus may cause recurrent sore throat but it does not cause tiredness between episodes. One of her episodes of sore throat could have been infectious mononucleosis caused by EBV infection (or, less commonly, CMV or toxoplasma infection); this usually causes one continuous episode of illness and recurrence is rare beyond 12 months after the initial episode but it can cause tiredness persisting for up to 6 months. Many patients are anxious that recurrent upper respiratory infections indicate a disorder of the immune system. This is not so in the absence of recurrent candidiasis and it is not necessary to undertake immunological investigations to prove it but reassurance is often helpful. Simple causes of tiredness such as anaemia and hyper- or hypothyroidism can be excluded by examination and confirmed by appropriate tests. Rather than requesting a wide range of investigations, it is advisable to target them at excluding diseases which have been a particular cause of anxiety to the patient if the anxiety can not be allayed by reasonable discussion. Assessment by a sympathetic psychiatrist can be helpful and should be regarded as a part of the overall investigation of patients with very prolonged symptoms. Chronic fatigue syndrome is diagnosed when the combination of symptoms illustrated by the above patient is present with negative investigations for organic disease. Many patients have the
somatic symptoms of depression but deny the state of depression or attribute it to the presence of physical symptoms. Sometimes anxiety seems to be a more important factor. The term myalgic encephalomyelitis (ME) should be avoided since none of these patients has encephalomyelitis. The patient was reassured by a wide range of normal investigations (including FBC, ESR, CRP, U&E, LFTs, thyroid function, auto-antibody screen, CXR, negative IgM antibodies to EBV, CMV and toxoplasma and negative throat swab). She was seen by a psychiatrist who found no evidence of depression but she discussed some family stress at Christmas and uncertainty about her career; when she was on holiday at Christmas, there was a family row in which she acted as mediator between her brothers and her mother which she found very stressful. Later she was able to resolve this but she missed her holiday because of the stress and her illness (flu). At work she had been considering whether she should go part-time because of her symptoms or aim for promotion to a deputy school headship. Her symptoms had been improving slowly and she now felt optimistic with the summer holidays looming. She was offered counselling which she attended and found useful. She also undertook a graded exercise programme and at review sessions she was encouraged to work through her fatigue. By end of the year, she was working full-time in the same job and coping despite some persistent tiredness.
SEXUALLY TRANSMITTED DISEASES Sexually transmitted diseases (STDs) are infections commonly transferred through sexual contact. They are discussed in detail in Chapter 11.
CHRONIC FATIGUE SYNDROME (POSTVIRAL SYNDROME, MYALGIC ENCEPHALOMYELITIS) This syndrome is seen most often in young adults. There is a prolonged period of lethargy, often with muscle pains and fatiguability, usually after an episode reminiscent of a viral illness but sometimes in the absence of an evident acute illness. The problem causes great distress to patient and relatives because an explanation is lacking and there is prolonged inability to work or play at expected levels, often coupled with an unreasonable need for sleep. Doctors are frustrated by their inability to establish a positive diagnosis or to give any specific treatment, and the patient often turns to alternative medicine.
Aetiology The syndrome is heterogeneous and no single explanation will fit all patients. The term 'myalgic encephalomyelitis' is misleading as there is no evidence of encephalomyelitis and myalgia may not be present. A number of infections have been associated with this syndrome and they are not all viral. Infectious mononucleosis is the best known and studied, but CMV infection and toxoplasmosis have been suspected, and it is likely that many other organisms can act as triggers in susceptible individuals. Enteroviruses, particularly of the Coxsackie group, have also been suspected but
evidence is inconclusive. Often the only evidence for infection at the onset is a history of febrile illness, perhaps with pharyngitis or lymphadenopathy, and a full blood count may have revealed some atypical mononuclear cells. The relationship of postviral syndrome to depression is complex. There is no doubt that some patients develop the symptoms and signs of depression and benefit from antidepressant treatment. More commonly the patient becomes depressed as a result of the illness but lacks many of the features of primary depression. In this situation antidepressant therapy is unlikely to be beneficial.
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Clinical features The central symptoms are profound lethargy and easy fatiguability. Often these are accompanied by muscular pains, headaches and symptoms suggestive of fever, such as sweating. This is usually mild, and when the temperature is recorded it is normal or only minimally elevated in the evenings. Exertion exacerbates tiredness, and the patient often goes to bed early and wakes late still feeling tired.
Management Patients benefit greatly from having their illness taken seriously, and if a precipitating infection can be positively identified this also helps. Sometimes the greatest problem is anxiety about the outcome or about whether there is an underlying disease that has not been diagnosed, so reassurance is important. When patients have restricted their activity it is worth trying to rehabilitate them by a programme of daily exercise, starting with something light such as walking or swimming, and gradually increasing it in a documented way. The patient is assured that exercise is not harmful and advised to sleep as required. Most patients recover spontaneously within weeks rather than months, but a few continue to suffer for over a year.
VIRUS INFECTIONS Viruses are usually classified according to their nucleic acid content and morphology. The classification of viruses used in this section is shown in Tables 9.17A and B. Arboviruses (arthropod-borne) are viruses transmitted by the bite of an insect vector. Most arboviruses are togaviruses, but bunyaviruses and orbiviruses (RNA viruses in the reovirus family) are also included.
ENVELOPED DOUBLE-STRANDED DNA VIRUSES HERPES VIRUSES Six herpes viruses cause disease in humans: • Varicella zoster virus (VZV)
• • • • •
Two herpes simplex viruses (HSV 1 and 2) Epstein-Barr virus (EBV) Cytomegalovirus (CMV) Human herpes virus 6 Herpes virus associated with Kaposi's sarcoma (HHV8).
Morphologically, herpes viruses are very similar and indistinguishable by electron microscopy. They are similar in some aspects of their behaviour, notably their ability to establish latent infection with the potential for reactivation. During latency in dorsal root ganglia VZV shows no demonstrable evidence of viral replication for many years. With HSV there is evidence of a low level of replication, and reactivation is more frequent. EBV infects B lymphocytes, and EBV and CMV replicate at a low level continuously. CMV can often be detected in the urine of asymptomatic carriers, and herpes simplex in saliva. The mechanisms by which virus replication is suppressed are
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TABLE 9.17A Classification of viruses:DNA
TABLE S.176 Classification of viruses: RNA
Morphology
Virus
Morphology
Virus and disease
Enveloped double-stranded
Herpesviridae Varicella zoster (VZV) Herpes simplex (HSV I, II) Epstein-Barr (EBV) Cytomegalovirus (CMV) Human herpes virus 6 (HHV6) Human herpes virus 8 (HHV8) Poxviridae Vaccinia Variola (smallpox) Orf Parvoviridae Hepadnaviridae
Enveloped single-stranded
Orthomyxoviridae Influenza Paramyxoviridae Parainfluenza Respiratory syncytial disease Mumps Measles Togaviridae Rubella Alpha (equine encephalitis) Flaviviridae Dengue Yellow fever Encephalitis Hepatitis C Bunyaviridae Arenaviridae Lymphocytic choriomeningitis Lassa Filoviridae Marburg Ebola Retmviridae Lentiviruses (HIV 1 and 2) Oncoviruses - type C (HTLV1 and 2) Rhabdoviridae Rabies Vesiculostomatitis Coronaviridae Coronavirus Reoviridae Rotavirus Reovirus Picornaviridae Rhinovirus Enteroviruses Coxsackie A, B Echo Polio Enterovirus 70, 71 Hepatitis A Caliciviridae Norwalk Hepatitis E virus Astroviridae Astroviruses
Enveloped single-stranded
Hepatitis B Hepatitis D
Non-enveloped double-stranded
Adenoviridae Papovaviridae Papilloma Polyoma
incompletely understood, but T cell-mediated immune mechanisms probably have an important role, as all the herpes viruses are liable to reactivate in patients with depression of cell-mediated immunity, such as those with lymphoma or leukaemia.
Varicella zoster virus infection Chicken pox (varicella) This illness is easy to recognize, common and highly infectious. It is a febrile illness with a vesicular rash (Fig. 9.6). During the primary infection there is a viraemic phase when VZV becomes widely disseminated in white cells. In normal subjects it only produces significant lesions in the skin and mucous membranes, but infection of cutaneous sensory nerves leads to infection of dorsal root ganglia, and here the virus enters a latent state. Reactivation later causes herpes zoster (shingles). During primary infection VZV is present in nasopharyngeal secretions and is transmitted readily by coughing and sneezing. It is also in vesicle fluid in chickenpox and shingles, and this can be a source of transmission. The incubation period of chickenpox is 15-18 days and the patient is infectious from a few days before the rash erupts until new lesions cease to appear. The severity of chickenpox is determined by the age and immunological state of the patient. It is most severe in neonates if they have no maternal antibody to VZV, and in patients immunocompromised by disease such as leukaemia or by immunosuppressive therapy. It is usually a mild disease in children, but it becomes increasingly severe after puberty. 284
Clinical features In children chickenpox starts with the appearance of the
Non-enveloped double-stranded Non-enveloped single-stranded
rash, which is often sparse and not accompanied by constitutional symptoms. The most troublesome feature of the illness is itching. In adults there is a notable prodromal illness lasting 2-3 days, during which headache, backache, shivering and fever occur, sometimes with a sore throat and cough. The more severe the prodromal illness, the more profuse is the rash that follows. The rash starts on the trunk and spreads to the face and limbs (Fig. 9.6). Lesions appear in crops which progress rapidly through the sequence macule, papule, vesicle, pustule, scab. Often the first visible lesions are vesicles containing clear fluid with little surrounding erythema, but the pustular stage is reached within 24 hours. Vesicles on the
9
FIG. 9.6 Vesicles and pustules in a patient with chickenpox
palate, tonsils and pharynx rapidly burst, leaving superficial ulcers. Crops of skin lesions erupt over 2 or 3 days, but it takes several more days for them all to heal. Constitutional symptoms, if present, lessen with the onset of the rash and disappear within 2 days. Complications Secondary infection of the skin lesions, including the scalp, occurs because of scratching, but it usually responds to cleaning and bathing and rarely requires antibiotics. Chickenpox pneumonia occurs in one-fifth of adults, and more frequently in immunocompromised patients. It varies in severity from transient dyspnoea to a fulminant pneumonia. Postinfectious encephalitis is extremely rare and has a variable course, but it is often severe or fatal. Its onset is within a week of the rash and cerebellar involvement is characteristic. Bleeding into the skin, nose or intestine, also rare, is due either to steroid-responsive thrombocytopenia or to consumptive coagulopathy, when the prognosis is much worse. Neonatal chickenpox Most women are immune by the time they reach childbearing age, but if a mother develops chickenpox within a few days of having a baby the child is born without the protection of maternal IgG antibodies transferred across the placenta, and it is immediately exposed to the virus. If the child becomes infected during the first 5 days of life disease is severe, with multi-organ involvement. Disease can be prevented or made milder by the administration of varicella immune globulin 250 mgi.m. at birth. Aciclovir l0mg/kg is given intravenously 8-hourly for 7 days if any signs of infection (e.g. fever) appear. This does not seem to prevent the virus becoming latent. Congenital chickenpox Rarely, VZV can cross the placenta during the first 20 weeks of pregnancy, causing fetal damage or death. Diagnosis and management A clinical diagnosis of chickenpox suffices in most cases.
FIG. 9.7 Dermatomal distribution of varicella zoster lesions
Electron microscopy is the quickest way to establish that a herpes virus is present in vesicle fluid, but does not establish its type. The virus can be identified by tissue culture inoculation, and antibodies are detected by a complement fixation test. Treatment with aciclovir (p. 268) is required only in severe cases susceptible to complications such as chickenpox pneumonia, in immunocompromised patients (such as children with malignant disease), and in neonates (Table 9.5, p. 268). Intravenous treatment (l0mg/kgt.d.s in adults; 500mg/m2 for children aged 3 months to 12 years; l0mg/kg for children less than 3 months) is needed in order to achieve adequate serum concentrations. Many patients with chickenpox pneumonia need ventilation (see Ch. 14) and antibiotic treatment for secondary bacterial infection, the most common organism being Staphylococcus aureus. Shingles (zoster) When VZV reactivates within a dorsal root ganglion it migrates down the nerve into the skin and causes a crop of lesions identical to those of chickenpox but confined to the dermatome (Fig. 9.7). Pain within the dermatome may precede the eruption by a few days and is often severe. One or two adjacent dermatomes on the trunk are most commonly affected, but involvement of the ophthalmic division of the fifth cranial nerve is important because the eye can be damaged by the virus or by secondary bacterial infection.
285
In the elderly it is common for a mild viraemia to occur, causing a few scattered lesions to appear outside the involved dermatome. More serious dissemination with visceral involvement is seen in immunocompromised patients. Patients with Hodgkin's disease are particularly susceptible to shingles, especially during chemotherapy. The skin heals over 2-3 weeks and there is often some residual pain for a few weeks. Rarely, intractable pain continues for years (post-herpetic neuralgia). This is more common following ophthalmic zoster, and after severe infections in immunocompromised patients. 1 Management Most patients do not require admission to hospital and treatment of pain is the main concern. Continuous treatment with simple analgesics such as paracetamol is often effective and should be tried before drugs that have more side-effects. Oral treatment. A small increase in the rate of healing has been demonstrated when oral aciclovir is used in high dose, 800 mg five times daily for 7 days. This benefit may be enhanced with the use of newer alternatives such as valaciclovir, as higher serum levels of aciclovir are achieved. Less frequent administration is needed with famciclovir 250 mg thrice daily. Intravenous treatment. Intravenous aciclovir (l0mg/kg t.d.s for adults) should be given to immunocompromised patients for 1 week. It reduces pain, shortens the healing time and limits dissemination of the virus. Evidence for the benefit of prednisolone in reducing post-herpetic neuralgia is controversial and it is not recommended. Topical treatment • In ophthalmic zoster it is important to combine an antibiotic (e.g. chloramphenicol drops) with aciclovir ointment. • Pruritus treatment, e.g. calamine, is soothing for a few minutes. • Antivirals, e.g. idoxuridine and aciclovir, are impractical and of limited value. 0
Herpes simplex virus infection HSV 1 and 2 cause patterns of disease that differ clinically and epidemiologically but share some characteristics. Both establish permanent, latent infection within sensory nerve ganglia following primary infection, with reactivation causing episodes of disease in the area supplied by the nerve. These viruses are indistinguishable morphologically but can be separated by differences in antigen expression. Infection with HSV 1 is more common. Antibodies are detectable in 80-100% of adults in lower socioeconomic groups, and in 30-50% in higher socioeconomic groups. Both viruses are readily transmitted, mainly in vesicle fluid. HSV 1 is usually acquired during childhood, but HSV 2 infection is mainly transmitted sexually and is most common in sexually promiscuous adults. Clinical expression of infection with these viruses is strongly influenced by age, nutrition and the immunological state of the patient. An immunologically immature neonate is overwhelmed by disseminated HSV infection acquired during parturition. Infection in older children is often asymptomatic or causes localized disease which is most severe in the presence of malnutrition. 0 Primary infection with HSV 1 Acute herpetic gingivostomatitis in children 2-4 years old presents with fever, sore throat, and submental and anterior cervical lymphadenopathy. Clusters of vesicles appear around the lips and in the mouth from gums to pharynx (Fig. 9.8). Inside the mouth lesions rapidly ulcerate, causing pain and dysphagia with consequent drooling of saliva. The child is miserable and may become dehydrated if not encouraged to drink through a straw. The lesions heal over 1-2 weeks. Primary infection can occur anywhere on the skin and, on the finger, a herpetic whitlow can closely mimic a bacterial paronychia. Widespread involvement of the skin can occur in individuals with atopic dermatitis (eczema herpeticum, p. 399) and, particularly in infants, this can be associated
SUMMARY 4 Varicella zoster and herpes simplex infection
286
Primary
Reactivation
VZV HSV 1
Chickenpox Acute or asymptomatic gingivostomatitis Keratoconjunctivitis Encephalitis
Shingles Cold sores Keratoconjunctivitis
HSV 2
Genital
Genital
1
Fig. 9.1
2
MCQ 9.8
4
Fig. 9.3
5
Fig. 9.4
3
Fig. 9.2
FIG. 9.8 Gingivostomatitis caused by primary herpes simplex 1
with systemic symptoms. In the eye keratoconjunctivitis can cause scarring of the cornea and loss of vision. Herpetic encephalitis in adults presents a characteristic clinical picture owing to necrotic lesions in the temporal lobe. This rare manifestation of primary HSV infection is described on page 1422. Primary infection with HSV 2 Although HSV 1 and 2 can cause identical disease, HSV 2 is largely associated with genital infection (see p. 456). 4 Infection of neonates can occur during parturition when the mother has genital herpes, particularly if her infection is primary rather than recurrent. The infant develops scattered clusters of vesicles which recur in the same sites subsequently. Alternatively there may be rapid deterioration as the virus disseminates to all the viscera, causing encephalitis, pneumonia and hepatitis, with a high mortality. Usually this severe illness starts in the first few days after birth, but occasionally onset is delayed several weeks. Reactivation of HSV The mechanisms involved in maintaining latency are not fully understood. Reactivation may occur after exposure to ultraviolet light, an episode of infection or trauma to the sensory nerve. Many episodes have no identifiable precipitant. Reactivation is more common in irnmunocompromised patients, particularly those with leukaemia undergoing treatment. The characteristic lesion of reactivated HSV 1 is a cold sore. Patients often experience minor discomfort in the form of tingling or itching up to 24 hours before a lesion appears. Lesions can occur anywhere on the skin or mucous membranes, but are commonly adjacent to the lips. 5 A macule rapidly progresses to a papule and then to a cluster of vesicles which involute, ulcerate and scab. The whole process takes 1-2 weeks. See Chapter 11 for symptoms of reactivation of genital herpes (p. 456).
underdeveloped countries and in crowded living conditions, but infection is delayed in more prosperous environments. Infection in adolescents and adults usually causes infectious mononucleosis (glandular fever). Other diseases related to EBV infection are nasopharyngeal carcinoma, Burkitt's lymphoma, the very rare syndrome of X-linked recessive progressive combined variable immunodeficiency, and lymphoid interstitial pneumonitis in children with AIDS.
9
Infectious mononucleosis Infectious mononucleosis is an acute febrile illness caused by EBV and characterized by a severe sore throat and generalized lymphadenopathy. Pathology and pathogenesis EBV enters through the pharyngeal epithelium and replicates in B lymphocytes, causing them to proliferate. Fifteen per cent or more of blood mononuclear cells appear 'atypical' during acute infection: these are T lymphocytes reacting to the presence of infected B lymphocytes. EBV does not establish a true latent state but maintains a low level of replication throughout life. During infectious mononucleosis, the spleen and lymph nodes are intensely infiltrated with mononuclear cells and the spleen is unusually friable. Haemorrhage may occur into the subcapsular area, and rarely this leads to intraperitoneal haemorrhage. Clinical features Infectious mononucleosis is most common in adolescents and young adults, but children as young as 5 years old may be affected. The illness is more severe in older patients. The incubation period is uncertain but is probably 1-2 weeks. There is a gradual onset of malaise, general aching and fever. The throat becomes painful and engorged with enlarging lymphoid tissue, so that speech is nasal and swallowing is inhibited by pain. The tonsils are large and coated with thick, white exudate (Fig. 9.9). Petechiae may be seen on the soft palate. There is generalized lymphadenopathy
Management of herpes simplex HSVs are highly sensitive to aciclovir and other DNA polymerase-inhibiting drugs. Only serious primary infections with HSV 1, such as encephalitis in adults, severe eczema herpeticum or disseminated neonatal infection, warrant treatment with systemic antiviral drugs. The usual dose of aciclovir for intravenous treatment of herpes simplex is 5mg/kgt.d.s., but for encephalitis l0mg/kg is needed. Initial attacks of genital herpes are treated with 5 days of aciclovir, with an antibiotic if secondary infection has occurred. For recurrences attention to local hygiene is all that is required and 5% aciclovir ointment may be helpful for local lesions.
Epstein-Barr virus infection Epstein-Barr virus (EBV) is a herpes virus which is transmitted by close oral contact. Infection is frequently acquired asymptomatically during early childhood in
FIG. 9.9 Acute tonsillopharyngitis caused by primary Epstein-Barr virus infection
287
in most patients and splenomegaly is common. Uncommon features (occurring in less than 15% of patients) are rash, jaundice and tender hepatomegaly. Thrombocytopenia or autoimmune haemolytic anaemia occur rarely. The acute stage of the illness lasts 2-3 weeks and most patients are entirely well within a month. A small proportion of patients, particularly when older, make a slower recovery, continuing to feel lethargic for a variable period (see Chronic fatigue syndrome, p. 283). Differential diagnosis Other viral causes of sore throat and lymphadenopathy, such as adenovirus, influenza virus and rhinovirus, must be considered (see Table 9.16). Streptococcal infections can cause an identical appearance in the throat, but the lymphadenopathy is mainly in the anterior cervical region. Streptococci are found on throat swabs in 10% of patients with infectious mononucleosis and their role is unclear. Many virus infections are associated with atypical lymphocytes on the blood film, but these can be distinguished from glandular fever cells by an experienced observer. Atypical lymphocytes are also seen in acute CMV infection and occasionally in toxoplasmosis. Both of these conditions can cause lymphadenopathy but they rarely produce sore throat. Laboratory features Atypical mononuclear cells are usually present in the blood film at some stage of the disease. Tests for heterophil antibodies, i.e. antibodies to heterologous erythrocytes, are the Paul-Bunnell and Monospot tests. Heterophil antibodies are present in 90% of patients by the third week of illness, but in only 30% during the first week. Specific IgM antibody measurements are not reliable. Liver function tests are often abnormal. Management No specific treatment is available. Simple analgesic therapy is used to relieve discomfort in the throat, and frequently the patient can only take fluids in the early stages. Occasionally the degree of congestion is such as to threaten the airways; a short course of prednisolone, starting at 30 mg daily and tailing off over 2 weeks, can produce a rapid reduction in the size of the tonsils. If penicillin therapy is indicated for treatment of concurrent Streptococcal infection, ampicillin and amoxicillin should be avoided as they cause a severe maculopapular rash. X-linked recessive progressive combined variable immunodeficiency (Duncan's disease) This rare inherited disease is now recognized as an abnormal response to EBV infection. Patients either die of overwhelming EBV infection in the acute stage or develop
288
1
MCQ 9.9
4
MCQ 9.10
2
Fig. 9.5
3
Fig. 9.6
a progressive immunodeficiency following infection. Lymphoma may complicate the late stages. 1
Cytomegalovirus (CMV) infection CMV is a herpes virus which rarely causes significant disease in immunologically competent subjects. Infection is usually asymptomatic, but it may be associated with a mild febrile illness during which atypical mononuclear cells appear in the blood; these cells are similar to those seen in infectious mononucleosis. Primary infection in the neonate causes serious disease, and primary infection of pregnant women can cause congenital defects in the fetus. As with other herpes viruses, infection is lifelong. CMV replicates at a low level throughout life, but when immunity is suppressed the rate of replication increases. Patients with kidney or heart transplants are particularly at risk, and CMV sometimes causes severe disease in patients with AIDS (pp. 446-448). Transmission The virus is present in blood during primary infection and can cross the placenta. It can also be transmitted in blood used for transfusion. Infected organs transplanted from seropositive donors can cause primary infection in the recipient, but most CMV disease in renal transplant patients is caused by reactivation. The virus is shed from the cervix during active infection and is also present in semen and urine. Acute infection in normal adults There may be a mild febrile illness which is recognized as viral infection when atypical mononuclear cells are seen in a blood film. Sore throat, generalized lymphadenopathy and splenomegaly occur in less than one-third of patients. Abnormal liver function tests show that there is usually a mild hepatitis, but jaundice is rare. The average age for symptomatic infection is 30 years, about 10 years older than for infectious mononucleosis. Complications are rare in immunocompetent patients, and when they occur they are mild. Pneumonitis, myocarditis, meningoencephalitis, Guillain-Barre syndrome, thrombocytopenia and haemolytic anaemia have all been described. Infection in immunosuppressed patients Both primary infection and reactivation can cause disease in immunosuppressed patients, but in renal transplant recipients the more severe disease is seen during primary infection. Asymptomatic reactivation is common and is shown by culture of virus from urine. Fever, sometimes with atypical mononucleosis, is the most common presentation of disease, followed by interstitial pneumonitis. Interstitial pneumonitis presents with insidious onset of fever, a non-productive cough and dyspnoea. Chest radiography shows bilateral diffuse interstitial changes indistinguishable from those of many other opportunistic
infections. Diagnosis is usually made by transbronchial biopsy. Hepatitis is usually mild, but occasionally causes hepatic failure. CMV may be a harmless passenger in the gastrointestinal tract of patients. Its association with enteritis is strongly suggested by the coincidence of seroconversion and haemorrhagic lesions anywhere from the stomach to the rectum, causing a severe diarrhoeal disease and blood loss. A response to treatment with antiviral drugs supports the existence of this clinical entity. In the mouth and oesophagus of AIDS patients, CMV can cause large punched-out ulcers. 2 Severe choroidoretinitis causes progressive loss of sight, starting in one eye and then affecting the other. Large white exudates containing haemorrhagic areas occur. 3 Diagnosis Virus can be cultured from urine, throat washings or buffy coat during active replication, and IgM antibodies are detectable in serum by an immunofluorescence test. In histological sections 'owl's eye' cells are strongly suggestive of CMV infection. Management Intravenous ganciclovir, 5mg/kgb.d. for 14-21 days, is the treatment of choice for immunocompromised patients with CMV disease. AIDS patients with retinitis have a high risk of relapse with loss of vision, and maintenance treatment can be given with oral ganciclovir 1gt.d.s. Bone marrow toxicity is common and an alternative treatment is foscarnet 200mg/kg for 14-21 days, with monitoring of renal function and serum calcium. 4
Human herpes virus 6 infection Human herpes virus 6 (HHV6) has recently been identified in patients with AIDS and has subsequently been found to be widely distributed. It is the cause of roseola, a common febrile illness of young children characterized by the appearance of a rash when the fever and illness are resolving. The temperature is high but the child is relatively well. There is often cervical and postauricular lymphadenopathy. When the temperature starts to fall, or within 2 days, a maculopapular erythematous eruption appears on the trunk: this lasts for a few days. Blood count reveals neutropenia initially, which may be followed by mild leukocytosis. The illness resolves without complications.
Human herpes virus 8 (HHV8) or Kaposi's sarcoma (KS)-associated herpes virus HHV8 has been identified consistently in KS lesions of AIDS patients and it is now thought to be the cause of this spindle cell tumour. Epidemiological studies show that asymptomatic infection is common in Mediterranean and African countries where KS occurred independently of
HIV infection. It is likely that cofactors are required for the development of KS, but these have not yet been identified. Despite the relationship between KS and AIDS in homosexual men, transmission of HHV8 between individuals is likely to be similar to that of EBV, as infectious virions have been found in saliva. It is rarely detected in semen even though viral DNA is detectable in the prostate. Treatment of AIDS patients with antiretroviral drugs, particularly protease inhibitors, results in regression of KS lesions (see Chapter 11).
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POX VIRUSES Variola and vaccinia Variola virus is the cause of smallpox, an infection of low infectivity transmitted between humans by close contact. Immunization introduced globally using the refined vaccine containing vaccinia virus led to the eradication of smallpox in 1979, and only accidental laboratory infections have occurred since then. Vaccination against smallpox is no longer justified.
Orf virus infection Orf virus causes a single nodular lesion at the site of an abrasion which has been in contact with an infected lamb.
ENVELOPED SINGLE-STRANDED DNA VIRUSES PARVOVIRUS The association between infection with human parvovirus and disease has only been recognized since the 1980s. The virus was first noticed in sera from normal subjects during screening by electron microscopy (1975), but in 1983 it was reported to be the cause of erythema infectiosum ('slapped cheek disease' or 'fifth disease'). A more serious consequence is that the virus can cause aplastic crises in patients with sickle cell disease.
Clinical features of erythema infectiosum Parvovirus infection is probably transmitted between humans by nasopharyngeal secretions and causes a range of illness ranging from asymptomatic to a febrile systemic illness with a rash. After a mild prodromal illness consisting of fever, headache, upper respiratory symptoms and myalgia lasting 2-A days, a rash appears on the arms and chest, spreading peripherally, even to the palms and soles. The classic 'slapped cheek' appearance of erythema infectiosum is seen in less than half of infected patients. Elsewhere the rash is maculopapular and fluctuates in intensity. It often develops a lacy reticular pattern on the limbs
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and leaves a short-lived pale brown pigmentation as it fades over a week. The rash is frequently pruritic. Other features during the rash are generally mild, but include fever, malaise, headache and sometimes arthralgia, lymphadenopathy and splenomegaly.
Complications Complications are rare. Adult women may develop symmetrical peripheral polyarthritis, which can be the sole manifestation of infection. Although it usually resolves within 3 months it may continue for several years. Aplastic crises are not a feature of infection in patients who are otherwise normal haematologically, but when the red cell life is reduced, as in sickle cell disease or hereditary spherocytosis, arrest of erythropoiesis for 5-10 days causes a significant fall in haemoglobin level. The same effect has been observed in patients with advanced AIDS.
Diagnosis and management IgM serum antibodies detected by enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA) are diagnostic of recent infection and persist for about 2 months. A change in litre of IgG antibodies also indicates recent infection. Virus isolation is not feasible and detection of viral protein is reserved for research purposes. There is no specific treatment at present.
NON-ENVELOPED DOUBLE-STRANDED DNA VIRUSES
affects adults and often follows minor trauma to the eye. Type 8 is the usual pathogen. Haemorrhagic cystitis. Caused by types 11 and 21, haemorrhagic cystitis is a childhood infection. Adenoviruses are also uncommonly associated with diarrhoeal disease, intussusception, and meningitis or encephalitis. Diagnosis of adenovirus infection is usually made on clinical grounds. It can be confirmed by virus isolation or by identification of viral antigen by immunofluorescence where these techniques are available, or by detecting a rise in serum antibody titre. There is no effective antiviral treatment, but most disease is mild and self-limited.
PAPOVAVIRUSES The important members of the papovavirus group are papilloma or wart viruses and polyoma viruses. Palmar and plantar warts are benign infections, common in childhood, which often regress spontaneously with increasing age. They are caused by viruses which are distinct from the anogenital warts viruses; the latter are sexually transmitted (see Ch. 11, p. 456, and Ch. 10, p. 393).
Genital warts See Chapter 11 (p. 456).
ENVELOPED SINGLE-STRANDED RNA VIRUSES ORTHOMYXOVIRUSES
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ADENOVIRUSES
Influenza virus infection
Adenoviruses are a common cause of upper respiratory infection in children and cause a variety of other illnesses, depending on the serotype of virus and the age of the patient. Over 40 serotypes have been isolated from humans, and many of these are known to have pathogenic potential. Virus can frequently be isolated from the posterior pharyngeal lymphoid tissue of asymptomatic subjects, suggesting that it can remain latent for long periods. Upper respiratory infection. Common cold and pharyngitis occur in all age groups, and serotypes 1-6 are the usual cause. Lower respiratory infection. Tracheobronchitis and pneumonia are rare in children but young adults may be affected. This is one of the differential diagnoses of atypical pneumonia. Types 4 and 7 are the most common causes. Pharyngoconjunctival fever. An acute infection spreads among young children in close contact, often caused by adenovirus type 3. Epidemic keratoconjunctivitis. Epidemic keratoconjunctivitis is a more severe form of eye infection which
Influenza types A and B are the main viruses in this family, but there is also a type C virus. Influenza is an ancient disease characterized by regular winter epidemics, with occasional much larger outbreaks (pandemics) when there is a major shift in antigenic type against which there is little immunity in the population. Although the disease is normally mild and self-limiting, the elderly and those with chronic chest disease are susceptible to complications, resulting in a considerable mortality. Epidemiology Epidemics of influenza start with cases in children and spread to the adult population. As the epidemic progresses, vulnerable adults start to present in hospitals and the size of the epidemic becomes apparent when absenteeism causes problems at work and in schools. Epidemics usually peak within 3 weeks and last about 6 weeks. They occur in winter - December to April in the northern hemisphere and May to September in the southern hemisphere. In tropical countries virus isolates can be obtained year
round, but epidemics tend to occur after changes in weather, whereas in temperate climates it is rare to find the virus in the community between epidemics. Surprisingly, several variants of the virus are found to be circulating during an epidemic, but they are sufficiently similar to previously recognized viruses for some crossimmunity to exist. Variants that appear late in the course of an epidemic are sometimes the ones responsible for an outbreak during the following winter. Pandemics have occurred infrequently over the last century, in 1889, 1918, 1957, 1968 and 1977. They result from the emergence of new viruses in which there are major changes in the surface proteins, mainly neuraminidase and haemagglutinin, against which the populations of the world have no immunity. The mechanism for these changes is likely to be genetic reassortment and some evidence suggests that this occurs in animal reservoirs, such as birds and lower mammals. Two neuraminidases and three haemagglutinins have been detected at various times in the last century and these are recognized in the name given to a subtype of virus. For example, the virus responsible for the 1918 epidemic was H1N1, and another severe epidemic in 1957 was caused by H2N2. The severity of an outbreak is determined by the extent of change in antigenicity of the virus, so that if the neuraminidase and the haemagglutinin both undergo a major change, the severity of disease and the size of the epidemic are greater than if only one determinant changes. After a major antigenic shift causing a pandemic, smaller variations in antigenicity known as antigenic drift occur over a variable period (9-30 years in the past century) and the population gradually builds up immunity to the possible variants of the new virus subtype. The scene for the next major antigenic shift may be set by the level of herd immunity to the subtype variants, but other factors probably make a contribution also. Clinical features Influenza is transmitted by droplets of respiratory secretions and the incubation period is 1-3 days. Influenza A and B cause a similar illness, but influenza C only gives rise to sore throat. The onset of influenza is rapid, with symptoms of fever, including chills, sweats and sometimes rigors accompanied by malaise, anorexia, headache and marked myalgia. The severity of general symptoms varies greatly between individuals, from mild to prostrating. They are worst in the first 3 days and usually disappear within a week. Cough and sore throat are variable features which tend to increase as other symptoms subside and resolve over 2-3 weeks. On examination the patient is initially febrile, flushed and tachycardic, with minor nasal discharge. The pharynx may be inflamed and cervical lymph nodes palpable and tender. Complications The elderly are more vulnerable to all complications. The
most common is exacerbation of chronic bronchitis, and this is responsible for most adult admissions to hospital in influenza epidemics. Asthma is also exacerbated. Bacterial pneumonia, often caused by Strep, pneumoniae, Staph. aureus or H. influenzae, can occur in chronic bronchitics or patients with no previous history of chest disease, but it is more common in smokers. Viral pneumonia caused by influenza virus itself is a severe complication which usually occurs in patients with underlying disease of the chest or cardiovascular system, although in some epidemics it has affected previously healthy adults, suggesting that virus virulence is a factor. This type of pneumonia is bilateral, with opacities on the chest radiograph which do not correspond to clinical signs, low diffusing capacity and a progressive course. Other rarer complications include myositis, myocarditis, pericarditis, Guillain-Barre syndrome and encephalitis.
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Diagnosis Influenza virus can be cultured from respiratory secretions, but the diagnosis is more often made by serum antibody measurement using paired sera. When an epidemic is in progress a clinical diagnosis suffices. Management and prevention Zanamivir (Relenza) has been the subject of controversy, as governments have been unconvinced that it should be licensed for general use. It is a competitive inhibitor of viral neuraminidase which is active against a range of influenza A and B subtypes, giving it a clear advantage over amantidine which is only active against influenza A. Zanamivir, given by inhalation and intranasally, has been shown to be effective in reducing virus shedding, shortening the duration of symptoms, and in prophylaxis. Trials have not been completed in groups at highest risk from influenza, including the elderly, and the cost/benefit ratio has been judged too high to justify licensing the drug at present. Amantadine and rimantadine, which interact with the M2 membrane protein of influenza A, have more sideeffects than zanamivir and are rarely used. Comparative trials have not been carried out. Symptomatic treatment with analgesics such as paracetamol and maintaining adequate hydration are important. Aspirin should be avoided in children because of the danger of precipitating Reye's syndrome. Secondary bacterial infection causing bronchitis or pneumonia is the most serious complication which requires antibiotic treatment with co-amoxiclav (250 mg amoxicillin t.d.s.) or a macrolide such as erythromycin (250 mg q.d.s.) in penicillin-allergic subjects. If staphylococcal pneumonia is suspected, flucloxacillin (250mg q.d.s.) should be given. Inactivated viral vaccine containing the currently prevalent strains of influenza A and B is recommended for persons at special risk, especially the elderly and those suffering from chronic pulmonary, heart or renal disease, diabetes, and those with some forms of immunosuppres-
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sion. The vaccine is usually given in the autumn and confers about 70% protection for a year. O
PARAMYXOVIRUSES Para influenza virus infection There are four types of parainfluenza virus and the organisms are a common cause of mild upper respiratory infection in children under 2 years of age (Ch. 13). Types 1-3 occasionally cause more severe lower respiratory tract disease, such as croup and bronchiolitis. Although there is little antigenic variation in parainfluenza viruses, immunity is poor and reinfection causing mild disease is common.
Respiratory syncytial virus infection Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in young children. Outbreaks occur annually, usually in late winter or spring, and about half of primary infections result in pneumonia, bronchiolitis or tracheobronchitis. Upper respiratory involvement is also common and otitis media is a frequent complication. Children over the age of 3 usually suffer milder disease, and adults are occasionally infected. Severe infection can occur in adults following bone marrow transplantation. RSV is highly infectious and is commonly transmitted to other patients in hospital. Respiratory isolation procedures should be applied and management is general support, with oxygen as required and maintenance of hydration. Successful therapy for RSV has been described in immunocompromised adults using ribavirin administered as an aerosol, but in practice this is difficult to apply.
Mumps Mumps is a systemic paramyxovirus infection which commonly causes inflammation of the salivary glands. It is transmitted by droplets from the mouth. Infection in childhood is common but infectivity is low, and many people reach adulthood without becoming affected. Clinical features The incubation period is about 18 days (Fig. 9.1, p. 261). Mumps is a mild disease in childhood and about one-third of children infected have no symptoms. In its mildest form there is fever with discomfort and swelling in the parotid glands, which lasts a week or less. In more severe forms there is considerable malaise, the glands are painful and there may be trismus. Other salivary glands are often inflamed and glands are sometimes involved sequentially.
1
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MCQ 9.11
2
Fig. 9.7
Swollen parotid glands can be distinguished from lymphadenopathy because the angle of the mandible is obliterated by the former. The mouth is dry and there may be redness around the orifices of the parotid ducts, but there is no purulent discharge. About 20% of adult males develop orchitis in the course of mumps, but oophoritis is rare. Usually orchitis starts a few days after the onset of parotitis, but it may be earlier and may occur in the absence of parotitis. The swollen inflamed testicle is exquisitely tender and remains so for 3-4 days before gradually recovering. Orchitis is accompanied by fever and malaise, and the latter often persists for some weeks. Orchitis is bilateral in 15-30% of cases, but even in these patients sterility is extremely rare. Although some shrinkage of involved testicles may be detected shortly after the illness, this does not imply complete loss of function and it is important to reassure patients on this point. Mumps virus is highly neurotropic and involvement of the CNS is the most common complication of this infection. There are two distinct entities, meningitis and encephalitis. Lymphocytic meningitis occurs in about 5% of patients with mumps parotitis, but this figure underestimates its prevalence as it also occurs in the absence of parotitis. There is some seasonal variation in the clinical manifestations, meningitis with parotitis being more common in spring, whereas meningitis alone is seen more in summer. The time of onset of meningitis varies, but it usually becomes apparent a few days after parotitis. The CSF shows a lymphocytic pleocytosis and virus can be isolated from it. The course is invariably benign. Encephalitis is rare. It either occurs during parotitis as a result of direct viral invasion of the brain, or its onset is 7-10 days after that of parotitis, when it represents a postinfectious encephalitis. Most patients recover completely, but there is a mortality of 1-2%. Pancreatitis is rarely severe but may account for some of the abdominal symptoms in mumps. Some degree of abdominal pain is not infrequent and may be accompanied by vomiting. In severe cases there is marked abdominal tenderness and the serum amylase and lipase levels are elevated. Diagnosis A clinical diagnosis usually presents little difficulty, but if necessary the virus can be isolated from saliva and throat washings, or from CSF in cases of meningitis. Complementfixing antibody detection can be used to make a retrospective diagnosis. Management There is no specific treatment, but oral hygiene is important both for comfort and to prevent secondary infection. Orchitis requires testicular support and adequate analgesia. There is little evidence that corticosteroid treatment is beneficial in orchitis.
SUMMARY 5 Mumps
SUMMARY 6 Clinical features of measles
Fetal death possible if infection in first trimester
• • • • •
Gland involvement Parotid Submandibular Epididymo-orchitis Oophoritis Pancreatitis
65% 10% 25% (postpubertal) 5% (postpubertal) ?%
Meningitis Encephalitis
<10% 0.1%
Prevention Vaccination with a live attenuated vaccine was adopted as part of the routine programme in the UK from 1988. It is given in combination with measles and rubella in the second year of life.
Measles Measles is an easily recognized, highly infectious disease of childhood caused by measles virus, an RNA virus of the paramyxovirus group. Epidemiology Infection is spread by droplets coughed on to mucosal surfaces of the conjunctiva and nasopharynx, and because cough is a feature of the illness from the onset it is not surprising that infection spreads rapidly between non-immune subjects. One of the interesting features of the disease in older epidemics was the high mortality rate. It is not clear whether measles virus has changed to a more benign form or whether environmental factors are responsible, but the latter is more likely as the disease is still severe in Africa. The size of the pool of non-immune humans determines whether there is an epidemic of measles. In the past, epidemics have occurred in Britain every 2 years or so, but immunization has made this pattern less apparent. Pothogenesis Measles virus can infect many different cell types and during the incubation period, which is 8-11 days from infection to the onset of prodromal symptoms (Fig. 9.1, p. 261), the virus multiplies, becoming widely disseminated. It reaches most tissues, including skin, mucous membranes, lungs, gut, brain and lymphoreticular tissue. The lesions of measles, containing mononuclear and giant cells, are caused by a combination of viral cytopathic effect and non-specific and specific inflammatory reactions. The role of immune mechanisms is demonstrated by the modified or absent skin rash in immunodeficient subjects, who may nevertheless die from a giant cell pneumonia. Antibody is detectable in serum 24-48 hours after the onset of rash, and virus is rapidly cleared during this period.
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Incubation period 8-11 days Initial symptoms of upper respiratory infection Koplik's spots on buccal mucosa Rash spreads from face to trunk to limbs Complications (pneumonia, otitis media, encephalitis) more common in malnourished children
Clinical features In Britain measles is most common at the age of 3-5 years but the age is lower in underdeveloped countries. In the 2-4 days before eruption of the rash the features are similar to those of many upper respiratory infections. The patient feels unwell and has a fever, red eyes, swollen eyelids, a congested streaming nose, diffuse redness in the mouth and a hacking cough. Koplik's spots, 1-2mm white spots like a grain of salt on a red background, may be seen on the buccal mucosa. Their number varies from a few to hundreds, and they often persist after the rash appears. The worst of the illness is during the first few days after eruption of the rash, when there is a spiking fever and the child is irritable and miserable. Spots appear first behind the ears and on the forehead and then spread to the rest of the face, on to the trunk and out to the limbs over 24-72 hours. © This pattern of spread is characteristic, but the rash of rubella (German measles) spreads in the same direction. Measles spots are red macules and maculopapules initially a few millimetres in diameter, which enlarge and coalesce to form irregular blotches, the most striking of which are on the cheeks. As the rash fades and the patient starts to feel better there is transient brown staining of the skin and sometimes fine desquamation. At the height of the eruptive stage the mucous membranes and eardrums are red, and there is generalized lymphadenopathy, a barking cough and widespread crackles in the chest. Complications Major complications are rare in Britain today. All complications are more common in malnourished children, and severe skin desquamation with secondary bacterial infection, diarrhoea, appendicitis, laryngitis, stomatitis and major weight loss all occur frequently in Africa. Measles sometimes precipitates the onset of kwashiorkor. Secondary bacterial infection usually manifests itself 3-4 days after the rash and prolongs the illness. The timing is an important clue, as renewed fever heralds a third phase of illness. Bronchopneumonia and otitis media are examples. Giant cell pneumonia is rare and usually affects immunocompromised children, such as those with leukaemias. Febrile convulsions may occur as the temperature rises in the incubation period or at the beginning of the eruptive phase. Encephalitis is rare and varies in severity. It occurs in the convalescent phase and in fatal cases virus is not recovered from the brain, so encephalitis may be
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caused by an immune reaction to viral antigen in neural tissue. Subacute sclerosing panencephalitis (SSPE, p. 1426) is a progressive fatal form of encephalitis affecting older children who had measles many years before. High litres of measles antibodies and recovery of a measles-like virus from the brain suggest that it is related to measles. Diagnosis Clinical diagnosis of measles is usually straightforward. The rash of rubella has a similar distribution, but lesions are smaller and they tend to remain discrete. Rubella is a milder illness with a characteristic distribution of lymphadenopathy (occipital and posterior cervical). Laboratory confirmation of measles is rarely necessary, but measles virus can be cultured from nasopharyngeal specimens during the prodrome and for about 2 days into the eruptive phase. A blood count normally shows leukopenia, and neutrophilia suggests secondary bacterial infection. Antibody litres are measured by a complement fixation test. Management Most children with measles are looked after at home, but if hospital admission is required for social reasons or because of complications, the patient should be nursed in isolation. Antiviral treatment is not available at present and management is directed at providing comfort and maintaining hydration. Prophylactic antibiotics have no place, but appropriate antibiotics must be given for secondary bacterial infection. Important organisms in respiratory infection and otitis media are Strep, pneumoniae, H. influenzae and, less commonly, Staph. aureus. Therefore, the usual first choice of antibiotic is a broad-spectrum penicillin (e.g. amoxicillin) or erythromycin. Management of encephalitis is described on page 1423. Passive immunization with 500 mg normal human immunoglobin intramuscularly (250 mg for children less than 1 year old) attenuates or prevents clinical manifestations if it is given within 6 days of contact. This is useful in children under 18 months and in those made susceptible to severe forms of measles by immunosuppression. Protection lasts for about 3 weeks.
SUMMARY 7 Management of measles • • • •
General support including hydration Antibiotics for secondary bacterial infection Respiratory isolation Normal human immunoglobulin for children under 18 months if within 6 days of contact or immunosuppressed
1 294
MCQ 9.12
2
MCQ 9.13
FIG. 9.10 Notifications of, and deaths from, measles in England and Wales, 1940-2000 The impact of MMR vaccination is clearly visible.
Active immunization Live attenuated measles virus vaccine is given in the second year of life in Britain. In parts of the world where the disease is common in younger children immunization is recommended at an earlier age. A single subcutaneous or intramuscular dose gives prolonged protection. Contraindications are immune deficiency disease (primary or secondary), immunosuppressive therapy, and severe egg allergy. Atopy and febrile convulsions do not preclude use of the vaccine. The uptake rate for immunization has increased since the introduction of MMR vaccine in the UK and measles has become uncommon (Fig. 9.10), following the same pattern as in the USA. O
TOGAVIRUSES The togavirus group comprises the rubella virus, alphaviruses and flaviviruses. Rubella is the commonest togavirus infection in the western world. Alphaviruses are the cause of Eastern, Western and Venezuelan equine encephalitis. Flaviviruses cause dengue and yellow fever.
Rubella Postnatal rubella (German measles) is a mild illness occasionally complicated by arthritis or encephalitis. By contrast, infection in utero can have devastating effects on the fetus. Pathogenesis Rubella virus infects nasopharyngeal secretions, where it is found during subclinical as well as overt infection. During the viraemic phase it is disseminated widely and, as for
measles, the clinical illness corresponds in time with the development of immunity. The incubation period for rubella is 14-16 days. Clinical features Like measles, rubella is associated with fever, lymphadenopathy, rash and conjunctival suffusion, but it is a mild, short-lived illness which may be asymptomatic. The lymphadenopathy of rubella is characteristically suboccipital, postauricular and posterior cervical. It may persist long after the rash has faded. Although, as in measles, the rash starts on the face and behind the ears, spreading downwards and outwards over the trunk and limbs, the spots are paler red, circular macules which remain discrete and do not coalesce into brighter irregular blotches. The rash varies from hour to hour, fading and reappearing for up to 4 days. It is common to find petechiae on the soft palate (Forchheimer spots), but these are not diagnostic. Complications Arthritis is the only common complication of rubella. It usually affects young women, who develop polyarthritis of small joints, especially those of the fingers and wrists, although larger joints may be affected. It is easily confused with acute rheumatoid arthritis, especially in the absence of rash. It usually subsides within a few days but can last up to 3 months. Encephalitis and thrombocytopenic purpura are very rare complications. Congenital rubella Both the risk and the severity of damage to the fetus are closely related to the time of infection. Following infection during the first month of pregnancy over half of fetuses are affected, whereas by the fourth month only 5% have defects, although this is still twice the frequency in control groups. Minor damage can result from later infection. During the viraemic phase of the maternal illness rubella virus invades the placenta, causing villous placentitis, and then disseminates through the fetal circulation. The degree of damage is variable, even in twins infected at the same time. The common major abnormalities resulting from infection in the first trimester are cataracts, patent ductus arteriosus with or without pulmonary stenosis, and deafness. Rubella virus can be isolated from the baby's pharynx for several months, a much longer period than in acquired rubella. The virus is present in all other secretions, and these babies can readily infect nurses handling them. Diagnosis Serology is the mainstay of diagnosis in both congenital
SUMMARY 8 Clinical features of congenital rubella Cataracts Cardiac abnormalities - patent ductus, pulmonary stenosis. Deafness
and acquired rubella. In the haemagglutination inhibition (HAI) test, the virus agglutinates chick red cells. Serum antibodies inhibit this agglutination. A rise in total antibody titre or the presence of specific IgM antibodies indicates recent infection. In acquired infection antibody is detectable by HAI 14-16 days after infection and reaches a peak 6-12 days later. The fetus starts to produce IgM antibody at about the 20th week of life, and as only IgG antibody can cross the placenta the presence of IgM antibodies to rubella virus in the fetus or infant implies active infection. Rubella virus can be cultured from clinical specimens, but this is rarely used for diagnosis.
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Immunization Live attenuated virus vaccine is given routinely as part of the measles/mumps/rubella (MMR) vaccination to boys and girls aged 15 months. This was introduced in 1988 and replaces the policy of immunizing girls aged between 11 and 13 years. Vaccine virus can cross the placenta so it should not be given during pregnancy, and pregnancy should be avoided for 2 months after immunization. Exposure to rubella during pregnancy Definite exposure to rubella of a non-immune pregnant woman during the first trimester is an indication for termination of pregnancy. If the woman does not know whether she is immune to rubella, the following course of action is recommended: • If possible, establish by serology the diagnosis of rubella in the patient with whom the pregnant woman was in contact. Find out whether contact was close enough to allow transmission of virus. • Test the pregnant patient for rubella antibodies: - // positive by HAI within 14 days of exposure to rubella, the patient was immune previously and she can be reassured. - // negative by HAI then test a further sample 2-3 weeks from contact. If the second serum is positive or if IgM antibodies are detected, discuss risks and offer termination. Some women prefer to continue with the pregnancy despite the risk to the fetus. In this case intramuscular rubella immunoglobulin should be given as soon as possible after exposure. 2
FLAVIVIRUSES Dengue Dengue is an arthropod-borne (arbovirus) flavivirus infection characterized by an acute febrile illness with severe bone pain, rash and lymphadenopathy. The vectors are Aedes mosquitoes. The dengue virus is a 50 nm RNAcontaining flavivirus. Four serotypes are recognized, and these can be differentiated in a range of standard serological tests. The serotypes are closely related antigenically,
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FIG. 9.11 World distribution of dengue fever, 2000 (Source: Centers for Disease Control and Prevention)
but cross-protection between serotypes is lacking. The dengue shock syndrome and haemorrhagic fever occur in patients, particularly children, experiencing a second infection with a different Dengue serotype. Distribution and incidence Over the last three decades epidemics of dengue have occurred in all continents in the tropics, Africa, Asia, the Americas and the Pacific (Fig. 9.11), such that it is now the commonest mosquito-borne infection, and 50% of the world's population live in endemic areas. With the spread of dengue there has been a corresponding spread in the incidence of dengue haemorrhagic fever (DHF) which until the 1970s was confined to southeast Asia. The reasons for this spread are incompletely understood, but include the increase in travel worldwide distributing the serotypes to new areas, decline in mosquito control so that Aedes aegypti has proliferated, and the rise of densely populated periurban slums with no sanitary facilities except those that encourage the proliferation of A. aegypti. Transmission and epidemiology The most common vector is Aedes aegypti, a day-biting mosquito that breeds in small collections of water in tin cans, car tyres etc. peridomestically, but other species have more limited roles in transmission. Eight to 11 days after ingesting dengue virus in a human blood meal the mosquito is infective; it remains infective for the rest of its life. Peak biting times are the 2-hour periods after dawn and before dusk. Both sexes and all age groups are susceptible to dengue provided they have not been infected before with that serotype. Dengue haemorrhagic fever has been predominantly a disease of children, but with spread to new areas
1
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Fig. 9.8
second infections, and hence DHF, are occurring in older age groups. Pathology and pathogenesis After inoculation the virus replicates in local lymph node cells. Viraemia follows and reticuloendothelial cells in skin and other tissues become infected. Local inflammatory changes occur around small vessels in the skin. Dengue haemorrhagic fever occurs in children who have previously been exposed to infection with a different serotype of the virus, or who have acquired antibody passively from their mother. Immune enhancement causes more cells to become more heavily infected through immune complex binding to Fc receptors. Cytotoxic T-cell memory is activated, causing enhanced clearance of virus but also resulting in excess cytokine release, with tissue-damaging consequences: increased vascular permeability, causing hypovolaemia and coagulation defects owing to the release of cytokines with procoagulant properties. Clinical features The incubation period is about 7 days prior to the onset of high fever, headache, eye pains, backache and chills. Limb pain is often severe in dengue and this gives rise to its common name, 'breakbone fever'. A blanching erythematous macular rash may appear on the third or fourth day of the illness. 1 Lymphadenopathy may be present. Encephalopathy, cardiomyopathy and liver damage also occur. Leukopenia is usual in the peripheral blood. In dengue haemorrhagic fever the patient is more ill, and blood pressure falls as a result of transudation of fluid from the vascular compartment. This fluid can accumulate in the abdominal cavity or in the pleural spaces. Monitoring blood pressure, haematocrit and platelet count in addition to urine output and conscious level give warning of its onset. There may be spontaneous bleeding into the skin and at other sites. The loss of circulating blood volume causes shock, with low blood pressure, rapid pulse, restlessness and abdominal pain (the dengue shock syndrome), which can have a mortality of 50% if untreated.
Diagnosis Virus can be isolated from blood using Aedes or mammalian cell lines. Virus can also be identified in blood using the polymerase chain reaction, and IgM antibody or a rising antibody titre in paired sera obtained 10-14 days apart are serological indicators of the diagnosis, although the serological response may not be so clear-cut in areas where populations are exposed to other flaviviruses. Management Patients with uncomplicated dengue require supportive measures, such as attention to nutrition and hydration and relief of pain. Paracetamol, not aspirin, should be used for pain relief and as an antipyretic. Intensive management of severe dengue haemorrhagic fever can reduce the mortality from 10% to 1% without highly sophisticated facilities. Intravascular volume is restored with Ringer's lactate, giving a volume equal to daily requirements plus 5% of body weight, and monitoring pulse, blood pressure and respiration to avoid overload. Plasma protein fraction and dextran 40 may also be given to replace colloid losses. Haematocrit should be monitored to assess progress. The need for fluid replacement may last only 1-2 days. No specific antiviral treatment is beneficial. Control Live attenuated vaccines are under development. It is important that they contain all four serotypes of the virus to avoid the risk of dengue haemorrhagic fever. Vector control comprises the removal of mosquito breeding sites, which are often collections of water in tins, tyres, tubs and water storage vessels around homes, and larviciding.
Yellow fever Yellow fever is an acute arboviral (arthropod-borne) infection caused by the yellow fever virus, a flavivirus. The illness is characterized by high fever, jaundice and encephalopathy in its severe form. The disease occurs in focal outbreaks in Africa, the Caribbean and Central and South America. This condition is prevented by the 17D attenuated live vaccine strain, which should be given to travellers to endemic areas and to indigenous populations in outbreaks. There are infrequent occurrences of importation of yellow fever to Europe, which can present as PUO or viral haemorrhagic fever. Distribution and incidence Sub-Saharan tropical Africa (especially West Africa), the Caribbean islands (most recently Trinidad) and South America (Brazil, Peru, Bolivia, Ecuador, Venezuela and Colombia) are the areas affected by yellow fever. Relatively small numbers of cases occur every year in these areas, although cases in isolated areas may go unreported. Transmission and epidemiology Transmission is shown in Figure 9.12. In South America, and Central and East Africa, a jungle cycle involves
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FIG. 9.12 Cycle of transmission of yellow fever virus Infected humans bring the virus from the jungle. Mosquitoes can breed peridomestically in small collections of water such as puddles and water pots.
monkey-mosquito-monkey and maintains the virus in the mosquito reservoir. Haemagogus mosquitoes are the vector. The epidemiology in savannah and forest-savannah areas involves other Aedes species with humans and monkeys. The insect vector passes infection to the next generation of mosquitoes by transovarial transmission. Non-immune persons of all races, all ages and both sexes are susceptible to infection. Prior exposure to other flaviviruses produces some degree of cross-protection. Men are at particular risk of infection because of occupations that take them into forests. Pathology and pathogenesis The liver is the main organ involved and shows mid-zonal necrosis of hepatocytes. Councilman bodies result from the degeneration of hepatocytes. The kidneys show acute tubular necrosis which may relate to shock and hypovolaemia. There may be haemorrhage into mucous membranes and the skin, associated with the bleeding tendency that is common in yellow fever. The underlying pathogenic mechanisms are poorly understood. Clinical features There is a range of severity of disease, from mild to severe life-threatening illness. The latter constitutes a minority of all those infected. The incubation period is about 6 days before the onset of headache and fever. More severe illness is associated with marked limb pains. Proteinuria is usual. High fever, headache, severe limb and back pain, chills associated with fetor, haemorrhages in the gums, and nosebleeds are early features in severe cases. There may then be a short period of remission of symptoms for up to 24 hours before the recurrence of fever with vomiting and jaundice. Bleeding into the gut, skin and other sites is usual in severe cases. Occasional cases are seen with organ damage limited to the heart or kidneys, causing cardiac or renal failure. Bleeding and renal failure are the main causes of the high mortality (up to 50%) in severe cases. Resolution in severe cases can take from 3 days to 6 weeks.
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Diagnosis The clinical features in severe cases suggest the diagnosis, but in milder cases without evidence of organ dysfunction the diagnosis may not be made. Virus can be isolated most often from blood taken in the first 4 days of clinical illness. Rising antibody titres in paired sera may also give the diagnosis, but serological tests may not be easy to interpret in people exposed to related viruses. Differential diagnosis In mild cases the range of febrile illnesses to be considered is extensive and includes malaria, typhoid, the prodromal phase of viral hepatitis, leptospirosis and rickettsial diseases. The presence of jaundice with fever prompts consideration of leptospirosis, malaria, East African trypanosomiasis, typhoid, biliary tract sepsis and Marburg virus diseases. Ebola virus fever and Lassa fever are other causes of haemorrhagic fever, although marked jaundice is not usual. Laboratory features Anaemia, leukopenia and thrombocytopenia are usual features in more severe cases. Conjugated bilirubin levels and transaminases are high in jaundiced cases. Coagulation abnormalities comprise prolonged prothrombin time, reduced fibrinogen levels and detectable fibrin degradation products. Renal failure with proteinuria, oliguria and raised creatinine and urea may occur. Prevention and control All travellers to endemic areas - apart from pregnant women, infants under 1 year and immunosuppressed patients - should receive the attenuated 17D yellow fever vaccine. Patients with yellow fever should be nursed under mosquito nets to prevent mosquitoes becoming infected. Vaccination is used to help control epidemics. Other arthropod-borne (arboviral) infections There are a considerable number of arboviruses that affect humans. In these infections the main clinical manifestations are fever, chills, joint pain and a maculopapular rash. Mild forms of the diseases are frequent. Vaccines are not available. Infections may emerge in cities if stagnant water is infected by mosquito larvae. The primary virus hosts are birds. A recent outbreak of acute viral encephalitis in New York is an example. 1
VIRAL HAEMORRHAGIC FEVERS (VHF) In the patient who has acquired a febrile illness in Africa, consideration must be given to the possibility of infection
1
298
MCQ 9.14
TABLE 9.18 Risk assessment for VHF A Strong suspicion Patient left a known endemic area in the previous 3 weeks, particularly healthcare personnel from such an area. Contact of confirmed case Laboratory worker who handled VHF viruses B Moderate suspicion Patient left tropical Africa in the previous 3 weeks, but from a rural area or small town not considered endemic Where the onset and clinical course of the fever are consistent with VHF C Low suspicion Patient left a major city in tropical Africa in previous 3 weeks where risk of VHF is negligible
with one of the agents of VHF, Lassa fever, Ebola or Marburg. It is necessary to make an assessment of risk based on information about the area visited, contact with sick people etc. (Table 9.18). In an endemic area (Table 9.19) isolation and observation of the patient will be necessary, depending on the likelihood of some other clinical diagnosis. Public health authorities should be informed to arrange serological and virological testing, epidemiological investigation, and initiate additional measures. For a patient seen in a non-endemic area the risk assessment outcome will determine where the case is nursed; for A and B (Table 9.18) that will probably be a high security isolation unit, whereas for C side-room accommodation with strict barrier nursing precautions will be adequate. The viruses causing VHF, a group of clinically similar infections, are from the bunyaviridae, arenaviridae and filoviridae (Table 9.20). They are characterized in the most severe forms by a bleeding tendency with purpura, ecchymoses in the skin, bleeding from mucosal surfaces, and often bleeding into lungs, gut and other internal organs; haemoglobin levels fall rapidly. Disease onset is abrupt, with severe headache, rigors, myalgia, and an erythematous flush of the face and chest. Often patients have been treated for infections over the first 10-12 days with antimalarials initially, followed by an antibiotic for typhoid. Progressive renal failure can occur. Not all patients with these infections develop severe clinical disease: some have a febrile illness which settles without these severe features. Treatment in severe cases is supportive, with restoration of blood volume by transfusion with platelet support if possible, and dialysis if there is renal failure. Lassa fever is an exception in which ribavirin is known to be effective. In managing such patients it is essential at the outset to diagnose more common, treatable, causes of fever, particularly falciparum malaria.
Lassa fever This acute febrile illness was first described in patients who came from the village of Lassa in eastern Nigeria near the border with Cameroon. It is an arenavirus (RNA) infection characterized by high sustained fever, ulcerative pharyngitis and swelling of the neck in typical cases.
TABLE 9.19 The distribution of viral haemorrhagic fever viruses Lassa fever virus Ebola virus
Marburg virus Arenaviral haemorrhagic fevers in South America Hantaviral haemorrhagic fever with renal syndrome
Guinea, Liberia, Sierra Leone, Nigeria Congo, Gabon, Sudan, Cote d'lvoire, Uganda Reston strain in monkeys from Philippines (infectious but avirulent in humans) Uganda, western Kenya, ?Zimbabwe Brazil, Argentina, Bolivia Asia, the Americas, Europe
TABLE 9.20 Causes of viral haemorrhagic fever Type of virus
Bunyaviridae Hanta Crimean-Congo HF Rift Valley California encephalitis Arenaviridae Lymphocytic choriomeningitis Lassa Junin Machupo Guanarito Sabia Filoviridae Marburg Ebola
Disease HF with renal failure HF Fever (+retinitis in 10%); HF in 1% Encephalitis/meningoencephalitis Aseptic meningitis Lassa fever Argentine HF Bolivian HF Venezuelan HF Brazilian HF
HF HF
HF = haemorrhagic fever
Transmission and epidemiology Mastomys nataliensis, the multimammate rat, is the reservoir of infection and persistently excretes virus in its urine, which contaminates food eaten by humans. Person-toperson spread occurs through contact with body fluids. Infection can occur through cuts and needle-stick injury, or contact of body fluids with mucosal surfaces. In endemic areas, which include Nigeria, Sierra Leone, Liberia and other west African countries, there is a range in severity of disease with appreciable numbers of mild infections; severe infection occurs in 5-10% of cases with a hospital mortality of 15%. Children develop less severe disease than adults. Clinical features After an incubation period of up to 17 days there is a gradual onset of fever with anorexia, lethargy and headache. In the second week of illness ulcerative pharyngitis and swelling of the neck and face may occur. Vomiting, diarrhoea, cough and abdominal and chest pain also occur. A maculopapular rash may appear on the face, trunk
and upper limbs in the second week. Bleeding occurs in the third week and affects gums, nasal mucosae, gut and other sites. Fatal cases show declining renal function and oliguria, declining conscious level and secondary bacterial infections. Leukopenia, low albumin, raised urea and elevated transaminases with normal platelet counts are also evident. Neutrophil leukocytosis can be a feature later in the course. Platelet function is abnormal. An aspartate transaminase of greater than twice normal is associated with rising mortality.
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Diagnosis This may have to depend on clinical features in endemic areas, but virus can be identified in body fluids by electron microscopy, in cell culture and by PCR. Serological testing is also used. Management Supportive measures are used, with maintenance of fluid balance, analgesia and antipyretics, avoiding aspirin because of impaired platelet function. Ribavirin given intravenously reduces mortality if given in the first week of the illness: 30mg/kg as a loading dose, followed by 15mg/kg 6-hourly for 4 days, then 7.5mg/kg 8-hourly for a further 6 days. Close contacts should be treated immediately they develop a fever. Diagnosed cases in Europe and North America are managed in secure isolation facilities to give maximum protection to staff caring for the patient, but in endemic areas standard barrier nursing precautions are adequate. Oral ribavirin treatment may be given to staff and others exposed to the virus by needle-stick or other injury.
Marburg and Ebola virus disease These viruses also cause VHF. They are members of the filoviridae. Marburg was first recognized in 1967 as causing an outbreak among staff at a laboratory in Marburg, Germany, as a result of handling a recently arrived shipment of African green monkeys from Uganda. There were also cases in former Yugoslavia as a result of exposure to monkeys from the same shipment. The next outbreaks were of Ebola virus infection. These occurred in southern Sudan and in what was then Zaire in 1976; despite the similar temporal occurrence these outbreaks were caused by different strains of the same virus. Subsequently there have been outbreaks in Sudan, Gabon, Cote d'lvoire and Zaire. There were also outbreaks of disease in non-human primates. Epidemiology and transmission No reservoir has been identified for filovirus infection, though it is likely to be an animal. Chimpanzees and a range of monkey species die of the disease and so are not the reservoir. The average incubation period in one outbreak was 7 days. During the 7 months of the outbreak 80% died, with a decline in mortality over the 7 months. The mean duration from onset of disease to death was 10
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days. A quarter of all the cases were healthcare workers and this was largely due to contact with blood and body fluids. Reuse of contaminated needles and instruments and not wearing gloves for procedures were also factors in nosocomial transmission. Direct contact with body fluids from patients and with the bodies of dead patients were additional factors in transmission. Aerosol transmission was not thought to be a major factor. Subclinical infection is very uncommon. Seropositivity rates were only 2% in the nearby town and 9% in surrounding villages. Clinical features Three manifestations present relatively early in the course are conjunctival injection, a maculopapular rash, and sore throat with marked pain on swallowing. Severe muscle pain is often present. The rash appeared towards the end of the first week on flanks and in inguinal and axillary regions, then rapidly spread to cover the whole body apart from the face over hours. This is evident on white skins but not on black skins. Bleeding from mucosae and puncture sites, anuria, hiccup and tachypnoea were features indicating that death was likely in days, with defervescence over the last 2 days before death. Fever, asthenia, nausea, vomiting and diarrhoea - often dysenteric - and headache were additional common symptoms. Diagnosis Intense viraemia is the rule in cases, and so antigen detection using ELISA-based technology is the most valuable diagnostic technique, particularly when processing large numbers of samples. Serology, PCR and virus isolation are other methods for diagnosis. Management This is essentially supportive. Paracetamol and not aspirin should be used as antipyretic. Fluid intake and nutrition should be maintained and blood transfusion given where there is anaemia. In an endemic situation there may be very little that can be offered, and the major efforts need to go into protecting healthcare workers and family members from infection by caring for cases in hospital with strict barrier nursing precautions and attention to disinfection. No antiviral agents are effective in this infection. 1
RHABDOVIRUSES
Rabies Rabies is an acute encephalomyelitis caused by an RNAcontaining rhabdovirus. It is characterized by paroxysms of muscle spasm that particularly affect muscle groups associated with swallowing and inspiration, in response to attempts to drink water, as well as the sight, sound or mention of water. For practical purposes it is invariably fatal. Aetiology The rabies virus is an RNA-containing rhabdovirus which, with five related viruses, comprise the Lyssavirus genus. The virus can be grown in cell culture. Distribution and incidence Antarctica and Australasia are free of rabies, otherwise all continents are endemic; the UK, Scandinavia, Japan and Taiwan are free of the disease. The incidence of human rabies is difficult to estimate. Occasional cases occur in Europe and North America. It is a considerable health problem in Asia, Africa, and Central and South America. Transmission and epidemiology Rabies virus is inoculated in saliva by the bite of a rabid animal, most often a dog, less often a cat (Fig. 9.13). Licking abraded or cut skin can transmit infection. Virus can penetrate mucous membranes of the mouth and eyes. Endemic canine rabies is the major determinant of risk for human infection. All mammals can become infected, but transmission to humans is mainly related to biting animals, commonly stray dogs in the tropics. Wolves, jackals, mongooses, bats (insectivorous, vampire and fruit eating), monkeys and ungulates (sheep, cattle and deer) can all become infected and pose a greater or lesser degree of risk to humans. Apart from bats all species die of this infection. In Europe the red fox is the reservoir of infection. Vampire bats infect cattle in
FURTHER READING Peters C J, LeDuc J W, eds. 1999 Ebola: the virus and the disease. J Infect Dis 179; Suppl 1:288.
1
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Case 9.2
FIG. 9.13 Cycle of transmission of rabies The commonest routes of spread are shown in solid lines. Humans are usually infected by dog bites.
the countries of South America, causing considerable economic losses through cattle rabies. Human infection has been acquired directly from vampire bats and following exposure to aerosols containing virus excreted by bats in bat caves. Pathology Virus first penetrates skeletal muscle cells and then enters nerves through the fibres supplying muscle spindles and travels centripetally to infect nerve cells. Virus replication occurs and then ruptures cells, releasing virions to infect other neurons. Neuropathological changes are not gross. Collections of inflammatory cells are seen around small vessels; dead neurons and phagocytosis of degenerating neurons are seen especially in the medulla and the midbrain. Viraemia is not thought to contribute to spread of the virus; rather, it occurs through centrifugal spread via fibres of the autonomic nervous system to cornea, skin and salivary glands. Clinical features The incubation period is 20-60 days on average, ranging up to 1 year. Initial symptoms are headache, fever, insomnia, anorexia and paraesthesiae or altered sensation at the site of the bite or some peripheral site. After 2 or 3 days the patient may become markedly agitated, hyperexcitable, anxious, confused and lucid by turns. The earliest hint of hydrophobia may be evident at this stage, with rapid progression to overt hydrophobia, with involuntary contraction of the main and accessory inspiratory muscles in a sustained spasm brought on by attempts to drink water or at the sound, sight or mention of water. Variations of mood persist. Saliva may be continuously spat out as it cannot be swallowed. The spasms can be provoked by fanning air across the face. Cranial nerve palsies, paralysis and bizarre patterns of breathing follow. Ascending paralysis without hydrophobia occurs in a few patients, and this can pose problems in diagnosis. Death occurs in 7-14 days from respiratory failure or cardiac arrhythmias. Differential diagnosis Tetanus, other causes of ascending paralysis, and encephalitis and rabies hysteria are the main things to consider. Laboratory diagnosis Virus may be grown from saliva, nasal washings, CSF and urine. Viral antigen can be identified in skin biopsies, preferably taken from the hairy skin of the neck, where hair follicles contain peripheral nerves, or less easily in corneal impression smears using fluorescent antibody labelling techniques. The sensitivity of this method for antemortem diagnosis is not ideal. Corneal impression smears and skin biopsies for antigen detection should be refrigerated immediately after collection. In specialist centres PCR is available using reverse transcriptase PCR technology, and this method can detect virus in saliva. Blood and CSF should also be tested for rabies antibodies, and in the unvaccinated patient a positive test supports the diagnosis.
Prevention, control and treatment Correct management at the time of biting prevents rabies.
9
First aid The wound should be washed under running water for 5 minutes with soap or detergent. Where the wound is washed with soap all traces of this must be washed away if a quaternary ammonium compound is to be subsequently applied, as soap inactivates cetrimide. Primary suture and scrubbing of the wound should be avoided if at all possible. Alcohol 40-70% or an aqueous solution of iodine or a quaternary ammonium compound with known lethal effect on rabies virus, such as 0.1% cetrimide solution, should then be applied and the wound covered with a dressing. Tetanus prophylaxis should be given and antibiotics as indicated. The need for rabies vaccine must then be considered. • Low risk: following licks of the skin, abrasions or scratches, minor bites on covered areas of arms, trunk and legs, start vaccine (schedules given below) if animal is rabid or suspected rabid. If the animal is rabid at the time of exposure, or is wild or not available for observation, then vaccine plus rabies imimmoglobulin (RIG) should be started together. If the biting animal is a dog or cat and is healthy after 15 days of observation, then further vaccination can be stopped. • High risk: following licks of the mucosa, major bites, i.e. multiple bites, or bites to the head, face, fingers or neck by a suspect or rabid domestic or wild animal, or by an animal that is not available for observation, give vaccine plus rabies immunoglobulin. Again treatment can be stopped if the biting cat or dog is healthy at 15 days. Rabies vaccination The vaccine used now is human diploid cell vaccine (HDCV). • For pre-exposure vaccination (e.g. prior to travel etc.) the recommended schedule is three doses of 1.0 mL of HDCV given by deep subcutaneous or intramuscular injection (deltoid region, not gluteal region) on days 0, 7 and 28. • For low-risk cases HDCV should be given; for those who have not received full pre-exposure immunization give five doses of 1.0 mL of vaccine intramuscularly, starting on the day of biting, day 0, and thereafter on days 3, 7, 14 and 30. The vaccine is given by deep subcutaneous or intramuscular injection. If intramuscular, the injection is given into the lateral aspect of the thigh or the deltoid but not the gluteal region. For those who have had full pre-exposure vaccination, i.e. three doses of HDCV, two doses of vaccine are given on days 0 and 3-7. When RIG is needed it is given as detailed below. • For high-risk cases human RIG is given, 20iu/kg body weight, up to half infiltrated in and around the wound after cleansing and half given intramuscularly. In some parts of the world human RIG will not be available and equine RIG will be used. The dose is worked out on the
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basis of 40iu/kg body weight. As reactions to equine RIG are not uncommon a test dose should be given first. HDCV is given as five doses of 1.0mL of vaccine on days 0, 3, 7, 14 and 30 to those with no or incomplete preexposure vaccination for rabies. For those with full preexposure vaccination two additional doses of 1.0 mL of HDCV are given on days 0 and 3-7, RIG is not usually needed. While patients with established rabies can be kept alive by intensive care, the fatal outcome is unaltered. Postmortems carried out in patients managed in this way have shown extensive destruction of nervous tissues. Practical management in an endemic area comprises sedation and pain relief. Close contacts of cases should be vaccinated. The problem of controlling reservoirs of infection remains. The capturing and killing of stray dogs in endemic areas has reduced an important source of human rabies. Vaccination of household dogs and cats is a helpful measure but does not exclude the possibility of the animal contracting rabies. Good results have been obtained in the control of fox rabies in Europe by putting down baits containing an oral antirabies vaccine. The incidence of rabies in sentinel species has declined markedly. Advice about rabies vaccination etc. can be obtained in the UK from Virus Reference Division, Central Public Health Laboratory, Colindale, London NW9 5HT (Tel: 020 8200 4400).
NON-ENVELOPED SINGLE-STRANDED RNA VIRUSES PICORNAVIRUSES Rhinovirus infection Rhinoviruses are the most common cause of colds (p. 631). There are over 90 serotypes and reinfection with the same serotype can occur. Infection is usually confined to the nasal mucosa, but complications such as sinusitis and otitis media can occur as a result of mucosal swelling and
obstruction to drainage of secretions. Rhinoviruses can also cause exacerbations of chronic bronchitis but the mechanism for this is not clear.
Enterovirus infection Coxsackie A, Coxsackie B and Echoviruses, of which there are 24, 6 and 34 types, respectively, cause a wide variety of clinical infections, but overall most are asymptomatic. A febrile illness with upper respiratory symptoms is another common manifestation of infection with many different serotypes. More specific disease associations are shown in Table 9.21. Polio viruses types 1, 2 and 3 cause poliomyelitis, which is described on page 1426. Acute meningitis Enteroviruses are a common cause of lymphocytic meningitis (more than 70% of cases), which is a benign disease. Enteroviral meningitis is common in young children and rare over the age of 40. The clinical features are described on page 1422. Other neurological disease Encephalitis is a rare manifestation of enteroviral infection which may occur with or without meningitis. Flaccid motor paralysis is only seen with any frequency in poliomyelitis. Fever and exanthem A variety of skin rashes occur. Maculopapular eruptions associated with fever are more common with Echo than with Coxsackie viruses. Petechial or purpuric eruptions are uncommon. The most distinctive exanthem is the vesicular eruption of hand, foot and mouth disease caused by Coxsackie virus A16 (and occasionally others). Lesions are found in the mouth consistently, and on the palms, soles and extensor surfaces of the hands and feet. Vesicles are sometimes surrounded by a ring of erythema and lesions may be slightly tender. The child feels unwell for 1 or 2 days and has a fever, but recovers completely. Virus can be isolated from vesicles, throat washings or stools. Respiratory tract infection Most enteroviruses can cause non-specific upper respiratory infection, but group A Coxsackie viruses are the
TABLE 9.21 Enterovirus types and their disease associations Virus types most commonly associated
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Disease
Coxsackie A types
Coxsackie B types
Echo types
Acute meningitis Encephalitis Herpangina (pharyngitis) Hand, foot and mouth disease Pleurodynia (Bornholm's disease) Pericarditis/myocarditis Chronic meningoencephalitis in hypogammaglobulinaemics
Most One-fifth 2-6, 8, 10, 22 5,7,9,10,16 None None None
All Most None None 1-5 1-5 None
Most One-third None None None None One-third
common cause of herpangina, an acute painful vesicular eruption on the fauces and soft palate associated with fever, malaise and myalgia and lasting up to 10 days. Pleurodynia (Bornholm disease) Pleurodynia (sometimes known as epidemic myalgia) is an acute febrile illness that usually affects young adults and is characterized by 'pleuritic' chest pain; it is caused by infection with group B Coxsackie viruses which occurs mainly in late summer. The pain is due to infection of muscle and there is no pleural inflammation. About half of patients have pain in an area of the thorax but upper abdominal pain occurs in others, especially children, and this may mimic an abdominal emergency. Tenderness over involved muscles is the characteristic sign. Chest X-ray is normal. The illness is usually over in 5 days, but it may last up to 3 weeks and sometimes recurs. Non-steroidal antiinflammatory drugs such as ibuprofen 400 mg t.d.s. are helpful in treating the pain. Myopericarditis Enteroviruses, mainly group B Coxsackie, are an important cause of acute myocarditis and pericarditis in young adults. Usually the two conditions occur simultaneously, but one predominates in the clinical presentation. The clinical features are described on page 570.
SUMMARY 9 Management of rotavirus diarrhoea Clinical assessment No dehydration
Management Encourage ingestion of fluids orally Encourage normal feeding
Some dehydration (5-10% body weight lost)
ORS 80 ml/kg body weight over 4 hours + 400 ml ORS after each diarrhoeal stool + water to provide for insensible and renal losses
Severe diarrhea (>10% body weight lost)
Intravenous fluids (e. g. Ringer's lactate) 30 ml/kg over 30 minutes and then 70mL/mg over 2 hours
(Note: dehydration is not usually severe in adults with viral gastroenteritis)
Epidemic haemorrhagic conjunctivitis This epidemic form of acute conjunctivitis, which is associated with pain, subconjunctival bleeding and oedema of the eyelids, lasts about 1 week and is usually caused by enterovirus 70. The virus is highly infectious and is spread by contact and fomites rather than by droplet.
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NON-ENVELOPED DOUBLE-STRANDED RNA VIRUSES REOVIRUSES Rotavirus diarrhoea Rotavirus diarrhoea is an acute dehydrating diarrhoeal disease caused by a 70 nm RNA-containing virus. This organism is the commonest cause of diarrhoea in children up to 2 years old in the tropics. It is spread by the faecal-oral route and possibly by droplet transmission. The infection occurs in both endemic and epidemic forms worldwide. Clinical features After an incubation period of up to 5 days (most often 2 days) anorexia, vomiting, diarrhoea and fever begin suddenly. There may also be a blocked nose and sore throat. The stools are watery and non-dysenteric. The illness is self-limiting, terminating in about 5 days in most cases. Moderate dehydration is the usual consequence of the illness, but a number of fatalities from severe dehydration have occurred. The organism may be found in faeces by immune electron microscopy and viral antigen detection using an enzyme-linked immunosorbent assay. Management Management comprises assessment of the degree of dehydration (see Table 9.14, p. 280) and replacement of that volume of fluid in the first 4-6 hours after presentation. Continuing fluid losses must also be replaced until diarrhoea ceases (see p. 280).
CHLAMYDIAL, MYCOPLASMA AND RICKETTSIAL INFECTIONS CHLAMYDIA Chlamydia are bacteria which contain both DNA and RNA (unlike viruses) but which are unable to replicate extracellularly (Table 9.22). They are Gram-negative and have a lipopolysaccharide endotoxin. Chlamydia psittaci, a common pathogen of birds and animals, can infect humans, causing psittacosis (ornithosis). Chi. trachomatis is transmitted between humans by sexual contact or from a mother's infected genital tract to her
newborn infant, causing conjunctivitis or occasionally pneumonia. Different serotypes of Chi. trachomatis cause lymphogranuloma venereum (LGV; see p. 457) and trachoma. The role of chlamydial infection in non-specific genital infection (NSGI) is discussed in Chapter 11 (p. 457).
Psittacosis Although ornithosis is a commonly used name for infection with this organism, this is a misnomer because a wide range of animals other than birds are infected by Chi. psittaci.
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TABLE 9,22 Chlamydial infections Type
Transmission
Disease
Clinical features
Chlamydia psittaci Chlamydia trachomatis Types A, B, C Types D-K
Zoonosis
Psittacosis
Pneumonia
Fingers, flies, fomites Sexual Mother-to-infant Sexual
Trachoma Non-gonococcal urethritis, salpingitis
Keratoconjunctivitis Urethritis, pelvic inflammatory disease, Reiter's syndrome, perihepatitis (rare) Conjunctivitis, pneumonia (rare) Suppurative inguinal lymphadenitis
Types L1, L2, L3
Lymphogranuloma venereum
Epidemiology Psittacosis occurs sporadically worldwide, but it is most common in people closely associated with birds. Infected birds are usually ill, but continue to shed organisms in excreta and feathers for months after recovery. Humans are infected by inhalation. Clinical features After an incubation period of about 2 weeks there is fever, malaise, headaches, myalgia and sometimes arthralgia. Dry cough and variable dyspnoea occur, with confusion and clouding of consciousness if severe hypoxia develops. There are few abnormal signs in the chest, although there may be fine crackles in the lower zones. The chest radiograph shows unilateral or bilateral patchy infiltrates, especially in the lower zones, but occasionally there is the appearance of lobar consolidation. Gastrointestinal symptoms occur uncommonly. Rarely the disease is complicated by aortic or mitral valve endocarditis. Abortion in pregnant women may occur. Diagnosis and management Diagnosis is suspected from the history and evidence for atypical pneumonia, and confirmed by testing for serum antibodies by immunofluorescent or complement fixation tests. Tetracyclines given for at least 10 days are the most effective treatment.
Trachoma Trachoma is a chronic infection of the conjunctiva of the globe and eyelids caused by Chl. trachomatis serotypes A, B, Ba and C. It is widespread throughout the tropics and subtropics, and is primarily a disease related to poor personal and public hygiene. It is one of the commonest causes of blindness in the world, with 500 million affected, 2 million blind and 100 million with severe visual impairment. Transmission and epidemiology The organisms present in ocular secretions infect other people by direct contagion on contaminated fingers or
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1
Fig. 9.9
4
Fig. 9.11
2
Fig. 9.10
3
MCQ 9.15
clothes. Lack of water for washing means that infected secretions are wiped on to hands and clothes. Flies may also carry the organisms from one person to another. Infection occurs early in life, and subsequently there are episodes of reinfection and secondary bacterial infection. Pathology and pathogenesis Acute inflammation is present in the conjunctiva. This progresses to a chronic state, with lymphoid aggregates around infected conjunctival cells. It is likely that damage due to trachoma is exacerbated by repeated bacterial infections. The tarsal plates fold inwards due to fibrosis (entropion) and the cornea is continually damaged by the inverted eyelashes, resulting in corneal opacity from scarring. There is evidence that cell-mediated immune responses to this intracellular pathogen are important in pathogenesis, with evidence of genetic factors determining the expression of reactivity. Clinical features The earlier features are hypertrophic follicles on the upper tarsal conjunctiva and at the corneoscleral junction superiorly. 1 With time and repeated reinfection this inflammatory response leads to fibrosis. The scarring disorganizes the arrangement of Meibomian glands, and their orifices are pulled away from the lid margin. The eyelid is inverted and sites of eyelash trauma on the cornea are seen. New vessels grow into the cornea (pannus formation) and corneal scarring follows. 2 Diagnosis Diagnosis is made on the appearances described above. Giemsa staining of scrapings from the affected conjunctiva shows intracytoplasmic inclusion bodies. Antigen can be detected by enzyme-linked immunoassay. Management and prevention Topical 1 % tetracycline eye ointment, applied two to four times daily for 3 weeks and repeated at 1-month intervals up to six times, is effective but it has been shown that a single dose of oral azithromycin, 20mg/kg, was as effective as 6 weeks of topical 1 % tetracycline eye ointment, though neither gave permanent cure and relapse is frequent. Continued trauma to the cornea must be prevented. Removal of the offending eyelashes helps. Surgical reconstruction of the eyelid may be needed.
Education concerning the importance of washing with soap and water is an important measure in preventing transmission. This depends on the availability of an adequate water supply sufficient for all domestic needs. The use of antibiotics in infected persons reduces the inflammation in the eyes and prevents progression of the disease while eradicating sources of infection for others. 0
MYCOPLASMAS Mycoplasmas are the smallest organisms able to grow in cell-free media, wherein they differ from viruses. They differ from bacteria in lacking a cell wall. Mycoplasma pneumoniae is an important cause of atypical pneumonia and a number of other clinical syndromes described in Chapter 13. M. hominis and Ureaplasma urealyticum can cause non-specific genital infection (see p. 457), prostatitis, pelvic inflammatory disease and postpartum fever. They are sensitive to tetracycline, the treatment of choice (p. 304).
RICKETTSIA Rickettsial infections comprise a group of acute infectious diseases caused by small bacteria which are transmitted by arthropods that in some cases act as reservoir and amplifying hosts. Fourteen rickettsial infections are currently recognized, eight have been described in the last decade, and there may well be more to be discovered. Some rickettsiae are currently regarded as non-pathogenic, but it may well be that all are pathogenic to some degree. The main groupings recognized are the typhus group of infections and the spotted fever group. The agent of scrub typhus has now been assigned to a new species, Orientalis tsutsugamushi. Current approaches to taxonomy have placed much reliance on homology between ribosomal 16S RNA sequences. The rickettsiae produce diseases with a range of severity from mild to severe and life-threatening. All are obligate intracellular parasites living free in host cell cytoplasm, not confined within a parasitophorus vacuole, and can only be grown in cells in vitro. They are Gram-negative organisms and, like Gram-negative bacteria, produce endotoxin which may contribute to the pathogenesis.
Typhus Distribution and incidence (Table 9.23) Typhus group Louse-borne typhus (Rickettsia prowazekii) occurs in louse-infested populations. These are usually relatively poor people living where night-time temperatures are low even though it may be hot in the day; people wear as much clothing as they can to keep warm, and do not change or
TABLE 9.23 Geographic distribution of the main rickettsial infections Epidemic typhus (R. prowazekii) Murine typhus (R. typhi) Rocky Mountain spotted fever (R. rickettsii) Mediterranean spotted fever (R. conori)
9
Highland regions: South America, Africa and Asia Texas (USA), Africa, Asia, Europe USA, Canada, Mexico, Panama, Costa Rica, Brazil, Colombia Countries of the Mediterranean littoral, sub-Saharan Africa, India, around the Black Sea, Vladivostok
wash their clothing. Body lice are frequent biters and feeders and are very sensitive to dehydration. If clothes are changed and washed then transmission of louse-borne typhus is prevented. Mountainous areas of South America, the Himalayas and highland regions of Ethiopia are endemic areas. Louse-borne typhus had become less common, but there was a large outbreak of 30000 cases in Burundi in relation to the civil war there, with large numbers of displaced persons crowded together in unsanitary conditions. In louse-borne typhus humans are the reservoir of infection, with latent infections recrudescing under the stress of displacement and war (Brill-Zinsser disease), infecting body lice which spread from person to person carrying the infection. Murine typhus (R. typhi) is widely distributed in warmer climates in Africa, Asia, Europe and southern parts of the USA. The rat flea spreads the infection. Spotted fever group Rocky Mountain spotted fever (R. rickettsii) occurs most often in the hills and mountains of the eastern seaboard and southern states of the USA. South American countries are also affected. African tick typhus affects the countries of North Africa, and eastern, central and southern Africa. The incidence is unknown. African tick typhus, caused by either R. conori (Mediterranean spotted fever) or R. africae, is the commonest imported rickettsial infection in the UK. Rickettsial pox (R. akari) infections occur in Asia, Asian regions of the CIS (former USSR) and Korea. With increased interest in rickettsiae, pathogens such as R. helvetica, first described from Switzerland, with a widespread distribution through Europe, R. sibirica in Siberia and China, and R. slovaca from the Balkan region, have been recognized. Transmission and epidemiology Typhus group Louse-borne typhus is transmitted by Pediculus humanus, the body louse (Fig. 9.14). The head louse does not transmit this infection. After taking a blood meal the louse defecates, and R. prowazekii in the faeces of an infected louse is scratched into the bite site or abrasions in the skin. 4 Humans are the reservoir for R. prowazekii, and infection
305
Reservoir Humans
Reservoir Small mammals
Reservoir Larval mites
Reservoir Ticks
Body louse
Fleas
Larval mite
Tick
Louse-bome typhus
Murine typhus
Scrub typhus
Tick typhus
FIG. 9.14 Transmission of rickettsial infections
passes from one person to another as the lice pass between people. The louse dies by 14 days after infection. Epidemic disease occurs when infection is introduced into a large group of people not previously exposed. Refugee camps present an ideal situation for such epidemics. Spotted fever group This is transmitted by the bite of infected ticks, which are also the reservoir of infection. Occupational and leisure activities, such as walking, camping, farming, lumber work and hunting, take people into tick-infested areas in North America. Tourism, tending animals and gathering wood take people into similar areas in Africa. Pathology and pathogenesis These organisms replicate within vascular endothelial cells of small vessels in many tissues, and vasculitic responses and blood vessel damage underlie the pathogenesis. R. rickettsii infection is more invasive than other organisms, and causes more severe illness owing to full-thickness vessel wall damage. The effect of blood vessel damage is a rash that may become purpuric and haemorrhagic, even ecchymotic in louse-borne typhus and R. rickettsii infection. Gangrene with loss of fingers and toes can occur in Rocky Mountain spotted fever. Leakage of protein-rich fluid from the vascular compartment into the interstitium causes hypovolaemia, hypotension and reduced tissue perfusion. Thrombotic lesions occur in a variety of organs, including the brain. Renal and liver damage from vasculitis occurs in severe cases. Clinical features Typhus group The incubation period is usually about 12 days, with a range of 10-14 days. Headache and mild fever are the usual initial symptoms, followed after 48 hours by a sharp rise in temperature to 40°C, which is sustained. Conjunctival suf-
1
306
Fig. 9.12
2
Case 9.3
3
Fig. 9.13
fusion is seen. Meningism and photophobia also occur. The rash occurs on about the 6th day and begins as red macular lesions on the axillary folds and trunk, spreading on to the limbs, with the palms, soles and face affected in the most severe cases. The rash may evolve through purpuric stages to form ecchymoses. Initial bradycardia progresses to tachycardia in hypotensive patients. Haemorrhagic manifestations and hypotension lead to renal involvement, with rising blood urea and falling urine output. Mild cases get better in the second week of the disease, but untreated severe cases may go into the third week before recovery begins. Death from shock, cerebral involvement or renal failure occurs in the second or third week. Mortality rates of 10-40% without treatment are recorded, and increasing age is associated with higher fatality rates. Brill-Zinsser disease is a mild form of louse-borne typhus caused by the recrudescence of latent infection, and in this condition recovery is the rule. Spotted fever group The incubation period is about 7 days for Rocky Mountain spotted fever (RMSF) and African tick typhus, and rather longer (around 13 days) in rickettsial pox. Fever and headache with generalized limb pains are usual early in the course. The clinical features are similar to those of typhus. There is early deterioration in those with severe RMSF. Death may occur between 3 and 6 days of onset, occurring in up to 25% of patients not receiving specific treatment in RMSF. African tick typhus is generally mild and selflimiting. Fever, systemic upset and headache are the usual presenting features. Rash may occur, causing macular lesions which have a widespread distribution on the trunk and limbs. The palms and soles may be affected. A black ulcerated eschar is usually found marking the site of the tick bite. Diagnosis The clinical features usually lead to suspicion of a rickettsial infection. This can be confirmed by serological tests using group-specific rickettsial antigens. The main differential diagnosis in RMSF is meningococcal septicaemia, which also requires urgent treatment. Laboratory features Severely affected patients with all forms of rickettsial disease will show generalized derangement of coagulation and evidence of liver and renal dysfunction. Platelet counts are low, in association with prolongation of the prothrombin time, reduced fibrmogen levels and elevated levels of fibrin degradation products. Anaemia is usual. Plasma albumin levels fall. Declining urine output indicates renal failure. Management Doxycycline (100 mg 12-hourly orally or i.v. for 7 days, or for 2 days after defervescence) is effective against all forms of rickettsial infection. Doxycycline 200 mg as a single dose is effective in epidemic typhus. Pregnant women and children under 8 years should receive chloramphenicol
(50mg/kg/day in divided doses for 7 days or for 2 days after defervescence; 25mg/kg/day in divided doses for infants under 1 month). Supportive measures Prompt administration of antibiotics is essential in RMSF and louse-borne-typhus. Additional management is essentially supportive, depending on the facilities available, and comprises restoring blood volume with infusions of plasma and fluids, and restoring coagulation mechanisms by fresh blood transfusions or fresh frozen plasma. Prevention and control Delousing is the main way to control louse-borne typhus. Thorough and regular washing of clothes in hot water with detergent kills lice and their eggs. DDT 10% or malathion 1% can be applied to clothed people with good effect. Appropriate clothing should be worn to prevent ticks reaching the skin. In tick-infested areas the skin should be carefully inspected at the end of the day. Any ticks that are found should be removed by gentle pulling to keep them intact. The duration of tick attachment, which can last 5 days, is important in relation to development of disease and strength of attachment, with 20 hours being the length of time needed to give a greater chance of infection.
Scrub typhus Scrub typhus (Orientalis tsutsugamushi) occurs throughout Asia and is probably one of the commonest causes of fever there. Studies in Malaysia showed that it accounted for 23% of patients with febrile illnesses presenting at rural hospitals. In most cases it is a self-limiting infection, with resolution in up to 14 days. Mortality has been reported in up to 60% of severe cases. It is transmitted by chiggers, the larvae of leptotrombiculid mites. Occupational exposure in rural areas (farming, animal tending, rubber plantation work etc.) and military personnel deployed in rural areas are associated with increased risk of infection. The incubation period is about 10 days (range 6-18). Fever, headache, chills and general body pains are the usual symptoms. Conjunctival suffusion, macular skin rash 1- pneumonitis and hepatosplenomegaly may occur, and cough with pulmonary infiltrate on chest radiographs is seen. An eschar at the site
of biting is often seen, with enlarged, tender regional adenitis. 2 Treatment with doxycycline is effective, with chlo- 9 ramphenicol as an alternative (see above). Resistance to these agents has been documented in northern Thailand. 3
Q fever Q fever is an acute illness caused by Coxiella burnetii; it is transmitted between animals by ticks and to humans from domestic animals by close contact, particularly with aborted placentas or with infected carcases in abattoirs or, more often, by inhalation of the endospores, which are resistant to desiccation and persist in the environment. Q fever has a range of clinical manifestations: atypical pneumonia, prolonged fever of undetermined cause, granulomatous hepatitis and culture-negative endocarditis. The main clinical features of acute infection are high fever with severe headache and myalgia, after an incubation period of about 20 days. Hepatosplenomegaly is common, with biochemical evidence of hepatitis and histologically granulomatous liver disease with very well denned granulomas that can suggest the diagnosis. Pneumonia is less common but may be severe and bilateral. Q fever may present as PUO (p. 274) with a prolonged course. Epididymo-orchitis can occur and so must be differentiated from brucellosis, which also produces prolonged fever. The natural history of the disease is to resolve spontaneously within 2 weeks in most patients, but a slower recovery with progression to chronic disease may occur. The main feature of chronic Q fever is endocarditis, which is usually fatal if left untreated (p. 574). Diagnosis Diagnosis is usually made by serology with positive responses to the phase II antigen in acute disease, IgM and IgG, and positive serology to the phase I antigen in chronic disease, with raised IgA litres suggestive of endocarditis. Laboratory handling of the organisms is dangerous. Treatment Doxycycline 100 mg twice daily for 14 days is the treatment of choice, but it is not known whether it prevents progression. Endocarditis is very difficult to eradicate by antibiotic therapy alone, and surgery is often required.
BACTERIAL INFECTIONS Despite the proliferation of antibiotics since the discovery of penicillin in 1941, bacterial infections remain a challenging problem. The continuing emergence of resistance to antibiotics, particularly but not exclusively in the hospital environment, is one aspect of the problem which is discussed earlier in this chapter (p. 264). Another is the rapid development of serious illness leading to multiorgan failure when antibiotics administered too late are relatively
ineffective. Gram-negative septicaemia is a classic example of this, and much research has been focused on the pathogenetic mechanisms involved, with recent advances defining the influence of cytokine release and highlighting the central role of nitric oxide in the vascular microenvironment. The disastrous consequences of failure to treat very early draw attention to the value of prophylactic measures, which are widely used in the form of antibiotics for surgery.
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TABLE 9.24 Classification of bacteria
TABLE 9.25 Streptococci
Gram-positive cocci Streptococci Strep, pneumoniae Strep, pyogenes Strep, viridans group Anaerobic Staphylococci Staph. aureus Staph. epidermidis
Gram-positive bacilli Bacilli B. anthracis B. cereus Corynebacterium diphtheriae Listeria monocytogenes Clostridia (anaerobic) Cl. tetani Cl. botulinum Cl. perfringens Cl. difficile Cl. septicum
Gram-negative cocci Neisseria N. meningitidis (meningococcus) N. gonorrhoeae (gonococcus)
Gram-negative bacilli Enterobacteria Escherichia coli Klebsiella Proteus Salmonella Shigella Parvobacteria Haemophilus Bordetella Brucella Yersinia Pseudomonas P. aeruginosa Burkholderi pseudomallei Francisella tularensis Bartonella bacilliformis Cat-scratch bacillus Vibrios V. cholerae Campylobacter jejuni Anaerobic bacteria Bacteroides Fusobacteria
Mycobacteria Spirochaetes Treponema T. pallidum T. pertenue T. carateum Borrelia Leptospira icterohaemorrhagiae
Vaccines have been developed against some bacteria and this will be an area of rapid development during the lifetime of this edition of the textbook. A classification of bacteria is given in Table 9.24.
GRAM-POSITIVE COCCI
STREPTOCOCCI
308
B-Haemolytic streptococci are classified by the Lancefield grouping system, which detects polysaccharide antigens on their surface by a panel of antisera. Table 9.25 shows these
Group and name Group A S. pyogenes
Group B S. agalactiae Group D Enterococci, e.g. S. faecalis S. pneumoniae (pneumococcus) S. viridans group, e.g. S. milleri, mitior, mutans, salivarius, sanguis
Characteristics
Disease/syndromes
p-haemolytic Secrete enzymes, e.g. hyaluronidase, and toxins e.g. erythrogenic
Pharyngitis Scarlet fever Otitis media Sinusitis Erysipelas/impetigo Lymphangitis Puerperal sepsis
p-haemolytic Common vaginal commensal
Neonatal infection (puerperal sepsis)
B- or non-haemolytic Anaerobic Normal bowel flora Antibiotic resistance oc-haemolytic Common throat commensal More than 80 serotypes a- or non-haemolytic Dental commensals
Urinary tract infection Septicaemia Endocarditis Pneumonia Acute meningitis Otitis media/mastoiditis Endocarditis Cerebral abscess and empyema (S. milleri)
and other streptococci which are a-haemolytic or nonhaemolytic. Not all group D streptococci are P-haemolytic. Cutaneous streptococcal infections are described in Chapter 10.
Scarlet fever Scarlet fever is a febrile illness with a characteristic rash caused by infection with an erythrogenic toxin-producing strain of Strep, pyogenes. Infection is usually in the throat, but the skin or genital tract may be the primary site. It is now a much milder disease than it was 50 years ago. Its severity is probably determined by variations in the microorganism, but host factors also play a part. The same bacterium may be a harmless passenger in one subject, or produce a sore throat or scarlet fever in another. Host antibodies are largely responsible for these differences. Antibodies to the erythrogenic toxin prevent the rash of scarlet fever but not tonsillitis. Clinical features Infection is spread by droplets. After an incubation period of 2-4 days there is an abrupt onset of sore throat, pain on swallowing and fever. There is tender cervical lymphadenopathy. The tonsils are enlarged, congested, and often covered with exudate. The tongue is coated and initially red papillae are visible, but later the fur is lost, leaving the classic 'strawberry tongue' appearance. The rash (Fig. 9.15) appears on the face within 2 days. It is a diffuse erythema, often with perioral pallor (not specific for this con-
TABLE 9.26 Invasive disease due to Staph. aureus Site of infection
Disease
Skin
Impetigo Boils and carbuncles Surgical wound infections Septicaemia Pneumonia with abscesses Abscess Acute endocarditis
Blood Lungs Liver, bone and other Heart
9
Diagnosis and management Strep, pyogenes can readily be cultured from a throat swab, and the presence of neutrophilia helps to distinguish the condition from infectious mononucleosis, which can cause an identical appearance. Retrospective diagnosis can be made by measuring antistreptolysin O antibodies. Treatment with oral penicillin is commonly used, but may not eliminate streptococci unless given in high dose for 10 days. Eradicating the organism is less important since complications have become so uncommon. Erythromycin is an alternative agent for penicillin-allergic patients. FIG. 9.15 Scarlet fever rash
dition). On the trunk it is a punctate erythema which is less brightly coloured. Superficial peeling of the skin starts on about the 4th day. The illness resolves within a week, although the patient may continue to feel unwell for several more days. Complications Complications are uncommon in the temperate world, perhaps because of prompt treatment with antibiotics, but post-streptococcal glomerulonephritis is well recognized in the tropics and sub-tropics where infected insect bites, infected scabies etc. are common. Soft tissue infection due to this organism can be serious and life-threatening in the context of necrotizing fasciitis. This may occur without any obvious site of entry for the organism, but the process begins with localized pain in the muscle of the affected area. There is spreading cellulitis accompanied by severe haemodynamic disturbance with shock. Nausea, vomiting and diarrhoea may be present early in the course. Progressive increase in the severity of pain is a clinical indicator of this condition. Bullae can develop over affected skin. Outcomes differ but include tissue destruction, severe systemic illness, loss of the affected limb as a result of gangrene, and sometimes death. Prompt treatment with intravenous antibiotics should include clindamycin. Septic complications include otitis media. Late complications are rheumatic fever (p. 1069) or acute glomerulonephritis, which may develop 2-3 weeks after the infection.
STAPHYLOCOCCI
Staph. aureus and Staph. epidermidis are the clinically important staphylococci. Both are common skin commensals, but Staph. aureus is more virulent and is commonly associated with disease.
Staphylococcus aureus infection In most conditions where host susceptibility to infection is increased, Staph. aureus is an important pathogen. This applies particularly to the skin after surgical or accidental trauma and burns, and after skin infection such as chickenpox. More general predisposition is seen in diabetes mellitus, uraemia, alcohol excess, malnutrition and malignancy. When a surgical foreign body is present, for example an intravenous catheter, a heart valve or a prosthetic joint, both Staph. aureus and epidermidis can take root, with potentially disastrous consequences. There are two distinct mechanisms by which Staph. aureus can cause disease. Most often it is by direct invasion of tissues (Table 9.26), when some of the enzymes produced by Staph. aureus may be important in pathogenesis, e.g. catalase,coagulase,hyaluronidase. Less often, the major disease manifestations are the result of toxin secretion (Table 9.27). Management of deep Staph. aureus infections When Staph. aureus localizes in deep tissues it quickly causes acute inflammation and necrosis, leading to abscess formation. If an abscess can be seen on scanning (e.g. ultrasound, isotope or CT) it may be possible to aspirate pus as
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TABLE 9.27 Staph. aureus toxin-mediated diseases Disease
Manifestations
Organism
Pathological effect
Site of infection
Staphylococcal scalded skin syndrome
Skin erythema; may progress to bullae, exudate, crusting, positive Nikolsky sign
S. aureus phage group II, often phage type 71 (produce epidermolytic exotoxins)
Split skin at stratum granulosum
Skin
Toxic shock syndrome
Diarrhoea and vomiting Hypovolaemia Erythema of mucosae and skin leading to peripheral desquamation Fever and myalgia
5. aureus phage group I, often phage types 29 and 52 (produce enterotoxin F, identical to exotoxin C)
Uncertain
Vagina, skin or other (occurs mainly in young women using tampons)
Food poisoning
Vomiting and diarrhoea
S. aureus phage group III (produce enteroxins A, B, C, D, E)
Uncertain
Food (toxin ingested)
both a diagnostic and a therapeutic measure. Antibiotic treatment is more likely to be successful if this can be achieved, and it may substitute for open surgery. In some sites, such as a heart valve, early surgery is essential because the valve is destroyed and a new one cannot be inserted if the surrounding valve root tissue has been destroyed. The decision whether to operate or aspirate and give antibiotics, or to give antibiotics alone, for a deep Staphylococcal infection is determined by the amount of pus formation, the accessibility of the site and the delicacy of adjacent tissue. For example, drainage of some CNS abscesses may lead to unacceptable damage, in which case the neurosurgeon would opt to try to sterilize the lesion with antibiotics in the first instance. Staph. aureus often produces pMactamase, particularly in hospital-acquired infections, and so treatment is usually started with a B-lactamase-resistant antibiotic such as flucloxacillin. Methicillin-resistant Staph. aureus (MRSA) is less pathogenic but it can cause deep-seated infection in vulnerable patients. The cutaneous syndromes of Staphylococcal infections are described on page 384. The management of septicaemia is discussed on page 274. Lung abscess is described on page 647.
Staphylococcus epidermidis infection Staph. epidermidis is a skin commensal. It is now clear that it causes serious infections in patients who are immunocompromised and in patients with intravenous cannulae, prosthetic heart valves, pacemaker wires, CSF shunts and other foreign materials in place for long periods. Staph. epidermidis produces B-lactamase and is usually resistant to a wide range of antibiotics, including methicillin. Resistance to methicillin is mediated by alteration to penicillin-binding proteins. The mainstay of treatment is vancomycin.
1
310
Fig. 9.14
2
MCQ 9.16
FIG. 9.16 Necrotic haemorrhagic lesions in meningococcal septicaemia, also showing the unusual features of gangrenous terminal phalanges
GRAM-NEGATIVE COCCI NEISSERIA Neisseria gonorrhoeae (gonococcus) infection is described in Chapter 11 (p. 458).
Neisseria meningitidis (meningococcus) infection There are three types of meningococcus - groups A, B and C - which are the most common cause of acute bacterial meningitis (p. 1413). They also cause septicaemia with or without meningitis (Fig. 9.16). Disease occurs sporadically or in epidemics, and the epidemiology is poorly understood.
FIG. 9.17 Incidence of meningococcal disease, England and Wales, 1989-2001 (source PHLS Meningococcal Reference Unit)
Meningococcal disease affects predominantly young children, although it can occur at any age. Its epidemiology varies between different countries, and particularly between Africa and European countries or the USA. In the meningitis belt of Africa it is a disease of young schoolaged children caused by serogroup A, which occurs in major epidemics at intervals of 8-10 years during the dry season, affecting 500/100000 people. In the UK, disease caused by serogroups B and, increasingly, C is endemic (Fig. 9.17), affecting 1-3/100000, with sporadic increases in incidence (hyperendemicity) in small areas from time to time, mainly during the winter months. About 50% of cases are in the under-5 age group. Clinical features Meningitis, which is the most common form of disease, is described on page 1415. It can occur with or without meningococcal bacteraemia, but it is important to recognize that meningococcaemia also occurs without meningitis in nearly 10% of cases. This can cause a range of illness, from almost asymptomatic bacteraemia to fulminant septicaemia with disseminated intravascular coagulation. The central feature is rash on any part of the body or mucous membranes which varies from maculopapular to petechial to ecchymotic. 1 In chronic meningococcal septicaemia there is persistent bacteraemia, together with rash, arthritis and low-grade fever. This may last for some weeks before progressing to more severe disease. Other syndromes rarely associated with meningococcal infection are pneumonia, pharyngitis, pericarditis, osteomyelitis and endophthalmitis. Diagnosis is made by blood cultures or Gram stain and culture of aspirates from skin lesions. Cultures from other sites may be indicated in particular situations, e.g. joint aspirate in arthritis.
Management and prevention Benzyl penicillin is highly bactericidal for meningococci and it should be the first choice of antibiotic. It is given intravenously at a dose of 2.4g 4-hourly initially in very sick patients, reducing to 1.2g after about 24 hours and then to 6-hourly (adults). If there is good evidence that the patient has penicillin sensitivity, cefotaxime or ceftriaxone can be used. Treatment is continued for 5-7 days. Nasopharyngeal carriage is not terminated by penicillin treatment, which should therefore be followed by rifampicin 600 mg b.d. for 2 days. This may need to change as resistance to rifampicin emerges, and an alternative would be a single dose of ciprofloxacin 500 mg. Polysaccharide vaccines are available against serogroups A and C meningococci but not against group B and there is a conjungate vaccine against serogroup C. The polysaccharide vaccines provide only short-lived protection but they are useful in curtailing the kind of limited outbreaks seen in European countries and the USA. Mass vaccination of villagers in Africa ahead of the spread of epidemics has been attempted, but it is more difficult to achieve success. 0
9
GRAM-POSITIVE BACILLI
BACILLI
Bacillus anthracis: anthrax Few cases of anthrax are seen in western countries but about 100000 cases occur in the world each year. The Grampositive rods of B. anthracis give rise to endospores in conditions unfavourable for replication, and these can survive for many years in the soil. Making use of this property they have been used in warfare in both world wars during the 20th century, and as a terrorist weapon on other occasions. The spores can contaminate the hides, hooves and bones of herded animals, and contact with these can cause cutaneous anthrax both in the endemic areas and in industrialized countries to which these animal materials are taken for processing. Bacilli are found in the tissues of animals dying of systemic infections. Transmission to humans is by skin contact with infected material such as hides or meat, by inhalation of spores or by ingestion of infected meat, causing skin, respiratory and gastrointestinal disease, respectively. Disease onset is within 5 days in all forms, and is usually about 2 days. Pathogenesis depends on the expression of virulence factors coded by two plasmids. Oedema toxin, lethal factor and protective antigen are the products of these plasmids. Endospores ingested by macrophages become vegetative and rupture macrophages, releasing organisms that replicate further in lymphatics and in the bloodstream, producing massive septicaemia, up to 108/mL. Expression of virulence factors is increased by elevated host temperature.
311
Cutaneous anthrax Cutaneous anthrax is the most common form of the disease and the most benign. A red macule or papule develops at the contact site, e.g. the neck of a meat carrier in a slaughterhouse. A pruritic vesicle develops, satellite lesions appear, and the whole evolves into an ulcer, then a black eschar. There is usually some surrounding oedema, but occasionally there is a severe local reaction with gross oedema, and general toxaemia ensures. Despite the size and appearances of the lesion it is painless unless secondarily infected. Inhalation anthrax At first there are mild general symptoms and a nonproductive cough. Improvement over a few days is followed by abrupt decline. The patient rapidly becomes very ill, with cough, fever, tachypnoea, cyanosis, tachycardia, vomiting and chills. Diffuse crackles are heard over the affected lung fields. The spleen may enlarge. There is massive enlargement and oedema of the neck and chest wall. Untreated, the patient often dies within 24 hours. There is an 80% mortality in this form. Gastrointestinal anthrax This may occur in clusters if a family or tribal group eat contaminated meat. Following ingestion, lesions can occur anywhere in the gastrointestinal tract, including the throat. There is diffuse abdominal pain, with rebound tenderness. Ascites can develop, and with this the abdominal pain declines. There are varying degrees of gastroenteritis with haemorrhage, and mortality is high. Symptoms resolve after about 14 days in those surviving. Haematogenous dissemination of organisms can sometimes cause meningitis with bloody CSF. Diagnosis Many cases probably go undiagnosed in the tropics and subtropics. The cutaneous form is probably most often diagnosed on the clinical appearances. Occupational exposure may be suspected from the nature of the patient's job. The severity of a pneumonic illness may prompt consideration of pulmonary anthrax. The organisms are readily found in Gram-stained smears from skin lesions and grow well in blood culture samples.
312
Management The cutaneous form may resolve without treatment. Penicillin V, 2 g/day in divided doses, is very effective. For more severe infections benzyl penicillin, 4.8-7.2 g in divided doses intravenously, is used. When the patient is allergic to penicillin, ciprofloxacin 400 mg twice daily intravenously or 500 mg twice daily by mouth, tetracycline 2 g/day or chloramphenicol lOOmg/kg/day in divided doses orally or intravenously can be used. The latter is given to children and pregnant women. Pulmonary or intestinal cases will require supportive care, with maintenance of oxygenation, giving normal saline, plasma or blood transfusions as necessary to maintain blood volume and hydration. Prevention is by elimination of the infection from
animals. Immunization is available when there is danger of occupational exposure. Vaccines are available for those who may be exposed to anthrax.
Bacillus cereus infection B. cereus is one of the causes of food poisoning (see Gastroenteritis, p. 278). Two illnesses are associated with different incubation periods. A short incubation period (1-6 hours), vomiting and abdominal pain caused by heatstable enterotoxin are often related to the ingestion of reheated rice. Longer incubation (8-16 hours), diarrhoea and abdominal pain are caused by a heat-stable toxin formed in the infected intestine. The treatment is directed at maintaining the patient's hydration. There is no specific therapy.
CORYNEBACTERIUM DIPHTHERIAE INFECTION
Corynebacterium diphtheriae is the cause of diphtheria, a toxin-mediated disease which is rare in countries with an effective immunization programme. Transmission is mainly person to person by nasopharyngeal droplets, but skin infection is also important in tropical countries. Pathogenesis C. diphtheriae (korynee - club, refers to the shape of the bacteria; diphtheria = leather, refers to the pharyngeal membrane) infects the nose, throat, larynx and trachea or the skin. It causes local inflammation, but its major effects result from the production of a protein toxin of MW 62000 which inhibits ribosomal polypeptide chain production by inhibiting elongation factor 2. The toxin is elaborated only by C. diphtheriae strains infected by a bacteriophage carrying the toxin production gene. Its main effects are on the myocardium and nervous tissue. Clinical features After an incubation period of 2-6 days there is a slow onset of malaise and fever, sometimes with mild sore throat. Immunized subjects develop disease at the site of infection but no toxin-mediated effects. In the unimmunized, at an early stage the predominant findings are profound weakness, restlessness and irritability, with fever, pallor and a rapid thready pulse. The pharynx shows the characteristic membrane which is adherent; attempts to scrape it off result in bleeding. In laryngeal diphtheria the membrane involves the larynx and trachea, causing respiratory obstruction which may require tracheostomy. The primary infection may also involve the nose, larynx or bronchi. ECG abnormalities suggesting myocarditis (flattening or inversion of T waves) or first-degree heart block appear after the first week and can progress to major dysrhythmias and circulatory collapse. Neurological complications start later, with paralysis of the palate, followed by the ocular muscles, then the pharynx, larynx and respiratory muscles, and lastly the limbs.
Diagnosis C. diphtheriae can be isolated from sites of infection but demonstration of toxin production takes several more days - too long to delay management decisions. Polymerase chain reaction for the tox+ gene has revolutionized management, as it can demonstrate the presence of the bacteriophage on the same day that a positive culture is obtained. Management and outcome Diphtheria antitoxin is administered without waiting for bacteriological confirmation in suspected cases, but it is no longer used for prophylaxis because of the danger of hypersensitivity reactions. The treatment dose is 1000030000 units i.m. for mild disease, increasing to as much as 100000 units for severe cases of more than 3 days' duration. For doses greater than 30000 units the remainder is given intravenously after an interval of 0.5-2 hours. Penicillin or erythromycin will eradicate the organism from the primary infection site but the patient must be isolated until the risk of cross-infection has been removed. Intensive nursing is required to protect the airway, and tracheostomy may be needed. ECG monitoring is used to detect dysrhythmias, and physiotherapy to preserve the range of movement in paralysed limbs. Contacts must be traced, treated if infected, and immunized. If the patient survives the acute illness, recovery from complications such as paralysis is complete. LISTERIA MONOCYTOGENES INFECTION
Listeria monocytogenes is a Gram-positive bacillus which is commonly dismissed as a diphtheroid contaminant on examination of CSF specimens. Microbiologists are now aware of its significance as a cause of serious disease, particularly in immunocompromised patients, pregnant women and neonates. The bacillus is a common contaminant of soft cheeses, especially if these are unpasteurized. It causes septicaemia, often associated with meningoencephalitis. Ampicillin or penicillin is the drug of first choice, with erythromycin in reserve for penicillin-allergic patients.
Epidemiology and pathogenesis Cl. tetani is found in human and animal faeces and its spores abound in soil. It is anaerobic and proliferates in ischaemic or necrotic tissue, usually in a poorly tended wound. In rural areas farm workers or gardeners are infected, but in cities the disease has been observed in drug addicts. Because immunization against tetanus toxin is standard in western countries, tetanus is rare. In poorer countries immunization is variable. Tetanospasmin is a neurotoxin which acts in several different ways. It inhibits the release of acetylcholine from nerve endings in muscle, but more importantly it interferes with synaptic reflexes in the spinal cord, causing disinhibition which results in muscle spasms. Clinical features The incubation period can be up to 3 weeks, depending on inoculation dose and site. Disease is most severe in the completely non-immune, in drug addicts and at extremes of age. The outcome is worst when the incubation period is short and there is rapid onset of the first spasm. The first (and sometimes the sole) sign of tetanus is often muscle spasm local to the wound; in most the CNS is involved, and trismus (lockjaw) heralds the onset of generalized tetanus. The patient notices difficulty in opening the mouth and swallowing, followed by stiffness in the neck, and back. Examination reveals the initial site of infection and 'risus sardonicus', the facial expression caused by trismus and contraction of facial muscles. The muscles of the back and abdomen become stiff, and painful spasms, provoked by sudden movement or noise, occur in the back muscles, causing opisthotonos. Autonomic involvement causes sweating and cardiovascular instability. Death is from exhaustion, aspiration or secondary infection.
Tetanus
Management Further toxin production is prevented by local debridement of wounds and treatment with metronidazole 500 mg intravenously 6-hourly. Human immunoglobulin containing antibodies to tetanus toxin in high titre is given to neutralize free toxin; 500 units are administered i.m. If surgery is indicated, it should be delayed for an hour after the administration of antibody. The patient is nursed in a quiet room to avoid stimuli likely to provoke spasms. Benzodiazepines such as diazepam are used to control spasms, as well as for their anxiolytic and amnesic effects. Neuromuscular block may be required, and then the patient is ventilated (see p. 737). Because prolonged ventilation is usual, tracheostomy is performed early. Nutrition is maintained enterally or parenterally. An attack of tetanus does not render the patient immune and a full course of immunization should be given after recovery.
Tetanus is a potentially fatal disease dominated by muscle spasm caused by an exotoxin, tetanospasmin, produced by Clostridium tetani.
Prevention Immunization with tetanus toxoid is the only way to
CLOSTRIDIA Clostridia are a group of obligate anaerobic bacteria that cause illness largely through toxins which act locally or enter the circulation. Clostridia are frequent wound contaminants without necessarily causing disease; when disease occurs, however, it is severe.
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prevent the disease altogether. A full course of toxoid confers immunity for at least 5 years. Neonatal tetanus can be prevented by immunizing the mother during pregnancy. Patients with wounds at risk from Cl. tetani infection are managed according to their state of immunity. All patients require local wound toilet. Fully immunized patients receive a booster dose of toxoid. Unimmunized patients with a wound considered susceptible to Cl. tetani receive human tetanus immunoglobulin, and active immunization with adsorbed tetanus toxoid is started simultaneously. Injection of long-acting penicillin, followed by a course of oral penicillin, is also indicated in these cases.
Botulism Botulism is a virulent form of food poisoning caused by heat-labile neurotoxins of Cl. botulinum. Disease follows ingestion of food containing toxin (usually tins of meat), ingestion of bacterial spores which germinate and produce toxin in the intestine, or contamination of a wound by spores which germinate there. The highly potent toxins interrupt cholinergic neurotransmission. There are seven antigenic types, A-G, but only A, B, E and F cause human disease. They consist of two polypeptide chains linked by a disulphide bond; the heavy chain binds to presynaptic receptors and the toxin is endocytosed. It inhibits acetylcholine release and the cell cannot release transmitters, so that there is motor paralysis and autonomic dysfunction. Damage to the synapse is permanent and repair requires the formation of a new synapse. These long-term effects of botulinum toxin are being used in the treatment of conditions in which there is sustained, inappropriate muscle contraction, such as torticollis. In the case of food-borne botulism the initial illness is an afebrile gastroenteritis that develops within 12-36 hours of ingestion in one-third of patients, but the remainder have only malaise and dizziness (with postural hypotension), progressing to extreme dryness caused by autonomic paralysis. Other neurological symptoms appear during the next 3 days: • Diplopia followed by bulbar signs • Symmetrical weakness of the limbs • Bulbar and respiratory muscle weakness may lead to inhalation pneumonia. Treatment is essentially supportive, with maintenance of the airway, including incubation or tracheostomy as required. Autonomic dysfunction does not usually cause severe problems (cf. tetanus). Antitoxin therapy is normally given although its value has not been established in controlled trials. Hypersensitivity reactions are common,
1 314
MCQ 9.17
particularly in those with a history of atopy, and skin testing is recommended. Trivalent horse antitoxin active against types A, B and E is given intravenously, 20 mL by slow infusion, followed by lOmL 2-4 hours later and further doses at 12-24-hour intervals if necessary. Infants who have ingested spores do not have circulating toxin, and antitoxin is of no benefit. Antibiotic therapy with penicillin or metronidazole is also of uncertain value, but wound debridement should be carried out in wound botulism. Recovery of muscle strength is extremely slow, occurring mainly in the first 3 months but continuing sometimes for up to a year. Prophylaxis with antitoxin may be needed in subjects thought to have ingested toxin. 1
Other clostridial syndromes Gas gangrene Cl. perfringens (welchii) is one of a number of gasproducing clostridia that contaminate wounds containing necrotic, anoxic material. Cl. perfringens produces 12 toxins, alphatoxin being the one associated with gas gangrene. It proliferates rapidly, producing myonecrosis. Gas infiltrates neighbouring tissues, causing crepitus. Toxins entering the circulation cause profound toxaemia, with a high mortality. Skin and soft tissue infections Local infections, often involving muscle, occur in amputated stumps, diabetic ulcers of the foot, decubitus ulcers, perirectal abscesses and abscesses at injection sites in drug addicts. Such infections frequently contain multiple organisms, including clostridia. Gut infections Pseudomembranous colitis is a diarrhoeal disease caused by toxins from strains of Cl. difficile which colonize the large intestine after antibiotic therapy. Cl. difficile produces two toxins, an enterotoxin (A) and a cytotoxin (B), both of which probably contribute to the pathogenesis of disease. Although the association with clindamycin therapy is well recognized, most antibiotics have caused this disease. It is particularly likely to occur in debilitated and elderly patients, but can affect any age group. It can be transmitted nosocomially, so patients should be isolated. The onset of watery diarrhoea (without blood), abdominal pain and fever is usually within a few days of exposure to an antibiotic, although it is delayed by 4-6 weeks in some cases. There may be severe systemic toxicity. In the majority of cases sigmoidoscopy reveals an inflamed mucosa covered by a white membrane, but this is absent in the 20% where only the ascending colon is involved. The diagnosis is confirmed by culture of the organism and identification of toxin in stool specimens, but as about 5% of healthy people carry the organism some laboratories just look for toxin. If symptoms continue after the offending antibiotic has been stopped, treatment is with oral metronidazole 400 mg
9
TABLE 9.28 Syndromes of enteric infection Organism
Toxins
Mechanism of action
Syndromes
ETEC
Heat labile Heat stable
Cholera-like; cyclic-AMP mediated Activates guanylate cyclase; cyclic GMP increases
EHEC (0157:H)
Shigella-like
?; toxic for Vero cells
Cholera-like Travellers' diarrhoea Infant gastroenteritis Haemorrhagic colitis Haemolytic-uraemic
t.d.s. for 7 days. Oral vancomycin has a slightly higher cure rate but is much more expensive than metronidazole. For severely ill patients who cannot take oral antibiotics, intravenous metronidazole 500 mg is given every 8 hours initially. Suppurative intra-abdominal infection caused by clostridia is particularly associated with carcinoma of the colon or pancreas. Neutropenic patients may develop severe enterocolitis caused by Cl. septicum.
GRAM-NEGATIVE BACILLI ENTEROBACTERIA The enterobacteria group comprises Escherichia coli (E. coli), Klebsiella, Proteus, Salmonella and Shigella. E. coli causes a wide variety of diseases, usually as a result of autoinfection. Urinary tract infection is the most common, but systemic infection is a major problem in hospitals. Septicaemia arises from the bowel when there is a bowel disease or when surgery has been carried out, or from the urinary tract as a complication of infection or surgery there. In neonates, E. coli is a common cause of septicaemia and meningitis. Several strains of E. coli cause gastroenteritis by a number of mechanisms; they are referred to as enteropathogenic (EPEC) (or alternatively enteroadherent - EAEC), enteroinvasive (EIEC), enterohaemorrhagic (EHEC) and enterotoxigenic (ETEC). EHEC and ETEC produce toxins (see Table 9.28). Klebsiella causes urinary tract infection, septicaemia and pneumonia. Kl. pneumoniae causes an acute severe cavitating pneumonia, most frequently seen in alcoholics (p. 638). Proteus is mainly associated with urinary tract infection. Salmonella is found in several hundred strains. Salmonellae other than S. typhi and S. paratyphi are amongst the most common causes of gastroenteritis related to food poisoning (see Gastroenteritis, p. 278). They cause disease by direct invasion of the intestinal mucosa, and some strains, e.g. S. typhimurium, cause septicaemia, but usually disease remains localized. Typhoid (enteric fever) is caused by S. typhi, and is described below. Four strains of Shigella are the cause of bacillary dysen-
tery, a form of acute diarrhoeal disease characterized by severe, bloody, purulent diarrhoea and abdominal pain.
Shigella dysentery Shigella sonnei and S. flexneri are the common organisms in the UK, the incidence of S. flexneri infection having increased in recent years; the other species are S. dysenteriae and S. boydii. Shigella infections occur worldwide, and epidemics are common where conditions are crowded and hygiene poor. Faecal-oral transmission results from lack of handwashing and the organism is highly infectious, ingestion of fewer than 200 organisms causing disease in healthy adults. The infection localizes in the colon, where the epithelium is invaded and becomes inflamed. There is an acute inflammatory exudate which produces diarrhoea containing large numbers of leukocytes. Enterotoxin production contributes to the intestinal damage, and the organisms may also produce a neurotoxin. Clinical features After an incubation period of 2-3 days there is a rapid onset of vomiting, abdominal colic and diarrhoea, which is usually bloody and purulent. Severity ranges from mild to fulminant. The most severe illness is caused by S. dysenteriae. Although the main illness is usually over within 1-2 weeks, diarrhoea and abdominal discomfort may persist for several weeks. Fever is common in the first few days and dehydration can occur rapidly, especially in children. Complications include haemolytic-uraemic syndrome (HUS), seen in children and the elderly, with a leukaemoid reaction in the blood frequently preceding the onset. Post-infective aseptic arthritis and Reiter's syndrome (conjunctivitis, urethritis and arthritis) are complications that vary in frequency in different epidemics but which are more common in HLA-B27 positive individuals. The diagnosis is made when organisms are cultured from faeces. Management Patients are managed as for any severe form of gastroenteritis, rehydration being the key factor (see Gastroenteritis, p. 278). This can usually be achieved using oral fluids, but if the patient is severely ill, and particularly if vomiting cannot be controlled, intravenous rehydration
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may be required. Antibiotics are given as they shorten the duration of and ameliorate symptoms. They also reduce the risk of transmission, making a case for their use in milder disease, but plasmid-mediated resistance is common and transfers rapidly, so it is important to know the local antibiotic sensitivity pattern. Currently the first choice of antibiotic is ciprofloxacin 500 mg b.d. orally for 5 days. Other possibilities are co-trimoxazole, ampicillin or tetracycline. In the acute stage of invasive infection inhibitors of intestinal motility such as codeine phosphate and loperamide may exacerbate symptoms, and even precipitate toxic dilatation of the colon. Pain management can therefore be difficult, but regular paracetamol may help. Codeine is much more effective but it should be used only with great caution.
Typhoid Typhoid (enteric fever) is a serious, prolonged systemic infection with the Gram-negative bacillus S. typhi. Epidemiology Typhoid is endemic in many poor countries, and although uncommon in Britain (about 200 cases reported per year) it is an important cause of fever in returning travellers. Humans are the reservoir of infection and spread of infection is by contamination of water or food by human faeces. Epidemics usually occur when a common water supply is contaminated. Small outbreaks sometimes results when a chronic excreter of the organism works as a food handler. Pathogenesis Ingested organisms invade the small intestinal mucosa. In the absence of specific immunity, organisms phagocytosed by macrophages survive and proliferate. After an incubation period varying from 1 to 3 weeks (usually 10-14 days), determined by the infecting dose, septicaemia develops and foci of infection may be established in any organ. The gallbladder is an important site, as it is the source of chronic excretion when this occurs. Necrotic inflammation of Peyer's patches may be so vigorous as to cause intestinal perforation or haemorrhage. Clinical features In Britain typhoid usually presents as a pyrexia of insidious onset in a patient returning from abroad, often from the Indian subcontinent, although there have been small outbreaks in the United Kingdom related to take-away food outlets with a chronic carrier as the source. The classic stepwise rise in temperature is rarely seen but the untreated illness has a remorseless progression. Headache and dry cough are common in the first week, and
1
316
MCQ 9.18
the patient is often vague and withdrawn. Constipation is usual. In the second week the spleen is often palpable, and the elusive rash consisting of rose spots is seen in less than half of patients. The rash is sparse - fewer than a dozen spots in all - and consists of 1-2 mm pale red macules, which are hard to discern on a pigmented skin. By the third week diarrhoea may develop and the patient, now extremely ill, may lapse into coma. The overall mortality in untreated typhoid is about 10%, but with appropriate antibiotic therapy it is less than 5%. Spontaneous remission is often followed by relapse within 2 weeks. An unusual form of typhoid is encountered in patients infected with schistosomiasis, caused by S. mansoni or haematobium, in which fever is less dramatic but the illness more prolonged. Typhoid in children Typhoid is even more featureless in children than in adults, and presents as an abrupt severe septicaemic illness. The mental state is striking, the child initially being irritable but later frankly delirious. Febrile convulsions may be the presenting feature, and some degree of meningism is not uncommon. Diarrhoea is perhaps more frequent than in adults with typhoid, although intestinal infection with other organisms complicates the issue. Complications The most serious complications in the acute phase are intestinal haemorrhage or perforation. In severe cases there may be myocarditis or bone marrow suppression. Later complications are relapse, even after correct antibiotic treatment, in 15% of cases, and local sepsis in any organ as a result of septicaemia. Osteomyelitis is slow to cause symptoms. Chronic carriage Faecal excretion of S. typhi often continues several weeks after resolution of the illness and, rarely, patients excrete the organism for years. Chronic carriage is defined as excretion of the organism for more than 6 months after an acute episode. The organism is not detected in faeces during antibiotic treatment but reappears after therapy is stopped. The source of organisms in long-term carriers is probably the gallbladder, and gallstones readily become infected. Chronic excretion has obvious epidemiological consequences. Diagnosis The diagnosis is usually made by blood culture. The organism is not present in stools initially but can be isolated in
SUMMARY 10 Complications of typhoid • Relapse • Local sepsis, e.g. lobar pneumonia, meningitis, acute cholecystitis, urinary tract infection, osteomyelitis • Intestinal perforation and haemorrhage (2-3% with antibiotic therapy)
the second to third weeks. Bone marrow culture is particularly useful for identifying S. typhi in patients who have received antibiotics. It may also be cultured from urine in 30% of patients. Serology is rarely helpful in diagnosis. The blood count is helpful as neutropenia is common. Managemenf Patients must be nursed in isolation, preferably in an isolation unit, even though person-to-person transmission is uncommon. Intravenous fluids are given to correct dehydration. Currently ciprofloxacin 500 mg b.d. for 10 days is the drug of first choice. Treatment is started when there is a strong suspicion of the diagnosis and appropriate samples have been taken for culture without waiting for the results. Although duration and severity of symptoms, as well as mortality, are reduced by treatment, the response to treatment is not immediate. Controlled trials have shown the efficacy of dexamethasone 6 mg 6-hourly given to very toxic patients with typhoid. Relapse can be treated with the original antibiotic provided the organism was sensitive. Stools are collected for culture twice weekly after treatment to detect prolonged carriage. This is difficult to treat, but success has been reported with high-dose amoxicillin and ciprofloxacin for 4-6 weeks. Cholecystectomy may be necessary. Three negative stool specimens are considered to indicate that bacteriological clearance has been achieved. Perforation of the intestine is dangerous and carries a high mortality. Good results have been achieved by resuscitation followed by laparotomy, oversewing of single perforations or resection when a length of intestine is involved, and lavage of the peritoneum. When typhoid occurs in a patient with concurrent schistosomiasis the latter must also be treated to allow the antibiotic to be effective. Prevention A monovalent whole-cell heat-killed vaccine gives 75% protection against S. typhi for 1 year but causes local pain, fever and malaise in a high proportion of recipients after both primary vaccination and booster doses. This vaccine is no longer available in the UK. Another parenteral preparation containing Vi polysaccharide antigen is effective for 3 years. A live oral vaccine which uses the mutant strain of S. typhi,Ty 21a, gives similar protection after three doses but may not be as long-lasting. The protection may be overcome if the infecting dose of organisms is high enough, emphasizing the importance of clean water and thorough cooking in prevention.
Haemophilus infection
Haemophilus organisms are normal colonizers of the upper respiratory tract. H. influenzae is a major human pathogen; other Haemophilus species rarely cause disease, although H. parainfluenzae can cause illness similar to H. influenzae. A small proportion of H. influenzae isolated from humans are encapsulated and six antigenic types are recognized. The most important is type b, which can cause septicaemia and several clinical syndromes in children under 5 years old (Table 9.29). Older children acquire immunity to the capsular antigens. Untypable (nonencapsulated) H. influenzae are potential pathogens in the lower respiratory tract. Strains of H. influenzae have become increasingly resistant to antibiotics in recent years: 5-15% of strains are resistant to amoxicillin. This is particularly relevant to children with life-threatening diseases such as acute meningitis, in which a delay in treatment with the right antibiotic could be fatal. Resistance is mediated by pMactamases. Vaccine containing the polysaccharide capsular antigens has now been introduced in the UK for children below the age of 4 years, and this has greatly reduced the incidence of H. influenzae disease. Whooping cough (pertussis)
Whooping cough is a prolonged lower respiratory tract infection caused by the Gram-negative coccobacillus Bordetella pertussis. It is highly infectious and is transmitted by droplet. Epidemiology Spread of infection is entirely human-to-human and the disease is endemic, cases occurring continuously. Epidemics in susceptible children occur every 4 years in the UK (Fig. 9.18). Since reports of a possible association between pertussis immunization and encephalopathy in
TABLE 9.29 Diseases caused by H. influenzae Type
Disease
Type b
Acute meningitis Epiglottitis Septic arthritis Orbital cellulitis Pneumonia Exacerbations of chronic bronchitis Otitis media and sinusitis Conjunctivitis Rarely pathogenic
Salmonella paratyphi infection
S. paratyphi B is the most common paratyphoid infection in Britain. Other strains are called S. paratyphi A and C. Paratyphoid has a shorter incubation period than typhoid and is a milder disease with fewer complications. Diarrhoea tends to occur early, in contrast to typhoid. Treatment is with ciprofloxacin. 1
9
PARVOBACTERIA
Non-encapsulated
Other encapsulated types
Age
Up to 5 years
Any age
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prolonged coughing spasms may cause convulsions. Minor complications are subconjunctival haemorrhages, periorbital bruising and frenal ulcer, all of which result from prolonged spasms of coughing.
FIG. 9.18 Incidence of whooping cough in England and Wales, 1940-2000 Note the effect of immunization on incidence. The death rate was falling before immunization was introduced (Communicable Diseases Surveillance Centre, Colindale).
1973, the rate of immunization has fallen off and epidemics have been larger. The disease may affect any age group but is most common in children under 5 years and most severe in those below 1 year. Pathogenesis The infection is concentrated in the bronchial walls, producing damage to the epithelium and accumulation of viscid mucus. Toxins produced by B. pertussis probably have a role in the tissue damage. Collapse of segments of lung distal to obstructed bronchioles is common. Clinical features After an incubation period of 7-10 days there is sometimes a prodromal illness that resembles a cold and lasts 2-3 days (catarrhal stage). This is followed by onset of the characteristic cough, with long spasms of coughing interrupted by rapid inspiration, which sometimes produces a whooping sound. This is often followed by vomiting. During a spasm of coughing the child becomes pink and then blue, and small babies may become apnoeic after a spasm. Between spasms the child looks and feels deceptively well. Whooping cough lasts about 2 months on average, and in the later stages the cough is mainly at night. It is distressing to watch small children rendered helpless by the spasmodic cough, and anxiety and disruption of sleep cause a major disturbance to family life. Complications Secondary bacterial infection causing pneumonia, or mucus plugging with segmental collapse, are the most common serious complications. Cerebral hypoxia during
1 318
MCQ9.19
Diagnosis Clinical diagnosis rests on recognition of the pattern of cough and is fairly simple when whooping is heard. However, in the early stages in babies and in adults the whoop may be absent. Laboratory support comes from the lymphocytosis and culture of B. pertussis from a pernasal swab; the latter is taken by passing a special swab through the nostril to the nasopharynx. Management Attentive nursing is the most important aspect of treatment, and parents need help and reassurance to learn to manage coughing spasms. Babies frequently feed poorly and lose weight, necessitating feeding through a nasogastric tube. The organism is sensitive to erythromycin, and early treatment with 125mg every 6 hours (up to 2 years) or 250 mg every 6 hours (over 2 years old) may be beneficial. Erythromycin can be used for secondary bacterial pneumonia if it has not already been started, or co-amoxiclav can be added. Prevention Pertussis vaccine is a crude preparation of killed organisms, but it is 80% effective in preventing whooping cough and often ameliorates the disease if not wholly preventing it. There is a small risk of convulsions after immunization (1 in 6000 doses) and a minute incidence (1 in 100000 doses) of encephalitis with lasting consequences. As there is severe morbidity and a small mortality in whooping cough epidemics the vaccine is strongly recommended. Prophylactic erythromycin treatment of close contacts has proved ineffective. 1
Brucellosis Brucellosis (undulant fever) is a septicaemic infection caused by Brucella abortus, Br. melitensis or Br. suis. Br. abortus is acquired from cattle, Br. melitensis from camels, llamas, sheep or goats (Malta fever), and Br. suis from swine. Most northern European infection is by Br. abortus acquired during occupational exposure in vets, farm workers and slaughterhouse employees, by ingestion of raw milk or by accidental infection in the laboratory. Most herds in the UK are brucella free, and pasteurization is an additional insurance against infection of milk. As a result of control measures the disease is now very rare in the UK but it remains a major problem in parts of Europe, the Middle East, and Central and South America. Brucellae are small Gram-negative coccobacilli which proliferate intracellularly. The incubation period of the disease is about 3 weeks.
Clinical features Some people have asymptomatic infections but the common presentation is an acute illness with persistent, swinging fever and profuse sweats. Back pain is common. There are no specific physical signs but 40% of patients have hepatosplenomegaly, 20% have splenomegaly only, and 20% have arthritis in one large joint. Less common manifestations are epididymo-orchitis, spondylitis, an erythematous papular eruption on the extremities, endocarditis, and neurological involvement with a range of manifestations, including meningitis, encephalitis or radiculitis. If no treatment is given the fever may persist for weeks or months, although it gradually declines, only to relapse again in many cases. A prolonged debilitating illness can be associated with depression. Depressed patients with moderate brucella antibody litres rarely have chronic brucellosis in the absence of a preceding history suggestive of acute brucellosis. Diagnosis There is neutropenia and lymphocytosis in the acute phase, and brucellae can be cultured from blood in 50-60% of cases and also from bone marrow in over 90% of cases. Complement fixing and agglutinating antibodies can be detected in rising titre following acute infection, and an ELISA-based serological test is also being used. Managemenf Inadequate treatment is associated with a high rate of relapse within 3 months, and some relapses occur despite the best known therapy. Doxycycline 200 mg daily combined with rifampicin 600 mg daily for 6 weeks, or doxycycline 200 mg daily for 6 weeks with streptomycin Ig intramuscularly daily for the first 3 weeks, gives the lowest relapse rates. Rifampicin is an enzyme inducer and may induce enzymatic breakdown of doxycycline reducing blood levels and hence its efficacy. Treatment is continued for 6 weeks in uncomplicated cases or 12 weeks in those with joint or spinal involvement. Endocarditis requires at least 12 weeks of therapy and probably surgical removal of the valve. In pregnancy rifampicin is given alone, and children less than 8 years old should receive co-trimoxazole plus rifampicin or streptomycin. There have been indications that rifampicin plus doxycycline has a greater relapse rate than streptomycin plus doxycycline. The explanation for this may be enzyme induction of doxycycline metabolism by rifampicin and so this effect could be overcome by increasing the doxycycline dose to ensure blood levels of the latter; this has not been tried. Because of susceptibility of brucella to other aminoglycosides such as gentamicin and netilmicin, these have been used for 5 to 7 days with good results although there are no controlled trials comparing these aminoglycosides with streptomycin. Some authors have suggested that for abscess, spondylitis, endocarditis and neurological disease treatment with three drugs, adding rifampicin to a doxycycline plus aminogly-
SUMMARY 11 Treatment of Brucellosis in adults Doxycycline 200 mg daily + rifampicin 600-900 mg daily
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6 weeks uncomplicated 12 weeks complicated
or Doxycycline 200 mg daily + streptomycin 1g i.m. daily for first 3 weeks
6 weeks uncomplicated 12 weeks complicated
In patients with spondylitis Streptomycin 15mg/kg up to 1 g/day maximum i.m. (reduced dose in those under 50kg, over 40 years old or with renal impairment; drug level monitoring indicated in renal impairment) Children less than 8 years old Rifampicin 10-20 mg/kg/day for 8 weeks, together with cotrimoxazole for 6 weeks - every 12 hours, 6 weeks to 5 months, 120mg; 6 months to 5 years, 240 mg; 6-12 years, 480 mg.
coside regimen. For children, rifampicin plus co-trimoxazole can be used, adding an aminoglycoside when a third drug is needed. Preventive measures concentrate on elimination of brucellae from domestic animals, ideally by testing and slaughter of positive reactors, with compensation for the financial losses. Pasteurization of milk also prevents transmission, although in countries where the traditional custom is to drink milk and make other products using unpasteurized milk, changing these practices is immensely difficult. Vaccination of animals: the 19S strain of B. abortus in cattle or the Rev 1 strain of B. melitensis in sheep or goats is effective, but it should be noted that although these are attenuated strains for animals they are pathogenic for humans if accidentally injected.
Yersinia infection Yersinial infections are zoonoses. The important human pathogens are Y. enterocolitica and Y. pseudotuberculosis, which are enteric pathogens, and Y. pestis, the cause of plague. Y. pseudotuberculosis and Y. enterocolitica Infection with Y. pseudotuberculosis and Y. enterocolitica (see also p. 816) is less common in the UK than in some other European countries, notably Scandinavia and Belgium. The organism is a common commensal in the pharynx and tonsillar tissue of pigs, which are included in ground pig meat. Other foods, including milk and seafoods, have been incriminated in human outbreaks. Y. enterocolitica causes febrile enterocolitis in young children (less than 5 years old), but in adolescents an illness which is difficult to distinguish from acute appendicitis is caused by mesenteric adenitis. The latter is also the most common manifestation of Y. pseudotuberculosis infection. The presence of exudative pharyngitis may give a clue in
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Y. enterocolitica infection. Many laparotomies have been carried out for these self-limited infections, which may be partially responsive to gentamicin therapy (often given as blind treatment or as prophylaxis for surgery). Reactive polyarthritis and erythema nodosum are well-recognized complications which are more common with Y. enterocolitica.
Plague An acute severe infection caused by Y. pestis manifests by either lymphadenitis with suppuration (bubonic plague) or by necrotizing pneumonitis (pneumonic plague). It is a zoonosis. Aetiology The organism is a Gram-negative aerobic bacillus of the parvobacteria family. It grows well at 28°C. At 37°C it produces an antigen which inhibits phagocytosis. It has a lipopolysaccharide capsular endotoxin. Distribution and incidence Asia, Africa, the Middle East and the Americas (South America and the southern states of the USA) are endemic areas with comparatively small numbers of reported cases each year. The disease is probably under-reported. Plague is considered a re-emerging disease because the number of cases being reported to the WHO is increasing, and since 1994 it has reappeared in several countries such as Malawi, Madagascar, Mozambique and India, where it had not been experienced for 15-30 years. Also, the number of foci have increased in some countries, including the United States. The last pandemic started in 1894, and by the middle of the twentieth century public health measures had led to it being purely sporadic. Transmission The infection is transmitted to man by the bite of the rat flea (Fig. 9.19). The natural hosts are rodents and the vector is the rat flea, Xenopsylla cheopis, which takes blood meals from its rodent hosts. Infected rats die and the fleas leave the dead rats for other hosts. The organisms produce a coagulant which prevents the flea taking a full blood meal. The flea bites the host repeatedly, encouraging transmission. The coagulant is inactive above 28°C and transmission diminishes. Pathology
Necrosis and haemorrhage are the main features, together with marked inflammatory changes. An eschar is occasionally found at the bite site. Buboes are grossly enlarged, inflamed lymph nodes draining the site of the flea bite. The normal lymph node architecture is destroyed and necrotic, with large numbers of bacilli. The pathological changes in pneumonic plague are very similar, with haemorrhagic necrosis of lung tissue. 320
Clinical features The incubation period is 2-8 days before the onset of
FIG. 9.19 Cycle of transmission of plague
systemic upset, fever, chills and headache. Within 24 hours of this the patient finds a bubo, which is exquisitely tender. Any group of lymph glands can be involved. Tachycardia and high fever are usual, with hypotension and shock in severely affected patients. Purpura may occur. Pneumonic plague results from haematogenous spread of organisms to the lungs. Cough, chest pain and haemoptysis in a severely ill patient are usual features. Patchy shadowing is seen on the chest X-ray. Aerosol spread can occur from patients with pneumonic plague. Septicaemic plague has a high mortality. There is a neutrophil leukocytosis. Some degree of disseminated intravascular coagulation is common, although spontaneous bleeding is uncommon. Diagnosis The organism may be found in material aspirated from the necrotic centre of buboes and in blood films. Smears made on slides can be stained with Giemsa stain, which shows the Gram-negative coccobacilli. The organism grows readily on standard media. Antigen (F1) can be detected in sputum by the second day of symptoms using a dipstick test which is simple and highly practical. Management The high mortality in untreated plague (over 50%) has been altered by antibiotics. Streptomycin 15mg/kg twice daily i.m. for 10 days is the treatment of choice. Defervescence occurs by the third or fourth day. Tetracycline and chloramphenicol are alternative choices but there are reports of multiple resistance to antibiotics mediated by a plasmid. Supportive treatment is needed in those with low blood pressure and shock, with volume replacement using saline or plasma. Buboes should be aspirated.
Prevention and control A vaccine is available for those working with plague in the laboratory or in the field. Proven cases are not infectious unless there is pneumonic involvement, when isolation of cases, with respiratory precautions to avoid aerosol spread, is necessary. Antibiotics rapidly reduce infectivity. Vector control with insecticides and rat control will minimize transmission in towns and cities.
followed by chloramphenicol 10mg/kg four times daily, doxycycline 2mg/kg twice daily, and co-trimoxazole (trimethoprim 10mg/kg/day + sulfamethoxazole 50 mg/ kg/day) given for up to 20 weeks. The efficacy of maintenance therapy depends on full compliance over this long period. There is evidence to suggest that co-amoxiclav plus extra amoxicillin gives equally good results, as good as the conventional regimen, with fewer side-effects, though full compliance is again necessary over 20 weeks.
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PSEUDOMONAS TULARAEMIA Pseudomonas aeruginosa infection
Pseudomonas aeruginosa is an opportunist organism which rarely causes disease in immunocompetent subjects. It causes serious infection in patients with deficient immunity and in those who have had surgery. Septicaemia, osteomyelitis, infection of burns and pneumonia are examples. Skin changes due to Ps. aeruginosa are described in Chapter 10. Patients in intensive care units may become colonized superficially and treatment with antibiotics is often counterproductive, as resistance develops rapidly.
MELIOIDOSIS Burkholderi (Pseudomonas) pseudomallei is a Gramnegative aerobic bacillus with bipolar staining. It is found contaminating surface water, particularly in southeast Asia and northern Australia, although cases have been reported from a much wider geographical range. It has a very low host specificity and will infect a very wide range of animals, including humans. Infection occurs by ingestion or inhalation of contaminated water, or by contact of infected water with abraded skin. If health is good there may be subclinical infection, shown by seroconversion without systemic upset. Debilitating illness, for example diabetes mellitus and cirrhosis, and immunosuppression enhance susceptibility, and the development of clinical infection, which can be acute or chronic, may follow. After a 2-3 day incubation period there is fever, myalgia, vomiting, confusion or delirium. Diarrhoea may also occur, as may shock with features of endotoxic shock. Pustular skin lesions may occur. The lungs may be involved, with consolidation, cavitation and pus formation. Suppurative parotitis is seen in children. Chronic and relapsing sepsis may occur, with abscess formation affecting lymph glands, lungs, skin, liver, genitourinary tract and bones. Multiple small abscesses tend to form, producing multiple small cavities on liver ultrasound scanning. The organism is a dangerous pathogen which may be grown from pus, lymph gland biopsies, liver biopsy material and bone marrow aspirate. Serological responses using indirect haemagglutination (IHA) or complement-fixing antibody techniques are available. Antibiotic treatment comprises initial treatment with ceftazidime 2g t.d.s. intravenously for at least 2 weeks,
Francisella tularensis is a Gram-negative bacillus that infects a wide range of wild animals; humans are occasionally infected in rural areas of the northern hemisphere (North America, Sweden, Norway, northern Europe, Russia and Japan). Infection occurs by the bite of an infected deerfly or tick, by mucosal or skin contact with an infected animal, by inhalation, and by eating inadequately cooked meat. The effects in humans may be localized cutaneous pustular disease with regional adenopathy, a pneumonic illness, or a systemic illness sometimes with diarrhoea. Inapparent (subclinical) infections occur. The North American rabbit strain produces severe disease, with a mortality of up to 10% without treatment. Mortality is negligible (except for the American rabbit strain) even without treatment. The diagnosis is made by finding the organisms in material from infected tissues. Direct immunofluorescence may be used. Serological tests may also be used to detect antibodies to the organism by ELISA and agglutination techniques. Great caution is needed in handling specimens to avoid the risk of laboratory infection. Streptomycin (lOmg/kg twice daily for 14 days) is very effective. Tetracycline and chloramphenicol are effective. Patients need to be isolated until they have been on treatment for 48 hours to minimize the risk of cross-infection.
BARTONELLOSIS
Bartonella bacilliformis is a Gram-negative aerobic bacillus transmitted by the bite of the female sandfly Lutzomyia verrucarum. The disease is limited to the valleys of the western Andes, mainly in Peru, Colombia and Ecuador, between 2500 and 8000 feet above sea level. Humans are the reservoir of infection. There are two manifestations of the disease: haematological and cutaneous. After a 21-day incubation period there is sudden onset of systemic upset. The onset of fever is often followed by acute severe intravascular haemolysis, which may last up to 4 weeks before resolution. Several weeks to several months later the eruptive phase of the disease appears, with nodular lesions of various sizes over the body in the miliary form, or fewer nodular, deep lesions particularly
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concentrated on the extensor aspects of the limbs. Mucous membranes of the mouth and gut, and serous cavities can be affected. The organisms can be grown in blood cultures taken in the first week of the illness and can be readily found in Giemsa-stained thick and thin blood films, or in material obtained from skin lesions. Treatment with antibiotics kills the organisms and produces rapid defervescence and clearance of organisms from the blood. Penicillin, streptomycin and chloramphenicol are effective; the latter is recommended in view of the reported association between systemic salmonellosis and bartonellosis. Treatment is for at least 7 days. Bartonella quintana This organism, formerly known as Rochalimaea quintana, was recognized as the cause of trench fever among troops in the First World War. The vector is the body louse, and so infections can occur when levels of sanitation are low. The organisms are present in louse faeces and infection occurs by introducing B. quintana through skin abrasions by scratching. There is no identified animal host. The organism causes a range of febrile conditions, including a febrile illness lasting 4 days or so, a relapsing febrile illness with three to five episodes of fever, and a continuous febrile illness lasting up to 21 days. Despite the association with the First World War the condition occurs worldwide among communities where sanitation is poor. Doxycycline or erythromycin are the treatments of first choice. This agent and the related B. henselae have been recognized as the cause of cutaneous bacillary angiomatosis among patients with HIV infection (see Ch. 11). Infection of deep organs such as the liver produces similar lesions.
itself appear ill. The cat is probably infectious for about 3 weeks. Clinical features Most cases occur in children or young adults. There is gross enlargement of a single group of lymph nodes, which are usually tender. Lymphadenopathy develops about 2 weeks after the scratch and usually lasts for 2-4 months, but it may persist for up to a year. A papule may occur at the site of the scratch; it appears about a week after the scratch and persists for 1-3 weeks. Although most patients remain well, one-third have a low-grade fever for a few days and may experience malaise, headache and sore throat. Rare manifestations are conjunctivitis and preauricular lymphadenopathy (oculoglandular syndrome), encephalopathy, thrombocytopenic purpura, osteomyelitis and pneumonia. Diagnosis The diagnosis is usually based on the histology of excised lymph node with negative cultures for bacteria and mycobacteria. The Warthin-Starry silver impregnation stain may reveal the CSD bacilli but they are present in small numbers. There may be a mild neutrophil leukocytosis, but other tests are unhelpful. Antibody tests are being developed. Management Because the disease resolves spontaneously the only treatment usually required is analgesia if the lymph nodes are painful, and reassurance. Antibiotics do not help.
VIBRIOS
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CAT-SCRATCH DISEASE
Cholera
Cat-scratch disease (CSD) is a benign lymphadenopathy in a site determined by an area scratched by a cat, most often in the neck or axilla.
Cholera is due to infection with the Gram-negative bacillus Vibrio cholerae, which causes acute secretory diarrhoea with death due to dehydration.
Aetiology and pathogenesis Histology of affected lymph nodes reveals scanty small pleomorphic rod-shaped Gram-negative bacilli which are normally seen using the Warthin-Starry stain. These have now been identified as Rochalimaea henselae (possibly to be renamed Bartonella henselae) in most cases, although a small number may be a related organism called Afipia felis. The organism has been identified in lymph nodes from patients by culture, polymerase chain reaction for DNA, and by immunocytochemistry; serum antibodies are detectable in 84-96% of those affected. This organism is also one of the causes of the skin condition called bacillary angiomatosis which affects immunocompromised subjects such as AIDS patients (see Ch. 11). The infection is transmitted by scratching or licking by a young cat with chronic bacteraemia which does not
Aetiology V. cholerae is a curved Gram-negative motile bacillus. Two biotypes are recognized, the classic biotype and the El Tor biotype. The organism is present in vast numbers in the faeces of infected patients. The El Tor biotype tends to cause more asymptomatic and mild infections, which resolve spontaneously and leave the patient excreting vibrios to infect others. The organism is sensitive to desiccation but survives in saline waters. Vibrio cholerae 0.139 has been recently recognized in India and Bangladesh. Until that time the 0.1 serotype was the sole pathogenic organism and 0.2 to 0.138 were non-pathogenic. Distribution and incidence Distribution and incidence are shown in Figure 9.20. Cholera has been imported into European countries but
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FIG. 9.20 World distribution of cholera 1994 (WHO)
no outbreaks have resulted, apart from that in Naples in 1974. Transmission and epidemiology Organisms are ingested in contaminated food and water. In India, Bangladesh and Pakistan, where cholera is endemic, it is predominantly a paediatric disease. In epidemic cholera all ages are affected. Individual susceptibility is governed by the infecting dose and by the gastric acid barrier. The 0.139 serotype affected adults and children in India and Bangladesh, indicating that there was no cross-protection between the usual serotype and the new one. Pathogenesis V. cholerae secretes an exotoxin which binds to the GM1 ganglioside, a glycolipid on the surface membrane of jejunal enterocytes (Fig. 9.21). The effects of cholera toxin are mediated by several mechanisms, one of which may be accumulation of cyclic AMP in the cell. Local neurohumoral stimuli may also contribute to the diarrhoea. The outcome is that the upper small intestine becomes a site of net secretion, with the accumulation of isotonic fluid containing Na+, Cl-, HCO3- and water. This fluid passes down the intestine and in the colon K+ exchanges for Na+ under the influence of aldosterone. Stooling rates of 500mL/h are common, and up to 1 L/h may be produced. The effect of cholera toxin lasts for the duration of the life of the enterocyte, which is 3-4 days; during this time the cell migrates from the crypt to villous tip, where it is desquamated into the gut lumen. There are no histological changes in the affected mucosa. Cholera is a secretory diarrhoea with no mucosal inflammation. Secondary changes in a range of tissues, e.g. kidney, occur as a result of hypovolaemia and shock. Clinical features The incubation period is about 2 days. Diarrhoea begins
FIG. 9.21 Mechanism of action of cholera toxin on intestinal cells A Attachment of cholera toxin to receptor on enterocyle. B Activation of cAMP - note different effects on villous and crypt cells.
suddenly, with vomiting during the first 24 hours of illness. Faecal residues disappear, and opalescent rice-water stools are passed. There are no pus cells in faecal smears. The abdomen may be distended and bowel sounds are increased. Stool losses are maximal within the first 48 hours of the illness and decline spontaneously thereafter, but death can occur from dehydration within 24 hours in the most severe cases. The clinical features are due to isotonic volume depletion (Table 9.14, p. 280). Haematocrit and plasma specific gravity rise with haemoconcentration. Hypoglycaemia may occur in young children and may be associated with convulsions. Loss of bicarbonate causes acidosis. There is prerenal uraemia. Colicky abdominal pain and slight fever are features of infection with the serotype 0.139. There is a considerable range in the severity of diarrhoea in cholera, particularly the El Tor biotype, which is the cause of many mild cases.
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Diagnosis Severe diarrhoea causing rapid progression to dehydration suggests that cholera is the cause in severe cases. Milder cases will not be diagnosed unless a stool is cultured or immediate dark-ground microscopy of a fresh faecal smear shows the characteristic morphology of V. cholerae. Differential diagnosis All the acute infective causes of diarrhoea need to be considered, including ingestion of staphylococcal enterotoxin, invasive bacteria such as Salmonella, Shigella and Campylobacter, which are usually readily distinguished because of the presence of systemic upset and colicky abdominal pain, and enterotoxigenic strains of E. coli. Rotavirus infection may also be difficult to distinguish from cholera.
the duration of both diarrhoea and faecal excretion of Vibrio cholerae. In pregnancy and childhood ampicillin or furazolidone may be given. Co-trimoxazole is also effective. Prevention and control Adequate clean water supplies and the safe disposal of faecal waste would do much to prevent the occurrence of cholera. Concurrent education of the population about the relationship between infective diarrhoeal disease and personal and general sanitation practices is essential. The widespread use of ORS early in the course of all diarrhoeal illness reduces mortality. Vaccination with the current killed vaccine is of no benefit, either for prophylaxis in the traveller or for the control of epidemics.
Management Mild to moderate dehydration can be managed with oral rehydration solution (ORS) (p. 280), but patients with severe dehydration need intravenous infusions, e.g. Ringer's lactate, to restore blood volume. The aims of rehydration are: • To replace estimated fluid losses in the first 4 hours after presentation; • To replace continuing intestinal fluid losses with equal volumes until diarrhoea stops. Frequent small amounts of ORS are better tolerated than less frequent large volumes, especially if the patient is vomiting. Additional fluid, such as water, fruit juice, tea or breast milk, but not ORS, should be given to allow for insensible losses and obligatory urinary losses. The glucose in ORS is not sufficient to counter hypoglycaemia and so extra sugar should be given orally. A solution prepared using rice flour as the source of glucose is capable of reducing faecal fluid losses by producing net absorption of sodium, glucose and water from the gut. Bowel sedatives merely paralyse smooth muscle, leaving fluid containing organisms and the toxin in the intestinal lumen, and should not be used in management. Tetracycline, 250 mg four times daily for 3-5 days, will reduce
SUMMARY 12 Managing dehydration in cholera
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Clinical assessment No dehydration
Management Encourage fluid intake Encourage normal diet
Some dehydration (5-10% body weight lost)
ORS 80mL/kg body weight over 4 hours + 400 mL ORS after each diarrhoeal stool + water to provide for insensible and renal losses
Severe dehydration (>10% body weight lost)
Ringer's lactate 30 ml/kg body weight over SOmin, then 70 ml/kg over 2 hours
CAMPYLOBACTER Campylobacter are curved rods morphologically similar to Vibrios but regarded as a separate genus, as they have different biochemical characteristics. There are six species, of which C. jejuni and C. fetus are important human pathogens. C. jejuni is a major cause of prolonged severe enterocolitis, frequently associated with bloody stools and abdominal pain and tenderness suggestive of peritonitis. It is now the pathogen most frequently isolated from patients with gastroenteritis and the incidence of infection peaks in late summer to autumn. Infection may be acquired from food or drinks, but there is often a relationship with domestic animals, a wide variety of which are normally colonized (e.g. dogs, fowl and cattle). In the tropics. C. jejuni can often be isolated from the faeces of asymptomatic subjects, but it frequently causes diarrhoea in children less than 5 years old, implying that asymptomatic infection occurs in those with some degree of immunity.
Pathogenesis The incubation period is up to a week, this and the severity of the illness being determined by the infecting dose of organisms. The infecting dose required to cause illness is about 104, but this may be reduced by conditions of low acidity in the stomach. Human bile encourages growth of the organism, and the small and large intestine are colonized and the mucosa is invaded. Although toxins are produced, they are not thought to contribute to pathogenesis. C. fetus sometimes causes bacteraemia but rarely C. jejuni, usually in the very young or elderly. Excretion in the stools continues for 2-3 weeks after infection in the absence of immunity, which causes more rapid clearance.
Clinical features Fever, headache and malaise begin 2-5 days after infection, shortly followed by diarrhoea, often with blood, cramping
abdominal pain and tenderness. The severity of pain and tenderness before the onset of diarrhoea sometimes suggests an abdominal emergency, such as appendicitis. The symptoms usually resolve within a week, but in a significant minority the duration is longer and there may be relapse in the absence of antibiotic treatment. Guillain-Barre syndrome is an uncommon complication of C. jejuni infection (about 1 in 2000 cases), although because the incidence of this infection is high it is linked to nearly 50% of cases of GBS.
Diagnosis The diagnosis is established normally by microscopy and culture of stools under microaerobic conditions, but occasionally blood culture is positive.
Management As with other forms of gastroenteritis, the first priority is rehydration and correction of electrolyte disturbances (see p. 280). Appropriate analgesia is required when abdominal pain is a prominent symptom. Drugs such as codeine phosphate which reduce gut motility should be used with caution in the acute phase. Simple analgesics (paracetamol) may be adequate. Antibiotics are indicated for severe cases when there is fever together with systemic symptoms. Erythromycin 40mg/kg/day in four doses may alleviate symptoms in children, and it terminates the excretion of organisms in the faeces. If treatment is clinically indicated before the organism has been identified, ciprofloxacin, 500 mg b.d. for adults, is more likely to improve symptoms and reduce the duration of illness, but there is increasing resistance to quinolones which necessitates local surveillance.
ANAEROBIC BACTERIA
Bacteroides fragilis is the most commonly encountered pathogenic anaerobe but many others are found among the normal flora of the gastrointestinal and genital tracts; these include other Bacteroides, Fusobacteria and some anaerobic cocci, such as peptostreptococci and microaerophilic streptococci. Anaerobic organisms often cause wound infection, abscesses and septicaemia in patients who have had abdominal surgery or intestinal perforation. Antibiotic sensitivity is restricted; metronidazole is very useful, as it is well absorbed orally or rectally and B. fragilis is usually sensitive to it. Clindamycin is also useful.
Mixed infections Infection may involve several different bacteria, including anaerobes. Abscesses associated with the bowel, especially the colon, or the vagina are examples. Some tissue infections, especially in debilitated patients, may also contain
multiple pathogens. Severe stomatitis, one form of which is known as Vincent's angina, commonly occurs in malnourished patients with poor dental hygiene. The pathogens responsible are members of the normal mouth flora, including anaerobes and spirochaetes which are sensitive to penicillin. Metronidazole is an alternative treatment. Necrotizing fasciitis is a rapidly spreading subcutaneous infection; it results in extensive necrosis, which may involve any part of the body. Type I is caused by mixed infection and type II by group A streptococci (see p. 386). Type I occurs particularly in diabetics, common sites being on the feet, spreading upwards, and on the perineum. Scrotal infection is called Fournier's gangrene. The organisms involved are mixed anaerobic bacteria, mainly Bacteroides or peptostreptococci. Treatment is by a combination of aggressive surgery and antibiotics aimed mainly at anaerobes, for example clindamycin plus ampicillin.
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MYCOBACTERIA Mycobacteria are classified as a group because they contain mycolic acids. They are bacilli which are mostly slow-growing and able to survive within macrophages. On staining by the Ziehl-Neelsen method they are acid and alcohol fast. The most important pathogens within the group are Mycobacterium tuberculosis and M. leprae. Tuberculosis is still relatively uncommon in the western world but a major problem in less developed countries. The disease is discussed fully on page 640. M. bovis is rarely incriminated now but can cause similar disease. Other nontuberculous mycobacteria, sometimes called atypical, such as M. kansasii, are less pathogenic than M. tuberculosis but can cause disease. M. avium intracellulare has become more familiar in recent years because it is one of the infections that afflict patients with AIDS. Mycobacteria other than M. tuberculosis are often resistant to standard antituberculous drugs, so their treatment presents difficult problems in immunocompromised patients.
LEPROSY Leprosy (Hansen's disease) is a chronic infection of the skin and cutaneous nerves caused by M. leprae. The manifestations in the patient may be localized or generalized, and are determined largely by the host response to the infecting organism. Aetiology Mycobacterium leprae is an acid-fast bacillus that cannot be cultured in vitro. Ziehl-Neelsen staining of smears of the organism differentiates viable (solid staining) from non-viable (granular) organisms. In humans the cooler superficial regions of the body are the preferred sites for
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Among those developing clinical disease there appears to be a racial variation in the type of leprosy occurring: up to 50% of cases in Asia have lepromatous disease, compared with 10% in Africa. The male-to-female ratio is 2:1 in adults and unity in children. Pathogenesis and pathology The host's cellular immune response determines the outcome of infection. If macrophages are able to kill the infecting organisms there is either no clinical disease or the lesions of indeterminate leprosy at most (Fig. 9.23). Those in whom the infection progresses further develop one of the forms of disease described in Table 9.30 and classified as one of the following: FIG. 9.22 Geographical distribution of leprosy
bacterial proliferation. The generation time is about 13 days. M. leprae was one of the first pathogenic bacteria to be identified, and yet in vitro culture remains elusive. Our knowledge of the organism's sensitivity to antimicrobial agents is gained from the response of mouse foot-pad lesions induced by injection of suspensions of M. leprae to antileprosy drugs given in water. It is known that M. leprae is a very hardy organism capable of surviving prolonged drying in the shade in south India, and capable of prolonged carriage in the noses of 5% of the general population and 16% of leprosy workers. Distribution and incidence Leprosy is mainly a disease of the tropics and subtropics (Fig. 9.22). It is relatively common in Africa and Asia, with a prevalence of 2-9 per 1000 in most areas and higher rates in a few countries. There are about 600000 new cases per year, including a considerable number of childhood cases, which indicates persistence of transmission. Lepromin skin test positivity rates in endemic areas are much higher than rates of clinical cases, suggesting that host factors do much to influence the outcome of the disease. The disease has almost completely disappeared from Europe, although cases do occur in Europeans who have had prolonged exposure in an endemic area. Transmission and epidemiology There is little evidence to support skin-skin contact as the route of infection. Aerosol spread from the upper respiratory tract of patients with multibacillary (lepromatous) leprosy is the likely source of infection. There is considerable variation in the course of infection from person to person, and the majority of those infected develop no clinical disease.
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1
Fig. 9.15
2
Fig. 9.16
4
Fig. 9.18
5
Fig. 9.19
3
Fig. 9.17
• • • • •
Tuberculoid (TT) Borderline tuberculoid (BT) Borderline (BB) Borderline lepromatous (BL) Lepromatous (LL).
It should be noted that the clinical disease is a biological continuum between the two polar extremes of pure tuberculoid and pure lepromatous. Few bacilli are found in the tuberculoid forms, whereas large numbers are found in patients with lepromatous leprosy. Host cellular responses to mycobacterial antigens determine the form of disease that develops, with delayed-type hyper sensitivity at the tuberculoid end of the spectrum and anergy at the lepromatous end. The borderline forms are immunologically unstable, and without treatment will deteriorate to the lepromatous end of the spectrum. The pathology of leprosy is a granulomatous response. At the lepromatous end of the spectrum the granuloma comprises macrophages laden with solid staining bacilli and globules of fatty products of bacillary metabolism, including phenolic glycolipid 1. This appearance of the macrophages is called foamy macrophages. Although lymphocytes are conspicuous by their absence from lepromatous lesions they are well represented in tuberculoid lesions. The earliest lesions in leprosy begin in cutaneous nerves in the Schwann cells which have phagocytic functions and ingest bacilli. The most marked damage to nerve trunks is seen in TT leprosy. At the lepromatous end of the spectrum the involved nerves are not so large. The auriculotemporal, ulnar, median, radial cutaneous, lateral popliteal and sural nerves are preferentially involved at sites where the nerve trunks are close to the skin and therefore cooler. The bacterial load and the morphology of the organisms need to be assessed, initially for classification purposes and subsequently to determine the response to treatment. Slit skin smears are obtained from the edges of lesions. Numbers of bacilli and their viability can be graded. Lepromin is a skin test antigen obtained from M. leprae. The antigen is injected intradermally and the test is read at 3 weeks; a nodule at the site of injection indicates a positive response, meaning delayed hypersensitivity and supporting a classification at the tuberculoid end of the spectrum.
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FIG. 9.23 Evolution of leprosy lesions with and without treatment (TT = tuberculoid; BT = borderline tuberculoid; BB = borderline; BL = borderline lepromatous; LL = lepromatous) (After Ridley D S 1977 Skin biopsy in leprosy. Ciba-Geigy, Basle.)
TABLE 9.30 Major features in leprosy Feature
Tuberculoid leprosy (TT)
Borderline leprosy (BB)
Lepromatous leprosy (LL)
Lesions Nerve involvement Numbers of bacilli Lepromin test Reactions Reversal Erythema nodosum leprosum (ENL)
Few (1-3) Local Fragmented only +++
More numerous Present in nerves of predilection Viable bacilli present in lesions -
Large numbers Diffuse, symmetrical, late in disease Vast numbers of viable bacilli -
-
+++
Two types of acute reaction are recognized in leprosy: • Erythema nodosum leprosum (ENL) is an immune complex-mediated vasculitis that occurs in LL patients and, less often, in BL, either during treatment or in the untreated patient. There is inflammation with oedema and a prominent infiltrate of neutrophils. • A reversal reaction indicates a change in cellular responsiveness to the infecting organism, either increasing (after starting treatment) or decreasing responsiveness. Skin lesions and affected nerves become more inflamed. The swollen lesion resolves completely in time, becoming smaller in 'upgrading' and bigger with 'downgrading'. Clinical features Indeterminate leprosy Indeterminate leprosy is manifest as a hypopigmented macule on a dark skin, and as a slightly reddened macule on a light skin, with either normal or mildly reduced sensation. The lesions may regress spontaneously or progress to one of the stages described below. Tuberculoid leprosy Tuberculoid leprosy (TT) is characterized by a hairless, hypopigmented anaesthetic lesion with a flat centre and a well-defined raised edge with minimal inflammation. 1 The skin of the lesion does not sweat. Single lesions are usual, but up to three may be found. Common sites are the extensor aspect of the arms, around the elbow and the
+++
knee. A thickened cutaneous nerve supplying the affected area may be felt. 2 To feel an enlarged nerve the examining fingertip should be moved to and fro over the nerve trunk at right-angles to the direction of the nerve. Neural TT leprosy occurs with a single thickened nerve as the only physical sign. Borderline tuberculoid leprosy Borderline tuberculoid (BT) lesions are similar to those of TT but more numerous and asymmetrically distributed. The edges of the lesions are inflamed and irregular. 3 The nerves preferentially involved in leprosy are usually thickened and damaged, causing anaesthesia, loss of function and deformity to a variable extent in hands and feet. Penetrating ulcers in the soles of the feet, burns and skin sepsis are often present. There may be osteomyelitis of the bones of the feet caused by an infected penetrating ulcer. Borderline leprosy Borderline leprosy (BB) produces multiple lesions that vary in form, size and shape. Papules, plaques and lesions with elevated wide outer rims and depressed, well-defined anaesthetic centres are seen. The lesions may be hypopigmented or hyperpigmented. 4 There is diffuse involvement of the peripheral nerves. Borderline lepromatous leprosy Borderline lepromatous leprosy (BL) causes numerous asymmetrically distributed inflamed or hyperpigmented lesions, which may be papules, nodules or plaques. 5 Sen-
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sation over the lesions may be normal. Vague macules that vary in size are present in some patients. Peripheral nerves may only show slight enlargement. Lepromatous leprosy Lepromatous leprosy (LL) is associated with numerous symmetrically distributed skin lesions. 1 At the earliest stage, numerous slightly reddened hypopigmented macules and nodules occur. Without treatment these evolve into papules and plaques. The eyebrows are lost and the skin of the face and ears becomes diffusely thickened (leonine facies). Involvement of the nasal mucosae may block the nose and cause a bloodstained nasal discharge. Destruction of the nasal cartilage may occur later. Iritis and keratitis are often present. The voice may alter because of inflammation and thickening of the laryngeal mucosa. Testicular atrophy and gynaecomastia occur because of testicular damage. Bilateral oedema of the legs is often present. Nerve involvement occurs late in the course of the disease. Renal failure due to glomerulonephritis and amyloid disease are late complications in LL. Reactional states In reversal reactions the skin lesions and involved nerves become more inflamed and swollen. These reactions may also be accompanied by swelling of the face, hands and feet. Involved nerves become very tender, often with further deterioration in function. This type of reaction may persist for 2-3 months before subsiding. ENL produces acute inflammation of existing skin lesions in BL. The lesions become swollen and painful and slowly evolve through a livid appearance to residual hyperpigmentation of the affected skin. Bullae form over some lesions; these ulcerate and are slow to heal. New papules appear in LL cases, typically on the extensor aspects of the limbs. They may evolve over 2-3 days, through a bullous stage, to indolent ulcers which are slow to heal. Uveitis, lymphadenitis, orchitis and neuritis are also features of ENL. Diagnosis Diagnosis is based on the clinical features, characteristic histology, a positive lepromin test (at the tuberculoid end of the spectrum) and acid-fast bacilli in slit skin smears taken from the edge of lesions and other sites, the earlobes, elbows and knees (BB, BL and LL). In pure neural leprosy the diagnosis can be made from a biopsy of a few fascicles of an affected distal cutaneous nerve with no motor function, such as the radial cutaneous nerve at the wrist, or the sural nerve. Management
Multidrug therapy is now the rule and the current WHO
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1
Fig. 9.20
2
4
Figs 9.23, 9.26
MCQ 9.20 5
3
Fig. 9.27
Figs 9.21, 9.22
TABLE 9.31 Treatment of leprosy Type Paucibacillary Tuberculoid (TT) and borderline tuberculoid (BT) Multibacillary Borderline (BB), borderline lepromatous (BL), lepromatous (LL)
Drugs Rifampicin, 600 mg monthly, supervised + dapsone, 100mg daily, unsupervised both for 6 months Rifampicin, 600 mg monthly, supervised + dapsone, 100mg daily, unsupervised + clofazimine, 300 mg monthly, supervised + clofazimine, 50 mg daily, unsupervised All drugs are continued for 2 years from time of diagnosis and thereafter until slit skin smears contain no bacilli
recommendations are set out in Table 9.31. These drugs are generally well tolerated. Dapsone occasionally causes haemolysis. Clofazimine may stain the skin a rather reddish hue. Mild upgrading reactions may be controlled with aspirin or non-steroidal anti-inflammatory drugs. More severe reactions that threaten nerve function require oral steroids. ENL may be controlled by steroids, but sometimes thalidomide is needed. The patient needs careful instruction regarding the care of hands and feet, prevention of cracking and infection of the skin of the feet and appropriate footwear. Where the cornea is exposed as a result of facial nerve palsy, early lateral tarsorrhaphy is essential to prevent corneal damage. Tendon transplants may help in managing foot and hand deformities. Prevention and control There is still a considerable stigma attached to leprosy; this is based on ignorance. Education of the public regarding the disease and the efficacy of treatment is being attempted. BCG vaccination reduces the incidence of leprosy. Currently there are efforts to define protective antigens which may result in a genetically engineered vaccine. 2
MYCOBACTERIUM ULCERANS
M. ulcerans causes chronic ulceration, usually on an exposed area of the body, often the lower limbs. The condition has a wide distribution in the tropics and is often called Buruli ulcer. The pathogenesis of M. ulcerans disease is related to its unique ability to produce a tissuedamaging toxin, mycolactone, recently characterized as a macrolide molecule which causes cell death by apoptosis. Histology shows numerous acid-fast bacilli within extensive areas of necrotic fatty tissue with little inflammatory reaction. The organisms can be grown in Lowenstein-Jensen medium at 30-33°C. Clinical lesions begin as a subcutaneous nodule which ulcerates through the skin.
© Subcutaneous extension produces an ulcer with markedly undermined edges. Patients (most commonly children aged 5-15) are systemically well unless there is secondary bacterial infection. Long-term complications are determined by the site of the lesion; facial ulcers can destroy an eye; limb lesions may require amputation; scars around a joint lead to contractures. The disease is a major cause of morbidity in West Africa. Standard treatment is surgical and excision of early lesions is usually curative. Established ulcers require extensive debridement to remove all infected tissue, followed by grafting. Antibiotics have not been shown to be effective despite in vitro sensitivities, but there have been few formal trials. Local heat may encourage healing, as the bacteria are killed by temperatures over 33°C. Many topical treatments have been tried but there is little evidence about their benefit. Recent evidence suggests that topical nitric oxide treatment may be beneficial. When the lesion affects a region near to a joint, active and passive movement of that joint must be encouraged to prevent contractures.
SPIROCHAETES Syphilis, caused by infection with Treponema pallidum, is primarily transmitted sexually and is discussed in Chapter 11 (p. 458).
YAWS Yaws is a chronic infection due to Treponema pertenue; it is characterized by a primary site of skin infection, with later dissemination to other cutaneous sites and periosteum. Unlike syphilis, cardiovascular and nervous systems are not affected and congenital infection does not occur. Distribution, incidence and transmission Following mass eradication campaigns yaws became very uncommon, but there has been a resurgence of cases in South America, west and central Africa, Indonesia and the Pacific region. The organism must be introduced into the skin by contact between an infective lesion and an abrasion in the skin of the recipient. Clinical features 4 The primary papillomatous lesion or 'mother yaw' develops at the site of infection. This lesion is highly infectious. Other forms are a localized area of dry papules or a localized maculopapular rash. Regional lymph nodes are often enlarged. Secondary infectious lesions appear within a few weeks, either before or after the primary lesion has healed. Rashes continue to appear over the next 5 years. Condylomata form at moist sites, and are highly infectious. Later periostitis may occur, affecting fingers, tibia (causing sabre
tibia) and nose (a destructive lesion called gangosa). Painful, deep fissures in the soles of the feet also occur.
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Diagnosis and management The organisms are readily found in serous material from primary and secondary lesions examined by dark-ground microscopy. Serological tests for syphilis are positive. Penicillin aluminium monostearate is very effective given once only in a single dose of 1.5 g (0.75 g for children under 10 years). Tetracycline (2.0g/day in divided doses for 14 days) can be used in those allergic to penicillin, apart from pregnant women and children under 8 years, who should receive erythromycin for 2 weeks.
ENDEMIC SYPHILIS (BEJEL) Endemic syphilis is due to non-venereal infection with an organism that is intermediate between T. pallidum and T. pertenue. It is present in the desert regions of North Africa and the Middle East. Infection probably occurs by personto-person spread among children and older women who look after children. The first lesions are mucous patches in the mouth. Later, moist raised lesions of various sizes in axillae, groins, perineum and between the buttocks are seen. Hyperkeratotic lesions, like those of yaws, affect palms and soles. Bone involvement (periostitis) is associated with pain in the knees and shins. Destructive lesions of the nose, similar to gangosa in yaws, may occur. Congenital transmission does not occur, and late disease affecting the cardiovascular and nervous systems is very rare. Treatment with penicillin aluminium monostearate, as in yaws, is effective.
PINTA Pinta is a treponemal infection caused by T. carateum. Geographically it is localized to the drier regions of Central and South America. Transmission occurs by direct contagion from infectious skin lesions, and breaks in the skin may be a route of entry for the organism. The primary skin lesion is a papule sited on the extremities, around which smaller, similar lesions appear. 5 Spirochaetes may be found in serous material expressed from the erythematous and violaceous lesion. Serological tests for syphilis are positive. Treatment is with a single dose of benzathine penicillin (1.5g intramuscularly, or 0.75 g for children under 10 years).
RELAPSING FEVER Relapsing fever is an acute infectious illness caused by Spirochaetes of the genus Borrelia. Borrelia recurrentis is the cause of louse-borne relapsing fever, and a range of other species cause the tick-borne variety.
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Aetiology and transmission Borrelia are spiral organisms which can be identified in peripheral blood smears using Giemsa and Leishman stains; they can also be readily identified using dark-ground microscopy and cultured on artifical media. Humans are the reservoir of infection of louse-borne relapsing fever. The human body louse, Pediculus humanus, is the vector. Sudden mass migrations of people grouped together in adverse conditions encourage the spread of lice and louse-borne diseases, relapsing fever and typhus. Tick-borne relapsing fever is a sporadic zoonosis in humans in areas where there is a cycle of transmission between ticks and wild rodents. The disease has a worldwide distribution, except for Australia and the Pacific region. Pathogenesis and pathology During the incubation period spirochaetes divide intravenously. Platelets are sequestered, intravascular coagulation occurs, and a bleeding tendency results. After 4-5 days of symptoms there is a crisis associated with massive phagocytosis of Borrelia, helped by opsonizing antibody. Following the crisis there is an afebrile period during which numbers of organisms expressing different surface antigens build up and symptoms recur. This can occur up to five times. The spleen, liver, heart and brain are the main sites of pathological lesions, which consist of macrophages surrounding and ingesting large numbers of organisms. Clinical features After an incubation period that varies from 4 to 18 days the illness begins suddenly with rigors and a fever which rises rapidly to 40°C. Headache, joint pains, anorexia, malaise, nausea and vomiting are usual features, with mental confusion frequently present. Hepatosplenomegaly is common, with jaundice present in some patients. A petechial rash, most prominent on the trunk, is seen. Bleeding from the nose, the respiratory tract or the gut may occur, as may focal neurological signs. The first febrile period lasts about 5 days before spontaneous defervescence. This follows a severe febrile paroxysm with cold extremities, a rising pulse rate and blood pressure, and tachypnoea. An afebrile period lasting about 7 days recurs before the first relapse. Tick-borne disease is milder than louse-borne disease. In both, death can occur during the initial rigor or during defervescence. Diagnosis Organisms can be found in Giemsa-stained peripheral blood smears. 1 Dark-ground microscopy can be used to demonstrate the motile spirochaetes in a fresh blood smear.
1
330
Fig. 9.28
2
MCQ 9.21 3 Fig. 9.29
Management Antibiotics kill spirochaetes readily. Tetracycline can be used in patients over 8 years old. Erythromycin can be used in pregnant women and young children. Louse-borne relapsing fever requires a single dose of 500 mg of either drug. Tick-borne relapsing fever requires treatment for 10 days. Supportive care is needed, particularly in patients with louse-borne disease, as they can develop severe reactions, including Jarisch-Herxheimer, after being treated. Central venous pressure monitoring is essential if facilities are available. Hypoxia is corrected by giving oxygen continuously. Vitamin K is given if the prothrombin time is prolonged. Prevention Delousing by washing with soap and water, followed by dusting with 10% DDT, is effective. Clothes should be washed with soap in water at 55°C to kill lice and nits (lice eggs), which are found in the seams of clothes. Lice cannot survive on a person who has two sets of clothes worn on alternate weeks.
LYME DISEASE Lyme disease is caused by infection with Borrelia burgdorferi, transmitted by the tick Ixodes dammini. It is described on page 1160.
LEPTOSPIRAL INFECTION Infection with Leptospira icterohaemorrhagiae is discussed on page 879. 2
ACTINOMYCOSES Actinomyces species, despite their name, are bacteria which are often confused with fungi because of their filamentous appearance and their propensity to produce chronic suppurative infection with sinuses discharging purulent material. Most human disease is caused by Actinomyces israelii, an oral commensal, and occurs in the presence of chronic lack of dental hygiene. The characteristic pathological feature is that tissue boundaries are crossed and bone is infected. There is a fibrotic reaction around suppurating areas which accounts for the induration detected in palpable lesions. Three major forms of disease occur: cervicofacial, thoracic and disseminated actinomycosis. In cervicofacial actinomycosis the characteristic lesion is a painless swelling below the border of the mandible, bluish, fluctuant and slowly enlarging. Sometimes the abscess is painful and is usually apparent long before there is any spontaneous discharge. Thoracic actinomycosis may result from aspiration of oral debris, or may occur after thoracic surgery; it is easily
SUMMARY 13 Actinomycosis • • • • •
Cervicofacial form associated with poor dental hygiene Thoracic form may follow surgery Abdominal form is usually ileocaecal Discharging sinuses occur Prolonged penicillin treatment is needed
confused with carcinoma. The chest radiograph shows unilateral consolidation, with evidence of chest wall involvement. Nowadays the disease is usually diagnosed before discharging sinuses develop. Actinomycosis may be disseminated haematogenously and lesions may occur at almost any site. The abdomen is the most common, usually in the ileocaecal region. Because of the chronic course and the difficulty of diagnosis, sinus or fistula formation is still seen in abdominal actinomycosis. Other rare sites of infection are the pelvis, CNS and bones. Diagnosis and management Microscopy of tissues reveals the Gram-positive organisms, with surrounding acute or chronic inflammatory reaction and foamy macrophages. The organism can be cultured from tissues and, rarely, from blood. Penicillin is the drug of choice and prolonged treatment in high dose is necessary. Intravenous administration of 2.4-3.6 g every 6 hours for 4-6 weeks is followed by oral treatment with amoxicillin 500 mg every 8 hours for at least 6 months. Tetracycline, erythromycin and chloramphenicol are alternatives in penicillin-allergic subjects. Relapse is uncommon if this rigorous approach is adopted. Surgery is rarely required but may have to be considered in severely ill patients who fail to respond to medical therapy, and possibly in those with CNS disease.
MADURA FOOT This is a descriptive term for a group of chronic infections of the subcutaneous tissues and bone of - usually, but not invariably - the limbs. Two groups of organisms cause this condition: • Actinomycetes cause 60% of cases; these are bacteria and respond to antibiotics. • True fungi such as Madurella mycetomatis, which are almost totally unresponsive to antifungal drugs. These two groups of organisms are found in the soil and enter the skin by penetrating injuries. Pathology and clinical features The main features are chronic inflammation with microabscesses and granulomatous reactions around collections of the organisms. The organisms spread slowly along fascial planes and not via lymphatic or haematogenous routes.
Collections of organisms forming adjacent to bone produce local resorption, and small lytic areas visible on X-ray. 3 There are also areas of reactive sclerosis. Sinuses form and organisms are extruded. There is swelling of the affected area, with often prominent subcutaneous nodules. The time course is slow, and although there may be recollection of a penetrating injury, such as a thorn going deeply into the foot in childhood, there is often no such history and presentation may occur years after the patient has left an endemic area.
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Investigations and management The most important investigation is an adequate surgical biopsy of diseased tissue, which must usually go down to bone. This specimen is divided to give samples for histology and culture for the two groups of organisms. Actinomycetoma responds well to prolonged courses of antibiotics. Co-trimoxazole is effective (two tablets twice daily for 9 months, with streptomycin 1 g intramuscularly daily for the first 2 months). Dapsone, 100mg daily, is an alternative to co-trimoxazole. Pigmented grains fungi may respond to ketoconazole, whereas non-pigmented species are treated with itraconazole. Madurella mycetomatis has responded to ketoconazole 200 mg twice daily, and Aspergillus nidulans, A. flavus and Fusarium species have responded to 100 mg twice daily, in prolonged courses. Surgical removal of diseased tissue in addition to antifungal agents is recommended for some fungal infections.
NOCARDIOSES Nocardiosis is a systemic infection caused by species of Nocardia (N. asteroides and, less often, N. brasiliensis and N. caviae). N. brasiliensis is the common cause of actinomycetoma in the tropics and subtropics. Nocardia are higher bacteria which exist in a filamentous and coccobacillary form, depending on culture conditions. Aetiology, pathogenesis and epidemiology Nocardia are aerobic, filamentous branching Gram-positive bacteria and grow well on standard culture media. The organisms are found in rotting vegetation and infection is acquired by inhalation in most cases, although inoculation via the skin occurs. Initial pulmonary lesions may lead to dissemination of infection by the bloodstream. Necrosis and suppuration are the typical pathological changes. Adults are most often affected. Infection occurs mainly in immunosuppressed individuals. Clinical features Acute and sometimes fulminant or chronic suppurative pulmonary disease occurs in nocardiosis. Fever, cough with viscid sputum, night sweats and weight loss are usual features. Pleural thickening and empyema may develop, and the affected lung may cavitate. Haematogenous dissemination to cause brain abscess, kidney lesions, bone lesions and subcutaneous sepsis is reported.
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Actinomycetoma due to Nocardia presents with longstanding swelling of the extremity, most often the foot or ankle, and sinuses discharging on to the skin.
diagnosis and can give information about the response to treatment. An adequate deep biopsy will give the best chance of isolating the organism concerned.
Diagnosis Diagnosis depends on finding the organism in discharges, exudates, bronchial washing or biopsy sections. Nocardia grow well on media used for growing tubercle bacilli and on Sabouraud's medium. Serological tests are helpful in
Management Co-trimoxazole is effective (two double-strength tablets every 8 hours). Prolonged treatment is the rule, with relapse being less common after 3 months, medication. Minocycline (100-200 mg twice daily) is also effective.
SYSTEMIC MYCOSES Mycoses are infections caused by organisms that are classified morphologically as yeasts or filamentous fungi. Yeasts are round or oval and reproduce by budding. Filamentous fungi grow by branching and longitudinal extension of hyphae. This is not a simple distinction, as several organisms can grow in either form, depending on conditions. 1
CANDIDA INFECTIONS The range of diseases caused by Candida albicans is very broad. It is a common commensal of the oral and vaginal mucosae at one extreme, and at the other it can cause pneumonia, endocarditis, septicaemia and death. Candida can become a pathogen on damaged skin, in severely ill patients, in patients who have specific immune deficiency (especially AIDS), and in patients receiving
SUMMARY 14 Candida infections Skin
Secondary infection of damaged skin Mucocutaneous candidiasis (specific T cell deficiency)
Oral
Broad-spectrum antibiotic use Topical corticosteroids (e.g. inhalers for asthma) Immune deficiency (e.g. AIDS) Severe illness
Vaginal
Antibiotics or contraceptive pill Spontaneous (no immune deficiency)
Pneumonia
Due to severe illness with secondary immune deficiency
Septicaemia
Severely ill patient; multiple antibiotics Intravenous cannulae Neutropenia
1
332
Figs 9.30, 9.31
2
Fig. 9.32
broad-spectrum antibiotics when the local microbial ecology is disturbed. Both cell-mediated and humoral immunity participate in control of Candida. Inherited deficiency of T-cell function causes severe but localized disease. In combined immune deficiency the infection becomes disseminated. Severely ill patients under intensive care frequently have a mixed immune deficiency and are also receiving antibiotics that predispose to Candida infection. Disseminated infections are also seen in intravenous drug abusers. Cutaneous and mucosal surface candidiasis is described in Chapter 10. Diagnosis of systemic Candida infection Candida septicaemia is often a terminal event and over half of patients are diagnosed at postmortem. Clinical signs are usually minimal, but there may be endophthalmitis with fluffy yellow/white retinal spots resembling cottonwool spots, or small abscesses may be detected elsewhere, such as in the liver, where ultrasound-guided biopsy or aspiration can clinch the diagnosis. Pulmonary infiltrates may occur on chest X-ray, with Candida in bronchial washings. Isolation of Candida from a single site on one occasion does not necessarily indicate serious infection, even when it comes from a blood culture. The judgement that Candida is responsible for disease manifestations remains clinical. In view of the difficulty in diagnosis, treatment is given for disseminated Candida infection if Candida is cultured from more than one site in a severely ill patient in whom there is new evidence of infection (e.g. fever) but bacterial infection is judged to be unlikely. Management Fluconazole is the first choice for disseminated candidiasis. It is given intravenously, 400 mg by infusion initially, followed by 200 mg daily until oral therapy can be substituted. Maintenance treatment is needed until antibiotics are stopped. Toxicity is very uncommon. If there is no response to this drug amphotericin B is substituted, starting at 0.25 mg/kg daily infused over 1 hour, increasing rapidly to about 0.8 mg/kg daily. The maximum dose is limited by sideeffects such as fever, uraemia and bone marrow toxicity. For management of local Candida infections and the emergence of drug resistance, see pages 391 and 453.
ASPERGILLUS Aspergillus is a less common fungal pathogen which can cause disseminated disease in terminally ill patients. However, its more common manifestations are a range of respiratory diseases, the nature of which is determined by the immune response of the host (see Ch. 13). 2
CRYPTOCOCCOSIS Cryptococcosis (torulosis) is a systemic infection with the yeast-like fungus Cryptococcus neoformans. The organism is commonly found in soil contaminated by bird droppings, notably those of pigeons. Disease occurs following inhalation of the organism, but it is unusual in immunocompetent people and currently is seen most often in patients with AIDS (Ch. 11, p. 448). Clinical features CNS infection causes chronic meningitis with very lowgrade symptoms on presentation. Cranial nerve palsies may cause visual abnormalities, loss of acuity or diplopia, or facial weakness and numbness. The course is slow or rapidly progressive, depending on the patient's immune status. Corticosteroid therapy accelerates progression. Respiratory infection usually occurs in the absence of CNS involvement. It is more chronic and may regress spontaneously. Skin lesions are found in 10% of patients. The face and scalp are the most common sites of the painless lesions, which are variable nodules, sometimes ulcerating. Diagnosis Routine culture is often negative. In the CSF little abnormality is found, apart from a few cells, mainly lymphocytes, mildly reduced glucose compared with the blood, and slightly raised protein. The organisms are shown by India ink preparations, but the most sensitive method of diagnosis is by detection of antigen in CSF and sometimes in blood. Management Treatment is started with fluconazole 400 mg daily, by mouth if the patient is not vomiting, or intravenously at the same dose. If there is no response after 2 days amphotericin B is substituted, giving up to 1-1.5 mg/kg/day until there is a clinical response, and then reducing to three times weekly to a total dose of 1-2.5g (see Candidiasis).
HISTOPLASMOSIS Histoplasma capsulatum is a common environmental fungus found in the soil in a filamentous form, but when it infects humans it behaves as a yeast. It multiplies rapidly in soil containing the droppings of birds and bats, and humans are usually infected by inhalation of spores in
infected dust. Infection has been shown to be common by skin test surveys in the eastern central part of the USA, but there are also scattered areas of infection in both temperate and tropical areas of the world. H. capsulatum var. duboisii is a variant found in central Africa. H. capsulatum infects macrophages, and the pathogenesis of disease is similar to that of tuberculosis. Delayed hypersensitivity skin tests show that the majority of infected individuals are asymptomatic. Clinical features of H. capsulatum Acute pulmonary infection in normal hosts causes febrile illness with headache, often accompanied by cough and chest pain, with malaise, myalgia and weight loss. Erythema nodosum or multiforme may occur. Symptoms usually last less than a week, but occasionally severe infection is seen following a large infecting dose and it may even be fatal. Radiological changes occur in only 25% of acute infections, with scattered pulmonary infiltrates and hilar and mediastinal lymphadenopathy. The histoplasmin skin test is not helpful in diagnosis, but a complement fixation antibody test may be useful. Treatment is often not required but, now it is established that the azole drugs, ketoconazole and itraconazole, are beneficial, they can be given more easily than amphotericin B and with less risk of toxicity, and they may make patients feel better earlier than if they receive no treatment. Ketoconazole (400 mg daily) or itraconazole (200 mg daily) is given by mouth for 3-6 weeks. Amphotericin B (0.8mg/kg daily) is reserved for severe illness. Concurrent prednisolone therapy, tapering from 60-80 mg/day, is given if there is a marked hypersensitivity reaction to the infection. Chronic pulmonary histoplasmosis affects normal individuals with structural defects of the lung. Infection of emphysematous lesions causes chronic destructive disease in the lung apices, similar to tuberculosis. Fever may be accompanied by night sweats; one-third of patients have chest pain. Diagnosis requires repeated sputum cultures. Antibody and skin tests are usually unhelpful. Treatment is with ketoconazole, 400 mg daily for 6-12 months, or longer if there is evidence of relapse. Itraconazole is more expensive but may cause fewer side-effects. The need for treatment is judged on the basis of clinical severity. Disseminated histoplasmosis is a rare and often fatal manifestation of infection in immunocompromised hosts. It may be acute, subacute or chronic, depending on the age of the patient (acute is more frequent in infants) and the degree of parasitization of macrophages (more severe parasitization causes more acute disease). Fever, hepatosplenomegaly, anaemia, leukopenia, thrombocytopenia and interstitial pneumonia are most common in the acute disseminated form. Intestinal ulceration, Addison's disease, meningitis and endocarditis occur in the subacute form, and oropharyngeal ulcers occur in chronic disseminated disease. Diagnosis is by histology and culture of relevant tissues, and treatment is as for the other forms
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of the disease. Amphotericin B is reserved for the most severe cases where the prognosis is poor, and it is the first choice of treatment for progressive disseminated histoplasmosis associated with AIDS, which does not respond satisfactorily to ketoconazole.
Histoplasma capsulatum var. duboisii H. capsulatum var. duboisii infection occurs in Africa. The route of infection is poorly defined; asymptomatic pulmonary infection, with later spread to the skin and bones or inoculation into the skin, is a possibility. Skin, subcutaneous tissues and underlying bone can be affected, causing: • Superficial, cutaneous granulomas (papules or ulcers) • Subcutaneous granulomas and abscesses • Osteomyelitis with discharging sinuses which heal intermittently. Smears from exudate or discharges show numerous large yeast cells. Histological sections of infected tissue show giant cell granulomas with the large yeast cells. Treatment with ketoconazole (400 mg daily) or amphotericin B may be needed in lesions that show no signs of regression.
COCCIDIOIDOMYCOSIS Coccidioidomycosis is a fungal infection caused by Coccidioides immitis. Its distribution is confined to arid areas of the western hemisphere, including the southwestern USA, Central America and some countries of South America. Dust contaminated with fungal spores is the source of infection. Granulomatous responses occur around fungal spherules, and suppurative lesions with leukocytes characterize the tissue response to endospores. The host response to the organism determines the outcome of disease. Asymptomatic infection occurs in about three-fifths of patients and is detected by skin testing. A smaller number of those infected present with respiratory symptoms, cough, fever and chest pain, with malaise, muscle pains, night sweats and chills. A macular erythematous rash, erythema nodosum and erythema multiforme also may be seen (p. 407). Radiographic appearances include pneumonitis, hilar adenopathy and pleural effusion. In most of these patients the disease resolves spontaneously. In some cases pulmonary infiltrates and systemic symptoms persist, sometimes with cavitation. The diagnosis is made by finding the endospore of the organ-
1
334
MCQ 9.22
ism in material from affected lung. There is a considerable risk of laboratory infection with this organism. Serological tests are an aid to diagnosis. Dissemination of infection from an initial site of pulmonary disease may occur. Pregnant women show an increased incidence of dissemination. All tissues and organs of the body may be affected. Meningitis is one of the most severe manifestations of disseminated infection. Amphotericin B is used in treatment. The main difficulty lies in deciding which patients will benefit from treatment. Persistent, symptomatic pulmonary infection and disseminated infection require chemotherapy.
PARACOCCIDIOIDOMYCOSIS Paracoccidioidomycosis, or South American blastomycosis, is unrelated to Coccidioidomycosis. It is caused by Paracoccidioides brasiliensis and occurs exclusively in the area between Mexico and Argentina. The natural environment of the pathogen is uncertain. Its mode of acquisition is probably through inhalation. Clinical features, diagnosis and management Adults usually present with progressive respiratory symptoms, sometimes accompanied by ulcers in the mouth and nose, dysphagia, voice changes, skin lesions and cervical lymphadenopathy. Diagnosis is usually made by culture or histology, and treatment is with imidazole (particularly itraconazole), sulphonamides or amphotericin B.
BLASTOMYCOSIS Blastomycosis is a primarily pulmonary disease caused by the dimorphic fungus Blastomyces dermatitidis. It is much less common than histoplasmosis and occurs mainly in the eastern USA. The organism has been isolated from soil, and infection may be by inhalation of dust. Clinical features Primary infection may be asymptomatic, or it may lead to an acute pneumonia which either resolves spontaneously or progresses to chronic pulmonary disease, which may be confused with tuberculosis. Extrapulmonary manifestations are caused by haematogenous spread from the lungs, and the most common is skin disease with verrucous or ulcerative lesions. Diagnosis is by demonstration of the yeasts in sputum or other specimens, or by culture of the organism. Amphotericin B is the mainstay of therapy, but imidazoles have been used successfully.
SPOROTRICHOSIS
MUCORMYCOSIS
Sporothrix schenckii is a dimorphic fungus found in soil, on plants and on plant debris. Infection is uncommon and is seen in the Americas and Africa. Disease usually results from traumatic inoculation into the skin, and the common form is a red painless papule at the site which enlarges and forms a granulomatous plaque that commonly ulcerates. Further lesions often appear proximally along the course of the lymphatic channels, which are often palpably thickened by inflammatory infiltrate such that they could be mistaken for thrombosed superficial veins, and in regional lymph nodes. Disseminated disease is rare and usually only occurs in immunosuppressed patients. Diagnosis is by culture of the organism from skin lesions. Cutaneous lesions are treated with a saturated solution of iodine, 5-10 drops t.d.s. orally and gradually increasing to 50 drops t.d.s. for up to 3 months, and extracutaneous disease with amphotericin B. Itraconazole can also be used.
Mucormycoses are a group of similar diseases caused by members of the order Mucorales. The organisms are common in the environment, often growing on fruit or bread. They cause disease almost exclusively in immunosuppressed patients.
9
Clinical features In rhinocerebral disease in an uncontrolled diabetic the fungus invades the palatal, nasal and paranasal sinus mucous membranes, and destructive lesions spread directly back towards the brain. Black necrotic lesions are visible, and from these a variety of secondary bacterial pathogens are often isolated. Pulmonary, cutaneous and intestinal disease may occur. Diagnosis is made by examination of scrapings and biopsies, and cultures are often negative. Successful treatment depends on management of the underlying cause. Amphotericin B is the only useful drug in treatment, but the response is often poor. 1
PROTOZOAL INFECTIONS
Protozoa are single-cell organisms that have adapted to a range of ecological niches in the human host (Table 9.32). They are an important cause of human disease, especially in the developing world.
PROTOZOAL INFECTION OF THE GUT
GIARDIASIS Infection with the flagellate protozoan Giardia lamblia can cause asymptomatic infection or diarrhoeal disease of variable severity, from mild to severe with malabsorption. Aetiology The parasite is a flagellate, pear-shaped protozoan (Fig. 9.24) which is found in the lumen of the upper small intestine. Some trophozoites encyst, to be passed in the faeces. The cyst is infective and can survive for 2 months at 8°C in water. It is resistant to normal levels of chlorination, and sand filtration is used to clear municipal water supplies of this and other parasites. The parasite can now be grown in culture. Distribution ana1 incidence The distribution is worldwide, although it is more common in the tropics. It is endemic in the countries of eastern Europe. Epidemics have occurred at daycare nurseries, on cruise ships and in towns in the USA. Giardiasis has
occurred in children in inner-city populations in Britain, and can cause diarrhoea in the elderly. Transmission ana1 epidemiology Spread is by the faecal-oral route. As few as 10 cysts will cause infection, and 1000 cysts consistently cause infection. Contaminated food and water are vehicles of infection. Person-to-person spread is common in childhood, particularly when children are not toilet trained. Mothers are often infected by changing the nappies of an infected child. Any circumstances in which standards of personal and public hygiene (such as water treatment) are low lead to transmission. In the tropics children are most often infected, although both indigenous and visiting adults can develop symptomatic disease. Male homosexuals and retarded children are other risk groups. Hypogammaglobulinaemia and reduced gastric acid secretion are host factors that increase susceptibility. Pathology and pathogenesis The main abnormalities relate to the function and morphology of the upper small intestine. Markedly symptomatic patients have impaired absorption of fat, o-xylose and vitamin B12, and lactose maldigestion. The jejunal mucosa is abnormal, with a ridged or convoluted mucosa, reduced villous height with increased crypt depth, and an increased infiltrate of plasma cells in the lamina propria. Subtotal villous atrophy may occur with giardiasis but is uncommon. Patients with mild or no symptoms have
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TABLE 9.32 Classification of protozoa Gut protozoa Giardia lamblia Cyclospora cayetanensis Cryptosporidium Entamoeba histolytica Balantidium coli Isospora belli Sarcocystis Non-pathogenic gut protozoa Entamoeba coli Entamoeba hartmanni Endolimax nana lodamoeba butschlii Chilomastix mesnili Blastocystis hominis Entamoeba dispar Genital tract protozoa Trichomonas vaginalis Tissue and blood protozoa Toxoplasma gondii Pneumocystis carinii Plasmodium species
Babesia species Trypanosoma gambiense, rhodesiense and cruzi Leishmania species Free-living protozoa causing human disease Naegleria fowleri Acanthamoeba
normal jejunal morphology and function. Lactose maldigestion may be present. The pathogenesis is not well understood. The parasite itself may damage the enterocyte surface membrane to impair function and fat digestion intraluminally. Jejunal colonization with bacteria may also contribute to some of the mucosal dysfunction. Antigiardia IgA from the mucosa and in bile may control parasite numbers. Clinical features The incubation period is usually about 10-14 days, although it can be much longer. Many patients with giardiasis are asymptomatic or have minimal bowel upset. Acute giardiasis is characterized by the sudden onset of anorexia, nausea, abdominal distension, discomfort and diarrhoea with frequent yellow, offensive, frothy stools by day and night. Lethargy is often severe and weight loss is usual. After about 3 weeks there may be the beginnings of spontaneous improvement. This may progress to complete resolution over a month, but some patients remain mildly symptomatic, often because of continuing lactose intolerance. Some patients remain markedly symptomatic and fail to regain lost weight or continue to lose weight. The abdomen is distended and bowel sounds are prominent. The stools 1
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MCQ 9.23
FIG. 9.24 Scanning electron micrograph of Giardia lamblia (Reproduced by kind permission of Dr David Warhurst.)
are yellow and offensive. Testing confirms malabsorption. Children are occasionally brought to medical attention because of failure to thrive. Giardiasis has been reported as a cause of chronic diarrhoea in elderly persons in the UK. It is not a major cause of diarrhoea in AIDS. Diagnosis Diagnosis depends on finding the parasites. Stool microscopy shows cysts in most patients, although examination of several samples may be necessary. Trophozoites may be found in diarrhoeal stools. When the parasite is not found and symptoms are marked, investigation of intestinal morphology and function is indicated. Jejunal juice and jejunal mucus obtained at the time of biopsy can be examined for trophozoites. Giardia may be seen in the intervillous space of the sections of the biopsy. Giardia antigens can be detected in stools by immunological techniques. Differential diagnosis Other causes of gastroenteritis are discussed on page 278. Cryptosporidiosis causes self-limited diarrhoea in healthy persons (see below). Cyclosporiasis causes a similar acute illness (see below) Campylobacter species can cause a small bowel type of diarrhoea but usually cause systemic upset. The differential diagnosis of malabsorption syndrome is discussed in Chapter 15. Laboratory features Laboratory investigations show malabsorption of fat, Dxylose and vitamin B12 in severely affected patients. DXylose malabsorption and lactose maldigestion may also be present in those with mild symptoms. Occasional patients are seen who have marked malabsorption and folate deficiency. Barium follow-through examinations show nonspecific changes, with dilatation of small bowel loops and thickened mucosal folds in patients with malabsorption.
SUMMARY 15 Giardia
SUMMARY 16 Treatment
Anorexia Lethargy Weight loss Diarrhoea Yellow mushy to watery stools Abdominal distension Sulphurous eructation Foul-smelling flatulence
First choice Tinidazole 2g single dose with evening meal Repeat 1 week later Precautions: no alcohol for 48 hours after dose, as it can make people 'woozy'. Also, patients should not ride a bike, drive a car or operate any dangerous machines for 48 hours after doses
Note: These are typical symptoms; in an acute severe case there is a range of severity, as indicated in the text.
Management Tinidazole is effective and can be given in a single dose of 2g (50mg/kg) which can be repeated after 1 week. A cheaper alternative is metronidazole, 2g as a single dose on 3 successive days. A second course after 10 days may increase the cure rate. Both drugs cause nausea and a metallic taste in the mouth, and have a disulfiram-like interaction with alcohol. Asymptomatic giardiasis in pregnancy need not be treated. When there is symptomatic disease in pregnancy associated with weight loss or failure to gain weight, then metronidazole (200 mg three times a day for 10 days) may be given. Symptoms due to giardiasis improve rapidly after treatment. Dietary measures are sometimes helpful for continuing gut symptoms. Avoidance of alcohol, spicy foods and lactose is often helpful. Repeat stool microscopy 6-8 weeks after treatment provides a test of cure. Abnormalities in intestinal structure and function disappear over 6-12 weeks after treatment. Prevention and control Travellers in areas where the tap water is not safe to drink should avoid salads, uncooked foods, unpeeled fruits and ice cubes in drinks. Sterilization of drinking water with 2% tincture of iodine (0.5 mL/L of water and allow to stand for 30 minutes) may be necessary. Treatment of asymptomatic cyst excreters is worthwhile, particularly in a non-endemic area, as it reduces the risk of transmission to others. 1
CYCLOSPORIASIS Cyclospora cayetanensis is a coccidian protozoan parasite which has been recognized as a cause of acute and persisting diarrhoea. The organism is an intracellular pathogen that infects the enterocytes. It has a complex lifecycle involving sexual and asexual forms, similar to that of Toxoplasma gondii. Infection occurs by ingestion of oocysts. It causes an acute small bowel type of diarrhoea with features suggesting malabsorption. It is not associated with systemic upset, dysentery or a faecal cellular exudate. It is likely to have a widespread geographic distribution
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Second choice Metronidazole 2g single dose with evening meal for 3 days Repeat 1 week later Same precautions Third choice Mepacrine 100 mg tds for 7 days Causes abdominal discomfort: stains the skin yellow Contraindicated in patients with psoriasis If the above fail, try albendazole 400 mg bd for 5 days
throughout the world. The diagnosis is made by finding the oocysts, which contain four sporozoites in the mature form, in faeces which stain a pinkish colour with a modified Ziehl-Neelsen method. Treatment with co-trimoxazole, two tablets twice daily for 7 days, is effective.
CRYPTOSPORIDIOSIS Cryptosporidiosis is an infection of the gastrointestinal tract with the sporozoan parasite Cryptosporidium. It causes enteritis in humans and a range of other animals. It is a zoonosis with a worldwide distribution. Its life cycle is complex, with asexual and sexual cycles. Infection is by the faecal-oral route. Ingested oocysts are disrupted in the intestinal lumen, liberating four sporozoites which enter the apical regions of intestinal cells within a membrane-bounded vacuole. Trophozoites develop from the sporozoites and undergo asexual reproduction. Merozoites liberated by schizogony can undergo further asexual cycles, or become gametocytes which fuse to form oocysts which are passed in the faeces. Transmission and epidemiology Many reports recognized this organism as a gut pathogen causing persistent watery diarrhoea in immunosuppressed patients, especially those with AIDS. Other studies showed that Cryptosporidiosis was associated with diarrhoea in 4-9% of otherwise healthy children and adults. Children at nursery school may transmit infection person to person. Susceptible animals include calves, lambs, goats and birds, although a history of contact with animals is often absent. Clinical features An acute watery diarrhoeal illness, often with offensive
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stools, is the usual history. There may be fever and vomiting. The disease is self-limiting, with a median duration of about 12 days, but prolonged diarrhoea with weight loss occurs in patients with humoral and cellular immunodeficiency states, especially AIDS (p. 446). Diagnosis and management Faecal smears stained by the modified Ziehl-Neelsen technique show the pinkish-red-staining oocysts. Other forms of the parasite are seen at the luminal surface of enterocytes in intestinal biopsies. In most patients the disease is self-limiting and symptoms resolve spontaneously in 10-12 days. There is no effective drug therapy for the chronic infection seen in AIDS patients though diarrhoea may regress with the institution of effective anti-retroviral treatment. Rehydration, nutritional support and symptomatic treatment may be needed. Handwashing is the most important factor in limiting the spread of infection by the person-to-person route. FIG. 9.25 Scanning electron micrograph of Entamoeba histolytica
AMOEBIASIS
(Reproduced by kind permission of Dr David Warhurst.)
The different manifestations of amoebiasis have long been a paradox. The following have been recognized:
not with non-invasive strains has been developed. These findings give support to the view that there are two separate species, one consistently a pathogen, E. histolytica, and the other a commensal, E. dispar.
• Non-invasive, asymptomatic and confined to the lumen of the colon, with amoebic cysts in the stools; • Invasive ulcerative colonic disease (amoebic dysentery) with amoebic trophozoites in stools and scrapes from the ulcers; • Invasive, causing amoeboma; • Invasive, causing amoebic liver abscess (ALA). Hitherto all these forms have been ascribed to infection with Entamoeba histolytica, but research over the past two decades has produced evidence for the existence of two separate species accounting for invasive and non-invasive conditions, respectively. Aetiology Entamoeba histolytica has two forms, a motile trophozoite (Fig. 9.25) and an encysted trophozoite. The motile trophozoite is found in the stools of a person with amoebic dysentery and contains ingested red cells. The cyst is the infective form. It is resistant to the chlorine in potable domestic water supplies. Sand filtration is the best method of removing cysts from water. Isoenzyme analysis of strains from patients with invasive disease and persons who excrete cysts only has shown two separate patterns that segregate invasive from non-invasive organisms. Subsequently a DNA probe which hybridizes with invasive amoebae but
1
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Figs 9.33, 9.34
2
Distribution and incidence Amoebiasis has a worldwide distribution. It is common in those areas of the world where standards of sanitation are low. Most instances of invasive disease occur either in endemic areas or in travellers who have recently been exposed. Occasional cases are seen in people who returned from endemic areas years before, or who have never left a country such as Britain. Transmission and epidemiology Faecal-oral spread by ingestion of amoebic cysts in contaminated food and water, or on fingers or other direct personal contact, is the route of infection. With the new classification of amoebae noted above we now need information about the prevalence of Entamoeba histolytica, particularly the frequency of excretion of cysts. People excreting cysts are the source of infection to the community. There is an ELISA-based technique for detecting E. histolytica. Asymptomatic amoebiasis (E. dispar) is not uncommon in male homosexuals in Britain with transmission by person-to-person spread. It is also common in the tropics and subtropics. Amoebiasis is more common in adults than children. Men are affected by ALA more often than women, but dysenteric disease occurs in both sexes. Invasive amoebiasis can be more severe in pregnancy.
Fig. 9.35
Pathology and pathogenesis There are no pathological changes in E. dispar cyst
excreters. Their amoebae live on the colonic mucosa but do not invade. There is now a need to review the pathological findings in asymptomatic E. histolytica cyst excreters. These individuals maintain infection in communities without apparently being diseased themselves. In amoebic dysentery trophozoites invade the colonic epithelium and lyse host cells, causing necrosis. Areas of the mucosa are excavated, leaving multiple flask-shaped ulcers. 1 Amoebae are found in the slough and in the advancing edge of the lesions. The rectum and caecum are commonly affected areas, but the extent can vary from localized proctitis to a pancolitis with a diffusely inflamed ulcerated mucosa. 2 The mucosa over a variable length of the colon is occasionally sloughed off and passed per rectum, leaving exposed denuded submucosa. Amoeboma is an uncommon late complication that occurs after amoebic dysentery has resolved. The lesion consists of a mass of granulation tissue containing few amoebae. The caecum is a usual site, but any part can be involved and lesions may be multiple. ALA results from the haematogenous spread of amoebae from the colonic mucosa via the portal vein. Amoebae reach the liver, and on contact with amoebae liver cells are lysed. The affected area enlarges progressively and the necrotic cells liquefy in the abscess cavity, which may be unilocular or multilocular. A single abscess in the right lobe is usual. The pus is typically odourless, pinkish-brown, sterile on culture and with few pus cells. A carbohydrate containing lectin on the surface of amoebae helps attachment to epithelial cells. The mechanism of cell damage then appears to be the result of insertion of a large permanent ion channel into the host cell membrane, and the host cell dies rapidly. This ion channel is referred to as an amoebapore. Clinical features No symptoms are attributable to the commensal amoeba. In patients with amoebic dysentery symptoms vary according to the extent and site of colonic involvement. The usual symptoms are abdominal discomfort and increased frequency of bowel action, with softer stools. Blood may be noticed in the stools: sometimes flecks of blood or bloodstained mucus on the outside of stools, and sometimes overtly bloodstained stools. Physical signs usually consist of mild colonic tenderness. Sigmoidoscopy may show the typical appearance of scattered ulcers surrounded by mucosal erythema with normal mucosa intervening, but the mucosa may be diffusely inflamed and ulcerated. With increasing extent of colonic disease, symptoms and signs are more marked. When sloughing of areas of the mucosa occurs loss of protein-rich fluid from the denuded mucosa is marked. Acute onset of diarrhoea with systemic upset is almost certainly not due to amoebic dysentery, even if there is blood in the stools. It tends to have a more indolent onset with, in some patients, the development of more severe symptoms and signs as the extent of colonic involvement increases.
Dehydration, anaemia and septicaemia may occur in severe disease, and perforation, toxic dilatation and significant haemorrhage may complicate the clinical course. Rarely the superficial part of the mucosa may be sloughed over a variable length of colon and passed per rectum. Occasionally ulceration can extend from the anal canal to affect the perianal skin. Late complications of amoebic dysentery are colonic stricture and amoeboma, where a mass of granulation tissue forms in response to the presence of relatively few amoebae. Localized pain and blood in the stools are usual symptoms, and one or more masses may be felt in the abdomen or rectally.
9
Symptoms and signs in ALA Symptoms and signs in ALA relate to the site and size of the abscess. There may be no history to suggest past or present intestinal amoebiasis, and many patients do not have amoebic cysts in their stools. Fever, sweats, lethargy and anorexia are usual early symptoms and examination may reveal no abnormal physical signs, or only tenderness on springing the right lower ribcage. With larger abscesses pain becomes a more prominent feature related to the site of the abscess. Abscesses sited laterally or superiorly cause chest pain which may be pleuritic, or referred pain in the right shoulder indicating diaphragmatic irritation. Rigors occur with multiple large abscesses. Some patients have no systemic symptoms. The liver may be enlarged and tender, with a localized tender mass on the surface. With superiorly sited abscesses there may be dullness to percussion and impaired movement at the right lung base. Left lobe abscesses may present with symptoms and signs related to the epigastrium or left hypochondrium. Complications The main complication in ALA is extension outside the liver (Fig. 9.26). Spread to the brain may occur, producing a necrotizing abscess-like lesion. Rarely the skin of the chest or abdominal wall is involved after percutaneous rupture of ALA. Diagnosis Cyst passers are usually diagnosed when stool microscopy is carried out during screening after overseas travel or residence, investigation of diarrhoea due to some other microbial pathogen, or examination of other groups at risk of infection, e.g. male homosexuals. Serological tests for amoebiasis are negative. Antigen detection tests can be
SUMMARY 17 Amoebiasis • Cyst passers. Asymptomatic. Cysts in stools. • Amoebic dysentery. Diarrhoea, dehydration, anaemia. Motile trophozoites in faeces and scrapes from ulcers. • Amoebic liver abscess. Fever, pain, tenderness. Ultrasound shows abscess. Positive serology.
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CASE STUDY 9.3 TRAVELLERS' DIARRHOEA
A 26-year-old man had travelled extensively in India over a 4-week period. He presented to an infectious disease unit in London 21 days after his return with increased frequency of bowel action that had begun in the third week of his stay. He was passing stools that were softer than normal and which for the previous week had contained obvious external blood. There was no abdominal pain, appetite and weight were normal and he experienced no systemic upset. Abdominal examination was normal. On rectal examination the mucosa felt slightly granular and a limited sigmoidoscopy showed an inflamed mucosa to 15 cms, with haemorrhagic areas and some obviously ulcerated areas. Questions 1. What is the differential diagnosis? 2. What further investigations should be performed?
FIG. 9.26 Sites of spread of amoebic liver abscess
1
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Figs 9.36, 9.37
2
MCQ 9.24
Comment This history is in marked contrast to that of in Case study 9.1 (p. 279), which was invasive bacterial infection. The history is very suggestive of amoebiasis. Abdominal examination was normal. The endoscopic features are typical. Nonspecific inflammatory bowel disease (ulcerative colitis or Crohn's disease) could present like this and histological findings would be diagnostic. He could have postinfective gut symptoms and be bleeding from a colonic polyp, and so had amoebae or another source of bleeding not been found then colonoscopy would be the next step. Schistosoma mansoni affects the colon but only rarely causes rectal bleeding. This parasite occurs in Africa, the Middle East and South America, but not in India. In older patients presenting with rectal bleeding whether they have travelled to tropical areas or not colonic cancer always needs to be excluded
and colonoscopy is essential where no immediate source is found. A rectal biopsy was taken and a scraping from an ulcerated area and mounted on a slide in saline for immediate microscopy. A faecal smear was made from flecks of bloodstained mucus on the stool specimen provided, and microscopy of this showed motile trophozoites with ingested red cells. In the cellular exudate there were red cells but very few pus cells. The rectal scrape also showed motile trophozoites with ingested red cells. Histological examination showed an ulcerated mucosa with amoebic trophozoites in the surface layers. He was treated with tinidazole 2g as a single dose with food daily for 3 days, followed by diloxanide furcate 500 mg tds for 10 days.
used to identify E. histolytica cysts; most of those detected are E. dispar. Some cysts are, however, untypable using the currently available kit. Amoebic dysentery is diagnosed by finding motile trophozoites with ingested red cells in faecal smears or scrapes from ulcerated colonic mucosa. Amoebae can be seen in the edges of ulcers in rectal biopsies, where they are seen as large cells at the edges of ulcers and in slough. They are PAS-stain positive. Serological tests for amoebiasis (e.g. indirect fluorescent antibody test, or IFA) are positive in 60% of cases, and so diagnosis cannot depend on serology but rather upon finding the parasite. With amoeboma, cysts may be found in the stools. Colonoscopy allows the lesion to be visualized and biopsied. Serology for amoebiasis is positive in over 90% of cases and is a reliable test in this situation. Diagnosis of ALA depends on the clinical features suggesting an intrahepatic lesion and strongly positive amoebic serology (found in over 95% of cases). Cases seen early in the course of disease occasionally have a negative IFA but have a definitely positive test 7 days later. Additional investigations Intestinal disease With increasing extent of colonic involvement there is
increasing exudation of protein-rich fluid into the gut. Plasma albumin levels fall; normochromic, normocytic anaemia and a raised ESR develop. These investigations are normal in more localized disease. Plain abdominal X-rays are useful in giving an indication of the extent of the inflammatory process, indicated by the extent of colon devoid of faecal shadows. Barium enema studies show non-specific features with ulceration in dysentery. Amoeboma appears as one or more mass lesions causing narrowing of the colon, simulating colon cancer, and so if cancer is not demonstrated in biopsies from a stenosing lesion amoebic serology should be performed to prevent resection of something that would respond to metronidazole or tinidazole. Amoebic liver abscess There is neutrophil leukocytosis, a normochromic, normocytic anaemia and raised ESR. Bilirubin levels are usually normal, but aminotransferase levels are slightly raised; alkaline phosphatase levels are raised and plasma albumin levels are low. A chest X-ray will show elevation of the diaphragm above an abscess in the right lobe superiorly, and sometimes basal linear atelectasis or consolidation or pleural effusion. Ultrasound and CT scanning give more accurate information about an abscess, and its precise site and size. 1 Ultrasound can be repeated to assess changes and to guide the insertion of a needle for percutaneous aspiration. Differential diagnosis Intestinal disease Shigella, Salmonella, Campylobacter and Yersinia infections may all cause colitis, but the onset of symptoms is rapid in these infections and pus cells predominate in the faecal cellular exudate. Non-specific inflammatory bowel disease, Crohn's disease and ulcerative colitis must be considered. Amoebic infection should be rigorously excluded in a patient who could have been exposed to amoebiasis in the past, before treatment for inflammatory bowel disease, as steroids may promote rapid progression of invasive amoebiasis with perforation and death. Where the distinction cannot be made then treatment for both conditions may be appropriate. Carcinoma of the colon, pericolic abscess, Crohn's disease of the colon, tuberculosis of the ileocaecal region or colon, and schistosomiasis are possible causes of a colonic mass. Amoebic liver abscess Subphrenic and intrahepatic pyogenic abscess and infected hydatid cyst cause similar symptoms and signs. Often the history is more acute and the patient more toxic, with chills and rigors. Pyogenic liver abscess may be secondary to some other focus of intra-abdominal infection. Hepatocellular carcinoma and bacterial infection of a hydatid cyst may present like ALA, particularly when the carcinoma has undergone necrosis or there has been bleeding into it. Management The drug treatment of amoebiasis is set out in Table 9.33. Patients who can be shown to harbour E. dispar do not
TABLE 9.33 Drug treatment of amoebiasis Clinical situation
Drug
Cyst passer (E. histolytica)
Diloxanide furoate for 10 days 500 mg 3 times a day (8mg/kg3timesaday) Metronidazole 800 mg 3 times a day for 5-10 days (40mg/kg per day in 3 divided doses) or Tinidazole 2g (50mg/kg) single daily dose for 3 days (abscess) or 5 days, (dysentery amoeboma) followed by Diloxanide furoate 500 mg 3 times a day (8mg/kg3timesaday)
Amoebic dysentery Amoeboma Amoebic liver abscess
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need treatment. Symptoms and signs improve rapidly within 48 hours. Surgical treatment of amoebic dysentery is rarely needed, except where large areas of mucosa are sloughed; in this case resection of the affected colon can be life-saving. When ALAs are very large, pointing or likely to rupture, percutaneous aspiration is needed. This is done using a large-bore needle inserted under local anaesthetic, if possible under ultrasound guidance. Variable amounts of fluid can be removed. Amoebae are sometimes found in the material aspirated from the edge of the abscess. Aspiration has a low morbidity. Rupture of ALA dramatically increases the mortality, which is low in uncomplicated cases. Prevention and control The provision of clean water and safe disposal of faecal waste would do much to prevent transmission. Patients with invasive amoebiasis should always receive diloxanide furoate to eradicate any pathogenic amoebae remaining in the gut lumen. Where water supplies are not treated, boiling and filtering drinking water is advised. Tincture of iodine (2%) is effective in killing amoebae, used as above. Salads, unpeeled fruits and ice cubes are possible sources of infection and should be avoided in endemic areas. 2
BLASTOCYSTIS HOMINIS The pathogenicity of this organism is questioned. There do appear to be some infected patients whose diarrhoea settles with eradication of the organism after a single dose of tinidazole 2g on two occasions a week apart. However, there are also patients excreting B. hominis whose diarrhoea persists after eradication, and in others the organisms persist despite resolution of the diarrhoea. The organism is very commonly found in healthy individuals with no gut problems.
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BALANTIDIUM COLI INFECTION The ciliate Balantidium coli is the largest protozoan parasite in humans. It can be seen with the naked eye in cultures. It is a parasite of pigs, and humans who have close contact with pigs become infected. In most cases it causes no disease. Occasional cases of enteritis due to B. coli affecting the small and large intestine are reported. Death occurs as a result of bacterial peritonitis after ulceration and perforation of the gut. Metronidazole is effective in symptomatic cases.
Trichomonas infection is discussed in Chapter 11 (p. 462).
ISOSPORA BELLI INFECTION
NAEGLERIA FOWLERI INFECTION
Isospora belli is a sporozoan parasite of the gastrointestinal tract in humans. It has a worldwide distribution and humans are the only reservoir of infection. The life cycle has asexual and sexual phases. Infection occurs by ingestion of oocysts containing sporozoites, which are released in the small intestine and invade epithelial cells; there they undergo asexual reproduction, or schizogony. The host cell ruptures, releasing merozoites which invade other epithelial cells and reproduce asexually to form oocysts. These are released into the gut lumen by the normal desquamation of epithelial cells and passed in the faeces. Infection occurs by ingesting oocysts in contaminated food and water. Most infections cause no symptoms. Some cause a diarrhoeal illness, with weight loss, pale stools, lethargy and low-grade fever. Patients with immunodeficiency syndromes, including AIDS, exhibit chronic diarrhoea with more marked symptoms. The diagnosis is made by finding oocysts in stools, in jejunal juice, and in stained sections of jejunal biopsies. Co-trimoxazole, two tablets twice daily for 10 days, appears to be effective. Longer courses of treatment may be needed in patients with immunodeficiency.
Naegleria fowleri is a free-living amoeboflagellate, 6-9 mm in diameter, which causes the rare primary amoebic meningoencephalitis. It is found in water from hot springs as well as in ponds and pools, and has a worldwide distribution. Amoebae in fresh water are carried into the nasal passages by activities such as swimming. They adhere to areas of the nasal mucosae and then migrate through the cribriform plate along the nerve fibres. The amoebae replicate asexually and spread through the subarachnoid space. The olfactory bulbs show massive invasion with amoebae and necrotic changes. There is a superficial encephalitis of the affected area. Abscess formation can also occur. In the meninges there is a prominent fibrinous and purulent reaction that is most marked over the inferomedial regions, with particular involvement of the basal subarachnoid cisterns.
SARCOCYSTOSIS
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of muscle cysts, and thorough cooking of meat prevents infection.
The two parasites of humans are Sarcocystis bovihominis and S. suihominis, which have cattle and pigs as their respective intermediate hosts. They have a worldwide distribution, with high infection rates in cattle and pigs. However, the infection is probably uncommon in humans. The parasites have a complex lifecycle involving both asexual and sexual reproduction. Abdominal discomfort, distension, nausea and diarrhoea occur within hours of infection, and sporocysts are found in the stools 14-18 days later. Diagnosis is by finding the small numbers of cysts shed in the faeces. Treatment with pyrimethamine and sulfadiazine or nitrofurantoin has been successful in patients with chronic symptoms. Freezing meat reduces the infectivity
GENITAL TRACT PROTOZOA
FREE-LIVING PROTOZOA CAUSING HUMAN DISEASE
Clinical features Patients are often children or young adults. Fever, headache, nausea, vomiting and lethargy are usual early features, followed by deterioration of conscious level. Neck stiffness is usual. Papilloedema may be present. Lumbar puncture in shows features suggesting acute pyogenic meningitis. The CSF is turbid, with a very high neutrophil count. Protein levels are very high and sugar levels are reduced or normal. The amoebae are readily seen on phase contrast microscopy from a direct smear of CSF. They can be grown in special culture media. Management Amphotericin B for 6 weeks at least, depending on the response, is effective in treatment, possibly in combination with miconazole. The high mortality in this condition is probably related to delay in diagnosis and initial trials of antibiotics as for pyogenic meningitis.
ACANTHAMOEBA INFECTION Acanthamoebae are free-living amoebae commonly found in soil and water in tropical and temperate regions. Infec-
tion may occur by ingestion or inhalation of cysts, which are very light and may be distributed on the wind. A considerable range of clinical features have been reported for this infection. Cerebral abscess, granulomatous meningoencephalitis, meningitis and involvement of the scalp, orbit and middle ear have occurred. Acanthamoebae have most often been identified in corneal ulcers, and the increased use of contact lenses has perhaps increased the frequency of amoebic keratitis. The amoebae are difficult to kill. They have been known to cause a radial keratitis, with spread of the organisms alongside nerve fibres, seen on confocal microscopy of the cornea. Lung involvement has also been reported. Amoebae may be identified in smears from CSF or from corneal ulcers, or in stained tissue sections. A modified Field's stain is effective in showing the amoebae. Amphotericin B is used in systemic infections. 0.1% hexamidine isethionate, dibrompropamidine isethionate and chlorhexidine have all been used with varying degrees of success for corneal lesions. There appears to be little correlation between in vitro and in vivo activity of compounds.
NON-PATHOGENIC GUT PROTOZOA There are a number of protozoa that infect humans but cause no disease. These are listed in Table 9.30. When they are found in patients with abdominal symptoms, the symptoms should not be ascribed to these parasites and further investigations should be undertaken.
TISSUE AND BLOOD PROTOZOA TOXOPLASMOSIS Toxoplasmosis is caused by Toxoplasma gondii. It is a zoonosis, the definitive host in the lifecycle being cats (Fig. 9.27). Primary human infection is acquired by ingestion of oocysts derived from animal excreta or from undercooked meats such as pork or mutton, the pig or sheep having acted as an intermediate host. Infection is common, 20-40% of adults in Britain having antibodies. The most serious effects are seen after congenital infection or in immunocompromised patients. Pathology and pathogenesis Trophozoites released at the site of entry multiply and spread via blood and lymphatics to all tissues. They can invade any cells, and intracellular proliferation leads to cell death. Development of immunity results in restriction of proliferation and the organism is eliminated, or forms tissue cysts. Cysts 10-200 mm in diameter, containing several thousand organisms, may remain in the tissues for life. Depression of CMI results in reactivation.
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FIG. 9.27 Transmission of toxoplasmosis Infection can occur in either sex and at any age. Reactivation causes disease in immunosuppressed patients.
Clinical features Congenital infection Congenital infection usually follows primary asymptomatic infection of the mother during the third trimester of pregnancy. The effect on the fetus may be spontaneous abortion, stillbirth, premature birth, or normal birth with subsequent illness. The latter is most frequent and results in disease of the eye, usually bilateral choroidoretinitis, or of the brain, with hydrocephalus, microcephaly, cerebral calcification or convulsions. Fever, lymphadenopathy, hepatosplenomegaly and rash may also occur. Acquired infection Asymptomatic infection is common in adults, but there may be a mild chronic febrile illness with lymphadenopathy. Often a group of enlarged lymph nodes in a single area is the only finding, although more diffuse adenopathy may occur with splenomegaly. Sore throat does not occur. Choroidoretinitis is now recognized as a manifestation of acquired infection. Reactivation in the immunosuppressed patient Most toxoplasmal disease in patients with deficient immunity is caused by reactivation of latent cysts. The most common manifestation, especially in AIDS, is necrotizing lesions in the brain, often presenting as intracerebral mass lesions. Primary infections in the immunocompromised host cause disseminated infections. This has been recognized in cardiac transplantation when a seropositive donor is the source of a heart for a seronegative recipient. This is prevented by chemoprophylaxis. Myocarditis and possibly pneumonitis also occur. Diagnosis This is by serology. The Sabin-Feldman dye test, indirect haemagglutination or fluorescent antibody test (FAT) are used to measure IgG antibodies, and an ELISA is also available for measurement of IgM antibodies. Histology of affected lymph nodes shows reactive changes which are
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not specific for toxoplasmosis. The organisms are rarely seen in tissue sections. Diagnosis of cerebral lesions is by CT or MRI scan. 1 A/loncrgfemenf
Treatment of acquired infection in normal adults does not affect outcome and is rarely required. Severe infections are treated with the synergistic combination of pyrimethamine 50 mg daily and sulfadiazine 1.0-1.5g every 6 hours by mouth for 3 weeks, together with folinic acid 15 mg daily, as pyrimethamine is a folic acid antagonist and can cause bone marrow suppression. Clindamycin 600 mg every 6 hours orally or i.v. can be used as an alternative to sulfadiazine in the event of toxicity. Patients with AIDS may need a longer course of treatment and the cerebral lesions are monitored by CT or MRI. These patients also require maintenance therapy with pyrimethamine 75 mg twice per week and sulfadiazine 1.5g twice daily once a satisfactory response has been achieved. Tissue cysts are not killed by this treatment, but they may be susceptible to azithromycin or atovaquone. 2
PNEUMOCYSTIS CARINII INFECTION
sive interstitial shadowing. The diagnosis should be suspected in immunosuppressed patients, especially those with AIDS, and confirmation is obtained from examination of bronchial washings obtained at bronchoscopy or in sputum induced using nebulized hypertonic saline. Management The treatment is adequate oxygenation and ventilatory support when necessary, and chemotherapy with either high-dose co-trimoxazole (four tablets four times a day) or pentamidine given by intramuscular injection or slow intravenous infusion in 250 mL of normal saline or 5% dextrose over 1-2 hours. Corticosteroids are added in moderate or severe cases. Fever, rash and leukopenia have been seen in AIDS patients after about 7-10 days on co-trimoxazole, and a change to pentamidine may be necessary, as treatment for at least 21 days is required. Pentamidine side-effects include renal and hepatic failure and prolonged hypoglycaemia. There is a 20% mortality in AIDS patients in their first episode of Pn. carinii, irrespective of treatment. Prophylaxis with co-trimoxazole for this infection has been effective in patients with acute leukaemia. Primary prophylaxis in AIDS patients with the combination of an antifolate and a sulphonamide/sulphone is of value, and nebulized pentamidine has also been used successfully.
Pneumocystis carinii is a common organism that is found worldwide. Although previously classified as a protozoan, evidence suggests that it may be fungal in nature. It infects the lungs and causes no problems in normal human hosts. The organism is found in autopsy material from healthy people in up to 4% of cases, and serological studies in Europe have shown up to 75% seropositivity in healthy children. The reservoirs of infection and the mode of transmission are poorly defined, but it seems likely that personto-person droplet infection occurs. It causes interstitial pneumonitis in premature and young infants, in children with protein-energy malnutrition, in immunosuppressed patients during treatment for haematological malignancies, and in AIDS patients in the west. It is uncommon in AIDS in Africa. In normal lung the organisms are found singly or in clusters on the alveolar septal wall, with no surrounding host response. When there is pneumonitis large numbers of parasites are found in the alveoli, with desquamation of alveolar cells and accumulation of proteinaceous material in the alveolar spaces. Clinical features and diagnosis The clinical features of Pn. carinii pneumonia are progressive dyspnoea, cough, fever and weight loss. Chest examination is often normal; chest radiographs may be normal initially but progress fairly rapidly to show exten-
1
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Fig. 9.38
FIG. 9.28 World distribution of malaria, 2000 Chloroquine-resistant malaria occurs in all areas.
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FIG. 9.29 Malaria in the UK, 1981-2000, showing the progressive rise of falciparum importations (Communicable Diseases Surveillance Centre, Colindale and Malaria Reference Laboratory, PHLS.)
MALARIA Malaria is an acute febrile illness characterized clinically by paroxysms of fever, the consequence of rupture of infected red cells due to asexual reproduction by species of Plasmodium (schizogony). Plasmodium vivax, P. ovale and P. malariae are associated with morbidity but no major mortality, but P. falciparum causes both morbidity and considerable mortality. The infection is transmitted by the bite of the female anopheline mosquito. Distribution and incidence Malaria occurs widely throughout the tropical areas of the world, in the Americas, Africa, Asia and the Pacific area (Fig. 9.28). Falciparum malaria is particularly common in tropical Africa, where it causes at least 1000000 deaths per year, mainly in children. The resurgence of malaria in the Indian subcontinent was led by a rising incidence of vivax malaria in the 1970s, and now falciparum infection is more widespread in the region. Ovale malaria is predominantly a west African disease. Malariae malaria is the least common form. Malaria is imported into temperate regions by tourists, people employed overseas, business travellers and immigrants. The numbers of cases have risen progressively over the past 20 years (Fig. 9.29). Transmission and epidemiology Life cycle The life cycle of malaria is shown in Figure 9.30. Vivax and ovale life cycles are similar, with primary exoerythrocytic schizogony (EES) in hepatocytes leading to infection of the peripheral blood with merozoites. These enter red blood cells (RBCs) and undergo erythrocytic schizogony (ES) every 48 hours; this is benign tertian and ovale tertian malaria. Some of the sporozoites produce latent forms, the hypnozoites, within liver cells, which produce EES and then ES up to 2 or 3 years after infection, i.e. relapsing malaria.
FIG. 9.30 Life cycle of malaria
Falciparum malaria has no hypnozoite form, and so the infection is cured when parasites are cleared from the blood by treatment. ES has a periodicity of less than 48 hours ('subtertian'). Malariae parasites also lack the hypnozoite stage but can cause reappearance of parasitaemia (parasites in peripheral RBCs) up to 20 or more years after infection. Small numbers of parasites persist in RBCs to
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cause this. The periodicity of ES is 72 hours (quartan malaria). Vivax, ovale and malariae parasites invade 1-2% of RBCs at most. Falciparum parasites invade any proportion of RBCs, accounting for the severity of disease and the high mortality. Host A baby born of an indigenous mother in an endemic falciparum area will be protected against infection during the first year of life by maternal antimalaria IgG crossing the placenta in the last trimester of pregnancy. After the first year the child is fully susceptible. Without chemoprophylaxis the child experiences repeated attacks of malaria, and by the age of 4 or 5 years will have acquired protective immunity, which persists as long as they remain in the endemic area. Parasites are often found in the peripheral blood of an asymptomatic child, so that there is disease immunity without immunity to reinfection; indeed, reinfection is necessary to maintain antigenic challenge and the immune status. The immunity declines if an individual leaves the endemic area. Maternal immunity declines during pregnancy, particularly in primiparae, with transplacental transfer of IgG. Anaemia, fever and intense parasitization of the placenta make miscarriage, premature labour and low birthweight common, especially in areas such as West Africa, where there is heavy seasonal transmission with a high risk of infection. Where transmission is not so intense, effective immunity is not built up and all ages in the exposed population are at risk. Any individual, of any age, from a malaria-free area may contract severe malaria. Splenectomy enhances susceptibility to maleria to a considerable degree. Sickle cell trait haemoglobin C trait, and the heterozygous state for glucose-6-phosphate dehydrogenase (G6PD) deficiency protect against severe malaria. Vector Climatic factors have a profound influence on the transmission of malaria through effects on survival and reproduction of the mosquito population, and on the development of the parasite in the vector. Mosquitoes survive up to several months and their lifespan is not affected by malaria parasites. Ambient temperatures in the range 20-30°C, with a relative humidity of 60% or more, are ideal. In most areas of tropical Africa malaria is transmitted all year round, with upsurges of incidence with the dramatic increase of anopheline numbers during rainy seasons. In Asia transmission is seasonal with the rains. Sporogony will not occur below 16° or above 33°C. The vector species vary considerably in different localities. Anopheles gambiae is one of the most efficient vectors because of its long lifespan and preference for biting humans rather than other animals. 1
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Fig. 9.39
Additional routes for transmission of malaria are: • Transplacental, which is uncommon • Transfusion associated, which is uncommon in Europe and North America but common in endemic areas • Syringe transmitted, among intravenous drug abusers. Mention should be made of 'airport malaria', which has been documented in a range of temperate countries, including the UK and France. Malaria can occur in people who have never been to an endemic area and who are not at risk as a result of transfusion, shared syringes etc. Such cases have occurred around airports, and it is thought that malarious mosquitoes that have been carried on international flights survive in the temperate country and bite individuals there, infecting them and causing disease. Pathogenesis and pathology The pathogenesis of falciparum malaria is complex and incompletely understood. The initial step is adhesion of the merozoite to the erythrocyte membrane. Glycophorin A, the major glycoprotein on erythrocyte membranes, is a receptor for binding specific surface proteins of falciparum merozoites. RBCs deficient in glycophorin A are resistant to invasion. The Duffy blood group antigen is a specific receptor for invasion by P. vivax merozoites, and the absence of this antigen among populations from west Africa explains the absence of vivax infections there. Changes in the parasitized RBC result in sequestration of RBCs containing mature falciparum trophozoites in the postcapillary venules. 1 Parasitized cells are less flexible than normal cells. In addition, as the parasite matures the RBC becomes deformed and knobs develop on its surface. These knobs are an expression of a parasite-derived adhesion-promoting molecule which binds to molecules such as ICAM-1, VCAM-1 and thrombospondin expressed on the vascular endothelium of the postcapillary venule. This adhesion phenomenon explains why mature trophozoites and schizonts are usually absent from peripheral blood films. Maximum numbers of adherent RBCs are found in venules in brain, liver, spleen, kidney and lung. The placenta is heavily parasitized with chondroitin sulphate A serving as a specific receptor for adhesion of infected RBCs. The trophozoite matures into the schizont and at schizogony the RBC membrane bursts, releasing merozoites, malaria antigen, malaria pigment and RBC cytoplasmic constituents. The cycle continues, progressively building up the numbers of parasitized RBCs. How these changes lead to altered consciousness in cerebral malaria is not clear. CT of the brain in patients with cerebral malaria has not shown oedema, although among children in Kenya intracranial pressure recording has shown raised pressure. Diffuse irreversible vascular obstruction is also an unlikely cause, in view of the normal cerebral flow and complete recovery without neurological deficit in most survivors. CSF lactate levels are increased in cerebral malaria, which may indicate some degree of anaerobic cerebral glycolysis. At the molecular level, high levels of TNF and other cytokines are found in the
blood of patients with the most severe forms of malaria, especially cerebral malaria. The extent to which these molecules cause severe malaria is not yet known. It is recognized that quantitative differences in cytokine production, particularly TNF, are genetically determined, indicating possible inherent predisposition to severe disease. Renal damage occurs because of prerenal and renal factors. Acute tubular necrosis is the usual effect of severe malaria on the kidney. This may occur both with and without severe intravascular haemolysis. Vessels in the heart are parasitized but cardiac function is well preserved. Reduced peripheral vascular resistance and dehydration from sweating, vomiting and reduced fluid intake may contribute to hypotension. In cerebral malaria post mortem the brain shows swelling with small haemorrhages throughout the white matter. The spleen is enlarged and has a slate-grey hue over the normal red colour. Centrilobular necrosis is seen in the liver with the accumulation of malaria pigment in Kiipffer cells. The pulmonary venules contain large numbers of parasitized RBCs. Pulmonary oedema of the ARDS type occurs but the cause is not understood. The placenta is usually heavily parasitized. The anaemia of malaria has several causes, which include rupture of parasitized RBCs in schizogony; sequestration of RBCs in tissue venules; destruction of parasitized and non-parasitized RBCs in the reticuloendothelial system (especially the spleen); haemolysis due to the presence of malaria antigen, antibodies and complement on RBCs; and marrow suppression. Abnormalities of coagulation are usual, with low platelet counts due to peripheral consumption and consumption of clotting factors. Disseminated intravascular coagulation does occur in a few patients with severe malaria but is probably not a major factor in pathogenesis in most severely ill patients. Clinical features Vivax and ovale • After an incubation period of about 13 days (vivax) or 18 days (ovale), prodromal symptoms begin with headache, fever, shivering without rigors, and general aches. These last for up to 3 days before the first paroxysm of coldness, then extreme heat, then defervescence with a profuse sweat. • Forty-eight hours later the full paroxysm occurs, with a feeling of extreme coldness and a rigor beginning in the late afternoon. Headache, nausea and vomiting are usually present. The temperature is high, the pulse rapid and low in volume, and the skin is cold. This phase lasts for 45 minutes to 1 hour. When the rigor ceases, peripheral dilatation occurs; the patient feels very hot and thirsty. The pulse is rapid and of full volume. The skin is hot and dry. This lasts about 1 hour and defervescence follows, with a profuse sweat. The symptoms settle completely and the patient will usually sleep. The following day there may be a little weakness. One day later the malaria paroxysm recurs. Daily paroxysms occur when
parasite broods are undergoing schizogony on successive days. • Untreated, the paroxysms continue for 6 weeks and die out spontaneously, only to recur 2-3 months later. By the time symptoms have been present for a week the spleen is usually palpable and there may be mild anaemia. Rupture of the enlarged spleen is reported in vivax malaria.
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Malariae malaria The incubation period is usually about 28 days. Nonspecific prodromal symptoms last for 2-3 days before the onset of the first paroxysm, which is accompanied by a rigor. The periodicity of symptoms is every 72 hours. The spleen is enlarged when symptoms have been present for 7-10 days. Falciparum malaria • The incubation period is about 12 days, range 9-17 days. • Headache, anorexia, nausea, vomiting, weakness and fever are prominent symptoms. • The periodicity of symptoms is less than 48 hours, and periodicity is an unreliable clinical feature, being present in only 30% of cases. • The patient feels ill all the time, with exacerbation of symptoms at the time of paroxysms, which are similar to those described above but usually more severe. • Convulsions occur in children. Vomiting and diarrhoea are sometimes prominent features in the history. Herpes simplex vesicles may appear on the lips during the illness. Complications Complicated malaria occurs in falciparum infections. • Altered consciousness in the presence of falciparum malaria must be taken as a clinical indication of cerebral malaria. Neck rigidity is not a feature, although mild neck stiffness may be present. Raised intracranial pressure is not seen and focal neurological signs are uncommon. Generalized convulsions occur in children and adults. • Hypoglycaemia occurs in children, pregnant women with severe malaria and, less often, in adults with severe infection. • Jaundice may be a prominent physical sign in some patients with severe malaria. Haemolysis can cause this, but tender hepatomegaly and abnormalities of liver function suggest liver involvement. • Some degree of uraemia is common, but this resolves after treatment. Uraemia with oliguria indicates renal involvement. • Pulmonary oedema can result from overhydration, but can also occur in the patient whose infection is coming under control. • Blackwater fever, due to acute massive intravascular haemolysis, became less common after chloroquine replaced quinine for prophylaxis and treatment of malaria, suggesting that quinine itself contributed to pathogenesis. It does, however, occur in people who have not taken quinine. The urine is black, the haemoglobin
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SUMMARY 18 Main features of malaria • • • • • • • • •
Fever Chills and rigors Headache Vomiting Diarrhoea sometimes Jaundice* Anaemia* Falling urine output* Passing black urine*
* Indicative of severe infection.
falls rapidly and jaundice appears. Hypotension and tachycardia are usual, and renal failure may follow. • Gram-negative septicaemia has been reported in patients with severe malaria and may be responsible for hypotension. Late complications Tropical splenomegaly syndrome (TSS) occurs in areas of endemic falciparum malaria. There is considerable splenomegaly, a lesser degree of hepatomegaly, anaemia and pancytopenia. Malaria antibody titres are high, with polyclonal elevation of serum IgM. Quartan nephrotic syndrome is related to P. malariae infections, and presents with gross oedema and proteinuria in children aged 4-6 years. The histological features are segmental endothelial proliferation with obliteration of capillary loops by periodic acid-Schiff (PAS)-positive material. There is segmental thickening of the basement membrane. Progression of the glomerular lesion leads to diffuse glomerulosclerosis. Immunoglobulins and complement are deposited in the glomerulus, and P. malariae antigen is detectable in 25% of biopsies. The prognosis is poor, with progressive deterioration in renal function. Treatment of malaria and chemoprophylaxis do not influence the course of established disease.
TABLE 9.34 Differential diagnosis of malaria Fever alone Any cause of pyrexia of unknown origin (see p. 274)
Fever and renal failure Septic shock Leptospirosis Viral haemorrhagic fevers
Fever and jaundice Yellow fever Typhus Leptospirosis Biliary sepsis Septicaemia
1
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Fig. 9.40
Fever and impaired consciousness Meningitis Encephalitis Brain abscess
2
Case 9.4
Diagnosis The clinical diagnosis of malaria is based on the history of a febrile illness after exposure in an endemic region. Differential diagnosis is shown in Table 9.34. Cases in non-endemic areas present most often in the first 3 months after leaving the endemic area. Persons who have taken mefloquine as malaria prophylaxis may experience attacks of malaria up to 3 months after returning from the endemic area. Ovale and vivax infections may present later, and the latency in malariae malaria may be prolonged. The diagnosis is confirmed by the finding of parasites in stained blood films. If falciparum malaria is diagnosed, the percentage of RBCs parasitized should be determined and the film should be carefully examined for schizonts, which may be seen in the blood film from patients with severe malaria. Severe malaria is defined parasitologically as over 5% of RBCs parasitized, although complicated malaria can occur with fewer; clinical assessment is therefore very important. Because of binding of RBCs containing mature ring forms to vascular endothelium, the peripheral blood film in falciparum malaria is an uncertain guide to the severity of infection. Low initial parasitaemia can rise dramatically within hours when schizogony of sequestered parasites occurs. The blood is positive on the first occasion in most cases. The peripheral blood film gives only a guide to the severity of infection. If the parasitaemia is high the interpretation is straightforward but, if low, parasitaemia is not always indicative of mild malaria as many RBCs containing maturing parasites may be sequestered in deep venules, and so parasitaemia alone may not give a true picture of the severity of infection. A blood film should be made and examined as soon as the diagnosis of malaria is considered. 1 It is not necessary to wait for fever to occur. An antimalarial drug taken before blood films are obtained may clear the blood of parasites. If necessary, further blood films should be made and examined once or twice daily until the febrile illness either is diagnosed or resolves. During a period of observation in hospital, prophylactic antimalarial drugs should be stopped to give the best chance of demonstrating parasites. It may be necessary to start treatment as soon as blood films have been taken or on the basis of clinical diagnosis if laboratory confirmation is not readily available or the patient is very sick. Microscopy of stained blood films has been the gold standard for malaria diagnosis and in skilled hands is 100% specific and very sensitive, capable of detecting parasitaemia as low as 0.0001%. However, expertise is very variable and antigen detection methods for malaria diagnosis have been developed and can be used as an adjunct to microscopy. These depend on using monoclonal antibodies to various parasite epitopes. Compared with expert microscopy these methods have a 90% sensitivity in detecting parasitaemias in the range 0.01-0.001%, i.e. 50-500 parasites per microlitre of blood.
Laboratory features Laboratory investigations are normal or mildly abnormal in vivax, ovale and malariae malaria, but consistently abnormal to some degree in falclparum malaria. Haemoglobin levels may be normal or slightly reduced at presentation, but fall thereafter. Reticulocyte counts may be low before and after treatment, while haemoglobin levels are falling, suggesting a period of marrow suppression, followed by reticulocytosis with rising haemoglobin. Platelets are low in falciparum malaria, sometimes as low as 20 x 109/L, but other coagulation tests are usually normal. Occasional patients do have coagulopathy with spontaneous bleeding. Plasma sodium levels are low in falciparum malaria and urea may be raised. Globulin levels rise and albumin falls. Abnormalities in liver function tests are frequent, and there may be a minor elevation in both total and unconjugated bilirubin in mild infections or greater elevation in more severe falciparum. Azotaemia is common in falciparum malaria but oliguria is not. Elevation of urea and creatinine may reflect the hypercatabolic state of severe malaria, but urine output must be monitored as renal failure, most often due to acute tubular necrosis, is well recognized in severe malaria. Serological tests for malaria have no place in diagnosis of individual cases but may be helpful in assessing previous exposure. 2
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Management Drug treatment Vivax, ovale and malariae. The aim of treatment is to stop further ES cycles (Table 9.35). There is usually a prompt response following chloroquine treatment of vivax, ovale and malariae malaria. Where radical cure of relapsing malaria is required G6PD levels should be checked and, if normal, primaquine given. When there is severe G6PD deficiency, primaquine should not be given because of the risk of severe haemolysis; chemoprophylaxis can be given to prevent relapse, e.g. pyrimethamine (25mg weekly). Primaquine is not recommended in pregnancy and a chemoprophylactic should be given. Falciparum. P. falciparum malaria is a serious infection demanding urgent treatment. Quinine is the drug of first choice for treatment because chloroquine resistance is now so widespread. The route of administration must be chosen carefully. When the patient is vomiting, is clinically ill with fever >39°C, is hypotensive or has specific complications of malaria, or has more than 2% of RBCs parasitized or schizonts in the peripheral blood, intravenous treatment is needed. The dosage regimens used are set out in Table 9.35. Impairment of renal or hepatic function will prolong
TABLE 9.35 Treatment of malaria Type of malaria
Drug
Dose
Additional treatment
Vivax and ovale
Chloroquine base
Malariae Falciparum Chloroquine-resistant or sensitivity unknown Mild
Chloroquine
600 mg (10mg/kg) stat, then 300 mg (5mg/kg) 6 hours later, then 300 mg (5mg/kg) daily for 2 days As above
Primaquine. 7.5 mg twice a day for 14 days (children 250ug/kg per day) Nil
Quinine salt
700 mg max (10mg/kg) 3 times a day for 7 days orally
or Malarone (atovaquone 250 mg + proguanil 100mg) or Mefloquine Quinine salt
4 tablets once daily for 3 days (reduced dose for children)
Fansidar. 3 tablets as a single dose for adults: reduced doses for children Nil
Severe
Known chloroquine-sensitive Mild Severe
Chloroquine base Chloroquine base
1,5g (125mg/kg) in 2 divided doses 6-8 hours apart Initial loading dose 1400 mg max (20mg/kg) in 250-500 ml of fluid in over 4 hours then 700 mg max (10mg/kg) by i.v. infusion in 250-500 ml fluid over 4 hours given 8-12-hourly until the patient can take oral quinine giving a total of 7 days treatment As above 300 mg (15mg/kg) given by i.v. infusion in 250-500 ml fluid, repeated 12-hourly Change to oral Chloroquine as soon as the patient's condition permits
Nil Fansidar as above
Nil
Note: (1) Loading doses of quinine should not be given to patients who have previously received quinine or therapeutic doses of mefloquine: in that case standard doses of i.v. quinine should be given. (2) Blood glucose levels must be monitored during intravenous quinine therapy as it can stimulate insulin release and hypoglycaemia.
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CASE STUDY 9.4 COLLAPSE AND DYSPHASIA A 61-year-old man had travelled for 3 weeks in southern Africa visiting Zambia, Zimbabwe and South Africa. He had been in South Africa for a week before his return to UK. He had taken no antimalarial chemoprophylaxis. He became unwell 4 days before his return flight, with shiveriness, headache and anorexia. Towards the end of his flight from Johannesburg he collapsed, and on arrival was admitted to hospital. He was found to be very drowsy, with dysphasia and a divergent squint. He was febrile, 38°C, with no other localizing signs in the nervous system. Examination was otherwise unremarkable.
Questions 1. What is the differential diagnosis? 2, What further investigations would be needed?
It was thought that he had a stroke. Six hours later his sister visited and gave the information that he had just returned from an African holiday; blood films were then examined for malaria. These were positive, showing 11% asexual parasitaemia with schizonts, typical of falciparum malaria. Also on review deep jaundice was apparent, not noted previously. At this time his conscious level had declined further and he showed withdrawal responses to painful
stimuli. There were no retinal haemorrhages. Chest and cardiovascular examination was normal, BP 125/70. A urinary catheter was inserted and 59 mL of urine drained. Additional investigations showed Hbl2g/dL, with an increased white cell count at 15.3 x 109/L and low platelets, 13 x 109/L; coagulation screen normal; bilirubin 306 mmol/L, alanine transaminase 50 uL, albumin 37g/L, sodium 128 mmol/L, urea 27.6 mmol/L, creatinine 292umol/L.
Question 3. What Would be your immediate steps in management?
The patient was sedated, intubated and ventilated. Comment This case is typical of severe falciparum malaria, which very often occurs against a background of no prior chemoprophylaxis. The rapidity of progression of disease, particularly in the final hours before hospital admission, is in contrast to the much more indolent course of the vivax malaria case described below. The high level of parasitaemia is typical of falciparum, but the presence of schizonts in the peripheral blood is not usual and is indicative of more severe disease. Usually severe
the half-life of the two main schizonticidal drugs, and so the dosage regimen may need to be modified, reducing the amount given and, if necessary, the frequency of administration after 48 hours of medication. As soon as the patient's condition has improved sufficiently, oral treat1
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MCQ 9.26
malaria is associated with high parasitaemias, but this is not invariable and severe disease can be seen in patients with less than 2%. This patient had cerebral malaria with renal failure due to acute tubular necrosis. Although platelets were low there was no bleeding. Management comprises termination of parasite replication and supportive care until the disordered physiology starts to return to normal. Great care is needed with fluid balance to avoid overhydration, with the risk of pulmonary oedema, and intraoesophageal Doppler is a valuable means of assessing fluid status, giving 200 mL boluses of colloid to optimize systolic ejection parameters. Quinine 1400mg was given as a loading dose over 4 hours, with 700 mg 12-hourly thereafter until all asexual parasites had been cleared, when a single dose of three Fansidar tablets was given. A six-unit exchange transfusion was carried out. Blood sugar was monitored during the quinine infusion. Haemofiltration was commenced. He was unconscious for 12 days before starting to wake up. Haemofiltration was required for 3 weeks. This man returned to his normal work. One of the concerns is how much irreversible cerebral damage occurs after cerebral malaria. In adults the clinical impression is surprisingly little, but 5-10% of children surviving this condition in East Africa do have residual cerebral abnormalities, e.g. cortical blindness, deafness.
ment should be given. Tinnitus, deafness and headache are common side-effects of quinine, and if they are very troublesome the frequency of administration of the drug can be reduced. Quinine alone is used in pregnancy (Table 9.35). Quinine alone will not cure falciparum malaria and is followed by a single dose of Fansidar (pyrimethamine plus sulfadoxine) as in Table 9.33. Doxycycline, 100 mg daily for 7 days, or lesser doses, is an alternative for older children and adults. Mefloquine, 20mg/kg up to a maximum of
1.5g, in two divided doses 6-18 hours apart, can be given as sole treatment. Malarone (a combination of atovaquone 250 mg plus proguanil 100 mg per tablet) is effective in mild falciparum malaria, giving four tablets as a single dose with food or a milky drink at the same time daily for 3 days. The problems of multiple drug resistance in strains of P. falciparum are maximal in southeast Asia. Compounds derived from Artemesia annua, qinghaosu, are very important in treatment. Although these drugs produce rapid defervescence and parasite clearance there is a relatively high recrudescence rate for monotherapy, and so to use them most effectively they must be given with another drug, for example artemether plus lumefantrine. Atovaquone and proguanil are combined in malarone (see above). It has been proposed that in order to try to maintain the efficacy of currently available antimalarial drugs combination therapy should become the rule, giving both selected drugs together from the beginning. Chloroquine is generally well tolerated by mouth; nausea and blurring of vision are transitory side-effects. Upper abdominal discomfort may occur after taking the drug. Pruritus is common in Africans taking chloroquine. This is not associated with a rash and is not a manifestation of allergy. Chloroquine can be used in pregnancy. The route of administration is determined by the severity of the illness, judged by the criteria detailed above. Additional measures Patients with severe or complicated malaria should be managed in an intensive care unit. Apart from effective malaria chemotherapy, management is essentially supportive. When the patient is unconscious intubation is necessary to secure the airway. Convulsions should be controlled with diazepam. There is no specific additional treatment. Dexamethasone is contraindicated and at present there are no grounds for recommending the use of mannitol. Hypoglycaemia has been reported in severe cases, both before and during treatment with quinine, particularly in young children and pregnant women. Quinine causes insulin release. Blood sugar should be monitored regularly and 50% glucose given i.v. as needed. Dialysis is needed when there is renal failure. Attention to fluid balance is essential to prevent fluid overload. Pulmonary oedema can occur because of fluid overload, but can also occur without evidence of heart failure - an adult respiratory distress syndrome picture. Mechanical ventilation may be needed when pulmonary oedema occurs. Transfusion is indicated when there is acute intravascular haemolysis and when the haemoglobin falls below 7.0g/dL. Fresh frozen plasma and platelet transfusions are given when there are major clotting defects requiring correction. Whole blood exchange transfusion, six units in adults, appears to be effective in reducing parasitaemia as well as removing plasma containing immune complexes, cytokines, malaria antigen and products of red cell schizogony in severely ill patients, and is indicated when more than 30% of RBCs are parasitized and at lower levels of parasitaemia when complications are present. Although
there are no controlled trials demonstrating its efficacy there is logic to it and it should be considered where supplies of adequately screened blood are available.
9
Management of other complications Quartan nephrotic syndrome has a poor prognosis, with progressive deterioration of renal function to end-stage renal failure. Fluid restriction, diuretics and albumin infusions may be helpful in relieving the oedema and fluid retention. The idiopathic tropical splenomegaly syndrome is treated with maintenance antimalarial chemoprophylaxis. With this, the splenomegaly regresses, haematological indices improve, and abnormal serological findings return towards normal. Cessation of chemoprophylaxis may cause relapse. Prevention and control For the traveller to endemic areas prevention comprises the avoidance of mosquito bites and chemoprophylaxis. Everything possible must be done to prevent mosquito bites (p. 272). With the increasing problems posed by drugresistant malaria, these measures occupy a central place in prophylaxis and their importance must be stressed to travellers and residents in endemic areas. This applies particularly for infants, children and pregnant women. Chemoprophylaxis in pregnancy prevents maternal anaemia, prevents the abortifacient effects of fever due to malaria and prevents intrauterine growth retardation. The use of permethrin-impregnated bed nets is very effective in reducing attacks. Permethrin has a residual insecticidal effects lasting 6 months before retreatment is needed. The drugs currently used for chemoprophylaxis are listed in Table 9.36 but up-to-date information should be obtained by those advising travellers to endemic areas. A malaria vaccine remains elusive. As indicated above, there is clear evidence for effective antidisease immunity in populations in endemic areas but this needs to be maintained by constant antigenic challenge. It is likely that any vaccine developed will comprise antigens from several stages of the parasite lifecycle, but the sporozoite stage seems to be important in stimulating immunity. Eradication is no longer perceived as an achievable goal and control is the current aim. Insecticide resistance among mosquitoes, particularly to the cheapest compound, DDT, and chloroquine resistance among falciparum parasites, have contributed to the problems of controlling malaria. The main methods used are: • Reduction of vector breeding sites • Larviciding pools that cannot be drained • Spraying insecticides inside houses and on other sites where mosquitoes rest • Treating cases in humans. 1
FURTHER READING ON MALARIA White N J et al. Averting a malaria disaster. Lancet 1999; 353: 1965-1967. World Health Organization. Severe falciparum malaria. Trans Roy Soc Trop Med Hyg 2000; 94: suppl 1.
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TABLE 9.36 Prophylactic regimens against malaria in adults (Reproduced with permission of the PHLS Communicable Disease Surveillance Centre) Regimen Areas of chlomquine resistant P. falciparum: Mefloquine* Proguanil plus chioroquine Pyrimethamine-dapsone (Maloprim)+ plus chioroquine Doxycycline++ Atovaquone-proguanil (Malarone)** Areas without drug resistance: Chioroquine Proguanil
Dose for chemoprophylaxis
Usual amount per tablet (mg)
1 tablet weekly 2 tablets daily plus 2 tablets weekly 1 tablet weekly§ plus
250 (228 in US) 100 150 (base) 12.5(pyrimethemine) plus 100 (dapsone) 150 (base) 100 250 (atovaquone) plus 100 (proguanil)
2 tablets weekly 1 tablet daily 1 tablet daily
2 tablets weekly 2 tablets daily
150 (base) 100
All antimalarials to be avoided in severe hepatic and renal impairment. Chioroquine doses are given as the base. Folate supplements should be given to those taking proguanil or Maloprim when pregnant. * Avoid during pregnancy, during lactation and avoid pregnancy for 3 months after stopping it. Do not prescribe mefloquine if there is a history of epilepsy, depression or severe, psychiatric disorder. Appropriate for up to 1 year abroad. Caution in cardiac conduction disorders. + Best avoided in the first trimester of pregnancy. (Maloprim is only available for travellers who have epilepsy and cannot take alternatives.) + Contraindicated during pregnancy and lactation and for children less than 12 years. § Never exceed one tablet of pyrimethemine/dapsone (Maloprim) weekly. ** Licensed for up to 28 days in malarious area. Do not give in pregnancy. Begin 1-2 days before departure. Continue for 1 week after return.
FIG. 9.31 World distribution of trypanosomiases
matic infections also occur. Prodromal features include headache, malaise and gastrointestinal upset prior to the onset of fevers and rigors, with jaundice, haemoglobinuria and renal impairment in B. divergens infections. B. microti produces a more prolonged but less severe illness. Increasing age is associated with more severe clinical illness. The laboratory diagnosis is made by finding organisms similar to malaria parasites in Giemsa-stained peripheral blood films. Treatment with clindamycin, 600 mg 6-hourly intravenously or intramuscularly (20mg/kg/day in children), and quinine, 600 mg 8-hourly (10mg/kg 8-hourly in children) is effective in treatment of severe B. microti infections. For all severe cases intensive supportive therapy to maintain circulation, organ perfusion and oxygenation is essential. The efficacy of drug therapy in B. divergens is less certain.
TRYPANOSOMIASES African trypanosomiasis (sleeping sickness)
BABESIOSIS Babesia are intracellular protozoa that invade, divide asexually within, and finally rupture host erythrocytes. There are 70 species, affecting a wide range of vertebrates including cattle (B. diver gens) and rodents (B. microti). The parasites are transmitted by the bite of hard-bodied (ixodid) ticks. Babesia are widely distributed geographically, with reports of cases in humans from many countries, including Scotland and the USA. Babesia may occur concurrently with Borrelia burgdorfei infection. The incubation period is up to 4 weeks, less in patients who have had a splenectomy. There is a considerable range in the severity of infection, from mild to severe. Asympto-
1
352
Fig. 9.41
2
Fig. 9.42
Infection with Trypanosoma gambiense causes an initial febrile illness which progresses slowly to a chronic phase dominated by infection of the CNS, causing neuronal death and a variety of organic neurological syndromes. Neurological involvement occurs early in T. rhodesiense infections, within weeks of inoculation of parasites and, untreated, there is rapid deterioration and death. The two species cannot be distinguished on morphological grounds. Various species of tsetse fly, Glossina, are the vectors. Distribution and incidence The specific names of these parasites suggest a West African (T. gambiense) or East African (T. rhodesiense) origin for the infections, but there is a considerable overlap of the distribution of the two species in Central Africa (Fig. 9.31). The total numbers of cases are far fewer than malaria, but rhodesiense infections have a considerable economic impact as valuable farming and grazing lands
cannot be used because of the high risk of infection. There have been increases in both forms recently with imported cases seen in Europe.
Epilepsy occurs. In the terminal stage the patient is scarcely reusable, unable to swallow or feed him/herself. Bronchopneumonia is a common cause of death.
Transmission and epidemiology Tsetse flies become infected by ingesting trypanosomes in a blood meal. Once infected, a fly remains infective for life. About 1 % of flies in an area are infected. Humans are the reservoir in gambiense infections, whereas a variety of wild mammals, including bush buck and hartebeest, are the reservoir of rhodesiense infection, and humans are an incidental host. Transmission of gambiense trypanosomiasis occurs in wooded areas around rivers and streams that are water sources for local populations. Blood transfusion and transplacental transmission are also possible routes of infection.
Diagnosis Diagnosis depends on finding trypanosomes. Early in the course of infection with either species, parasites may be found in peripheral bloodfilms.0 There are usually many more parasites in rhodesiense than in gambiense infections. Repeated examinations must be made to detect the low levels of parasitaemia in gambiense infection. Gambiense parasites may be seen in bone marrow smears. Smaller numbers of parasites can be detected in smears of the buffy coat. Material aspirated from a lymph node can be smeared on a slide and stained. CSF must also be examined. The cell count is determined and the stained deposit examined for trypanosomes. An increased white cell count (>5/mm3) and/or an increased CSF protein (>250mg/L) indicates CNS infection in a patient with parasites in the blood or tissues. Serum immunoglobulin concentrations are increased, with IgM levels being very high. Increased CSF IgM indicates nervous system involvement. Serological tests do not have diagnostic value for individual patients.
Pathology and pathogenesis There is an early marked inflammatory response at the site of inoculation and in the lymphoid tissues of the body, lymph glands, liver and spleen. Trypanosomes may be seen in tissue sections. Rhodesiense infections progress rapidly to involve the heart and brain. Myocarditis and pericarditis are common. An obliterative endarteritis with vascular occlusion is found in the CNS, causing the degenerative changes. The neuropathological features include thickening of the meninges, which are infiltrated by lymphocytes and plasma cells. This infiltrate extends into brain substance in a perivascular distribution. The parasites continuously shed surface antigens which evoke antibody responses in the host, but the antigens change sequentially, a possible mechanism of evading host immune responses. Autoantibodies to brain and heart may cause tissue damage. Disseminated intravascular coagulation can occur in rhodesiense infections. Clinical features With both species, fever, chills and weakness are usual initial symptoms, beginning about 10 days after the bite. An inflamed lump is present at the bite site - the trypanosomal chancre 1 - and there is regional adenopathy. On white skins it is possible to see transient irregular areas of circinate erythema in both types of disease. Posterior auricular and posterior cervical adenopathy develop after 1-2 months of infection in gambiense infections. Unpleasant dysaesthesia follows squeezing of the calf muscles. Hepatosplenomegaly is often present in both infections early on. Jaundice occurs in rhodesiense infections. Purpuric rashes on the extremities are occasionally seen in severe rhodesiense infections. Neurological involvement appears within weeks of infection in rhodesiense infections, but it may be months or years later with T. gambiense. Indifference, lassitude, personality changes and altered behaviour are early features. Sleep rhythm is reversed. The basal ganglia, cerebellum and brainstem regions are most affected, producing tremor, incoordination, and problems with speech, balance and walking. Parkinsonian features may be prominent.
Management Suramin is used to kill parasites in blood and lymph nodes, and cures patients early in the disease. After an initial test dose of 100-200 mg given by slow intravenous infusion to ensure that the drug does not cause anaphylaxis or cardiovascular collapse, 1g doses are given by slow intravenous infusion on days 1, 3, 6,14 and 21. Pentamidine is the first-line drug for use in T. gambiense infections, giving 3-4mg/kg of pentamidine base daily by slow intravenous infusion or intramuscularly until 7-10 doses have been given. Sterile abscesses can occur at sites of intramuscular infection. Pentamidine stimulates insulin release from the pancreas, with the consequent risk of hypoglycaemia. Although pentamidine is used for early disease there is evidence that it crosses the blood-brain barrier and has worthwhile actions in early neurological disease in rhodesiense infections. Melarsoprol treatment regimens are complicated. Treatment is given intravenously. There is a significant incidence of arsenical encepholopathy with its use. For T. gambiense the drug is given in doses of 3.6mg/kg, maximum 180mg, for 3 days, repeating the series after a week without drug in patients with 6-19 WBC/cu mm CSF, and giving a third series for those with > 20 WBC/cu mm. For T. rhodesiense the regimen builds the dose up slowly from 0.36mg/kg (day 1), 0.72 (day 2), 1.1 (day 3), 1.8 (days 10,11 and 12), 2.2 (day 19), 2.9 (day 20), and 3.6 to a maximum of 180mg (days 21, 28, 29 and 30). The incidence of reactive arsenical encephalopathy is reduced by giving prednisolone 1 mg/kg before and throughout treatment. Eflornithine is effective in CNS disease due to T. gambiense with none of the arsenical toxicity, and should replace melarsoprol in this infection; initial treatment is with
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400mg/kg/day in divided doses, 6-hourly for 14 days, followed by 300mg/kg/day in divided doses for 30 days. This amounts to a lot of drug! Examination of blood films, IgM levels, CSF and the patient's condition is helpful in assessing the response to treatment. Improvement in the patient's condition and resolution of the abnormalities indicate a good response. Relapse is indicated by a rise in the CSF protein or cell count, and further treatment should be given. When patients are treated early, complete recovery is the rule. In more advanced cases treatment arrests progression of the disease. Prevention and control Appropriate clothing in endemic areas is essential to minimize the area exposed to biting. Tsetses can bite through thin material. Pentamidine has been used as a prophylactic agent against gambiense infection in those heavily exposed. Efforts to control vectors by destruction of habitats and trapping flies may be helpful.
American trypanosomiasis (Chagas' disease) Aetiology American trypanosomiasis is an infection caused by T. cruzi, which exists in several forms during its lifecycle. The trypomastigote is found in the blood and has similar appearances to the African trypanosome. Amastigotes are found within host cells. Human blood forms are ingested by the vector species of reduvid bug, 1 when it takes a blood meal. The bug defaecates infective faeces on the skin after taking a blood meal, and the metacyclic forms enter the host through the bite or other skin abrasion, or through the conjunctiva if the faeces are carried to the eye on fingers. Distribution and incidence American trypanosomiasis is most common in the countries of South America among people living in poorly constructed housing, as the bugs live in roof thatch and cracked mud walls. Many people are infected in South America, with about 6000000 cases in Brazil, although not all those infected develop disease (see Fig. 9.28). Transmission and epidemiology Contact with infected bugs (the most important source), transplacental infection and blood transfusion are the routes of infection (Fig. 9.32). Infection in bugs is maintained from a reservoir of T. cruzi in dogs. Infection of children in the first decade of life is common. The bugs live in the thatch and cracked mud walls of basic village housing.
1 Fig. 9.43
354
4
MCQ 9.27
2
Fig. 9.44
3
Fig. 9.45
Animal reservoir (e.g. dog)
Proliferates in gut
TRIATOMID BUG HUMAN Trypomastigotes enter histiocytes and divide asexually
Cells rupture, releasing more trypomastigotes
Trypomastigotes released and invade other cells AUTONOMIC CELLS INVADED AND DENERVATION RESULTS FIG. 9.32 Lifecycle of Trypanosoma cruzi
Hundreds if not thousands of bugs can be found when these houses are demolished. Chagas' disease is essentially a disease of the rural poor. Pathology and pathogenesis Trypanosomes invade cells, including myocardial and gut smooth muscle cells. Rupture of the cell releases trypomastigotes and evokes inflammatory responses in the surrounding tissues. The trypomastigotes circulate, invade other cells, and replicate as amastigotes. Phagocytic cells in any tissue, as well as heart muscle, skeletal and smooth muscle and CNS, are among the tissues involved. Pericarditis and cardiomegaly are often present. A meningoencephalitis can occur in acute disease. The heart and the gut are the organs severely affected in chronic Chagas' disease. The heart is enlarged, with apical ventricular aneurysm commonly present. Thrombus is often present in the atrial appendage and in the ventricles. There is diffuse myocardial cell necrosis, with fibrosis and involvement of the conducting system. Parasympathetic plexuses of the gut are destroyed, causing dilatation of the intestine, frequently the oesophagus or colon (the mega-syndrome). Involvement of the conducting system of the heart is common and may be the only evidence of disease. Evidence of disease may come on at any time, even decades after infection. The pathogenesis of the disease is complex. There are several different strains of T. cruzi, some of which cause the cardiac and mega-syndromes. Other strains cause lifelong infection but no disease. Autoimmune mechanisms are probably involved in damaging tissues. Clinical features Acute infection may be inapparent in young children, but in older children and adults there may be an acute febrile illness. The patient may find a lump in the skin marking the site of the infected bite and initial parasite replication (the chagoma). Unilateral periorbital oedema indicates a conjunctival route of infection. Local adenopathy and hepatosplenomegaly are found.
Cardiomegaly, heart failure, arrhythmia and conduction defects indicate myocarditis in the acute illness. This may cause sudden death. Meningoencephalitis may occur. The local signs at the bite site, hepatosplenomegaly and fever subside in 6 weeks. Chronic Chagas' disease presents with heart and gut disease. Right- and left-sided cardiac failure are common. There may be signs suggesting pulmonary or systemic embolization from thrombus in the cardiac chambers. Conduction abnormalities are often present and may cause Stokes-Adams attacks and sudden death. Megaoesophagus causes dysphagia and aspiration pneumonia in the most severely affected. 2 Megacolon causes constipation and faecal impaction. 3 Volvulus of the sigmoid megacolon may occur. Diagnosis Acute infections can be diagnosed by finding parasites in the peripheral blood film. Trypanosomes may also be found on microscopy and culture of CSF, even when evidence of CNS involvement is lacking. Xenodiagnosis is also used to make a specific parasitological diagnosis. Laboratoryreared bugs, known to be free of infection, are fed on the patient, up to 20 bugs being used. They are then kept in the laboratory, dissected after 3 weeks and the hindgut examined for metacyclic forms. The polymerase chain reaction offers a valuable technique for detecting low levels of infectious agents and has been adapted for use in Chagas' disease. Serological tests are usually positive in both acute and chronic cases by indirect imrmmofluorescence, indirect haemagglutination and complement fixation techniques, and may be the only indication of infection. Management Treatment is unsatisfactory. Two drugs are available, nifurtimox and benznidazole. Both will clear the blood of parasites in the acute phase, but prolonged follow-up suggests that neither gives a radical cure. There is now evidence from a prospective randomized controlled study that benznidazole treatment, 8mg/kg body weight in divided doses for 3 weeks given to children with positive serology, will reduce the frequency of development of ECG changes during follow-up and, with time, be followed by a decline in antibody litres. In adults with positive serology nonrandomized studies have shown a reduction in the frequency of development of ECG changes during follow-up after benznidazole therapy. However, the extent to which these findings indicate a definite benefit for treatment is still uncertain. Control of arrhythmias and heart failure is all that can be done for cardiac disease in the chronic phase. Relief of obstruction at the oesophagogastric junction by dilatation or surgery may help the patient with megaoesophagus. A dilated segment of small or large intestine can be excised. Prevention and control Brick-walled houses with corrugated iron roofs would prevent the transmission of Chagas' disease. Residual
spraying of existing houses with y-benzene hexachloride is a useful method of vector control. 4
9
LEISHMANIASIS The Leishmania are obligate intracellular protozoan parasites that infect humans and other mammals, including dogs, foxes, gerbils and rats. Infection is transmitted by the bite of infected sandflies. The generalized lifecycle is shown in Figure 9.33. These organisms invade the mammalian host, parasitize cells of the reticuloendothelial system and evoke granulomatous responses in infected tissue. Genetic factors controlling the host cell-mediated responses determine the outcome of infection, with only a proportion of those infected developing clinically apparent disease. The geographical distribution is shown in Figure 9.34. Two forms of disease are recognized. Cutaneous leishmaniasis denotes infection with species of Leishmania that affect primarily reticuloendothelial cells in the skin, whereas visceral leishmaniasis denotes infection with a species that primarily infects reticuloendothelial cells of deeper tissues (Table 9.37). The species causing cutaneous disease are geographically distinct between the Old and the New World.
Cutaneous leishmaniasis Cutaneous leishmaniasis is a granulomatous infection of the skin caused by various species of Leishmania, resulting in one or more chronic ulcerating skin lesions (Fig. 9.35). In time, the ulcers usually heal with scarring.
Proliferation in gut
SANDFLY
Promastigotes regurgitated or contaminate mouth parts while feeding
Ingestiqn of parasitized cellwithamastigotes
HUMAN
Rupture of host cell. Other reticuloendothelial cells invaded
Reproduction by binary fission
FIG. 9.33 Generalized lifecycle of Leishmania
Promastigotes taken up by reticuloendothelial r.fills
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FIG. 9.34 World distribution of leishmaniasis FIG. 9.35 Cutaneous leishmaniasis producing ulcerating skin lesions
(copyright S.G. Wright)
TABLE 9.37 Forms of Leishmania infection Location
Cutaneous leishmaniasis
Visceral leishmaniasis
Old World
Leishmania tropics Leishmania major
Leishmania donovani
Leishmania aethiopica Leishmania infantum Leishmania mexicana
Leishmania infantum
New World
Leishmania chagasi
Leishmania braziliensis Leishmania peruviana
Aetiology The organisms causing cutaneous leishmaniasis are listed in Table 9.37. Morphologically they are identical, but distinctions can be made using polymerase chain reaction (PCR) methods. Distribution and incidence The incidence is difficult to estimate, as many self-healing cases never come to medical attention. World Health Organization figures put the incidence at 100 cases per 10000 of the population in endemic areas (Fig. 9.31). Transmission and epidemiology Female sandflies of the genera Phlebotomus (Old World) and Lutzomyia (New World) transmit these infections by their bite. Apart from L. tropica (transmitted in towns and cities, with humans as the reservoir), these are zoonotic infections; humans are infected when they move into areas where there is a mammal-sandfly cycle. Urban infections tend to be more common among children. Pathology and pathogenesis Promastigotes change to amastigotes after inoculation into
1
356
Fig. 9.46
the skin and are phagocytosed by macrophages, where they replicate (Fig. 9.30). 1 The local granulomatous reactions produce a subcutaneous nodule and then the overlying skin ulcerates. The lesion persists as long as amastigotes proliferate within macrophages. This occurs despite the presence of sensitized T lymphocytes, shown by a positive delayed hypersensitivity reaction to a leishmanin skin test antigen. In most infections healing occurs spontaneously with time. It is likely that factors that contribute to TNF production, often genetic, determine the natural history of infection. Clinical features Persisting cutaneous ulceration on an exposed part of the body continuing for more than a month is the usual feature. The ulcer is painless and may crust over, only for the crust to separate again. There may be small nonulcerated satellite nodules around the primary lesion, and in both Old World and New World forms there can be involvement of draining lymphatic channels, which may be both palpably thickened and the sites of secondary lesions along their course. Lymph nodes on these lymphatics can be enlarged. Secondary bacterial infection is surprisingly uncommon. These infections will heal spontaneously in 2-8 months, leaving a residual scar. Recidivans leishmaniasis caused by L. tropica infection is characterized by a chronic relapsing course in spite of T-cell immunity. In contrast, diffuse cutaneous leishmaniasis causes numerous nodular or plaque-like lesions which tend not to ulcerate. These patients represent a kind of 'lepromatous' cutaneous leishmaniasis (p. 326). It is caused by L. aethiopica in Africa and L. mexicana in Central and South America. Leishmanin tests are negative. The South American species cause lesions similar to those of L. major (Fig. 9.35). L. braziliensis causes an initial ulcerating skin lesion which heals, but may subsequently produce a recurrence of disease with destruction of tissues at a mucocutaneous junction (mucocutaneous leishmaniasis). This can occur at the time of presentation with the primary skin
lesion, or months or even a year or so later. Another feature of cutaneous disease is the tendency to form lesions at the sites of chronic inflammation in the skin or at sites of trauma. For example, cutaneous leishmaniasis can develop in the perianal region, when there is recurrent perianal sepsis. Laryngeal disease due to leishmania has also been recognized. Diagnosis Parasites can usually be found in Giemsa-stained smears of material from slit skin smears, material aspirated from the edge of the lesion, or touch impression smears from the surface of a biopsy. Material from the biopsy can also be cultured in Novy-McNeal-Nicolle (NNN) medium. PCR on DNA extracted from biopsies or from cultured material can be used to make the diagnosis or to characterize the species complex involved. Serological tests for leishmaniasis are positive at low litre in most forms of cutaneous leishmaniasis. Differential diagnosis A variety of infective disorders can cause indolent ulceration. Among these are • • • • • • • • •
Yaws Tertiary syphilis Lupus vulgaris Histoplasma duboisii Diphtheritic ulcers (desert sore) Sporotrichosis Blastomycosis Malignant ulcers Tropical ulcers.
Diffuse cutaneous leishmaniasis can be mistaken clinically for lepromatous leprosy unless the causative organism is demonstrated in skin smears. Management The treatment of cutaneous leishmaniasis is unsatisfactory, not least because the commonly used drug, sodium stibogluconate, 20mg/kg, has to be given by daily intravenous injection for 20-30 days. Intralesional antimonials, in Old World disease, and y-interferon have also been used. Sodium stibogluconate (Pentostam) is the first choice of drug for both Old and New World leishmaniasis, and usually results in healing in most types of disease. Diffuse cutaneous leishmaniasis is often resistant and pentamidine is the alternative drug. Amphotericin-B is also very effective, given as a solution rather than in the liposomal formulation which is very effective in visceral disease (see below). Prevention and control Among Old World cutaneous leishmaniasis cure is usually associated with immunity to reinfection with the same strain, but vaccination is not yet available. Destruction of the burrows of rodent vectors can be successful in removing reservoirs. Removal of sandfly breeding sites around houses and spraying with insecticides will help to control
peridomestic transmission. Protection against the bites of sandflies may be helpful, e.g. mosquito nets and insect repellants, although the insects will bite through a shirt.
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Visceral leishmaniasis (kala-azar) Visceral leishmaniasis, an infection caused by L. donovani, is spread by the bite of an infected female sandfly and can cause a prolonged febrile illness with wasting, hepatosplenomegaly and lymphadenopathy. In South America visceral disease is caused by L. chagasi, which is probably identical to L. infantum which causes visceral as well as cutaneous disease in the countries of the Mediterranean littoral. Distribution, incidence and transmission The areas affected are shown in Figure 9.31. This condition is endemic in countries of southern Europe and Mediterranean islands that are regularly visited by tourists. Infections acquired in these areas are seen in the UK. Leishmaniasis has been recognized as an opportunist infection in AIDS in southern European countries. A major epidemic has been continuing over 10 years in the southern Sudan. Children are commonly affected in the endemic areas. Subclinical cases probably exceed clinical cases by 5 to 1. Endemic, epidemic and sporadic forms of the disease occur. All ages and both sexes are susceptible to infection. The dog seems to be an important reservoir throughout the endemic areas. Humans are the reservoir for L. donovani in northeastern and eastern India. The vectors are female sandflies of the genus Phlebotomus in the Old World and Lutzomyia in the New. These insects, guided by scent plumes, bite at night. Pathology and pathogenesis Promastigotes transform to amastigotes when they are injected into the skin and ingested by phagocytic cells. Amastigotes replicate asexually within macrophages and are carried to lymph nodes draining the site of the bite; they then disseminate to macrophages in other tissues, particularly the liver, spleen, nodes and marrow. There is progressive enlargement of liver and spleen. Wasting of the muscles and low plasma albumin are metabolic responses to the infection. The malnutrition will impair immune responses to the parasite and to other diseases such as tuberculosis or pneumococcal pneumonia, which may complicate the patient's illness. Leishmanin tests (a delayed hypersensitivity skin test) are negative before treatment and become positive after cure. Clinical features The incubation period is very variable, from 2 weeks to 2 years or more. Latent infections are common and are particularly likely to give rise to disease in the context of AIDS. Early symptoms are lethargy, sweats, and fever, with a typical pattern of two peaks in a day. Within weeks of onset the liver and spleen are palpable and progressively enlarge. Body weight falls. Lymphadenopathy may be
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found. Emaciation is obvious in more long-standing cases. Darkening of the skin of hands, feet, face, and abdomen is common in eastern India ('kala-azar' means 'black sickness' in Hindi). Poorly nourished patients should be carefully examined for coexisting tuberculosis or other infection, such as pneumonia. Investigation shows anaemia and pancytopenia due to hypersplenism, low plasma albumin and high globulin (e.g. 50g/L) with polyclonal elevation of IgG. Serological tests for leishmaniasis are positive in most cases. Parasites are readily found in patients with co-existing AIDS. Diagnosis The clinical features, together with exposure in an endemic area, suggest visceral leishmaniasis. The parasites are usually found on examination of Giemsa-stained smears of bone marrow aspirate, which should also be put into NNN culture medium. 1 Percutaneous splenic aspiration has a high yield of positive results (95%); it can be done safely in a cooperative patient whose prothrombin time is not more than 3 seconds prolonged and whose platelet count is 40 x 109/L or more. Again, material should be cultured and used for making smears. Management For many years sodium stibogluconate has been the drug
of first choice, giving 20mg/kg intravenously daily for 30 days, though longer courses may be needed. Liposomal preparations of amphotericin B are very effective, much less toxic than the conventional formulation, and can be given for shorter courses, 2-3mg/kg/day for 10 days, while 4mg/kg/day for 5 days plus an additional dose at day 10 is very effective. Relapse occasionally occurs; the options are to give more sodium stibogluconate for longer periods, or to give a second-line drug, e.g. pentamidine or amphotericin B. One of these is certainly needed if there is no response to a second course of sodium stibogluconate. Preliminary results with miltefosine, an anticancer drug, are promising. Although there may be good responses to treatment in patients with AIDS, relapse is likely as parasites are unlikely to be eradicated. However, there is little experience to date of antileishmanial treatment given with concurrent highly active antiretroviral treatment (HAART), and the improvements in CD4 counts seen with HAART may possibly allow parasite killing. Prevention and control Prevention is difficult. Where humans are the reservoir, finding and treating cases and insecticiding homes may help in control. Control of canine reservoirs can be of help. Vaccines are under study but not yet in clinical use.
HELMINTH INFECTIONS
A large number of helminthic parasites affect humans (Fig. 9.36). Humans are the definitive host in most instances, and the sexual phase of the lifecycle takes place in the human host. A classification is given in Table 9.38. Less commonly humans are an inadvertent intermediate host, infected either with larvae that do not develop any further because they are in the wrong host, e.g. Toxocara canis, or with larvae that are unlikely ever to be consumed by the definitive host, as with hydatid disease. The lifecycles of these parasites differ markedly. Faecal-oral transmission by ingested eggs or percutaneous infection by infective larvae are characteristic of the soilassociated gut nematodes. In contrast, the filariases have blood-sucking insect vectors in which they develop to infective larvae that will infect humans when later blood meals are taken. The lifecycles of the trematode platyhelminths are more complex, involving more than one intermediate host in many instances. The climatic conditions favouring transmission are warmth and humidity. These factors promote the survival of the soil-transmitted helminths and the insect vectors of
1
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Fig. 9.46
TABLE 9,38 Classification of helminth infection Nematodes (roundworms) Human intestinal Ascaris Ancylostoma Necator Strongyloides Enterobius Trichuris
Filariai Onchocerca Wuchereria Brugia Loa loa
Animal intestinal Trichinella Toxocara
Trematodes (flukes) Schistosoma Clonorchis Opisthorcis Fasciola Fasciolopsis Paragonimus Cestodes (tapeworms) Human intestinal Taenia species Diphyllobothrium Hymenolepis
Larval tissue cestodes Taenia solium (cysticercosis) Hydatid (Echinococcus)
the filarial parasites. Local traditions in food preparation and consumption are important in the transmission of a number of parasites, such as eating raw meat or lightly cooked or raw fish and crabs. Among sheep and goat
9
FIG. 9.36 Example of helminths A Rhabditiform larvae of Stmngyloides stercoralis passed in faeces (copyright S.G. Wright). B Adult roundworms, Ascaris lumbricoides. The larger female is about 15cm long. C Taenia saginata, the beef tapeworm, after expulsion from the gut (copyright S.G. Wright).
herding communities where dogs are used, definitive and intermediate hosts of Echinococcus granulosus are brought together, and it is common for sheep and goat offal containing hydatid cysts to be fed to dogs. Dog faeces containing E. granulosus eggs contaminate the environment around houses, with the consequent risk of infection of humans, particularly children. It is apparent that the burden of infection is not evenly distributed in communities. There is a small group, often children, with persistent heavy infections, and it is among this group that the morbidity and any mortality of helminthiasis are seen. Studies have shown adverse effects on nutrition and growth, and there are associations between intestinal helminthiasis and impairment of intellectual development, although a causal link has not been shown. These effects have been well shown for Ascaris lumbricoides and for Trichuris trichiuria, particularly in the setting of the trichuris dysentery syndrome. Additional studies are extending these observations to consider a similar role for schistosome infection. In addition, the availability of ultrasound scanning and endoscopy has allowed recognition that migration of ascarids into biliary and pancreatic ducts is more common than hitherto realized. The filarial worms produce disease as a result of inflammation caused either by adults in main lymphatic channels, e.g. Wuchereria bancrofti, or by larval microfilar-
iae dying in the skin in Onchocerca volvulus infection. Additional morbidity in onchocerciasis is the result of onchocercal larvae dying in the cornea to cause the ocular complication sclerosing keratitis, which can progress to blindness. The chemotherapy of helminthic infections has become progressively simpler. The benzimidazoles - tiabendazole, mebendazole and albendazole - are broad-spectrum antihelminthics active against the soil-transmitted helminths. The incidence of side-effects decreases in the order given, the most marked side-effects occurring with tiabendazole, which should be avoided unless absolutely necessary. Praziquantel has actions in a range of cestode and trematode infections, with a low incidence of side-effects. It is the first drug to be effective in cysticercosis.
NEMATODES HUMAN INTESTINAL NEMATODE INFECTION Ascariasis Ascariasis is infection of the gut lumen with the nematode parasite Ascaris lumbricoides.
359
Aetiology The adult female worm measures up to 400mm long by 6mm wide at its thickest (Fig. 9.36B). The male is up to 300mm long by 2-4 mm. They live for about 1 year. Both are a greyish-white colour. The female lays up to 200000 eggs per day. The worms do not attach themselves to the gut mucosa but maintain their position by actively moving against the flow of intestinal contents. The eggs survive well in warm moist soil but are killed by heating to 50° C. Distribution and incidence Ascariasis is common in the tropics and subtropics, and up to 90% of people may be infected. Poor or absent sanitation and frequent faecal contamination of the environment with vast numbers of Ascaris eggs lead to a high frequency of infection, often with large worm loads in children. Transmission and epidemiology Eggs are ingested in food or water or from fingers, and the larvae are released in the small intestine. They enter the mucosa and then blood vessels to reach the lungs, where they leave blood vessels and enter air spaces. Here they undergo two further moults and then ascend the bronchial tree to the pharynx. They migrate down the oesophagus and through the stomach to reach the small intestine. An excess of infections is found in a small proportion of the population, the reasons for which are uncertain. However, among this group there is evidence of undernutrition, perhaps because of the effect of the worm bulk creating a sense of satiety, with consequent reduction in food intake. Pathology No intestinal mucosal lesions are attributable to the adult worms. Pulmonary infiltrates with eosinophils are found during the larval migratory phase of the lifecycle, but this rarely has a clinical correlate. Clinical features Symptoms due to the migrating phase of ascariasis are very uncommon. Pulmonary infiltrates on X-ray, eosinophilia and restrictive pulmonary function defects can occur. This can be seen when humans are infected with the pig ascaris, Ascaris suum. There are also few symptoms attributable to established infection. Worms may be vomited, or passed with the stools, or may even emerge from a nostril. Bolus obstruction of the small intestine occurs, particularly in children with very heavy infections. A mass of matted worms in a segment of gut can cause intestinal obstruction, volvulus and infarction. Occasionally an adult worm will migrate
1
360
Figs 9.47, 9.48
into the common bile duct, causing pain, obstructive jaundice and ascending cholangitis, or into the pancreatic duct to cause pancreatitis. Ascarids can also migrate through intestinal suture lines to cause leakage from an anastomosis. Ascaris egg granulomas are occasionally found in the peritoneal cavity, presumably related to ectopic development of an adult female.
Diagnosis Diagnosis is made by finding eggs in faecal samples. The complications of ascariasis are usually diagnosed on surgical exploration or endoscopic examination. Eosinophilia is uncommon, apart from at the stage of tissue migration. Management Mebendazole (100 mg twice daily for 3 days) or albendazole (400 mg as a single dose) is effective. Both drugs are relatively expensive. Piperazine hydrate elixir (750 mg of hydrate per 5mL) is effective. The dose depends on age and weight. Where a mixed infection of ascaris and hookworm is being treated with piperazine and tetrachlorethylene (TCE) for hookworm, it is usual to treat the ascaris first, as TCE may stimulate ascaris migration into biliary or pancreatic ducts. Prevention and control The use of latrines would prevent infection. Regular administration of drugs, e.g. albendazole, in affected communities is being used. Faecal contamination of the environment and the use of human faeces as fertilizer on crops encourage transmission. Before use as fertilizer, faeces can be treated with sodium nitrate or calcium superphosphate to kill the eggs of gut parasites. Education of the community about the control efforts, and their active cooperation, are essential to the success of control programmes.
Hookworm This is infection of the gut with either Ancylostoma duodenale or Necator americanus. Both grip the wall of the mucosa with their mouth parts and take a small amount of blood from the host each day. A relatively small number of people develop disease related to hookworm infection. Aetiology The worms are about 9 mm long. The female Ancylostoma produces 30000 eggs per day and Necator 9000 eggs per day. Eggs must be passed into warm, moist soil for the ovum to develop into the larval stage. The lifecycle is shown in Figure 9.37. Larvae of Necator grow in the lungs. Ancylostoma larvae can be ingested with food and develop in the gut lumen without tissue migration. Epidemiology Both species occur worldwide where temperature and soil conditions are suitable. Ancylostoma eggs are capable of resisting desiccation to some extent. Infection rates of 80-90% are common in endemic rural areas. The use of
Growth of larvae
Larvae penetrate alveoli, pass via the trachea to the pharynx and are swallowed
Larvae in upper small intestine, mature to adult stage
Venous circulation to heart and lungs Larvae penetrate skin HUMAN
Egg passed in taeces
SOIL Eggs mature and hatch in soil FIG. 9.37 Lifecycle of hookworm
untreated faeces as fertilizer on crops accounts for the high infection of farm workers.
(TCE), giving 0.5mL/kg to a maximum single dose of 5.0mL. Eradication of the worms is not the priority if anaemia is present. Packed cell transfusion may be needed after giving diuretics. Where there is heart failure, diuretics and cautious blood transfusion with packed cells are needed. Exchange transfusion is another way of correcting anaemia without risking the adverse effects of fluid overload. Later, iron stores will need replacing.
9
Prevention and control Safe disposal of faeces prevents transmission. Where night soil must be used to fertilize crops, prior chemical treatment kills ova (see Ascariasis, above). Wearing shoes or sandals also prevents infection. A diet with meat as a regular constituent would prevent anaemia, but in the tropics and subtropics this is often beyond the means of many families and so vegetables with a high content of ferrous iron, e.g. soya beans, should be introduced into the diet. Regular deworming is increasingly used.
Cutaneous larva migrans Pathogenesis and pathology Each worm takes a small amount of blood from the host. Nutrients are removed by the parasite and the residue passes into the gut, where it can be digested and absorbed. Iron deficiency anaemia occurs when iron losses exceed intake and iron stores are depleted. Anaemia may be severe, with haemoglobin levels of less than 5.0g/dL. Hypoalbuminaemia is usual at this stage, but malabsorption does not occur. Clinical features No symptoms are attributed to hookworm infection. Hookworm anaemia appears to cause few symptoms until oedema due to hypoproteinaemia develops. Salt and water retention exacerbates the oedema and causes some degree of exertional dyspnoea. The findings are those of severe iron deficiency anaemia, with mucosal pallor and koilonychia. Some patients present with high-output congestive cardiac failure. Diagnosis and investigation Diagnosis is confirmed by finding eggs in the faeces. Worm burden can be assessed from 24-hour faecal egg outputs. Hypochromic microcytic anaemia is present. It is important to distinguish between iron deficiency and p-thalassaemia trait, which is common in the tropics. Eosinophil counts can be normal or increased, though they are often markedly raised during the phase of migration.
Management Mebendazole (100 mg twice daily for 3 days) or albendazole (200 mg twice daily for 2 days) is effective. Bephenium hydroxynaphthoate granules (5.0g) are given on an empty stomach. The cheapest treatment is tetrachlorethylene
The hookworm parasite of dogs and cats, Ancylostoma braziliensis, produces eggs which are passed in the animal faeces; they hatch in warm, moist soil conditions to release larvae which mature to the infective stage and can penetrate the skin of humans. The larvae cannot follow their usual migration in humans and instead meander around in the subcutaneous tissues close to the site of entry until they die. This can go on for several months. The feet are the most common site for this condition, but any part in contact with contaminated soil or sand can be affected. This is often seen in people who have recently had a tropical beach holiday. Occasionally the infective hookworm larvae of Ancylostoma and Necator will produce the same appearance. The appearances are readily recognized. A red papule marks the tip of the track produced by the migrating worm, and is in fact a little way behind the migrating worm. A raised, red, serpiginous track, about 3 mm across, stretches out behind. 1 The affected skin is itchy and may be blistered. Secondary bacterial infection can occur. Sometimes when the lesion is deeper in the skin a subcutaneous nodule is all that can be felt, with none of the signs described. The lesion can be active for several months. The larvae can migrate through the fabric of a swimming costume and so lesions are seen on areas that have been covered. The diagnosis is made on the appearances. Treatment with oral albendazole, 400 mg daily for 3 days, is effective, as is a single dose of ivermectin 200u,g/kg body weight, though with more numerous worms longer treatment is needed. Tiabendazole topically as a 5% cream applied twice daily for 7 days is also effective. Following effective treatment worm migration ceases and the track will slowly disappear. Secondary bacterial infection requires antibiotic treatment.
361
Migration via blood to lungs and then to gut
Adults in gut
Autoinfection through anal mucosa and perianal skin
Rhabditiform larvae in gut
Invasive infective larvae HUMAN SOIL Free-living larvae Sexual reproduction FIG. 9.38 Lifecycle of Strongyloides stercoralis
Strongyloidiasis Strongyloidiasis is an infection of the small intestine with the nematode parasite Strongyloides stercoralis, which is distributed worldwide but flourishes particularly in a hot humid climate. Most people are asymptomatic. A small number have cutaneous manifestations, and immunosuppressed patients may develop massive systemic invasion with filariform larvae. A particular characteristic of this helminth is its capacity to produce prolonged infections for decades after exposure as a result of autoinfection (e.g. former prisoners of war of the Japanese in Thailand and Myanmar). Aetiology Strongyloides stercoralis adult females are small (2mm long) and are found in the intestinal lumen, where they insinuate their anterior ends between the villi. The lifecycle is described in Figure 9.38. A variation of the lifecycle involves rhabditiform larvae developing into filariform larvae during transit down the gut. These larvae penetrate the rectal or anal mucosa or the perianal skin, and then enter the usual migratory tissue phase. It is this variation of the lifecycle that gives rise to prolonged infection, because filariform larvae develop into new adults that maintain infection. When it occurs in immunosuppressed patients very large numbers of filariform larvae develop and give rise to the massive autoinfection syndrome. Transmission and epidemiology Transmission and epidemiology are broadly the same as those of hookworm but tend to be focal, depending on soil
362
1
Fig. 9.49
2
Fig. 9.50
4
MCQ 9.28 5 Fig. 9.51
3
conditions. The occurrence of autoinfection in Strongyloidiasis allows infection to persist for 30 years or more, successive generations of adults maintaining infection. It has wide distribution in the tropics but is particularly common in Asia. Pathology The migrating larvae in the lung evoke some degree of eosinophilic pneumonitis. Markedly raised eosinophil counts are usually seen during the phase of migration, and lesser but elevated counts persist in established infection. Adult larvae provoke a mild inflammation in the gut. Maiabsorption may occur but the mechanism is not understood. Diarrhoea, hypoproteinaemia and oedema of the small bowel wall occur in children. 1 Massive autoinfection with filariform larvae can occur in immunosuppressed patients who are taking steroids or are taking steroids with cytotoxics as part of chemotherapy for tumours, with dissemination of larvae to the gut, lungs and CNS, and concurrent septicaemia from the gut. There is a clear relationship between infection with HTLV-1 infection (see p. 1237), Strongyloidiasis and massive autoinfection. Clinical features Most patients are asymptomatic and the diagnosis is made by stool microscopy finding rhabditiform larvae (see Fig. 9.36A) or in the investigation of eosinophilia. Some patients present with a transient, linear or serpiginous urticaria that comes and goes within 40-60 minutes. Lesions are seen on the trunk, buttocks and upper thighs. This is caused by subcutaneous migration of infective filariform larvae, larva currens 2 (cf. Cutaneous larva migrans, above). Intermittently rhabditiform larvae develop into infective filariform larvae during their passage down the intestine, and these then invade the rectal wall and perianal skin causing autoinfection. The massive autoinfection syndrome occurs most often in people on steroids or immunosuppressive drugs. Fever, abdominal distension, diarrhoea, vomiting and ileus are common presenting symptoms. There may be signs of meningitis. Dyspnoea, cyanosis and pulmonary infiltrates indicate pulmonary involvement. Septicaemia with organisms from the colonic microflora is common. There is a range of disease severity, and the earlier it is recognized and treated the better the outlook though, overall the prognosis tends to be poor. Diagnosis Diagnosis is usually made by finding rhabditiform larvae in stools or juice obtained from the duodenum by intubation. Eosinophilia is usual in normal persons but absent in patients with massive autoinfection. Larvae are readily found in sputum, jejunal aspirate or faeces in massive autoinfection.
Case 9.5
Management Albendazole (400mg twice daily for 3 days) is effective and
causes few side-effects. There is evidence to suggest that ivermectin, 200ug/kg as a single dose may be more effective. Treatment with albendazole is continued for 7 days or longer in massive autoinfection. There is no experience with ivermectin given over days, but adverse reactions to the drug are not common. Occasionally in those very severely affected the parenteral veterinary preparation of ivermectin has been given with good effect, though relapse is all too common and some form of maintenance therapy is often needed, e.g. intermittent ivermectin. Intensive care is also needed for these patients. Prevention Safe disposal of faeces would prevent S. stercoralis infection, and wearing sandals would help to prevent skin-soil contacts. Treatment with cytotoxic or immunosuppressive drugs for leukaemia, lymphoma and other malignancies, reactional states in leprosy or organ transplantation should be preceded by albendazole or ivermectin treatment in patients from or in the tropics. 3 4
Threadworms Infection with the intestinal nematode Enterobius vermicularis causes pruritus ani. Children are most often affected, but adults can also become infected. The lifecycle is described in Figure 9.39. The full cycle can take 14 days. Transmission Autoinfection maintains the parasite in the host. Personto-person spread is the likely route of infection in children and other family members, or by handling pyjamas, sheets or towels with adherent eggs. Clinical features Intense pruritus ani is the usual symptom of this infection and often disrupts sleep. When symptoms are present the worms may be seen on the perianal skin. In females vulvovaginitis and vaginal discharge may occur. Diagnosis Diagnosis is made either by identifying a female worm obtained from the perianal skin or the faeces, or by finding eggs. The perianal skin should not be washed before the swab is taken. Eosinophilia does not occur. Management A number of drugs are available and it is usual to treat the whole family. Mebendazole (100 mg as a single dose, fol-
SUMMARY 19 Effects of nematode infection on child health • Growth impairment • Increasing evidence for impaired intellectual function
Airborne dust
9
INGESTION Sexual reproduction in small bowel
Scratching
Adult worms Deposit of eggs on perianal skin
Gravid females migrate down colon and through anus
FIG. 9.39 Lifecycle of threadworm
lowed by a second dose 2 weeks later) is effective. Piperazine citrate (65mg/kg to a maximum dose of 2.0g/day for 6 days, repeated after 3 weeks) can be used. Pyrvinium pamoate (5mg of base/kg as a single dose) is also used. In addition to chemotherapy it is helpful to prevent ringer sucking and nail biting. The importance of handwashing after going to the lavatory and before eating should be stressed. Occasionally one child is chronically afflicted by enterobiasis, and this causes both child and family great distress. This may occur in families that are particularly careful about washing. Reassurance is needed that this is not uncommon, and that enterobiasis is occasionally difficult to treat.
Trichuriasis Trichuriasis is infection of the intestinal lumen with the nematode Trichuris trichiura. Most patients are asymptomatic. Malnutrition is associated with heavy infections, causing symptomatic disease which can include stunting of growth and rectal bleeding. Eggs are swallowed and the larvae hatch. They mature during their transit down the small intestine, and adults are found in the terminal ileum and colon. The eggs mature in soil and are ingested. The adult worm has a long thin anterior end and a short thick posterior end. This appearance is described by the common name of the parasite, the whipworm. The thick posterior end grips the colonic mucosa. 5 Clinical features Most people are asymptomatic and eggs are found on faecal microscopy. Malnourished children may become infected with large numbers of these worms, and diarrhoea with blood in the stool may result. These children often have stunted growth. On proctoscopy large numbers of worms can be seen adhering to the rectal mucosa. Rectal prolapse is sometimes seen in these malnourished children. It is difficult to know if the worm burden is the cause or the result of malnutrition. Diagnosis and management Diagnosis is made by finding eggs in faecal smears or concentrates. Mebendazole (100mg twice daily for 3 days) is effective. A marked catch-up in growth occurs in stunted children after their infection is cleared.
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Microfilariae penetrate stomach wall. Migrate to thoracic muscles. Mature to infective larvae in fly's thoracic muscles
FILARIAL INFECTION The filariae are a group of helminthic parasites whose adult and larval forms are found in humans, the sole reservoir for all but one filarial species. Transmission occurs by the bite of blood-sucking insects. The first-stage larvae, microfilariae, develop into infective third-stage larvae by two further moults in the vector. The infective microfilariae migrate out from the insect's mouth parts on to the skin when the insect is taking a blood meal, and then enter the skin through the puncture site. Development from infective larva to the adult takes up to 6 months. The adult worms are very long-lived; shedding of microfilariae begins about 6 months after infection and lasts for many years. The severity of disease relates to the burden of adult worms in the host.
BLACKFLY HUMAN Microfilariae in skin and eyes
Sexual reproduction in subcutaneous nodules containing male and female microfilariae released
Third-stage larvae mature in subcutaneous tissue to adult form
FIG. 9.40 Lifecycle of Onchocerca
Onchocerciasis Infection with the filarial parasite Onchocerca volvulus causes chronic intense pruritus with a papular eruption due to the death of microfilariae in the skin. Death of microfilariae in the eye causes a range of ocular disease; microfilarial death in the cornea over a prolonged period results in scarring of the cornea and unilateral or bilateral blindness. 1 Microfilarial death in the retina causes choroidoretinitis, and in the optic nerve optic atrophy. 2 The latter two complications are relatively rare. Aetiology and transmission Infective larvae escape on to the skin from the proboscis of an infected Simulium blackfly when it takes a blood meal, and enter the skin through the bite site (Fig. 9.40). The infection is maintained in the vectors when adult blackflies ingest microfilariae in blood meals. These develop into infective larvae over about 9 days. In humans the larvae develop into adults over 6 months and then start to shed microfilariae into the skin. These migrate out from the adult, and only when the larvae die do symptoms start to occur. Adult worms survive for up to 15 years and may shed microfilariae for most of that time. Distribution Tropical Africa and Central America are the main endemic areas, with foci of disease in Yemen, Colombia, Venezuela and the northern Amazonian region of Brazil. In Africa, two distinct areas are affected: the savannah area throughout West Africa, where ocular involvement is common, and the tropical rainforest area where ocular involvement is less common (Fig. 9.41).
364
1
Fig. 9.52
2
Figs 9-53-9.54 3 Fig. 9.55
4
Fig. 9.56
5
Figs 9.57, 9.58
FIG. 9.41 World distribution of filariasis Onchocerciasis distribution is very local and not uniform over the areas shown.
Epidemiology The distribution of the disease relates closely to the ecology of the Simulium vector, which requires fast-flowing freshwater streams and rivers for breeding. Most human cases occur in people who live close to such water sources and use them to collect water, wash clothes or play. Pathology and pathogenesis The changes in the skin and eyes are caused by the death of microfilariae. Following an acute response to microfilarial death there is granuloma formation and fibrosis. Over a number of years the result is destruction of elastic fibres, fibrosis, and thickening in the affected skin. Microfilariae die in the cornea, leading to irreversible corneal scarring. Worms also may die in the iris and ciliary body, causing uveitis with secondary glaucoma as a further complication. Choroidoretinitis and optic atrophy are also recognized. Some heavily infected patients have no symptoms, whereas others have marked symptoms and signs. Anti-
body and eosinophils are the important effector cells in killing microfilariae.
Clinical features The earliest symptom is pruritus, which may be made worse by a hot bath. Examination shows a papular eruption with excoriation. When the arm or leg is affected the limb may be obviously swollen in the early phase of the infection. As this process goes on over years there is destruction of the elastic fibres in the skin, giving the appearance of premature ageing. 3 In Yemen a variant of onchocerciasis called sowda occurs in which there is marked hyperpigmentation of the affected limb. 4 Regional glands are often enlarged and non-tender. The lateral corneoscleral junction should be examined with a slit lamp for keratitis, which appears first as small diffuse white spots. Slit-lamp examination may show microfilariae in the anterior chamber. The posterior segment of the eye should be examined for retinal lesions. The adult worms are found in nodules that consist of the adult female surrounded by fibrous tissue of host origin. 5 These nodules are felt over bony prominences such as the skull, shoulder blades, ribs, pelvic girdle and knees. When they are not palpable they must lie deep to scapulae and muscles of the gluteal region, for example. The papular rash is less apparent in chronic cases where fibrosis has produced inelastic thickened skin. There may be patchy destruction of the pigment layer in a black skin, giving a 'leopard skin' appearance. Destruction of the elastic fibres of skin in the inguinal region creates pouches containing enlarged inguinal glands, and predisposes to inguinal hernia.
bamazine (DEC). Ivermectin is given in a single dose of 200 ug/kg body weight; most adults receive 9 mg. There may be some local swelling of affected skin, but much less than that with DEC. Like DEC this drug only kills microfilariae, not adult worms, and so relapse is likely in about 50% of cases over the next year; these patients are then retreated. Diethylcarbamazine is given with a starting dose of 50 mg, increasing the dose on alternate days to a maximum of 200 mg thrice daily for 21 days. When there is marked local reaction with exacerbation of ocular involvement, topical or systemic steroids may be needed. Severe and even fatal reactions are seen in malnourished and sick patients given DEC, and so it is essential that intercurrent infection and nutritional status are improved before DEC is given. Suramin (Antrypol) is effective against adult worms and microfilariae but is used mainly for its ability to kill adult worms when ocular involvement is present. Anaphylaxis to the drug can occur and the drug is nephrotoxic. Excision of onchocercal nodules is recommended, particularly those on the head and shoulders. Early trials suggest that doxycycline may have a role in treatment, as it kills Wolbachia, bacteria within Onchocerca volvulus filariae, on which they are dependent for survival (Figs 9.42 and 9.43).
9
Prevention and control The Onchocerciasis Control Programme in West Africa has been very successful in reducing transmission of the
Diagnosis The parasitological diagnosis is confirmed by examining skin shavings from affected areas for microfilariae. These can be obtained using a needle and scalpel blade, but skin snips taken using a corneal punch is perhaps easier for the patient. Eosinophilia and a positive serological test for filariasis are usually found in the peripheral blood but are not diagnostic for onchocerciasis. Differential diagnosis Scabies and lichen planus are common or relatively common itching skin diseases in the tropics and should be considered. Nodules and ocular disease are not found, and the appearance and distribution of lesions in both conditions is different. Loa loa infection (p. 368) causes transient soft tissue swelling that produces short-lived pruritus. The lymphatic filarial infections cause unilateral limb swelling with regional adenopathy but no pruritus or papular rash. Treatment Ivermectin is now the drug of first choice because it exacerbates clinical signs much less than does diethylcar-
FIG. 9.42 Immunohistology, midbody cross-section of 'live' female Onchocerca volvulus filaria in onchocercomas Numerous bacteria are stained red in the hypodermis (arrows); some are visible as individual red dots. Note that the bacteria are located over the whole width of the hypodermis, in contrast to mitochondria (see Fig. 9.43), which also stain with antihsp60 antibodies because they have the chaperone hsp-60. Note the presence of normal embryogenesis, such as morulae (single arrow head), coiled embryos (double), and microfilariae (transverse sections, triple arrowheads). (Reproduced with permission of Dr A. Hoerauf and Professor D.W. Buttner.)
365
Microfilariae mature in mosquito thoracic muscle to become infective larvae
MOSQUITO HUMAN
Microfilariae shed by female in lymphatics enter bloodstream FIG. 9.43 Immunohistology, midbody cross-section of 'live' female Onchocerca volvulus filaria in onchocercomas Worm from a doxycycline-treated patient 8 months after the end of doxycycline treatment (100 nig P.O., daily for 6 weeks). No bacteria are detectable in the hypodermis. There is only some staining in areas towards the cuticle (c), where mitochondria (also expressing hsp-60) are located (arrow). Uteri (u) contain only remnants of degenerated embryonic stages (coiled embryos, single arrowheads, degenerated mf, double arrowheads). (Reproduced with permission of Dr A. Hoerauf and Professor D.W. Biittner.)
disease by the application of insecticides to vector habitats and by treating cases. The success is evidenced by a striking reduction in infection rates among children, but the costs involved are considerable. Insecticide resistance may become a serious handicap to further progress.
FURTHER READING Hoerauf A, Volkmann L, Hamelmann C et al 2000 Endosymbiotic bacteria in worms as targets for a novel chemotherapy in filariasis. Lancet 355:1242-1243
Lymphatic filariasis Lymphatic filariasis is a group of filarial infections in which adult worms, found in major abdominal lymphatic vessels, shed microfilariae which are carried to the bloodstream. In contrast to onchocerciasis, it is the adults that cause the pathological changes resulting in lymphoedema. This occurs in a relatively small proportion of those infected. The three species involved are Wuchereria bancrofti, Brugia malayi and B. timori. Geographical distribution of W. bancrofti is shown in Figure 9.41.
1
366
Fig. 9.59
2
Adults develop in lymphatic channels
FIBROSIS AND INFLAMMATION CAUSED BY ADULTS IN LYMPHATICS -> ELEPHANTIASIS FIG. 9.44 Lifecycle of lymphatic filariasis
Aetiology and transmission W. bancrofti (Fig. 9.44) females measure 80-100 mm long by 0.3mm. The males are smaller, 40-50 mm long. The adults live in lymphatic channels and the female sheds about 50000 sheathed microfilariae per day; these are carried to the bloodstream in lymph. They circulate in the blood and are taken up by mosquito vectors of the genera Culex, Anopheles and Aedes. The infective larvae moult twice after they enter a human host when the insect bites. W. bancrofti exhibits periodicity of microfilaraemia throughout most of its geographic distribution, releasing microfilariae during the night hours; maximal counts are at about 1 am, in close relation to the nocturnal feeding habits of the mosquito vectors. Subperiodic strains release microfilariae throughout the 24-hour period. Brugia malayi and B. timori have similar adult morphology and a similar lifecycle. Distribution ana1 incidence (Fig. 9.41) Bancroftian filariasis has the widest geographical distribution, covering tropical Africa, Asia east of Pakistan as far as eastern China, Indonesia, the Philippines, Papua New Guinea, the Caribbean and the northeastern regions of South America (all periodic forms). Subperiodic forms are widely distributed in southeast Asia and the Pacific. Current estimates indicate that about 905 million people live in endemic areas, about 10% of whom are infected. Of these, 90% have W. bancrofti. Two-thirds of all those infected live in China, India and Indonesia.
Fig. 9.60
Pathology and pathogenesis Obstructive lymphoedema of the arms, breasts, genitalia
or legs is the main outcome of inflammatory changes in the main lymphatic channels elicited by the presence of adult worms. Adult worms may be found in lymphatics or lymph nodes. Distal to this obstruction the lymphatics are dilated. Inflammatory changes in the epididymis can be an early manifestation of the host response to W. bancrofti. Similar histological features occur in infection with Brugia species, but these most often affect the legs. In established infections episodic non-bacterial lymphangitis and lymphadenitis occur, evoked by allergy to filarial antigens. Eosinophils, giant cells, dead adult worms and fibroblasts are seen in the affected lymphatics and glands. Established lymphoedema predisposes to and is exacerbated by bacterial cellulitis and lymphangitis. Minor cuts and abrasions and tinea pedis are routes for entry of streptococci and staphylococci. Bacterial infections add to the irreversible changes caused by the filarial obstruction of lymphatic channels. In the chronic phase lymphatic channels are obstructed by fibrosis with distal lymphoedema. There is fibrosis in the lymphoedematous tissue. Clinical features Many infected people have no symptoms related to the disease. The earliest feature is often generalized painless swelling of the leg. There is no rash, and inguinal glands may be normal. The swelling is worst in the evening and declines while the patient is recumbent overnight. This occurs within months of infection, before microfilariae are shed, which indicates a response to adult worms. Without treatment this swelling may progress to the chronic lymphoedema of filariasis. Filarial lymphangitis is another presentation of filariasis. Lymphatics are red and tender, and inguinal glands are swollen and painful. The lymphangitis may spread distally in a limb, which is the opposite of spread in bacterial lymphangitis. Epididymitis, which may or may not relapse, is another manifestation of the same process. The end stage is non-pitting lymphoedema with thickened, lichenified skin. 1 The penis, scrotum or labia may be involved. The breast is sometimes involved. Infection with Brugia species tends only to affect the lower limbs. Filarial abscesses can develop along the line of lymphatic channels, more often proximally in the limb. These rupture and discharge, and the ulcerated area heals well. W. bancrofti infection may cause intermittent chyluria, in which anastomoses between intestinal and renal lymphatic channels are open; these are due to more proximal obstruction in main lymphatics leading to the cisterna chylae and thoracic duct. An uncommon presentation of filariasis is referred to as tropical pulmonary eosinophilia (TPE). It occurs with both bancroftian filariasis and with Brugia malayi infections. It takes 6 months before TPE develops with bancroftian infections, but only 3 months with Brugia. The manifestations of this condition are almost entirely pulmonary. Dyspnoea with cough, predominantly nocturnal, is the major
symptom. There may also be some night sweats. Wheeze is not a usual feature. Chest X-rays may show a fibronodular pattern and peripheral blood eosinophil counts are markedly raised (6.0 x 109/L is not uncommon), with strongly positive filarial serology. Day and night bloods are free of microfilariae. It is thought that this is a manifestation of hypersensitivity on the part of the host's immune system to the microfilariae, resulting in retention and destruction of the nocturnally released larvae within the pulmonary vasculature.
9
Diagnosis Diagnosis is usually made on the history, physical signs and marked peripheral blood eosinophilia when patients are seen at the early lymphoedema stage. Later, when there is relapsing lymphangitis or epididymitis, microfilariae are found in the blood, 2 maximally at 1 am in the periodic forms, and by day and by night in the subperiodic forms. When there are many microfilariae they are readily found in stained blood smears. Filtration of blood through a filter to retain the microfilariae may demonstrate parasites in lighter infections. In patients with scrotal nodules, ultrasound scanning can sometimes visualize adults which are motile, the 'filarial dance sign'. The adult parasites may have died out in patients with end-stage disease, and so parasites cannot be found. Serological tests are not specific for filarial infections and cross-reactions with Strongyloides are common, so that a positive test should stimulate a further search for parasites. In TPE the history, with relevant exposure in endemic areas plus marked eosinophilia plus strongly positive filarial serology, are the features required for diagnosis.
Differential diagnosis Tuberculosis, malignancy and chronic bacterial lymphangitis may all cause lymphoedema in the tropics. Management Diethylcarbamazine (DEC) is used, as for onchocerciasis (p. 364) though 12 days' therapy is sufficient. Reactions due to death of worms do occur. Lymphoedema is best controlled by elevation of the affected limbs at night and pressure bandaging. Albendazole and ivermectin are also effective. Surgery to excise the lymphoedematous tissue is not satisfactory and is only a final resort. Prophylactic penicillin V, 250 mg twice daily, is helpful in patients who have had repeated attacks of bacterial lymphangitis. Meticulous care of the feet, and particularly the skin between the toes, is essential. Staphylococci and streptococci are the common causes of bacterial infection in the affected limbs. TPE responds to DEC in the same dosage regimen, though it may be necessary to give prednisolone as well to inhibit exacerbations of pulmonary symptoms. Prevention and control Traditionally these have depended on vector control and
367
treating cases. Recent work in Indonesia and Kenya has shown that low-dose DEC can be used to control the infections.
Loiasis Loiasis is a filarial infection characterized clinically by transient soft tissue swellings at sites of adult Loa loa worm death or migration of adult worms across the eye, subconjunctivally. Chrysops flies are the vectors. Aetiology Loa loa adults measure about 60 x 0.5mm (female) and 30 x 0.4mm (male). They migrate freely in subcutaneous tissues. 1 Six months after infection adults have developed and fertilized females start to shed microfilariae, which are found in peripheral blood during the daytime. Chrysops flies ingest microfilariae in blood meals. Development to adult worms takes place in subcutaneous tissues, and shedding of microfilariae begins by 90 days after infection. Adults live for up to 15 years. Epidemiology The endemic areas (Fig. 9.41) cover the tropical rainforest regions of West and Central Africa, extending as far east as the southern Sudan and Uganda. The vectors live in the forest canopy and descend to lower levels to feed. The prevalence in some populations is 100%. Animal reservoirs do not play a part in the cycle of transmission. Clinical features Transient itchy soft tissue swellings up to 7cm across, on the limbs or less often the face, are a common presentation; these are called 'Calabar swellings' and are most often seen in people who have lived in endemic areas for a relatively short time. In indigenous residents of endemic areas a more typical presentation is migration of an adult worm across the globe of the eye beneath the conjunctiva, causing local irritation, a feeling of movement and some alarm. 2 Occasionally a worm dies immediately beneath the skin, producing a linear swelling in the skin. Problems can arise in patients who have large numbers of microfilariae in the peripheral blood (over 25-50/mm3), beginning a short time after starting treatment with DEC. Encephalitis or encephalomyelitis can occur, probably because of dead microfilariae occluding vessels of the brain and spinal cord. Cerebral oedema and granulomatous reactions around microfilariae are found in fatal cases. Diagnosis The diagnosis is confirmed by finding typical sheathed microfilariae in peripheral blood samples taken during the day. 3 When there are few microfilariae, millipore filtra-
368
1
Fig. 9.61
2
Fig. 9.62 3 Fig. 9.63
4
MCQ 9.29
5
Fig. 9.64
tion of blood may show parasites (see above). Eosinophilia in the peripheral blood is usual and a positive serological test, e.g. filaria indirect fluorescent antibody test, provides only indirect evidence of infection. Management DEC (p. 365) is the most active drug in the treatment of loiasis. It kills microfilariae well and adult worms more slowly. While the patient is on DEC, Calabar swellings may appear. Also, worms dying close to the skin may be seen. When microfilariae counts are above 25-50/mm3 DEC cannot be given alone because of the danger of precipitating cerebral complications. Removal of microfilariae from the circulation is recommended. Whole blood exchange transfusion, or apheresis using a blood separator, can be used to remove large numbers of microfilariae. This makes it safe to give DEC. Prednisolone in doses of 40-60 mg/day, beginning 24 hours before starting DEC and continuing till the top dose is reached, is usually more convenient. Prevention and control Measures for the control of loiasis have not been successful. Vector control is difficult. Mass chemotherapy is not appropriate because of the need for individual supervision of treatment in people with heavy infections, and because of the coexistence of onchocerciasis in the same endemic areas. Other measures include protection from biting by clothing and the use of insect repellants. 4
ANIMAL INTESTINAL NEMATODE INFECTION' Trichinosis Aetiology Trichinella spiralis is a nematode parasite with very low host specificity that will infect over 100 species of animals, particularly carnivores. Human infection occurs by consumption of undercooked meat containing encysted larvae (Fig. 9.45). These hatch in the human gut and mature to the adult stage. Fertilized females shed viviparous larvae for up to 14 weeks until the adults are expelled. The larvae penetrate the gut mucosa to reach the circulation and are disseminated to all the tissues, where they excite inflammatory responses. Larvae encyst and survive in skeletal muscles. 5 Distribution, incidence and transmission T. spiralis is widely distributed in nature through the Americas, Asia, Africa and the Arctic. Sporadic cases and epidemics occur. Outbreaks also occur in Europe. All ages and both sexes are susceptible but children seem to have milder attacks, probably related to a lower infecting dose of larvae in their smaller meals. Exposure to infection is more likely among those nationalities whose cuisine involves eating raw or lightly cooked meats. Smoked sausages made from wild boar are common sources of infection in European countries.
positive. Differential diagnosis includes polyarteritis and other causes of eosinophilia. Eats infected food
Encysted larvae eaten in raw or undercooked pork
A/loncrgemenf Albendazole 400 mg twice daily for 10 days will eradicate adult warms from the gut and thus cut off the production of invasive larvae. There is evidence that anthelminthics affect larvae in the tissues. Steroids may be needed when inflammatory responses in the tissues are very marked.
Larvae moult in intestinal mucosa to become adults in gut
Prevention and control Thorough cooking or freezing (-15°C for 20 days) of meat will prevent trichinosis. Public health measures include boiling pig swill and inspecting meat.
PIG
HUMAN
Larvae encyst in striated muscle Larvae invade intestinal mucosa and travel to muscles via lymphatics and blood vessels FIG. 9.45 Lifecycle of Trichinella spiralis
Pathology Granulomas form around worms dying in the tissues. Focal interstitial myocarditis is found in the heart, with a marked infiltrate of eosinophils. A non-suppurative meningitis with granulomas and capillary thromboses is seen in fatal cases. Invasion of the eye muscles may contribute to the periorbital oedema. Skeletal muscles show encysted larvae, myositis with marked eosinophil infiltrate, and patchy degeneration of muscle fibres. Calcification may occur in the capsule of the cyst or in the larvae by 6 months after invasion, but larvae can remain viable in muscle for 10-15 years. Clinical features Four main features of the disease are fever, orbital oedema, myalgia and eosinophilia. Bowel upset is variable. Vomiting occurs, and the alteration in bowel habit may be diarrhoea or constipation. In the phase of muscle invasion the affected muscles are tender on movement. Fever, urticaria, splinter haemorrhages in fingers and toes, difficulty with swallowing and difficulty with breathing may all be present. Invasion of the nervous system can cause a meningitislike picture. Fits, paralysis, disturbed conscious level, difficulty with balance and personality disorders may occur. Heart failure can result from severe cardiac involvement. Symptoms due to reactions to larvae in the tissues start to resolve gradually from about 14 days onwards in milder cases, but can take several months to settle completely. Diarrhoea and a malabsorption syndrome have been described. Diagnosis Trichinosis is suspected clinically and confirmed by examination of muscle biopsy for encysted larvae. Muscle biopsies can be obtained under local anaesthetic using a Trucut needle and are examined immediately, squashed between microscope slides. Eosinophil counts are very high and muscle enzymes are raised. Trichinella serology is strongly
9
Toxocariasis Aetiology Toxocariasis is caused by infection with larval forms of Toxocara canis or T. cati, which are primarily parasites of dogs and cats. The adult worms are found in the gut lumen and eggs are shed in the faeces. Humans are infected by ingesting eggs, and the larvae released burrow into the gut wall to enter vessels and disseminate. Larvae mature outside the host over 14 days and then are infective to the definitive host or to humans. Distribution, incidence and transmission The distribution is worldwide in dogs and cats, although there is considerable variation in the frequency of animal infection and contamination of the environment. Studies in Britain showed that 17% of soil samples were contaminated with toxocara eggs. Moist soil conditions are more suitable for transmission than hot, dry conditions. Children are most often infected. Infection is likely to occur when fingers are contaminated with soil or sand containing eggs during play and then put in the mouth. Dog faeces deposited in public parks, especially around playgrounds, represent a potential source of infection. Dog breeders and people who work in kennels are at risk of infection. Toxocariasis due to T. cati is much less common. Pathology and pathogenesis Disease in humans relates to the number of infecting larvae and the host response. Clinical manifestations are due to dying and dead larvae, which evoke granuloma formation with eosinophils, macrophages and lymphocytes. The eye, brain, liver, spleen and lungs may be involved in toxocariasis, but granuloma formation may occur in any organ of the body. Clinical features Ocular toxocariasis and visceral larva migrans (VLM) are two clinical presentations of this disease, which is often a subclinical infection. Unilateral visual impairment is the usual symptom in ocular toxocariasis. Lesions directly on the visual axis will cause severe impairment. A child may
369
develop a squint. The granuloma can form in relation to the lens and ciliary body, or on the retina itself. A cataract may develop secondary to a granuloma affecting the ciliary body. Visceral larva migrans is due to a heavy infection with larvae. Fever, anorexia, chills, night sweats and weight loss are usual features. Examination shows hepatosplenomegaly as the main physical sign. Pneumonitis may also be present. There is usually a marked eosinophilia in the peripheral blood in VLM, but eosinophilia is less common with ocular disease. Serological testing is valuable, the ELISA technique using a toxocara secretory antigen being a sensitive and specific test. Differential diagnosis Toxoplasmosis usually causes bilateral choroidoretinitis with destruction of the retina. 1 Lymphoma, tuberculosis and sarcoidosis are usually considered in the differential diagnosis of VLM, although the gross eosinophilia is against the former conditions and supports a helminthic infection. The toxocara antibody test is strongly positive. Management DEC is the usual treatment, giving initial doses of 50 mg and doubling the dose on alternate days till the maximum (lOmg/kg/day in three doses for 21 days) is reached. Ocular disease is not specifically affected by DEC because the worm is dead. There may be some spontaneous improvement as inflammation and granuloma size reduce. DEC is given in these cases to kill any worms that are still migrating. Prevention and control Regular deworming of dogs, particularly pregnant bitches and puppies, reduces the numbers of eggs contaminating the environment. Dog owners should try to ensure that their dogs defaecate somewhere where the faeces will not contaminate open spaces, playgrounds and parks.
Dracunculiasis (Guinea worm infestation) Dracunculus medinensis, the Guinea worm, is a tissue nematode widely distributed through Africa and Asia. Humans are infected by drinking water containing minute crustaceans of the Cyclops genus infected with Guinea worm larvae. The larvae penetrate gut tissues and migrate through host tissues, maturing to the adult stage. The female is fertilized by the male, which dies, and the gravid female migrates out into a limb, producing a painful, fluid-filled blister about 3cm across which then bursts and about 5 cm of the female protrudes. 2 Vast numbers of larvae are released from the worm. Patients often put
370
1
Fig. 9.65
2
4
Figs 9.68, 9.69
Fig. 9.66
3
Fig. 9.67
the affected limb into cold water to relieve the pain; this stimulates the discharge of larvae, providing the opportunity for larvae to continue the lifecycle by infecting other cyclops. The diagnosis is made on the clinical appearances. Treatment comprises relief of pain, treatment of secondary bacterial infection with antibiotics, and administration of tiabendazole. This does not have any direct effect on the worm but reduces inflammation around it, allowing it to be gently wound out of the subcutaneous tissues on a stick. O Control of Guinea worm is a realistic prospect using very simple methods. Cyclops can be filtered from drinking water using simple filters with nylon mesh of appropriate pore size. These can be made locally from materials that can be supplied by Ministries of Health. Village communities can all be involved in disseminating information about the disease, making the filters, and how to avoid disease by simple water filtration.
TREMATODES Schistosomiasis Infection with digenetic flukes of the genus Schistosoma affects the bladder and urinary tract (S. haematobium) or intestine (S. mansoni, S. japonicum). These worms cause disease because of the host's response to eggs retained in the tissues. The severity of disease relates to the number of eggs in the tissues, which is proportional to the worm burden. Aetiology Eggs are passed in stools or urine; those deposited in still or slow-flowing fresh water hatch to release the ciliate miracidium, which can survive for up to 48 hours before it dies (Fig. 9.46). During this time it must find an aquatic snail of the appropriate genus: Biomphalaria for S. mansoni, Bulinus for S. haematobium, and Oncomelania for S. japonicum. Cercariae are released from the snail and these penetrate the skin of a suitable host, almost always human, becoming schistosomules during penetration. These migrate via the blood vessels to the pulmonary vasculature, where some traverse the pulmonary circulation to enter the systemic circulation. Schistosomules of mansoni and japonicum mature in the hepatic branches of the portal vein, and by 6 weeks after infection they are mature. They migrate out of the liver against the flow of blood in the portal vein to small veins around the colon and small intestine. The colon is mainly involved in mansoni infections, and both colon and small intestine are involved in japonicum infections. The lifecycle of S. haematobium is similar, but maturation takes place in pelvic veins. The worm pairs migrate into small branches of the internal iliac vein, principally around the bladder, although other pelvic structures such
Schistosomules reach venous circulation via lungs. Become sexually mature and mate
9l
Male and female migrate to lay eggs in vesicle veins (S.haematobium) cr intestinal veins (S.mansoni, S.japonicum)
Blood and lymphatics
Eggs reach water in urine (S.haematobium) or faeces (S.mansoni, S.japonicum) HUMAN
Cercariae penetrate skin
FRESH WATER Eggs hatch, liberating ciliate miracidia SNAIL
Sporocysts rupture on to external surface of snail, releasing cercariae
Miracidia penetrate foot piece of one of several species of snail (intermediate hosts), where sporocysts form
Cercariae develop within sporocysts FIG. 9.46 Lifecycle of schistosome parasites
as the prostate and seminal vesicles in men, and the uterus and adnexal structures in women, may be involved. Adult worms survive for about 7 years on average, but survival of over 30 years has been reported. Distribution and incidence The distribution is shown in Figure 9.47. There is considerable overlap in the endemic areas of haematobium and mansoni, but japonicum has a distinct Asian distribution. The prevalence and incidence of infection vary considerably, with rates up to 70% or more in the endemic areas. Infection rates tend to be highest in children and decline with increasing age. Transmission and epidemiology Freshwater contact is the major factor in infection and maintenance of transmission. Children are infected early in life by playing in infected water. They are also likely to urinate and defecate in and around pools and streams, further enhancing the local intensity of transmission. The highest rates and intensities of infection are found in the second and third decades of life. Pathology and pathogenesis The pathological changes relate to the presence of eggs in the tissues. Eggs laid in the small branches of veins may: • pass through the wall of the viscus to reach the exterior in faeces or urine
FIG. 9.47 World distribution of schistosomiasis
• be retained in the tissues • embolize through vessels to lodge in presinusoidal branches of the portal vein in mansoni and japonicum infections, or in pulmonary arterioles in haematobium infections. The egg excites a granulomatous response with macrophages, lymphocytes, plasma cells and eosinophils. Granuloma formation is important for the transition of the egg through the mucosa to the lumen of the viscus. The chronic inflammation they may cause in the epithelium may be a factor in carcinogenesis of the bladder (haematobium). Eggs retained in the tissues within granulomas gradually break down until all that may remain is remnants of the egg case. The granuloma heals by fibrosis. Early in the course of infection exuberant granuloma formation can cause colonic polyps in mansoni and japonicum infections, and bladder polyps in haematobium infection. These resolve after treatment and may also resolve spontaneously. Fibrotic polyps and strictures are not often seen in mansoni infection, although they are more common in japonicum infection. Haematobium infection causes fibrosis of the bladder, which is often shrunken, with a thick wall. Bladder stones may form and cystitis is common. Unilateral or, less commonly, bilateral ureteric strictures cause obstructive uropathy. Stones may form in the dilated ureters. Distortion of the ureterovesical junction may allow vesicoureteric reflux of urine with associated recurrent pyelonephritis. Squamous cell carcinoma of the bladder is common in highly endemic S. haematobium areas. It is suggested that schistosomiasis acts with dietary factors to produce malignancy. This has not been found in S. mansoni infection or in S. japonicum, despite earlier reports from China. Mansoni and japonicum eggs embolize to the liver. The granulomas that form around eggs 4 add to the volume of the liver and increase its size, and obstruct the flow of blood through the portal circulation in the liver, causing congestive hepatosplenomegaly in those with heavy worm burdens. Granulomas resolve with local fibrosis, and when
371
this process goes on over years periportal fibrosis results, causing irreversible portal hypertension. The anatomy and architecture of the hepatic lobules are not altered and there are no regenerating nodules, therefore cirrhosis is not caused. In the lungs granulomatous reactions in the vessels cause fibrosis and pulmonary hypertension. Involvement of the CNS occurs in S. japonicum, S. mansoni and S. haematobium, in descending order of frequency. Disease of the central nervous system is most probably the result of an ectopic worm pair laying eggs in or around the brain or spinal cord. Mansoni and haematobium infections are associated with spinal cord and cauda equina lesions. Clinical features Cercarial invasion of the skin may cause a local irritant papular eruption, but this is uncommon. Most patients have no symptoms related to the phase of migration and maturation. Occasionally non-immune people develop the Katayama syndrome with the phase of worm migration. There is malaise and lethargy, and fever, profuse sweats, muscle pain, abdominal pain, joint aches, unproductive cough, urticaria, swollen eyelids and hepatosplenomegaly occur in more severely affected patients. These symptoms begin 3-4 weeks after exposure and persist for up to 3 months, with reducing severity. Chest X-rays may show coin lesions caused by worms dying in vessels and evoking local inflammatory reactions. Marked eosinophilia is common. Eggs are not found until 3-6 weeks after infection. S. mansoni and S. japonicum Many infected patients go through life without any symptoms related to this infection. Rectal examination is normal; sigmoidoscopy is normal or shows scattered mucosal haemorrhages. Occasional patients present with anaemia and oedema because of bleeding and protein loss from schistosomal polyps. The most common physical sign in infected patients in endemic areas is hepatomegaly, which correlates with the intensity of infection in the first two decades but not in older age groups. Similar findings are noted in S. japonicum infection. Abdominal pain and subacute intestinal obstruction occasionally occur in the rare patient who develops fibrotic strictures in the colon or, less often, the small intestine. Hepatosplenomegaly with congestive splenomegaly suggests end-stage schistosomal hepatofibrosis. These patients often present with haematemesis and ascites. Portosystemic encephalopathy is not a usual feature after variceal bleeding in schistosomiasis. Severe pain over a grossly enlarged spleen may indicate splenic infarction.
372
1
Fig. 9.70
2
Fig. 9.71
4
Fig. 9.74
5
MCQ 9.30
3
Fig. 9.72, 9.73
S. haematobium Dysuria, frequency and haematuria occur in some patients at the start of egg laying. More commonly, the presenting symptom is terminal haematuria, i.e. the last drops of urine passed are bloodstained. Physical examination is usually normal. Most people have light infections and suffer no long-term adverse effects. Reversible granulomatous polyps and obstructive uropathy occur in the early stages of heavier infection. This appears to be spontaneously reversible, and is certainly reversible after treatment. Those with heavy infections develop fibrotic and obstructive complications which can cause recurrent urinary tract infections, stone formation, and finally renal failure. 1 In these patients the infection is associated with an increased risk of bladder cancer. Excretion urography often shows bladder polyps and obstructive uropathy, either unilateral or bilateral, in older children and teenagers. Chronic infection causes 'sandy' patches on the trigone as a typical cystoscopic finding. 2 Calcification in retained eggs is seen in the bladder wall as a rim of calcium in the pelvis on a plain abdominal X-ray. Tramline calcification in the ureter may also be seen. Other manifestations Pulmonary involvement may be subclinical up to the stage when significant pulmonary hypertension develops. Right heart failure develops, and this is difficult to treat. Cutaneous involvement is indicated by a collection of subcutaneous papules. In haematobium infection the skin of the scrotum and perineum may be affected. 3 Symptomatic involvement of the CNS is uncommon. Intracranial disease occurs with S. japonicum infections, with a frequency of 2-4%. It is much less common in mansoni and haematobium infections. Focal signs and jacksonian epilepsy may occur with involvement of the cerebral hemispheres, whereas posterior fossa lesions are associated with raised intracranial pressure, cerebellar signs and brainstem compression. Lesions of the spinal cord may present with features suggesting cord compression, transverse myelitis or spinal artery occlusion. Granulomas may also form around the cauda equina. The occurrence of focal signs in the neuraxis in a patient in or from an area endemic for schistosomiasis should prompt a search for schistosome eggs in stools and urine that would indicate active infection. Eosinophils in the CSF suggest the possibility of schistosomiasis affecting the CNS. The empirical use of antischistosomal drugs plus steroids also need to be considered. Diagnosis Diagnosis is made by finding schistosome eggs. Eggs of S. mansoni and S. japonicum are found in concentrates of faecal samples. Eggs of S. haematobium are found in the centrifuged deposit of terminal urine samples. Eggs of all three species may be found in rectal snips. Squash preparations can also be made from fragments of bladder mucosa obtained at cystoscopy.
Eosinophilia is a common finding in the peripheral blood but occurs in several helminthic infections. Serological tests can be helpful. An ELISA for antibodies to schistosome egg antigens is useful because it indicates that infection has progressed to the stage of ovideposition. The test takes 18 months at least to revert to negative after treatment, and so is not helpful in assessing cure. Excretion urography, isotopic renography, ultrasound and CT scanning give anatomical and functional detail of the urinary tract in chronic schistosomiasis. Colonoscopy and barium enema can be used to examine the colon in more detail. Ultrasound scanning of the liver demonstrates the presence of periportal fibrosis. 4 Chest radiographs show dilatation of the pulmonary arteries and right ventricular hypertrophy in pulmonary hypertension. MRI or CT allow localization of schistosomal lesions of the neuraxis. Eosinophilia in the CSF supports the diagnosis of CNS involvement in schistosomiasis. Management Three safe, effective drugs are available for use in schistosomiasis (Table 9.39). Their safety in pregnancy has not been confirmed, and so treatment should be delayed until after delivery unless there are urgent indications for prompt treatment. All cases should be treated, even the advanced ones, as further ovideposition causes further urinary tract, intestinal, liver or pulmonary damage. Ideally, stools and rectal snips should be examined for viable ova 3 months after treatment. Prevention and control Control measures are expensive and require a change in the behaviour pattern of the exposed population. Education regarding the reasons for the measures is essential. Dams and irrigation projects for the improvement of the
SUMMARY 20 Schistosomiasis
9
• Infection by exposure to freshwater pools, lakes • Invasion usually inapparent: occasionally itching at sites of invasion (swimmer's itch) • Worm burden determines morbidity and mortality • Tissue damage is caused by host granulomatous response to retained eggs • Bladder (S. haematobium): polyps, strictures, fibrotic and contracted bladder squamous cell carcinoma associated with heavy prolonged infections • Intestine (colon S. mansoni; colon and small intestine S. japonicum) Polyps and stricture in gut uncommon • Liver: schistosomal hepatofibrosis causing portal hypertension, congestive splenomegaly, hypersplenism with variceal bleeding and ascites • Ectopic disease related to the site of a worm pair with CNS disease is the most serious manifestation
economy of an area may create new habitats for snail hosts of schistosome parasites. Molluscicides can be used, but are expensive and may have detrimental effects on other water creatures. Regular, community-based treatment with praziquantel has reduced morbidity. 5 Clonorchiasis
Aetiology Clonorchis sinensis is a hermaphroditic trematode parasite of the biliary tract in humans. The adult fluke is 10-25 mm long by 3-5 mm wide. The lifecycle is shown in Figure 9.48. Transmission ana1 incidence Fishponds into which human faeces are poured as fish feed are an important source of infection, as eggs, snails
TABLE 9.39 Drug treatment of schistosomiasis Drug
Active against
Dose
Side-effects/contraindications
Oxamniquine*
Schistosoma mansoni
West Africa and South America 15mg/kgx1 (adult) 20mg/kgx1 (child) Elsewhere 20mg/kg per day x 3
Occasional febrile episode 5 days post treatment
Metrifonate*
S. haematobium
7.5mg/kgx3 (2 weeks between doses)
Anticholinesterase actions may prolong neuromuscular blockade after surgery. Avoid elective surgery for 3 days post treatment and provide ventilatory support after emergency surgery within 48 hours of administration
Praziquantel*
S. mansoni S. haematobium S. japonicum
40mg/kgx1
Dizziness, nausea and occasional vomiting beginning 1 hour after dosing, lasting up to 4 hours
20mg/kgx3 (4 hours between doses)
*The safety of these drugs has not been confirmed in pregnancy; treatment should be delayed until after delivery unless there are urgent indications for prompt treatment.
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FIG. 9.48 Lifecycle of Clonorchis and Opisthorcis
and fish are conveniently found together. The disease occurs in Asian countries. Dogs and cats are also important hosts. Pathology The worms obstruct small branches of the biliary tree, and bile accumulates in cysts proximal to the obstruction. Hypertrophy of the bile epithelium with adenomatous proliferation occurs. Later there is cellular infiltrate of the bile duct wall with chronic inflammatory cells. Pigment stones and biliary sludge form. Flukes obstructing the pancreatic ducts can cause pancreatitis. Long-standing heavy infections are associated with malignant change in the adenomatous hyperplasia, leading to cholangiocarcinoma. Clinical features Clinical features relate to the worm burden. Mild infections cause no symptoms. Upper abdominal discomfort, diarrhoea and weakness occur with heavier infections; with the heaviest worm burdens upper abdominal pain, diarrhoea, weight loss, obstructive jaundice, hepatomegaly, cholangitis and Gram-negative septicaemia occur. Diagnosis The eggs are found in faeces or in duodenal aspirate. Eosinophilia is usual in the peripheral blood. Endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography shows dilated branches of the biliary tree, and the worms appear as filling defects.
1
374
Fig. 9.75
FIG. 9.49 Lifecycle of Taenia species
Management Praziquantel is the treatment of choice, giving 25 mg/kg on three occasions 4 hours apart on one day. When there is obstructive jaundice with cholangitis and septicaemia, relief of biliary obstruction, vigorous treatment of the bacterial infection and circulatory support for the patient are needed. Prevention and control Transmission can be interrupted by safe disposal of faecal wastes. Usually this involves a major change in social habits, which is difficult to achieve. Thorough cooking of fish before it is eaten prevents infection, as does freezing fish, -10°C for 5 days, and salting in 10% saline.
Opisthorciasis Opisthorcis viverrini and O. felineus have similar lifecycles to that of C. sinensis, and in humans they parasitize the intra- and extrahepatic branches of the biliary tree (Fig. 9.49). Raw, pickled, smoked and undercooked fish are the sources of infection. The pathological changes and consequences are those of chronic irritation and obstruction of the biliary tree, with ascending cholangitis in severely affected patients. Cholangiocarcinoma occurs in O. viverrini patients. The diagnosis is made by finding eggs of the parasite in stools or duodenal aspirate. Praziquantel is used for treatment as for clonorchiasis.
Fasciolidsis Fascioliasis is an infection of the biliary tree with the
hermaphroditic trematode Fasciola hepatica. It is primarily an infection of sheep. The lifecycle is similar to that of Clonorchis (Fig. 9.46). Aetiology and distribution The parasite measures 3 x 1.5cm. 1 Eggs are released in the biliary passages and pass to the exterior in the faeces. The miracidium hatches in fresh water and penetrates the tissues of a freshwater snail (Lymnaea species). After a cycle lasting 4 months in the snail, cercariae are released. These encyst on the leaves of watercress and other types of aquatic vegetation. Humans are infected by eating watercress with encysted metacercariae. Maturation to the adult stage in bile ducts takes about 4 months until egglaying starts. Sheep are the normal hosts of this infection, and human infections are likely wherever sheep are herded in wet pasturelands. Pathology There is hepatic parenchymal necrosis in the phase of migration through the liver. The liver tissue regenerates. The worm burden determines the severity of disease. In the bile ducts there is chronic inflammation, with regenerative hyperplasia of the epithelium and some degree of duct obstruction. Clinical features Pain in the liver area, fever, chills, tender hepatomegaly and marked eosinophilia are usual features during the tissue migration phase. Upper abdominal discomfort and hepatomegaly are present in mild to moderate infections, whereas heavy infections may cause obstructive jaundice and cholangitis as well. Diagnosis Eggs of the parasite are found in stools or duodenal aspirate, though they can be difficult to find in relatively light infections. Endoscopic retrograde cholangiopancreatography may show filling defects in the biliary tree and flukes may be extracted from ducts using a stone basket. Eosinophilia is usual and serological tests for this infection are usually positive. Management and prevention Triclabendazole, 10mg/kg b.d. x 1 day, or bithionol, 40 mg/kg in 2 divided doses on alternate days for 15 dosage days, are effective. Watercress production must be separate from sheep pastures. Wild watercress should not be sold for human consumption.
when these are eaten uncooked. After about 3 months the adult has matured in the small intestine; egg production begins and lasts for most of the 6-month lifespan of the adult. Upper abdominal discomfort, diarrhoea, preprandial upper abdominal pain relieved by food, and symptoms and signs of intestinal obstruction may occur, more marked symptoms being found with heavier infections. Eggs are found in the faeces. Tetrachloroethylene is effective in treatment. Praziquantel may prove to be effective.
pj
Paragonimiasis Paragonimus westermani is a hermaphrodite fluke usually found in the lungs but occasionally in other sites, e.g. CNS. It has a wide distribution in South America, West Africa, south east Asia and the Pacific. Human infection occurs when raw or undercooked freshwater Crustacea with metacercariae encysted in their muscles are eaten. The development cycle outside the host involves a freshwater snail: from the snail the cercaria is released and then finds a suitable crustacean host. In humans the metacercaria excysts and penetrates the full thickness of the gut wall to enter the peritoneal cavity. The phase of tissue migration continues with the parasites reaching and crossing the diaphragm to enter the lungs. Where the worm finally comes to rest in lung tissue it elicits first a cellular response and then fibrosis, so that the worm is enclosed but for a connection to an airway. Dead worms calcify. Radiological appearances comprise pleural thickening, infiltrates at the site of recent invasion, nodular lesions (encysted adults), fibrosis and finally calcification. Eggs released by the worms are coughed up or swallowed. Cough productive of sputum, dyspnoea and chest discomfort are usual features. Bacterial infection of the affected area causes fever, systemic upset, purulent sputum and haemoptysis on occasions. Abdominal organs and brain are affected less often. Diagnosis and management Eggs are found in the sputum in most cases. Serological tests are available. Praziquantel is effective in doses of 25 mg/kg given three times daily for 3 days.
CESTODES
HUMAN INTESTINAL CESTODE INFECTION Taenia saginata
Fasciolopsiasis Fasciolopsis buski is the largest trematode parasite, measuring up to 7.5cm long by 3.0cm wide. It has a wide geographic distribution throughout eastern Asia, with a reservoir of infection in pigs. The metacercariae are found on bamboo shoots or water chestnuts, and infection occurs
Human infection with T. saginata is common in Africa, the Middle East, Asia and South America. The infective stage is the cysticercus in beef, and humans are infected by eating rare or undercooked beef (Fig. 9.46). The cyst is released in the gut and the scolex everts from the cyst. It adheres to the gut wall and proglottids start to develop. Each segment
375
has testes and ovaries, and is self-fertile. The worm may be 5-10 m long. The distal segments are full of eggs. Lengths of worm are passed in the stools, and when defaecation occurs in pasture, cattle may eat the gravid segments and develop cysticercosis bovis. The infection causes no symptoms in humans although often a variety of vague abdominal symptoms have been attributed to it. Occasionally a patient will present with pruritus ani and find segments in underwear, the motile segments having wriggled out of the anus. The diagnosis is confirmed by examining segments. T. saginata segments have 15-20 lateral branches to the uterus. The eggs are occasionally found in the stools or on the perianal skin, but are identical in saginata and solium infections (see below). Treatment with praziquantel (10-20 mg/kg as a single dose) is effective in 96% of patients. Niclosamide is also effective. Both praziquantel and niclosamide destroy the scolex and it is not present in the expelled worm remnants. If segments have not been passed by 4 months after treatment the infection is cured. Thorough cooking of meat and freezing meat to -10°C for 10 days kills cysticerci. Meat inspection is also an effective control measure.
Taenia solium The lifecycle is the same as that of T. saginata, except that the pig is the intermediate host (Fig. 9.46). Infection with T. solium in adults causes no symptoms. The segments are distinguished from those of T. saginata by the small number of lateral branches of the uterus: 7-13. Treatment is the same as for T. saginata, with the addition of an antiemetic prior to dosing and a purge 2 hours after dosing. Thorough cooking of pork or freezing to -10°C for 10 days prevents infection. Cysticercosis is discussed below in the section on larval cestodes.
Diphyllobothrium iatum
376
The fish tapeworm has a more complex lifecycle than the other intestinal cestodes: coracidia released from eggs infect water fleas (copepods). Further development takes place in fish that eat the copepods, and in bigger fish that eat plerocercoid-infected fish. Mammals are infected by eating the plerocercoid-infected fish. Digestion releases the plerocercoid, which adheres to the gut wall and starts to produce proglottids. Proglottids break up, releasing eggs which are passed in the stools. Humans are infected by eating uncooked fish. A variety of abdominal and general symptoms are attributed to this infection, including abdominal discomfort, fatigue, weakness, sensations of hunger and diarrhoea. It is associated with deficiency of vitamin B12 and, less commonly, with overt megaloblastic anaemia. When the worm is sited in the upper gastrointestinal tract it can take up both free and intrinsic factor-bound vitamin B12. Features of vitamin B12 deficiency appear when body stores are exhausted.
The diagnosis is made by finding eggs or, less often, typical segments in faecal samples. Purging may provide a sample of segments. Praziquantel gives a high cure rate. Niclosamide is also effective. Thorough cooking of fish and freezing fish to -10°C for 48 hours kills plerocercoids.
Hymenolepiasis Hymenolepis nana and H. diminuta are two species of small tapeworm. H. nana is predominantly a parasite of humans, with person-to-person transmission, whereas H. diminuta is predominantly a rodent parasite, with humans as an occasional host. Children are most often infected with H. nana. Heavy infection causes abdominal pain, anorexia, diarrhoea, irritability, pruritus ani and urticaria. Eosinophilia is found in heavy infections. Treatment with praziquantel (15 mg/kg as a single dose) is effective. H. diminuta has a more complex lifecycle involving an insect intermediate host that ingests eggs with rodent faeces. Most infections cause no symptoms and are diagnosed when eggs are found in faeces. Treatment with niclosamide is effective.
LARVAL CESTODE INFECTION Cysticercosis Infection with the intermediate state of the T. solium parasite (see above) can occur in two ways: • By ingestion of the eggs of the worm, which hatch in the gut to release the cysticercus; • By regurgitation of gravid segments into the stomach to initiate the process of egg digestion and release of cysticerci. The cysticerci released by either route of infection then invade host tissues. The first route is more likely. Occasionally patients are seen with a vast number of cysticerci in a wide range of sites, in those instances it is most likely that the patient has swallowed a proglottid. The development of subcutaneous lumps is a common presentation. Uniocular disturbances of vision occur with cysticerci in the eye. The most serious consequences occur in cerebral cysticercosis, causing epilepsy, raised intracranial pressure and localizing signs related to space occupation. Frequently numerous cysts are found in the brain. The diagnosis is based on the geographic history, a positive serological test for cysticercosis on serum, and the finding of cystic lesions by CT or MRI (Fig. 9.50). In endemic areas where CT is not available the diagnosis would be made on the clinical picture. Antibodies to cysticerci can be detected in CSF, which contains increased amounts of protein, a normal glucose and a normal or increased cell count. Skeletal muscles are often involved in cysticercosis. Usually this causes no symptoms, and calcified cysticerci are seen on X-rays. There may be muscle pain at the
9
FIG. 9.50 MRI scan of cerebral cysticercosis, showing cystic lesions
time of invasion. If cysticerci are found at any site in the body a CT brain scan should be done to detect cerebral involvement. Praziquantel, 50mg/kg/day in divided doses for 10-14 days, and albendazole, 20mg/kg/day in divided doses for 14 days, are both effective in killing cysticerci, and when this happens surrounding inflammation may increase enhancing neurological signs. For this reason steroids are started prior to treatment with either drug to reduce these effects. This should be carried out in a centre where neurological expertise is available. Two-thirds of cerebral cysts disappear after treatment, and clinical improvement follows. The efficacy of drug treatment in this condition has not been proven in prospective studies.
FURTHER READING ON CYSTICERCOSIS Del Brutto O et al 1993 Therapy for neurocysticercosis: a reappraisal. Clin Infect Dis 16:730-735
Hydatid disease Aetiology and distribution Echinococcus granulosus is a tapeworm of dogs. The lifecycle is shown in Figure 9.51. The ingested eggs release the onchosphere, which penetrates the gut mucosa and spreads by vascular or lymphatic channels to other organs, most often the liver, with lung, spleen, brain, eye, bone and other tissues infected less often. Cyprus, Turkey, Middle Eastern countries, the Turkana area of Kenya, and South America are among the endemic areas. Clinical features The clinical presentation is very variable. Unexplained painless hepatomegaly is fairly common, but an expanding cyst can cause right upper quadrant abdominal discomfort.
FIG. 9.51 Lifecycle of Echinococcus granulosus
Rupture of the cyst may produce pleuritic discomfort, abdominal pain and tenderness, and allergic manifestations such as urticaria and anaphylaxis. Rupture of hydatid cysts is infrequent, although the consequences of release of daughter cysts to seed the peritoneal cavity are serious. Pulmonary hydatids may be symptomless and may be found on chest X-ray. They may rupture spontaneously. Hydatid material, membranes and scolices with booklets may be coughed up and disseminate endobronchially to seed the lungs bilaterally, causing numerous small cysts in both lung fields. Bone and joint hydatids cause pain, swelling, and sinuses that discharge hydatid material. The latter may follow surgical exploration. The cyst wall may calcify. Diagnosis There may be blood eosinophilia and positive serological tests, but a viable cyst may be present without eosinophilia or positive serology. Ultrasound and CT scanning (Fig. 9.52) allow accurate localization and measurement of hydatid cysts in internal organs. Bone hydatid produces areas of lucency surrounded by sclerosis. Joints are destroyed. Management Management is difficult. Albendazole is given in doses of 400 mg twice daily for 12 weeks and appears to be effective. However, surgical treatment is probably needed for most cases. There is increasing experience with percutaneous aspiration of cysts under ultrasound guidance. Solitary pulmonary hydatids can often be excised with the relevant segments or lobe. Excision of hepatic hydatids is
377
able, vigorous antibiotic treatment is needed first, followed by safe surgical drainage of the cysts. Hydatid disease of bone is very difficult to treat, as it causes pain and destruction of affected areas. Neither drug treatment nor surgery is very effective, although on occasion, when disease is limited to the femur, total excision of the affected bone with prosthetic replacement, including hip and knee joints, can be carried out.
FIG. 9.52 CT scan showing hydatid cysts in the liver
more difficult. Surgery for hydatids of the CNS requires great care to avoid rupture. Complications Secondary bacterial infection of a hydatid cyst is not uncommon. Amoebic abscess, pyogenic abscess and perihepatic sepsis must be considered in the differential diagnosis when liver cysts are concerned. Gallium scanning may help to indicate bacterial infection and blood cultures should be taken. Amoebic serology is strongly positive in amoebic liver abscess. When infected hydatid cyst is prob-
378
Prevention and control Regular deworming of dogs, killing of stray dogs, and safe disposal or boiling of offal are important control measures. These measures, plus effective communication of the dangers of hydatid disease among populations in Iceland and New Zealand, have controlled the disease.
FURTHER READING ON INFECTIOUS, TROPICAL AND PARASITIC DISEASES Cook G C 1996 Manson's tropical diseases, 20th edn. London: W B Saunders Lambert H P, Farrar W E 1982 Infectious diseases illustrated. London: W B Saunders Mandell G L, Douglas R G, Bennet J E, Dolin R 1994 Principles and practice of infectious diseases, 4th edn. New York: Churchill Livingstone Strickland G T, ed. 2000 Hunter's tropical medicine, 8th edn. London: W B Saunders
Skin Disease Cameron T C Kennedy and Robin A C Graham-Brown
Biology of the skin 379 Examination of the skin 381 Dermatological diagnosis 381 Dermatological therapy 382 Bacterial diseases 384
Internal malignancy and the skin 420 Sunlight and the skin 426 Pigmentation 427 Pressure sores 428 Leg ulceration 429
description of those skin diseases that are either common or important. Diseases presenting as changes in the skin but whose major impact is on other systems, are discussed in other chapters. Because of the great importance of the visual aspects of dermatology, a colour atlas or, whenever possible, patients, should be viewed in conjunction with the text. Therapy is considered in terms of general principles.
BIOLOGY OF THE SKIN The skin is a protective barrier between a hostile environment and internal tissues. Its principal functions are to reduce the loss of water, electrolytes and other solutes, and the entry of unwanted molecules, microbes and radiation. It has a complex and specialized sensory innervation and contains a network of antigen-processing cells. The cutaneous vasculature and sweat glands are vital to heat regulation. Vitamin D is synthesized in the skin. By virtue of its smell, colour and texture, the skin has psychological and sexual roles. The skin is composed of three layers: epidermis, dermis and fat (Fig. 10.1).
Superficial fungal diseases 389
Acne vulgaris 431
Viral diseases 393
Hyperhidrosis 431
Arthropods and the skin 394
Hidradenitis suppurativa 432
Psoriasis 395
Rosacea 432
Epidermis
Eczema and dermatitis 399
Pruritus 433
Ichthyosis 405
Alopecia 433
Reaction patterns 405
Hirsutism and hypertrichosis 434
Blistering diseases 410
Nails and disease 435
Miscellaneous disorders of unknown cause 413
Psychological causes of skin disease 436
Skin changes in diabetes 415
Genodermatoses 436
The epidermis is a stratified epithelium comprised mainly of keratinocytes, which are of ectodermal origin. These divide in the basal layer, where they are separated by the basal lamina from the dermis, progressively produce the sulphur-rich fibrous protein keratin, and become flattened and dead by the time they reach the surface. These cells have a lipid-rich envelope and are linked to one another by specialized cell junctions, notably the desmosomes, and in health the horny layer is tough, flexible and relatively impermeable. At the surface they are constantly shed as squames. Removal of the horny layer virtually destroys the barrier function of the skin with respect to water and solutes. The effectiveness of the horny layer is reduced if its production is faulty (e.g. in psoriasis), if the water content drops below a critical level (e.g. chapping), or if it is damaged (e.g. by detergents and lipid solvents). Resident in the epidermis are the melanocytes, Langerhans' cells and Merkel's cells.
Drug eruptions 416
Skin disorders are a common reason for seeking medical advice (Table 10.1). Apart from diseases that primarily affect the skin, many systemic diseases may produce dermatological manifestations. When a skin disease is widespread and interfering with skin functions, systemic consequences follow - sometimes, as in untreated pemphigus vulgaris, with fatal results. More limited skin diseases can cause distress or hardship. The psychological impact of readily visible skin lesions, even if biologically trivial, should not be underestimated. Another common problem associated with skin disorders is fear (often not expressed) that a skin disease is contagious, or a manifestation of cancer. This chapter gives a brief account of the biology of the skin, the principles of diagnosis and therapy, and then a
• Melanocytes migrate early in fetal life from the neural crest and become established along the basal layer, so that there is approximately one melanocyte per 10 basal keratinocytes. Via their dendritic processes, the yellow or brown-pigmented protein melanin is passed in membrane-bound particles, called melanosomes, into the keratinocytes; here most of it is distributed over the surface of the nucleus that faces the sun. Melanin absorbs ultraviolet radiation and thus helps protect against DNA damage. In its absence, in albinism, skin cancer on exposed sites is common at an early age.
379
TABLE 10.1 Prevalence of skin diseases* Rates of consultation (general practice) per 1000/year All skin diseases Alopic dermatitis and related conditions Contact dermatitis and other eczema Viral warts Psoriasis Urticaria Chronic ulcer Malignant neoplasms Some comparisons Asthma Osteoarthritis Irritable bowel Diseases of stomach (functional) Rheumatoid (and other inflammatory) arthritis
229 43 27
18 11
9 4 1.4
91 58 32 22 11
* Date from Morbidity Statistics from General Practice, Fourth National Study 1991-2. OPCS, HMSO, 1995.
FIG. 10.1 Cross-section of the skin
RECENT ADVANCES IN MEASURING DISABILITY IN SKIN DISEASE An important new approach to the assessment of skin disease has been the application of techniques that measure the impact of the process on the quality of life (see Further Reading). Such methods are being used in other branches of medicine too, and can help doctors: • Gain an understanding of what having a chronic skin disease such as psoriasis or eczema is really like; • Gauge the usefulness of treatments in terms of improvements in life quality (which may improve the ability to judge therapy in terms of risk/benefit ratios and cost-effectiveness); • Compare the effects of skin disease with other medical problems and apportion resources.
FURTHER READING Finlay AY 1997 Quality of life measurement in dermatology: a practical guide. Br J Dermatol 136:305-314. Anderson RT, Rajagopalan R 1997 Development and validation of a quality of life instrument for cutaneous diseases. J Am Acad Dermatol 37:41-50.
1
380
MCQ 10.1
• Langerhans' cells, also dendritic, are of bone marrow origin. They are located in the mid-epidermis, function as antigen-trapping and antigen-presenting cells, and can migrate to regional lymph nodes. Together with lymphocytes, they constitute a vital outpost of the immune system. • Merkel's cells, best recognized on electron microscopy by their dense-cored granules, are closely associated with sensory nerve endings, and may represent a mechanoreceptor system. They are most numerous on the lips, on digital pads and in hair follicles. The epidermis is separated from, and attached to, the dermis by a basal lamina, across which all nutrients must pass. A component of the basal lamina is the target of immunological attack in the blistering disease bullous pemphigoid (p. 411).
Dermis The dermis is a three-dimensional fibrous tissue network of collagen and elastin associated with water-rich glycosaminoglycans, in which are embedded the blood and lymphatic vessels, neural elements and epidermal appendages - sweat glands, sebaceous glands and hair follicles (Fig. 10.1). The dermis is manufactured by fibroblasts, and other cells seen in normal tissue include dermal phagocytes and mast cells. The dermis has viscoelastic properties,
allowing body movements without permanent distortion, yet considerable mechanical strength. It is essential to the wellbeing and repair of the epidermis. The superficial part of the dermis, containing capillaries and nerve endings, is more loosely woven than deeper layers, and projects into the undersurface of the epidermis as papillae. Blood flow through the skin can be greatly in excess of nutritional demands, and skin vasculature contributes to thermoregulation and the maintenance of blood pressure. There are networks of blood vessels at the levels of the deep fascia, the fat-dermis junction and in the papillary dermis, where capillary loops follow the contour of the dermoepidermal junction. There are also numerous arteriovenous shunts that allow blood to bypass capillaries, thereby conserving heat. Vascular control is by autonomic nerves and chemical mediators. The skin is also provided with an extensive plexus of lymphatics, which act both as a drainage system for lymph and in the recirculation of lymphocytes. There are afferent sensory nerves subserving touch, pain, temperature and itch, and also the specialized Meissner and Pacinian corpuscles, which are probably mechanoreceptors. The autonomic supply is sympathetic, with adrenergic, cholinergic and purinergic terminals. Collagen and elastin disorders are described on page 71.
Epidermal appendages Eccrine sweat glands consist of secretory coils connected by straight ducts to the surface. There is a rich blood supply and a predominantly cholinergic sympathetic innervation. Because of the sodium-resorptive properties of the ducts, sweat is hypotonic. The basal level of fluid loss through the skin of about 600mL/day can be greatly increased in response to the need for heat loss. Apocrine sweat glands are found in the axillae, anogenital regions, on the breast and on the scalp. They open into hair follicles and on to the skin surface. Their secretion is low in volume, and after bacterial alteration it has a characteristic odour. Very similar glands produce wax in the ears and occur on the eyelids. The pilosebaceous follicles produce both hairs and sebaceous glands. In humans hair is largely of cultural and sexual significance. There are three types: lanugo, which covers the fetus; vellus, which is fine and short; and terminal hair, which is coarse and occurs on the scalp, eyebrows, axillae and pubic regions. A residual protective value of hair is seen when its absence in bald males is accompanied in later life by sun-induced neoplasms. An important characteristic of hair follicles is their cyclical activity: for each follicle a period of active growth (anagen) is followed by a transition period (catagen) and then a resting phase (telogen), when the hair is shed and a new hair begins. Individual follicles are normally asynchronous, hence humans do not moult. Nails are hard plates of keratin which protect the ends of the digits and facilitate many of the functions of the hands. 1
FURTHER READING ON BIOLOGY OF THE SKIN
10
Eady R A J , Leigh I M, Pope F M 1998 Anatomy and organisation of human skin. In: Champion R H et al, eds. Textbook of Dermatology, 6th edn. Oxford: Blackwell Science, pp. 37-111.
EXAMINATION OF THE SKIN It is essential to examine all the skin, together with the mouth, genitalia, hair and nails, in a good light. The skin should be palpated as well as inspected, to appreciate the thickness of lesions and of the whole skin. Being touched can help some patients to shed a 'leper complex'. Skin lesions should be described in terms of: • The individual characteristics (shape, colour, etc.) • Their arrangement in relation to each other (if any) • Their distribution. The terms used have precise meanings (Table 10.2). Distribution The following points should be noted: • Is the rash localized, regional or generalized? • Is there symmetry? Endogenous disorders are often symmetrical. • Is there localization by exposure to light, cold or some other environmental factor? • Has non-specific trauma, e.g. scratching, caused new lesions (Koebner's phenomenon), as in psoriasis and lichen planus? • Is there an underlying anatomical basis, e.g. the vascular or nerve supply, the flexures or hair follicles? Many conditions have characteristic patterns of distribution, the basis for which is obscure, e.g. dermatitis herpetiformis on elbows and knees, scalp, shoulders and buttocks.
DERMATOLOGICAL DIAGNOSIS There is a great variety of dermatological diagnoses. However, the practised observer can describe changes that suggest a diagnosis or differential diagnostic group. The history is important, narrowing the possibilities (Table 10.3). Diagnostic procedures and investigations may be useful. Diascopy When the skin is pressed with a microscope slide or Perspex spatula, purpura (which does not blanch) can be distinguished from erythema (which does). Nikolsky sign The Nikolsky sign involves the production or extension of a blistering process by the combination of pressure with a
381
TABLE 10.2 Terms used to describe skin lesions Skin lesion Appearance Erythema Macule Papule Plaque Nodule Vesicle Bulla Pustule Weal Angioedema Purpura
Telangiectasia Atrophy Sclerosis Ulcer Excoriation Crust Scaling Burrow
Definition Redness due to vasodilatation Flat, circumscribed, impalpable area of colour change. There may be scaling, as in pityriasis versicolor Small (less than 0.5cm), solid, elevated lesion, most of which is above the plane of the skin Elevated lesion with relatively large surface area in relation to height Large (greater than 0.5cm diameter) solid lesion Blister less than 0.5cm diameter Blister greater than 0.5cm diameter Elevation of the skin containing fluid and leukocytes, usually yellow or green in colour, but not necessarily infective Elevation due to dermal oedema, lasting minutes to several hours Massive oedematous reaction in loose dermis or subcutaneous tissue Extravasated red cells (see Diascopy, p. 381). Small purpuric lesions are called petechiae, large ones ecchymoses. They are not obliterated by pressure. The colour varies from red, through purple and brown, to yellow, depending on the age of the lesion Permanent dilatation of capillaries Thinning, often with loss of normal skin markings, and increased transparency Hardening due to changes in the dermis Loss of (at least) the epidermis Scratch mark Dried exudate Desquamating horny layer Irregular linear elevation of horny layer, characteristic of scabies
Shape and arrangement Linear In a line Annular Ring-shaped Erythematous ring or rings separated by relative pallor with a Target purplish centre Herpetiform Clustered, like herpes simplex Zosteriform Clustered and following a dermatome Reticular Net-like
sliding action. It is characteristic of pemphigus and some other blistering diseases.
382
Wood's light Wood's light is produced by a long-wave UV lamp, which shows red fluorescence with erythrasma, green fluorescence with some common scalp fungal infections, and pale yellow fluorescence with pityriasis versicolor. It enhances the pallor of vitiligo and is helpful in screening for the ash-leaf macules of tuberous sclerosis.
TABLE 10.3 Taking a history History of the skin eruption When and where did the problem start? Has it spread, and how? Has it changed in character? What was it like if different before? Does it itch? Does it come and go? What has been used or taken for it (prescribed and self-medication)? Have any other medications - oral, injected or topical - been used? Is there any relation to sunlight? Any past history of skin disease? Does anyone the patient knows have anything similar? What does the patient think is the cause? Background Age, sex, race. Pregnant? Pubertal? General medical, past and family history Personal and family history of eczema, asthma or hay fever Social history: occupation, hobbies, travel Any known allergies?
Biopsy Biopsies are carried out for histopathology and, when relevant, immunological studies, microbiological culture and electron microscopy, cell culture and molecular biological studies such as gene analysis. Mycological techniques Mycological techniques are described on page 389. Patch testing Patch testing is described under 'Contact
dermatitis'
(p. 400). Scabies mite scraping Scabies mite scraping is described on page 395.
DERMATOLOGICAL THERAPY Dermatological treatment includes topical and systemic pharmacy, physical modalities such as liquid nitrogen cryotherapy, ultraviolet radiation, radiotherapy, laser and surgical procedures, and dietary measures. Topical therapy is the traditional province of the dermatologist.
Vehicles Active ingredients are applied to the skin in a vehicle (Table 10.4). A vehicle may be used therapeutically: a lotion to cool and dry, a cream to soothe, an ointment to moisturize dry skin, and a paste to protect. When an active ingredient is included, the vehicle must
TABLE 10.4 Composition and properties of vehicles for topical treatment Vehicle
Composition
Properties
Lotion
Liquid (water or alcohol)
Cools inflamed skin. Useful in hairy areas. Miscible with exudate
Shake lotion
Water + powder
Powder increases area for evaporation, so has cooling properties
Cream
Water + grease + emulsifier
Aqueous phase gives some cooling effect and miscibility with exudate. Grease increases hydration. Properties will vary depending on whether the emulsion is oil-in-water or water-in-oil
Ointment
Grease
Moisturizes dry skin by trapping water passing through the epidermis. Hydrophobic (e.g. vaseline) or hydrophilic (e.g. lanolin)
Paste
Grease + powder
Moisturizing and protective
Dusting powder
Powder
Reduces friction. Absorbs water
deliver it appropriately and maintain its integrity against oxidation and bacterial contamination. Therefore vehicles, especially creams, often contain preservatives and stabilizers. Some preparations contain substances to enhance drug penetration, e.g. urea. When adverse reactions to topical agents occur, it should be remembered that not only the active ingredient but also the components of the vehicle should be considered as possible causes. For most active ingredients the major barrier to penetration is the horny layer. Penetration is greater through facial and genital skin and flexures (e.g. axillae, crural folds) and is increased by occlusion (e.g. by rubber gloves), diseases that alter the horny layer (e.g. eczema and psoriasis), and pharmaceutical penetration enhancers such as urea. In contrast, when the horny layer is very thick, as on the palms and soles, there is reduced penetration.
TABLE 10.5 Potency of topical corticosteroids Group
Potency
Examples
1 2
Very high High
3 4
Moderate Low
Clobetasol propionate Betamethasone valerate Hydrocortisone butyrate Clobetasone butyrate Hydrocortisone
10
TABLE 10.6 Adverse effects of topical steroids Adverse effects
Factors increasing risk
Pituitary-adrenal axis suppression; growth suppression in children
Potency group 1 Potency groups 1 and 2 with occlusion Widespread skin inflammation Infancy Hepatic failure
Spread of skin infection
Overt infection Body folds
Atrophy (thin, red, fragile skin)
High risk sites, e.g. face, body folds Occlusion Prolonged and continuous use
Striae (stretch marks)
Potency groups 1 and 2 Body folds
Increased hair growth (hypertrichosis)
Potency groups 1 and 2 Prolonged use
Peri-oral dermatitis
Face
Exacerbation of skin disease on withdrawal
Psoriasis Facial dermatoses
tration, the vehicle, and also by factors favouring increased absorption. Adverse effects (Table 10.6) are very unlikely with topical 1 % hydrocortisone.
Other topically used drugs
Topical corticosteroids
A selection of drugs used topically is shown in Table 10.7.
Topical corticosteroids have anti-inflammatory and other actions, with useful suppressive effects in a number of skin disorders, but they do not cure disease. They can worsen skin infection and modify physical signs, and the more potent preparations easily produce side-effects. In general, the efficacy of topical steroids goes hand in hand with the ability to cause side-effects, and a preparation of the lowest potency that is effective should be used (Table 10.5). Applications are usually once or twice daily, with bland creams or ointments at other times if necessary. Efficacy is determined by the steroid molecule, its concen-
Cryotherapy Many benign and some malignant skin lesions can be quickly and successfully treated by accurately applied low temperature. The most satisfactory agent is liquid nitrogen, whose temperature is -196°C, applied on a cottonwool swab, by a spray or a probe. The procedure can be painful and is often followed by swelling and blistering, but longterm cosmetic results are generally good. Hypopigmentation and some sensory loss can be troublesome consequences.
383
TABLE 10.7 Some topical preparations used in skin diseases Topical drug
Use
Tars Dithranol Calcipotriol Benzoyl peroxide Adapalene Metronidazole Calamine Aminobenzoic acid esters Salicylic acid
Chronic eczema, psoriasis Psoriasis Psoriasis Acne Acne Rosacea Pruritus Sunscreens Viral warts, other localized hyperkeratotic conditions Viral warts Scabies Some dermatophyte infections Some dermatophyte and yeast infections; seborrhoeic dermatitis Dermatophyte infections Candidiasis Localized superficial Gram-positive bacterial infection Some herpes simplex and zoster infections
Podophyllum Permethrin Compound benzole acid ointment Antifungal imidazoles Terbinafine Nystatin and amphotericin B Antibiotics, e.g. fusidic acid, mupirocin Aciclovir
BACTERIAL DISEASES Bacterial infection can produce skin lesions at or near the portal of entry, as in impetigo. Lesions may also be due to organisms deposited in the skin during septicaemia, bloodborne spread of a toxin, and hypersensitivity phenomena, such as the vasculitic Osier's nodes and splinter haemorrhages of subacute bacterial endocarditis's. Normal intact skin is colonized by diphtheroids and nonpathogenic staphylococci and, in some sites such as the anterior nares, axilla and perineum, by potentially pathogenic Staphylococcus aureus. In moist areas there are often some Gram-negative bacilli. Overt infection nearly always follows some kind of injury, albeit trivial. If it is associated with some obvious pre-existing skin lesions, such as eczema, it is referred to as secondary infection. Host factors, particularly the immunological status, are important in determining the degree and extent of infection. Some skin diseases, such as hidradenitis suppurativa, are a non-specific reaction to bacteria, which, although contributory, are not the primary cause. The types of staphylococcal and streptococcal skin infection are shown in Table 10.8. 1
384
1
MCQ10.2
2
Fig. 10.1
3
Fig. 10.2
4
Fig.10.3
RECENT ADVANCES IN DERMATOLOGICAL THERAPY There have been a number of important advances in the treatment of skin diseases in the last 5 years. • The introduction of newer 'azole' derivatives (itraconazole, fluconazole) and the allylamine terbinafine has resulted in a wider range of more effective and safer systemic options for the treatment of cutaneous (and other) fungal infections. • Ciclosporin, which suppresses T-lymphocyte activity, has an established role in the therapy of severely affected patients with psoriasis and atopic dermatitis, and can be effective in several other skin diseases in which immune dysfunction is important, e.g. pyoderma gangrenosum. Other drugs with immunomodulatory effects useful in dermatology include tacrolimus (similar in action to ciclosporin) which can be used topically (e.g. for atopic dermatitis) and thalidomide (helpful in Behcet's syndrome and cutaneous lupus erythematosus). • The vitamin D3 analogues can now be regarded as first-line agents in the management of plaque psoriasis. Examples include calcipotriol and tacalcitol. • Retinoids are the most important cell-signalling molecules in dermatology. Two newer retinoids of clinical value are tazarotene for psoriasis and adapalene for acne vulgaris. • Better laser technology has improved the results of treatment for vascular lesions such as port wine stains. Other lasers are used to eliminate tattoos and some pigmented lesions.
Impetigo Impetigo (Fig. 10.2) is a primary superficial bacterial skin infection, initially vesicular or bullous and later crusted. It may only involve the openings of hair follicles and is caused by Staph. aureus, Streptococcus pyogenes group A, or both. In some tropical regions the streptococci can cause nephritis. Bullous impetigo is usually due to phage group II staphylococci. Impetigo occurs predominantly among children and is highly contagious. Spread is mainly from skin to skin, although in streptococcal cases infected individuals may acquire the disease from pharyngeal colonization. Trauma, for example from scratching insect bites, and infestation commonly predispose to the infection. Exposed parts are mainly affected. The early lesions are clear or turbid blisters which soon become crusts, often golden yellow, with a surrounding zone of erythema. In bullous impetigo there are larger blisters with no erythema. The lesions tend to heal centrally but spread peripherally. Regional lymphadenopathy is common. Diagnosis is by Gram stain and culture of a swab, which will help to distinguish impetigo from other lesions such as tinea and varicella.
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FIG. 10.3 Staphylococcal scalded skin syndrome This shows characteristic crusting and radial fissuring around the mouth. FIG. 10.2 Impetigo: ruptured flaccid blisters and crusts on a red base
TABLE 10.8 Staphylococcal and streptococcal bacterial infections of the skin Due to direct bacterial infection Staphylococcus aureus Impetigo Ecthyma Follicular infections Streptococcus pyogenes Impetigo Ecthyma Erysipelas Cellulitis Necrotizing fasciitis
Due to toxin
Due to hypersensitivity
Staphylococcal scalded skin syndrome Toxic shock syndrome Staphylococcal scarlatina Scarlet fever
Erythema Vasculitis Erythema nodosum
Treatment Gentle removal of crusts is helpful. If localized, a topical antibiotic, such as fusidic acid or mupirocin, is adequate. For widespread impetigo, oral flucloxacillin (or erythromycin if the patient is allergic to penicillin) is required. Improvement of hygiene may be advisable, e.g. not sharing towels.
Ecthyma Ecthyma is a vesiculopurulent condition similar to impetigo, but the infection extends deeper, producing ulceration 2; it is caused by Strep, pyogenes, often with Staph. aureus. The condition is common in hot, humid climates, affects mainly children and the elderly, and is often associated with poor hygiene and/or insect bites. The initial vesicular lesion soon becomes a punched-out ulcer with an overlying crust. The legs are commonly affected. The differential diagnosis includes ecthyma gangrenosum 3, caused by Pseudomonas septicaemia (see below),
and other causes of ulcers (p. 430). Treatment is with a penicillinase-resistant antibiotic, such as flucloxacillin or erythromycin. If there is surrounding cellulitis penicillin should be added.
Staphylococcal scalded skin syndrome Staphylococcal scalded skin syndrome is a generalized skin reaction to bloodborne Staphylococcal epidermolytic toxins, which cause a split in the superficial epidermis; unlike impetigo, there are no organisms in the accumulating fluid. It is caused by a focus of infection of Staph. pyogenes of phage group II, which may be cutaneous but can be elsewhere. Children, especially infants, are most susceptible (Fig. 10.3). Clinical features A few days after the initiating Staphylococcal infection there is a sudden onset of widespread tender erythema with fever. Twelve hours or so later there may be widespread flaccid bullae, and the horny layer begins to detach in sheets. 4 Differential diagnosis Toxic epidermal necrolysis due to drugs (p. 417) can be distinguished by the histology of a blister roof, which shows a deeper level of split in the epidermis in the drug-induced type, and by the history. Treatment Treatment is with parenteral flucloxacillin (or equivalent), and careful attention to fluid balance and temperature regulation.
Erysipelas Erysipelas (Fig. 10.4) is a dermal infection, usually with group A streptococci. There is often a recognizable portal of entry, such as a fungal infection between the toes or a fissure at the corner of the mouth. There may have been a previous upper respiratory tract streptococcal infection. The onset is often sudden, with fever, malaise and rigors,
385
FIG. 10.5 Cellulitis Spreading soft tissue infection due to B haemolytic streptococcuslor which the portal of entry was a venous leg ulcer.
Cellulitis
FIG. 10.4 Erysipelas: tender erythema and oedema
together with a bright red, tender swelling. The face and lower legs are common sites. The skin becomes oedematous and a well-defined, raised, sometimes blistering edge advances rapidly. There are often red streaks due to lymphangitis. Diagnosis Leukocytosis is usual. Surface culture is useless, but the organism can sometimes be cultured from aspirated fluid. There is usually an antibody response to streptococcal proteins, with rising litres of antideoxyribonuclease B; antistreptolysin O is less often elevated. Differential diagnosis Acute contact dermatitis and angioedema of the face may simulate erysipelas but do not produce fever. Herpes zoster, before the outbreak of vesicles, is associated with pain or paraesthesiae. Erysipeloid (p. 387) occurs in meatand fish-handlers, and systemic symptoms are much less severe. Complications Erysipelas is usually self-limiting but can produce suppurative and widespread infection. There is involvement of the lymphatics, and this predisposes to persistent swelling (lymphoedema) and recurrent attacks. Treatment The treatment of choice is penicillin, parenterally in severe infections, unless contraindicated by hypersensitivity, in which case erythromycin or another macrolide should be suitable.
1
386
Fig. 10.4
Cellulitis is a deeper dermal/subcutaneous infection than erysipelas, usually with group A streptococci. In practice there is no absolute distinction between erysipelas and cellulitis. There is usually an obvious portal, e.g. a leg ulcer (Fig. 10.5) or wound, or oedema of lymphatic, venous or renal origin. There is spreading erythematous oedema as in erysipelas, but without the sharply denned edge or vesiculation. There may be similar constitutional symptoms and lymphangitis. Untreated, gangrene may occur. Treatment is the same as for erysipelas, unless the cellulitis is caused by bacteria other than group A streptococci.
Necrotizing fasciitis Necrotizing fasciitis (streptococcal gangrene) is a necrotizing process usually caused by group A streptococci; it involves the deep fascia and vessels within it, with secondary death of overlying skin. This uncommon process can occur in healthy subjects, but arterial insufficiency and diabetes predispose. Necrotizing fasciitis usually begins like cellulitis, but after about 2 days the area becomes purplish, haemorrhagic bullae appear, and there is tissue death. 1 Untreated, there is a high mortality. The diagnosis is often based on clinical suspicion alone, but streptococci can commonly be found in exudate or the blood. Treatment by urgent and adequate surgical debridement is essential. There has been some debate over the antibiotic of choice in necrotizing fasciitis, with some recommending vancomycin or clindamycin. However, most authorities recommend high-dose intravenous benzylpenicillin, with vancomycin being reserved for the penicillin-allergic individual.
Progressive bacterial synergistic gangrene Progressive bacterial synergistic gangrene is gangrenous ulceration due to synergistic infection with microaerophilic
streptococci and Staph. aureus, usually associated with an abdominal or thoracic operation wound. One to 2 weeks after surgery there is a slowly spreading area of ulceration which has a rim of gangrenous skin surrounded by purplish erythema. The main differential diagnosis is pyoderma gangrenosum (see p. 407). Treatment is by surgical debridement plus i.v. highdose penicillin, gentamicin and metronidazole. For the penicillin-allergic patient, clindamycin and gentamicin are recommended.
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Follicular infections A furuncle (boil) is an acute necrotizing infection of a follicle. A carbuncle is more extensive, involving contiguous follicles and the tissues around them. Infection of the hair follicle opening is termed superficial folliculitis. The usual infecting organism is Staph. aureus, and there is often nasal, axillary or perineal carriage of the organism. Friction, as at the nape of the neck, and moisture, as in the flexures, are important predisposing factors. Obesity, poor hygiene, widespread skin disease, immune deficiency and diabetes mellitus may predispose in severe cases. Superficial folliculitis can be non-infective; causes include contact with oils and other irritant chemicals. Furuncles are tender red papules or nodules, which become pustular centrally and often heal with some scarring. Furunculosis may be chronic, as in sycosis barbae, a pustular eruption due to Staph. aureus that occurs on the male face. Carbuncles are often associated with fever and malaise, and with an underlying systemic illness such as diabetes or immune suppression. Follicular infections can produce bacteraemia and, rarely, bony and cerebral abscesses, and endocarditis. Swabs should be taken from pus and from the anterior nares, axilla and perineum of both the patient and household contacts (potential reservoirs of infection) in chronic cases. Differential diagnosis The differential diagnosis includes dermatophyte infection (the fungi can be demonstrated by microscopy and culture of hairs) and pseudofolliculitis, a non-infective papulopustular condition on the face and neck caused by cut hairs growing back into the skin. The latter is very common in black people because their hair is tightly curled. Acne vulgaris (p. 431) can usually be distinguished by the presence of comedones, and the pustules are sterile. Hidradenitis suppurativa is discussed on page 432. In anthrax (see Ch. 9) there is a haemorrhagic crust and vesicular margin, and a swab will establish the diagnosis. Treatment Furuncles and carbuncles may need incision and drainage. Superficial staphylococcal folliculitis should respond to flucloxacillin (or an equivalent) for 1-2 weeks, but chronic cases may need treatment for longer, and treatment of
FIG. 10.6 Erythrasma Well-defined brownish erythema which fluoresces pink by Wood's light.
reservoir sites, e.g. chlorhexidine for the skin and mupirocin for the nose.
Erythrasma Erythrasma (Fig. 10.6) is a common surface infection caused by Corynebacterium minutissimum. Sharply defined red or reddish-brown patches, sometimes with slight scaling, are seen in the axillae, groins, toe webs, and sometimes other body folds. There are usually no symptoms. The diagnosis is readily made with Wood's light; the affected skin fluoresces pink. Most cases respond to a topical imidazole, e.g. clotrimazole, but if the condition is widespread oral erythromycin for 10 days may be more effective.
Erysipeloid Erysipeloid is an acute cutaneous infection with Erysipelothrix insidiosa. This Gram-positive bacillus causes infection in several animals and in salt-water fish. Transfer to the skin occurs mainly to veterinary surgeons, butchers, fish-handlers and housewives.
387
The hand is the common site. A few days after inoculation there is a well-defined, slowly spreading, dusky erythematous oedema with little or no general upset (in contrast with erysipelas). Treatment is with penicillin or tetracycline.
Pseudomonas infection of the skin Pseudomonas aeruginosa is not normally found on the skin but can become pathogenic, with the production of a characteristic bluish-green pus and a fruity odour in circumstances of increased moisture. Examples may be found at the base of the nail in those whose hands are often immersed in water, in toe spaces, beneath dressings for ulcers, and very importantly on raw surfaces following burns. Prior eradication of Gram-positive flora may also predispose. A pruritic pseudomonas folliculitis can be acquired from contaminated whirlpool baths. Localized infection usually responds to simple antiseptic measures, such as acetic acid, silver nitrate or silver sulfadiazine, together with drying. Pseudomonas septicaemia can produce solitary or widespread vesicles with surrounding red haloes. Subsequent necrosis, often with haemorrhage into the tissues, producing black crusts, is known as ecthyma gangrenosum. The lesions, as well as the blood, should yield Pseudomonas on culture, and prompt treatment can be life-saving.
Mycobacterial and treponemal diseases Tuberculosis (see also p. 640) leprosy (p. 325) and syphilis (p. 458) all have important cutaneous manifestations. Cutaneous tuberculosis Involvement of the skin by Mycobacterium tuberculosis is relatively uncommon in developed countries but is often seen in the developing world, where the overall prevalence of tuberculosis is much higher. The condition still needs to be considered in the west, particularly in those who have migrated from the Indian subcontinent and Africa. Many descriptive terms have been applied to the wide variety of clinical presentations that can occur, and to some extent these reflect the mode by which the skin may be affected: haematogenous spread from a deep source (most lupus vulgaris); direct spread from underlying organs, e.g. lymph nodes, bones, respiratory or gastrointestinal tract (scrofuloderma, tuberculosis cutis orificialis); direct inoculation from outside (some lupus vulgaris, tuberculosis verrucosa cutis and warty TB). The commonest form is lupus vulgaris, which presents as an area of indurated, reddish-brown skin, characteristically on the head and neck (Fig. 10.7), although lesions may
1
388
Fig. 10.5
FIG. 10.7 Typical lupus vulgaris involving ear and cheek
occur elsewhere. The lesions gradually spread and have a tendency to produce scar tissue, which results in distortion of normal anatomy and loss of hair follicles in hair-bearing areas. When the microorganism is inoculated directly into the skin, lesions sometimes have a warty surface. Tuberculosis may result in a number of skin changes in which the microorganisms are not directly involved (known as tuberculides}: • Erythema nodosum (see p. 407), in which the lesions usually appear in association with primary infection; • Erythema induratum (or Bazin's disease), in which the nodular, ulcerative lesions appear on the lower legs, involving the calves as well as the shins; 1 • The rare papulonecrotic and lichenoid forms. Investigation of suspected cutaneous tuberculosis involves biopsies for histology and culture and a search for involvement of internal organs (see Ch. 13). Treatment should be with standard antituberculous chemotherapy (p. 645), even if a deeper focus is not found. Atypical mycobacterial infections The skin may become infected by direct inoculation of other mycobacteria, especially Mycobacterium marinum, an organism responsible for a systemic infection in fish. An indurated nodule or nodules appear, usually on the hand or arm of a fish-fancier (Fig. 10.8). In some patients, further nodules appear along the lines of lymphatic drainage (socalled sporotrichoid spread). Occasionally lesions may be more widespread, especially in those who catch the organ-
10
FIG. 10.8 'Fish-tank granuloma' These lesions are caused by mycobacteria acquired from fish.
ism from swimming. Biopsy for histology and culture should be performed, but the tissue must be incubated on special media at low temperature for the organism to grow. Lesions often resolve spontaneously, but this is a slow process and therefore treatment with antibiotics may be indicated. Various drugs have their advocates: minocycline, co-trimoxazole and rifampicin are all considered to be effective. Treatment should be for about 6 weeks.
Fungal infections involving the skin are broadly classified into superficial and deep. The former include the ringworm fungi (dermatophytes), candidiasis and pityriasis versicolor. Except for Candida, these fungi rarely invade deeper than the horny layer of the epidermis. Nails and hair, as well as the skin surface, may be involved (see Fig. 10.12, p. 391). The clinical manifestations depend partly on the infecting species, on the body part affected, and on the host response to substances diffusing from the fungi into the skin. Deep fungal infections are discussed in Chapter 9. Diagnosis Diagnosis is by microscopic examination of scrapings to show fungal hyphae, and species identification is by culture. The dermatophytes are grown on Sabouraud's medium. With skin lesions scale is collected by scraping with a blade, hair is plucked and clippings are taken from nails. Material is sent to the laboratory dry in folded paper. Microscopy is performed on small samples after clearing with a few drops of 30% potassium hydroxide. For some species of scalp dermatophyte infection and for pityriasis versicolor the Wood's light is valuable (p. 382).
Tinea The fungi that cause the characteristic annular lesions
FIG. 10.9 The annular lesions of tinea (ringworm)
known as tinea or ringworm (Fig. 10.9) are also known as dermatophytes, as they have the ability to digest keratin. There are three genera - Trichophyton, Microsporum and Epidermophyton - and numerous species, which are recognized by their culture characteristics. Humans are the primary host for some (the anthropophilic species), but with others the fungi are incidental pathogens to humans, being primarily animal parasites (zoophilic) or found in soil (geophilic). The immune response is most marked against zoophilic species, and these tend not to recur. With very inflammatory ringworm there can be so-called 'id' reactions, owing to the immune response. These are widespread, often follicular, papular lesions which do not contain fungi. Probably for similar reasons, a vesicular eruption on the hands can be associated with ringworm of the feet. The distinctive appearance of ringworm infections can be greatly modified by topical steroids. Treatment Successful treatment requires attention to sources of reinfection and measures to deal with acutely inflamed macerated skin, such as aluminium acetate soaks, as well as specific antifungal preparations. Topical agents, including Whitfield's ointment, and various imidazoles are suitable for localized skin infection. The most rapid, effective and expensive agent is terbinafme. Oral terbinafine is the treatment of choice for hair, nail, widespread and chronic skin infections, but is not yet licensed in the UK for use in children. Itraconazole and griseofulvin are alternatives. A weak topical steroid, together with antifungal therapy, may be useful if there is much inflammation. Tinea pedis Tinea pedis is a dermatophyte infection of the feet, some-
389
FIG. 10.10 Tinea pedis Macerated hyperkeratosis and scaling in the lateral toespace.
times with concurrent bacterial infection. This very common, often chronic condition is frequently acquired where bathing facilities are shared, and infection is favoured by maceration. It is much commoner in males than in females. The most common pattern is an itchy, inflamed, fissured, moist toe space, usually between the fourth and fifth toes (Fig. 10.10). It is often unilateral. A vesicular pattern may occur involving the instep, dorsum of the foot or sides of the toes. A very chronic pattern may be seen, with hyperkeratosis and fine white scaling accentuating skin creases on the soles. 1 Tinea pedis may be accompanied by cellulitis. Tinea pedis can resemble eczema, contact dermatitis, candidal infection and psoriasis. Endogenous eczema and psoriasis are more likely to be bilateral. Most toe space infections respond to a topical antifungal agent, but extensive involvement of the soles needs oral treatment. Regular cleansing of communal bathing facilities and prophylactic use of antifungal powders help reduce transmission of infection. Tinea cruris Tinea cruris is a dermatophyte infection of the groins and adjacent skin. Like tinea pedis, with which it is often associated, tinea cruris is much more common in males. Itching is very common. There is inflammation, with a well-defined margin which is scaly, vesicular or occasionally pustular, often with central clearing. The differential diagnosis includes candidiasis, in which there is a less well defined edge and outlying tiny pustules. Erythrasma is not usually inflammatory. Intertrigo, an inflammatory process common in the obese, in which friction sweating and minor bacterial infection cause erythema
1
390
Fig. 10.6 2 Fig. 10.7
FIG. 10.11 Tinea corporis Ring-shaped lesions with erythematous scaly borders and some central clearing.
TABLE 10.9 Types of tinea capitis Representative species
Wood's light fluorescence
Patchy baldness, with broken-off hairs and scaling of the scalp
Microsporum canis
Blue-green
Microsporum audouini
Green
Puppies, kittens Humans
Patchy baldness with black dots
Trichophyton tonsurans Trichophyton violaceum Trichophyton verrucosum Trichophyton schoenleinii
-
Humans
-
Humans
-
Cattle
Dull green
Humans
Clinical pattern
Kerion Favus
Source
in body folds, can mimic tinea cruris, but scrapings will be negative. Eczema and psoriasis can usually be recognized by their characteristic appearances on non-flexural skin elsewhere. For limited infection treatment with a topical imidazole is sufficient. For extensive involvement, topical steroidtreated cases, or when therapy fails, however, oral therapy is needed for 3-6 weeks. Tinea corporis Tinea corporis is often of animal origin, and is then selflimiting. Lesions are usually multiple and often, but not always, ring-shaped (Fig. 10.11). Because the appearances are so variable, scrapings should be taken from any red, scaly rash that cannot be readily diagnosed. If the disease is limited in extent, a topical agent is usually sufficient; if widespread, then oral terbinafine or itraconazole is preferable. Tinea capitis Many different fungal species can infect hair and scalp skin (Table 10.9). In the UK, tinea capitis is nearly always a
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FIG. 10.12 Distal thickening and yellow discoloration due to fungal infection FIG. 10.13 Candidiasis, a superficial fungal infection
disease of children. Affected hairs may break off a few millimetres above the scalp, producing short stubble, or flush with the scalp, giving bald patches with black dots in dark-haired patients. 0 When there is a marked degree of inflammation, producing an appearance like that of a carbuncle, the lesion is called a kerion, and in this circumstance there may be concurrent staphylococcal infection. An appearance known as favus is now very rare in the UK. In this form yellowish cup-shaped crusts develop, together with hair loss. Both kerion and favus can produce permanent alopecia. Fungal infection can be distinguished from other causes of patchy hair loss by microscopy and culture.
Tinea of the hand A diffuse hyperkeratosis with fine powdery accentuation of the palmar creases, usually of only one hand, is the commonest pattern of tinea of the hand. If there is diagnostic doubt, scrapings should be taken.
Tinea of nails In many cases nail infection (onychomycosis) occurs in conjunction with fungal disease elsewhere. Predisposing factors include previous trauma and poor peripheral circulation. The toenails are more commonly affected than fingernails. The changes spread proximally from the free edge. The nailplate becomes discoloured and usually thickened, and may crumble away. It may also separate from the nailbed (onycholysis) (Fig. 10.12). Confirmation of the diagnosis by microscopy and culture of clippings should precede treatment. The differential diagnosis includes psoriasis, in which there is often a distinctive pattern of fine pitting. Candidal infection produces changes that begin proximally. Eczema can simulate fungal infection. Treatment is with oral terbinafine or griseofulvin.
Candidiasis Most human candidal infection is caused by Candida albicans (Fig. 10.13). This yeast is a common commensal in the
TABLE 10,10 Some factors facilitating candidal infection Local Maceration of skin Topical steroids Dentures Poor oral hygiene High oral carbohydrate levels
General Debility Extremes of age Immunosuppression by drugs or disease, particularly HIV Broad-spectrum antibiotics Corticosteroids Diabetes mellitus Iron deficiency Cushing's syndrome Hypocalcaemia/hypoparathyroidism Pregnancy
gastrointestinal tract, mouth and vagina, but not on the skin. However, it may become pathogenic (Table 10.10). Unlike the dermatophyte fungi, Candida invades living tissue. In some circumstances serious systemic infection can occur (see also p. 332). Some of the clinical patterns of candidal infection of the skin and mucosal surfaces are shown in Table 10.11. When infection is widespread and refractory to treatment this may be due to an immune deficiency. The skin lesions in such patients often resemble ringworm, and nails as well as nailfolds tend to be affected. There are several clinical/genetic types. In group I there is a well-defined major primary immune defect, e.g. Swiss-type agammaglobulinaemia. Group II comprises those cases without such a clear-cut primary immune defect. Subgroups include: • The Candida endocrinopathy syndrome, with hypoparathyroidism and Addison's disease being the commoner associated organ-specific autoimmune diseases • Autosomal recessive • Autosomal dominant
391
TABLE 10.11 Clinical patterns of Candida infection Type Oral Thrush Atrophic candidiasis Chronic hyperplastic candidiasis Angular stomatitis Skin Flexural
Anogenilal Vulvo-vaginitis Balanitis
Nails Paronychia Onychia
Pattern of infection
Features
White patches (Fig. 10.9) Painful red atrophic mucous membrane Thickened white adherent plaques Soreness and fissuring at the angles
Can be scraped off to reveal inflamed mucous membrane Common with antibiotic treatment and dentures Needs differentiating from leukoplakia Occurs in folds, usually due to ill-fitting old dentures
Sore, red, marginated skin, often with outlying pustules
Due to maceration
Itchy, sore with curd-like discharge Tiny red papules and pustules on glans and prepuce
Commoner in pregnancy
Painful swollen nail folds with loss of adhesion of cuticle Thickened, discoloured nails
Maceration predisposes. May have poor peripheral circulation Uncommon, often associated with immune detects
Usually from sexual partner
• Diffuse (severe) mucocutaneous candidiasis • Late-onset candidiasis, in which thymoma and HIV infection should be considered. Treatment of Candida infections Any remediable predisposing factors should be dealt with. Locally active agents include nystatin, amphotericin B and the imidazoles. For chronic oral candidiasis prolonged treatment is often necessary. Oral agents, including itraconazole and fluconazole, are usually required for chronic mucocutaneous candidiasis, a common problem in patients with symptomatic HIV infection. Long-term treatment is required.
Pityriasis versicolor Pityriasis (tinea) versicolor (Fig. 10.14) is a superficial infection caused by the mycelial form of the commensal yeast Pityrosporum orbiculare (also known as Malassezia furfur).
1 MCQ 10.3 2 Figs 10.8,10.9 392
FIG. 10.14 Slightly scaly macules of pityriasis versicolor; brown on a white skin (A) and pale on a tanned skin (B)
For most patients who have the disorder it is assumed that there has been a change in the pathogenicity of their surface commensal yeasts. Young adults are the most affected, and it is seen more in the tropics and subtropics. The distinctive hyper- and hypopigmentation is due to the diffusion into the epidermis of azelaic acid, a fatty acid from the fungus, which affects the melanocytes. Clinical features The upper trunk, arms and neck are the commonest sites. Lesions are macular and sharply demarcated, and have fine scaling. They may become confluent over large areas. On sun-protected 'white' skin the patches are skin-coloured or pale brown, but after sun exposure and in darker races they are hypopigmented. Scrapings show a mixture of clustered spherical yeasts and short mycelia. Under Wood's light the affected areas
fluoresce, and it is often apparent that the infection is more widespread than can be seen by visible light. Treatment Selenium sulphide 2.5% in a detergent base applied to affected areas and the scalp (a reservoir of yeasts), left on overnight and repeated a week later, usually clears the condition. Alternatives include topical imidazoles and oral itraconazole. 1 FURTHER READING IN SUPERFICIAL FUNGAL DISEASES Elewski B E. Hay R J, eds. 1999 Novel treatment strategies for superficial mycoses. J Am Acad Dermatol 40: Sl-42. Evans G V, Dodman B, Williamson D M, Brown G J, Bowen R G 1993 Comparison of terbinafine and clotrimazole in treating tinea pedis. Br Med J 307: 645-647.
VIRAL DISEASES
dysplasia verruciformis, predispose to squamous carcinoma. The hands, feet, face, around the knees, perianal and genital skin are the commonest sites for warts (Table 10.12). Because most warts resolve spontaneously, caution is needed in assessing therapy, and methods such as scalpel surgery and radiotherapy should be abandoned. For many non-genital warts, salicylic acid paints (or plasters for large plantar warts) are effective. Cryotherapy (p. 383) is uncomfortable but often more rapidly successful. Recently, intralesional bleomycin has proved effective. In selected cases curettage and minimal cautery may be needed. Genital and anal warts are frequently associated with other sexually transmitted diseases, requiring appropriate investigations. These lesions usually respond to liquid nitrogen cryotherapy or careful applications of podophyllin paint at weekly intervals, but this agent should be avoided during pregnancy because of the enhanced risk of absorption and fetal damage.
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Molluscum contagiosum Skin lesions are a common feature of many viral infections and may represent the direct consequences of virus replication (e.g. warts), the immune response to a virus, or interaction between the two. Only those where the skin or adjacent mucous membranes are the sole target are discussed here; the remainder, including herpes simplex and zoster, 2 are considered in Chapter 9.
Warts Warts arise because of hypertrophy of the prickle cell layer of the skin (or adjacent mucous membranes) induced by human papilloma virus. Warts are transmissible, inoculation being favoured by mild trauma. They are commoner in children and young adults, and are usually self-limiting and benign. However, some subtypes of virus (defined by DNA hybridization techniques), particularly those found in the genital tract and the rare condition epidermo-
Molluscum contagiosum (Fig. 10.16) is a contagious papular eruption caused by a DNA poxvirus. It occurs mainly in children but is also common in AIDS patients. The lesions are smooth, dome-shaped papules, often craterlike, with a central keratinous plug or depression. When multiple, they are typically in groups. Lesions are ultimately self-limiting. Direct microscopic examination of the cheesy contents or an entire curetted lesion reveals the characteristic eggshaped molluscum bodies. (These are epidermal cells filled with virus particles.) Electron microscopy can also be used. Single lesions can mimic benign or malignant epithelial tumours, e.g. keratoacanthoma or basal cell carcinoma. In young children it is often best to leave the lesions. Treatment is local destruction, e.g. with liquid nitrogen or by mildly traumatizing the papules and then painting with iodine.
TABLE 10.12 Viral warts Type of wart
Main site
Appearance
Common Plane (flat)
Hand Face and backs of hands Face and neck Scalp and neck Soles
Dome-shaped, papilliferous surface Flat-topped smooth papules (Fig. 10.15) Elongated Elongated with horny cap Circumscribed, often painful papules or nodules with altered surface pattern, sometimes with black dots Aggregation of numerous adjacent plantar warts Soft, velvety, vegetative papules and plaques
Filiform Digitate Plantar (verruca)
FIG. 10.15 Plane warts Multiple reddish-brown barely elevated lesions with a rough surface.
Mosaic plantar
Soles
Anogenital
Anal and genital regions
393
FIG. 10.17 Scabies burrows on wrists
FIG. 10.16 Domed umbilicated papules of molluscum contagiosum
Orf and milkers' nodules Orf is a poxviral disease of sheep, usually acquired directly from the perioral lesions that occur on lambs. Milkers' nodule is a similar condition acquired from infection of the teats of cows and ulcers in the mouths of calves. It is caused by a parapoxvirus. Several days after animal contact, a red papule appears and evolves into a 1-2 cm diameter smooth, bluish-red nodule, the centre of which may develop a crusted surface. There is often a whitish ring around the central crust with orf nodules 1 There may be lymphangitis and lymphadenopathy, and sometimes a rash on the limbs resembling erythema multiforme (p. 407). Resolution occurs in 3-4 weeks. Diagnosis is usually evident from the history but can be confirmed by electron microscopy. No treatment is required.
ARTHROPODS AND THE SKIN Numerous arthropods can inflict skin lesions on man, by the mechanisms listed below:
394
1
Fig. 10.10
4
Fig. 10.12
2
Fig. 10.11
3
MCQ10.4
• Mechanical trauma (e.g. horsefly, tungiasis) • Injection of toxins (e.g. some spiders, bees, wasps, ants) • Hypersensitivity (local and generalized) to injected materials (e.g. many arthropods, such as fleas, bedbugs); contact reactions (e.g. locusts); to an invading parasite (e.g. scabies); to retained mouth-parts, etc. (e.g. tick bite granulomas) • Secondary infection (e.g. many insect bites, scabies) • Transmission of disease (e.g. leishmaniasis, erythema chronicum migrans - caused by a spirochaete). Insect bite reactions should be suspected when there are grouped or linear arrays of itchy weals or papules. The lesions last longer than urticaria. Fleas and mites, often from domestic pets, mosquitoes, gnats, midges and bedbugs are frequent causes of this common problem. A careful history and examination of brushings from pets, their bedding and house dust can help identify the cause.
Scabies Scabies (Fig. 10.17) is an itchy dermatosis caused by the human mite Sarcoptes scabiei. Clinical features The female mite, just visible to the naked eye, makes the necessary journey from one human to another during close bodily contact and burrows into the horny layer, producing a serpiginous greyish elevation 1-10 mm long. Burrows are most commonly seen on the finger webs, wrists, elbows, around the nipples in women and on the male genitalia. In children the palms, soles and even the face may be colonized, and vesicles and pustules may be evident. In addition there is a widespread papular rash and extensive excoriation 0, probably the result of an allergic reaction to mite products. Generally there are only a few burrows at a time, but in so-called crusted or Norwegian scabies there are vast numbers, particularly on the hands. This mainly occurs in patients with learning difficulties, the immunosuppressed, the elderly and those who are unable to scratch.
With an initial attack there is a latent period of about 2 months before itching begins, but this period is reduced in subsequent episodes. The itching is often severe and tends to be worse at night. The distinctive burrows are usually overshadowed by widespread excoriations, eczematization and secondary infection.
The lesions following their bites often do not appear until well into the next day. They occur mainly on the face and upper limbs. The environment should be treated with an insecticide.
Diagnosis Mites can be extracted from burrows with a needle; somewhat easier is scraping the area after applying a drop of mineral oil or 30% potassium hydroxide and viewing the material microscopically for mites, eggs, faeces etc.
Lice are obligate human parasitic wingless insects. The itchy reactions are a result of sensitization. There are two species: Pediculus humanus, which occurs in two varieties - the head and the body louse - and Phthirus pubis, the pubic or crab louse.
Treatment The patient and all close contacts should be treated with a scabicide such as permethrin, lindane (gamma benzene hexachloride), malathion, or benzyl benzoate from the neck downwards. Properly applied, one dose is usually curative, but sometimes two applications 3 days apart are needed. Pruritus may continue for up to 2 weeks and can be helped by crotamiton (a less effective scabicide which also has antipruritic properties) or a topical steroid. 3
Other mites Dogs, cats, birds, grain and stored foodstuffs are sometimes sources of mites that can attack humans, producing itchy papules, often topped by tiny vesicles, and weals. Harvest mites, minute red creatures found in grass and other low vegetation, can produce similar and often very florid lesions. Diagnosis involves finding the offending mite, e.g. from brushings of pets.
Fleas Fleas include varieties that can burrow into skin (e.g. Tunga penetrans, found only in the tropics) and those that feed on the skin. In general the human flea is unusual, but occurs in overcrowded communities with poor hygiene. Bites from fleas living on pets, birds and occasionally wild animals, such as hedgehogs, are very common. The reaction to a flea bite is a hypersensitivity response. Individual lesions are like urticaria, but often have a haemorrhagic central punctum and last a week or two. They characteristically occur in groups, and often leave hyperpigmentation as they resolve. Troublesome itching can be treated with an oral antihistamine and secondary infection with an antibiotic. When the domestic pet is the source, the diagnosis can often be confirmed by examination of brushings from the animal. Flea faeces in this material stain damp white blotting paper red. Both the pet and the environment need appropriate treatment.
Bedbugs Bedbugs (Cimex lectularius) are nocturnal, wingless, bloodsucking insects that live in crevices in the walls, floor and furniture, and can best be seen in the middle of the night.
10
Lice
Head lice Head louse infection is very common in children, presenting as intense irritation, particularly at the back of the scalp. Secondary infection is frequent and may be mistakenly diagnosed as impetigo of the scalp. The insect is 3-4 mm long, but usually the eggs and egg cases (nits) are much more easily seen, firmly cemented to the hairs. Treatment is with malathion, a pyrethroid or carbaryl. Contacts should also be treated. Body lice The body louse is rare in developed countries, except in cases of self-neglect. There is widespread irritation, with papules and excoriation. The lice and their eggs are found on the clothing, particularly the seams, and are best treated by hot tumble drying. Pubic lice Pubic lice have legs somewhat like crabs' pincers, with which they are often found clinging to hairs. Secondary infection is common, and as these creatures are often acquired during sexual intercourse other venereal disease should be excluded. Treatment is with lindane (gamma benzene hexachloride), malathion or a pyrethroid.
PSORIASIS Psoriasis is a non-infective, usually chronic inflammatory skin disease with a number of clinical manifestations, the most common of which is red plaques covered by silvery scales (Fig. 10.18). 4 A distinctive arthritis may occur, and nails are often involved (Fig. 10.19). Genetic and environmental factors interact to account for the capricious natural history.
Aetiology Psoriasis occurs in about 2% of the population in Britain, but is less common in other countries, notably West Africa and Japan. The condition may present at any age, but onset is most common at puberty and the menopause. Additional triggering factors, of both onset and recurrence, are infection, especially streptococcal pharyngitis, which character-
395
Pathology and pathogenesis In the well-established psoriatic lesion there is epidermal thickening with increased mitoses, retention of nuclei in the horny layer (parakeratosis) accounting for the silvery scales, small collections of neutrophil polymorphs in the epidermis, tortuous dilated dermal capillaries and a dermal inflammatory infiltrate. Cell kinetic studies show that epidermal turnover occurs in 5-7 days, compared with the normal 30-45 days. Epidermal maturation is also abnormal, not just as a consequence of the rapid throughput. There is no comprehensive theory to account for the many abnormalities demonstrated in the epidermis, dermis, circulating granulocytes and lymphocytes, and the humoral immune system. CD4 helper lymphocytes in the dermis produce cytokines which initiate many of the inflammatory and proliferative events. From work in which psoriatic skin is explanted on to athymic nude mice it seems that the increased proliferation is intrinsic to the skin. It is likely that circulating factors determine the overall activity of psoriasis and maintain the inflammatory process in the plaques.
FIG. 10.18 Psoriasis Well-defined red plaque with silvery scales.
Clinical features The different patterns of psoriasis result from variations in expression of the disease (guttate, erythrodermic and pustular types) and modification of the features at certain sites, notably the scalp, flexures, palms and soles. The extent and duration are usually unpredictable, although some patterns are more likely to improve spontaneously, e.g. guttate psoriasis. Psoriasis means a condition (-iasis) of itching (psor-), but pruritus is not inevitable. 1 FIG. 10.19 Psoriatic arthritis Red swollen tender terminal interphalangeal joints with associated dystrophic nails.
istically provokes guttate psoriasis; trauma to the skin, generating new psoriatic lesions (Koebner's phenomenon, see below); and some drugs, notably lithium salts, systemic corticosteroids followed by their rapid withdrawal, and antimalarials. In some subjects UV radiation can initiate psoriasis on exposed skin. Rarely, hypocalcaemia provokes psoriasis. The importance of stress is disputed, but sudden psychological trauma can play a part in initiating the disease and causing relapse. The tendency to develop psoriasis is genetically determined but the mode of inheritance remains unclear. There is a close association with HLA-CW6 and HLA-DR7, the former conferring a 5-10-fold increased risk. HLA-B27 is seen in 70% of those patients with psoriasis and an ankylosing spondylitis pattern of spinal arthritis.
1 396
MCQ 10.5
2
Fig. 10.13
3
Fig. 10.14
Discoid or plaque psoriasis The well-defined, silvery-scaled red plaques may be found at any site, but the knees, elbows, extensor surfaces of limbs and the lower back are commonly affected. Scratching the scales reveals many tiny bleeding points. Flexural psoriasis Psoriasis of the axillae, groins and beneath the breasts is less readily recognized because the plaques are smooth, but usually remain more sharply defined than eczema. Lesions are typically symmetrical. Scalp psoriasis Scaling often becomes very thick, beneath which are telltale areas of well-defined erythema. 2 Psoriasis of palms and soles This may be more hyperkeratotic, without the silvery scale, but usually remains well defined. Guttate psoriasis There are numerous scaly papules and small plaques. 3 This type of psoriasis mainly occurs in children and adolescents. Erythrodermic psoriasis Total involvement of the skin can cause hypothermia and hypoproteinaemia (see also p. 410).
Pustular psoriasis Pustules occur when the neutrophil collections become clinically visible. The main varieties are a form localized to the palms and soles, in which yellow, white or greenish pustules (sterile) arise on erythematous scaly skin (Fig. 10.20), and a generalized type. In the latter the patient is ill, with fever and leukocytosis, and large areas of erythema develop myriad small sterile pustules which soon dry up and desquamate, to be followed by further waves of pustules. As with erythroderma, management entails rest, the prevention of hypothermia, and maintenance of fluid, electrolyte and protein balance, as well as control of the disease process. Localized pustular psoriasis of the palms and soles is probably genetically distinct, there being no association with HLA-CW6 or HLA-DR7, and often occurs without psoriasis elsewhere. Tar and dithranol are contraindicated in generalized pustular psoriasis, and generally unhelpful in palmoplantar pustular psoriasis. Psoriatic nail changes Common patterns are: • Multiple small pits, resembling a thimble (Fig. 10.21) • Onycholysis (separation of the nail), often with an adjacent zone of orange discoloration • Subungual (nailbed) keratosis • Thickening and distortion of nails. Nail changes are very common with psoriatic arthropathy involving the fingers.
FIG. 10.20 Pustular psoriasis of the soles Circumscribed areas of erythema, some scaling and pustules.
Psoriatic arthropathy Probably about 5% of psoriatics have a seronegative arthritis, although a much higher proportion have abnormalities detected by isotopic bone scans. Different patterns include:
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• Distal arthritis - terminal interphalangeal joints of fingers and interphalangeal joints of toes • Simulation of rheumatoid arthritis, but more asymmetrical • Sacroiliitis and ankylosing spondylitis • Arthritis mutilans, involving multiple joints with marked bone resorption. Diagnosis and management are discussed on page 1151.
Management The choice of treatment will depend on many factors. These include the capabilities and lifestyle of the patient, as well as the type, location, extent and severity of the psoriasis. The options shown in Table 10.13 will not be appropriate for every patient, and are often used in combination. Some patients will prefer not to have any treatment. Nails do not respond well to topical therapy, but may improve with the rest of the psoriasis, especially when systemic treatments are used. Topical therapy Rest and bland applications are important in acutely inflamed psoriasis, erythrodermic and generalized pustular psoriasis. Many cases with discoid lesions respond well to tar and dithranol preparations, although, particularly with the latter, it is wise to begin with a weak preparation and gradually increase the potency to minimize irritation. Topical steroids are less likely to clear psoriasis completely, but with due attention to their potential hazards they are useful for areas that are readily irritated, such as the flexures, genitalia, ears and face; they are often more effective on the palms and soles. The most potent preparations are
FIG. 10.21 Psoriatic nail showing thimble-like pitting
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CASE STUDY 10.1 A WIDESPREAD RASH IN A 35-YEAR-OLD WOMAN FOLLOWING AN UPPER RESPIRATORY TRACT INFECTION A 35-year-old married woman presented complaining of the sudden onset of a widespread rash, beginning 2 weeks after a severe sore throat for which she had received a course of penicillin. There was no previous history of skin disease but her mother and older sister both had psoriasis. On examination there were numerous well circumscribed, discrete red scaly plaques on the trunk, elbows and knees. There were also lesions in the scalp (Case Fig. 10.1.1).
Questions 1. What is the most likely diagnosis? 2. What other condition should be considered? 3. What treatment should be instituted?
Discussion The most likely diagnosis is guttate psoriasis. The sudden onset following a sore throat (probably streptococcal) is typical and the patient has a positive family history. Pityriasis rosea can also present in this way and can sometimes be difficult to distinguish, especially in the first week or two. However, lesions on the limbs and the scalp are rare in pityriasis rosea. The most effective treatment in this case would probably be the combined use of topical tar preparations and ultraviolet B (UVB) phototherapy, although some dermatologists would also use moderately potent topical steroids and/or vitamin D analogues (calcipotriol or tacalcitol), either as well as or instead of the tar. The phototherapy would normally be administered in a specialist facility
1
398
MCQ 10.6
twice weekly, initially for 6-8 weeks, before an assessment of the response was made. If the condition failed to settle satisfactorily, further measures might need to be considered. Questions 4. What therapies might be offered to this woman if firstline therapy fails? 5. What additional factors need to be considered in reaching the appropriate decision? Discussion It may be necessary to commence topical therapy with dithranol, an anthracene derivative which can eradicate psoriatic plaques completely. However, the treatment is messy, time-consuming and can, if mishandled, result in burns and staining of both skin and clothes. This woman was a busy executive with an international marketing company and was unable to accept the inconvenience dithranol would have caused. There is a case to be made for at least a short course of
CASE FIG. 10.1.1 Plaques of psoriasis
systemic therapy with acitretin (a retinoid), methotrexate or ciclosporin. It is important to discuss the implications of each of these drugs with the patient and her husband. They need to understand that acitretin is teratogenic. It may also cause hyperlipidaemia and a (usually mild) hepatitis. It is important to avoid pregnancy while on the drug and for 2 years after stopping. Methotrexate can, in exceptional circumstances, cause severe bone marrow suppression, but its main problem is hepatotoxicity if used over long periods. Ciclosporin is expensive and may cause renal and cardiovascular damage. In the circumstances this woman and her husband agreed that it was sensible, after all, to try to use dithranol at home under the supervision of a specialist nursing team from the hospital. Although progress was slow, the psoriasis reduced considerably in extent and the woman was able to manage her disease effectively thereafter with a combination of topical steroids and vitamin D analogues.
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TABLE 10.13 Treatment choices in psoriasis Form
Site
First choice
Second choice
Third choice
Plaque
Face, flexures genitalia Scalp Trunk, Limbs: few plaques Trunk, limbs: many plaques
Topical steroid Tar gel or pomade Dithranol or calcipotriol Calcipotriol Dithranol ± UVB UVB Topical steroid Tar Dithranol
Mild tar or weak dithranol Dithranol or calcipotriol Tar PUVA
Topical steroid Topical steroid Systemic therapy, e.g. methotrexate cyclosporin
PUVA
Oral retinoid
Guttate
Calcipotriol ± UVB
UVB ± tar
Topical steroid
Erythrodermic with systemic complications
Oral retinoid
Methotrexate
Systemic steroid
Topical steroid Oral retinoid
PUVA Methotrexate
Oral retinoid Other systemic therapy
Palms and soles
Pustular psoriasis
Palms and soles Generalized
best avoided, except on the palms and soles, and even there they should be restricted to short courses. The vitamin D analogue calcipotriol is effective and provides an effective alternative to tar and dithranol. Ultraviolet (UV) radiation and photochemotherapy Ultraviolet B (p. 426) is used both alone, e.g. for guttate psoriasis, and together with other modalities. Photochemotherapy (also known as PUVA) is the combination of long-wave UVA and the photosensitizing drug psoralen, usually taken orally 2 hours previously. It is a powerful treatment for psoriasis, but prolonged use is likely to age the skin prematurely and to induce non-melanoma skin cancer. Photochemotherapy is valuable for extensive plaque psoriasis when topical therapy is poorly tolerated or has failed, and can be successful for erythrodermic and pustular forms. Systemic therapy For the most severe forms of psoriasis, antimitotic and immunosuppressant drugs are used. Methotrexate is effective and reasonably safe. In long-term use hepatic fibrosis can occur and liver biopsies are recommended every 1-2 years to identify this before it is irreversible. Alcohol should be avoided. Ciclosporin has recently been introduced for the treatment of cases where methotrexate is unsuitable. This drug is not antimitotic, and probably works by modulating the immune system. The main hazard is nephrotoxicity. Vitamin A derivatives (retinoids) with less toxicity than vitamin A itself have been found to be of value in pustular and erythrodermic psoriasis, and useful in combination with other treatments, e.g. photochemotherapy. Retinoids have a number of side-effects and, like methotrexate, are teratogenic, but they are not cytotoxic or immunosuppressant. They probably influence the disturbed maturation of the epidermis in psoriasis. 1
FURTHER READING ON PSORIASIS Greaves N W, Weinstein G D 1995 Treatment of psoriasis. N Engl J Med 332:581-588. Stern RS 1997 Psoriasis. Lancet 350:349-353. Workshop of the Research Unit of the Royal College of Physicians of London: Department of Dermatology, University of Glasgow, British Association of Dermatologists 1991 Guidelines for management of patients with psoriasis. Br Med J 303: 829-835.
ECZEMA AND DERMATITIS Eczema is a pattern of inflammation with many possible causes, rather than a disease. The different types are unified histopathologically by the presence of spongiosis in the epidermis. The term 'dermatitis' is often used to imply an eczema of external origin, but it should always be qualified, as in 'contact allergic dermatitis', as 'dermatitis' is used in many other contexts, e.g. dermatitis artefacta, dermatitis herpetiformis etc. Eczema is usually itchy and red; when the inflammation is intense, vesicles are seen and there is oozing from the surface (Fig. 10.22). If the process continues, scaling and thickening occur, and with rubbing and scratching lichenification (the development of leather-like plaques) is common. The earliest and most distinctive pathological change is spongiosis, the accumulation of oedema fluid within and between keratinocytes. Viewed in microscopic section, this produces an appearance somewhat like a sponge. In acute eczema the process extends to produce intraepidermal vesicles. In the dermis, and to a lesser extent the epidermis, there is an inflammatory infiltrate in which lymphocytes
399
contact allergen. The face is often affected, even when not directly exposed to a causative agent.
EXOGENOUS ECZEMA Irritant contact dermatitis When the skin changes are a direct result of exposure and allergic mechanisms are not involved, the rash is termed irritant contact dermatitis. Not all reactions to irritants are eczematous; for example, the agent may produce necrosis or urticaria. Because obvious irritants tend to be avoided, the main problems occur with those that require prolonged and repeated contact, e.g. detergents, alkalis, mineral oils and organic solvents. Atopic individuals are particularly susceptible, as are housewives, hairdressers and those in a number of industrial occupations. Even when a period of avoidance produces healing, chronic irritant dermatitis tends to recur readily with re-exposure.
Allergic contact dermatitis
FIG. 10.22 Eczema With intense inflammation there are vesicles and oozing. If the process continues, scaling and thickening occur.
are prominent. With time, both the epidermis and dermis become thickened. Aetiological factors in eczema include: • • • • • • •
400
Skin irritants Contact allergens Friction, low humidity, UV light Infections (bacterial, dermatophytes, yeasts) Atopic constitution Drugs and foods Local factors: venous stasis, ichthyosis.
Several factors may act in concert, particularly with eczema of the hand and lower leg, and not infrequently treatment is an inadvertent contributory factor. A careful history is essential in the evaluation of eczema. Several different clinical patterns of eczema and dermatitis (with eczematous features) are recognized. The basis for these patterns is well understood in some instances (e.g. contact allergic dermatitis) but obscure in others (e.g. discoid eczema). Because successful management depends on recognizing external factors that are contributing to the skin disease, it is helpful to classify according to whether the disease process is primarily exogenous or endogenous, although these distinctions are somewhat artificial. Whatever- the cause, while active, eczema tends to spread, often beyond any recognizable stimulus such as a
Allergic contact dermatitis is the response to a substance to which the individual has become sensitized. Most such substances are of low molecular weight and penetrate the skin to behave as haptens. After conjugation with a skin protein the complete antigen is taken up by Langerhans' cells, which migrate to regional lymph nodes and act as antigen-presenting cells in a T lymphocyte-mediated (type IV) immune response. All subsequent contact with the sensitizer results in an acute eczematous reaction. This type of response is uncommon in children, although contact urticaria is frequent in atopies (see below). Contact allergic dermatitis usually begins at the site of contact, but the clinical picture can at times be deceptive, e.g. nail varnish resin, which causes no trouble locally but gives rise to eczematous patches when it is transferred to the face and neck by the fingers. Many factors determine the acquisition of contact allergy. Some substances, e.g. epoxy resin and poison ivy, are inherently more likely to sensitize. Occlusion (e.g. a hand in a glove) and skin damage (e.g. from irritants) enhance penetration. It is possible that some individuals are more likely than others to be sensitized. The thick horny layer of the palms renders them less likely than the dorsa of the hands to be affected. Once initiated, repeated exposure tends to produce increasingly severe and widespread dermatitis, and sites far removed, such as the eyelids, can be involved. The allergic state usually persists for life. Some common sensitizers are listed in Table 10.14. Investigation: patch testing The allergic state is reproduced in miniature by the application of a non-irritating dose of a suspected chemical beneath an occluding disc or patch placed on the back for 48 hours. Because some allergens are ubiquitous, a
CASE STUDY 10.2 A 25-YEAR-OLD NURSE WITH AN ITCHY RASH ON HER HANDS A 25-year-old nurse developed an itchy rash that particularly involved her hands. She had been working on the labour ward for the previous 3 months. She reported to the hospital occupational health department one morning because of pain and swelling in her right hand. She had been feeling unwell, had been shivery, and had had aching muscles for the previous few hours. She had a past history of eczema in childhood and urticaria when given penicillin. She had bouts of sneezing when near furry animals. In her family history there was a sister with asthma. On examination she appeared unwell, had a temperature of 38.5°C, an erythematous, swollen, tender right hand, and both hands showed areas of erythematous thickening, fissuring and yellow crusts (Case Fig. 10.2.1). There were erythematous and excoriated patches and plaques on the chest and, back, and behind the knees. Questions 1. What is the most likely reason for the febrile illness and swollen right hand? 2. What investigations would be appropriate in this case? 3. What would be your immediate management? She has cellulitis secondary to a breach in the skin owing to hand eczema. The most likely cause is Bhaemolytic streptococcus group A, but Staphylococcus aureus, both organisms, or less probably some other bacteria, e.g. from her workplace, are also possible causes. Bacteriological confirmation is valuable, especially since she is systemically unwell; works in a hospital environment; and has a history very suggestive of allergy to penicillins. Useful investigations at the outset are swabs from crusted lesions, blood cultures, a full blood
count and serum antistreptolysin O titre (ASOT) and antideoxyribonuclease B (ADB). It was decided to admit her to hospital for parenteral therapy with i.v. cefuroxime. She tolerated this well and made a full recovery over the next 5 days. Investigations gave the following results: Hb 13.5 g/dL, WBC 23 x 10"/L, neutrophils 95%, ASOT 300, ADB >1200. Cultures from the skin showed Staph. aureus, sensitive to flucloxacillin. Blood cultures were negative. Note that she had a neutrophil leukocytosis, and of the two serological tests for evidence of acute streptococcal infection only the ADB was unequivocally positive. In general, ASOT is more commonly positive with pharyngeal infections. She was discharged and returned to work 1 week later. Shortly thereafter, she found that her hands became red and itchy again, but this time the eruption was over both hands and extended on to the wrists. She saw her GP, who prescribed betamethasone valerate cream (a potent topical corticosteroid) to use twice daily and an emollient for the dryness, but her hands did not improve. A referral
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letter was sent to the local dermatologist but before she could be seen she had an episode of acute shortness of breath and collapsed while eating a salad in a restaurant. She was taken to the nearest A & E department and was found to be hypotensive, dyspnoeic, with grossly swollen lips and tongue, and with an extensive urticarial eruption. Anaphylaxis was diagnosed; she was treated with parenteral adrenaline (epinephrine), chlorphenamine (chlorpheniramine) and hydrocortisone, and made a rapid recovery.
Questions 4. What is the likely mechanism for the acute anaphylactic reaction? 5. How can it be investigated? Release of inflammatory mediators, especially histamine, from mast cells and basophils is the most common cause of acute anaphylaxis. In this case the release was probably IgE mediated. Other mechanisms include the direct action of some pharmaceutical agents (e.g. opiates) and circulating immune complexes.
CASE FIG. 10.2.1 Lymphoedema of the hands following recurrent eczema and infection
401
CASE STUDY 10.2 CONTINUED Investigations for IgE-mediated reactions include prick tests and in vitro methods such as the RAST (radioallergosorbent test). When the patient was evaluated by the dermatologist, the history revealed that she had had an acute swelling of the lips when blowing up balloons a few weeks earlier, and had also noted that her hands were becoming red and itchy immediately after she put rubber gloves on. Serum was sent for a RAST to latex proteins, and was strongly positive. As well as being relevant to her immediate reactions to rubber gloves and balloons, her hypersensitivity to latex proteins probably explains her episode of anaphylaxis in the restaurant: she had eaten avocado in the salad, and this is one of a number of plants which have proteins that cross-react with latex protein. Others include banana, chestnut and kiwi. She was also patch tested and had a positive reaction to sorbic acid (the preservative in her emollient cream). Discussion This case illustrates a number of problems that can occur in the atopic individual. Having had self-limiting eczema as an infant, the patient developed it again as an adult when her hands were subjected to repeated hand-washing with detergents and soaps in her work as a theatre nurse.
The skin in someone with atopic eczema commonly becomes colonized with Staph. aureus and sometimes Strep. pyogenes group A, and this led on to acute soft tissue infection (cellulitis). It is common for streptococcus not to be cultured from either the surface or the blood, and diagnosis only to be confirmed serologically. The interpretation here is that the cellulitis was due to B haemolytic streptococcus; the Staph. aureus was a superficial infection only. In a patient known to be allergic to penicillins there is some risk of cross-hypersensitivity with other antibiotics containing the (3lactam ring in their structure, but the risk was thought to be low because she had had urticaria without systemic symptoms many years ago. There is also a possibility that the causative organism would not be sensitive to a macrolide (e.g. erythromycin), which would otherwise be a reasonable choice. Hence the decision to admit her and give cefuroxime, a cephalosporin, albeit with a small risk of an allergic reaction. If she had been working on a medical ward there could well have been a significant risk of her being infected with a multiresistant Staph. aureus (MRSA), in which case i.v. vancomycin would have been the drug of choice. In a patient with continuing hand eczema, patch testing was the
selection of common sensitizers is tested as well as any chosen on the basis of the patient's history. A positive reaction does not prove the cause of a patient's rash, but does help confirm suspicions and suggest unsuspected materials. Positive reactions may be of past relevance only. Light-induced eczema Eczema on light-exposed skin may be due to:
1
402
Fig. 10.15
appropriate step to take to evaluate whether contact allergy (type IV hypersensitivity) was playing a part in addition to atopy and irritant exposure. She was tested for a large number of potential allergens, including those in her treatments. When it was found that she was allergic to the preservative in her emollient, this was changed to a soft white paraffin product with no preservatives, and all the areas where she had been applying the bland cream to dry skin improved. Type I allergy to the low molecular weight proteins in latex has become increasingly common over the past decade, especially in atopies, and is a significant hazard for nurses and doctors because of their frequent use of rubber gloves. Direct exposure of the allergenic material to internal surfaces (e.g. introduction of a rubber catheter) can be fatal. In this patient, whereas contact with rubber produced urticarial reactions, limited to the skin (her hands and lips), the ingestion of avocado led to acute anaphylaxis. With avoidance of allergens, use of a soap substitute, soft white paraffin as emollient and a mild corticosteroid ointment, the patient's hands recovered and she was able to return to work. She now uses vinyl gloves, rather than rubber ones, for hand protection.
• Photocontact allergy, e.g. sunscreen medicaments. The essential role of UV radiation is shown by patch testing with and without UVR • Photosensitive drug eruption, e.g. chlorpromazine, sulphonamide, thiazide • Exacerbation of existing eczema, e.g. atopic dermatitis. Phototoxic reactions, which resemble sunburn rather than eczema, can occur following contact with tar and its derivatives, some dyes and plants, and with drugs (p. 418). Sensitivity to airborne allergens can closely mimic light reactions, but areas normally spared from sun exposure, such as the skin beneath the ears, under the chin and
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TABLE 10.14 Some common sensitizers Chemical
Source
Nickel Chromate Epoxy resin Paraphenylenediamine Rubber antioxidants Preservatives Lanolin Perfumes Topical drugs
Jewellery, watch bands, silver coins Wet cement, many engineering processes, leather Two-part glues Hair dyes Gloves, shoes Cosmetics and medicaments Cosmetics and medicaments Cosmetics and medicaments Neomycin, antihistamines, sulphonamides, some local anaesthetics Sticking plasters, newsprint
Colophony
around the eyes, are involved. Dermatomyositis may occasionally mimic a light-induced eruption.
ENDOGENOUS ECZEMA Atopic eczema/dermatitis Atopic eczema/dermatitis (Fig. 10.23) is closely associated with asthma, hay fever, urticaria and dry skin. There is usually a family history of one or more of these. The separate condition ichthyosis vulgaris (p. 405) is probably more common in atopic individuals than in the rest of the population. The skin readily becomes itchy in response to a number of allergic and non-allergic stimuli, and the pruritus may be disproportionate to the physical signs. High levels of circulating IgE antibodies are very common, as are multiple positive prick tests. The disorder is very common, most cases beginning in infancy, and at least 10% of the population are affected to some degree. There is often a fluctuating course, but most cases clear up by adulthood, the majority within the first 5 years of life. Aetiology There is much evidence for a genetic basis for the atopic state, although how this is translated into the various clinical manifestations is unknown. A number of immunological abnormalities have been described, including the overproduction of IgE, reduced numbers of suppressor/cytotoxic T lymphocytes, and cutaneous basophil hypersensitivity, e.g. to house dust mite antigen. Environmental factors are important determinants of fluctuations. These include ingested proteins (e.g. dairy products and eggs), and exposure to house dust mites, pollens and pet hair. Wool next to the skin frequently causes irritation. Extremes of climate often worsen the disease. Beyond a certain level of colonization, Staph. aureus may produce flares of erythema and pruritus.
FIG. 10.23 Atopic dermatitis in a young child: erythema, weeping and crusting
Clinical features Onset is often in the first 3 months of life. Itching is the major symptom and at times there may be little rash. In infancy the skin is often patchily dry and red, with episodes of vesiculation and crusting. By 1-2 years the elbow and knee flexures, wrists, hands and tops of the feet are typically involved. With prolonged rubbing and scratching, papules and then leathery plaques (lichenification) are seen. 1 At any stage secondary infection may occur, with superimposition of impetigo and follicular pustules. Urticaria from contact, e.g. with a pet or foods, is also common. Complications Eczema may be complicated by erythroderma (p. 409). Severely affected children are often growth retarded. Herpes simplex infection can be widespread (eczema herpeticum) and, particularly in the very young, may be disseminated to internal organs, with potentially fatal outcome. If eczema herpeticum is suspected, treatment with aciclovir (i.v. if the patient is unwell) should be commenced immediately. When eczema begins in infancy or early childhood the prognosis for recovery is generally good. Adults can be affected, especially when the skin is exposed to irritants, e.g. in nursing and hairdressing. Management The mainstays of management are the avoidance of irri-
403
SUMMARY 1 Classification of eczema Exogenous Irritant contact dermatitis Allegic contact dermatitis Light-induced dermatitis
Endogenous Atopic eczema/dermatitis Discoid (nummular) eczema Seborrhoeic eczema/dermatitis Pompholyx Asteatotic eczema Gravitational eczema
tants such as bubble bath, mild topical steroids, plentiful use of emollients when the skin is dry, antibiotics when necessary, tar preparations for the more chronic and less inflamed lesions, and a sedative antihistamine at night. Cotton clothes and the use of a soap substitute, e.g. emulsifying ointment or aqueous cream BP, are helpful. Current evidence suggests that children of atopic families should be breastfed, at least up to 3 months if possible. Subsequent supervised dietary manipulation may be helpful.
Discoid eczema Discoid (nummular) eczema consists of discrete rounded patches of eczema, usually symmetrically distributed, for which there is no apparent cause. The aetiology is unknown and treatment is symptomatic. A group 1 or 2 potency topical steroid is often needed, and infection, if present, should be treated with an antistaphylococcal antibiotic.
Seborrhoeic eczema/dermatitis Seborrhoeic eczema/dermatitis (Fig. 10.24) is distinctive in both appearance and location. The cause is unknown, but Pityrosporum yeasts play a part. There is usually no correlation with sebaceous activity, although it is a disorder of areas where sebaceous glands are plentiful. Severe seborrhoeic dermatitis is an early feature in about one-third of AIDS patients. There is less itching than with other eczemas. The lesions are yellowish-red, scaly away from flexures, and involve some or all of the following sites: scalp, eyelids, eyebrows, sides of nose, ears, axillae and groins, beneath the breasts, front of the chest, and upper back. The differential diagnosis will depend on the sites affected. In the scalp, psoriasis can be very similar. In the flexures, psoriasis, contact allergic dermatitis, dermatophyte infections and candidiasis may need to be excluded; the truncal form can resemble pityriasis rosea and pityriasis versicolor (the latter diagnosed from a scraping). Methyldopa can produce a seborrhoeic dermatitis-like drug eruption.
1 Fig.10.16 404
2
MCQ 10.7
FIG. 10.24 Nasolabial erythema and scaling of seborrhoeic dermatitis
The addition of sulphur, a mild tar, salicylic acid or an imidazole to a suitable topical steroid is often helpful. Shampoos containing ketoconazole, selenium sulphide or zinc pyrithione are useful for scalp involvement.
Pompholyx Pompholyx is an eruption of vesicles on the sides of fingers, palms and soles. Itching may be severe. The condition is usually episodic. Causes of pompholyx include the onset of warm weather; dermatitis or fungal infection of the feet (producing pompholyx of hands); ingestion of a contact allergen, e.g. nickel; and stress. Often no cause can be found. Treatment is symptomatic. If weeping is present, potassium permanganate soaks are helpful, followed by a group 1 or 2 potency topical steroid. Secondary infection is common and should be treated with a systemic antibiotic.
Asteatotic eczema Asteatotic eczema is a mildly inflammatory condition that occurs mainly in the elderly on the shins, as erythema with a crazy paving-like pattern of superficial fissuring and scaling. It may be a result of reduced epidermal lipids. Hypothyroidism, uraemia, dehydration, low humidity and overzealous cleansing may contribute. It often responds to less bathing and to emollients. A mild topical steroid ointment can be added if necessary.
Gravitational eczema 1
10
Eczema often occurs on the lower legs as a response to chronic venous hypertension, in association with haemosiderin staining, patchy atrophy, sclerosis, oedema, and perhaps ulceration. It is particularly common near the medial malleolus in patients with previous deep vein thrombosis, but may also be seen in relation to varicose veins and incompetent perforating veins (p. 429). Patches indistinguishable from those of discoid eczema may spread elsewhere. Important in management are improvement of the venous hypertension, e.g. with support hosiery, and the avoidance of potent topical steroids and potential sensitizers, such as neomycin, lanolin and preservatives. Symptomatic treatment of eczema Any causative and aggravating factors should be removed if at all possible. Acute weeping eczema can be soothed with wet compresses, e.g. aluminium acetate lotion BNF or 1:10000 potassium permanganate solution, followed by a topical steroid cream. In some cases, particularly contact allergy, when a cause has been recognized and dealt with, a short course of systemic steroids is justified. For less acute eczema, a topical steroid of the lowest effective potency is needed, often in a greasy base. If the surface is dry, additional applications of an emollient are helpful and reduce the likelihood of steroid overuse. For chronic lichenification, tar preparations (e.g. as impregnated bandages) are valuable. Secondary infection is usually best treated with a systemic antibiotic, e.g. flucloxacillin or erythromycin. 2
FURTHER READING ON ECZEMA AND DERMATITIS Brehler R et al 1997 Recent trends in the treatment of eczema. J Am Acad Dermatol 36:983-994 Charman C 1999 Clinical evidence: atopic eczema. Br Med J 318:1600-1604 Friedmann P S 1998 Allergy and the skin II - contact and atopic eczema. Br Med J 316:1226-1229 McHenry P M et al 1995 Management of atopic eczema. Joint Workshop of the British Association of Dermatologists and the Research Unit of the Royal College of Physicians. Br Med J 310:843-847
ICHTHYOSIS The term ichthyosis is used for a number of conditions in which there is either a disorder of keratinization or shedding of the horny layer, producing persistent, generalized scaly skin (Fig. 10.25). Most types of ichthyosis are inherited and present in infancy or childhood. Onset in adulthood can be associated with an underlying neoplasm (p. 423). Ichthyosis vulgaris is the only common type, occurring in about 1 per 300 of the population. It is inherited as an auto-
FIG. 10.25 Rough skin and scaling of ichthyosis
somal dominant trait and has distinctive histology: absence of the granular cell layer of the epidermis. Individuals have rough skin with white scales, maximal on the extensor surfaces and sparing the antecubital and popliteal fossae. There are often rough follicular papules (keratosis pilaris) on the upper arms and thighs. The physical signs are worse in winter. Avoidance of soap and regular use of emollients are helpful measures. Sex-linked recessive ichthyosis occurs in about 1 per 6000. Female carriers may show mild changes, but the fully developed condition, as seen in males, is more severe than ichthyosis vulgaris, with large brownish scales; the flexures are involved. The condition is characterized by steroid sulphatase deficiency. Acquired ichthyosis has a similar clinical pattern to ichthyosis vulgaris. As well as being associated with neoplasia, particularly Hodgkin's disease, it can occur in gross nutritional deficiency.
REACTION PATTERNS Despite the large number of named diseases, as an organ the skin has a limited range of reactions to noxious stimuli such as circulating immune complexes and infections. Some of these reaction patterns have sufficiently few common causes that their recognition can be helpful in arriving at a diagnosis. This may be particularly true when the patient has other symptoms, e.g. cough or malaise, for which there is no obvious cause.
405
SUMMARY 2 Reaction patterns • • • • • •
Urticaria and angioedema Erythema multiforme Erythema nodosum Pyoderma gangrenosum Cutaneous vasculitis Erythroderma
A single aetiological factor may produce one or more of the reaction patterns described below. For example, the hepatitis B virus may lead to urticaria if the effect on dermal blood vessels is fully reversible, but purpuric vasculitis if the damage is more profound. FIG. 10.26 Urticaria: arcuate weals
URTICARIA AND ANGIOEDEMA The characteristic lesion in urticaria is a weal (Fig. 10.26). This is caused by oedema in the dermis, so weals are raised and often pallid but surrounded by a zone of erythema. Urticaria is evanescent, usually lasting from minutes to a few hours (rarely more than 24 hours) and fades without trace. Itching may be severe. Lesions initially like urticaria may occur in vasculitis, arthropod bites and stings, and lupus erythematosus, but in these circumstances they are more long-lasting. If there is doubt, a skin biopsy can be helpful in distinguishing these conditions. Urticaria lasting more than 3 months is regarded as chronic, and in most cases no cause is found. Angioedema occurs in the subcutaneous tissues, particularly where they are rather loosely organized, such as in and around the mouth, around the eyes and on the scrotum. 1 The lesions are larger, less well defined and not necessarily itchy. Common causes of urticaria and angioedema are listed in Table 10.15. Many cases of chronic idiopathic urticaria are now recognized to be due to IgG autoantibodies directed against the high-affinity IgE receptor and, less commonly, IgE itself. The basis for urticaria and angioedema is vasodilatation and extravasation of fluid owing to release of mediators from mast cells and/or basophils. In some circumstances the mediators responsible can cause hypotension and bronchospasm, constituting anaphylactic shock (p. 97). Mechanisms include IgE and immune complex-mediated reactions, and direct effects of chemicals, e.g. toxins and drugs. Symptomatic treatment is with H1 antihistamines. Hereditary angioedema is a rare but potentially lifethreatening condition, in which non-pruritic swellings
TABLE 10.15 Common causes of urticaria and angioedema Drugs Penicillin, aspirin, X-ray contrast medium Foods Azo dyes, benzoate preservatives (chronic urticaria) Arthropod reactions Transfusion of blood products and foreign proteins
Plants Stinging nettles Systemic disease Hepatitis B, other virus infections systemic lupus erythematosus Contact urticaria Some foods and pet saliva on atopies Latex Inhalants Grass pollens, house dust
Physical stimuli Light pressure (dermographism), cold, light, increase in body temperature (cholinergic urticaria)
occur in the gastrointestinal and respiratory tracts as well as the skin and adjacent mucous membranes. A careful family history may suggest the diagnosis. There is either deficiency or an abnormality of the inhibitor of activated complement component Cl. The best laboratory investigation is the measurement of Cl esterase inhibitor by antigenie activity or functional assay. Also useful is the demonstration of low C4 and C2, the substrates of activated and unopposed Cl. Acute episodes may respond to Cl esterase inhibitor concentrate, and danazol can be used to suppress attacks. © FURTHER READING ON URTICARIA
406
1 Fig. 10.17 4 Fig. 10.19
2
MCQ 10.8
5
MCQ 10.9
0 Fig. 10.18
Kaplan A P 2002 Chronic ruticaria and angioedema New Engl J Med 346:175-179. Sabroe R A, Greaves M W 1997 The pathogenesis of chronic idiopathic urticaria. Arch Dermatol 133:1003-1008.
10
FIG. 10.27 Erythema multiforme: target lesions with central blisters
ERYTHEMA MULTIFORME AND STEVENS-JOHNSON SYNDROME The causes of erythema multiforme include: • • • • •
Herpes simplex Other infections, e.g. mycoplasma Drugs, e.g. sulphonamides Pregnancy Collagen vascular disease, e.g. SLE.
The distinctive features of erythema multiforme are the target lesion (Fig. 10.27), the distribution of the rash and the histology. It is an acute eruption that usually lasts about 3 weeks, maximally involving the hands and feet, forearms, 3 elbows and knees. Among a variety of erythematous lesions there are usually some target lesions. These have a purplish or blistering centre inside one or more red rings. The mucosae of the mouth, 4 genitalia and eyes may be involved (Stevens-Johnson syndrome, Fig. 10.28) with blistering and haemorrhage. Sometimes internal organs, e.g. the kidney and lungs, are affected. There is an interval of about a week between the stimulus and the eruption, but this is shorter with recurrences. The pathogenesis is not fully understood. When erythema multiforme is recurrent, the most common cause is herpes simplex. The condition is self-limiting but supportive care is needed, especially if there is eye and oral involvement. This will include oral toilet, analgesia, antibiotics, treatment of ocular complications and, in cases with widespread blistering, management as for burns on an intensive care unit.
FIG. 10.28 Stevens-Johnson syndrome Severe muco-cutaneous erythema multiforme due to mycoplasma infection. Note the conjunctivitis, haemorrhagic crusting on the lips and target lesions.
nodosum is often accompanied by fever, malaise and painful joints. Lesions disappear over 3-6 weeks, with the same colour changes as in a resolving bruise. It is mainly a condition of young adults. Most cases are probably due to circulating immune complexes lodging in or near the venules in the deep dermis and subcutaneous fat. Causes include: • • • • •
Sarcoidosis Streptococcal infection Ulcerative colitis and Crohn's disease Tuberculosis Other infections, e.g. yersinia, deep mycoses (where e.g. blastomycosis occurs commonly), Chlamydiapsittaci and lymphogranuloma venereum • Drugs (uncommon), e.g. oral contraceptives, sulphonamides • Leukaemia and Hodgkin's disease. 0 Similar but smaller nodules are seen in Behcet's disease (p. 1153). Erythema nodosum leprosum is clinically and histologically quite different (p. 327). The lesions of nodular vasculitis are more persistent and occur more on the calves. Bed rest is advisable at first, and a non-steroidal antiinflammatory drug may be helpful. Further management will depend on the cause.
ERYTHEMA NODOSUM The plaques and nodules of erythema nodosum (Fig. 10.29) are red, hot and tender. They typically occur over the shins but may be more widespread on the legs, on the outer aspect of the arms and sides of the neck. Erythema
PYODERMA GANGRENOSUM Pyoderma gangrenosum (Fig. 10.30) is an uncommon, noninfective ulcerating condition frequently associated with an
407
FIG. 10.30 Pyoderma gangrenosum: ulcer with purplish undermined edge
small lesions topical and intralesional corticosteroids can be effective; minocycline can be a valuable agent in milder cases.
CUTANEOUS VASCULITIS FIG. 10.29 Erythema nodosum Tender erythematous nodules over the shins in a young woman due to streptococcal pharyngitis.
underlying systemic disease. 1 The lower limbs and face are the most common sites, but any part of the body may be affected. The necrotic area often begins as a sterile pustule which breaks down and spreads, sometimes to form a huge ulcer, with a characteristic ragged, purplish overhanging edge. Lesions may be multiple. The pathogenesis is unclear, but many patients have evidence of a depressed immune system. Causes include: • • • • •
Ulcerative colitis Crohn's disease Rheumatoid arthritis Other forms of arthritis Leukaemia, lymphomas, monoclonal gammopathies and myeloma.
The differential diagnosis includes infective causes of ulceration (e.g. postoperative gangrene, p. 386) and vasculitic disorders (e.g. Wegener's granulomatosis). Cultures for aerobic and anaerobic bacteria and other organisms, and a biopsy, should be taken before treatment. Treatment is with high-dose corticosteroids, although for
1
408
4
Case 10.1 MCQ 10.10
2 5
Fig. 10.20 Fig. 10.22
0 Fig. 10.21
Palpable purpura is the hallmark of cutaneous vasculitis (Fig. 10.31) 2 but, depending on the type and degree of vessel wall damage, other lesions, not all of which are purpuric, may occur; these include livedo reticularis, weals, papules, pustules, infarcts and ulcers. Aetiological factors of cutaneous vasculitis include: • Bacteria, e.g. streptococci, gonococci, Mycobacterium tuberculosis (erythema induratum) and M. leprae (erythema nodosum leprosum) • Viruses, e.g. hepatitis B • Neoplasia, e.g. lymphoma • Drugs, e.g. sulphonamides,thiazides,captopril (see p. 418) • Food additives, e.g. tartrazine • Autoimmune diseases, e.g. lupus erythematosus, polyarteritis nodosa, scleroderma. The initial event is damage to the endothelium of the vessel. Both circulating and resident extravascular inflammatory cells are then activated to release mediators, some of which have destructive effects whereas others contribute to repair. The net result depends on many factors; these include the nature of the initial insult, the type and location of the vessels affected, and the adequacy of the collateral blood supply. One of the most common histological appearances is the accumulation of neutrophils, their breakdown products, and nuclear debris around damaged venules, an appearance termed leukocytoclastic vasculitis. Sometimes vasculitis occurs because there is inadequate clearance of a potential cause, such as circulating immune complexes, from the circulation, or there is a deficiency in repair mechanisms, e.g. removal of fibrin is
TABLE 10.16 Some multisystem vasculitides that may involve the skin Clinical patterns
Other organs commonly involved
Henoch-Schonlein purpura Polyarteritis nodosa
Joints, gut, kidney Kidneys, gut, cardiovascular system, nervous system, muscles and joints Eyes Kidneys and respiratory tract Gut and brain
Temporal arteritis Wegener's granulomatosis Malignant atrophic papulosis (Degos' disease) Lupus erythematosus
10
Widespread
are characterized by a leukocytoclastic vasculitis, and in many cases there is deposition of IgA around venules. There is no specific treatment, but some authorities use high-dose corticosteroids if there is severe renal disease. O
FIG. 10.31 Vasculitis: purpuric papules and nodules
too slow to maintain patency of affected vessels. A defect in the reticuloendothelial system may account for the occurrence of vasculitis in lymphomas, other malignancies and sarcoidosis. Sometimes the localization of vasculitic lesions can be explained by circumstances that slow blood flow, e.g. in the lower limbs and where skin is cooled by overlying fat. As well as attempting to find the cause, it is clinically important to know whether other organs are being affected, especially the brain, heart, kidneys, lungs and gut. There is no entirely satisfactory classification of multisystem vasculitis (see Ch. 22, p. 1181 for a further account of the vasculitides). Most multisystem vasculitides can involve the skin (Table 10.16).
Clinical features Henoch-Schonlein purpura Henoch-Schonlein purpura comprises arthralgia, abdominal pain and vasculitic rash, often with renal involvement (see p. 1076). Children are predominantly affected. A streptococcal sore throat and upper respiratory virus infections are the most common recognizable causes. The rash is mainly on the buttocks and extensor surfaces of the limbs. ©As well as purpura there are usually erythematous macules and papules, and urticarial weals. The lesions
Polyarteritis nodosa Polyarteritis nodosa, or PAN (see pp. 1076,1181), is a multisystem disorder in which there is necrotizing vasculitis of small and medium-sized arteries. 0 The distinctive feature in the skin is the occurrence of nodules along the course of subcutaneous arteries, best felt on the lower limb. In addition to nodules there are often purpuric papules, weals, or plaques of gangrene. Livedo reticularis, a net-like arrangement of bluish venules, is common. Malignant atrophic papulosis Malignant atrophic papulosis (Degos' disease) is a rare but very distinctive condition in which insignificant-looking red papules become slowly necrotic with a greyish-white central scale, and heal with porcelain-like white scars. Similar lesions occur internally, particularly in the intestine, and much of the high mortality is due to perforation or haemorrhage. The brain and kidney may also be affected. Rheumatoid disease Small purple or black spots around the nailfolds are very characteristic of rheumatoid disease (p. 1138), although they are also seen in other vasculitic diseases.
ERYTHRODERMA Erythroderma, or exfoliative dermatitis, is redness of all or nearly all the skin. There is usually some degree of scaling. Most cases of erythroderma evolve from more limited eczema or psoriasis. The principal causes include eczema; psoriasis; drugs, especially gold, allopurinol and sulphonamides (see p. 417); and lymphoma and leukaemia. The cause can usually be determined from the history and a skin biopsy, but in some cases no aetiology is found.
409
SUMMARY 3 Causes of erythroderma • • • • •
Eczema/dermatitis Psoriasis Drugs, e.g. gold, allopurinol Lymphoreticular neoplasia, e.g. mycosis fungoides Miscellaneous
The skin is red, hot to the touch and often oedematous; itching can be severe and scaling is variable. Patients feel uncomfortably cold and shiver. Erythroderma can have serious metabolic consequences, particularly in the elderly. The greatly increased blood flow through the skin, with loss of normal capacity for vasoconstriction, leads to hypothermia in a cold environment and can cause high-output cardiac failure. Blood flow to other organs can be greatly diminished. There is increased fluid loss from the skin surface, with compensatory thirst and oliguria. Anaemia is common, and in part is due to a state of malabsorption secondary to the skin disease (dermatogenic enteropathy). Serum albumin falls as a result of loss from shed skin scales and reduced synthesis. The skin is more prone to infection, and thrombophlebitis is common. Lymphadenopathy is usual. Systemic corticosteroids are needed for severe cases. Maintenance of fluid balance and body temperature is important and use of appropriate emollients can be helpful (p. 383). More specific treatment will depend on the underlying cause.
BLISTERING DISEASES Blisters are focal collections of free fluid in the skin. By convention small ones are called vesicles and larger ones bullae. They are the result of a defect or disturbance in the normal mechanisms that hold the components of the skin together. Extensive blistering produces a serious loss of normal skin function, and before effective treatment was available some of the bullous diseases had a high mortality. Many different pathological processes can result in the clinical appearance of a blister. The diagnosis may be obvious from the history, such as in an insect bite reaction, but often there is a differential diagnosis and investigations are necessary. Light microscopy of an early blister, preferably one less than 24 hours old (before re-epithelialization has begun), will provide useful evidence of the level of the split in the skin and sometimes details of the pathogenetic mechanism, e.g. spongiosis (Fig. 10.32). Electron
1
410
Fig. 10.23
2
MCQ 10.11
3
Fig. 10.24
A Sub-corneal: impetigo B Mid-epidermal: viral infections (e.g. herpes simplex, varicella zoster), eczema, friction blister C Supra-basal: pemphigus vulgaris D Basal lamina: pemphigoid, dermatitis herpetiformis E Sub-basal: porphyria F Variable: erythema multiforme, epidermolysis bullosa, blistering drug reactions G Variable: thermal burns (depends on severity of burn) FIG. 10.32 Examples of blistering diseases at different levels in the skin
microscopy allows a much more detailed analysis of blister formation and is particularly important in the accurate diagnosis of epidermolysis bullosa, a heterogeneous group of inherited blistering disorders. Immunological phenomena are central to some of the bullous diseases, particularly pemphigus, pemphigoid and dermatitis herpetiformis, and these are best demonstrated on a sample of unfixed skin from just beyond the edge of a blister (peribullous skin). Other tests that may be indicated include serum for antibodies (see below), bacteriological and viral studies on blister fluid, and, when appropriate, porphyrin estimations and patch testing.
Pemphigus vulgaris Pemphigus vulgaris (Fig. 10.33) is an uncommon, chronic intraepidermal blistering disease of unknown aetiology, characterized by the presence in affected skin and mucosa of an IgG antibody which localizes to the cell wall of keratinocytes (Fig. 10.34). A split forms within the epidermis. Aetiology and pathogenesis The disease is most common in middle age and in Ashkenazi Jews. The characteristic antibody is usually found in the bloodstream, and antibody titres correlate approximately with disease activity. Relapse is sometimes shown to be preceded by an increased titre. The pemphigus antibody probably brings about separation of keratinocytes by
10
FIG. 10.33 Erosions due to pemphigus vulgaris
activating proteinases. Occasionally pemphigus is associated with other immunological diseases, e.g. thymoma, myasthenia gravis and SLE. Clinical features Pemphigus often begins in the mouth and sometimes other mucous membranes, with non-healing erosions. Blisters appear sooner or later on previously normal-looking skin, and when the disease is active sideways pressure with a finger on unblistered skin can produce new blisters (Nikolsky sign). Increasing numbers of flaccid blisters appear and, when they burst, leave erosions. The resultant problems of infections and fluid loss are similar to the consequences of extensive burns. 1 2 Diagnosis The diagnosis is made from characteristic histology, showing a suprabasal split and free-floating keratinocytes (acantholysis). 3 Immunohistochemical techniques show that the keratinocytes are coated with IgG. In all but localized or treated disease the pemphigus antibody can be demonstrated in the serum. Treatment Treatment is with high doses of corticosteroids (about 80mg prednisolone daily), together with an immunosuppressant such as azathioprine, with subsequent gradual reduction of the steroid. Gold salts have also been used with success, but toxicity is a problem. Even with treatment pemphigus remains a serious disorder, up to 25% of patients dying from the disease or the consequences of treatment. Most patients need maintenance therapy for lengthy periods, although in some a true remission occurs.
FIG. 10.34 The lesions of pemphigus vulgaris A, pemphigoid B and dermatitis herpetiformis C (IF = immunofluorescence).
Bullous pemphigoid Bullous pemphigoid (Fig. 10.28) is a fairly common subepidermal blistering disease characterized by an antibody that localizes to the lamina lucida of the basement membrane (Fig. 10.35). Pathology In pemphigoid the complement system is activated, and C3a and C5a attract and activate eosinophils. Eosinophil products and mast cell mediators contribute to the split that occurs in the basement membrane and the clinically evident inflammatory reaction. Clinical features Pemphigoid is mainly a disease of the elderly. It is usually preceded by an erythematous itchy rash, which can be mistaken for urticaria or eczema. It may be localized for some weeks before becoming generalized. The blisters are tense, clear or bloodstained, and often remain intact for several days. Unlike pemphigus, pemphigoid does not usually involve the mucous membranes. When blisters do
411
RECENT ADVANCES IN UNDERSTANDING BLISTERS AT THE MOLECULAR LEVEL The structural integrity of cells is greatly dependent on the three-dimensional network of intermediate filaments within them, and defects in these filaments can result in mechanical weakness. The keratins are a family of intermediate filament proteins maximally expressed in the keratinocytes, and contribute greatly to the strength of the skin. Some forms of epidermolysis bullosa, a group of mostly inherited blistering diseases, have now been attributed to mutations in keratin genes, and the split in the epidermis occurs at the site where the particular keratin is maximally produced. The molecular genetic basis for the most severe types of epidermolysis bullosa, EB letalis and recessive dystrophic EB, has also been discovered recently. EBL is usually due to a defect in the basement membrane protein laminin 5, and RDEB is due to mutations in the gene coding for collagen type 7. In some families it is now possible to make a prenatal diagnosis from a firsttrimester chorionic villus sample. The molecular basis for the immunobullous diseases is now better understood. In pemphigus vulgaris the antigen is desmoglein 3, a transmembrane component of the specialized keratinocyte attachment zones, the desmosomes. In pemphigus foliaceus the antigen is desmoglein 1. In bullous pemphigoid the target antigen is either a 230 or 180 kDa protein in the basement membrane zone.
FURTHER READING Huilgol S C, Bhogal B S, Black M M 1995 Immunofluorescence of the immunobullous disorders. Eur J Dermatol 5:186-195. Mellerio J E 1999 Molecular pathology of the cutaneous basement membrane zone. Clin Exp Dermatol 24:25-32.
break, the skin usually heals and the prognosis is better than that of pemphigus. There is a localized variant of pemphigoid, involving the mucous membranes, in which scarring occurs. Treatment Treatment of pemphigoid is with prednisolone and azathioprine to facilitate steroid withdrawal.
Dermatitis herpetiformis Dermatitis herpetiformis is an uncommon, chronic, intensely itchy disorder in which subepidermal blistering usually occurs.
1 412
MCQ 10.12
2
Fig. 10.25
FIG. 10.35 The blisters of bullous pemphigoid are tense, clear or bloodstained, and often remain intact for several days
Aetiology and pathogenesis There is a close association with HLA-B8 and DRW3, gluten-sensitive enteropathy, and deposition of IgA in the dermal papillae throughout the skin. The enteropathy may not be symptomatic, but it is likely that absorbed products derived from gluten are important in the pathogenesis of the skin lesions. Abnormal immunity in patients with dermatitis herpetiformis is suggested by an increased incidence of organ-specific autoimmune disease, and a few patients (as with coeliac disease) develop small bowel lymphoma. The skin lesions are a result of activation of dense clusters of neutrophils in the dermal papillae, producing damage and then fluid accumulation. Clinical features Dermatitis herpetiformis usually begins in young adults, but can begin at any age and can persist indefinitely. The initial lesions are very itchy grouped weals or papules, on which arise small blisters (Fig. 10.36). Extensor surfaces are the characteristic sites, especially the elbows, knees, shoulders, buttocks and scalp. Oral lesions are sometimes seen. 1 Diagnosis The diagnosis is best made from finding typical histology in an early lesion and IgA deposition in unaffected skin. (In the lesions the IgA can disappear as a result of the inflammatory infiltrate.) A jejunal biopsy usually shows
10
FIG. 10.37 Pityriasis rosea Pink plaques with characteristic scaling centrally.
suggests an infective cause, and a viral aetiology is likely but unproven.
FIG. 10.36 Dermatitis herpetiformis: itchy papules and vesicles
subtotal villous atrophy. Potassium iodide, both systemically and topically, provokes dermatitis herpetiformis and has occasionally been used as a diagnostic test. Treatment Dapsone has a dramatic beneficial effect in this condition, probably by modulating the neutrophil myeloperoxidase enzyme system, and/or the alternative pathway of complement activation. Haemolytic anaemia can occur, in which case sulphamethoxypyridazine is an alternative. A glutenfree diet is helpful in most patients and may reduce the likelihood of intestinal lymphoma.
Clinical features The first lesion to appear, known as the herald patch, is red, circumscribed, slightly scaly and larger than those that will follow about 10 days later. The generalized eruption is maximal on the trunk and proximal aspects of the limbs, and usually includes distinctive ovoid patches (Fig. 10.37) whose long axes are parallel to the major skin creases. 2 This produces a pattern somewhat like a Christmas tree on the back. The pink borders of these lesions are separated from the slightly brown centres by collarettes of scale. There is usually an admixture of smaller pink papules. Itching may occur, and occasionally there is malaise and lymphadenopathy. The rash usually lasts 4-6 weeks. Recurrences are very unusual. Differential diagnosis There are no diagnostic tests. Conditions that may resemble pityriasis rosea include drug eruption, seborrhoeic dermatitis, guttate psoriasis, tinea corporis and secondary syphilis. Treatment A mild topical steroid may be helpful.
FURTHER READING ON BULLOUS DISEASES
Lichen planus
Nausari H C, Anhalt G J 1999 Pemphigus and bullous pemphigoid. Lancet 354:667-671.
Lichen planus (Fig. 10.38) is a fairly common disease that may affect the skin, hair, nails and mucous membranes. The histology is distinctive and shows damage to the basal epidermal cells, with a dense band of lymphocytic infiltrate immediately beneath. There are close similarities to the skin changes seen in graft-versus-host disease and some drug reactions (p. 418).
MISCELLANEOUS DISORDERS OF UNKNOWN CAUSE Pityriasis rosea Pityriasis rosea, a common self-limiting disorder, occurs mainly in children and young adults. Clustering of cases
Clinical features The skin lesions are usually very itchy, and typically form purplish, polygonal, shiny, flat-topped papules. They are usually found on the flexor aspect of the wrists, the lower
413
FIG. 10.38 The lesions of lichen planus typically form purplish, polygonal, shiny, flat-topped papules
back and the shins. Individual lesions often show distinctive fine white lacy patterning (Wickham's striae). Larger, more warty plaques are sometimes found on the lower legs. Induction of new lesions by injury to the skin (Koebner's phenomenon) is often seen. In the mouth lichen planus is seen mainly as a network of white lines on the buccal mucosa and white patches on the tongue, 1 but occasionally can cause chronic ulceration. The scalp may be involved, producing patches of inflammation from which hair fall is usually permanent. The nails can also be affected, usually with longitudinal areas of thinning; in some cases nails also can be permanently lost. Lichen planus often lasts a year or more, and to some extent it is steroid responsive. Postinflammatory hyperpigmentation is common. Treatment Topical steroids may help the pruritus. For widespread symptomatic lichen planus a course of prednisolone, 2030 mg daily for 4-6 weeks, then tapering, can shorten the course of the disease.
Granuloma annulare There are two forms of granuloma annulare, localized (Fig. 10.39) and generalized; as a rule both are asymptomatic. Histologically there is palisading granuloma formation around focal areas of dermal necrosis. Localized granuloma annulare presents as rings of smooth firm papules. The backs of the hands and the tops of the feet are common sites. The commonest misdiagnoses are warts and fungal infection, in which epidermal changes are prominent, in contrast to the smooth surface of granuloma annulare.
414
1
Fig. 10.26
2
Fig. 10.28
2
Fig. 10.27
3
MCQ 10.13
FIG. 10.39 Granuloma annulare, localized form Note the ring-shaped arrangement of dermal papules.
In generalized granuloma annulare the papules are much more widespread and not necessarily in ring-shaped configurations. 2 This is often associated with diabetes mellitus. Diagnosis is confirmed by biopsy. Treatment A potent corticosteroid, topically or by injection, can be used for symptomatic lesions, but granuloma annulare is self-limiting and most cases need no treatment.
Necrobiosis lipoidica This condition (Fig. 10.40) occurs in about 3 per 1000 diabetics, and more than half of patients with necrobiosis lipoidica are overtly diabetic (see Ch. 19). The pathology is similar to that of granuloma annulare but with more pronounced dermal necrosis. The most common site is the shin. The lesion begins as a purplish plaque which gradually enlarges and becomes atrophic, with yellowish areas centrally. Ulceration is quite common. The condition is chronic, and when there is associated diabetes careful control of blood glucose has no effect on the progress of the skin lesions. Treatment The active advancing edge may be responsive to topical or intralesional corticosteroid. Older lesions can sometimes be disguised by cosmetic camouflage.
Sarcoidosis The skin can be invaded in sarcoidosis (Fig. 10.41). Sarcoidosis is discussed on page 682.
10
FIG. 10.40 Necrobiosis lipoidica Subcutaneous vein visible due to central atrophy, bordered by dermal inflammation.
Lichen sclerosus Lichen sclerosus is a distinctive inflammatory condition in which lesions are usually white. The commonest site is the anogenital skin. The cause is unknown. Clinical features Most patients are female, and present either in middle or later life or, less commonly, before puberty. Whereas patients in the older age group tend to have a more protracted course, in prepubertal girls the disease may resolve spontaneously at or around puberty. Usually the vulva is affected, often together with the perianal skin, giving a figure-of-eight appearance. The initial lesion is a white papule; lesions tend to coalesce, and involved skin often becomes wrinkled and atrophic. In the vulva, purpura is common and resorption of the labia may occur. Pruritus is very common. Scratching will often produce excoriations and erythema, which can mask the characteristic whiteness. Dysuria, dyspareunia and, in children, constipation are complications. In the male, involvement of the foreskin and glans can lead to balanitis, phimosis and meatal stricture. Squamous carcinoma is a risk in both sexes. Extragenital lesions occur in a minority. There is an increased likelihood of organ-specific autoimmune diseases. Differential diagnosis Vitiligo can involve the genital skin but does not cause pruritus, and apart from the pallor the skin is otherwise normal. When the pallor is not evident, eczematous conditions, intraepidermal neoplasia and lichen planus may need to be excluded. A biopsy is usually diagnostic.
FIG. 10.41 Sarcoidosis Note the shiny brownish-red indurated swelling of the ala and the two hyperpigmented dermal nodules on the left cheek.
Treatment A superpotent topical corticosteroid twice daily for several weeks initially, and then for shorter periods as necessary, can reverse clinical and histological manifestations in the genital area. Circumcision is often indicated for phimosis. Long-term follow-up is worthwhile in view of the risk of carcinoma. ©
SKIN CHANGES (N DIABETES There are a number of cutaneous problems that occur in diabetics, one of the most common being recurrent infections. Mucosal candidal infections may occur, 4 as may recurrent staphylococcal boils (p. 387). Indeed, in developed societies, the carbuncle (p. 387) is only seen with any frequency in diabetics. Injection sites may become infected, and occasionally deep abscesses may form. Patients with sensory neuropathy may fail to notice repetitive trauma (usually from footwear). This predisposes to ulceration, commonly on the sole (p. 1016). Necrobiosis lipoidica (Fig. 10.33) and granuloma annulare (Fig. 10.32) have histological features in common, and both occur in diabetics (see above). The term 'diabetic dermopathy' refers to small, duskybrown, scar-like lesions that often appear on the shins in diabetics. The patients usually have microangiopathy.
415
TABLE 10.17 Pathogenesis of drug eruptions - some examples
Mechanism Direct effects Immunological IgE-mediated Immune complex Effector pathway stimulation Side-effect Overdosage Cumulative toxicity FIG. 10.42 Xanthelasma Creamy yellow dermal lipid deposits in a diabetic with hyperlipidaemia.
Indirect effects Drug interaction Metabolic effects Ecological disturbance
'Diabetic sclerosis' or 'cheiroarthropathy' occurs in at least 30% of juvenile-onset insulin-dependent diabetics. The fingers and toes become stiffened and sclerodermatous. The patient is unable to straighten the fingers completely, and cannot place them flat on a table. A rarer condition is scleroedema, in which the skin of the neck and upper back suddenly becomes stiff and thickened. These changes gradually spread on to the face, trunk and upper arms. Rarely, diabetics develop distinctive non-inflammatory blisters on the extremities. Hyperlipidaemia is a common complication of diabetes, and lipid deposits in the skin may occur in the form of eruptive xanthomata, most commonly on the buttocks and extensor surfaces. Palpebral xanthelasmata may also be seen in diabetics (Fig. 10.42). Injection-site lipoatrophy and lipohypertrophy are discussed on page 992. Rarely, glucose intolerance and diabetes are part of a constellation of changes, including generalized fat reduction (lipodystrophy) and acanthosis nigricans. Such patients often have marked insulin resistance. There is an association between vitiligo and maturity-onset as well as insulin-dependent diabetes.
DRUG ERUPTIONS
416
Drug eruptions are a frequent occurrence in hospital practice and can produce skin changes in many ways (Table 10.17). Some of these, such as the predisposition to candidal infection by a broad-spectrum antibiotic, are not direct effects of drugs on the skin, but are none the less a consequence of drug exposure. Often the exact mechanism of a drug eruption is unknown. Some drugs - such as antibiotics, thiazides and sulphonamides, gold, allopurinol, phenylbutazone and other non-steroidal anti-inflammatories - are relatively
Exacerbation of existing disease
Drug
Clinical pattern
Penicillin Sulphonamides Acetyl salicylic acid
Urticaria Vasculitis Urticaria
Cytotoxic drugs Anticoagulants Corticosteroids
Alopecia Purpura Striae
Aspirin-displacing warfarin Isoniazid Broad-spectrum antibiotics Hydralazine
Purpura
Lithium
Pellagra Candidiasis Lupus erythematosus Psoriasis
SUMMARY 4 Skin changes in diabetes mellitus • Cutaneous infections
• • • • • • • • •
Neuropathic ulcers Necrobiosis lipoidica (diabeticorum) Disseminated granuloma annulare Diabetic 'dermopathy' Diabetic sclerosis (cheiroarthropathy) Scleroedema adultorum (of Buschke) Bullae (bullosis diabeticorum) Xanthomata and xanthelasmata Effects of insulin injections
- candidiasis - staphylococcal infections - injection site infection
lipoatrophy lipohypertrophy (Insulin tumours') infections and abscesses
• Generalized lipodystrophy (lipoatrophy not due to insulin injection)* • Acanthosis nigricans* • Vitiligo * When these cutaneous signs accompany diabetes, there is usually gross insulin resistance
common causes of rashes, and others very rare, but in all patients who develop a rash the drug history is of great importance. Not only prescribed drugs, but also medicines and tablets bought over the counter, must be considered.
TYPES OF DRUG ERUPTION Urticaria The mechanisms whereby a drug can cause urticaria include IgE-mediated immediate hypersensitivity, immune complex-mediated generation of activated complement components (serum sickness), a direct action on mast cells causing them to release histamine, and modulation of arachidonic acid metabolism. The drugs commonly implicated in urticaria are: • Penicillin and related antibiotics • X-ray contrast media • Enzymes • Blood products
• Opiates • Non-steroidal antiinflammatory drugs • Pollen vaccines • Iodides.
Angioedema and anaphylaxis may accompany urticaria, particularly when the drug has been injected, and can be life-threatening. Urticaria usually begins within minutes or hours of the drug being given, but when it is immune complex-related it occurs several days after the challenge and is often associated with fever, lymphadenopathy, joint symptoms and haematuria as a result of renal damage.
Ampicillin, amoxicillin and derivatives, e.g. talampicillin, are common causes, especially when the patient has infectious mononucleosis or lymphatic leukaemia, or is also taking allopurinol, and can begin up to a few days after the antibiotic has been stopped. The common causes of morbilliform (exanthematic) drug eruptions are: • • • • • •
Allopurinol Antituberculous drugs Captopril Carbamazepine Gold salts H2 antihistamines
• • • • • •
10
Penicillamine Penicillins Phenothiazines Phenylbutazone Sulphonamides Thiazides.
Erythroderma When caused by a drug, erythroderma, or exfoliative dermatitis (p. 409), tends to begin several weeks after the drug has been started. Important causes of drug-induced erythroderma are: • • • • • •
Allopurinol Carbamazepine Phenytoin Isoniazid Lithium Gold salts
• • • • • •
Chloroquine Barbiturates p-aminosalicylic acid Captopril Sulphonamides Methyldopa.
Morbilliform eruption A widespread, symmetrical, blotchy, maculopapular erythematous rash (Fig. 10.43) is probably the commonest drug eruption. There is often a mild fever, but serious consequences are uncommon. The mechanism is usually obscure but does involve delayed hypersensitivity in some cases, especially when the onset is within a few days of the drug being started. Morbilliform eruptions usually begin within a week of the onset of the drug, and may progress to erythroderma if the drug is continued.
Erythema multiforme Erythema multiforme (p. 407) is a reaction distinguished by target lesions. Most cases are not due to drugs. The commonest drugs to cause erythema multiforme are: • • • •
Sulphonamides Phenytoin Phenylbutazone Barbiturates
• • • •
Penicillins Carbamazepine Rifampicin Gold salts.
Toxic epidermal necrolysis
FIG. 10.43 Morbilliform drug eruption Maculopapular erythema brought on by co-trimoxazole.
Toxic epidermal necrolysis is a rare drug reaction which has a high mortality. There is often a brief prodrome of malaise and fever, followed by widespread, tender erythematous areas which then blister. Large sheets of epidermis readily rub off with light pressure, to leave painful denuded dermis. Mucous membranes as well as skin may be involved. Fluid imbalance, septicaemia and pneumonia are the most common problems. Differentiation from staphylococcal scalded skin syndrome (p. 385) can be made histologically on a blister roof because in toxic epidermal necrolysis the roof consists of the whole epidermis. Butazones, Sulphonamides, allopurinol, gold salts and phenytoin are examples of drugs that can cause the syndrome, which can also be due to infections, graft-versus-host disease and lymphoma. Management is similar to that of widespread burns, with treatment of fluid and protein loss and of infection.
417
Allopurinol Thiazides Phenytoin Thiouracil Non-steroidal antiinflammatory drugs
Photosensitivity The most common photosensitivity drug reaction resembles sunburn and is usually phototoxic, i.e. does not involve immunological mechanisms. Occasionally drugs produce photoallergic reactions which may look like eczema on light-exposed skin. Drugs which can induce phototoxic and photo-allergic reactions include: Phenothiazines Thiazides Sulphonamides Tetracyclines Sulphonylureas
• • • • •
Nalidixic acid (bullous) Amiodarone Azapropazone Protriptyline Psoralens.
Drugs can also induce photosensitive diseases, e.g. procainamide can induce lupus erythematosus, and isoniazid pellagra.
Fixed drug eruption The characteristic feature of a fixed drug eruption is that inflammation occurs in exactly the same place or few places each time the drug is taken. The reaction is usually a round red patch, which may blister (Fig. 10.44), and after the inflammation has subsided there is often prolonged hyperpigmentation. The causes change with variations in drug use, but a recent survey in the UK identified several common offenders - paracetamol, non-steroidal anti-inflammatory drugs, fluconazole, terbinafine, sulfasalazine, tetracylines, trimethoprin, diltiazem and proton pump inhibitors.
• • • •
Sulphonamides Hydralazine Quinidine Captopril.
Erythema nodosum Drugs are rarely responsible for erythema nodosum, and other causes should be sought (p. 407). Oral contraceptives and Sulphonamides are the drugs most likely to be involved.
Pigmentation changes induced by drugs Colour change (Table 10.18) can be produced by deposition of the drug in the skin and mucous membranes, stimulation of melanin production and alteration of the distribution of pigment so as to make it more apparent, as in postinflammatory hyperpigmentation (p. 427). The hyperpigmentation after fixed drug eruption may be the presenting feature. In some situations the pigmentation is only evident in light-exposed skin. In many examples of drug-related pigment change the mechanism is unknown.
Lichenoid drug eruption
Vdsculitis
The rash in lichenoid drug eruption is similar to that of lichen planus (p. 413). It usually begins weeks to months after the drug is started. As in idiopathic lichen planus, hyperpigmentation is common. Important causes of lichenoid drug eruptions are:
Drug-induced vasculitis (p. 408), usually in the form of palpable purpura, and often with urticarial and blistering lesions, can be accompanied by similar lesions in other organs and may be a serious illness. The commonest drugs to cause allergic vasculitis are:
• • • • •
Gold salts Antimalarials Thiazides Phenothiazines Methyldopa
• • • •
Furosemide (frusemide) p-Blockers Penicillamine Chlorpropamide.
Drug-induced lupus erythematosus
418
FIG. 10.44 Fixed drug eruption: dusky erythema with central blister
Drug-induced lupus erythematosus has some differences from the naturally occurring condition (p. 1172). It is likely that affected individuals have a genetic predisposition. This has been best documented in association with hydralazine and procainamide. With hydralazine the disorder is broadly dose-related, being seen in 5% of those on 100 mg daily, in 10% of those on 200 mg daily, but not in patients on 50 mg daily. Other common causes include penicillamine, phenytoin, methyldopa, B-blockers, sulfasalazine and oral contraceptives. In most cases druginduced lupus erythematosus occurs after the drug has been taken for at least a few months. On discontinuation, the disease resolves in most cases, but can persist for years. The condition is relatively less common in black people and more common in the elderly; renal and central nervous system disease are less likely to occur than in idiopathic
TABLE 10.18 Pigmentation caused by drugs
TABLE 10.19 Eczertia induced by topical drugs
Patterns
Eliciting drug
Source of topical exposure
Antibiotics, e.g. penicillin, streptomycin Antihistamines Aminophylline
Contents of medical and veterinary ampoules
Drug
Brown Similar to Addison's disease Similar to chloasma Light-exposed areas
Generalized Generalized, with patchy pigmentation Blue-grey Light-exposed areas
Generalized, maximal on light-exposed areas
Shins, nails and palate (and sometimes light-exposed areas) Yellow Generalized
Red Generalized
ACTH Phenytoin Oral contraceptives Phenothiazines Psoralens Cytotoxics Cytotoxics e.g. busulfan Pyrimethamine Arsenic
Minocycline Amiodarone Phenothiazines Gold Silver Bismuth Antimalarials
Mepacrine
Clofazimine Methysergide
lupus erythematosus. Antihistone antibodies are characteristic, and antinative DNA antibodies are not found. Complement levels remain normal.
Purpura When caused by a drug, purpura is usually a result of thrombocytopenia, vascular damage or both. Mechanisms include both toxic and allergic effects.
Pruritus Itching without a rash is considered on page 433. Drugs can cause generalized pruritus and the most common causes are: • Opiates • CNS stimulants • Antidepressants
• Oral contraceptives • Hepatotoxic drugs • Chloroquine.
For many drugs the mechanism is unknown, but some produce intrahepatic cholestasis.
Acne and acneform eruption In true acne there are comedones, papules and pustules in
10
In antipruritic creams, e.g. mepyramine Cross-reaction with ethylenediamine in Tri-adcortyl cream
a characteristic distribution (p. 431). Drugs exerting an androgenic stimulus, such as testosterone and some progestogens, can exacerbate or induce acne. An acne-like eruption, in which there are follicular lesions but in which the morphology or the distribution differs from true acne, is seen with a number of drugs, including corticosteroids and ACTH, halogens, antiepileptic drugs, isoniazid and lithium salts.
Alopecia Partial or complete hair loss is very common and appears early with cytotoxic drugs, but can occur, rarely and late, with other drugs, e.g.: • Cytotoxic agents (especially cyclophosphamide and anthracyclines) • Retinoids
• • • • •
Anticoagulants Oral contraceptives Antithyroid drugs Phenytoin Valproate.
Hypertrichosis Corticosteroids and androgenic steroids can produce hirsutism, but some drugs can induce increased hair growth on areas not dependent on a sex hormone stimulus. Minoxidil, ciclosporin, diazoxide, phenytoin and penicillamine are the main causes.
Eczema If sensitized via the skin to a 'drug' and then 'challenged' by an internal route, the patient can develop an often widespread eczematous eruption. Examples are given in Table 10.19.
Vesicular and bullous drug eruptions Blistering can occur in several different types of drug eruption already described, e.g. fixed eruption, erythema multiforme, photosensitivity and vasculitis. Bullae are common at sites subjected to prolonged pressure in drug-induced coma. Porphyria (p. 1026) can be precipitated by drugs, as occasionally can pemphigus (e.g. rifampicin) and acquired epidermolysis bullosa (e.g. furosemide [frusemide]).
419
INVESTIGATION AND TREATMENT OF DRUG REACTION The evaluation of a possible drug reaction should include the following: • A careful assessment of the risk to the patient, from the rash itself and from the involvement of other organs, e.g. kidneys and brain in a vasculitis; an assessment of the airway and maintenance of adequate circulation in urticaria/anaphylaxis. • A full drug history, including all current and recently completed treatments (tablets, mixtures, injections, suppositories etc.) and their timing in relation to the onset of the rash. Some drugs can cause a rash several days after they were last given, e.g. ampicillin, gold and depot preparations. • Past drug history and associated rashes. • Other possible explanations for the rash, e.g. a virus infection. • Consideration of which drugs can be stopped. Nonessential drugs should be stopped and essential drugs changed to structurally different ones if possible. • Laboratory investigations. Except for the investigation of drug-induced blood dyscrasias, these are disappointing. Blood eosinophilia, if present, is supportive of drug eruption. • A skin biopsy may help in some cases. • Treatment. The most immediately serious drug reaction is anaphylaxis. Emergency treatment is with 1:1000 adrenaline, 1 mL i.m., or slowly i.v. if the patient is moribund. Parenteral antihistamine and hydrocortisone are also given, and if necessary the patient is intubated and managed on ICU.
and vasculitis will require treatment with systemic corticosteroids. FURTHER READING ON DRUG ERUPTIONS Breathnach S M, Hintner H 1992 Adverse drug reactions and the skin. Oxford: Blackwell Scientific.
INTERNAL MALIGNANCY AND THE SKIN Skin abnormalities may be the first indicator of a systemic malignancy (Table 10.20). The cause of many other skin disorders associated with malignancy is unknown. Some are: • Generalized pruritus without a primary rash (p. 433). • Dermatomyositis, adult onset 1(p- 1180). • Acanthosis nigricans (Fig. 10.45). The skin becomes hyperpigmented and warty but feels soft. Body folds, e.g. axillae, are affected. There are other causes, such as obesity, some drugs and some inherited syndromes, but onset in a lean adult is highly likely to be associated with an adenocarcinoma or lymphoma. • Acquired hypertrichosis lanuginosa. This is a rare condition but one that has a strong association with malignancy, especially Hodgkin's disease. The patient
Depending on severity, some patients with erythroderma, bullous erythema multiforme, toxic epidermal necrolysis TABLE 10.20 Skin manifestations of malignancy Direct involvement e.g. Direct spread from breast carcinoma; plaques and nodules from lymphoma Genetic predisposition e.g. Multiple cysts and benign skin tumours occurring with colonic carcinoma with autosomal dominant inheritance (Gardner's syndrome) Carcinogen (also causing skin disease) e.g. Vinyl chloride skin eruption and angiosarcoma of the liver following exposure to vinyl chloride monomer (used in plastic manufacture) Metabolic products of tumour e.g. Flushing due to malignant carcinoid; migratory necrolytic erythema with glucagonoma - partly due to essential amino acid deficiencies induced by metabolic abnormality
420
1
Fig. 10.29
2
Fig. 10.30
3
Fig. 10.31
4
Figs 10.32,10.33
FIG. 10.45 Hyperpigmentation and velvety thickening due to acanthosis nigricans
•
• •
•
develops blond downy hair over the whole face and then elsewhere. Erythema gyratum repens. Here the skin develops irregular wavy bands of erythema, the overall appearance resembling wood grain. Nearly all cases have an associated malignancy. Acquired ichthyosis. The unexplained occurrence of dry, scaly but non-inflamed skin is often associated with lymphoma (p. 405). Pachydermoperiostosis with finger clubbing. The skin becomes thickened, with extra folds; the hands, elbows, knees and tongue enlarge and there may be painful periosteal new bone formation (see hypertrophic pulmonary osteoarthropathy, p. 619). These changes are associated with bronchial carcinoma. Pancreatic panniculitis. Tender red nodules of distinctive histology, owing to the effect on subcutaneous fat of circulating lipases from the pancreas, indicate either malignancy or inflammation in that organ. There is often arthritis and eosinophilia.
NAEVI AND TUMOURS OF THE SKIN Most primary tumours are either clearly benign or malignant, but occasionally some benign lesions evolve into malignant patterns of behaviour and are termed premalignant. Some of the known causes are listed in Table 10.22 (p. 424). A naevus is a circumscribed developmental defect, and the term has a similar meaning to hamartoma. Naevi are often, but not necessarily, evident at birth. There may be more than one cell type involved in the process. Each of the cell types in the skin can proliferate to produce a tumour, and the exact diagnosis usually rests with the pathologist. Many benign tumours and naevi are of little more than cosmetic importance, but in some instances they are pointers towards a genetic syndrome or multisystem disorder. Malignant skin tumours can be fatal, and often come to attention during a routine medical examination. Malignant metastases in the skin can occasionally be the presenting feature of a cancer elsewhere, and the histology can provide a valuable indication of the organ of origin.
The blue naevus is a slate-coloured lesion composed of a localized proliferation of melanocytes in the dermis which never reached the epidermis during development. Malignant melanoma (p. 424) may arise from a seemingly benign melanocytic naevus, but this is rare except from giant congenital pigmented naevi.
10
Vascular naevi There are several types of vascular naevi, some of which resolve in infancy or childhood (e.g. the salmon patch and strawberry naevus). The port wine stain is an area of permanent vascular dilatation, often on the face, where it may produce a disfiguring purplish discoloration. When the area affected is in the distribution of the ophthalmic division of the trigeminal nerve, there may be an associated vascular anomaly in the brain or meninges which can cause epilepsy, hemiplegia or retardation (Sturge-Weber syndrome), and various ocular abnormalities, especially glaucoma, can occur. The skin change can be successfully treated with the dye laser. Epithelial naevi Developmental malformations involving epidermal keratinocytes affect at least 1 in 1000 live births. They are usually circumscribed verrucous plaques which are often linear on the limbs, but may assume quite bizarre, whorled configurations, especially on the trunk. Occasionally lesions may be widespread. Such multiple lesions may be associated with developmental defects in the CNS and skeleton.
Naevi and multisystem disease
Naevi
Tuberous sclerosis Tuberous sclerosis is an autosomal dominantly inherited disorder in which mental deficiency is associated with an abnormality of many other organs. The first skin lesions to appear, often in early infancy, are the 'ash leaf macules. These well circumscribed, often irregularly shaped pale patches are best seen with Wood's light. From later childhood onwards, one or more of the following may appear: red angiofibromatous papules on the face (misnamed adenoma sebaceum), 2 thickened plaques on the trunk (shagreen patches) and periungual fibromas 3 (smooth nodules beside the nails). The skin lesions can be important in recognizing carriers of the gene.
Pigmented naevi Pigmented (melanocytic) naevi, or common moles, are occasionally evident at birth, but more commonly appear in childhood or adolescence. The naevus is initially brown, with clusters of proliferating melanocytes at the base of the epidermis. Melanocytic naevi that develop after birth are usually symmetrical in shape and colour and rarely grow to more than 1cm in diameter. In time the cells migrate into the dermis, and the lesion often becomes a fleshcoloured nodule.
Von Recklinghausen's disease (neurofibromatosis) The many features of von Recklinghausen's disease, or neurofibromatosis (Fig. 10.46), an autosomal dominantly inherited condition, include acoustic neuroma, glioma, spinal deformities and phaeochromocytoma. The skin shows multiple pale brown patches (cafe au lait macules}, especially in the axillae (a pathognomonic sign), and soft nodules (neurofibromas) 4 composed of nerve sheath cells.
421
FIG. 10.46 Neurofibromatosis is associated with localized areas of hyperpigmentation
Benign tumours and cysts The growth of these is usually slow, does not destroy normal tissues and is eventually self-limiting. The lesion produced is generally symmetrical in shape. Seborrhoeic warts are one of the commonest skin abnormalities, occurring with increasing frequency with advancing years. The lesions vary in colour from pale brown to very dark brown/black, and usually look as though they have been 'stuck on'. The surface is irregular and rather greasy to the touch. The simplest treatment is freezing with liquid nitrogen, although this is only necessary if the lesion is causing symptoms. Dermatofibromas (histiocytomas) normally present as firm papules, 0.5-1 cm in diameter (although occasionally they are significantly larger). The lesion moves easily within the skin and is never fixed to deeper tissues. If the diagnosis is certain dermatofibromas can safely be left, but excision is the treatment of choice if this is deemed necessary. Pyogenic granulomas grow rapidly, often following tauma and often on a digit. They are more common in children and young adults, but may be seen at any age.
1
422
Fig. 10.34
The surface is red, friable, and bleeds easily, consisting as it does of vascular proliferative tissue. In most instances a thin epithelium eventually extends to cover the raw surface, and lesions may involute spontaneously. It is more practical, however, to remove the whole lesion by curettage or by excision; the tissue should always be sent for histopathology. Smaller tumours may respond to cryotherapy. Skin tags develop in clusters around the neck, axillae and groins, more commonly in the obese (although there appears to be an inherited tendency in some families). Occasionally there may be a background of mild acanthosis nigricans (see p. 420). Lesions catch on clothing and jewellery and can be removed easily with a pair of scissors or by diathermy. Lipomas may be solitary or multiple, a tendency to numerous lipomas being inherited as an autosomal dominant trait in some families. They feel soft, subcutaneous and, as they enlarge, lobulated. Some lesions are mildly painful when knocked. There is no satisfactory therapy other than formal excision. Kemtoacanthomas are rapidly growing and, by definition, self-limiting tumours with a histopathology that may be difficult to distinguish from a well-differentiated squamous cell carcinoma. They arise most commonly on the head and neck, the hand and forearm and on sun-damaged skin in general. The normal course of events is for the lesion to grow rapidly over 4-6 weeks, reaching a maximum of about 2-3 cm in diameter. Growth then ceases, and a period of quiescence is followed by equally rapid shrinkage and disappearance. There is often a small pit left in the skin. The lesions are highly characteristic in shape, annular with a central keratin plug, 1 but these feaures are shared by some invasive squamous cell carcinomas (see below) and complete removal is recommended unless the patient is very old and frail. Epithelioid cysts and pilar cysts are both frequently called 'sebaceous cysts' by the terminologically inexact. Both consist of spheres of epithelium producing keratinous material internally. This results in a smooth, round swelling which moves easily over deeper structures in most instances. Occasionally inflammation and subsequent scarring leads to a tethered feel. Epithelioid cysts may occur anywhere, but are most common on the face, neck and trunk. They frequently follow in the wake of severe acne and there may be a small punctum on the surface. Pilar cysts are essentially a malformation of hair root sheath and are normally found on the scalp. There is often a positive family history. Another common keratinizing cyst is the milium, which are usually multiple (milia). They may arise in scars or other areas of trauma, but are most commonly found on the face, either in clusters around the eyes or more widely scattered, when they may be associated with signs of chronic sun damage. Keloid. A keloid is an excessive growth of connective tissue after an injury (including surgery or infection). Unlike a hypertrophic scar, it tends to grow beyond the limits of the initial trauma and can occur spontaneously.
Keloids are very long lasting. They are firm, smooth, rounded, protuberant swellings, often itchy and sensitive. In whites they tend to be purplish, and in dark-skinned patients they are often hyperpigmented. They are common in black races and at certain sites, e.g. the sternum, shoulders, upper back and the beard area. Treatments include injections of corticosteroid, compression and applications of silicone sheeting.
sites. In some cases there is an association with internal malignancy. Bowen's disease presents as a slow-growing, well-defined, red scaly or crusted patch. It is often solitary, although it can be multiple. The major differential diagnosis is psoriasis. Small lesions can be treated as for actinic keratosis, but for larger lesions excision is preferable.
10
Malignant and premalignant tumours Precursors to squamous carcinoma Actinic keratosis Actinic (solar) keratosis is a lesion that arises on skin chronically damaged by the harmful effects of UV radiation, in particular UVB (p. 426). The face (Fig. 10.47), bald scalp, backs of hands and forearms are common sites. Actinic keratoses are often multiple; they are more likely in the blue-eyed, fair or red-haired, and rare in darkskinned people. The individual lesion usually presents as a papule or plaque of hard, often brownish keratin. Transformation to squamous carcinoma is uncommon. Actinic keratoses can be treated by a number of modalities, e.g. cryotherapy, curettage and 5-fluorouracil cream. Bowen's disease Bowen's disease can be a consequence of previous ingestion of inorganic arsenic, usually given as a tonic many years ago. It is more common on covered than on exposed
FIG. 10.47 Solar keratosis A focal area of hard keratin accumulation with a zone of underlying erythema on sun-damaged skin.
Squamous carcinoma More than in other skin malignancies, there is likely to be an identifiable cause (Table 10.21) for squamous carcinoma (Fig. 10.48). The tumour often arises from a premalignant condition and is distinguished clinically by induration of the base and surrounding normal tissues. With growth, ulceration usually occurs. Squamous carcinoma is more liable to metastasize to regional lymph nodes than is basal carcinoma, and distant metastases can occur. Diagnosis is by biopsy. Keratoacanthoma (see Table 10.21) can be difficult to distinguish both clinically and histologically from squamous cell carcinoma. Treatment will usually be by surgical excision, although in some circumstances radiotherapy may be preferable. Basal cell carcinoma Basal cell carcinoma (BCC), or rodent ulcer (Fig. 10.49), arises from cells that resemble the basal layer of the epidermis, and may have its origin from skin appendage epithelium. It is the commonest malignant skin tumour in white skin, and although sunlight exposure is clearly a major aetiological factor, unlike squamous cell carcinoma it is not often seen on the backs of the hands. The face is the commonest site, although when there has been exposure to a systemic carcinogen, such as inorganic arsenic, BCC can be multiple and widespread.
FIG. 10.48 Squamous carcinoma is characterized by induration of the base of the tumour and eventual ulceration
423
TABLE 10.21 Factors predisposing to primary skin malignancy • • • • • • • •
Ultraviolet radiation X-rays Chemicals, e.g. hydrocarbons in mineral oil, inorganic arsenic Immunosuppression Genetic, e.g. xeroderma pigmentosum Scars, e.g. old burn scar Long-standing skin disease, e.g. lupus vulgaris, chronic leg ulcer Some human papilloma viruses (rare)
TABLE 10.22 The rising tide of melanoma USA lifetime risk (to age 75) 1935
1:1500
1991
1:105
2000
1:75
Melanoma is: • the commonest cancer in young adults aged 25-29 • the commonest cancer in males aged 30-34 • the second commonest cancer (to breast) in females aged 30-34
FIG. 10.50 Superficial spreading melanoma usually grows with an irregular edge and variable pigmentation
FIG. 10.49 Basal cell carcinoma is often translucent, with overlying telangiectatic vessels
The tumour is usually slow-growing, evolving from a translucent papule. Various growth patterns may occur, e.g. superficial spreading, nodular, infiltrative and sclerosing. Most nodular and infiltrative tumours ulcerate. Except for the sclerosing variety, BCC tends to retain a translucent raised margin as it extends into surrounding tissues. Telangiectatic vessels are often visible on the surface and
424
Fig. 10.36
1
Fig. 10.35
2
4
Fig. 10.37
0 Fig. 10.38
7
Fig. 10.39
3
Case 10.2
6 MCQ 10.14
may bleed on contact. 1 In some tumours there is an admixture of melanocytes, and the resultant lesion can simulate malignant melanoma. Local destruction can be extreme, 2 and very rarely BCC metastasizes. Treatment is usually by excision, radiotherapy, curettage or cryotherapy. Malignant melanoma Malignant melanoma (Fig. 10.50) usually arises either from previously normal-looking skin, 3 4 or from a benign melanocytic naevus. It may also arise from a naevus in a nailbed, in a mucous membrane or from the choroid or the iris. At present there is a rapidly rising incidence among white people (Table 10.22) and, aetiologically, short bursts of sun exposure, as during a hot, sunny holiday, may be important. There is not the same association with chronic sun damage as with squamous cell carcinoma, and to a lesser extent BCC. Conditions that can give rise to melanoma are lentigo maligna (Hutchinson's freckle) and dysplastic naevus. Lentigo maligna evolves as a flat, brown, variably pigmented patch, which slowly spreads on markedly sun-damaged skin. 5 Dysplastic naevi are
unusual-looking, often larger than average, with a distinctive histology; they are sporadic or inherited as an autosomal dominant characteristic, and may be a precursor to melanoma. Melanoma is often suspected when an enlarging pigmented lesion has one or more of the following: irregular notched border; irregular pigmentation, often with red and white as well as brown/black areas; itching or prickling sensation; inflammatory halo; ulceration and bleeding. The malignant cells spread laterally, in and just beneath the epidermis, and inwards. The prognosis depends on the depth of invasion, being excellent for completely excised, very superficial tumours. Metastasis occurs both to regional lymph nodes and distantly. ©
plaques and tumours appear (Fig. 10.51). Itching usually occurs. Erythroderma (p. 409) can develop, and if there are circulating neoplastic T cells this constitutes Sezary's syndrome. Lymphadenopathy and visceral involvement occur late and indicate a poor prognosis.
10
Metastatic malignancy Nodules, often ulcerating, may occur with many visceral malignancies. Paget's disease of the nipple The epidermis of the nipple becomes invaded by malignant cells arising from an underlying intraduct carcinoma of the breast tissue. The lesion is red, crusted and well defined, like Bowen's disease.
Lymphoma and leukaemia in the skin B-cell lymphoma, Hodgkin's disease and leukaemia may occasionally metastasize to the skin, or rarely present with cutaneous nodules. The skin is usually involved rather late in the course of the disease. The diagnosis is made from biopsy and other characteristic features of these diseases. T lymphocytes have an affinity for the epidermis and its appendages, and therefore T-cell neoplasia often involves the skin from the outset and may appear to be localized to the skin in some cases. Mycosis fungoides is the best-characterized T-cell cutaneous neoplasm. There is often a long phase of poikilodermatous patches (poikiloderma is a combination of erythema, atrophy and reticulate pigmentation) before
Kaposi's sarcoma Kaposi's sarcoma (Fig. 10.52) probably has a viral aetiology - humanherpesvirus 8. The lesions of this multicentric vascular neoplasm are usually purplish patches, plaques or nodules. Leakage of blood readily produces purpura and brown staining of the skin. The lymphatics can be affected, producing lymphoedema. Initially the lesions may be insignificant-looking, flat, reddish-brown or purple patches. ©A distinctive feature of AIDS-related Kaposi's sarcoma (p. 449) is a tendency for ovoid lesions to orientate along major skin creases, which on the trunk resembles the arrangement seen in pityriasis rosea.
FIG. 10.51 Mycosis fungoides This patient has numerous infiltrated plaques of T cell lymphoma in the skin.
FIG. 10.52 Kaposi's sarcoma in an AIDS patient There are multiple purple plaques and nodules.
425
Treatment, when indicated, is radiotherapy for localized lesions and, in some cases, cytotoxic chemotherapy for extensive disease. Primary sarcomas Malignant tumours arising from the various mesenchymal elements in the skin are all rare and present as enlarging masses.
AIDS AND THE SKIN
TABLE 10.23 Skin and oral lesions in AIDS Seborrhoic dermatitis (early feature in 30%) Itchy folliculitis (Fig. 10.53) Kaposi's sarcoma Infections Molluscum contagiosum Perianal warts Superficial fungal infection Herpes zoster and simplex Atypical mycobacteria
Severe drug eruptions Exacerbation of psoriasis Vasculitis Diffuse alopecia Dry skin (late) Oral hairy leukoplakia (see Fig. 11.9) Oral candidiasis Oral Kaposi's sarcoma
Skin and oral lesions are common features in patients with symptomatic HIV infection (Table 10.23). TABLE 10.24 Electromagnetic spectrum
SUNLIGHT AND THE SKIN For descriptive purposes, the continuum of electromagnetic radiation emitted by the sun is divided into segments according to wavelength (Table 10.24). Of the energy reaching the earth's surface, 99% is ultraviolet through to middle infrared. The shorter wavelengths of ultraviolet are filtered out by ozone in the stratosphere and by the atmosphere. The response of skin to solar radiation depends on the wavelength and on natural defences, the most important being melanin deposition. Ultraviolet B (UVB) is responsible for acute sunburn and the chronic changes of sun exposure: atrophy, dryness, blotchy pigmentation and wrinkling, solar keratoses and many skin cancers. The consequences of failure to repair damage inflicted on cellular DNA by UVB are seen in the rare autosomal recessively inherited condition xeroderma pigmentosum, in which sun-exposed skin becomes prematurely aged and skin cancers can appear in childhood. UVA has a much less obvious effect on normal skin, but is often responsible for photosensitive drug reactions and polymorphic light eruption. A clinical clue that UVA is playing a part is the provocation of a sun-related skin disorder behind window glass, as this filters out UVB. The action spectrum, i.e. the determination of exactly which wavelengths are responsible for a photosensitivity disorder, is known for only a few diseases. Visible light does not produce reactions on normal skin, but is responsible for photosensitivity in some diseases, notably the porphyrias, where the maximal reactivity is around 400 nm. Although most of the consequences of solar radiation on the skin appear harmful, one benefit is the synthesis of vitamin D3. UV radiation is essential to break the steroid
Type
Wavelength
Gamma Vacuum UV Ultraviolet C (UVC) Ultraviolet B (UVB) Ultraviolet A (UVA) Visible light Near infrared Middle infrared Far infrared Microwaves and radiowaves
0.1-100A 10-200 nm 200-290 nm 290-320 nm 320-400 nm 400-760 nm 0.74-1.5 um 1.5-5.6 um 5.6-1000 um >1mm
B ring and convert 7-dihydrocholesterol to previtamin D3, which then isomerizes spontaneously to vitamin D3. The immune system in the skin is modified by UV exposure, which may be important in the development of skin cancer.
Polymorphic light eruption Polymorphic light eruption is a common disorder that occurs mainly in females. Usually in spring, a day or so after sun exposure, itchy red papules, plaques and sometimes vesicles appear on sun-exposed sites. The condition gradually settles with continued sun exposure.
Drug photosensitivity It is usually not known whether allergic or toxic mechanisms are involved in drug photosensitivity. The drugs commonly responsible are given on page 418.
Phytophotodermatitis 1 426
1
Fig. 10.40
4
MCQ 10.15
2
Fig. 10.41
0 Fig. 10.42
Psoralens, a group of chemicals found in many plants, can be activated by UVA to produce inflammation and hyperpigmentation; 8-methoxypsoralen with UVA is used
TABLE 10.25 Causes of widespread hyperpigmentation Condition
Cause
Hypoadrenalism Cushing's syndrome
ACTH excess
Renal failure
Vitamin B12 deficiency
MSH Carotenoids Melanin Haemosiderin Melanin
Any debilitating diseasf disease
Melanin
Drugs
Melanin and sometimes the drug Keratin
Haemochromatosis
FIG. 10.53 Itchy folliculitis Excoriated follicular papules in a patient with AIDS.
therapeutically as PUVA (p. 418). Contact with a plant containing a psoralen (e.g. common rue, giant hogweed), together with sun exposure, produces erythema, often blistering, and then considerable hyperpigmentation.
Photoallergic contact dermatitis A number of cosmetics and even sunscreens contain chemicals which are activated by UV and, in combination with skin constituents, generate photoallergy. Investigation is by patch testing using two sets of patches, one of which is exposed to UV after a period of contact with the skin. Photocontact allergy produces positive results only in the set that has been irradiated. In some patients the state of photosensitivity persists long after the allergen has been withdrawn.
Metabolic disorders with light sensitivity Skin sensitivity to sunlight may occur in porphyrias (except the acute intermittent variety 2)> pellagra, carcinoid syndrome 3 and Hartnup disease.
Disorders aggravated by sunlight Many skin diseases may be worsened or triggered by sunlight. Common examples are lupus erythematosus and recurrent facial herpes simplex. Careful use of sunscreens can be helpful. 4
Acanthosis nigricans
10
Pattern Maximal in flexures, creases of palms and soles, sites of friction and pressure, and buccal mucous membranes Diffuse, maximal on hand and face Exposed skin and flexures Widespread, accentuated over knuckles Hypomelanosis of hair Generalized or Addisonian See p. 419, Table 10.18 Flexures, sides of the neck
the melanocytes and distributed in cellular organelles called melanosomes via cell processes (dendrites) to the keratinocytes of the skin and hair. All races have the same number of melanocytes - about 1 per 10 basal keratinocytes - the differences in skin colour being due to the amount of melanin formation in the melanosomes (maximal in dark races) and the way these are dispersed (singly in black people; in membrane-bound packages in white people). Apart from genetic factors, melanin production is stimulated by UV radiation and certain hormones, e.g. melanocyte-stimulating hormones (MSH), the chemically related ACTH, and female sex hormones. Hyperpigmentation is a common sequel to many inflammatory skin diseases, especially those in which the lower epidermis is damaged. There is both stimulation of melanogenesis and passage of melanin into dermal macrophages. Sometimes hyperpigmentation is due to substances other than melanin, e.g. haemosiderin (brownish-red) and drugs, e.g. amiodarone (grey). Many conditions associated with localized areas of hyperpigmentation are described elsewhere. These include neurofibromatosis (Fig. 10.38), xeroderma pigmentosum and Peutz-Jeghers disease. In practice the commonest are freckles, benign melanocytic naevi and postinflammatory hyperpigmentation. The causes of generalized or extensive hyperpigmentation are given in Table 10.25.
PIGMENTATION LOSS OF PIGMENT Normal skin colour is determined by haemoglobin, both oxygenated (red) and reduced (blue),carotenoids (yellow) and melanin (brown). Melanin is a polymer, synthesized from tyrosine in
Complete or partial loss of melanin pigment can have many causes. It is helpful to consider localized and generalized loss of pigment separately (Table 10.26).
427
TABLE 10.26 Localized and generalized pigment loss Condition
Causes
Clinical features
Localized hypopigmentation Vitiligo Loss of melanocytes
Pityriasis versicolor
Toxic effect on melanocytes
Well-defined white patches, often with hyperpigmentation of the bordering skin Personal or family history of organ-specific autoimmune disease common Slightly scaly macules mainly on the trunk, paler after sun exposure
Postinflammatory
(i)
(ii)
Faulty melanin transfer to keratinocytes Loss of melanocytes
Tuberous sclerosis 1 Poorly developed melanosomes Leprosy Decreased melanocytic activity Generalized pigment loss Albinism Faulty production of melanin in skin, hair and eyes Phenylketonuria Competitive inhibition of tyrosinase by phenylalanine ACTH and MSH Hypopituitarism deficiency
Pale patches with or after inflammation, e.g. eczema e.g. scarring after lupus erythematosus Leaf-shaped, pale macules and fibromas Pale patches are anaesthetic FIG. 10.54 Vitiligo shows sharply outlined areas of pigment loss Pale skin and hair, pink irises Pale skin with mental deficiency Associated endocrine deficiencies
Vitiligo Vitiligo (Fig. 10.54) is an acquired disorder in which melanocytes are lost from the basal layer of the epidermis. It occurs in about 0.4% of the population. A genetic basis is likely, as about 40% have a family history. In the individuals and their families there is an increased frequency of organ-specific autoimmune diseases, e.g. hypo- and hyperthyroidism. The precise pathogenesis is unknown. Clinical features Vitiligo has often begun by the age of 20. It is characterized by sharply defined areas of pigment loss, sometimes with mild hyperpigmentation of the adjacent normal skin. 0 The texture is normal and there is no scaling. In paleskinned individuals their first awareness may be sunburn in the depigmented skin. Any site can be affected and symmetrical involvement is common. Occasionally vitiligo
428
1
Figs 10.30, 10.31
3
MCQ10.16
0 Fig. 10.43
follows a dermatomal pattern. The face, axillae, groins, backs of hands, knees and elbows, and the genitalia are common sites. The condition is usually progressive, but repigmentation can occur spontaneously. 3 Diagnosis Diagnosis is usually straightforward. By Wood's light (p. 382) pityriasis versicolor (which is scaly) fluoresces yellow, and vitiligo is more strikingly white than the other causes of hypopigmentation (Table 10.27). The pale macules of leprosy are hypoanaesthetic. Treatment No treatment is entirely satisfactory. Cosmetic camouflage is helpful in a few. Sunscreens should be used on exposed areas to prevent burning and chronic sun damage, and in the pale-skinned this measure can improve the appearance by reducing tanning of the surrounding normal skin. Other measures used include psoralens and UVA (see PUVA treatment of psoriasis, p. 399) and the short-term application of potent topical corticosteroids.
PRESSURE SORES A pressure sore (bed sore, decubitus ulcer) is the consequence of sustained pressure to the tissues and is usually seen over a bony prominence, such as the ischial tuberosity, greater trochanter and elbow. The normal response to sustained pressure is movement to relieve that pressure. If
TABLE 10,27 Pathogenesis of pressure sores
TARLE 10,28 Causes of leg ulceration
Major factors Prolonged immobility e.g. Paraplegia Arthritis Operations and intensive care Plaster casts Apathy Loss of sensory stimuli e.g. Coma Multiple sclerosis Vascular disease e.g. Atherosclerosis
Cause
Example
Venous hypertension Arterial diseases Vasculitis Pyoderma gangrenosum Trauma Infections
Venous thrombosis Atherosclerosis, diabetes mellitus Rheumatoid disease, Wegener's granulomatosis See p. 407 Mechanical injury, burns, bites Ecthyma, tuberculosis, syphilis, deep fungal infection Leprosy, diabetes mellitus Disseminated intravascular coagulation, platelet disorders, sickle cell anaemia and spherocytosis, polycythaemia Cryoglobulinaemia Radiodermatitis Cutaneous carcinomas, Kaposi's sarcoma
Contributory factors Anaemia Hypoproteinaemia Severe weight loss
Neuropathy Blood disorders Plasma protein disorders Scarring disorders Neoplasia
discomfort is not felt or movement is not possible, then ischaemia is likely to occur. Friction (lateral pressure) exacerbates the tissue damage. Because fat and muscle are more susceptible, subcutaneous necrosis may be much greater than the surface changes suggest. Factors responsible for pressure sores are listed in Table 10.27. The earliest clinical sign is redness on an area subjected to pressure, the erythema not fading within 30 minutes. Action at this stage may prevent further damage. Progressive damage is manifested by blistering, ulceration and the formation of slough.
Management For any patient at risk, prevention is the chief aim. Frequent changes of position - with care not to exert friction by dragging the skin, and careful choice of the surface on which the patient is lying or sitting - are crucial. For the established pressure sore, these measures are equally important. In addition, anaemia and malnutrition should be corrected, slough should be removed and the sore kept scrupulously clean. In some cases excision of the entire necrotic area, with closure or grafting, should be considered.
10
VENOUS LEG ULCERATION Venous leg ulceration is also known as stasis or gravitational ulceration. The skin changes are due to the consequences of raised pressure in the venous system.
Aetiology and pathogenesis In most cases venous return is compromised by previous deep vein thrombosis. In a few cases ulceration is associated with varicosity of the superficial veins, or with defective communicating veins. Pressure in the venous system is raised because the valves are absent or destroyed, and this increased pressure is transmitted back to the capillary bed in the skin. There is extravascular deposition of fibrin, followed by fibrosis, and these changes are thought to impair transfer of oxygen and nutrients to the skin. It is also likely that venous distension produces reflex arteriolar constriction. This phenomenon occurs in normal individuals when standing still, and in them is promptly relieved by exercise, but this relief does not occur in those with persistently raised venous pressure. Patients who develop leg ulcers may also have decreased ability to lyse the fibrin, and this may contribute to the pathogenesis.
LEG ULCERATION
Clinical features Ulceration of the lower leg can have many causes, some of which are shown in Table 10.28. In the developed world most cases of leg ulceration are wholly or partly due to disorders of the venous system, but arterial insufficiency often coexists and may be the major factor in many patients. In the tropics, infective causes are much more important. Particularly in the elderly there can be multiple aetiological factors.
Venous ulceration is most common in middle-aged and elderly women. 'Interestingly, leg ulcers occur frequently and early in Klinefelter's syndrome (p. 68). Venous ulcers are usually preceded by varying combinations of oedema, prominent venules around the ankle, brown discoloration due to extravasation of red blood cells, eczema (p. 405), fibrotic thickening of the dermis and subcutaneous fat, and white plaques stippled with telang-
429
tional deficiency, anaemia, diabetes, obesity, hypertension, cardiac and renal disease, myxoedema, and any disease causing immobility. It is most important to assess the arterial system in the legs, as the compression that is valuable for venous insufficiency can be harmful if there is a poor arterial inflow. A simple Doppler device should be used, and if the ratio of inflow pressure in the ankle or foot to that in the arm is less than 0.8, compression should not be used without a vascular surgical assessment. Raised venous pressure can be counteracted by elevation of the legs at night and for periods during the day, and by careful use of compression bandages combined with exercise. If the ulcer is due to incompetent superficial or communicating veins rather than to deep vein thrombosis, surgical treatment may be indicated. Numerous treatments are available for the ulcer itself, and in most circumstances materials that do not contain potential sensitizers and maintain a moist surface should be used. Desloughing is often best achieved with a hydrocolloid dressing. Cellulitis requires systemic antibiotics. When venous ulceration has healed, the patient should continue to exercise and maintain compression with suitable stockings indefinitely. FIG. 10.55 Venous hypertension Ankle showing changes of venous hypertension: dilated veins, haemosiderin staining and atrophie blanche.
iectases (atrophie blanche) (Fig. 10.55). These signs occur most commonly near the medial malleolus, 1 but may be seen also on the lateral aspect of the ankle and over communicating veins. Another characteristic site is over the dorsum of the foot near the base of the toes. Ulceration may occur spontaneously or after trauma, which is often trivial. 2 Unlike ulceration due to arterial disease or vasculitis, venous ulcers are often painless. The base of the ulcer usually shows red granulation tissue and the edge is oedematous. The ulcer may be complicated by infection; cellulitis, usually due to Staph. aureus and/or Strep. pyogenes, can develop rapidly. Another common complication is contact allergic dermatitis due to medicaments applied to the ulcer, e.g. antibiotics and antiseptics (p. 400). In time the fibrotic process causes lymphoedema, and loss of movement at the ankle joint often occurs. Rarely, squamous and basal cell carcinoma can develop in chronic venous leg ulcers.
Management Patients with venous leg ulcers often have other disorders, correction of which facilitates healing. These include nutri-
1
430
Fig. 10.44
2
Case 10.3
3
Fig. 10.45
ARTERIAL ULCERATION When the arteriolar supply to a region of skin is insufficient or interrupted necrosis occurs, with resultant ulceration. The more profound process of gangrene is discussed on page 603. In general, vascular occlusion can occur because of changes outside the vessel wall, within the wall itself (as in atherosclerosis and vasculitis), and as a result of changes in the blood (as in cryoglobulinaemia and platelet thrombi). The symptoms and signs will be determined by the size of the ischaemic area and the speed with which the process occurs. The most common cause of arterial ulceration is atheromatous disease of the aorta and its tributaries.
Clinical features of ulceration due to atherosclerosis Arterial ulcers tend to be painful, sometimes severely so. There may be coldness, and pallor exaggerated by elevation of the limb, but cyanosis and blotchy erythema are also seen. Chronic ischaemia results in dryness and atrophy of the skin, loss of hair, and thickened, distorted nails. Intermittent claudication may be present (p. 602). Common sites for arterial ulceration due to atherosclerosis are the front or lateral aspect of the ankle, 3 and the toes. The ulcer tends to be well demarcated, with a grey sloughcovered base, which may expose deeper structures such as tendons. The management of arterial ulceration is usually the province of the vascular surgeon.
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ACNE VULGARIS Acne vulgaris primarily involves the pilosebaceous follicles, i.e. the sebaceous glands, ducts, and the distal part of the hair follicles into which they open. The lesions include keratinous plugs in the ducts (comedones), inflammatory papules, pustules, nodules, cysts and scars.
Pathogenesis The best-defined factors determining the occurrence of acne vulgaris are androgenic stimulation of the sebaceous glands and the commensal anaerobic bacterium Propionibacterium acnes, which heavily colonizes active pilosebaceous follicles. Although the onset of acne around puberty is explained by the increased output of androgens at that time, it is much less clear why the disease becomes quiescent without any measurable change in the hormonal milieu or numbers of propionibacteria. The basis for the disorder of keratinization in the sebaceous ducts which produces the comedones is uncertain. Inflammatory lesions are mainly derived from closed comedones (see below). Possible mediators of inflammation include free fatty acids, bacterial cell wall components and enzymes, and the patient's complement system. The pus in acne lesions is sterile and a consequence of inflammation, which is often so severe that scarring results.
Clinical features Acne can occur in infants, but is usually mild and due to the influence of transplacental hormonal stimulus. In older children acne often represents the beginnings of puberty, but may not occur until the mid-teens or beyond. The areas affected are those with maximal numbers of pilosebaceous follicles: the face, upper trunk and shoulders. Comedones are either open (blackheads) or closed (small whitish papules). The inflammatory lesions are erythematous, varying from papules through pustules to nodules and large collections of pus (wrongly) called cysts (Fig. 10.56). The more destructive lesions heal with scarring, which is usually pitted but is hypertrophic or keloidal in those so predisposed. The course of acne can be erratic and there are often premenstrual exacerbations. Lesions resembling acne can be provoked by halogenated hydrocarbons, mineral oils, tars, greasy cosmetics, and drugs (p. 419).
Management Acne can have serious psychological effects and should not be ignored on the basis that it will get better sooner or later. Mild cases often respond to topical agents alone, e.g. benzoyl peroxide 2.5-10% gel, or topical retinoic acid. The latter is more irritant, but often more effective when comedones are the predominant feature. If there is insufficient
FIG. 10.56 Acne Note the papules, pustules, cysts and nodules.
response after a few weeks' treatment, or if the acne is of moderate severity, an oral antibiotic should be used in addition (or instead, if topical therapy proves too irritant). Tetracyclines and erythromycin are equally effective, usually in a dose of 0.5 g twice daily for several months. Topical antibiotics, e.g. 1 % clindamycin, can also be effective. For females with moderate acne, hormonal modulation with the antiandrogen cyproterone acetate may be more effective. This drug must be given with an oestrogen in the form of a low-dose oral contraceptive pill. Patients with severe and destructive acne usually need treatment with oral isotretinoin. This vitamin A analogue is highly effective but has a number of adverse effects, notably teratogenicity, and in the UK is restricted to hospital use. Other measures sometimes used include intralesional corticosteroids for inflammatory nodules and cysts, and dermabrasion, a surgical technique to improve scarring.
HYPERHIDROSIS Excessive sweating can be a feature of several systemic illnesses, or an isolated complaint.
Generalized hyperhidrosis Sweating from much of the body surface is a feature of many febrile illnesses and may be the presenting symptom (e.g. of tuberculosis and malaria). Other diseases
431
associated with a similar pattern of widespread sweating include lymphoma, hyperthyroidism, hypoglycaemia, phaeochromocytoma, the menopause, diabetic autonomic neuropathy and acromegaly. Drugs that may cause sweating include alcohol (commonly) and fluoxetine (rarely).
Palmoplantar and axillary hyperhidrosis Emotional stress and mental activity typically produce excessive sweating to varying degrees from the palms, soles and armpits. Other areas that may be involved include the face and groin. This pattern of hyperhidrosis is common, not associated with underlying disease, but can cause significant disability.
Asymmetrical hyperhidrosis This can be caused by a variety of neurological lesions, from the brain downwards. A particular example is sweating on one side of the face associated with eating (gustatory hyperhidrosis). This often occurs after an injury that results in loss of the normal nerve supply to the parotid gland, the regenerating fibres instead supplying the sweat glands.
Treatment
and sinus tracts. The areas affected are the axillae, anogenital area and breasts. Tender inflammatory nodules, which discharge pus, are seen and blackheads are often present early on. Because bacteria play a perpetuating role in this disorder, courses of antibiotics (if possible governed by sensitivity testing) are helpful but not curative. Incision, marsupialization and even wide excision may be needed in chronic cases. Hormonal modulation, e.g. with antiandrogens in females, may have a role in treatment, and isotretinoin may help in some cases.
ROSACEA Rosacea is a common condition of the middle-aged and elderly, in which there are varying combinations of redness of the face with telangiectasia, papules and sterile pustules (Fig. 10.57). 1The facial erythema is often easily exacerbated by spicy foods, alcohol and emotional upset; chronic UV exposure may have an aetiological role. Unlike acne there are no comedones and no elevation of sebum excretion rate. Common associations are eye disorders (e.g. conjunctivitis and keratitis), facial lymphoedema and rhinophyma, a hypertrophy of the nasal skin and its appendages. Despite the cause remaining unknown, treatment with oral oxytetracycline (erythromycin is an
Axillary hyperhidrosis can sometimes be helped by 20% aluminium chloride in alcohol applied at bedtime. Palmar and plantar hyperhidrosis are usually better treated with iontophoresis, either using water alone or with the anticholinergic drug glycopyrronium bromide in solution. This treatment utilizes DC electricity to drive ions into the skin. Psychological methods and even psychotropic drugs are useful in some patients in whom anxiety is a prominent trigger. Transthoracic endoscopic sympathectomy can be very effective in selected patients with palmar hyperhidrosis. Recently, success has been claimed for localized injections of botulinum toxin.
HIDRADENITIS SUPPURATIVA Hidradenitis suppurativa is a chronic suppurative, inflammatory and scarring condition of blocked apocrine glands. There may be a genetic basis for this disorder, which has some similarity to acne vulgaris and may be associated with it. Following keratinous plugging of the apocrine glands there is bacterial infection, subsequent gland rupture, damage to surrounding tissues, and healing with scarring
1
432
Fig. 10.46
FIG. 10.57 Rosacea Rosacea is characterized by erythema, papules and pustules but there are no comedones. 1
TABLE 10.29 Systemic causes of generalized pruritus
TABLE 10.30 Causes of prurifus ani
Hepatic disease Obstructive biliary disease Pregnancy: oestrogen-induced cholestasis
Anorectal disease Fissure Haemorrhoids Rectal carcinoma Faecal soiling Skin disease Psoriasis Atopic dermatitis Irritant and allergic contact dermatitis (especially medicaments)
Endocrine disease Hyper- and hypothyroidism Diabetes mellitus (rare) Renal Chronic renal failure Parasitic Trichinosis Onchocerclasis Malignancy Hodgkin's disease Leukaemia and lymphoma Polycythaemia rubra vera Other neoplasms
Haematological Iron deficiency Polycythaemia rubra vera Drugs Opiates Subclinical drug sensitivity Psychiatric Neurosis Psychosis, e.g. delusion of parasitosis
alternative) is effectively suppressive in most cases. Topical metronidazole is also helpful. It is usually helpful to minimize the effects of sun exposure. Rosacea is slowly worsened by the use of topical steroids on the face, and a similar condition, perioral dermatitis, can be initiated by the more potent topical steroid preparations.
PRURITUS Pruritus, or itching, is the distinctive sensation whose outward manifestation is the act of scratching. Except for the role of histamine in some disorders, and bile salts in obstructive liver disease, we know disappointingly little about the mechanisms of this common symptom. When severe, pruritus can surpass pain in the distress it can cause. Many skin diseases can be itchy, and some, such as scabies, dermatitis herpetiformis, lichen planus and urticaria, severely so. Dry skin of whatever cause tends to be itchy, and this is a particularly common problem in the elderly and one of the reasons for pruritus in the atopic individual. Occasionally an external cause (such as fibreglass or scabies) can produce widespread pruritus with little to see. Itching can occur without any primary rash, the skin changes, if any, being those caused by rubbing and scratching. Generalized pruritus may be a pointer to systemic disease (Table 10.29). Wherever possible, the underlying cause of generalized pruritus should be treated. When symptomatic measures are called for the use of emollients can be helpful, probably because dry skin has a lower threshold for pruritus. Oral HI antagonists can provide some relief, particularly when sedative antihistamines are used. Uraemic pruritus
10 Infection Candidiasis Infestation Threadworms Psychogenic Anxiety Depression Unknown
TABLE 10.31 Causes of pruritus vulvae Diseases special to vulvaf skin Lichen sclerosus et atrophicus Leukoplakia Carcinoma Skin disease Psoriasis Atopic dermatitis Irritant and allergic contact dermatitis (especially medicaments)
Infection Candidiasis Trichomonas Infestation Pediculosis Psychogenic Anxiety Depression Unknown
can be helped by UVB. Pruritus due to cholestatic liver disease often responds to cholestyramine or colestipol. The itch in polycythaemia rubra vera may respond to antiserotonin agents, cyproheptadine or pizotifen. Localized pruritus without primary signs of skin disease is common in the perianal (Table 10.30) and vulval areas (Table 10.31). Sometimes there is a psychological basis for this.
ALOPECIA The evaluation of alopecia, or hair loss, takes account of the distribution, any abnormalities of the hair shafts, and the scalp.
Androgenic alopecia (common baldness) The prerequisites for this very common condition are an inherited tendency; some degree of ageing; and postpubertal androgen levels. The longer, coarser, pigmented terminal hairs on the scalp are progressively replaced by small, fine vellus hairs. In males there is recession of the anterior hairline and thinning over the crown, and ulti-
433
mately terminal hair may only be present at the back and sides of the scalp. In an endocrinologically normal female there is thinning over the top of the scalp, but baldness to the extent seen in males is uncommon, except in the elderly, and if present warrants careful evaluation. Treatment In a few, with a short history of hair loss, topical minoxidil can induce modest regrowth of hair, but even with sustained application the hair usually falls out eventually, and the treatment is expensive. Some resort to hair transplantation.
Diffuse alopecia Diffuse alopecia is a decrease in hair density over the whole scalp without changes in the skin or hair morphology. In some instances, e.g. a febrile illness, childbirth and severe emotional upset, the causative factor synchronizes a proportion of the follicles so that hairs are shed 2-3 months later, a phenomenon called telogen effluvium. Regrowth usually takes place in about 6 months. Normal hair growth requires a adequate nutrition, and diffuse alopecia accompanies malnutrition and wasting conditions. Iron deficiency, even in the absence of anaemia, has been associated with hair loss. Dry and progressively sparse hair is a feature of hypothyroidism. Many drugs (p. 419) can produce diffuse alopecia, sometimes (as with cytotoxic agents) within days of administration, or after several weeks (as with anticoagulants, antithyroid drugs and the retinoids). Stopping the oral contraceptive has been associated with mild hair loss, similar to the effect of childbirth.
Alopecia areata Alopecia areata (Fig. 10.58) is a common condition in which there is loss of hair in patches, typically with no skin changes. Hair on the face and body as well as the scalp may be affected. A distinctive feature is the presence of shortened hairs which taper markedly where they emerge from the scalp (exclamation-mark hairs). White hairs tend to be spared the process causing the loss. Alopecia areata is usually reversible, and when hair grows back it is often initially white. When the entire scalp becomes affected the condition is called alopecia totalis, and if all the body hair is lost as well the term alopecia universalis is applied. Regrowth usually occurs, but is less likely with these more severe forms. Nails may show a distinctive pattern of pitting and ridging. 1 There is sometimes an association with one or more organ-specific autoimmune diseases in the patient or family, such as vitiligo. The cause of alopecia areata is not known. Topical and intradermal corticosteroids can be helpful in selected cases. Treatment by induced contact allergic dermatitis, e.g. to diphencyprone, can be useful.
Inflammatory alopecia Fungal (p. 389) and bacterial infection can cause patchy hair loss with varying degrees of erythema, oedema and pustules. Lichen planus (p. 413) and lupus erythematosus (p. 1172) may affect the scalp, and characteristically produce atrophy. Occasionally metastatic neoplasia presents as inflammatory alopecia.
Traumatic alopecia Hair can be damaged by chemicals, e.g. those used in permanent waving, and physical trauma such as twisting between the fingers and pulling.
HIRSUTISM AND HYPERTRICHOSIS
FIG. 10.58 Alopecia areata A distinctive feature of alopecia areata is the presence of shortened 'exclamation mark' hairs which taper markedly where they emerge from the scalp.
Hair growth can be excessive by being coarser, longer and/or more profuse than is normal for age, sex and race at any particular body site. The term hirsutism is used to describe excessive hair growth in females on those areas where secondary sexual hair occurs in males, i.e. the upper lip, beard area, chest, around the nipples, upper back, lower abdomen etc. Hypertrichosis designates other patterns of excessive hair growth. Both hirsutism and hypertrichosis can have a familial basis and are commoner in certain races.
Hirsutism 1
434
Fig. 10.47
2
Fig. 10.48
When hirsutism occurs together with other symptoms and signs suggestive of an underlying endocrine cause, such as menstrual irregularities, infertility and virilization (clitoromegaly, deepening of the voice and male pattern baldness),
10
TABLE 10.32 Endocrine causes of hirsutism Ovarian Adrenal Pituitary Exogenous
Polycystic ovaries Virilizing tumours Congenital adrenal hyperplasia Adenoma and carcinoma Cushing's syndrome Acromegaly Corticosteroids, androgens, progestogens
appropriate investigations should be carried out. Table 10.32 lists some endocrine causes. In most cases hirsutism is an isolated finding, probably caused by an increased sensitivity of hair follicles to normal levels of circulating androgens, and in the absence of other symptoms investigation is unnecessary.
Hypertrichosis There is no known underlying cause for hypertrichosis. It can occur as an isolated event, e.g. over the lower spinal column in spina bifida occulta, in association with melanocytic naevi, and in areas of chronic inflammation; or as a more generalized phenomenon, e.g. in malnutrition, some porphyrias, and with certain drugs, notably ciclosporin and minoxidil.
Treatment When there is an underlying endocrine cause of hirsutism, treatment of this may help. For idiopathic hirsutism, treatment should be tailored to the needs of the individual. For mild cases counselling alone may be sufficient. Excessive hair can be removed by depilatory creams, waxing or shaving. Follicles can be destroyed by electrolysis or certain types of laser therapy. For some patients the antiandrogen cyproterone acetate (given together with ethinyl oestradiol to maintain a normal menstrual cycle) can gradually reverse hirsutism, but the effect only lasts as long as the treatment.
NAILS AND DISEASE The nail is a specialized sheet of keratin largely produced by an invagination of the epidermis called the matrix, which is located beneath the posterior nailfold and extends beneath the nailplate as the lunule (halfmoon). Disorders of the nails may result from local causes such as psoriasis, fungal infection and lesions beneath the nail (e.g. melanoma), or reflect a systemic disorder (see below).
Clubbing Normally the angle between the nail and the posterior nail-
FIG. 10.59 Koilonychia The nail plates are thinned and spoon-shaped depressions.
fold is less than 180°. In clubbing this angle increases, often becoming more than 180°. The causes are discussed on page 619.
Koilonychia Koilonychia is flattening or even depression of the normal slight convexity of the nail, and is usually due to iron deficiency (Fig. 10.59).
Beau's lines Beau's lines are transverse grooves in all the nails, reflecting a transient reduction in nail growth due to a severe illness. They may also occur after childbirth.
Yellow nail syndrome In yellow nail syndrome the nails become yellow, thickened and excessively curved, and virtually stop growing. 2 Cuticular attachment is lost and there is usually some separation of nail from nailbed. The nail changes are associated with lymphoedema, bronchiectasis and pleural effusions. It is more common to find yellow nails in circumstances such as psoriasis and dermatophyte fungal infection, these conditions being recognized by the associated skin changes and mycological investigations. Splinter haemorrhages Splinter haemorrhages are usually longitudinal or dotshaped areas of haemorrhage beneath the nails (Fig. 10.60). Most are the result of minor trauma, are painless, and appear beneath the distal third of the nail. Psoriasis and fungal infection of the nails may be associated with similar distal splinters. Painful and proximal splinter haemorrhages are much more likely to be associated with medical causes, of which the best established are subacute bacterial endocarditis, trichinosis, chronic mountain sickness and indwelling radial arterial catheters.
435
Dermatitis artefacta Dermatitis artefacta is mainly seen in females. The lesions are self-inflicted but this is denied, and they may indeed be produced subconsciously. They are often bizarre in appearance, resistant to therapy (except occlusive dressings, in which case lesions may appear at new sites), and often regarded with indifference. The patients tend to be immature or insecure, but the motivation behind dermatitis artefacta is often difficult to elucidate and the condition can be protracted. Self-inflicted damage is also seen in psychotics and the Lesch-Nyhan syndrome, a rare X-linked inherited disorder of purine metabolism associated with mental retardation and spasticity.
Delusions of infestation
FIG. 10.60 Splinter haemorrhages Elongated deposits of blood beneath the nail plate.
Paronychia Paronychia is a painful swelling of the posterior nailfold. When acute, staphylococcal infection is likely. A more gradual onset and chronic course is usually associated with Candida albicans. 1 Women are especially prone to chronic paronychia. Common predisposing factors are occupations in which the hands are frequently wet, diabetes mellitus and poor peripheral circulation.
This is the conviction that there are parasites on or in the skin, often supported by offerings of excoriated skin fragments. Such a delusion may be one element in a broader presentation of psychosis, including that due to organic disorders such as vitamin B12 deficiency, but can present in an isolated form (monosymptomatic delusional hypochondriasis). It is of course essential to exclude infestation such as scabies and pests in the home. The monodelusional state often responds well to the psychotropic drug pimozide.
Dermatological non-disease The term 'dermatological non-disease' describes a disproportionate anxiety about minor and often physiological skin changes. Such patients are difficult to manage, but can be seriously disturbed and at risk of suicide.
PSYCHOLOGICAL CAUSES OF SKIN
DISEASE
GENODERMATOSES
Many bona fide skin diseases, such as eczema and psoriasis, may worsen or be precipitated during periods of psychological stress. Similarly, anxiety and depression commonly accompany distressing skin disease, and can often be ameliorated by explanation, reassurance and encouragement. There is a direct psychological cause with dermatitis artefacta, many cases of delusions of infestation, and psychogenic pruritus. A diagnosis of psychogenic pruritus rests on exclusion of an organic cause as well as association with other psychoneurotic symptoms and signs.
1
436
Fig. 10.49
The skin is affected in a number of genetically determined syndromes, some of which are covered in this chapter or, because they most frequently present with the systemic manifestations, elsewhere in this book. However, there are some important disorders that often present with cutaneous features that should be discussed briefly here. Darier's disease is an autosomal dominant condition in which clusters of warty papules are seen on the face, neck and trunk, in association with abnormal nails (classically linear streaks and 'v'-notching) and palmar pits. The term palmoplantar keratoderma is used to describe diffuse or patchy thickening of the palms and soles. There are many variants, some of which are simply a nuisance and affect only the hands and feet. In some, however, there may be associated abnormalities, e.g. mental retardation and carcinoma of the oesophagus. Ehlers-Danlos syndrome is a name given to a group of disorders in which there are
10
TABLE 10.33 Syndromes associated with cancers Syndrome
Features
Cowden's syndrome Gardner's syndrome Rothmund-Thomson syndrome Xeroderma pigmentosum Xeroderma pigmentosum variant Bloom's syndrome Howel-Evans syndrome Muir-Torre syndrome Peutz-Jeghers syndrome
Multiple trichilemmomas; fibromas of the lips; acral keratoses; carcinoma of breast, pancreas, thyroid Multiple epidermoid cysts; intestinal polyposis Poikiloderma; photosensitivity; short stature; skin and soft tissue cancers (e.g. osteosarcoma) Early-onset photosensitivity; excessive freckling; multiple skin cancers; some variants also develop internal cancers and CNS defects Similar, but less severe changes; later onset Growth retardation; pigmentary anomalies; leukaemia Palmoplantar keratoderma with carcinoma of the oesophagus Sebaceous gland carcinomas; colonic carcinomas Intestinal polyps occasionally undergo malignant transformation
FIG. 10.61 Hereditary haemorrhagic telangiecstasia Papular telangiectases on the forehead. Unlike many spider naevi, these lesions do not fill from the centre when emptied by pressure.
abnormalities of connective tissue (see also p. 71). Some forms are mild, consisting largely of hyperextensible joints and rather lax, friable skin. Others, however, are associated with major vascular problems, including arterial rupture. Pseudoxanthoma elasticum (see also p. 71) is a condition in which the skin of the neck, the elbow folds and occasionally other sites, gradually becomes more and more papular. The final appearance is said to look like the skin of a plucked chicken. The condition may be entirely benign, but in some pedigrees the connective tissue defects lead to 'angioid' streaks in the retina, blood vessel rupture and mitral valve prolapse. Hereditary haemorrhagic telangiectasia presents with multiple telangiectases on the face (Fig. 10.61), especially the lips. There are often lesions in the respiratory and gastrointestinal tracts as well, which may bleed. The skin is affected in a number of inherited immunodeficiency syndromes, either with multiple infections (e.g. in agammaglobulinaemia and severe combined immune deficiency) or with more direct cutaneous changes (e.g. eczema in Wiskott-Aldrich syndrome or the telangiectases of ataxia telangiectatica). There are also a number of syndromes associated with cancers which have significant cutaneous features. Some of these are listed in Table 10.33.
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the western world male homosexuals are more likely to contract hepatitis B, syphilis and HIV infection than are their heterosexual counterparts. However, the incidence of newly acquired syphilis and gonorrhoea in homosexual men fell as trends in sexual behaviour changed in the 1980s. The basis of any STD service is the control of sexually transmitted infections. There are basic requirements:
Genitpironary
Disease I G Williams
Sexually transmitted diseases 439
Acquired immune deficiency syndrome (AIDS) 439
HIV neurological disease 448 Sexually transmitted infections 456
SEXUALLY TRANSMITTED DISEASES Sexually transmitted diseases (STDs) are caused by infections transferred through sexual contact. Our appreciation of the range of agents capable of being transmitted sexually has increased.
Epidemiology The prevalence and incidence of sexually transmitted infections vary in different parts of the world. This is due to variations both in the diseases found and in the methods of reporting such infections. The type of sexual behaviour and the sexual orientation of the person involved also influence the transmission of the infectious agents. This is clearly demonstrated by the fall in incidence of syphilis and gonorrhoea after the introduction of penicillin (Figs 11.la, 11.1b), the rise in incidence in the 1960s due to an increase in the number of people's sexual partners, followed by a substantial fall in the 1980s, when the AIDS epidemic resulted in a change in sexual behaviour in homosexual men. Figure 11.2 shows the most commonly found STDs treated at genitourinary medicine clinics. This is an underestimate of the problem. Morbidity associated with STD is more common in women and the agents responsible are more difficult to identify. Reported STDs are observed mostly in the 20-24-yearold age group, followed by 25-29 and 15-19-year-olds. In
• The patient needs ready access to a specialist centre for accurate diagnosis and treatment of any infection. Attendance needs to be voluntary. Treating the index case only partly helps in controlling an infection, and therefore sexual partners need to be identified and treated. • Patients are much more likely to cooperate in these matters if they are assured of absolute confidentiality. The STD service is the most confidential are in the health service, and details are generally only released with the patient's consent. • Education about STDs, both for an individual and as part of general health education, is important in helping to control the spread of infection. • The clinics keep a record of the number of patients seen with each infection, and these figures form part of a detailed national epidemiology report.
ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS) Definition The first recognized cases of the acquired immune deficiency syndrome (AIDS) occurred in the summer of 1981 in America. Reports began to appear of Pneumocystis carinii pneumonia and Kaposi's sarcoma in young men, who, it was subsequently realized, were both homosexual and immunocompromised. Even though the condition became known early on as AIDS, its cause and modes of transmission were not immediately obvious. The virus now known to cause AIDS, the human immunodeficiency virus (HIV), was discovered in 1983. The definition of AIDS has changed over the years as a result of increasing appreciation of the wide spectrum of clinical manifestations of infection with HIV. Currently AIDS is defined as an illness characterized by one or more indicator diseases (Table 11.1). In the absence of another cause of immune deficiency, and without laboratory evidence of HIV infection (if the patient has not been tested or the results are inconclusive), certain diseases, when definitely diagnosed, are indicative of AIDS. Regardless of the presence of other causes of immune deficiency, if there is laboratory evidence of HIV infection, other indicator diseases that require a definitive (or in some cases only a presumptive) diagnosis also constitute a diagnosis of AIDS.
439
TABLE 11.1 AIDS indicator diseases
FIG. 11.1 Incidence in England and Wales of A gonorrhoea 1918-1990, B infectious and early latent syphilis 1931-1998
Recurrent/multiple bacterial infections - child aged under 13 Candidiasis - pulmonary *Candidiasis - oesophageal Cervical carcinoma - invasive Coccidioidomycosis - disseminated Cryptococcosis - extrapulmonary Cryptosporidiosis - with diarrhoea persisting for more than one month *Cytomegaiovirus retinitis Cytomegalovirus disease - not in liver, spleen or nodes HIV encephalopathy Herpes simplex virus (HSV) infection - mucocutaneous ulceration lasting for more than one month or pulmonary, oesophageal infection Histoplasmosis - disseminated Isosporiasis - with diarrhoea persisting for more than one month *Kaposi's sarcoma tymphoid interstitial pneumonia - child aged under 13 Non-Hodgkin's lymphoma - Burkitt's or immunoblastic Primary cerebral lymphoma *Disseminated mycobacteriosis, e.g. Mycobacterium avium *Mycobacterial tuberculosis - extrapulmonary, pulmonary * Pneumocystis carinii pneumonia *Recurrent pneumonia within a 12-month period Progressive multifocal leucoencephalopathy Salmonella septicaemia - recurrent *Cerebral toxoplasmosis Wasting syndrome due to HIV * These diseases may be diagnosed presumptively if laboratory evidence of HIV exists.
Disease Genital warts Non-specific genital infection Chlamydia infection Genital herpes Gonorrhoea Trichomonas Syphilis FIG. 11.2 Number of cases of sexually transmitted disease seen in STD clinics in England and Wales, 1998 (excluding HIV)
440
In 1993 the Centers for Disease Control in the USA extended the definition of AIDS to include all persons who are severely immunosuppressed (a CD4 count <200 x 106/L), irrespective of the presence or absence of an indicator disease (Table 11.2). For surveillance purposes this definition has not been accepted within the UK and Europe, where AIDS continues to be a clinical diagnosis defined by one or more of the indicator diseases.
Epidemiology Transmission
HIV has been isolated from semen, cervical secretions, lymphocytes, cell-free plasma, cerebrospinal fluid, tears, saliva, urine and breast milk. This does not mean, however, that these fluids all transmit infection, as the concentration of virus in them varies considerably. Semen, blood, and possibly cervical secretions are particularly infectious. The commonest mode of transmission of the virus throughout the world is by sexual intercourse: whether this is anal or vaginal is unimportant. Other methods of transmission are through the receipt of infected blood or blood products and donated organs and semen. Transmission also occurs through the sharing or reuse of contaminated needles by injecting drug users or for therapeutic procedures, and from mother to child. Transmission from mother to child occurs in utero, at birth (intrapartum) and through breast milk. There is no well documented evidence that the virus is spread by saliva. It is not spread by casual or social contact. Health-care workers can, however, be infected through
TABLE 11.2 Centers for Disease Control (CDC) revised classification system for HIV infection (1993)
New HIV infections in 1999
Clinical categories
A Asymptomatic, acute (primary) HIV or PGL
B Symptomatic, not (A) or (C) conditions
C AIDSindicator conditions
1. >500x10 /L
A1
B1
2. 200-499 x10 6 /L
A2
B2
3. <200x10 6 /L
A3
B3
C1 C2 C3
CD4+Tcell categories 6
TABLE 11.3 Global summary of the HIV/AIDS epidemic during December 1999 (WHO/UNAIDS)
PGL = persistent generalized lymphadenopathy.
Adults (women Children <15 years TOTAL
People living with HIV/AIDS
Adults (Women Children <15 years TOTAL
11
5 million 2.3 million) 570000 5.6 million 32.4 million 14.8 million) 1.2 million 33.6 million
Deaths due to HIV/AIDS, 1999
2.6 million
Cumulative number of deaths due to AIDS/HIV
16.3 million
needle-stick injuries and by skin and mucosal exposure to infected blood or body fluids. Finally, there is no evidence that the virus is spread by mosquitoes, lice, bedbugs, in swimming pools, or by sharing cups, eating and cooking utensils, toilets or air space with an infected individual. In other words, HIV and AIDS are not contagious.
Size of the problem Worldwide The WHO and UNAIDS estimate that by the end of 1999, 32.4 million adults and 1.2 million children worldwide will be living with HIV, and that cumulatively since the start of the epidemic, 16.3 million people will have died from HIV/AIDS (Table 11.3). The largest burden of infection has fallen on the developing world, particularly subSaharan Africa, which has close to 70% of the global total for HIV-infected people but is home to just 10% of the world (Fig. 11.3). In adults aged between 15 and 49 years it is estimated that the prevalence of those living with HIV/AIDS in 1999 was 8% in sub-Saharan Africa, compared to 0.56% in North America and 0.25% in western Europe. Recent studies have shown that although in the developing world HIV is transmitted predominantly by heterosexual intercourse, the female-to-male ratio of infected persons in sub-Saharan Africa is 1.2:1. There are several factors that might account for this, including the greater efficiency of male-to-female HIV transmission through sex, and the younger age at first sexual contact for women. Elsewhere in the world, estimated new infections continue to increase markedly in south and southeast Asia, including India, although preventative programmes in Thailand are beginning to be effective. Eastern Europe and central Asia, constituting Russia and the other former states of the USSR, also saw a marked increase in the estimated reported number of HIV-infected people, rising by one-third, and largely driven by transmission through injecting drug use. United Kingdom and United States By December 1999, 724636 cases of AIDS in adults had
FIG. 11.3 Adults and children estimated to be living with HIV/AIDS as of December 1999 (WHO/UNAIDS)
been reported in the United States, and in the United Kingdom the total was 16457. These figures are thought to be reasonably accurate and complete. Both countries have seen a significant decrease in the number of new cases of AIDS reported, a result of clinically effective antiretroviral therapy; however, new infections with HIV continue to occur and the prevalent population of people living with AIDS/HIV is rising. In North America and the UK the first wave of the epidemic occurred in homosexual men. Although new infections among men who have sex with men still arise, this group now accounts for less than 50% of those newly diagnosed with HIV infection per year in both countries. In the USA an increasing proportion are among injecting drug users who share needles or equipment, and in the UK among heterosexuals (Fig. 11.4). The latter is driven largely by an imported epidemic from subSaharan Africa, with only small numbers having acquired the infection through heterosexual contact within the UK. In the USA, 16% of AIDS cases have occurred in women, although the commonest route of transmission among such women is injecting drug use (42%). The next most common is heterosexual contact (40%).
441
FIG. 11.4 A changing epidemic: cases of HIV infection by exposure category diagnosed in the UK 1989-1999
THE HUMAN IMMUNODEFICIENCY VIRUS The human immunodeficiency virus type 1 (HIV 1) was first isolated in 1983 at the Pasteur Institute, Paris. It has a cylindrical core surrounded by a bilayered lipid envelope acquired as the new virion buds from its host cell. Implanted into this envelope are viral glycoproteins (Gp41 and 120 - Fig. 11.5) carrying receptor sites for the CD4 antigen expressed on the surface of host cells. Only cells bearing this antigen are susceptible to infection. The inner core of the virus is made up of the capsid protein P24 encasing two strands of viral RNA and viral enzyme molecules. The nucleic acid of HIV 1 has been cloned and sequenced. It has a basic gene structure common to retroviruses but is very different from the other human retroviruses, human T-lymphotrophic viruses 1 and 2. A second human immunodeficiency virus (HIV 2) was isolated in 1986 and has similar biological properties to HIV 1, but is limited to west Africa or countries with links to that area. On entry to the infected cell the viral reverse transcriptase enzyme (hence retrovirus) makes a DNA copy (proviral DNA) of the RNA genome (Fig. 11.6). The pro viral DNA is able to integrate into the host cell DNA. Latent or non-productive or productive viral replication may occur. During productive replication RNA transcripts are made from the proviral DNA, and complete virus particles
1
442
MCQ 11.1
FIG. 11.5 Schematic representation of the Human Immunodeficiency Virus
are assembled and released from infected cells by characteristic budding. The virus has three main genes: • 'Pol', which encodes for the three viral enzymes: reverse transcriptase, integrase and protease; • 'env' which encodes for the envelope glycoproteins; • 'gag', which encodes for core proteins. In addition, there are accessory genes which encode for regulatory proteins that control HIV replication within the target cell. 1
IMMUNOLOGY OF AIDS In the weeks following infection there is a sharp increase in plasma viral load, widespread dissemination of the virus, and occasionally clinically an acute seroconversion illness. An immune response to HIV develops, followed by a fall in detectable plasma viraemia. Although a period of prolonged clinical latency then ensues, viral replication continues within lymphoid tissue, together with a gradual fall in the number of circulating CD4 T cells in the peripheral blood. Destruction of lymphocytes bearing the T4 or CD4 differentiation antigen and loss of specific T-helper cell function seems to be the primary abnormality of immune dysfunction. The CD4 molecule, however, is also displayed
TABLE 11.4 Immunological abnormalities In HIV infection
11
Lymphopenia: CD4 T lymphocyte (naive and memory) cytotoxic responses: cell-mediated T cells (CD8) natural killer cells T-cell antigen repertoire 4 proliferative responses (mitogens, antigens) decrease skin allergy to common recall antigens e.g. Candida, PPD, tetanus immunoglobulins: polycolonal B-cell activation decreased de novo antibody response cytokine e.g. TNF-a, interleukins
FIG. 11.6 HIV replication cycle The main targets for antiretroviral treatments are inhibition of the viral enzymes: 1. Fusion of virus with CD4 receptor molecule; 2. Reverse transcriptase, which facilitates the transcription of viral RNA to a DNA copy; 3. Protease, which is necessary for cleavage of pre-cursor viral structure proteins after budding of HIV virion.
at lower density on other cells, such as monocytes, macrophages and some B lymphocytes, some of which may act as reservoirs of HIV infection. The CD4 lymphocyte has a pivotal role in the immune response (interacting with macrophages, other T cells, B cells and natural killer cells, either by direct contact or via the influence of lymphokines such as y-interferon and interleukin 2, see Ch. 4). The other immunological abnormalities seem to be largely secondary to the disorder of CD4 lymphocytes (Table 11.4). In vitro, HIV produces a cytopathic effect in susceptible cell lines, multinucleate giant cells (syncytia) form and cell death occurs. The mechanism(s) by which it produces immune dysfunction in vivo are not yet fully understood, but may include a direct cytopathic effect of HIV on the CD4 lymphocyte, HIV-specific cellular immune responses directed towards infected cells, and the triggering of programmed cell death (apoptosis) by viral proteins. Different factors, both viral and host determined, are likely to influence the rate of disease progression. A small number of HIV-infected persons, however, show little evidence of immunosuppression many years after acute infection (long-term non-progressors). It is thought that the breadth of the immune response to the different HIV anti-
gens at the time of primary infection is pivotal in determining disease progression. In most infected persons there is a rapid loss of specific T-helper cell and CTL responses to multiple HIV antigens during primary infection, which do not recover during chronic established infection. In persons where these specific immune responses are preserved, plasma HIV RNA levels are low, viral replication is contained and clinical disease progression slow. A better understanding of these specific protective immune responses may lead to a more complete knowledge of the immunopathogenesis of AIDS and the possible development of a protective vaccine.
NATURAL HISTORY Acute infection with HIV may be accompanied by a transient non-specific illness similar to glandular fever; it includes fever, malaise, myalgia, lymphadenopathy, pharyngitis and a rash. A transient aseptic meningoencephalitis may also occur. Most acute infections, however, are subclinical. The acute infection is accompanied by the development of antibodies to the core and surface proteins, usually in 2-6 weeks, although delayed seroconversions have been observed. Antibodies are usually detected by enzyme-linked immunoassays, and their presence can be confirmed by immunofluorescence or Western blot. Molecular techniques (PCR) have been developed to measure quantitative levels of plasma viral RNA and cellular viral DNA. High levels of plasma viraemia are detectable at times of seroconversion and before the appearance of antibodies. Diagnosis of acute primary infection can be confirmed by a positive PCR test for proviral DNA (or viral RNA using assays of high specificity) together with either a negative antibody test or the presence of an evolving antibody response. Following acute infection plasma levels rapidly decline and a chronic infection ensues (Fig. 11.7) which is asymptomatic in the early stages. Physical examination may show no abnormality, but about one-third of patients have persistent generalized lymphadenopathy (PGL). This is defined as lymph nodes of 1 cm or more in diameter in
443
FIG. 11.8 Oral candidiasis in the patient with symptomatic HIV infection The figure shows scattered white plaques with underlying erythema on the soft palate. FIG. 11.7 Progressive depletion of CD4 T cells in AIDS Plasma viraemia in peripheral blood, CD4 levels following primary infection with HIV. Once the CD4 count falls below a certain level the risk of major opportunistic infections increases substantially (adapted from Pantaleo G, Graziosi C, Fauci AS. New Eng J Med 1993 328: 327-334).
two or more non-contiguous extrainguinal sites, which cannot be explained by any other infection or condition. The commonest sites of lymphadenopathy are the cervical and axillary lymph nodes; it is unusual in the hilar lymph nodes. Biopsy usually shows a benign profuse follicular hyperplasia. At some time after the initial infection non-specific constitutional symptoms develop. These may be intermittent or persistent, and include fevers, night sweats, diarrhoea and weight loss. Patients may also be affected by several 'minor' opportunistic infections or conditions that tend to affect the mucous membranes and skin, such as oral candidiasis (Fig. 11.8), oral hairy leukoplakia (Fig. 11.9), herpes zoster, recurrent oral or anogenital herpes simplex, and other skin conditions such as seborrhoeic dermatitis, folliculitis, impetigo and tinea infections. This collection of symptoms and signs, which are often a prodrome to the development of major opportunistic infections or tumours, is referred to as symptomatic non-AIDS (Table 11.5). Without treatment with antiretroviral therapy, about 75% of HIV-infected people developed symptomatic disease (either AIDS or non-AIDS) and 45-50% develop AIDS in 9-10 years from primary infection. Retrospective testing of stored blood samples from early prospective
FIG. 11.9 Oral hairy leukoplakia in a patient with symptomatic HIV infection The figure shows a corrugated white patch on the lateral border of the tongue.
cohort studies have shown that levels of plasma viral load, combined with the absolute CD4 count, are highly predictive of the risk of clinical progression (Fig. 11.10). Infected persons with low plasma viral load levels following primary infection, presumably reflecting a better-preserved specific immune response to HIV, have a much lower risk of clinical progression than those with substantially higher plasma viral load. 12
OPPORTUNISTIC INFECTIONS
1
444
Case 11.1
2
MCQ 11.2
The incidence of opportunistic infections in populations of HIV-infected persons has fallen significantly in the developed world over the last few years with the widespread use of more effective antiretroviral therapies and better predictive monitoring of the risk of clinical progression in
11
TABLE 11.5 Common complications of symptomatic HIV disease Early
CD4 count 100-500 x106/L *Constitutional symptoms (fever, diarrhoea, weight loss) *Herpes zoster *0ral hairy leucoplakia *0ral Candida *Skin problems
Late
CD4 count 200-50 x10 6 /L Recurrent bacterial pneumonia Pulmonary tuberculosis Pneumocystis carinii pneumonia Oesophageal Candida Kaposi's sarcoma Cryptosporidial-microsporidial diarrhoea Cryptococcal meningitis Cerebral toxoplasmosis *HIV peripheral neuropathy
Advanced
C D4 count <50x10 6 /L CMV diseases: retinitis, colitis, polyradiculopathy, encephalitis Disseminated MAI infection Severe wasting syndrome AIDS-related dementia Lymphoma
FIG. 11.10 Risk of progression to AIDS at 3 years by CD4 count and plasma viral load (adapted from Mellers JW, Munoz A, Giorgi JB et al. Ann of Intern Med 1997 126: 946-954).
Progressive multifocal leucoencephalopathy * Symptomatic non-AIDS.
Pulmonary complications an individual. Opportunistic infections, however, remain common in the developing world, and in those who are newly diagnosed in late-stage disease or who decline antiretroviral therapy or who have experienced multiple treatment failures. The organisms responsible for the opportunistic infections that occur in patients with AIDS are unusual pathogens. Most of the infections are due to reactivation of latent organisms in the host or, in some cases, to ubiquitous organisms to which we are continually exposed. The infections are often difficult to diagnose because conventional serological tests are unhelpful, and treatment often suppresses rather than eradicates the organisms. If patients are able to respond to effective antiretroviral combinations, then immune reconstitution can occur and relapse of opportunistic infections is uncommon. In the absence of effective antiretroviral therapy severe immune deficiency persists, and relapse of opportunistic infections is common and continuous treatment with prophylactic drugs may be necessary. Three main organ systems are affected: the respiratory system, the gastrointestinal tract and the central nervous system. In addition, patients may present with a history of night sweets, chronic ill health, fevers or weight loss.
Pneumocystis carinii pneumonia (PCP) is one of the commonest life-threatening opportunistic infections in patients who progress from symptom-free infection to AIDS. The presentation is subacute, and malaise, fatigue, weight loss and shortness of breath often develop over several weeks. Typical retrosternal or subcostal chest discomfort, associated with increasing shortness of breath, a dry cough and fever, finally cause the patient to seek help. The chest X-ray at presentation may be normal or show bilateral fine infiltrates, which are typically perihilar (Fig. 11.11). The arterial oxygen tension is usually depressed, and the carbon monoxide transfer factor, when available, is low. A fall in oxygen saturation levels from normal at rest to below normal on exercise is a useful sign of early infection. The diagnosis is confirmed by cytological examination of induced sputum or of bronchoalveolar lavage (BAL) from fibreoptic bronchoscopy. First-line treatment is high-dose co-trimoxazole for 18-21 days, but intolerance may be a problem owing to nausea, rash and bone marrow suppression. Pyogenic bacterial causes of pneumonia should always be considered, particularly as its presentation may be atypical. The radiological appearances may include diffuse infiltrates as well as the more typical focal or lobar patterns. Bronchoscopy is frequently helpful to differentiate
445
Gastrointestinal and hepatic complications Oral and oesophageal complications Oral candidiasis occurs frequently (see Fig. 11.8). Oesophageal candidiasis is the commonest cause of dysphagia or retrosternal discomfort and may frequently be the first AIDS-defining illness (Fig. 11.12). Oral candidiasis alone does not fulfil the criteria for AIDS. Oesophageal infection is best shown by culture or biopsy at endoscopy, although plaques of Candida albicans can often be seen during a barium swallow. Ulceration may be focal or diffuse. Cytomegalovirus and herpes simplex virus may both cause a similar pattern of ulceration in the oesophagus (and also may affect the stomach and duodenum), and should always be considered if oesophageal symptoms do not resolve on treatment with systemic antifungal agents.
FIG. 11.11 Chest radiograph of Pneumocystis carinii pneumonia, showing bilateral interstitial shadowing
between PCP, pyogenic bacteria and other infections, particularly in patients with an atypical presentation or who fail to respond to treatment. Cryptococcal pneumonia may occur in patients with cryptococcal meningitis and disseminated infection. Cytomegalovirus may be seen in BAL specimens, but appears not to be a major cause of pneumonia. 1 Infection with Mycobacterium tuberculosis occurs and, since 1993, has constituted a diagnosis of AIDS (see Case study Fig 11.1.1, p. 454). The downward trend of reported cases of tuberculosis in the United States has slowed at the same rate as the HIV epidemic has grown. Pulmonary tuberculosis can occur at different stages of immunosuppression, but tends to appear earlier in HIV disease than the atypical mycobacterial infections that complicate severe immunosuppression of advanced AIDS. In subSaharan Africa tuberculosis, both extrapulmonary and pulmonary, is a major cause of morbidity and death in HIV-infected persons. 2
Diarrhoea, malabsorption and weight loss Diarrhoea is a common symptom in patients with chronic HIV infection, with or without other manifestations of AIDS. In the majority of cases a pathogen is found, although an enteropathy with malabsorption may occur secondary to HIV infection. Cryptosporidium, a coccidian protozoal parasite, is probably the commonest pathogen isolated from patients with AIDS who have diarrhoea. It is the commonest of the protozoal causes of diarrhoea, which also include Isospora belli and microsporidia. In immunocompetent human
SUMMARY 1 Pulmonary infiltrates in HIV disease 1. Differential diagnosis Infective:
• Pneumocystis carinii pneumonia • Bacterial infection:
•
• • •
Streptococcus pneumoniae Haemoph/lus influenzae Pseudomonas aeruginosa Mycobacterial: M. tuberculosis Atypical mycobacteria M. avium-intracellulare M. kansasii M. xenopi Cryptococcus neoformans Toxoplasma gondii Cytomegalovirus
Non-infective: • Kaposi's sarcoma • non-Hodgkin's lymphoma • non-specific interstitial pneumonitis 2. Investigation
1
446
Fig. 11.1
2
MCQ 11.3
3
Fig. 11.2
Arterial blood gases or oximetry Sputum examination: Smear for acid-fast bacilli, Culture Fibre-optic bronchoscopy and broncho-alveolar lavage CT scanning, Nuclear medicine scanning Open lung biopsy
More recently, with improved diagnostic techniques, microsporidium, a small obligate intracellular protozoa, has been increasingly identified as a possible cause of diarrhoea and weight loss in patients with AIDS where no other pathogen had previously been found. Cytomegalovirus and herpes simplex virus can cause focal or diffuse ulceration of the gut, from the mouth to the anus. Herpes simplex virus most commonly causes mucocutaneous lesions at the upper and the lower ends of the gastrointestinal tract, whereas cytomegalovirus most frequently causes a colitis or oesophageal ulceration. Atypical mycobacteria of the avium intracellular complex are ubiquitous organisms that have little virulence for the immunocompetent host. Disseminated infection with Mycobacterium avium-intracellulare (MAI) of several organs occurs in patients with AIDS. Gastrointestinal infection may be associated with fever, weight loss, abdominal pain, diarrhoea and malabsorption. Diagnosis can be made by acid-fast staining of the stool or biopsy material, or both, or culture of blood or tissue. Shedding of atypical mycobacteria in stools alone does not indicate disseminated disease, but may often precede the presenting symptoms of disseminated infection. These are typically high fevers, anaemia and weight loss. 0 The diagnosis is most frequently confirmed on blood cultures or bone marrow examination. Mycobacterium tuberculosis infection of the bowel does occur, but is less common. Campylobacter and Salmonella species infections may cause diarrhoea, but the latter more commonly presents as a fever of unknown origin with bacteraemia.
FIG. 11.12 Barium swallow of oesophageal candidiasis The figure shows extensive oesophageal ulceration.
hosts cryptosporidium produces a transient diarrhoeal illness. In people infected with HIV it can cause transient, intermittent or persistent diarrhoea, ranging from loose stools to watery diarrhoea, colic, and severe fluid and electrolyte loss. Oocysts can be found in stools. If direct smears of unconcentrated faecal samples stained with iodine or modified acid-fast stains fail to show the oocysts the samples should be concentrated. The diagnosis should not be discounted without examining multiple specimens.
Hepatitis and cholestasis At all stages of HIV infection the commonest causes of acute hepatitis, both symptomatic and asymptomatic, are either drug toxicity or coinfection with viral hepatitis B or C. Treatment with many of the current antiretroviral agents is associated with a risk of drug-induced hepatitis, e.g. the nucleoside analogue stavudine, the non-nucleoside reverse transcriptase inhibitor nevirapine (usually in association with a rash and fever) and the protease inhibitor ritonavir. Severe acute hepatitis with liver failure secondary to hepatitic steatosis (in which the liver cells are filled with small fat droplets) is a rare complication of treatment with the reverse transcriptase inhibitors. Drugs used to treat specific acute opportunistic infections may also be implicated, and include the antimycobacterial agents, systemic azoles and high-dose co-trimoxazole. When multiple drugs are being taken then drug-induced hepatitis must always be considered. Acute primary infection with viral hepatitis A, B or C should be considered. Chronic infection with viral hepatitis B and C is more common among homosexual men and injecting drug users. In those coinfected with HIV there is a higher likelihood of progression to more severe chronic liver disease and cirrhosis. In patients with AIDS specific opportunistic infections
11
447
can cause hepatitis, which may present as fever, abdominal pain and hepatomegaly. If an ultrasound does not show dilated intra- or extrahepatitic bile ducts, suggesting obstruction, needle biopsy often shows granuloma hepatitis, usually caused by atypical mycobacteria rather than M. tuberculosis. The herpes viruses may also occasionally cause hepatitis as part of a disseminated infection. Acalculous cholecystitis and cholangitis show an endoscopic retrograde cholangiographic picture similar to that of primary sclerosing cholangitis, with strictures and dilatation of the biliary tree. Cryptosporidium and cytomegalovirus have been isolated and are implicated as a cause of this syndrome (Fig. 11.13).
tomatic disease. At necropsy up to 90% of patients dying of AIDS have chronic subcortical encephalitis, characterized by infected macrophages and microglial cells that fuse to form multinucleate giant cells. There is also patchy demyelination and astrogliosis.
Neurological complications Cerebral toxoplasmosis is the commonest cause of intracranial mass lesions and usually presents with focal symptoms and signs (Fig. 11.14). The main differential diagnosis is primary intracerebral lymphoma. Cytomegalovirus commonly causes a retinitis (Fig. 11.15) and presents with blurring and/or partial loss of vision. It may eventually lead to blindness. CMV may also cause a polyradiculoneuropathy or encephalitis, which is more rapid in onset and progression than HIV encephalitis alone. Differentiation may be helped by the detection of cytomegalovirus DNA by polymerase chain reaction (PCR) in the cerebrospinal fluid. Meningitis due to Cryptococcus neoformans should always be considered in patients with advanced disease presenting with headache and fever, although symptoms may be more non-specific. Infection with the papovavirus JC is responsible for progressive multifocal leukoencephalopathy (PML), a form of demyelination which causes progressive neurological impairment such as hemiparesis, with or without aphasia. 1 The majority of persons who develop PML have a positive PCR test for JC virus in their cerebral spinal fluid.
FIG. 11.13 ERCP of HIV associated sclerosing cholangitis The figure shows dilation of the common bile duct and dilation and stricture of the hepatiticbilarytree.
HIV NEUROLOGICAL DISEASE Apart from opportunistic infections, chronic HIV infection is associated with several syndromes that affect the nervous system, in addition to the transient meningoencephalitis, myelopathy and peripheral neuropathy of acute infection. These neurological diseases are due to the direct or indirect effects of HIV and not to opportunistic infection. AIDS-related dementia (HIV encephalopathy) has been estimated to occur in 10-40% of patients with symp-
448
1
Case 11.2
4
MCQ 11.4
2 Fig. 11.3 5 Fig. 11.5
0 Fig. 11.4 FIG. 11.14 CT brain scan of cerebral toxoplasmosis The figure shows multiple ring enhancing lesions with oedema.
11
FIG. 11.15 Cytomegalovirus retinitis in a patient with AIDS The figure shows extensive areas of white granular retinal necrosis and haemorrhage. ©
The clinical features are characterized by cognitive and behavioural changes that include memory loss, apathy and impaired concentration and attention. Neurological examination may show hyperreflexia, hypertonia and frontal lobe signs. CT or MRI often show cerebral atrophy © and non-specific changes in the white matter. The cerebrospinal fluid findings are non-specific. Opportunistic infections, intracranial mass lesions, metabolic encephalopathy and neurosyphilis should be excluded. Treatment with antiretroviral therapies may improve symptoms in those with early cognitive impairment, but probably have little impact on those with severe AIDS dementia other than to reduce their risk of subsequent opportunistic infections. HIV infection is also implicated in vacuolar myelopathy, affecting primarily the posterior and lateral spinal cord, an aseptic meningitis and the following neuropathies: axonal sensory, chronic inflammatory demyelinating and mononeuropathies. 45
FIG. 11.16 Cutaneous lesions of kaposi sarcoma in AIDS, appearing as purple raised plaques or nodules on the skin surface
TUMOURS Kaposi's sarcoma Kaposi's sarcoma (KS) is a presenting feature in 16% of patients, though the incidence has fallen over recent years. It is commoner in homosexual men than in the other groups at risk. The Kaposi's sarcoma of AIDS differs from classic Kaposi's sarcoma in that widespread skin (Fig. 11.16), mucous membrane (particularly the oral cavity and palate), visceral and lymph node disease occurs. Visceral, particularly gastrointestinal, lesions are present in as many as half of all patients at presentation. Nodules of Kaposi's sarcoma also occur in the lungs. Chest X-ray appearances vary from confluent irregular masses to interstitial nodularity and are better illustrated on a CT scan of the thorax (Fig. 11.17). CT of the thorax
FIG. 11.17 CT scan of pulmonary kaposis sarcoma The figure shows irregular masses and nodules in the lung parenchyma.
may be useful in differential diagnosis. At bronchoscopy, endobronchial lesions may be seen. Kaposi's sarcoma consists of spindle-shaped cells arranged in nodules and broad bands, and contains vascular slits filled with extravasated
449
erythrocytes. The diagnosis of Kaposi's sarcoma in very early skin lesions may be extremely difficult, as little more may be seen than a few irregular dilated vascular channels in the mid dermis and a mild inflammatory cell infiltrate. A herpes virus, kaposi sarcoma-associated herpes virus 8 (KSHV8), has been identified in kaposi sarcoma lesions of all forms, including both classic and AIDS associated. The incidence of positive serology to KSHV8 in different HIVinfected patient populations reflects the incidence of KS in these patient groups. The presence of KSHV8 in blood is predictive of the subsequent risk of developing KS. These observations suggest a causal role for KSHV8 in the development of KS.
Non-Hodgkin's lymphoma As in other chronically immunosuppressed patients, there is a greatly increased risk of non-Hodgkin's lymphoma. Although the tumour typically affects lymph nodes, extranodal disease is common and affects the central nervous system, bone marrow and gastrointestinal tract. The diagnosis should also be considered in patients with weight loss, constitutional symptoms and anaemia. These are B-cell lymphomas of high or intermediate grade. Response to cytotoxic drugs occurs, but treatment is difficult and usually unsuccessful because of profound immune suppression. In addition to secondary involvement of the CNS a proportion of AIDS associated Non-Hodgkin's lymphoma presents as primary CNS lymphoma; tumours which are intracranial parenchyma lesions limited to the CNS. Patients usually present with single large mass lesions in the brain (Fig. 11.18). 1
Other tumours Squamous carcinomas of the mouth and anorectum occur in homosexual men with antibodies to HIV. Human papillomavirus may play a part. There is a higher proportion of cervical intraepithelial neoplasia (CIN) in HIV infected women and a higher rate of progression from lower to high grade CIN.
TREATMENT AntiretroviraIs Acute primary infection Treatment with antiretroviral agents should be considered in patients with acute primary HIV infection.
1 Fig. 11.6 450
FIG. 11.18 CT brain scan of primary cerebral lymphoma The figure shows a large single ring enhancing lesion with mid-line shift.
There is, however, no substantial evidence that antiretroviral therapy started at this stage results in greater longterm clinical benefit than if treatment is initiated during established chronic infection. However, the initiation of therapy within a few weeks of infection can result in immunological benefit, with preservation of specific Thelper cell responses to HIV, higher T-helper (CD4) cell counts and better HIV-specific cytotoxic T-lymphocyte responses. Although these preliminary immunological observations are impressive, their relative importance in the long-term treatment of HIV infection is not known. It is also uncertain whether the treatment initiated during primary infection should be continued long term or can be stopped after 1-2 years, with preservation of immunological benefit. Trials are under way to evaluate this treatment strategy. Until further evidence is available the decision to start antiretroviral therapy at this stage is a balance between preserving immune responses and the possible risk of drug toxicity, therapy failure, and the lack of evidence of long-term clinical benefit. Chronic adult infection The treatment of HIV infection has improved markedly over the last few years, and has resulted in decreases in the incidence of opportunistic infections and an improvement in survival. The results of large randomized clinical trials in the mid-1990s established a strong relationship between falls in plasma viral load occurring on therapy and clinical benefit in the short to medium term. It is now accepted that the objective of therapy is to sustain the suppression of viral load to levels that are preferably below the limits of
detection with the currently available ultrasensitive assays (less than 50 copies per mL). The suppression of viral replication results in sustained increases in CD4 cell counts (both memory and naive T cells), increases in the T-cell antigen repertoire, and re-establishment of T-cell responses to various antigens (e.g. CMV, mycobacteria). Failure to suppress plasma viral load optimally is associated with subsequent rebound of the viral load, the emergence of viral isolates with reduced drug sensitivity and subsequent falls in CD4 cell counts, and continued damage to the immune system. Currently there are three classes of antiretroviral drug available. These are nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs) and the protease inhibitors (PIs). The NRTIs are direct competitive inhibitors of the viral enzyme reverse transcriptase. NNRTIs are indirect inhibitors that bind to a site distant to the active site of the enzyme. The protease inhibitors inhibit the viral enzyme protease, which is responsible for the post-translational cleavage of precursor structural core proteins following budding of the HIV virion (see Fig. 11.6). Clinical trials have shown that a combination of three or more antiretroviral drugs results in greater and more sustained falls in plasma viral load, and increases the CD4 count more than with mono or dual therapy. It is currently usual standard clinical practice to combine two NRTIs with either one NNRTI or one or two PIs (Table 11.6). Comparative trials have shown that a triple combination containing either a PI or an NNRTI have similar antiviral efficacy at 12-18 months. Although there is more substantial trial evidence of the clinical benefit of PIs, it is generally accepted that NNRTI-containing regimens will result in similar clinical benefit, in view of their similar effects on viral load and CD4 count. It remains unclear, however, which regimen is the better for patients who have never received treatment. Recent trials have also demonstrated that combinations of 3 NRTIs as initial therapy to have similar efficacy to certain combinations to 2 NRTIs + either 1 NNRTI or 1 PI. It is also not yet clear which regimen should be used in patients who have experienced one or two failures of therapy. Trials are under way to assess different treatment strategies in each of these situations. There is no evidence from randomized clinical trials that helps to decide with the current therapies when, in the natural history of HIV infection, to initiate therapy. Treatment guidelines (Table 11.7) have used surrogate (laboratory-based) data from prospective studies of the natural history of the disease to guide the time to start therapy. These data have been added to the current knowledge of the effectiveness and tolerability of current combination treatments and the willingness of an infected person to start therapy. Most patients will start therapy once their CD4 count is 350 x 106/L or below, but national guidelines vary and so do the motivation and willingness of individual patients. A significant proportion of patients present and are
11
TABLE 11.6 Antiretroviral regimens (2001) 1. 2 NRTIs plus either: 1 NNRTI or 1PI or
2 PIs 2. 3 NRTIs
e.g. zidovudine or stavudine + lamivudine or didanosine e.g. nevirapine or efavirenz e.g. nelfinavir or lopinavir/r e.g. saquinavir + ritonavir zidovudine, lamivudine, abacavir
Recommended antiretroviral regimens for the initial treatment of established chronic infection in adults (2001) NRTis, nucleoside reverse transcriptase inhibitors NNRTIs, nonnucleoside reverse transcriptase inhibitors PIs, protease inhibitors.
TABLE 11.7 Treatment guidelines for starting antiretroviral therapy adults (2001) Disease stage
BHIVA(1)
US DHHS (2)
Symptomatic Asymptomatic (i) CD4<200x10 6 /L (ii) CD4 200-350 x106/L
Treat
Treat
Treat Consider treatment depending upon VL, rate of CD4 count decline symptoms and patient wishes Definitely
Treat Treatment should be generally offered
(ii) CD>350x10 6 /L
Defer or consider treatment if high VL
(1) BHIVA, British HIV Association Guidelines (Oct 2001). (2) USDHHS, United States Department of Health and Human Services (Feb 2001). VL, viral load. Treatment guidelines are constantly reviewed and updated.
diagnosed in latent disease when symptomatic and have CD4 counts of <200 x 106/L. Even in patients who are newly diagnosed at a late stage of disease, starting antiretroviral therapy can result in substantial increases in CD4 count and sustained clinical benefit. Although clinically effective, current antiretroviral drugs are not ideal. In patients not previously treated with antiretroviral drugs only 50-60% will sustain falls in plasma viral load to undetectable levels, as measured by the current ultrasensitive assays at 1 year of therapy. Poor tolerability and side-effects account for a high proportion of therapeutic failures, together with poor adherence and limited antiviral potency. Excellent compliance with combination therapies is a major determinant of therapeutic success. Every effort should be made, in both choice of
451
TABLE 11.8 Treatment guidelines for major opportunistic infections Infection
Drug
Dose
Duration 14-21 days 6 weeks
Pneumocystis carinii pneumonia
Trimethoprim/sulfamethoxazole
15-20/75-100 mg/kg/day (divided doses)
Cerebral toxoplasmosis
Pyrimethamine + sulfadoxine orclindamycin
Cytomegalovirus retinitis
Ganciclovir cidofovir
200 mg on first day then 50mg o.d. 4-6 g daily 600mg q.d.s. 10mg/kg/day/i.v. 5mg/kg/weekly/i.v.
Cryptococcal meningitis
(i) (ii)
Amphotericin B ± flucytosine or fluconazole
Disseminated MAI
Clarithromycin + ethambutol + rifabutin
Oesophageal candidiasis
Ketoconazole Fluconazole
0.5-1.0mg/kg/day/i.v. 75-100 mg/kg/day 600-800 mg/day 500mg-1gb.d. 15 mg/kg/day 400-600 mg/day 200-400 mg/day 50-100 mg/day
2 weeks 6 weeks
Indefinite
7-14 days
Following treatment course all major opportunistic infections require maintenance treatment regimens at adjusted doses. With effective antiretroviral therapy CD4 counts increase and secondary prophylaxis and treatment for MAI infection may be discontinued.
therapies and clinical and psychological support, to aid adherence to treatment. The emergence of viral isolates which are resistant to antiretroviral drugs is common in patients experiencing therapy failure. Phenotype and genotype assays have recently become available, and initial studies have demonstrated better virological outcome from their use in guiding the choice of new antiretroviral regimens in patients who are experiencing treatment failure. Recently long-term toxicities with antiretrovirals have been increasingly recognized, with patients experiencing metabolic toxicity (e.g. diabetes, hyperlipidaemia and lactic acidosis) and fat redistribution syndromes (lipodystrophy). The pathogenesis for some of these toxicities, particularly lipodystrophy, is not fully understood. Several predisposing factors seem to be involved, including specific actions of antiretroviral drugs, the previous treatment history and age of the patient. Antiretroviral agents with new sites of action are being developed. The binding of HIV to the CD4 molecule on the cell surface has long been a potential target for therapy. Recently, fusion inhibitors have been developed (T20) which bind to the HIV transmembrane protein GP41, preventing the conformational changes necessary for viral entry into the cell. Initial trials of T20 in patients who have experienced multiple therapy failures have shown good
452
1
MCQ 11.5
2
Case 11.3
3
Case 11.4
4
Case 11.5
antiviral response in the short term, suggesting that this new class of drugs maybe beneficial clinically. Another approach is through chemokine receptors, which act as coreceptors for HIV binding and determine the susceptibility of the target cell to infection by different HIV strains. New drugs are being developed which block chemokine receptor binding. 12
Opportunistic infections In the developed world, treatment of major opportunistic infections associated with HIV infection is usually effective. Mortality remains highest in those who present late with previously undiagnosed HIV infection, and treatment is frequently associated with a high incidence of drug sideeffects which limit tolerability. Treatment guidelines for the major opportunistic infections are outlined in Table 11.8. Alternative regimens for the treatment of Pneumocystis carinii pneumonia in those intolerant to high-dose co-trimoxazole are combinations of clindamycin and primaquine, or intravenous pentamidine and atovaquone. Steroid therapy is indicated in those who present with severe hypoxia (Pao2 < 9.3kPa), as this has
SUMMARY 2 AIDS prevention strategies • Control of generally sexually transmitted infections • Promoting safe sex behaviour in people with known HIV infection and those not infected or of unknown status • Promoting early diagnosis of HIV infection in those at risk • Ensuring good and equal access to HIV treatment services
been shown to improve clinical outcome and response. Although Pneumocystis resistance to co-trimoxazole has been demonstrated, poor clinical response to treatment is usually associated with late presentation or coinfection with bacterial or viral pathogens. Either intravenous ganciclovir or cidofovir is effective for the treatment of a first episode of CMV retinitis or other CMV end-organ disease, such as colitis or oesophageal ulceration. Although the dose scheduling is convenient, renal toxicity with cidofovir is common and frequent laboratory monitoring for toxicity is mandatory. With the initiation of effective antiretroviral therapy, relapse of CMV retinitis is uncommon. In those who do experience relapse, switching anti-CMV agents to combinations of foscarnet and ganciclovir or ganciclovir ocular implants maybe effective. For patients who present with a single or multiple intracerebral space-occupying lesion where toxoplasmosis is a probable diagnosis, the use of steroids should be avoided if possible because the interval MRI brain scan at 2 weeks, to determine an antitoxoplasmosis treatment response, may be difficult to interpret as a result of the effect of steroids on cerebral odema. In those not responding, a diagnosis of primary CNS lymphoma should be considered, particularly if it is a single lesion or there is supporting evidence from a gallium scan. The appearances on an MRI brain scan unfortunately do not aid differentiation. Gastrointestinal infection with cryptosporidium usually results in a self-limiting illness in patients with less advanced immunosuppression. However, in those with severe immunosuppression (CD4 count < 200) chronic infection can result in frequent diarrhoea, severe weight loss, nausea, vomiting, and salt and water depletion. Treatment with specific anticryptosporidial agents is disappointing. Initiation with antiretroviral combination regimens has, however, been shown to be effective as an effect of the improvement in the immune system. It is important for any patient presenting with a major opportunistic infection to be started on an effective antiretroviral combination regimen. Immune reconstitution on antiretroviral therapy will substantially reduce the risk of relapse and of additional opportunistic infections, and may allow the discontinuation of secondary prophylaxis. Effective immune reconstitution with antiretrovirals can also result in disease as T-lymphocyte responses to different antigens are regained. In patients with advanced immune deficiency (CD4 < 100 x 106/L) started on effective antiretroviral therapy, clinically apparent CMV and mycobacterial disease have been reported in the first few months of therapy. This is a result of the immune system mounting effective responses to previously silent infections. It is routine practice for primary prophylaxis against certain opportunistic infections to be started once the CD4 count falls to below 200 x 106/L, irrespective of whether the patient is on an antiretroviral regimen or not. Approxi-
mately one in five persons not on antiretroviral therapy will develop Pneumocystis carinii pneumonia within 1 year of their CD4 count falling to below 200 x 106/L. Primary prophylaxis with cotrimoxazole 960 mg once daily or an alternative regimen (e.g. dapsone 100 mg once daily) reduces this risk to a few per cent. In patients with a CD4 count less than 100 x 106/L and positive serology to toxoplasmosis, once-daily cotrimoxazole is also effective prophylaxis against cerebral toxoplasmosis. Dapsone 100 mg once daily and pyrimethamine 25 mg three times per week is an alternative in patients intolerant of co-trimoxazole. In patients with CD4 counts less than 50 x 106/L prophylaxis with azithromycin 1200 mg once weekly against disseminated Mycobacterium avium intracellulare infection should be considered. Alternative regimens are clarithromycin 500 mg twice daily, or weekly azithromycin plus rifabutin 300 mg daily. Chemoprophylaxis against mycobacterial tuberculosis may also be considered, particularly in those with a high background risk of exposure, but active disease needs to be excluded first, as this requires combination treatment. National guidelines differ, and prophylaxis may not be appropriate in populations with either very high or very low prevalence rates of clinical tuberculosis. Both secondary and primary prophylaxis to most opportunistic infections may be safely discontinued when the CD4 count on antiretroviral therapy has risen persistently to above 200 x 106/L, or even above 100 x 106/L for some opportunistic infections such as CMV disease. Prevention of environmental exposure to certain opportunistic infections may be possible, particularly to cyptosporidium and toxoplasmosis. Outbreaks of cryptosporidial diarrhoea from public water supplies can occur. Patients with severe immune deficiency should be advised to boil their water or use bottled water where the risk of contamination at source may be less than with public supplies. HIV-infected persons who lack IgG antibody response to toxoplasmosis should be counselled about the various sources of toxoplasma infection, and particularly should be advised not to eat raw or undercooked meat. 3 34
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STRATEGY FOR CONTROL OF HIV AND AIDS Both HIV infection and other traditional sexually transmitted diseases (STDs) share similar risk factors in relation to their spread, but in addition they can potentate each other. Both of these facts need to be understood if effective control programmes are to be developed. The presence of an STD, particularly genital ulcers, can enhance both the acquisition and transmission of HIV by increased shedding of the virus within and from the genital tract. Several studies have shown that the risk of acquiring HIV in the presence of an ulcerative or non-ulcerative STD is increased 2-6-fold. The shared risk factors for the acquisi-
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CASE STUDY 11.1 ACUTE DIARRHOEA IN HIV INFECTION A 45-year-old homosexual man presented with a 6-week history of liquid diarrhoea (5-6 times daily), weight loss of 6 kg, episodic abdominal pain and, more recently, nausea and anorexia. He had no recent travel history and no previous history of chronic diarrhoea. He had not noticed blood in his stool, or fever. He was not taking any medication and had no other history. He was a non-smoker and drank 15 units of alcohol per week. He had been found to be HIV antibody positive 6 years ago, but had not attended for regular monitoring and follow-up. On examination he was afebrile, he appeared wasted, had pseudomembranous oral Candida in his mouth and seborrhoeic dermatitis on his face. His abdomen was mildly distended with active bowel sounds, but was otherwise soft and nontender. His CD4 count on this occasion was 110 x 106/L, with a plasma HIV RNA level of 75000 copies per mL. Questions 1. What is the differential diagnosis? 2. How would you manage this patient? Discussion This man presents with chronic diarrhoea, abdominal pain and weight loss. He is known to be HIV antibody positive, and recent tests show that he is severely immunosuppressed, with a CD4 T-cell count of 110 x 106/L. On examination he has oral Candida and seborrhoeic dermatitis - both indicators of clinical progression to symptomatic HIV disease.
454
It is important to exclude an infective cause for his diarrhoea. Several stool samples should be sent for both bacterial culture and microscopy for ova cysts and parasites. (If the patient had taken antibiotics recently then diarrhoea due to Clostridium difficile toxin would also be considered). If repeat stool samples are found to be negative for pathogens, colonoscopy and duodenoscopy with biopsy of the bowel mucosa should be undertaken. If no pathogens are identified then a diagnosis of wasting syndrome secondary to HIV enteropathy can be made by exclusion. Patients with HIV enteropathy have partial villous atrophy of the small bowel mucosa. Gastrointestinal infection with cryptosporidium is frequently responsible for weight loss and persistent diarrhoea in HIV-positive patients with severe immunosuppression. Cryptosporidial infection (Case Fig. 11.1.1) causing diarrhoea for more than 1 month is an AIDS-defining illness. Both the large and the small bowel may
become infected. The small bowel involvement is associated with persistent nausea and recurrent vomiting. Prior to effective antiretroviral treatment gastrointestinal cryptosporidiosis in patients with CD4 counts less than 200 x 106/L was difficult to treat, and severe disease was associated with high morbidity and occasional mortality. There is uncontrolled evidence that a 4-week course of paramomycin may be helpful, but symptom control with antidiarrhoeal drugs was previously the mainstay of treatment. Today, with the availability of effective antiretroviral treatment, this man should be started on a triple combination regimen and given symptom control for his nausea and diarrhoea as required. Subsequent immune reconstitution on therapy should result in clearance of the cryptosporidium and resolution of the diarrhoea. HIV-infected persons with CD4 counts less than 200 should be advised to boil their water as a prophylactic measure against cryptosporidial infection.
CASE Fig. 11.1.1 Cryptosporidial infection of the small bowel
tion of HIV and other STDs, and the interaction between them, has led to the setting up of integrated control programmes in the hope of reducing STDs and slowing the spread of HIV. This strategy was reinforced by the results
of one study in Africa which showed a significant reduction of HIV transmission rates with the provision of STD treatment services. Control of HIV has two elements, primary and sec-
ondary. Primary prevention is aimed at stopping infection occurring in the first place. This is achieved through health education and programmes to market and encourage the use of condoms. In the UK, initial health education campaigns resulted in homosexual men, in particular, adopting safe sex practices. However, such changes are not always easy to sustain, and repeated reinforcement and monitoring is required. Secondary prevention is aimed at promoting health-care seeking behaviour, so that those who could be infected recognize this, regardless of symptoms, and as a result come forward for HIV testing and care if required. This is particularly important, as primary prophylaxis can be offered for PCP, and combination antiviral therapy can have an effect on morbidity and mortality. Everyone is potentially at risk of infection: even though the prevalence among those without recognized risk factors is currently low, it requires sexual contact with only one infected person for transmission to occur. Those who are HIV seronegative and in a mutually monogamous relationship have nothing to fear. The sensible message to everyone else must be: to reduce your risk, reduce your number of sexual partners, know about your partner's previous sexual and drug use history, and use a condom. Condoms may not provide total protection, but they will help considerably if used properly and every time. Preventing the transmission of HIV among injecting drug users must rely on stopping the sharing of needles and other paraphernalia that go with injecting drugs (syringes, mixing bowls, spoons etc.), as well as advising on safer sex practices. Users need to be advised of the risk of sharing; this applies to any form of injection, whether intravenous, intramuscular or subcutaneous. Equally important is advice on the risk of transmitting or acquiring the virus sexually, as well as the potential risk of both male and female prostitution, as this may be used to finance a drug habit. For any individual the best primary prevention is to stop using drugs, but if this is unrealistic at the time, the next option is to stop injecting and switch to sniffing, smoking or swallowing drugs. In the realization that people still continue to inject, a large number of needle exchange programmes have been set up throughout the UK, and are currently thought to be useful in cutting down the sharing of needles. Vertical transmission from mother to child is uncommon in the UK. The risk of an HIV-positive pregnant woman transmitting HIV to her unborn child is thought to be about 13% in developed countries, but up to 30% in the developing world. Intrapartum transmission accounts for the majority of cases of vertical transmission. Factors associated with a higher risk include prematurity, the use of instrumentation during birth, maternal diagnosis of AIDS, maternal viral load levels and breastfeeding. Seropositive women, or women who are considering parenthood, need to be counselled about the risk of pregnancy, to both the mother and her unborn child. A seropositive woman who becomes pregnant can obviously be offered termination, but treatment interventions substantially reduce the risk of perinatal transmission and therefore many wish to go to term.
Early clinical trials showed that zidovudine monotherapy given to mothers from the second trimester up to and including the intrapartum period, together with 6 weeks of zidovudine therapy given to the infant, results in an approximately 70% reduction in transmission rates. Subsequent studies have shown a relationship between the level of maternal plasma viral load on treatment at birth and the risk of transmission. In the developed world it is now common practice to initiate triple combination antiretroviral therapy to achieve and sustain maximum suppression of maternal plasma viral load levels during pregnancy and through the intrapartum period. The avoidance of breastfeeding is essential to sustain this reduction in risk. The implementation of these measures, however, is only possible if both the mother and her physician are aware that she is seropositive during pregnancy. HIV antibody testing should routinely be offered to all pregnant women, irrespective of the perception of risk. In the developing world vertical transmission is a major problem and complex triple combination therapies are too costly. Recent studies have investigated simpler and shorter-course treatments. A single dose of the nonnucleoside reverse transcriptase inhibitor nevirapine, given to the mother at the onset of labour and to the infant aged 48 hours, has been shown to reduce perinatal transmission by approximately 50%, compared to a short course of zidovudine given to the mother during labour and postnatally to the infant for 7 days. Peripartum therapeutic intervention will have no effect on intrauterine transmission. The reduction in transmission rates in infants at 6 weeks is likely to be lost in a breastfeeding population at 2 years, as a result of continued postnatal transmission. The widescale implementation of an effective therapeutic intervention to prevent perinatal transmission in the developing world is a challenge that remains to be met. The risk of occupational transmission of HIV as a result of needle-stick injuries has been estimated to be 0.3%. Although there is no substantial evidence of clinical efficacy, and based largely on biological rationale, it is recommended that health-care professionals who sustain a significant exposure to a bodily fluid from an HIV-infected person should take a triple combination regimen as postexposure prophylaxis for 4 weeks after the incident. Prophylaxis should be started as soon as possible after the incidence, preferably within 1-2 hours. The relative benefit of such a regimen remains uncertain. Postexposure prophylaxis has also been considered after sexual exposure, but in the absence of any data to support a relative benefit no specific guidelines have been recommended.
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FURTHER READING Adler M W (ed) ABC of AIDS, 5th edn. London: BMJ Publishing, 2001. British HIV Association (BHIVA) Guidelines for the treatment of HIV infection. HIV infected adults with antiretroviral therapy. HIV Medicine 2001.
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Granziosi C et al. Immunopathogenesis of HIV infection. AIDS Res Hum Retroviruses 1998; 14(Suppl 2):5135-5142.
SEXUALLY TRANSMITTED INFECTIONS GENITAL HERPES INFECTION The biology of herpes simplex infection and herpes labialis is dealt with in detail in Chapter 9 (p. 286). Genital herpes simplex virus infection is the commonest ulcerative STI in England and Wales and reported cases have increased severalfold over the last 20 years, particularly in females aged 16-24 years.
FIG. 11.19 A clinical episode of genital herpes affecting the penis The figure shows multiple small shallow ulcers around the foreskin.
Primary genital infection HSV 2 is largely associated with genital infection. Primary genital infection, or the first clinical episode, is most common in young, sexually active adults, and the risk of infection is proportional to the number of sexual partners. After an incubation period of 2-7 days, clusters of vesicles with surrounding erythema appear at the site of virus entry, on the glans or penile shaft in men, or on the vulva and vaginal mucosa in women. Homosexual men may develop rectal and perianal lesions. The lesions are usually painful and there may be systemic illness, with headache, myalgia, fever and local lymphadenopathy. Occasionally paraesthesia may develop in areas supplied by infected nerves, and there may be associated urinary retention or constipation. Skin and mucosal lesions resolve over 2-3 weeks. Virus may be shed from the lesions for up to 12 days. Infection of neonates is discussed on page 286.
Recurrent genital herpes Recurrent clinical episodes cause lesions similar to, but milder than, those of the primary episode (Fig. 11.19), with more localized lesions occasionally accompanied by shooting pains in the buttocks or legs. Recurrent episodes are associated with less pain and are shorter in duration. Systemic manifestations are rare. Often patients notice prodromal symptoms of local paraesthesia 24-48 hours before lesions appear. The rate of recurrence is variable, although the majority of patients experience a recurrence within 12 months of the first clinical episode. Asymptomatic secretion of virus can occur in the mouth or in the vagina, but this is rarely a source of transmission.
1 456
MCQ 11.6
2
Case 11.6
Management of genital herpes First clinical episodes of genital herpes, when severe, are usually treated with 5 days of oral aciclovir (200 mg five times daily), with analgesics and saline baths. For recurrences, local hygiene is usually all that is required. If episodes are frequent and severe suppressive aciclovir therapy may be necessary. Counselling on the management of recurrences and the prevention of transmission is required.
MOLLUSCUM CONTAGIOSUM Molluscum contagiosum is an infection of the skin caused by a poxvirus. The incubation period is variable but is usually around 14 days. A typical lesion is a smooth, firm papule, with the vertex being umbilicated and containing a waxy substance. Lesions commonly appear on the genitalia, suprapubic area and inner thighs, but can appear anywhere on the skin surface. They appear to be more common in people who are HIV positive, when the face, including the eyelids, may be involved. Spontaneous regression may occur. Therapies include curettage and liquid cryotherapy, or the application of phenol after disruption of the lesions.
GENITAL WARTS Warts are caused by a small DNA virus (papillomavirus) belonging to the papovavirus group. Anogenital warts are sexually transmitted (p. 393) and are regarded as important in view of increasing evidence associating them with cervical cancer.
have increased significantly over the last few years, the highest among 16-19-year-old females.
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Clinical features Men usually have urethral discharge and dysuria about 10 days after exposure to infection. In women the infection is usually silent, but may present with an abnormal vaginal discharge or with symptoms of pelvic inflammatory disease. If uncomplicated rectal infection occurs there may be anal discharge, perianal dampness, irritation and tenesmus. Complications are more common in women than in men. In women they include bartholinitis, salpingitis and perihepatitis. In men the complications include epididymo-orchitis, prostatitis and sexually acquired reactive arthropathy (Reiter's syndrome, p. 1151). FIG. 11.20 Genital warts involving the vulva and perineum
In men warts can appear on any part of the genitalia, but especially the frenulum, the coronal sulcus and the inner surface of the foreskin. They are called condylomata acuminata. They may be found in the male urethra and appear as bright red lumps at the meatus. In women the vulva and cervix can be involved (Fig. 11.20), as can the perineal area in both sexes. Cervical condylomata may be flat and identifiable only by colposcopy. They may be associated with cervical dyskeratosis and koilocytosis.
Management Local application of cytotoxic agents such as podophyllin, or of destructive agents or methods such as trichloracetic acid, cautery, diathermy or cryosurgery, is still the main therapeutic approach. Ablation of cervical warts by laser therapy is effective. Sexual partners should be contact traced and treated. Women diagnosed with genital warts, and the female partners of men with genital warts, should also have cervical cytology.
CHLAMYDIA TRACHOMATIS Genital infection Chlamydia trachomatis is an obligatory intracellular parasite whose replication results in the death of the infected cell. During its lifecycle the infectious particle changes to an actively dividing form, which later reorganizes into the infectious form that is released on cell lysis. Non-specific genital infection (NSGI), of which chlamydia infection may account for up to 50% in the UK, may present as urethritis, cervicitis or proctitis. Other relevant organisms include mycoplasmas and uroplasmas. Genital chlamydia infection is thought to be the commonest STI in England, with prevalances of 2-12% detected in studies of GP attendees. The rates of diagnosis
Diagnosis In men a Gram-stained urethral smear shows an excess of polymorphonuclear leukocytes but no gonococci, and is supportive of a diagnosis of non-gonoccoal urethritis. In men and women chlamydial infection is confirmed by identifying antigen at the site of infection, or by culture. Management Chlamydial infection and most other NSGI responds to tetracycline therapy. The usual is doxycycline (100 mg daily) for at least 7 days, or azithromycin 1 g orally as a single dose. Erythromycin (500 mg twice daily) may be used as an alternative and is the first choice in pregnancy and in tetracycline allergy. Relapse or recurrent infection is common in both sexes. There may be symptoms of a postinfective urethritis, with no signs of infection. Sexual partners of both sexes should always be examined and treated to identify asymptomatic infection, to prevent serious complications of untreated infection in the contact, such as pelvic inflammatory disease, and to avoid reinfection of the index case.
Congenital Chlamydia trachomatis infection Chlamydia trachomatis infection is now frequently seen as a cause of ophthalmia neonatorum. The infected baby develops a conjunctivitis about 10 days after birth. Investigation should include culture of pus, or a monoclonal antibody test for Chlamydia trachomatis. The organism may also be a cause of pneumonia in the neonate. Treatment is with erythromycin syrup. The baby's parents should always be examined for Chlamydia and other genital infections. 12
LYMPHOGRANULOMA VENEREUM Lymphogranuloma venereum (LGV) is caused by L1, L2 or L3 serotypes of Chlamydia trachomatis. It is most prevalent in parts of Africa, Asia and South America.
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Clinical features The most common primary lesion of LGV is a shallow ulcer appearing on the genitals of men or women 3-10 days after exposure to infection. In men there may be an associated lymphangitis of the dorsal penis. More commonly in men there may be an inflammation and swelling of the inguinal lymph nodes 10 days to 6 months after infection. The inguinal bubo is unilateral in about 60% of cases and may enlarge, causing pain, and rupture. About 20% also have involvement of the femoral lymph nodes. This creates a groove over the inguinal ligament - the characteristic 'groove sign'. LGV may also cause a rectal infection. After initial inflammation of the rectal mucosa a chronic inflammatory process may follow; this invades the bowel wall, with noncaseous granulomas and crypt abscesses forming. A partial or complete stricture of the rectum may develop.
the extremities. Gonococcus is an important cause of acute septic arthritis (p. 1158). Disseminated gonococcal infection is commoner in women than in men. Signs include fever, pustular rash and arthritis. Infection in pregnancy may cause abortion or premature labour and is associated with high perinatal mortality. The baby can be infected in utero, at birth or postnatally, and at worst develops disseminated infection. Ophthalmia neonatorum is the more common sign of neonatal infection.
Diagnosis and management Diagnosis is based on a positive complement fixation or microimmunofluorescent (micro-IF) test. Doxycycline (100 mg daily for 2-4 weeks) is the therapy of choice.
Management A typical treatment regimen is ampicillin (3g) plus probenecid (1 g orally). This combination allows singledose treatment, probenecid delaying excretion of the penicillin. Recommended alternative regimens are ciprafloxacillin 500 mg orally, or ofloxacin 400 mg orally, both as a single dose. These are preferred for the treatment of pharyngeal infection as ampicillin (and spectinomycin) has poor efficacy in eradicating infection from this site. The prevalence of penicillinase-producing strains in the UK is less than 5%, and quinolones remain highly active against these resistant strains. The prevalence of quinolone-resistance strains in the UK is less than 2%, but has risen since 1993. The prevalence of strains resistant to both quinolones and penicillin is high in some parts of the world, particularly southeast Asia, and this needs to be considered in treating possible imported infection. In these cases alternative regimens include cefotaxime 500mg (i.m.) or spectinomycin 2mg (i.m.), both as a single dose. Coinfection with Chlamydia trachomatis occurs in up to 20% of men and 40% of women presenting with gonohorroea, and should be suspected if symptoms persist a week after treatment of gonoccocal infection. Combining effective anti-microbial therapy against Chlamydia with singledose therapy for gonorrhoea at first presentation may be appropriate, and should be considered if there is doubt about follow-up. Sexual contacts should be traced, examined and treated. 1
NEISSERIA GONORRHOEAE (GONOCOCCUS) INFECTION Gonorrhoea is an important STD that causes urethritis, endocervicitis or proctitis. The annual incidence of cases reported by clinics in the UK declined markedly in the 1980s, probably as a result of behaviour changes in response to the HIV epidemic. Since 1994 there has been a rise in the incidence of gonorrhoea cases, both heterosexually and homosexually acquired, suggesting that such behaviour modifications may not have been sustained. In 1998,20% of all cases of gonorrhoea were among homosexual men. Clinical features The incubation period is between 2 and 7 days. In men there is urethritis, with a creamy discharge, dysuria and frequency. Homosexual men also develop proctitis, with pruritus, tenesmus and rectal discharge, often containing blood. In women the infection is usually asymptomatic (discovered by contact tracing or during a routine examination at a GUM clinic) or causes vaginal discharge, dysuria, frequency and lower abdominal pain. Pharyngeal infection follows oral sex but is usually asymptomatic. Complications Ascending infection causes pelvic inflammatory disease, with salpingitis, peritonitis or abscess formation in 10-20% of infected women. Septicaemia may occur, with a rash on
1 458
MCQ 11.7
Diagnosis Microscopy of Gram-stained smears shows pus cells and both intra- and extracellular Gram-negative diplococci. Specimens should be taken from the endocervix in women: a high vaginal swab is inadequate. Culture is essential, as penicillin-resistant gonococci are becoming more common. Serology is not helpful in diagnosis.
Syphilis Syphilis is caused by Treponema pallidum (TP), one of a small group of treponemes. TP is 6-15 um in length and is narrow, with regular tight spirals, and mobile in all axes. Transmission is usually by sexual contact, although transplacental infection may occur. Exposure to moist mucosal or cutaneous surfaces is required; transmission is commonly during the first 1-4 years of infection. The incidence of syphilis in England and Wales fell after the intro-
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CASE STUDY 11.2 URETHRAL DISCHARGE A 22-year-old homosexual man presented to a genitourinary medicine clinic with a 2-day history of urethral discharge and dysuria. He had no other symptoms but reported a history of oral sex and protected receptive anal intercourse with a new male partner 10 days ago. He also had a history of a condom accident with a casual partner 6 months ago, but no other history of unsafe episodes of sexual intercourse. He had been treated 4 years previously by his GP for scabies, but otherwise had no other relevant history. On examination he had a mucopurulent urethral discharge. Testis, scrotum and anorectal examination was normal. Small bilateral inguinal lymph nodes were palpable. Questions 1. What is the differential diagnosis? 2. How would you manage this patient?
Discussion This 22-year-old man presents with a urethral discharge and a recent history of a new sexual partner. Clinically he has urethritis and the differential diagnosis includes infection with either Neisseria gonorrhoeae, or Chlamydia triachomatis, or a non-specific urethritis. Microscopy of a urethral smear will show polymorphonuclear leukocytes, and a Gram stain should be undertaken to look for Neisseria gonorrhoeae. In men presenting with symptomatic gonococcal infection urethral microscopy is diagnostic in 90% of cases. In asymptomatic men the diagnostic sensitivity of a urethral smear is lower. A urethral swab for culture of Neisseria gonorrhoeae should be taken to confirm infection and allow for antimicrobial sensitivity testing. Urethral screening tests for Chlamydia infection should be performed. In view of this man's sexual history, rectal and pharyngeal cultures for gonorrhoea and routine serology tests
duction of antibiotic therapy (see Fig. 11.1), but there was a resurgence during the 1970s in males. These cases were mainly in homosexual men with numerous sexual partners. In the 1980s and 1990s there was a decline in the incidence of syphilis, with homosexual transmission now accounting for only one-quarter of all cases diagnosed in GUM clinics in 1998. Fifty per cent of all infectious syphilis in England was acquired outside the UK. However, very recently, in 2000, there has been reported a 2-3 fold increase in the number of cases of infectious syphilis amongst homosexual men in different cities in the UK. Worldwide there was a marked increase in reported cases in eastern Europe and Russia in the 1990s. Clinical features Syphilis is classified as acquired or congenital. Acquired syphilis may be divided into early or late. The stages of early syphilis are primary, secondary and early latent (less than 2 years of infection), and of late syphilis are late latent (more than 2 years of infection), tertiary and quaternary. Primary The primary lesion is a chancre (Fig. 11.21a), which starts as a painless pink papule and may develop into an ulcer.
for syphilis should be undertaken. A full sexual history should be taken from any patient presenting with symptoms of a possible sexually transmitted infection, and the appropriate diagnostic screen for a coincident sexually transmitted infection be offered. Referral to a genitourinary medicine clinic for management is strongly encouraged. In this man an HIV antibody test should be discussed and offered. In addition, if serological tests for either viral hepatitis B or A show he is nonimmune, he should be offered appropriate vaccination. His recent sexual partner should be traced and screened for sexually transmitted infection. He should avoid sexual intercourse until he and his partners have completed treatment and follow-up. The opportunity should be taken to give further advice on safer sex practices.
The ulcer has a button-like feel on palpation. The base is initially pink and shiny, becoming grey later. Painless inguinal lymphadenopathy is common and may be unilateral. On occasions the chancres may be multiple and painful. A chancre usually appears about 3 weeks after exposure to infection (range 10-90 days), and heals. Men, especially homosexual men, are infected more often than women. In the male the common genital sites of infection are the coronal sulcus, glans penis and prepuce. In the female chancres may be found in the vagina, and on the labia, fourchette and cervix. In both sexes infection can occur in the pharynx and anus. In the anal area a chancre resembles a fissure and may be painful. Chancres, because they can be small and painless, are often missed. Secondary The secondary stage may take 3 months or more after infection to appear (average 6 weeks). At this stage there is bacteraemia. Systemic upset is common, including low-grade fever, malaise, headache, generalized lymphadenopathy, including the epitrochlear glands, and rarely hepatosplenomegaly and transient proteinuria. Arthralgia, acute meningitis and cranial nerve palsies are rare features.
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The skin is most frequently involved; a non-pruritic rash is common. The lesions are usually papules or plaques, and early on tend to be symmetrical and widespread. The palms, soles and face are often involved. Scaling is common and the lesions can resemble psoriasis. Later lesions tend to be fewer and asymmetrical. Patchy and partial hair loss can occur, giving a moth-eaten appearance (Fig. 11.21b). Other signs include patchy alopecia, erosive lesions of the mucous membranes (mucous patches), common in the mouth, and soft, flat-topped and highly infectious warts found in the perianal area, known as condylomata lata. At this stage all tests for syphilis are positive. The venereal disease research laboratory slide test (VDRL, see below) shows a very high titre. 1 12
skin ulcers, and may destroy the nasal septum. Lesions in bones and joints lead to fractures and joint destruction. Liver involvement causes fever and local tenderness. Gummas respond remarkably rapidly to treatment. Quaternary Quaternary syphilis is either neurosyphilis (p. 1428) or cardiovascular syphilis, which is due to endarteritis obliterans
Latent period If untreated, syphilis will go into a latent phase, when clinical symptoms and signs are absent. This is termed early latent syphilis if it is within 2 years of infection, or late latent after 2 years. Before the latent period there may be periods of infectivity: over 90% occur in the first year. These relapses may be characterized by rashes and lymphadenopathy. During the latent phase sexual transmission is rare, although fetomaternal transmission may occur. Transplacental passage becomes unlikely in late latent syphilis. The VDRL will be negative or have very low titre, e.g. 1:8. The T. pallidum haemagglutination assay (TPHA) and fluorescent treponemal antibody absorption test (FTA-Abs) - (see below) - are always positive. Late (tertiary) syphilis Tertiary syphilis is now rare, as effective treatment prevents progression. The characteristic pathological lesion at this stage is a gumma, which is a destructive granuloma sometimes associated with vasculitis. Treponemes are very scanty and not usually seen under the microscope. Gummas can involve any organ. They cause punched-out
SUMMARY 3 Sites of involvement in secondary syphilis The proportion of cases is given in parentheses Skin (90%) Lymph glands (50%) Mouth and throat (35%) CNS symptomatic (20%) asymptomatic (2%) Kidneys (rare) Gastrointestinal tract and liver (rare) Bones and joints (rare)
1
460
Case 11.7
2
Fig. 11.7
3
Figs 11.8,11.9
FIG. 11.21 Clinical features of syphilis A Chancre of primary syphilis B Alopecia in secondary syphilis.
of the vasa vasorum of the aorta. This causes aneurysm, most commonly of the ascending aorta (p. 600). Congenital syphilis TP crosses the placenta after the third month of pregnancy, usually when the mother has early disease. If she is not treated, infection of the fetus may cause abortion, stillbirth, or the birth of a child with congenital syphilis ©• The child may have signs of infection at birth, similar to those of secondary syphilis in adults, or may be asymptomatic but develop signs of late congenital syphilis, equivalent to adult tertiary, after the age of 2 years. The predominant signs in early presentation are snuffles and a rash, which may vesiculate. Possible late signs are facial abnormalities, including frontal bosses, saddle nose, protruding mandible, Hutchinson's incisors (peg-shaped, splayed), interstitial keratitis, eighth-nerve deafness, periostitis and Clutton's joints. As in adult syphilis, diagnosis depends on serology in the later stages. Diagnosis Primary syphilis is diagnosed by identifying TP with darkground microscopy. TP can be identified in serous exudate from the surface of the chancre. A negative result does not exclude the diagnosis, as topical (e.g. antibiotic ointments) or systemic therapy may alter the findings. The FTA-Abs is positive in approximately 70% of cases at this stage. Later stages require serological testing for confirmation of the diagnosis. Serological examination of the CSF is necessary if neurosyphilis is suspected. Antibodies to treponemal antigens are present, i.e. positive TPHA and FTA-Abs, in 80% of cases of primary syphilis. Two types of antibody test are employed (Table 11.9): • Non-treponemal tests (e.g. VDRL; rapid plasma reagin card test or RPR). These detect cardiolipin antibodies in serum. A high titre indicates an active infection. They
become negative after therapy or during the latent phase of untreated syphilis. False positive results may be found in acute febrile illness, autoimmune diseases, and after immunizations. False negative tests may occur in secondary syphilis due to the prozone phenomena from using undiluted serum. • Treponemal tests (e.g. FTA-Abs; TPHA). These detect antibodies against the treponemal antigen. They are positive earlier in the infection, but remain positive after therapy and in latent syphilis. Yaws, another treponemal disease caused by T. pertenue (see p. 329), gives a serological picture similar to that of untreated syphilis. A careful history is necessary to differentiate the cause, and if doubt about the diagnosis persists, treatment for syphilis is given. Management Table 11.10 shows acceptable treatment regimens. Benzathine penicillin does not effectively cross the blood-brain barrier. Patients may (but do not commonly) experience Jarisch-Herxheimer reaction (a transient fever) 1-2 hours after the first dose of penicillin. This is more commonly seen in secondary syphilis. In cardiovascular syphilis the inflammatory response to antibiotic therapy may result in small vessel occlusion in the coronary ostia. The use of prednisolone (24 hours before and up to 48 hours after commencing therapy) may prevent this. Serological examinations are repeated for at least 1 year after treatment, to
TABLE 11.10 Treatment for syphillis Primary, secondary or early latent syphilis Late latent syphilis or tertiary syphilis (not CNS) Neurosyphilis
TABLE 11.9 Serological tests for syphilis Test Disease/stage
VDRL or RPR*
TPHAf
FTA-Absf
Primary syphilis Secondary syphilis Latent (over 2 years) syphilis Latent (over 2 years) late syphilis Yaws Treated syphilis
Negative >1:64 <1:16
Positive/negative Positive Positive
Positive Positive Positive
Negative/<1 : 2
Positive
Positive
Negative/<1 : 2 Negative/<1 : 2
Positive Positive
Positive Positive
* Tests for cardiolipin antibodies: VDRL = Venereal Disease Research Laboratory slide test; RPR = rapid plasma reagin card test. Tests specific for treponemal antibodies: FTA-Abs = fluorescent treponemal antibody absorption test; TPHA = T. pallidum haemagglutination assay. f
11
HIV positive all stages Penicilin allergy Acquired syphilis <2yrs Penicilin allergy Acquired syphilis >2yrs Pregnant and penicillin allergy Acquired syphilis <2yrs Pregnant and penicillin allergy Acquired syphilis >2yrs
600 000 units procaine penicillin daily 600 000 units procaine benzylpenicillin (procaine penicillin) daily 2.4 million with procaine benzylpenicillin (procaine penicillin) daily 500 mg oral probenecid q.d.s. Neurosyphilis regimen Oral doxycycline 100 mg b.d. (or oxtetracycline 500 mg q.d.s.) Oral doxycyline l00 mg b.d. (or oxtetracycline 500 mg q.d.s.) Oral erymromycin 500 mg q.d.s. followed by oral doxycycline 100 mg b.d. after delivery* Oral erythromycin 500 mg q.d.s. followed by oral doxycycline 100 mg b.d. after delivery
10-14 days 14-21 days
17-21 days
21-28 days 14-21 days 30 days 15 days 15 days 30 days 30 days
* Treat newborn with procaine benzylpenicillin (procaine penicillin) at birth and advise mother not to breast feed during doxycycline treatment. An alternative to procaine benzylpenicillin (procaine penicillin) as first line therapy is: Eary syphilis: IM benzylpenicillin 2. 4 MU x 1-2 (days 1 & 8) Late latent syphilis: IM benzylpencillin 2.4 MU x 3 (days 1, 7, 14).
461
ensure treatment response and identify relapse. This is of especial value in primary and secondary syphilis. Tracing the partners of patients is an integral part of treatment. If the erythromycin regimen is used for a pregnant patient it is always advisable to treat the baby at birth with the appropriate dose of bicillin. Because erythromycin is not a fully reliable treatment, the mother should be treated with doxycycline after delivery. Like all tetracyclines, doxycycline is of course contraindicated during breastfeeding. 1
TRICHOMONIASIS Trichomonas vaginalis (TV) is a pear-shaped flagellate protozoan that causes vaginal discharge and urethritis in women and urethritis in men. It is a sexually transmitted infection. Clinical features Most women with TV have an offensive vaginal discharge associated with vulvovaginal pruritus, and occasionally
1 MCQ 11.8 462
dysuria and dyspareunia. Clinically the vulva is erythematous and excoriated; the vaginal discharge may be seen at the introitus. The discharge is grey, yellow or green and may be frothy. Vaginal erythema and punctate haemorrhages of the cervix may be seen. It is a rare cause of nonspecific urethritis in men. Diagnosis and management Examination of the discharge on a wet mount is essential. The trichomonads are easily seen. Metronidazole (2 g as a single dose, or 400 mg twice daily for 5 days) is effective, but recurrence is common. Sexual partners should be treated.
FURTHER READING ON GENITOURINARY MEDICINE Adler M W (ed) ABC of sexually transmitted diseases, 4th edn. London: British Medical Association, 1999. UK National Guidelines for Sexually Transmitted Infections and closely related conditions. Sexually Transmitted Infections 1999;75:Suppl 1.
12
Cardiovascular Didease J Malcolm Walker and Lip-Bun Tan
The scope of modern cardiology 463
Normal and disordered physiology
Complications of myocardial infarction 560
463
Prognosis after myocardial infarction 566
Symptoms and signs of heart disease 467
Management of myocardial infarction survivors 567
Cardiac investigation 476
Diseases of heart muscle 570
Heart failure 488
Infective endocarditis 574
Arrhythmia 500
Non-infective endocarditis 580
Resuscitation 517
Cardiac tumours 581
Valvular disease of the heart 520
Cardiac disease and pregnancy
Congenital heart disease 533 Cyanotic congenital heart disease
582
Secondary heart disease 583
536
Pericardial disease 586
Acyanotic congenital heart disease 538
Systemic blood pressure and hypertension 589
Coronary heart disease (CHD)
Vascular disease 600
542
Peripheral vascular disease 602
Myocardial infarction 554
THE SCOPE OF MODERN CARDIOLOGY More than 40% of patients admitted to medical wards in the UK have some form of heart disease. Coronary artery disease, heart failure and cardiac arrhythmias are among the commonest causes of emergency hospital admission. Ischaemic heart disease is the most important cause of death in the western world. It causes more than a million deaths per year in the USA and about 160000 deaths annually in the UK (Fig. 12.1), where it accounts for 40-50% of all deaths and is the main reason for men not reaching their seventh decade. A recent concerted effort to change lifestyles with respect to smoking, diet and exercise, as well as better control of hypertension, appears to have led to a decline in coronary artery disease deaths in the USA and the more
affluent northern European countries, but has yet to make a major impact in the UK. Rheumatic heart disease has declined rapidly in importance in the west over the last 30-40 years (p. 580). It now accounts for less than half the cases of heart valve disease coming to surgery and, with only a small number of new cases presenting, its importance will probably decline further. However, it is still a major cause of morbidity and mortality in the developing world. Congenital heart disease is one of the principal causes of neonatal death and is likely to remain a significant cause of morbidity and mortality in childhood. However, more cases are now treatable by cardiac surgery in childhood, and major cardiac defects can now be detected during pregnancy, raising the possibility of neonatal, or even antepartum, cardiac surgery. The development of sophisticated methods of investigation in cardiology now allows great precision in diagnosis, enabling full advantage to be taken of the advances in cardiac surgery and catheter-based treatments. Diagnostic methods have expanded from simple ECG and X-ray to include an ever-widening range of techniques, using ultrasound (both imaging and Doppler), isotope imaging, angiography, intracardiac electrophysiology and 24-hour ECG recording, pressure measurement and magnetic resonance imaging. Therapeutic options have also increased, to include complex cardiac surgery possible at all ages, pacemaker therapy and non-surgical interventions such as angioplasty. The efforts of cardiac surgeons and bioengineers have produced a generation of patients with prosthetic heart valves, implanted pacemakers, modified congenital heart disease and heart transplants. These present a new spectrum of pathology and altered natural history.
NORMAL AND DISORDERED PHYSIOLOGY CONTRACTION Cardiac muscle is striated and shares with skeletal muscle the same basic contractile unit, the sarcomere. The components of the sarcomere are the myosin thick filaments, and the thin filaments composed of actin, troponin and tropomyosin. A local increase in calcium concentration allows an interaction to occur between the heads of myosin molecules and the thin filaments, which produces crossbridges between the filaments. A confirmational change between the globular head of the myosin molecule and its rod-like tail causes a tension in the cross-bridge, making the filaments slide past each other (Fig. 12.2). Relaxation is brought about by a decrease in intracellular calcium and the hydrolysis of adenosine triphosphate (ATP) by myosin ATP-ase to produce adenosine diphosphate (ADP) and inorganic phosphate (Pi).
463
FIG. 12.2 Diagrammatic representation of sarcomere contraction A In the relaxed state (diastole) tropomyosin inhibitory subunits prevent the interaction of the myosin heads with actin. B In the presence of calcium, this interaction can take place enabling contraction (systole) to occur,
FIG. 12.1 Mortality from cardiovascular disease A Causes of death from cardiac disease (England and Wales, 1999). B Deaths due to coronary artery disease in Scotland and the USA in the years 1968-1992, England and Wales to 1999 (UK Government Statistics). Note the steep decline in mortality in males and females in the USA.
Energy for contraction ATP is stored in only small amounts in heart muscle, so its production must occur at a rate equal to its consumption. Free fatty acids (FFA) are the major source of myocardial energy, yielding 2.5 times more ATP per gram weight than glucose. Glucose breakdown can occur in the absence of oxygen, but only two molecules of ATP are produced per molecule of glucose metabolized to pyruvate (instead of the 36 obtained by aerobic metabolism of glucose to carbon dioxide and water). The normal heart consumes lactate, which, by the action of lactate dehydrogenase, yields pyruvate.
The action potential 464
Rhythmic contraction and relaxation of myocardial cells
is achieved by the sequential release of calcium near the myofibrils and its subsequent removal. The sequence of events is outlined in Figure 12.3. The action potentials from different regions of the heart have different configurations, the most important of which is the spontaneous depolarization during diastole in the pacemaker cells of the sinoatrial node (Fig. 12.4, action potential A). This rise in membrane potential in diastole triggers the next depolarization and sets the heart rate. Areas distal to the sinoatrial node are inhibited from showing their intrinsically slower pacemaker potential, but will do so if the impulse from the sinoatrial node is absent or delayed. The rate of sinoatrial node depolarization is greatly influenced by p-adrenoreceptors. Sympathetic stimulation increases this rate and therefore speeds the heart rate, whereas parasympathetic stimulation produces opposite effects mediated by acetylcholine. Circulating catecholamines and changes in serum potassium and magnesium are among the other factors that affect the basic electrophysiological properties of cardiac cells. In non-pacemaker cells the wave of depolarization from adjacent cells is the stimulus for the inward flow of sodium ions that starts the cardiac cycle. Periods of absolute and relative refractoriness follow the prolonged plateau phase. Average action potential durations are about 300ms, but shorten in response to increasing heart rate and adrenaline. The rate of conduction of impulses through the heart is determined by the action potential shape. Depolarization is accompanied by a short-lived inward current, producing the fast upstroke of the classic cardiac action potential (Fig. 12.4, B, D, E). The fast inward current is maximal when the
12
FIG. 12.4 Action potentials from different regions of the heart A Sinoatrial node; B atria; C atrioventricular node; D Purkinje network; E myocardium; F is the electrocardiogram. FIG. 12.3 Relationship between action potential, transmembrane ionic movements, sarcomere contraction and muscle tension A With the onset of the action potential, sarcolemmal sodium channels open. B This is followed by release of calcium from the sarcoplasmic reticulum into the cytosol and sarcomere shortening. c Relaxation follows resequestration of calcium into the sarcoplasmic reticulum. Repolarization is accompanied by loss of potassium from the cell.
foregoing resting membrane potential (Vm) is most negative, the situation found in the Purkinje cells of the ventricle, where conduction velocities are at their highest. In the specialized tissues of the sinoatrial and atrioventricular nodes the upstroke of the action potential is slow and dependent on calcium influx (Fig. 12.4, A and C). These features account for the slow conduction through the atrioventricular node. Ischaemic injury can cause depolarization of cells in affected regions of the heart, leading to regional variation in conduction velocities and areas of conduction block.
HEART PUMP PERFORMANCE Normal function The basic physiological factors that influence the power of myocardial contraction and pump performance are: • Inotropy. dependent on the neurohormonal and ionic environment • Preload: the myocardial fibre length at which the contraction begins • Afterload: the force against which the muscle contracts • Rate and rhythm: dependent on the rate and pattern of stimulation. Inotropy The myofibrils produce tension in proportion to the
free calcium released into the cytosol, until saturation is reached and tension rises no further. Calcium entry into the cell occurs during the action potential plateau, and variations in contraction strength occur by the release of variable amounts of calcium from intracellular stores, or by a change in sensitivity of the myofilaments to calcium. In a steady state, calcium entry into the cell with each action potential is balanced by a loss to the extracellular space. Accumulation of calcium in intracellular stores is facilitated by increased levels of extracellular calcium or by high intracellular sodium, which may occur when the sodium pump is blocked by digoxin. Under normal conditions extracellular calcium concentration plays no part in the beat-to-beat control of the heart's performance. This is mainly affected by sympathetic discharge and circulating catecholamines, which produce an increased heart rate (chronotropic drive) and also enhance myocardial contraction. The final common pathway of this latter effect is achieved by increased myofibrillar calcium sensitivity. Changes in extracellular concentrations of potassium and pH affect myocardial contraction, but, as these concentrations are generally kept constant by homeostatic mechanisms, they do not control heart activity in normal circumstances, although they may considerably affect it in disease. Preload Venous return to the heart is dependent on right atrial pressure. During inspiration intrathoracic pressure falls, causing an accentuation of venous return to the right heart. Standing up tends to diminish this, but in the upright posture exercising muscles provide extravascular compression and maintain venous return. Cardiac output in the normal heart is very responsive to venous return (the Frank-Starling curve), but the failing heart is less sensitive owing to a flatter ventricular function curve (Fig. 12.5).
465
FIG. 12.6 The relationship of LV volume to pressure in a normal cardiac cycle (A-B-C-D) At A systole begins. The pressure rises isovolumetrically until at B the aortic valve opens. The ventricle ejects to C and then isovolumic relaxation occurs until D at which point filling occurs. The dotted blue line shows the relationship in a failing ventricle with reduced inotropy and increased diastolic stiffness. Following the cardiac cycle A-B-C-D it can be seen that a smaller stroke volume is generated (ABCD). Increasing inotropy (dotted red line) would restore or increase stroke volume.
FIG. 12.5 Relationship between ventricular output and filling pressure A The black line shows a normal right ventricular (RV) function curve, where an RV output of 7 L/min (dotted line) is achieved with a filling pressure of 1 mmHg. The left ventricle (LV) must produce the same output (A1), so that the normal LV (blue line) requires a filling pressure of 8 mmHg. If the LV is failing (LVF, light blue line), a filling pressure of 18 mmHg (A2) is required to maintain this output. B A similar relationship is shown for the normal (black line) and failing (grey line) right ventricle.
An increase in intrapericardial pressure with the accumulation of an effusion impedes venous return and cardiac filling and, with marked effusion, a low stroke volume and cardiovascular collapse follow, a condition called tamponade (p. 587). Some drugs affect venous tone: for example, some of the therapeutic benefits of nitrates are related to venodilatation, lowering wall stress and thus reducing myocardial oxygen demand. Normal ventricular filling occurs principally in early diastole, with atrial systole giving a final 'top-up'. The latter may be particularly important in hypertrophied hearts, which fill poorly in early diastole. Here atrial systole provides a much greater fraction of ventricular filling. In these
1
466
MCQ 12.1
patients, loss of atrial contraction (due to atrial fibrillation) may lead to marked reduction in stroke volume. Afterload During systole the ventricles eject blood once the diastolic pressure in the arterial circuits is exceeded. Afterload is the load that affects the ventricles during ejection. This can be equated with the peripheral vascular resistance, which, together with vessel wall elasticity, determines the diastolic arterial pressure. Increasing afterloads (Fig. 12.6) decrease cardiac output, and this relationship is worse in failing hearts. The treatment of patients with impaired ventricular performance now includes the use of drugs that reduce the peripheral vascular resistance and hence reduce afterload (p. 496). Rate and rhythm Changes in the rate of stimulation of the heart muscle can alter contractile performance, independently of changes in muscle length (or preload). These mechanisms affect output to a lesser degree than preload and afterload. However, increases in heart rate may also change cardiac output by altering the time available for cardiac filling and coronary flow. 1
Ventricular dilatation The cardiac chambers dilate either with abnormal volume loads or as a consequence of impaired myocyte function,
as in cardiomyopathy. The larger-volume ventricle is an adaptive response, allowing the maintenance of stroke volume despite a reduction in the shortening capability of the myofibrils. However, although the response is initially adaptive, there is a cost. From the Laplace equation, a dilated ventricle with an increased diameter can only generate the same pressure with an increased wall tension. This increased wall tension can only be sustained by an increase in oxygen consumption, which may outrun the supply, leading to further ischaemia and dilatation.
Ventricular hypertrophy Cardiac myocytes hypertrophy in response to: • Loss of adjacent myocytes. • An increase in ventricular wall stress - the resultant increase in wall thickness effectively reduces the stress each sarcomere has to generate. With mild hypertrophy, the capillaries increase in density proportionally to the hypertrophy, but beyond a certain extent the capillary growth lags behind the hypertrophic process, thus rendering the less well supplied subendocardium liable to ischaemia. The hypertrophic process, accompanied by deposition of more collagen fibres, leads to reduced compliance and impaired diastolic function. • Cellular mechanisms of cardiac adaptation. The adult cardiac myocyte is not capable of cell division but remains synthetically active, regenerating contractile proteins every 30-90 days. Under conditions of increased stress the myocyte is stimulated by a large number of factors via sarcolemmal receptors. These include growth hormone, angiotensin II, noradrenaline (norepinephrine), tumour necrosis factor-a, interleukins, growth factors and nitric oxide, among others. Acting via intracellular second messengers, the cells revert to a more fetal phenotype, resulting in cell growth and hypertrophy, often accompanied by impaired contractile function.
SYMPTOMS AND SIGNS OF
HEART DISEASE Symptoms arising from the heart are not specific and it often requires a careful history to differentiate them from similar complaints arising from chest disease, dyspepsia or anxiety. Chest pain, breathlessness, oedema, palpitations, dizziness, syncope and fatigue can all be caused by heart disease. Exercise capacity is limited in most forms of heart disease, and the limiting symptom may be obvious, such as pain and breathlessness, or much more subtle, such as excessive exhaustion. The degree to which symptoms have begun to limit normal activities requires careful definition, as patients may not always volunteer the information, wrongly thinking that age alone is enough to account for their increasing inability to exert themselves without dyspnoea or dizziness. Others may prevent angina or
breathlessness by greatly restricting their lives. In assessing the effectiveness of treatment it is useful to have an idea of the activities that can and cannot be performed, using relevant examples from the patients' own lives, the ease with which they can walk and talk, or how they manage household chores. Improvements in patients' performance may then be judged by their own yardstick. Patients sometimes need considerable encouragement to re-establish more normal patterns of activity after being treated.
12
Chest pain Chest pain arising from the heart and great vessels may be caused by cardiac ischaemia, pericardial inflammation, aortic dissection or massive pulmonary embolism. The history may allow differentiation between the various possibilities, but the severity of the symptom has virtually no relationship to the potential severity of the underlying cause. Many patients suffer pains in the chest which are probably cardiac in origin but for which no adequate explanation is possible; for example, some patients may describe abnormal sensations produced by ectopic beats as pain. Cardiac ischaemic pain In a typical case the discomfort associated with myocardial ischaemia is described as a pressure or tightness in the chest, which may also be felt in the throat, producing the choking feeling that led to the symptom being called angina pectoris. The characteristics of angina include common patterns of radiation to the arms, more commonly the left, the jaw and teeth and, less commonly, through to the back. The pain, and its sites of radiation, are often reproducible, but incomplete or mild attacks may not have the same full distribution of the more severe episodes. In angina, which represents episodes of reversible ischaemia, the precipitating causes are typically those that will increase myocardial oxygen demand beyond the coronary supply. The patient may report discomfort only when having to run, or when they try to walk in the face of a cold wind or after a heavy meal. Emotional upsets are powerful precipitants of angina in some patients, even without physical exertion. The discomfort may be very severe and be associated with frightening feelings of impending death. It can also be a mild discomfort or ache in the chest, which may be thought trivial and ignored. Many patients do not experience their angina as a pain, and feel it as a faint constriction in the chest. Some attacks of myocardial ischaemia are unaccompanied by any discomfort (silent ischaemia}. Angina usually disappears fairly rapidly if the patient rests, or takes glyceryl trinitrate (GTN). Angina builds up over several seconds and is usually not greatly influenced by posture, unlike musculoskeletal chest pain (which may also occur with exertion). Although similar in nature and radiation, the pain of myocardial infarction
467
lasts much longer than angina. It is more intense and does not pass off with rest or GTN. In an attack, a patient with cardiac ischaemia usually looks pale and sweaty, unlike someone with an attack of indigestion, who often appears flushed. Other causes of chest pain Pericardial pain (p. 587) can be easily confused with the pain of myocardial infarction or angina, but is often influenced by posture, sometimes being relieved or worsened by leaning forwards, and aggravated by swallowing. It is more often described as a burning or dull pain, and is less likely to be associated with breathlessness than is myocardial ischaemia. The pain of dissection of the ascending aorta (p. 600) is a severe, tearing pain, often starting suddenly, usually felt retrosternally at first, and sometimes radiating through to the back or to the left shoulder. Massive pulmonary embolism can also produce a retrosternal constricting discomfort indistinguishable from myocardial ischaemia; smaller peripheral emboli may be responsible for more pleuritic-type pains (p. 681). Oesophageal spasm due to reflux can produce a severe retrosternal pain which may be confused with that of myocardial ischaemia, and may be relieved by GTN. The pain of oesophageal rupture can be confused with myocardial infarction. Sharp, stabbing precordial pains are common in highly strung patients. They may have a muscular origin, but occasionally coincide with the accentuated postectopic contraction of the heart, which is perceived by the patient as a knife-like pain. 1
Dyspnoea or shortness of breath This symptom is a feeling of laboured, or unnaturally difficult, breathing. In heart failure it is due to the lungs becoming stiff and difficult to ventilate, owing to the rise in pulmonary venous pressure. The reduced cardiac output limits the oxygen-carrying capacity of the circulation, precipitating anaerobic metabolism. The acidosis produced causes increased ventilation, which persists for longer than normal after exertion. Thus, even minor exertion produces disproportionate and prolonged dyspnoea. Finally, in severe left heart failure with pulmonary oedema, arterial oxygen desaturation adds to the distress. Dyspnoea (or angina) can be categorized using the New York Heart Association scale (Table 12.1). Severe forms of left heart failure are associated with dyspnoea at rest, worse when supine. This degree of pulmonary venous hypertension is commonly accompanied by a dry, nonproductive cough. Dyspnoea at night can be graded on
1
468
MCQ 12.2
TABLE 12.1 New York Heart Association grading of dyspnoea or angina Grade
Criteria
1
Symptoms only occur on severe exertion. Almost normal lifestyle possible Symptoms occur on moderate exertion. Patient has to avoid certain situations, such as carrying shopping up several flights of stairs Symptoms occur on mild exertion. Activity is markedly restricted Symptoms occur frequently, even at rest
2 3 4
the basis of the number of pillows required to enable the patient to sleep (orthopnoea). Patients with left heart failure may be woken from their sleep by severe dyspnoea resulting from pulmonary congestion. This passes off on sitting up, or walking about slowly, and is known as paroxysmal nocturnal dyspnoea (PND). This may be the first symptom of left heart failure and may be difficult to distinguish from nocturnal asthma, as some patients with left heart failure develop a considerable degree of wheeze with bronchospasm.
Palpitations A careful interpretation of what the patient means by the word 'palpitations' is essential. It may be simply an awareness of the normal heart beat, which may be more forceful or faster than usual because of anxiety. It may, however, be indicative of a serious cardiac arrhythmia. It may be useful to ask the patient to tap on the table to indicate the rate and rhythm during the attack. It is helpful to determine the following: • Onset and cessation of the attacks. Is it sudden, with a thump (ectopic), or gradual? • Are there any symptoms to suggest cardiac decompensation (failure) during the attacks? • Was there irregular thumping (ectopics or atrial fibrillation)?
• Was there chest pain (the occurrence of angina implies a very fast and potentially dangerous heart rate)? • Has there been any fainting or near fainting with the attacks? True syncope indicates an urgent need for investigation, as the arrhythmia is potentially fatal. Polyuria sometimes occurs on cessation of supraventricular tachycardias, but is not usually described by the patient unless a leading question is asked.
Syncope and presyncope (dizziness) Sudden collapse with loss of consciousness during exertion almost always has a cardiac cause. It is due either to an obstruction to outflow from the left or right ventricle, which prevents an adequate increase in cardiac output on exertion, or to a cardiac arrhythmia induced by the
exertion. Both may result in a sudden fall in blood pressure and cerebral perfusion. Some mental confusion due to cerebral anoxia is common. Syncope after exertion is not uncommon and may simply be due to blood pooling in the legs and a poor venous return. However, syncope under other circumstances may be cardiac, and an eyewitness account is invaluable. Cardiogenic syncope usually occurs without warning; the collapsed patient is vasoconstricted and grey, and the pulse is either absent or very slow. In a classic 'Stokes-Adams' attack (p. 503) the unconscious patient blushes dramatically with the return of circulation and subsequent return of consciousness. Syncope may also occur in severe tachycardia. A prolonged period of unconsciousness is unlikely to be cardiogenic, as cardiac asystole or a malignant cardiac arrhythmia sufficiently rapid to cause unconsciousness is unlikely to last long without proving fatal. Other forms of syncope 'Vasovagal' syncope. The common faint, often triggered by pain or an unpleasant sight, gastrointestinal upset, haemorrhage or pyrexial illness, is a vagal phenomenon, and the syncopal episode is followed by profuse cold sweat, a feeling of sickness or actual vomiting, and bradycardia. Micturition syncope and cough syncope are rarely cardiogenic, but are probably triggered by a Valsalva manoeuvre, the first when initiating micturition with a full bladder and the latter after repeated bouts of coughing, which inhibit venous return. Presyncope or dizziness is a common and much less well defined symptom, and has a variety of causes as well as heart disease. It may result from a cardiac arrhythmia, but even then is much more common in elderly patients with associated cerebrovascular disease.
Oedema Right heart failure causes pitting oedema of the feet and legs, worse at the end of the day and relieved by rest and elevating the legs. Unlike other causes of oedema it may be associated with other symptoms of heart failure, such as dyspnoea and fatigue. The oedema may spread to the thighs, abdominal wall, sacrum and back. There may be ascites and hepatic congestion, with abdominal distension. The hepatic congestion may be worse on exertion, with pain over the liver (usually epigastric) during exercise and for several minutes afterwards - hepatic angina. The differential diagnosis of cardiac oedema includes fluid retention from other causes, such as nephrotic syndrome and cirrhosis of the liver, oedema of one or both legs from venous insufficiency, or lymphatic insufficiency.
Fatigue Fatigue is a non-specific and often neglected symptom. It is, however, a very real feature of heart disease, a result of the reduced effort tolerance and lactic acidosis produced by anaerobic muscle metabolism and changes in the skele-
tal muscle. It is a prominent symptom in low cardiac output states, e.g. severe left ventricular failure.
12
EXAMINATION OF THE CARDIOVASCULAR SYSTEM The general examination Traditionally, and ideally, the cardiac examination is undertaken in a warm, quiet and well-lit room with the patient se'ated on the bed or couch with the upper body supported and at an angle of 45° to the horizontal. The general appearance of the patient and his or her comfort and general wellbeing or illness is noted. Certain cardiac diseases are associated with anormalities of habitus, specifically Marfan's syndrome (p. 526), where aortic dissection and mitral valve disease are to be expected, or other chromosomal abnormalities that produce associated congenital cardiac lesions, such as Down's and Turner's syndromes (p. 535). The 'mitral fades' A thin face with prominent 'rosy' cheeks, which on closer examination are tinged with blue (cyanosis), used commonly to be seen as a consequence of chronic mitral stenosis, but now is more frequently associated with any condition where the cardiac output is low and the venous pressure high. Skin - pallor As in any medical examination a note is made of pallor, as symptoms indistinguishable from those of cardiac failure and even angina may be caused by profound anaemia. A low cardiac output may itself produce generalized pallor, often associated with cool fingers, toes and nose. Skin - cyanosis Peripheral cyanosis can also be produced by low cardiac output, when the cool extremities take on the characteristic blue tinge. Central cyanosis is caused by intracardiac shunting (right to left heart, as in the Eisenmenger reaction, see p. 536); the lips and tongue are blue and the colouring made more intense by the frequently associated polycythaemia. The periphery is often warm in these circumstances, and in congenital cardiac defects clubbing of the finger- and toenails is found. Skin - hands and nails Clubbing may occur in cyanotic congenital heart disease, but may be acquired in chronic infective endocarditis (p. 576). Infective endocarditis also accounts for several other findings, including splinter haemorrhages, which appear as small dark subungual petechiae. They are also seen in other diseases, such as polyarteritis nodosa. The appearance of new splinter haemorrhages during an acute episode of pyrexia in a patient with a murmur strongly suggests endocarditis or persistent infection in an established treated case. Osier's nodes are tender palpable spots on the pulps of the fingers occasionally detected in endocarditis.
469
Skin - xanthomata and arcus senilis Characteristic firm nodules form on the tendons of the knuckles and over the elbow, and thicken the Achilles tendon in hypercholesteraemia. 1 Indeed, these xanthomata might be the first sign of familial hypercholesterolaemia (p. 1023) and bring the patient to the doctor before there are manifestations of coronary heart disease. More commonly there is arcus senilis, which is a pale ring, usually incomplete, encircling the iris in young persons with hyperlipidaemia; the ring is commonly present in older people even without any lipid disorder. In hyperlipidaemia the periorbital area may also develop flat, mildly raised, pale yellow xanthomata.
Arterial pulses The information sought in examining the arterial pulses includes the following:
Mouth Poor dentition and recent major dental work are documented sources of infection in endocarditis, so an assessment of the oral hygiene of patients is essential.
The pulse volume rate and rhythm are assessed from the right radial pulse. The contralateral radial should also be briefly examined to confirm its presence and volume. Some indication of the state of the arterial wall can be obtained from the thickness of the radial and brachial arteries. Next the carotid pulses are examined, where the pulse character can be appreciated. At the carotid pulses thrills may be felt and bruits heard. The same examination is made of the femoral arteries, where in addition the pulse is simultaneously felt in the radial and femoral arteries. Coarctation of the aorta (p. 540) produces either absence of the femoral pulse or a reduced volume beat, which is delayed in comparison to the radial pulse upstroke so-called radiofemoral delay. In the legs the popliteal arteries and both dorsalis pedis and posterior tibial arteries are examined.
Dyspnoea Movement, dressing and undressing may reveal breathlessness, and orthopnoeic patients may not be able to tolerate lying flat. Oedema Pitting oedema is classically seen in the dependent regions: the ankles and feet in ambulant patients, 2 and the sacral area in those in bed. The oedema may be extreme and involve the thighs, pudenda and lower abdominal wall, when a 'peau d'orange' effect is seen. In these circumstances ascites is nearly always present, but may surprisingly occur before much peripheral oedema has developed. Cardiac cachexia Although weight gain due to fluid accumulation is usual in heart failure, late stages of the severe disease may produce profound muscle wasting and weight loss closely analogous to disseminated malignancy; this condition is called cardiac cachexia.
Arterial pulses and blood pressure Blood pressure A mercury sphygmomanometer is usually used to measure the systemic arterial blood pressure. This is often performed early in the examination; however, blood pressure is often highest at this time, owing to an 'alerting' response in the patient, and a lower reading may be obtained at the end of the consultation. The room should be warm and the measurement repeated in both arms and again with the patient standing. Details of blood pressure measurement are to be found on page 590.
1 470
Figs 12.1-12.3
2
Fig. 12.4
• Presence and equality of volume of the pulses on both sides of the body • Rate, rhythm and character of the pulse waveform • The state of the arterial wall • The presence of arterial bruits • The carotid pulse, which can help to time events when auscultating the heart (S1 just precedes the upstroke of the pulse) • The presence or absence of radiofemoral delay.
Rate and rhythm It is important to count the pulse accurately when there is a tachycardia (pulse >100) or a bradycardia (pulse <60). Heart rates of 150 bpm (±5bpm) are almost always due to atrial flutter. A small variation of heart rate with respiration is normal, and more marked in young people (sinus arrhythmia). Intermittent irregularities in the pulse are often due to ectopic activity, producing a slight pause in the normal regular beat followed by a beat of larger than usual volume. A pulse which is totally irregular with constantly varying volumes is likely to be due to atrial fibrillation (AF) and is called the irregularly irregular pulse. Frequent ectopics can cause confusion with AF, and the irregular rhythm may be missed if the fibrillation is well controlled owing to therapy. The heart rate is best assessed by auscultation when the pulse is irregular, although the use of the difference in pulse rate measured at the wrist and by auscultation at the cardiac apex (the apex-radial deficit) is of limited practical value as there is always a difference in the presence of a fast apical heart rate in AF. Pulse amplitude The pulse amplitude at the wrist depends on the stroke volume, which varies with cardiac output and pulse interval. It also depends on the state of vasodilatation of the skin of the hands, with a smaller radial pulse volume when cold than when warm. A thready, low-volume and rapid
pulse may be felt in shock due to haemorrhage, and a largevolume pulse in thyrotoxicosis or CO2 retention in pulmonary disease. Pulse character With the exception of collapsing pulses, this is most reliably assessed by examining the carotid pulses in the neck, although the femoral and brachial arteries are useful when the neck is difficult to examine. The collapsing pulse. This is a sign of aortic regurgitation but may be present in any condition that produces the combination of a large pulse volume with a rapid run-off into the periphery owing to a reduced impedance to flow (e.g. pyrexia, pregnancy, thyrotoxicosis, arteriovenous fistula). The sign is best appreciated by gripping the forearm with the left hand, the examiner's fingers being pressed fairly firmly against the medial aspect of the forearm. The arm is then raised up by the examiner's right hand, which is holding the patient's hand in a handshake position. In the presence of a collapsing pulse the fingers will feel a 'knock' in the forearm muscles. Associated features are a low diastolic blood pressure reading and, in severe cases, visible arterial pulsations in the neck, Corrigan's sign. The slow rising, anacrotic or plateau pulse. This sign of aortic stenosis is usually most reliably found by examining the carotid pulses. The carotids are best felt with the patient sitting at 45°, resting the head on a pillow and looking straight ahead. The pulse is felt halfway up and medial to the sternocleidomastoid muscle at the level of the major skin crease. The slow rising pulse contrasts with the transient flick that the normal carotid systolic pulse produces. It can be a difficult physical sign to appreciate and, as its name implies, the pulse may be felt to caress the fingertips as it rises slowly to a more sustained peak. It is often of low volume and may have an associated thrill or judder. It may be masked in stiff arteries of the elderly. The jerky pulse. This is felt at the carotids as described, and is one of the few physical signs to be found in hypertrophic cardiomyopathy (p. 571). It is therefore potentially important, as it should alert the physician to the possibility of the presence of this serious condition affecting the young. Severe mitral regurgitation can produce the same physical sign. Rarer forms of abnormal arterial pulse. Pulsus alternans consists of a beat-to-beat alternating large and small pulse volume with a regular rhythm, and is seen in severe left heart failure. Pulsus paradoxus represents an accentuation of a normal physiological variation in the pulse volume with respiration. It consists of a greater than l0mmHg fall in systolic pulse pressure with inspiration and occurs in pericardial tamponade or constriction (pp. 587 and 588), but may be seen in cardiomyopathy, massive pulmonary embolism, and sometimes with normal cardiac function in severe asthma. It may be felt by the fingers on the radial pulse but, if mild, is better elicited by using a sphygmomanometer and detecting the different systolic pressures during inspiration and expiration. Pulsus bisfe-
riens is a pulse that can be felt to have a double systolic peak. It can be a feature of mixed aortic valve disease, where a degree of stenosis complicates dominant aortic regurgitation.
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The jugular venous pulse (JVP) The JVP can be a difficult physical sign to appreciate, and the subtleties of its waveforms have fascinated physicians and terrorized medical students for generations. Despite its archaic nature the JVP remains a useful bedside indicator of circulating blood volume, it being invisible in fluid depletion or haemorrhage and raised in fluid overload or heart failure. Its waveforms can indicate the nature of some cardiac arrhythmias and make the diagnosis of pericardial tamponade. The internal jugular is used; despite its being deep in the tissues under the sternocleidomastoid muscle, pulsations arising from this vein can be seen at the skin surface. The height of the JVP is measured vertically from the sternal angle; normally, in a patient seated at 45° it does not exceed 3cm. The normal waveform can be appreciated in most people at the root of the neck, but they may have to be lying rather flatter than at 45°. What is seen is a regular pulsation in the neck, with two peaks and two troughs for each radial pulse (if sinus rhythm is present). Unlike arterial pulses, the venous pulse is most obvious by the rhythmic inward movement of the skin overlying the vein; arterial pulses produce a dominant outward, brisk skin movement. Inspiration causes a fall in the JVP (Table 12.2). The JVP can be so high that the neck looks generally full and the upper limit of the venous column is not appreciated; sitting the patient upright or making him stand may make the top of the JVP column come into view. A low JVP can be made to appear by gentle abdominal pressure - hepatojugular reflux: in a normal person the JVP may rise 2-3 cm, but rapidly falls, whereas in cardiac failure the bolus of extra blood supplied to the right heart by squashing the splanchnic bed cannot be accommodated, so the JVP rises, and this is sustained for several seconds. When
TABLE 12.2 Differentiation of the JVP from an arterial (carotid) pulse
Waveform Pressing at root of neck? Variation with respiration? Palpable pulse? Change with posture? Pressure on abdomen (hepatojugular reflux)
Venous
Arterial
Two peaks per beat (in SR) Obliterates wave form Normal JVP falls with inspiration Not usually, except in tricuspid reflux May fall if patient sits up or stands JVP rises
Single peak No effect No effect Yes No change No effect
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• • • •
FIG. 12.7 Relationship of venous waveform to heart sounds The a wave of atrial contraction is followed by the x descent. The cwave is not usually visible. The I'wave coincides with ventricular systole.
the JVP is massively raised but does not show waveforms during the cardiac cycle, it is likely to be owing to superior vena caval obstruction, such as in malignancy. The JVP waveform The two peaks, a and v, are due to atrial and ventricular systole (Fig. 12.7). The two descents are x and y, with a transient pressure 'hump' on the first (x) descent being called the c wave. The a wave is generated by atrial systole, and therefore disappears in atrial fibrillation. Extra-large a waves are called cannon waves and are seen when atrial systole occurs with a closed tricuspid valve; this occurs intermittently in complete heart block, occasionally with ventricular ectopics, and regularly in nodal rhythm. Large, or giant, a waves are associated with a poorly compliant right ventricle increasing the impedance against which the atrium has to eject blood, such as in pulmonary hypertension. When the tricuspid valve leaks, the right ventricle is in communication with the great veins and the rise in pressure during systole produces a very large v wave, sometimes called the s wave. Abnormalities of the x and y descents can be difficult to time correctly. The y descent is slow in tricuspid stenosis, which is a rare valve lesion. In pericardial tamponade and constriction (pp. 587 and 588) the JVP is very high and demonstrates an abrupt fall in systole (x descent); complicated by myocardial involvement the dominant descent may occur in the early part of diastole (y descent). 1
The precordium Scars and deformities may give useful clues to the past history; the former might indicate a previous closed mitral valvotomy (generally a subtle left-sided inframammary thoracotomy scar) and the latter congenital heart defects. Pulsations of the apex beat or dyskinetic movements of a left ventricular aneurysm may be seen. Palpation is undertaken to detect the following: • Presence of thrills - these are palpable murmurs felt as high-frequency vibrations 1
472
MCQ 12.3
The position of the apex beat The character of the apex beat The presence of a parasternal heave Palpable heart sounds.
Thrills The commonest thrills are those arising from the aortic valve in aortic stenosis, and are felt either side of the sternum in the upper part of the anterior chest wall. Diastolic thrills down the sternal edge and at the apex can occasionally be felt in very severe aortic regurgitation; mid to low central sternal thrills may occur in small ventricular septal defects. The apex beat This is defined as the lowest, most lateral detectable cardiac pulsation; its position is normally in the fourth intercostal space at or medial to the midclavicular line, and is felt when the patient is sitting in the standard 45° position. Displacement of the apex downwards and laterally is due to left ventricular dilatation. Many adults, especially those who are obese or have overexpanded lungs, do not have palpable apex beats; in a very small minority this will be due to dextrocardia. The character of the apex beat can be determined in most cases by palpating the apical region with the patient in the left lateral position. It is generally a very localized pulsation covering no more than the pulp of two examining fingers. A thrusting apex beat pushes the fingers outwards with each systole and is a feature of left ventricular hypertrophy. In aortic stenosis the apex may be thrusting and not displaced. In a volume-overloaded ventricle, such as in mitral regurgitation, the apex beat is usually displaced and may be thrusting in nature. A tapping apex which is not displaced is a feature of mitral stenosis and is caused by a loud (palpable) first heart sound. Dyskinesia of the apex may affect larger portions of the precordium and are associated with ventricular aneurysms. The whole apex may then rock under the palpating hand, and the apex beat may have a double impulse. This latter sign may also be felt in hypertrophic cardiomyopathy. The apex beat is abnormal in dilated poorly functioning ventricles when it may be very diffuse, with a weak but widespread pulsation. Parasternal heave This is felt by applying the heel of the hand to the lower third of the sternum with modest pressure. Right ventricular hypertrophy produces a feeling of lifting of the hand during systole. Similar lifting sensations, slightly more to the left of the sternum, can be produced by the rapid expansion of the left atrium in systole due to severe mitral regurgitation.
Auscultation Successful cardiac auscultation requires a comfortable
and familiar stethoscope of good quality and a relatively quiet environment. The bell is designed to accentuate low-frequency sounds and is therefore particularly suited to detect third and fourth heart sounds, as well as the diastolic murmur of mitral stenosis, but it can perform more like the diaphragm if pressed hard against the skin, a feature used to advantage on occasion (see below). The diaphragm filters out low-frequency sounds and is therefore most suitable for listening to the first and second heart sounds, as well as high-frequency murmurs such as that produced by aortic regurgitation. The aim of cardiac auscultation is to detect the following:
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• Normality of the first (S1) and second heart sounds (S2), loudness and splitting - diaphragm; • Presence of added third (S3) and fourth (S4) heart sounds - bell, lightly applied; • Presence of clicks - diaphragm; • Presence of murmurs, their timing, location, intensity and radiation - both diaphragm and bell; • Other noises, such as rubs and venous hums - both diaphragm and bell. A suitable examination begins with the diaphragm applied to the upper left sternal edge to determine the first and second heart sounds - a finger or thumb on a carotid pulse will aid the timing. The diaphragm may then be moved over the chest, down the sternal edge to the apex; after listening to both S1 and S2 here, the change is made to the bell and the process repeated in reverse. At this point the patient can be moved into the positions necessary to bring out murmurs (see below). The relationship between the heart sounds and various types of murmurs is illustrated in Figure 12.8A. Heart sounds First and second heart sounds (SI and S2) The first heart sound slightly precedes the carotid pulse upstroke. It signals the beginning of systole (Fig. 12.9) and, although complex in origin, is produced mainly by the closure of the mitral and tricuspid valves. Normally, only the mitral component is audible, but delayed systolic events in the right heart (e.g. in right bundle branch block, or volume overload in atrial septal defect) may allow splitting of S1 to be heard (mitral followed by tricuspid closure). A loud S1 is heard in mitral stenosis (p. 522) and in situations where atrial systole is very close to ventricular systole, such as with a short PR interval; conversely, mitral regurgitation and long PR intervals are associated with a quiet S1. The second heart sound is caused by closure of the aortic and pulmonary valves. Audible splitting of S2 (aortic valve A2 followed by pulmonary valve P2) occurs in most normal people during inspiration and can be heard with the diaphragm applied to the upper left sternum (pulmonary area), but not at the apex where P2 does not
FIG. 12.8 Heart murmurs A Diagrammatic representation of murmurs. S1 and S2 = first and second heart sounds; A2 = aortic valve closure sound; P2 = pulmonary valve closure sound; OS = opening snap. B The precordial areas where murmurs are usually heard maximally. A = aortic; P = pulmonary; M = mitral.
radiate unless it is abnormally loud, e.g. in pulmonary hypertension. Third and fourth heart sounds (S3 and S4) Both these sounds are produced by ventricular filling, are very low pitched and require the bell to be lightly applied to be heard. It can be very difficult to tell them apart, particularly at fast heart rates. The third sound occurs early in diastole and can be heard in normal young
473
An opening snap is characteristic of mitral stenosis, where the valve remains compliant. It occurs early in diastole owing to the sudden tensioning of the mitral valve apparatus and can be differentiated from an S3 by its higher pitch and sometimes wide radiation. An opening snap is audible with diaphragm and bell, S3 only with the bell. Pericardial rubs are variously heard as creaky rustling, shuffling noises which can be differentiated from pleural rubs by their continuation even during breath-holding. Tumour plops can uncommonly be associated with a large atrial myxoma, when a curious 'plop' may be produced intermittently, and sometimes with a change in posture - usually as the patient takes up the left lateral position.
FIG. 12.9 Relationship between pressures in the aorta, left ventricle and left atrium The timing of the heart sounds (S1 and S2) are shown (a and v represent the a and v waves).
people and some slim athletic adults, who have a relative bradycardia. It is also heard in hyperdynamic states and volume-overloaded ventricles, such as with thyrotoxicosis and significant mitral regurgitation, respectively. In older people an S3 is taken as indicative of heart failure. A higher-pitched and loud S3, sometimes called a 'pericardial knock' is produced by the very abrupt end to ventricular filling that occurs early in diastole owing to pericardial constriction. The fourth heart sound is generated by atrial systole in the presence of a raised left ventricular enddiastolic pressure. It indicates an impairment of ventricular compliance, often due to hypertrophy. It is typically a feature of hypertension, but can also be heard during myocardial ischaemia. Gallop or triple rhythm In heart failure, if S3 and S4 are loud, a characteristic cadence of the heart sounds is heard which sounds like a galloping horse. A loud combination of the sounds leads to the summation gallop, which may be heard when a tachycardia complicates the cardiac failure. Other added sounds Ejection clicks are very high pitched and sound as their name implies. They are a feature of young patients with pulmonary and aortic valve stenosis when there is a pliable valve which domes upwards in systole. Midsystolic or non-ejection clicks may be single or multiple and are a feature of floppy or prolapsing mitral valves (p. 525), and much less commonly of tricuspid valves.
1
474
MCQ 12.4
Heart murmurs Murmurs are found where there is turbulent flow, and their radiation follows the direction of blood flow. Although the precordium is classically divided into various valve areas (Fig. 12.8B) they may not always be the sites where murmurs arising from those particular valves are best heard. Murmurs may be palpable and produce precordial thrills. Their full characterization and clinical importance may depend more on the associated physical signs elicited on examination than purely on their ausculatory features. Thus a loud ejection systolic murmur in a patient with a normal apex beat and carotid pulse is of less concern than a quieter but similar murmur associated with a displaced, thrusting apex and a slow carotid pulse upstroke. The former may be a benign flow murmur, the latter represent critical aortic stenosis. Causes of murmurs Murmurs may be generated by a high-velocity jet, such as a stenotic or regurgitant jet, passing from a high-pressure to a lower-pressure chamber or vessel. They may occur with increased flow velocity in a normal vessel, or with flow into a dilated or distorted vessel, such as the aorta in hypertension or the pulmonary artery in sternal depression. Murmurs do not therefore always indicate valve pathology. They may indicate a high flow, such as in pregnancy, or a minor anatomical distortion not amounting to true pathology, so-called innocent murmurs. Description of murmurs Murmurs are described in terms of their timing, precordial location, radiation, relative intensity and, if warranted, the influence of respiration and posture (Fig. 12.8). It is possible to grade the loudness of murmurs from 1/6 (almost inaudible) to 6/6 (a murmur which can be heard in a quiet room without using a stethoscope). These grades are, however, of limited value, as they are highly subjective and the loudness of a murmur varies considerably depending on circumstances. The length of a diastolic murmur can be expressed on a scale of quarters, 1/4 being very short, and 3/4 an almost full-length diastolic murmur.
Systolic murmurs Ejection murmurs are crescendo-decrescendo (diamondshaped) (Fig. 12.8) and are characteristic of flow across a stenotic aortic or pulmonary valve, or flow into a dilated aorta or pulmonary artery. They may also occur with increased flow across these valves (innocent murmur). Sometimes, in severe stenoses it is impossible to distinguish an ejection from a pansystolic murmur. The associated signs will often help. Pansystolic murmurs are generated by jets passing from a high-pressure to a low-pressure chamber throughout systole, including the normally isovolumetric phases of contraction and relaxation. The best example is mitral regurgitation, but tricuspid regurgitation and ventricular septal defects produce similar murmurs. The murmur obscures both S1 and S2 and is of almost even intensity throughout systole. Late systolic murmurs. Mitral valve prolapse and papillary muscle dysfunction give rise to a high-pitched murmur of even intensity starting halfway through systole, often preceded by a midsystolic click. Posterior papillary muscle dysfunction can give rise to a mitral pansystolic murmur, which may be loud in the aortic area. Diastolic murmurs Diastolic murmurs are always pathological, but are often much harder to detect than systolic murmurs. Mitral and tricuspid mid-diastolic murmurs. The mitral (and tricuspid) stenotic jets induce a low-frequency, largely subsonic vibration. These are heard as low-pitched, rumbling murmurs starting after the opening snap, best heard with the bell. They are localized and are often missed by the inexperienced, who are expecting to hear a much higher-pitched sound. The mitral diastolic murmur is accentuated by the patient lying on the left. If short, it can be confused with a third heart sound. Early diastolic murmurs start immediately after the second heart sound. They are high-pitched noises, which can be very short or persist throughout diastole. Aortic diastolic murmurs are often faint and are best heard with the patient leaning forwards in expiration. A soft aortic diastolic murmur is often missed. Other types of murmur Musical or mewing murmurs may occur in systole or diastole if a valve cusp adjacent to a jet vibrates at a characteristic frequency. These murmurs can be very loud, but the jet causing them may be small. A mewing murmur is characteristic of a small hole in an aortic valve cusp as a complication of endocarditis. 'Innocent' murmurs Many midsystolic and ejection systolic murmurs are unaccompanied by any signs or features of heart disease. These murmurs are common in children and in pregnancy. They are maximal in the pulmonary area, but may also be heard along the left sternal edge and at the apex, and often have a low-pitched vibratory quality. They are usually of low
intensity. If there is doubt as to their 'innocent' nature, an echocardiogram and, particularly, a Doppler study can rule out a small ventricular septal defect, pulmonary stenosis or unsuspected trivial mitral regurgitation.
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Accentuating murmurs - dynamic auscultation Unless murmurs are perfectly well heard with the patient sitting at 45°, all patients should be examined in the left lateral position (mitral murmurs) and sitting forward in exhalation (which accentuates the early diastolic murmurs of aortic regurgitation). Exercise, such as sit-ups, can be used to increase cardiac output and so increase the loudness of mitral stenotic murmurs. Increased venous return, with inspiration or passive leg raising, will transiently increase the loudness of many right heart murmurs. In hypertrophic cardiomyopathy the LV outflow tract murmur can be diminished by asking the patient to squat, whereas in mitral valve prolapse this manoeuvre will increase the murmur loudness. 1
Concluding a cardiovascular examination The examination is incomplete without examination of the lung bases for signs of cardiac failure, the sacrum and ankles for oedema, and assessment of the peripheral pulses, dentition, skin and nails. • The lungs are examined not only for signs of failure, but also because chronic lung disease can complicate and add to the symptoms and signs generated by heart disease. • A patient with angina may well have atheromatous peripheral vascular disease, shown by loss of pulses in the legs. Examination of the carotid arteries for signs of atheromatous carotid stenosis may reveal loss of a carotid pulsation, a carotid bruit or loud systolic murmur. Atrial fibrillation may have caused embolic loss of some pulses. If the patient is hypertensive with a systolic murmur, radial and femoral pulses should be felt to detect any delay and weakness of the femoral pulse indicating coarctation. Possible aortic aneurysm should lead to careful assessment of the pulses and the blood pressure in both arms. • Tricuspid regurgitation is confirmed by finding a pulsatile liver. If the patient has hypertension, the abdomen is examined for renal enlargement or bruits. A patient in right heart failure may well have ascites and considerable liver enlargement. • Atrial fibrillation or tachycardia may be caused by thyrotoxicosis, so the thyroid is examined for goitre and signs of thyroid overactivity. • If the patient is hypertensive, the optic fundi are examined for hypertensive retinopathy. They should be examined regularly in patients suspected of having endocarditis.
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FIG. 12.10 Normal ECG
CARDIAC INVESTIGATION THE ELECTROCARDIOGRAM The electrocardiogram (ECG) is a fundamental part of cardiovascular assessment. It provides information on the heart rhythm and underlying cardiac morphology. A 'normal ECG' (Fig. 12.10) at rest can be reassuring but also misleading, as it can be found even with life-threatening coronary disease; in the absence of symptoms, a routine ECG is thus of limited value.
Recording an ECG The patient should be relaxed and warm (not shivering) before the 10 skin electrodes are applied to skin previously mildly abraded with spirit. The limb leads provide an electrical 'view' around the heart in the frontal plane, and the
1
476
Fig. 12.5
2
Fig. 12.6
six ventricular leads view the heart from the complementary horizontal plane (Fig. 12.11). By convention, the lead connections have been made to show a positive deflection when the wave of depolarizing current travels towards the electrode. The final shape of the ECG is determined by the lead being sampled and by the angle (vector) at which it 'views' the activity in the heart; the magnitude of the recorded deflection is affected by the mass of tissue undergoing electrical activation. Understanding the ECG therefore requires that the anatomy of the heart, the route taken by electrical activation and the viewpoint of the electrode are known. Differences in anatomy and minor variations in lead positions can account for some of the variability in clinical ECGs; pathological processes account for the rest. Standard gain settings (1 cm/mV deflection) and paper speed (25 mm/s) complete the ECG recording.
Atria I activity and the P wave In the normal heart the dominant pacemaker is to be found in the high right atrium at the sinoatrial node. The depolarizing wave front moves through the right atrium first and arrives at the left atrium fractionally later. The wave front moves towards +60° (see Fig. 12.14). The surface ECG records a P wave which is positive and best seen in
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FIG. 12.12 Normal and abnormal P waves A On the left is shown the direction of atrial activation that produces the normal P waves shown in lead II. In P pulmonale (PP) the P wave is abnormally tall and peaked. When activation is retrograde (nodal rhythm shown by dashed line), the P wave is inverted, B In left atrial hypertrophy (e.g. in mitral stenosis) a broad bifid P wave is seen in lead II and a prominent negative deflection in lead V1; this is P mitrale (PM).
the depolarizing wave front, and may be seen when atrial activation is initiated at the atrioventricular (AV) node low in the right atrium. Other ectopic atrial rhythms may produce P waves of varying shapes.
The PR interval
FIG. 12.11 Position of leads and electrodes in the ECG [A] Frontal plane. B Horizontal plane. Four limb leads and six precordial leads are routinely used, the anatomical landmarks for the latter being: V1, right sternal edge, 4th intercostal space; V2, complementary position to left of sternum; V3, between V2 and V4; V4, midclavicular line, 5th space; V5, anterior axillary line; V6, midaxillary line, horizontally in line with V4.
leads II, V1 and I. Right atrial hypertrophy produces a tall (>2.5mm) peaked P wave, sometimes called the P pulmonale 1 from its association with the pulmonary hypertension of pulmonary disease. Left atrial hypertrophy (P mitrale) 0 produces a broad notched P wave (>0.12s duration) in leads II or III, with a negative secondary deflection in V1 which exceeds the right atrial positive deflection in that lead (Fig. 12.12). P waves that are inverted in lead II are caused by an abnormal direction of
Between atrial and ventricular depolarization, the ECG signal records a flat isoelectric line for 0.12-0.20 s (Fig. 12.13). This is the delay encountered by the depolarizing wave front in the AV node before rapid propagation to the ventricular myocardium. The PR interval will diminish at increased heart rates and under the influence of adrenaline (epinephrine). It increases in diseased AV nodes, with certain drugs and, occasionally, in normal people.
The QRS complex and ventricular activation Normal QRS The normal QRS parameters are shown in Figure 12.13. Ventricular activation is complete within 0.12s, with virtually simultaneous activation of the left and right ventricles owing to the system of specialized rapidly conducting muscle cells that form the bundle of His and the Purkinje network. Activation of the interventricular septum begins first from left to right and accounts for the small q wave (duration <0.04s and depth <25% of R wave height) seen in leads V5, V6 and, usually, V4. This wave is matched by the r wave in V1 and V2. Because the left ventricular
477
pattern, with a small initial r wave and large secondary R wave, is seen in the right-facing chest leads V1, V2 ± V3, as right ventricular forces occur late and unopposed by left ventricular contraction; this is also manifested by late deep slurred S waves appearing in V4 to V6. Left bundle branch block causes a delay in left ventricular activation, which occurs from right to left, causing a marked axis shift (greater than -60°) and loss of q waves in V5 and V6. Lead V1 shows only a qS wave and the lateral leads (V5 and V6) the characteristic slurred RsR or 'M' pattern. Left bundle branch block is virtually always pathological, the commonest cause being ischaemic heart disease. Right bundle branch block may be a normal finding, but the change from normal conduction to one or other of these patterns implies heart disease. FIG. 12.13 Normal PQRST parameters A Duration. QT interval varies with rate. B Height.
muscle mass is greater than that of the right ventricle, it is the left ventricular forces that dominate the chest leads, with rS waves in leads V1 and V2 and qR waves in leads V5 and V6, with an intermediate transition zone to be found between leads V3 and V4. The mean frontal plane vector (QRS axis) This is obtained from the limb leads and describes the direction of the dominant electrical forces. It can be determined for all the major ECG deflections (P wave, QRS complex and T wave), but is mainly used to summarize ventricular depolarization as the mean QRS axis. It is roughly estimated by choosing the lead with the smallest equiphasic deflection and assuming that the vector is at 90° to this lead. On this vectorial line the limb lead that shows a positive deflection indicates the direction of the axis. The units are degrees, with values above the equator (0°) being prefixed negative (Fig. 12.14). The vector is normally about +60°. Left axis deviation is variously defined, but a shift further than -30° is definitely abnormal; right axis deviation is definite at greater than 120°. The latter can be due to right ventricular hypertrophy or, less commonly, to abnormal patterns of activation caused by interruption of the posterior fascicle of the left bundle branch, in left posterior hemiblock. Left axis deviation is an 'electrical' phenomenon, caused by interruption of the anterior fascicle of the left bundle branch. It is associated with the loss of the normal septal depolarization and hence the loss of q waves in V5 and V6. This is called left anterior hemiblock; in these conditions the QRS duration remains less than 0.12s.
478
Bundle branch block Interruption of the right or left bundle branches produces a bundle branch block pattern characterized by broad QRS complexes of more than 0.12s duration (Fig. 12.15). With right bundle branch block an rSR or 'M'-shaped
Rate-dependent bundle branch block Occasionally, normal QRS morphology is present at low heart rates, but a bundle branch block pattern appears at faster rates. This is usually right bundle branch block, as its refractory period is generally longer than that of the left bundle branch. Rate-dependent bundle branch block may occur with a supraventricular tachycardia, where the broad QRS complexes may wrongly suggest the diagnosis of ventricular tachycardia. Ventricular hypertrophy The tallest R wave should not exceed 27mm, nor the deepest S wave 30mm, and the sum of the tallest R wave and the deepest S wave should not exceed 40mm (Fig. 12.13). Left ventricular hypertrophy (LVH) is diagnosed when these criteria are exceeded, with a normal total QRS duration of less than 0.12s. The intrinsic deflection is delayed by more than 0.04s in the left-facing leads, this measurement being taken from the onset of the QRS deflection to the point at which the R wave swings abruptly downwards. Associated ST segment depression and T inversion occur in the left-facing limb and precordial leads, particularly with pressure-overloaded ventricles, and is said to represent ventricular 'strain'. Right ventricular hypertrophy (RVH) is suspected when there is a dominant R wave in V1, associated with a rightward QRS axis shift (>+90°) in a QRS complex of less than 0.12s duration. There is also ST segment depression and T inversion in the right precordial leads, and often also clockwise rotation of the ventricular leads with the normal transition zone (V3-V4) moving towards V5-V6.
The ST segment The ST segment begins where the QRS ends, and is normally on the isoelectric line curving upwards into the T wave (the J or junction point). There may be 1-2 mm of elevation in the high anterior chest leads (V1 and V2), but greater elevation is seen with myocardial infarction, the so-called current of injury (p. 556, Fig. 12.63), and pericar-
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FIG. 12.14 Determining the mean frontal plane axis A Lead aVL has the smallest biphasic signal. The axis is perpendicular to this and its direction is given by the upward deflection produced in lead II. The axis, shown by the arrow, is therefore +60° (normal axis). B The axis is -90° (perpendicular to I and away from aVF). This is left axis deviation. C The smallest and most biphasic complex lies between II and aVF and the axis is therefore greater than 120° (severe right axis deviation).
ditis (p. 587, Fig. 12.66). A normal variant, in which there is marked anterior ST elevation, is frequent in young black men. Depression of the ST segment (p. 545, Fig. 12.57) is the hallmark of cardiac ischaemia. This can vary from subtle loss of the normal slight upward curvature and acute angulation with the T-wave origin, to more marked depression, sloping downwards before abruptly changing direction with the T-wave onset. The degree of depression of the ST segment is a rough indication of the severity of the myocar-
dial injury. The ST segment is encompassed within the QT interval. This shortens with increasing heart rate, but may be prolonged (>0.40s or >50% of previous R-R interval) by hypocalcaemia or hypomagnesaemia.
The T wave: myocardial repolarization There is more variability in T-wave amplitude and orientation than in other parts of the ECG, so that criteria for normality have to be more flexible. The T wave may be flat
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amplitude and shares the T-wave orientation. It is best seen in lead V3 and is enlarged in hypokalaemia. Its genesis is uncertain. 1
Exercise electrocardiography The normal 12-lead resting ECG often shows no abnormalities in patients who develop symptoms on exercise. The exercise test, on a treadmill or cycle ergometer, may be performed for the following reasons: • To reproduce the symptoms, so that the patient can describe them as they happen under standardized exercise conditions; • To assess 'functional capacity', i.e. the amount of work that can be performed before the patient becomes limited by symptoms, and also how rapidly the patient recovers from exercise; • To ascertain whether the symptoms are accompanied by any objective evidence of myocardial ischaemia, cardiac arrhythmia, hypertension or other events that would make unsupervised exercise hazardous; • To monitor treatment with serial studies; • To assess prognosis in patients with known cardiac disease.
FIG. 12.15 Bundle branch block A Left bundle branch block. B Right bundle branch block.
or abnormal in non-cardiac disease and in some normal patients. It is asymmetrical in shape, with a slower upstroke than downstroke and a smooth rounded peak. Symmetrical peaked T waves may indicate ischaemia, whereas notching may be a feature of pericarditis. T-wave height should not exceed 10mm in the precordial leads; larger heights without LVH suggest acute myocardial infarction or hyperkalaemia. T-wave orientation is normally upright in leads with R waves over 5 mm in height, so that, in the normal adult, T waves are upright in I, II and V3 to V6, are always inverted in aVR, and may be inverted in aVL, aVF, III, V1 and V2. The evolution of acute infarction (Fig. 12.63, p. 556) involves T inversion in leads affected by the injury, and these changes may persist.
The U wave The U wave follows the T wave (Fig. 12.13), is small in
1
480
MCQ 12.5
The exercise load is started at an easily managed level, kept stable for 1.5-3 minutes at each load, and then serially increased with the aim of 'exhausting' the subject within 15 minutes (although in submaximal tests exhaustion is not usually the end point). The patient is connected to an ECG monitor and the blood pressure is also recorded. A defibrillator is available. The absolute indications for stopping the test are: • • • • • • • • •
Severe ischaemic symptoms Fall in systolic blood pressure >10mmHg ST depression >3 mm New arrhythmia Patient requests it. The relative indications for stopping are: Achieves target heart rate Systolic blood pressure >220 mmHg Tired patient Angina.
Interpretation The exercise test is conclusively positive if the patient develops classic anginal pain, and downsloping ST segment depression (>2mm) is shown on the ECG (Fig. 12.57, p. 545). Minor degrees of upsloping ST segment depression are common, particularly in anxious individuals and especially in young women. T-wave inversion is not necessarily ischaemic in origin. A commonly used criterion is 1mm ST depression more than 0.08s after the previous QRS complex. Severe ischaemia is shown by widespread ST depression in several leads which takes several minutes to return to normal. There may be a sudden drop in blood
pressure during exercise; this may be unaccompanied by ECG changes but is diagnostic of severe ischaemia and is an absolute indication to stop the test.
CHEST X-RAY Because of the almost uniform density of its components, the cardiac shadow on a PA chest film is a silhouette of a three-dimensional structure displayed on a twodimensional film (Fig. 12.16). Examination of a cardiac X-ray requires a logical approach, and includes the following:
which may result in an abnormal appearance of the heart. Lateral films may show a depressed sternum or abnormal sternal segmentation. There may be rib notching, suggesting coarctation.
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Heart size and cardiothoracic ratio Minor variations in heart size can be technical in origin. It is usual to measure the cardiothoracic ratio (the maximum transverse diameter of the heart compared with that of the ribcage), which is 0.5 or less in normals. This commonly accepted criterion is, however, rather rigid and needs to be modified with athletes and people of African descent, many of whose hearts exceed this limit but are by other criteria physiologically normal. When comparing successive chest X-rays, an increase in transverse diameter of the heart of more than 1.5cm is regarded as significant.
• A check of the technical quality of the film (PA film, full inspiration, no rotation); • An assessment of heart size (and changes from previous films if available); • A search for evidence of specific chamber enlargement and abnormalities of cardiac anatomy; • An examination of the lung fields and vessels; • Identification of valve or other calcification.
Anatomy and specific chamber enlargement
An AP film is only of value in assessing the lung fields or gross changes in heart size. There may be evidence of thoracotomy, rib resection, scoliosis or severe kyphosis,
The border-forming structures of the cardiac silhouette in the PA and lateral views are shown in Figure 12.16. The approximate positions of the heart valves are also shown.
FIG. 12.16 Composition of the normal cardiac silhouette on chest X-rays [2 PA view. B Lateral view. RV and LV = right and left ventricles; RA = right atrium; LA = left atrium; SVC = superior vena cava; Ao = aorta; RPA and LPA = right and left pulmonary arteries.
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Left atrium (LA) LA enlargement may produce widening of the angle of bifurcation (carina) into the main bronchi, with lifting of the left main bronchus. The increased density of an enlarged LA may make it visible within the right heart border, or it may protrude beyond it. Enlargement of the LA can cause straightening, and even bulging, of the left heart border. On lateral chest X-ray, enlargement produces posterior displacement of the upper posterior cardiac border. Left ventricle (LV) The LV makes up the cardiac apex and part of the left heart border on PA X-rays, and much of the posterior heart border on lateral views. LV enlargement usually displaces the apex of the heart downwards and laterally on the PA view, whereas on the lateral view the LV produces a prominent convexity of the lower half of the posterior border of the heart.
Aorto In young adults the upper right cardiac border may not include the ascending aorta, but with ageing the aorta elongates and becomes more tortuous and prominent on chest X-ray. Prominence of the ascending aorta may thus be due to age as well as to hypertension, poststenotic dilatation or aortic dilatation from aortic valve disease, aneurysm or dissection. CT, ultrasound or angiography may be needed to define the cause of a prominent aorta. The aortic arch may also be prominent in any of these conditions. Calcification of the ascending aorta occurs in syphilis, but is very common in the arch and descending aorta in normal individuals.
Lung fields and vessels Assessment of pulmonary vascularity tends to be subjective and demands a good-quality film. Normal pulmonary vascularity will show larger vessels in the lower zones, with symmetry between the two lungs. There is a steady diminution in vessel size peripherally. Pulmonary venous hypertension If the pressure in the pulmonary veins rises above about 15mmHg the upper lobe vessels dilate and become larger than the lower lobe vessels, which constrict with perivascular cuffing. There is redistribution of flow to the upper lobes. If the venous pressure rises higher than about 20-25 mmHg the pulmonary lymphatics become engorged, and appearances of interstitial oedema are seen on the chest X-ray. These are the appearance of Kerley B lines (horizontal septal lines best seen at the costophrenic angles) and increased haziness of the perihilar regions, sometimes resulting in the classic but uncommon 'bat's wing' appearance of the chest X-ray, often with small effusions (Fig. 12.17). Further rises in pressure above 30 mmHg result in alveolar oedema, with dense opacification of the lung from fluid collection. Increased lung blood flow With increased blood flow to the lungs (as in a left-toright shunt) the lungs are vascular, with quite large vessels running to the periphery. This can be distinguished from left heart failure by the lower lobe vessels remaining larger than the upper lobe vessels. Pulmonary oligaemia Pulmonary oligaemia (as in severe pulmonary stenosis) is
Right atrium (RA) Enlargement of the RA is seen as prominence of the lower half of the right heart border and is usually accompanied by superior vena cava (SVC) prominence. The SVC forms the highest part of the right border of the cardiac silhouette and is prominent in right heart failure, SVC obstruction, or displacement of the SVC by the aorta. Right ventricle (RV) The RV is an 'internal' structure on the PA X-ray unless there is massive RV dilatation with the LV rotated posteriorly. RV dilatation results in a more globular appearance to the heart on PA film, with the cardiac apex being more elevated - the so-called coeur en sabot.
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Pulmonary conus and trunk The pulmonary trunk is more prominent in young subjects than later in life. A dilated pulmonary trunk may indicate a poststenotic dilatation, pulmonary hypertension, increased pulmonary flow, or can be idiopathic. It therefore needs to be interpreted along with the appearance of the lung fields.
FIG. 12.17 Radiological features of left heart failure PA chest X-ray showing bilateral shadowing spreading from the hila, typical of acute pulmonary oedema. The heart size is increased.
associated with an avascular appearance of the lung fields but normal-sized central pulmonary arteries (although the pulmonary trunk may be dilated as a poststenotic dilatation in pulmonary stenosis). A region of oligaemia (e.g. left upper zone) may be detected after a moderate or large pulmonary embolism. Pulmonary arterial hypertension The presence of pulmonary arterial hypertension gives rise to large central pulmonary arteries which are rapidly pruned peripherally, with relatively avascular-looking lung fields.
Calcification Calcification is usually best seen on penetrated PA and lateral films, as much of the calcification seen within the heart overlies the spine on PA films. The mitral and aortic valves may both calcify. On lateral films the latter is usually lying above a line joining the tracheal bifurcation and the costophrenic angle, whereas the mitral is predominantly below the line. Calcification is also sometimes seen in the great vessels, the wall of a rheumatic LA, the pericardium, and within the LV in thrombus in an LV aneurysm.
ULTRASOUND TECHNIQUES If a beam of ultrasound is directed into the thorax through a suitable 'acoustic window' the various tissue interfaces in the line of the ultrasound beam reflect some of the sound back towards the transmitting transducer, and the red blood cells in its path scatter the ultrasound. The reflected ultrasound takes varying times to get back to the transducer, depending on the depth of the interface from which the reflection occurs. Ultrasound imaging allows for a detailed, painless and safe investigation of the heart and great vessels which can be repeated many times. Anatomical and functional information can be obtained rapidly in virtually any circumstance, from the bedside in and out of hospital to intensive care units and operating theatres, and even in the unborn fetus. The limitation of obtaining a suitable imaging window on the chest wall (transthoracic echocardiography, TTE) has been surmounted, at least in part, by using small probes inserted endoscopically and viewing the heart from the oesophagus and stomach (transoesophageal echocardiography, TOE).
Echocardiography The method of obtaining the M-mode echocardiogram is illustrated in Figure 12.18. This imaging method remains important in producing a very accurate resolution of distance and time (the ECG provides the timing index) so that the movement of ventricular walls and valve leaflets can be measured to within 2mm and 10ms. The dimensions
of the left ventricular walls in systole and diastole, plus the size of the left atrium, proximal aorta and right ventricle, are the parameters most commonly taken from these recordings. Others, such as valve leaflet excursion and the extent of thickening and thinning of the LV walls, are also used. The two-dimensional echocardiogram, produced by swinging the ultrasound beam through an arc or sector, produces pictures that are immediately recognizable as cardiac anatomical structures (see Figs 12.19 and 12.20A). Their pattern of movement can also be seen in 'real time', adding to the value of the assessment. This method is particularly well suited to the demonstration of LV function, being able to demonstrate regional as well as global disturbances of contraction. Valves can be seen to open and close during the cardiac cycle, and vegetations of >3.0mm in size may be detected (see bacterial endocarditis, p. 574). It is the method of choice for the demonstration of pericardial fluid and atrial tumours, and can reveal intracardiac thrombus following myocardial infarction. Using peripheral venous injections of fluids containing microscopic bubbles (usually agitated normal saline in a bolus of 1025 ml) intracardiac shunts can be demonstrated - contrast echocardiography. Newer commercial contrast agents have been developed with echogenic particles of >6um which can pass through the pulmonary capillary bed (10 um). These agents may become useful in defining left ventricular function and viability. Echocardiography can be used to map regional left ventricular function to compare images obtained at rest with those immediately after exercise or during infusion of an inotropic agent such as dobutamine. Stress echocardiography can indicate the extent of regional dysfunction produced by ischaemia in coronary artery disease, particularly in patients with atypical symptoms and normal LV function at rest. An improvement in contraction of a region of LV with inotropic stimulation differentiates stunned from dead myocardium, an important difference if surgery or angioplasty (PTCA) is being considered.
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Doppler ultrasound The technique of Doppler ultrasound makes use of the change in frequency of the backscattered ultrasound energy from the red blood cells. This change of frequency is proportional to the blood velocity; thus, if the beam of ultrasound is aligned with the jet of blood within the heart, accurate measurements of blood velocity can be made and gradients across the valves calculated (Fig. 12.20B) from the equation P = 4V2
where P is the pressure gradient in mmHg and V the velocity in ms. The predicted pressure gradient from Doppler measurements is the instantaneous pressure gradient, whereas cardiac catheterization usually measures the peak-to-peak pull-back gradient (Fig. 12.22).
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FIG. 12.18 M-mode echocardiography The diagram shows the position of the transducer and directions of the ultrasonic beam. In A the beam traverses the left ventricle (LV) below the mitral valve. Systole (S) and diastole (D) are indicated. In B the beam is aimed to demonstrate the mitral valve (MV). In C the aortic valve (AV) and aorta (Ao) are shown.
FIG. 12.19 Two-dimensional echocardiography Parasternal long axis views of the heart in systole and diastole are shown. (The direction of the beam is equivalent to that shown by line B in Figure 12.18A.) The opening and closure of the aortic and mitral valves are clearly shown.
Doppler ultrasound is used predominantly for measuring pressure gradients and can also be used to demonstrate the presence and severity of valvular regurgitation. It is extremely sensitive in detecting minor degrees of regurgitation, which are often unexpected. Colour flow Doppler imaging Colour flow Doppler uses a form of pulsed wave Doppler to superimpose a colour image of the blood velocity and
1
484
Figs 12.7, 12.8
direction on a two-dimensional image of the heart. By convention, blood flowing away from the probe is coded blue and that towards it red. Very high velocities are associated with multicoloured pixels. This type of imaging does not lend itself to quantification, but is very sensitive at detecting regurgitant jets and unusually directed high-velocity jets such as appear in leaks around prosthetic heart valves. Colour flow Doppler has now become a routine part of the echocardiographic examination; it gives a rapid overall assessment of intracardiac flows and makes the rest of Doppler technology easier to use and appreciate. Transoesophageal echocardiography (TOE) All ultrasound techniques are limited by the size of the acoustic windows, which must avoid bone and lung. The windows are large in babies and children (almost complete in the fetus) but become smaller in adults, especially those with lung disease. Miniaturized probes mounted on endoscopes allow some of these deficiencies to be overcome (Table 12.3). Virtually all the imaging planes available transthoracically can be achieved, and in addition the atria, their appendages and the descending aorta can be seen. The technique is more invasive, being equivalent to an upper gastrointestinal endoscopic procedure. Doppler tissue imaging (DTI) This is a modification of conventional colour flow imaging where low-frequency motion is encoded and the high velocities of the red cells are filtered out. The velocity, direction and acceleration of motion of the myocardial
12 FIG. 12.20 Two-dimensional echocardiogram and Doppler ultrasound A Apical four-chamber view of the heart. B The continuous wave Doppler signal shows a diastolic jet (upwards towards the transducer). An abnormal systolic jet away from the transducer, due to mitral regurgitation, is also shown. The velocity trace indicates peak velocities of 2ms and 5ms respectively (corresponding to peak gradients of 16 and l00mmHg).
TABLE 12.3 Indications for transoesophageal echocardiography • • • • • • • • •
Poor views on transthoracic echocardiography Investigations of prosthetic heart valves, especially mitral and aortic Endocarditis (better resolution, to 1 mm with high-frequency transducers) Aortic dissection or aneurysm (to view descending aorta) Mitral stenosis - intra-atrial clot can be excluded prior to balloon valvuloplasty Mitral valve disease prior to surgical repair Systemic embolism (looking for a cardiac source) Suspected atrial mass (tumour or clot) Intraoperative, e.g. exclusion of mitral regurgitation during valve repair
cells and valve structures are colour coded, as in conventional colour flow imaging. This technique is used to detect regions of wall motion abnormality and is particularly useful in stress echocardiography as well as in quantifying regional diastolic dysfunction.
Limitations on use The combined techniques of echocardiography and Doppler ultrasound save many patients, particularly children, from invasive studies, as in many cases the complete pathology can be demonstrated with ultrasound. These techniques cannot, however, measure chamber pressures, such as the left ventricular end diastolic pressure, or show the coronary arterial anatomy.
NUCLEAR IMAGING Two major nuclear techniques are used in cardiology, myocardial perfusion imaging (MPI) and radionuclide ventriculography. Isotopes, principally y-emitting agents such as technetium-99m and thallium 201, are used to image heart function. The commonest use for nuclear techniques in cardiology is in coronary heart disease, where perfusion imaging can differentiate normal from reversibly ischaemic from infarcted myocardium.
Ventriculography, using gated pool scanning, is used to quantify ventricular function by calculating the ejection fraction (EF) of the ventricle. Very short-acting positronemitting isotopes have been used to measure myocardial metabolism and its alteration in ischaemic states, but they remain a research tool as the isotopes must be produced on site by a cyclotron.
Nuclear ventriculography Nuclear ventriculography uses intravenously injected 99m Tc-pertechnetate bound to erythrocytes. In the first-pass technique, a discrete bolus of labelled blood is followed through the heart and data are collected by an externally placed gamma camera for 30-50s. A fresh injection is required for each view. Short-lived isotopes such as 195 Au enable rest and exercise studies to be performed with relatively low cumulative exposure and background. In an equilibrium study the whole of the circulating blood is labelled and data collection can take much longer, with serial views obtained over time. Resolution of the gamma camera image is increased by taking a large number of images over several cardiac cycles, and the images from different phases of the cardiac cycle are averaged. This process is accomplished by 'gating' with reference to the ECG as a time marker and dividing the cardiac cycle into a series of time intervals. This provides a non-invasive assessment of the ventricular ejection fraction (EF) and wall motion. 1 Derived images and measurements Ejection fraction (EF) The ejection fraction is normally above 50%, and should rise with exercise by at least 5%. Regional wall motion abnormalities are' shown by quantitative colour coding of emission over the heart. Limitations of nuclear ventriculography In severe right heart failure, a peripheral venous injection of isotope is dissipated through a large mixing volume before it reaches the heart. Tricuspid regurgitation aggravates the problem, leading to greatly degraded imaging. Time-gating over many cycles is not usually possible in patients with atrial fibrillation or other significant arrhyth-
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mias. More than a minor degree of movement of the thorax relative to the gamma camera also tends to limit studies during exertion.
Myocardial perfusion imaging (MPI) The technique of myocardial perfusion imaging depends on the radionuclide being taken up by viable myocardium that is normally perfused. Generally two sets of images are required, one obtained at peak stress and the other at rest. 1 Areas of viable myocardium which are not perfused during stress appear as areas that 'fill in' during the resting scan. Stress defects on the scan that do not perfuse on the resting images represent infarcted myocardium. Although bicycle ergometry is the commonest stress used in MPI, those patients who are unable to exercise are given vasodilator agents such as adenosine or dipyridamole by infusion. Alternatively, catecholamine derivatives, dobutamine or arbutamine are used. Radionuclides used for MPIU studies are thallium-201 (201T1) and 99mTc-MIBI (Cardiolite) on 99mTc-tetrofosmin (Myoview). The latter two agents require reinjection, but no overall superiority of one agent over the others has been established. • Perfusion imaging has a high prognostic capability. The risk of a future cardiac event in a patient with normal myocardial perfusion is less than 1% per year, even in the presence of angiographically proven coronary artery disease. The converse is true, severe defects being associated with a poor prognosis. • In addition to providing vital prognostic information in patients with known or suspected stable coronary disease, MPI performed within 3 days of myocardial infarction can identify low-risk patients. It is used to stratify the risk of non-cardiac surgery in patients likely to have widespread vascular disease.
MAGNETIC RESONANCE IMAGING (MRI) Cardiovascular MRI (CMR) has the capacity to provide high-quality tomographic images of the heart and great vessels, combined with reproducible functional assessment. New technology means that scans may take only 20 minutes to acquire. The advantages of CMR include its non-invasive nature and freedom from ionizing radiation. Cost and patient tolerability (because of claustrophobia) have been limitations which are diminishing with speedier image acquisition. CMR has a particular role in the diagnosis and assessment of anatomical abnormalities, such as aortic aneurysm, dissection and coarctation. Its use in complex congenital
A Fig. 12.9 0 Fig. 12.10
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TABLE 12.4 Indications for MPI in chronic coronary artery disease • Detection and quantification of ischaemia in symptomatic or selected asymptomatic patients • Risk stratification prior to non-cardiac surgery • Selection of 'culprit' coronary lesion prior to PTCA • Symptom evaluation after PTCA or CABG • Evaluation of viable myocardium
heart disease is becoming routine in some centres. CMR can provide imaging where echocardiography is impossible, and it can usefully quantify valve regurgitation to a degree unobtainable with other techniques. Regional and global ventricular function can be obtained, as well as unique insights into myocardial tissue in diseases such as sarcoid and iron overload due to transfusion (e.g. thalassaemia) or haemochromatosis. Angiography of the neck vessels and the renal arterial system is now well established. Imaging of coronary arteries is improving but only superior to current radiological methods in certain rare circumstances, such as the assessment of aberrant coronary arteries.
COMPUTED TOMOGRAPHY X-ray technology using ultrafast CT scanners has developed to the point of allowing rapid scans of the heart, flow and morphological detail to be obtained. The spiral CT scan is now the diagnostic tool of choice in suspected moderate or large pulmonary embolism.
CARDIAC CATHETERIZATION Cardiac catheterization is a diagnostic procedure in which a flexible tube is introduced under local anaesthetic, into the brachial or femoral veins and passed into the right side of the heart, or from the brachial or femoral arteries to the left side of the heart. In children, the procedure may require a general anaesthetic. In right heart catheterization the catheter can be passed to the right atrium, right ventricle and pulmonary artery in turn. Using an end-hole catheter, an indirect LA pressure can be obtained by wedging the catheter in a small pulmonary artery. Left heart catheterization from a peripheral artery enables cannulation of the aorta, the coronaries and, by passing the catheter retrogradely through the aortic valve, the LV cavity.
Use of cardiac catheterization Catheterization allows pressure measurements to be made and cine angiograms performed by the injection of contrast agents. Selective catheterization of the coronary arteries provides high-quality angiographic views of the coronary
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FIG. 12.21 Radionuclide ventriculography: the multiple uptake gated acquisition (MUGA) scan The blood pool is labelled and counts over the left ventricle are related to defined proportions of the cardiac cycle (1-15 in the diagram). These are summated to give an average radioactivity for end systole (B) and end diastole (A), from which the ejection fraction can be calculated.
tree to demonstrate its anatomy. 2 This has become the major use of cardiac catheterization, complementing noninvasive techniques such as echocardiography and nuclear imaging. In addition to its diagnostic role catheterization is now the tool by which many therapies are achieved, in particular the use of angioplasty balloons and stents to dilate narrowed blood vessels in the heart and circulation. Devices can be introduced to close shunts, e.g. atrial septal defects or patent ducts, as well as instruments to retrieve foreign bodies lost in the circulation. In valvular heart disease many of the uses of catheterization have been supplanted by the non-invasive techniques discussed in this chapter. Nevertheless, catheterization may still be required to obtain the following information: • To measure chamber pressures and valve pressure gradients (Fig. 12.22); • To estimate valve areas in stenoses from the approximation: Valve area in cm2 =
Cardiac output in L/min Pressure gradient in nimHg mmHg
• To perform angiography by using radio-opaque contrast agents to show cardiac anatomy, assess valve or conduit regurgitation and assess ventricular function. • Measurement of oxygen content for demonstration of shunts (Fig. 12.23). Sampling in the different chambers of the right side of the heart can be used to demonstrate the presence and size of a left-to-right shunt by the rise in oxygen content (saturation) of the blood. Persistent arterial desaturation, despite the patient breathing 100% oxygen, demonstrates the presence of a right-to-left shunt. Measurement of pulmonary artery and systemic arterial blood oxygen content, together with mea-
FIG. 12.22 Cardiac catheter pressure tracing in aortic stenosis As the catheter is withdrawn from the left ventricle into the aorta, there is an abrupt drop in pressure demonstrating a gradient across the aortic valve of 140mmHg. Lower tracing is the ECG.
TABLE 12.5 Complications of cardiac catheterization • Peripheral arterial damage (dissection, haematoma) • Cardiac arrhythmia (SVT, VT, VF) • Thromboembolism, due to clot on catheter, air embolism, dislodged atheroma • Dissection of a coronary artery • Cardiac tamponade • Renal dysfunction - especially in diabetes, or - when performed in the presence of other nephrotoxic drugs, including biguanides.
surement of oxygen uptake by timed expired air gas collection (or, in many centres, estimated oxygen uptake from normograms of patient's surface area), are used to calculate cardiac output. The use of cardiac catheterization in coronary angiography is described on page 546.
Complications of cardiac catheterization The complications of cardiac catheterization are shown in Table 12.5. The risks are small (<0.1%) and are minimized by current techniques. They are increased if the patient has small vessels, is in heart failure, or has very severe coronary artery or valvular disease, and at the extremes of age (Table 12.6).
FURTHER READING ON CARDIAC INVESTIGATION ACC/AHA Task Force Report 1995 Guidelines for clinical use of cardiac radionuclide imaging. J Am Coll Cardiol 25: 521-547. ACC/AHA Guidelines for cardiac catheterization and cardiac catheterization laboratories 1991 ACC/AHA Ad Hoc Task Force on Cardiac Catheterization. J Am Coll Cardiol 18:1149-1182.
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treatment of heart failure is solely to correct these secondary defects and to relieve the symptoms, missing out therapy to improve the heart's function. Secondly, pathological states of the vasculature may produce syndromes similar to heart failure, but the heart may not actually be failing. Examples are severe hypertension (when there is excessive vasoconstriction) and the so-called 'high-output failure' (such as that produced by significant arteriovenous shunting). In these conditions the heart is required to perform supernormally and is unable to do so. To refer to these conditions as 'heart failure' is a misnomer, and to treat them in the same way as other forms of heart failure, e.g. by administering positive inotropic agents to augment cardiac pumping, is inappropriate. FIG. 12.23 Oxygen saturation in the cardiac chambers and great vessels in ventricular septal defect A step-up in saturation occurs in the right ventricle. Ao = aorta; PA = pulmonary artery; RV = right ventricle; LV = left ventricle; RA = right atrium; LA = left atrium.
TABLE 12.6 Relative contraindications to cardiac catheterization • Recent CVA • Significant renal impairment or worsening renal function • PUO • Anaemia, Hb<10g/dL • Uncontrolled hypertension • Significant electrolyte disturbance • Uncontrolled diabetes or thyrotoxicosis • Anticoagulated state (warfarin, INR < 2.0; heparin, ACT > 200s) • History of previous contrast reaction • Severe anxiety state or psychological disturbance • Use of biguanide drugs within 48 hours
Bellenger N, Pennell D J 1999 Magnetic resonance imaging in cardiology. J Roy Coll Phys (Lond) 33:12-18. Brown K A 1996 Prognostic value of myocardial perfusion imaging: state of the art and new developments. J Nucl Cardiol 3: 516-538. Chambers J B, de Belder M A, Moore D 1997 Echocardiography in stroke and transient ischaemic attack. Heart J 78(suppl 1): 2-6. Krahninkel W, Marwick T, Gulker H (eds) 1997 Stress echocardiography: a well established diagnostic tool. Eur Heart J 18(suppl D).
HEART FAILURE
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Heart failure can be defined simply as failure of the heart to function as it should to maintain an adequate circulation. Such failure has several physiological consequences, which together produce the clinical syndrome of heart failure. It is not enough to define heart failure as a clinical syndrome consisting of congestion and hypoperfusion. First, this might lead to the wrong assumption that the definitive
The spectrum of cardiac performance The main difference between the hearts of an elite athlete, a sedentary healthy subject and a heart failure patient lies in their peak cardiac performance, not in their cardiac performance at basal resting states (they all have comparable cardiac outputs of 5-7 L/min and cardiac power outputs of 0.8-1.3 W). Elite athletes can attain cardiac outputs of up to 35 L/min and power outputs of up to 11 W, whereas the values for normal subjects are 15-20 L/min and 4-6 W. Patients with moderate heart failure achieve 10 L/min and 2.5 W. It is the deterioration in peak cardiac performance that heralds the onset of heart failure; this deterioration is progressive. A point will be reached when, even at maximal stimulation, the hearts of some patients in severe heart failure or in cardiogenic shock are not able to attain the basal resting values observed in normals. These patients have a very grave prognosis.
PATHOPHYSIOLOGY OF HEART FAILURE The major effects of heart failure are organ hypoperfusion, arrhythmia, congestion, vasoconstriction and redistribution of regional blood flow. Arrhythmia in heart failure may be secondary to ischaemia, abnormal mechanical loads and the production of areas conducive to the formation of re-entry circuits (see p. 506). It is important to remember that the primary defect lies in the heart. The secondary defects, such as fluid retention and excessive vasoconstriction, are compensatory adaptive mechanisms invoked to maintain as normal a circulation as possible. They are mediated by neuroendocrine activation and produced by the primary cardiac dysfunction. Together with the primary defects, they produce the symptoms and signs of heart failure (see below). The tertiary defects are the detrimental effects of treatment. Categorizing the defects in this way is helpful in planning treatment (Table 12.7).
Primary defects The definitive treatment of heart failure should be directed
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TABLE 12.7 Defects in heart failure and their management Defect
Clinical response
Primary Pump dysfunction
Establish a cause and remedy if possible
Secondary Fluid retention Vasoconstriction Hypoperfusion Flow redistribution Arrhythmia Tertiary (usually due to treatment) Electrolyte imbalance (diuretic Px) Arrhythmia (diuretics and digoxin) Skeletal muscle deconditioning (bed rest)
Diuretics ACE inhibitors; other vasodilators (e.g. nitrates, hydralazine) Volume replacement (if acute); decrease diuretics Inotropes (if acute); ACE inhibitors Correct tertiary defect; antiarrhythmic drugs
Monitor biochemistry, potassiumsparing diuretics Review drug (proarrhythmic effects, e.g. digoxin) Exercise training
at diagnosing and correcting the primary defects. Examples might be the removal of cardiodepressant drugs, aspiration of pericardial fluid in tamponade, control of arrhythmias, a pacemaker for complete heart block, repair or replacement of faulty valves, stripping of pericardium in constrictive pericarditis, or surgical closure of intracardiac shunts. By far the most common defect causing heart failure is cardiac myocyte loss, as a consequence of myocardial infarction or cardiomyopathy. Because cardiac myocytes are unable to undergo regeneration, the necrotic myocytes are replaced by connective tissue. The remaining viable myocardium contracts harder and undergoes hypertrophy to compensate for the loss. There is as yet no definitive therapy for this type of defect. Ultimately cardiac transplantation or cardiomyoplasty may be necessary. The extent to which a primary defect compromises overall cardiac performance can be measured by how much cardiac reserve is reduced. A schematic representation of progressive damage to cardiac functional reserve by sequential myocardial infarctions is shown in Figure 12.24.
Secondary defects In the event of heart failure or a normal heart facing excessive haemodynamic burden, the heart relies on cardiovascular compensatory mechanisms to maintain an adequate circulation. The main mechanisms are: • Fluid and salt retention, invoking the Starling effect through an increase in ventricular filling. • Neuroendocrine responses (sympathetic stimulation followed by activation of the renin-angiotensin-aldos-
FIG. 12.24 Progressive damage to the heart by sequential myocardial infarctions With the first infarction there is initial loss of cardiac functional reserve with no compromise of cardiac performance at rest. Further damage results in more loss of reserve, which may be accompanied by depressed cardiac function at rest. Finally, when the cardiac reserve is insufficient even to maintain adequate output at rest (cardiogenic shock), death ensues.
FIG. 12.25 The renin-angiotensin-aldosterone system in cardiac failure Activation of the renin-angiotensin system by failing cardiac output leads to salt and water retention and worsening cardiac output (ACE = angiotensin-converting enzyme).
terone system; Fig. 12.25) to increase cardiac pumping rate and force, and increase vasoconstriction to maintain normal blood pressure and divert the limited blood flow to the vital organs. • Myocardial hypertrophy, which is variable and incompletely understood but may reduce ventricular wall stress and thus augment function. • Readjustment of skeletal muscle metabolism such that the same physical work can be performed with a reduced cardiac effort.
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Decompensation occurs in heart failure when some of these compensatory mechanisms become excessive. Too much fluid and salt retention results in tissue oedema, which impedes tissue perfusion and reduces vasodilatory capacity. Gut and hepatic congestion impairs absorption and metabolism, contributing to cardiac cachexia (and rendering enteral medication less effective). The ensuing hypoalbuminaemia further worsens the oedema. Pulmonary oedema causes orthopnoea and dyspnoea, impairs gaseous exchange and increases the work of ventilatory muscles, which in turn imposes an extra demand on cardiac performance. Excessive cardiac dilatation causes functional AV valve regurgitation, further reducing ventricular pumping efficiency. Excessive vasoconstriction (due to activation of the sympathetic, renin-angiotensin and vasopressin systems) imposes a higher afterload on the heart. Vasoconstriction is exacerbated by diuretic therapy, which stimulates the renin-angiotensin system and the release of vasopressin. Excessive vasoconstriction of the renal arterioles leads to reduction in renal blood flow and glomerular filtration rates. The resulting azotaemia and oliguria compounds the management of heart failure. Chronic overstimulation of the sympathetic system depletes myocardial noradrenaline (norepinephrine) and causes B-receptor downregulation, reducing myocardial chronotropic and inotropic responses. Excessive myocardial hypertrophy causes cardiac diastolic dysfunction and makes the subendocardial region more prone to ischaemia.
Tertiary defects
490
Pharmacological treatments that alter physiological homeostatic controls lead to complications, some of which can be detrimental. The commonest is probably electrolyte imbalance. The powerful loop diuretics lead to loss of potassium and magnesium, both of which can increase the likelihood of tachyarrhythmias. Dietary replenishment of potassium supplements does not fully compensate for the losses. A better way of avoiding this complication is to use the so-called potassium-sparing diuretics, which also conserve magnesium. Diuretic therapy in severe heart failure can also lead to significant hyponatraemia, which is associated with a poorer prognosis. Diuretics must be used carefully to avoid this pitfall. Arrhythmia is an important consequence of electrolyte imbalance. Hypokalaemia, hypomagnesaemia and hyponatraemia all cause arrhythmia, the latter being especially hard to treat. Overdiuresis can also produce hypovolaemia. This leads to further hypoperfusion, postural hypotension and worsening renal function. Vasodilators have preferential effects on different vascular beds. Such selective vasodilation may counter the 'natural' redistribution of blood flow that preserves flow to vital organs in low-output states. For example, a-adrenergic blockers such as prazosin counteract the redistribution of blood flow effected by noradrenaline (norepinephrine), but prazosin does not improve exercise
tolerance or the prognosis of heart failure patients. Vasodilators that redistribute blood into the splanchnic or cutaneous vasculature may help in acute severe heart failure, but do not improve exercise capacity or mortality in chronic heart failure. Angiotensin-converting enzyme (ACE) inhibitors are immensely useful, but can be counterproductive by worsening renal function in patients dependent on the angiotensin-induced renal efferent arteriole vasoconstriction to maintain glomerular filtration rates. Certain positive inotropic agents (e.g. catecholamines) are potentially toxic, causing arrhythmias and cardiac myocyte necrosis.
CLASSIFICATION There are three main ways of classifying heart failure: • Acute vs. chronic. Although this temporal classification may seem clinically obvious, the pathophysiology and therapy of the two conditions have important differences. In acute heart failure the haemodynamic derangement is severe enough to result in obvious symptoms at rest. In chronic heart failure, however, the circulation at rest is adequate but there is inadequate cardiac reserve to pursue daily activities. Acute heart failure may occur as a consequence of a sudden recent myocardial injury, e.g. myocardial infarction, or as an exacerbation of previously compensated chronic heart failure. • Systolic vs. diastolic (or forward vs. backward). Systolic or forward failure results in low output and low arterial pressure states, whereas diastolic or backward failure results in congestion. Systolic failure is due to inadequate overall myocardial contractile capability, and diastolic failure relates to abnormalities in relaxation. Although heart failure is due most often to systolic dysfunction, some patients have normal systolic function and the failure is due to abnormal diastolic function. The cause is either within the heart muscle itself (hypertrophy, restriction) or in the pericardium (effusion or constriction). In ischaemic heart disease systolic and diastolic dysfunction often coexist, because ischaemia also impairs myocardial relaxation. • Left- vs. right-sided. This classification arose from a simplistic clinical division into whether there is pulmonary congestion (left heart failure) or systemic congestion (right heart failure). However, the right and left sides of the heart are connected in series, and in juxtaposition, enclosed in the pericardium. This complicates the simple division into right and left heart failure. Marked hypertrophy and dilatation of the left ventricle can impinge on right ventricular filling (the Bernheim effect) and cause systemic congestion without intrinsic right ventricular dysfunction.
Epidemiology In western countries approximately 0.5-2% of the popula-
tion is affected by heart failure, and the prevalence is greater with increasing age to about 10% in those over 75 years old. The annual incidence of heart failure is about 3 per 1000 for men aged 45-65 years and 8 per 1000 for men aged 65-75 years. Both the prevalence and incidence have more or less doubled since the 1960s.
Aetiology The main causes of heart failure in the west are ischaemic heart disease, idiopathic cardiomyopathy, hypertension and myocarditis. In the Framingham (Massachusetts, USA) population study (1955-1971), over 75% of those who developed heart failure had antecedent hypertension. More recently the incidence of hypertensive heart failure has decreased markedly, which is probably owing to improved antihypertensive treatment.
Prognosis and natural history Like neural cells, cardiac myocytes do not undergo division: growth is by hypertrophy. In adulthood there is a natural attrition rate of cardiac cells with increasing age. It has been estimated that there is an aggregate loss of about 35% of myocyte cells in the ventricles from young adulthood to old age. This rate is increased by disease. The prognosis of patients with heart failure is poor, and is worse in those with advanced heart failure. Overall, the 5-year survival rate of patients with all degrees of heart failure is approximately 50%. In patients with severe heart failure, the 1-year mortality rate is greater than 50%. About half of these patients die suddenly and the other half die of progressive heart failure.
PROGRESSIVE VENTRICULAR DYSFUNCTION Clinical features The main symptoms and signs of heart failure are those related to congestion and hypoperfusion, either at rest (as in acute heart failure) or during exertion (as in chronic heart failure). In taking a history, the symptoms and signs must be noted and information about the likely cause of heart failure and the severity of its effect on the patient's life should be sought.
Symptoms and signs The symptoms of congestion in the lungs are exertional dyspnoea, orthopnoea (dyspnoea and cough on lying down), paroxysmal nocturnal dyspnoea (breathlessness that wakes the patient from sleep), 'cardiac asthma' (wheeziness due to congestion of the bronchial mucosa) and, rarely, haemoptysis (see p. 522). In some patients the dyspnoea at rest may be episodic, raising the possibility of paroxysmal arrhythmia. The physical signs of pulmonary congestion are fine
SUMMARY 1 Symptoms and signs of heart failure Symptoms • Fatigue • Shortness of breath - on exertion - on lying flat • Paroxysmal nocturnal dyspnoea • Haemoptysis • Weight gain • Swollen ankles • Abdominal distension • Abdominal pain • Lethargy
Signs • Raised JVP • Gallop rhythm • Pitting oedema • Hepatomegaly • Basal crackles • Positive hepatojugular reflux • Cardiomegaly • Ascites • Pallor • Peripheral cyanosis • Cold extremities • Pulsus alternans
inspiratory crackles at the lung bases, but throughout the lung fields in severe cases. These are usually associated with tachypnoea. Expiratory wheeze may be present and should not be assumed to be due to airways disease. Occasionally dyspnoea is atypical, more like Kussmaul respiration (deeper and slower), and is due to lactic acidosis secondary to marked tissue hypoperfusion. Some of these patients may be labelled 'hyperventilators' until the severity of the underlying left ventricular dysfunction is appreciated. In severe pulmonary oedema due to acute left heart failure the patient is in respiratory distress and producing white frothy sputum through the mouth or nostrils. They are pale and cyanosed, and, if pulmonary oedema is unrelieved they progress to a moribund or unconscious state. The clinical features of systemic congestion are raised JVP, peripheral pitting oedema, abdominal distension with discomfort or pain, and dyspnoea due to pleural effusion. In mild failure the oedema only involves the ankles and feet, and it may be dependent (occurring after prolonged upright posture). Patients with chronic leg oedema may develop lower leg ulcers with or without cellulitis. With more severe failure the oedema may involve the thighs, sacrum, abdomen and upper body. Abdominal distension may be due to ascites or hepatic congestion. The latter may induce pain, especially during exercise (hepatic angina). Long-term hepatic congestion and gut oedema lead to weight loss and cardiac cachexia. Occasionally there may be sparing of lower limb oedema, and the patient presents with abdominal and/or upper body congestive features. In bedridden patients oedema may only be found on the sacrum. The symptoms of hypoperfusion include fatigue, lethargy, cold peripheries and dizziness. The latter is often due to postural hypotension. The physical signs include tachycardia, hypotension with a small pulse pressure, pallor and feeble peripheral pulses. In more severe failure or cardiogenic shock, the signs are of cool, clammy and cyanotic peripheries, oliguria or anuria, and blunted mental function. Cardiac examination and the history alone may reveal
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491
SUMMARY 2 Treatment of acute pulmonary oedema Emergency measures • Sit patient upright, with the legs over the edge of the bed if necessary • Oxygen by 28% mask at 5-10L/min; non-invasive ventilation, it necessary • Reassure the patient whilst drugs are prepared • Apply one or two 10mg GTN patches • i.v. access by large-gauge cannula in peripheral vein (12-17 gauge in forearm or brachial vein) • i.v. bolus furosemide (frusemide) 40-80 mg or bumetanide 1-2 mg (higher dose only if previously known to require large doses, such as in renal failure patients) • i.v. bolus diamorphine 1-5 mg plus 10mg metoclopramide, if patient in pain or severe distress • Extreme hypertension can produce pulmonary oedema, especially if the pressure rise has been rapid. Lowering blood pressure has to be done progressively, and although i.v. GTN may be adequate to achieve this, more reliable and controllable pressure reduction can be performed by i.v. sodium nitroprusside infusion (40-75 g/min). The precise ideal rate of blood pressure reduction is not known. • Monitor EGG for HR & rhythm, BP, respiratory rate, oxymetry, urine output • Investigations: ECG, chest X-ray, blood gas (arterial), blood count and urea and electrolytes (venous) as emergency • Venesection of 200 ml aliquots of blood remains an effective and rapid method of alleviating pulmonary oedema in the volumeoverloaded or overtransfused patient. Pulmonary wedge pressure measurement helps to determine how much blood to remove. Stabilization period (10-20 minutes after emergency measures) • If systolic BP>100mmHg set up an i.v. infusion of nitrate: - i.v. GTN 1 mg/h (or isosorbide dinitrate). Titrate upwards to 10mg/h. Dose can be increased each 5min according to response, heart rate (aim <120) and systolic blood pressure (>90)
the cause of heart failure (valvular lesions, acute infarction, rhythm or conduction defects, pericardial effusion or constriction). Frequently, a chest X-ray, ECG, and, increasingly, echocardiography, are needed to diagnose the primary defect.
ACUTE HEART FAILURE Diagnosis and management
Pulmonary oedema Although the commonest cause of pulmonary oedema is acute left ventricular failure following acute myocardial infarction, there are many important non-cardiac causes. These include overtransfusion, shock lung in septicaemia,
O Figs 12.11,12.12
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0 Case 12.1
If systolic BP<100mmHg patient requires CCU or ITU care for Swan-Ganz catheterization via a central vein to monitor filling pressures of the right heart and the pulmonary capillary wedge pressure (the indirect measure of LA pressure), and possibly direct intra-arterial pressure monitoring SBP<100mmHg and oliguric/anuric- consider inotropic support: - i.v. infusion dobutamine: 2.5-10 g/kg/min and dopamine infusion at 2.5-5 g/kg/min - When severe hypotension is present (SBP <70mmHg) consider use of intra-aortic balloon pump in centres well practised in its use Arterial gases po2 < 9.3kPa or pco2 > 7kPa - consider positivepressure ventilation. It is worth trying the effect of mask positivepressure (nasal cPAP) or non-invasive ventilation first. Treat arrhythmia. Fast AF, VT or atrial flutter are all best treated by emergency DC cardioversion and maintained in sinus rhythm with drugs. Dual-chamber pacing may be required to treat heart block.
Maintenance and diagnostic stage • Establish the precise cause of left ventricular failure. If LVF has complicated acute myocardial infarction, there is a need to consider the use of ACE inhibitors, -blockers when haemodynamically stable. • Echocardiography is an important investigation to establish the nature and extent of left ventricular dysfunction and valve dysfunction, or the presence of other acquired defects, such as VSD, aneurysm, thrombus. • In the majority of patients, treatment with ACE inhibitors and blockers should be started and doses titrated up cautiously. Exceptions are those with renal artery stenosis for ACEI, and true asthmatics and claudication for -blockers.
aspiration of gastric acid, paraquat poisoning, and inhalation of certain toxic fumes. The common feature is accumulation of oedema fluid in alveolar spaces, leading to dyspnoea. The lungs become stiff, increasing the work of breathing. Gas exchange is impaired and, if unrelieved, progressive hypoxaemia and hypercapnia follow as the patients tires; this can lead to death. Not all inspiratory crackles are due to pulmonary oedema. Experienced clinicians may be able to distinguish crackles of oedema from other pulmonary pathology. Crackles in the absence of upper lobe blood diversion (pulmonary venous hypertension) on chest X-ray are most unlikely to be due to pulmonary oedema. Confirmation with direct measurement of pulmonary venous pressure may rarely be necessary. Pneumonia often coexists with pulmonary oedema, especially in elderly patients. The production of discoloured sputum (other than white and frothy) should alert the clinician. The chest X-ray shows upper lobe venous engorgement and blood diversion; intralobular oedema in the small horizontal lines best seen at the lung bases (Kerley's 'B' lines); severe intra-alveolar oedema
causing acute bilateral lung shadowing often most prominent in the perihilar regions. O
Treatment Treatment is summarized in Summary 2, page 492. In acute left ventricular failure initial management consists of manoeuvres to decrease left atrial pressure, increase oxygenation, increase cardiac output and BP if significantly depressed, and diminish fear and anxiety, which increase the sympathetic drive and lead to increased myocardial work. Diamorphine and morphine have threefold beneficial effects - anxiolytic, analgesic and venodilation - but are also powerful respiratory suppressants, which may precipitate Cheyne-Stokes respiration or respiratory arrest. They should therefore be used with great caution. Venodilation may be more safely achieved with i.v. nitrates and anxiolysis by agents such as benzodiazepines. Treatment of brady- or tachyarrhythmias is crucial. Maintenance of a regular sinus rhythm is the objective in the presence of haemodynamic compromise. Withdrawal and counteraction of culprit agents (e.g. digoxin) may be necessary. Physical therapy (DC cardioversion, artificial pacing) is usually more efficacious, but appropriate pharmacotherapy is often required to maintain sinus rhythm and to avoid recurrences. In general, the reduction in preload with diuretics and nitrates is associated with some impairment of tissue perfusion (demonstrated, for example, by minor elevations in urea and creatinine). This is usually transient. If the reduction in preload by diuretics and nitrates is excessive or prolonged, tissue perfusion may become greatly compromised and the patient develop multiple organ failure (e.g. renal failure) that is more difficult to treat than the original oedema. These situations can be avoided by reducing diuretics once euhydrate, maintaining adequate systolic pressures, or using inotropic support if necessary. The use of positive inotropic agents and, to a lesser extent vasodilators and diuretics, is contraindicated when treating hypertrophic cardiomyopathy, especially of the obstructive type. © Acute right heart failure Pulmonary embolism (see p. 675), cor pulmonale (see p. 662) or acute inferior or posterior myocardial infarction are the usual causes. The features of acute right heart failure in myocardial infarction include a raised JVP associated with a low blood pressure and usually clear lung fields. The right ventricular function curve has flattened (Fig. 12.5, p. 466), so that a higher right atrial filling pressure is needed to support the same cardiac output. These patients need expansion of the circulating volume with synthetic plasma expanders to improve output and blood pressure. Injudicious use of diuretics or nitrates to 'treat' the high JVP can lead to serious falls in cardiac output, and precipitate shock. Acute tamponade Cardiac tamponade presents as acute heart failure, and is described on p. 587.
Cardiogenic shock In cardiogenic shock severe cardiac pump dysfunction causes tissue perfusion to be so inadequate as to fail to meet basal metabolic demands. Clinically it is recognized by hypotension (systolic BP <80mmHg or mean BP <60 in normotensives, and <110 in chronically hypertensive subjects), associated with oliguria or anuria, cold sweaty skin, mental confusion and lactic acidosis. It is not necessary for all these features to be present before making the diagnosis of cardiogenic shock. Causes of cardiogenic shock are massive myocardial infarction (usually loss of >40% of total myocardial muscle), mechanical complication of infarction (e.g. VSD and papillary muscle dysfunction or rupture), severe brady- or tachyarrhythmia, rejection in the transplanted heart, myocarditis, and infiltration of the previously normal myocardium. It is important to exclude the effects of any myocardial depressant or vasodilatory agents (e.g. excessive diamorphine; -blockers or verapamil. In the presence of right ventricular infarction, a shift of blood volume centrally by elevation or the application of positive pressure to the lower body, or a fluid challenge to raise the pulmonary wedge pressure to >15mmHg should be made before making the diagnosis of cardiogenic shock. The incidence of cardiogenic shock in patients admitted with acute myocardial infarction is 5-10%. The advent of thrombolytic therapy has not altered this significantly. The hospital mortality rate is still 50-70%. The continuation of function in the heart is also dependent on its own output. When the aortic pressure falls below the critical pressure for coronary perfusion (mean 60mmHg), left ventricular myocardium becomes more ischaemic, further impairing performance. Medical therapy of cardiogenic shock is described on page 564. The following general principles are the basis of management:
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• Optimizing heart rate, ideally between 80 and 130bpm, with pacing if necessary (preferably AV sequential pacing; see p. 504). • Treating tachyarrhythmia using agents with minimal negative inotropic effects. Digoxin is still useful in fast AF. Give 500 g in 100 mL 5% dextrose over 30 minutes. If required, this may be repeated over 1 hour. A third dose over 2 hours is rarely given. Amiodarone i.v. is frequently used but requires central venous access to avoid serious thrombophlebitis. Give 300 mg (<5mg/kg) in 5%
SUMMARY 3 Clinical features of cardiogenic shock Hypotension (<60mmHg mean aortic pressure) Oliguria/anuria (<60mL/h) Cold sweaty skin Mental confusion Lactic acidosis Biventricular heart failure is the rule
493
•
•
• •
dextrose in 1 hour, 900 mg i.v. total in 2-4 hours, with a maintenance infusion of 1200 mg in 24 hours. Directcurrent cardioversion is preferred over 'cocktails' of antiarrhythmic drugs, provided the patient can be maintained in sinus rhythm afterwards. Optimizing LV filling pressure by monitoring PA wedge pressure using a balloon-tipped flotation pulmonary artery catheter (Swan-Ganz) and aiming to maintain PAW pressure between 15 and 20mmHg by balancing diuresis and fluid intake. Correcting metabolic acidosis with bicarbonate is rarely necessary. Intermittent positive-pressure ventilation, either non-invasively or via endotracheal intubation, may be required (although this may occasionally worsen the haemodynamic status). Avoiding pure vasodilators (e.g. nitroprusside, ACE inhibitors), negative inotropic agents (e.g. -blockers, verapamil, disopyramide). Using positive inotropic agents (see p. 497).
In managing cardiogenic shock it is important to investigate whether the heart, which is obviously depressed in the basal resting state, possesses any reserve function, and whether this reserve exceeds that necessary to sustain normal body basal metabolism (e.g. peak cardiac power output >1 W, see Fig. 12.25, p. 489). Cardiac reserve can be measured by stepwise infusion of dobutamine and noting the peak cardiac power output attained. If the peak is >1 W, medical therapy, including the use of inotropic agents to maintain adequate pressure and flow, can be sufficient. Nevertheless, remediable defects should be dealt with. If the peak is below 1W (or simple bedside observation of peak attainable systolic BP is <90mmHg despite maximal dobutamine stimulation), then death is expected unless urgent and appropriate definitive treatment of primary defects is obtained (e.g. urgent mitral valve replacement, coronary angioplasty, bypass surgery, other curative operation) or insertion of an artificial mechanical heart pump or cardiac transplantation. If the definitive treatment is delayed, artificial circulatory support in the form of intra-aortic balloon counterpulsation or ventricular assist devices should be instituted (p. 520). If the surgical option is ruled out, frantic therapeutic efforts should be avoided and the patient allowed to die peacefully.
SEVERE CONGESTIVE CARDIAC FAILURE
494
Many patients, particularly the elderly, are admitted to hospital with acute exacerbations of chronic heart failure. As in all cases, whether acute or chronic, the cause must be established to allow a rational approach to therapy. A frequently encountered syndrome consists of a patient with a dilated, poorly contracting ventricle, who suffers increasing degrees of fluid retention, sometimes to enormous proportions. Gross leg oedema may prevent walking, tense oedematous skin with poor perfusion is subject to accidental laceration, infection and the development of cel-
lulitis and venous thrombosis, both superficial and deep. Ascites may be present and contribute to poor breathing and orthopnoea due to diaphragmatic splinting. Associated oedema of the intestinal mucosa may produce diarrhoea, but more frequently accounts for variably poor absorption of drugs (especially diuretics). Many of these patients have been previously treated with diuretics and digoxin, so that electrolyte disturbance and digitalis toxicity may complicate the picture. The mainstay of initial management in hospital is to generate a gradual and progressive loss of oedema fluid, best monitored by daily weighing. A rate of weight loss of 0.5-1.5 kg per day is ideal. This is best achieved by using intravenous diuretics combined with fluid restriction to 1.5L/day and a reduction in salt intake. Daily or twicedaily bolus injections of frusemide 40-160mg or bumetanide 1-4 mg are common (patients with moderate to severe renal impairment may need very much higher doses, e.g. 120-500mg furosemide (frusemide)). Electrolytes are maintained by simultaneously prescribing a potassium-sparing diuretic (amiloride 5-10 mg daily, or spironolactone 25-100mg twice daily). Occasional patients are resistant to these measures. In these cases adding a thiazide diuretic orally for several days may initiate the diuresis (e.g. metolazone 5-10mg/day, or bendroflumethiazide (bendrofluazide) 2.5-5 mg/day). An alternative method is to infuse dopamine (2.5-5.0 g/kg/min) via a central line to avoid thrombophlebitis. Very rarely haemofiltration, ultrafiltration or dialysis may be needed to relieve the patient of intractable fluid congestion. Hypokalaemia needs to be corrected in patients who have been on long-term diuretics. Because of a simultaneous loss of magnesium, replacing the magnesium by infusion often helps restore potassium equilibrium and diminishes the tendency to arrhythmia. ACE inhibitors may need to be withheld during the acute phases of treating congestion because of their known effects of vasodilating the efferent glomerular arterioles, thereby probably diminishing GFR. ACE inhibition is (re)started as congestion resolves, unless the patient is hyponatraemic. Perindopril, because of its less first-dose hypotensive action, is the drug of first choice. After a test dose of 2mg the patient is kept under observation; blood pressure is checked every 15 minutes for 90 minutes, and 2-hourly thereafter. Provided that profound or symptomatic hypotension does not occur, maintenance perindopril or another ACE inhibitor is started and blood pressure checks revert to the routine 4-hourly observations. Uptitration of dose to the highest tolerated may be undertaken prior to discharge. Digoxin still has a role even in sinus rhythm; digitalization by 0.75-1 .Omg in the first 24 hours is followed by an appropriate maintenance regimen (125-250 g/day) monitored by plasma levels. Renal function should be closely monitored; overintense diuresis may decrease preload (and hence cardiac output and tissue perfusion) so much that prerenal failure is precipitated. It is worth emphasizing that medical
management of heart failure is almost impossible without functioning kidneys. Preservation of renal function should therefore be a high priority. Maintenance of systolic blood pressure above lOOmmHg is important and helps to avoid serious derangement of renal function. During the bed-rest stage anticoagulation with low molecular weight heparin by subcutaneous injection should be used. Once a stable balance is achieved, oral diuretics replace i.v. treatment. ACE inhibitors have a diuretic 'sparing' action, so that diuretic doses may well have to be reduced some days or weeks after starting ACE inhibitors, otherwise the patient may become dehydrated and develop fatigue, postural hypotension and worsening renal impairment.
CHRONIC HEART FAILURE IN OUTPATIENTS Management - general measures The cause of heart failure must be established and remediable causes sought and treated. These might include the replacement or repair of valves, stripping of the pericardium in constriction, or the closure of significant intracardiac shunts. The essential investigations are outlined in Summary 4. The overall aim of treatment in chronic (non-surgical) heart failure is to relieve symptoms, to improve quality of life and functional capacity, and lastly to improve longevity. The general measures should include stopping smoking, reducing alcohol intake, fluid restriction, and possibly regular exercise training. Bed rest is helpful only in acute myocardial infarction, active myocarditis, infective endocarditis and intractable congestion unresponsive to conventional doses of diuretics (see above). The disadvantages of bed rest (skeletal and myocardial deconditioning, muscular atrophy and weakness, bedsores, deep vein thrombosis, autonomic maladjustment) outweigh the benefits. Patients who are asymptomatic at rest should be encouraged to mobilize as soon as possible, as exercise rehabilitation may improve functional capacity even in severe chronic heart failure. Drug therapy to improve prognosis is now possible, and (3-blockers, ACE inhibitors, spironolactone and nitratehydralazine combinations are the most effective, although the prolongation of survival only averages 6 months. About
SUMMARY 4 Essential investigations in chronic heart failure • ECG • Chest X-ray
• Urea, electrolytes, creatinine, thyroid function? BNP • Echocardiogram • Direct/indirect measures of cardiac functional reserve.
20-50% of patients in heart failure die suddenly. No antiarrhythmic agent has been shown to be effective in reducing this incidence, although the use of amiodarone appears promising. Patients with life-threatening arrhythmia may need AICD.
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Drugs used in chronic heart failure Diuretics This class of drug is still the first-line treatment for symptomatic congestive cardiac failure because it is the most effective at relieving the symptoms of congestion, thereby producing the greatest impact on quality of life. They are all natriuretic and aquauretic; some of them conserve K+ and Mg2+, whereas others induce losses. Injudicious use of diuretics may lead to severe electrolyte imbalance (resulting in arrhythmias and sudden death) and hypovolaemia (resulting in tissue hypoperfusion and renal failure). Thiazide diuretics These are used principally to treat hypertension, but may occasionally have a role in controlling mild oedema and, when added to loop diuretics, may induce a diuresis when resistance to loop diuretics has arisen. Hypokalaemia and hyperuricaemia are two of the more commonly encountered problems with these drugs. To combat the former, combination with potassium-sparing agents is advised. Metolazone is a curious thiazide-like diuretic with a very powerful ability to induce diuresis when combined with loop agents in patients with renal impairment or resistance to loop diuretics. However, it is also remarkably potent in inducing electrolyte disturbances, and the most difficult one to correct is severe hyponatraemia. It should therefore be used sparingly, and stopped before hyponatraemia occurs. Bendroflumethiazide (bendrofluazide) Hydrochlorothiazide Metolazone
2.5-5.0mg per day 25-100 mg per day 5-10 mg per day
Potassium-sparing diuretics It is almost always necessary to add these agents to the treatment of patients taking diuretics alone. ACE inhibitors usually diminish the need for potassium-sparing agents and when used in this combination close monitoring of serum potassium (aimed between 4.5 and 5.5mmol/L) is essential because severe hyperkalaemia may occur. Spironolactone, an aldosterone receptor antagonist, at a dose of 25 ing/day, has been shown to be safe and extend the lives of patients with heart failure treated with loop diuretics and ACEI. Its antiandrogenic effects (e.g. gynaecomastia) may not be tolerated by some male patients, in which case amiloride may be used instead. Amiloride Spironolactone Triamterene
5-20mg/day 25-200 mg/day 50-250 mg/day
495
Loop diuretics These are the cornerstone of diuretic therapy in all but the mildest degrees of heart failure. They share with thiazides the tendency to produce metabolic disturbance and need the addition of potassium-sparing agents to avoid these pitfalls. Bumetanide Furosemide (frusemide) Torasemide
l-10mg/day 40-1000 mg/day 2.5-40 mg/day
Combination diuretics Combinations of diuretics, incorporating fixed doses of potassium-sparing agents, are very widely prescribed. It is accepted that combinations of diuretic with potassium supplements are likely to be less effective at maintaining potassium homeostasis, and unhelpful for magnesium homeostasis. Coamilofruse (Frumil) Frusene
1-2 tablets/ day 1-2
Dyazide
1-2
furosemide (frusemide) 40 + amiloride 5 furosemide (frusemide) 40 + triamterene 50 triamterene 50 + hydrochlorothiazide 25
A suggested management algorithm for chronic heart failure is illustrated in Figure 12.26. Vasodilators Vasodilator drugs are used to decrease both preload and afterload. Excessive preload reduction may result in loss of Starling's effect and compromise ventricular output. Excessive afterload reduction can cause hypotension, reduce coronary perfusion, and exacerbate myocardial ischaemia and cerebral hypoperfusion, leading to dizziness and syncope. ACE inhibitors ACE inhibitors are the vasodilators of first choice in the treatment of chronic moderate and severe heart failure. There are many ACE inhibitors available: Captopril Enalapril
6.25-50 mg t.d.s. 2.5-20mg b.d.
Lisinopril Perindopril
5-40mg o.d. 2-4 mg o.d.
Ramipril
1.25-5 mg b.d.
Short-acting Intermediate duration of action Long duration of action Long-acting, least firstdose hypotension Long-acting
It is still unclear whether the different properties exhibited by the different types make any significant difference to their clinical efficacy.
496
• Up to 10% of all patients do not tolerate ACE inhibitor therapy owing to unacceptable coughing. • First-dose hypotension at the start of ACE inhibitor therapy can occur unexpectedly in patients with chronic heart failure, especially in those with unsuspected renal artery stenosis. Certain precautions should be heeded.
ACE introduction should be avoided if the patient is relatively hypovolaemic (as judged clinically by the absence of oedema, low JVP, dehydration, postural hypotension, elevated serum urea with normal serum creatinine), in which case the diuretics should be withheld for a day or two before introduction. Patients with significant renal artery stenosis can present with the syndrome of heart failure, and ACE inhibition is contraindicated unless medical autonephrectomy is indicated. Patients with markedly elevated blood pressure (especially acutely) despite features of heart failure should be investigated to rule out renal artery stenosis before the introduction of ACE inhibitors. Sometimes hospital admission for close BP monitoring may be required. A suitable regimen might start with 2mg of perindopril, as this has been shown to be least likely to cause first-dose hypotension, and the dose subsequently increased to 4 nig o.d. or switched to another ACE inhibitor. • The most problematic adverse effect is impairment of renal function. In a significant minority inhibition of angiotensin-induced constriction of the efferent glomerular arteriole and overall renal function is affected. Rising creatinine (>200 mol/L) is a reason to withdraw this therapy. Nitrates In patients with heart failure secondary to coronary heart disease nitrates have a distinct role, particularly as ACE inhibitors do not have any specific antianginal activity. Long-acting nitrates are used, leaving a 6-8-hour nitratefree period to avoid tolerance to the haemodynamic effects of nitrates. Isosorbide mononitrate modified release
40-120 mg o.d.
Other agents The combination of high-dose nitrate with hydralazine (50-75 mg q.d.s.) has been shown to improve function and prognosis for severe heart failure, but the drug combination can be difficult to tolerate. Calcium antagonists are not generally useful in heart failure. p-Blockers With indication for use in heart failure, p-blockers can now be claimed to be a ubiquitous cardiological drug. Trial data have shown that they can improve the prognosis, in terms of survival and hospitalization. There are no conclusive data to show that they improve functional capacity or quality of life. Clinician concerns (which led to these drugs being previously categorized as contraindicated for use in heart failure) are still valid, as inappropriate use in some patients may precipitate exacerbation of heart failure. It is therefore vital that -blockers should be introduced by trained personnel, starting with the lowest doses, which may be increased very gradually if tolerated. Carvidelol is a non-cardioselective -blocker with ocreceptor blocking activity, which produces vasodilatation. It was the first to be reported to provide remarkable survival improvements in heart failure.
12 Blood tests: Biochem FBC TFT Chest X-ray ECG Urine dipstix Cause known? eg. previous Ml previous myocarditis elderly patient with BP
Another cause for symptoms No
No
Yes
Echo Yes
Regional ?IHD
Surgical cause e.g. aortic stenosis pericardial constriction
Global 3 cardiomyopathy
Look for reversibilit; e.g. FDG nuclear medicine scan Cardiac catheter
Revascularization for CAD
Primarily systolic failure? e.g. MI/IHD alcohol myocarditis or diastolic failure? e.g. hypertension hypertrophy HCM
No
Don't know
Echo
Yes
Surgical candidate?
No
Yes
REFER
Caution with diuretic ACE
Diuretic ACE I
May still need antifailure treatment
Sinus rhythm
?p-Blocker verapamil
No
YES
If severe HF
AF
Bradycardia & heart block
Tachyarrhythmia
Dual-chamber pacemaker
Antiarrhythmic agent ±AICD
FIG. 12.26 Management of chronic heart failure
Not all -blockers are equally prognostically beneficial to heart failure patients. Bucindolol has recently been shown not to confer similar benefit. Bisoprolol and metoprolol have been shown to be beneficial in improving survival.
Inotropic agents Positive inotropic agents are not without potential dangers (e.g. arrhythmogenicity, and liability to induce worsening cardiac myocyte necrosis). In viral myocarditis they should
497
TABLE 12.8 Digoxin dosage Digoxin • Loading dose 15 g/kg in 3 doses every 6 hours • Maintenance doses 62.5-3.75 go.d. depending on age and renal function • Dose adjusted according to plasma levels (therapeutic range 1.0-2.6 mmol/L) Digitoxin Mainly non-renal metabolism. Very long half-life and rarely used
be avoided, unless as a bridge to transplantation. With the exception of digoxin (see below and Table 12.8), chronic oral inotropic therapy (with 2 stimulants and phosphodiesterase inhibitors) has been very disappointing. Digitalis preparations (digoxin, medigoxin, digitoxin, ouabain) are now well established as of value as mild positive inotropic agents in chronic heart failure. Digoxin is still the only oral positive inotropic agent available. Antiarrhythmic agents These drugs often have to be used in heart failure patients. Most intravenous antiarrhythmic agents are cardiodepressant to varying degrees. The most negatively inotropic are p-blockers, verapamil and disopyramide, and these are generally avoided in severe heart failure. In therapeutic doses the following intravenous agents exert little negative inotropism, and may be used in heart failure: lidocaine (lignocaine), mexiletine and procainamide. Orally, amiodarone, digoxin, mexiletine and procainamide are virtually devoid of negative inotropic effects. In heart failure the most effective and least proarrhythmic antiarrhythmic agents for supraventricular and ventricular tachycardia are -blockers and amiodarone. The oral preparation of amiodarone is virtually devoid of negative inotropism and is therefore suitable for use in patients with severe heart failure who are intolerant of (3blockers. Their concurrent use with amiodarone requires a reduction in dose of digoxin and warfarin. O
CARDIAC TRANSPLANTATION Since the first human heart transplant in 1967, the technique has become an accepted form of treatment for patients dying of heart failure and for whom no other form of treatment offers any help. The current annual rate of cardiac transplantation worldwide is approximately 3000. The number of patients requiring transplantation each year in the USA alone is estimated to be 35 000-70000. The shortfall is mainly due to the shortage of donor hearts, and
Q MCQ12.6
498
is responsible for the plateauing of the transplantation rate in the USA and Europe. Cardiac transplantation will not become the panacea of heart failure treatment, and selection of recipients will necessarily remain strict.
Indications The vast majority of patients who undergo cardiac transplantation have either terminal idiopathic dilated or ischaemic cardiomyopathy. Other indications include peripartum cardiomyopathy, congenital heart disease and cardiac tumours. The patient must have reached end-stage heart failure and have a very limited life expectancy. The best available method of measuring the prognosis of these patients is estimation of their cardiac reserve (see p. 494). Contraindications to transplantation of the heart alone include increased pulmonary vascular resistance, blood group incompatibility, or any coexisting systemic illness that may significantly limit life expectancy.
Surgery There are two main surgical procedures: • Orthotopic transplantation. The recipient's heart (except the venous attachment side of the atria) is excised and replaced by the donor's heart. This is the commonest procedure. • Heterotopic transplantation. The recipient's heart is not excised and the donor's heart is anastomosed side to side to the corresponding atria and great vessels of the recipient's heart. Contrary to popular belief, the surgery itself is simpler than most open heart surgical procedures. The main operative problem is the preservation of the donor heart during transit.
Management By far the most difficult part of cardiac transplantation is the postoperative care. The two major complications are graft rejection and infection, which account for most of the early mortality. There is as yet no early and accurate noninvasive method of detecting rejection. Apart from clinical suspicion and loss of R wave in the ECG, the most reliable method of diagnosing rejection is by percutaneous endomyocardial biopsy. Immunosuppressive regimens include combinations of ciclosporin, azathioprine, corticosteroids, cyclophosphamide, antithymocyte globulin (ATG), use of monoclonal antibody against the CD3 molecule on mature T cells, and occasionally vincristine or methotrexate. The need for immunosuppression means that patients are at increased risk from bacterial infection. Opportunistic fungal infections and reactivation of primary viral infection (notably cytomegalovirus) occur. Late complications include accelerated coronary disease in the donor heart, hypertension, and an increased incidence of malignancies (especially
lymphoproliferative), and bone diseases (osteoporosis, a vascular necrosis).
Prognosis Current survival rates of cardiac transplantation are as good as those of renal transplantation, with overall 1-
and 5-year survival rates of about 80% and 70%, respectively, for orthotopic transplantation. The survival rate for heterotopic transplantation is less good, with a 5-year survival of about 50%. Factors that negatively influence prognosis include major HLA mismatch, prolonged cold preservation of the donor heart, the presence of preformed circulating antibodies and advanced donor age.
12
CASE STUDY 12.1 ACUTE ONSET OF BREATHLESSNESS AND ARRHYTHMIA A 66-year-old man presented to his GP feeling generally unwell and breathless. He felt he had 'flu'. Initially he had felt feverish with mild nausea and diarrhoea. This had been some weeks before his current presentation, which consisted of significant limitation in exercise tolerance. Anything other than minor exertion produced breathlessness without chest pain. His sleep was very poor. He would fall asleep then wake in the middle of the night with breathlessness. His abdomen felt bloated and he was unable to eat comfortably. He was aware that his heartbeat was much more forceful, fast and irregular. In the past he had had no significant medical history except for being a heavy cigarette smoker which he had managed to stop 10 years prior to presentation. Twenty years previously he had had a period of excess alcohol consumption, but this had been resolved and he was now teetotal. He was taking no medication. The GP found him to be dyspnoeic on minimal exertion. He had a pulse rate of 104 which was irregularly irregular. Blood pressure was 110/70. The jugular venous pressure (JVP) was elevated to the angle of the jaw and he noted mild ankle swelling and some abdominal distension. His heart sounds were rapid on auscultation and there was a suspicion of a systolic murmur. The chest revealed bilateral absent breath sounds and basal dullness above which there were a few fine crepitations. The GP referred him up to the cardiology clinic with a diagnosis of cardiac failure and atrial fibrillation.
Questions 1. Is this diagnosis appropriate? What differential diagnoses should be considered? 2. What investigations should be arranged? 3. What would be the principles of treatment for this patient assuming that there were no surgically remediable cause for his heart failure?
Discussion Heart failure is a clinical syndrome which was diagnosed confidently and correctly by the GP. The features in support were the symptoms of exercise limitation. His nocturnal symptoms could represent orthopnoea with some features of paroxysmal nocturnal dyspnoea (PND). The GP noted the findings consistent with right heart failure in that the JVP was elevated and he had peripheral oedema. The abdominal distension could represent ascites and possible enlargement of his liver. He had dull lung bases which could be bilateral pleural effusions and the crepitations heard above this area of dullness could be evidence of left heart failure producing pulmonary oedema. He was noted to have a fast irregular pulse most likely due to atrial fibrillation complicating the heart failure or indeed contributing to it. There was a possible systolic murmur. Having detected the clinical syndrome, it is important for the doctor to establish remediable causes. These might include non-cardiac causes of heart failure such as thyrotoxicosis, anaemia and excessive
alcohol intake. Cardiac causes of heart failure that need to be excluded would be ischaemic heart disease, valvular disease or pericardial disease. Investigations are designed to establish a diagnosis behind the presenting clinical syndrome of heart failure. Blood tests will exclude anaemia and thyrotoxicosis. The plasma biochemical profile should include renal and liver function to give baseline values because treatment may affect renal function adversely. When the presentation is relatively acute it is important to include cardiac enzymes in the investigation to exclude silent myocardial infarctions as a possible cause of heart failure. An ECG will confirm the presence of atrial fibrillation and also give clues to the aetiology of heart failure particularly if there are any changes consistent with either acute or chronic ischaemic heart disease. Chest X-ray would confirm the presence of pleural effusions and the clinical suggestion of pulmonary oedema. Calcification around the pericardial sac, or elsewhere in the heart, might be seen. The size of the cardiac silhouette and any contribution from coexistent pulmonary disease will be established. An echocardiogram can be used to establish whether the heart failure relates to valvular disease or is a primary problem of the heart muscle. In this patient the problem is likely to be due to viral myocarditis leading to the appearance of thin-walled, very poorly functioning left and right ventricles. A degree of mitral regurgitation was noted secondary to
499
CASE STUDY 12.1
CONTINUED
left ventricular dilatation and this accounted for the systolic murmur. In a man of this age, exclusion of myocardial ischaemia is important even in the absence of any other pointers such as chest pain or ECG change. This is because occasional silent presentations of the severe ischaemia can be adequately treated by revascularization, usually by cardiac bypass surgery. Consideration therefore would be given, in this age group, to a myocardial perfusion scan using thallium and to cardiac catheterization with coronary angiography. The treatment would begin by management of the acute symptoms produced by his presumed post-viral myocarditis. Fluid retention would be
treated by the use of loop diuretics such as furosemide (frusemide) with the addition of the potassium-sparing diuretic spironolactone. His atrial fibrillation should be treated. The heart rate should be controlled with digoxin and anticoagulation with warfarin is indicated. After adequate anticoagulation subsequent DC cardioversion to sinus rhythm would be an option if mitral regurgitation was not severe and if the left atrium was not severely dilated. ACE inhibitors should be introduced as they improve survival from myocardial failure and will allow the use of lower doses of diuretics in the long term. In addition -blockers should be introduced into treatment, although careful titration starting at
Heart-lung transplantation Patients with end-stage pulmonary vascular hypertension (primary or Eisenmenger's syndrome) and with parenchymal lung disease (mostly cystic fibrosis) have the option of heart and lung transplantation. The two classes of disease each constitute about half of the transplanted cases. The 1- and 3-year survival rates are currently about 65% and 50%. A major difficulty in management is that the diagnosis of rejection is more difficult in the lung than in the heart. FURTHER READING ON TRANSPLANTATION O'Connell J B, Bourge R C, Costanzo-Nordin M R, Driscoll D J, Morgan J P, Rose E A, Uretsky B F 1992 Cardiac transplantation: recipient selection, donor procurement, and medical follow-up. A statement for health professionals from the Committee on Cardiac Transplantation of the Council on Clinical Cardiology, America Heart Association. Circulation 86:1061-1079.
ARRHYTHMIA Arrhythmia is a general term for any cardiac rhythm or conduction abnormality. Anatomically the arrhythmia
O Fig. 12.13
500
very low doses is necessary in this context. The particular -blockers of use in this situation are carvedilol and propranolol. In randomized trials both of these drugs have shown improvement in prognosis when given in heart failure. Cardiac transplantation is an option although in this age group the success rate is greatly diminished. For this reason some centres do not accept patients in this age group for transplantation. Acute post-viral cardiomyopathy has been treated successfully by temporary mechanical ventricular assistance devices. This patient's chronic and slightly less severe problem is unlikely to be suitable for this management.
may originate supraventricularly (atria or AV junction) or ventricularly. The most compelling clinical feature is whether the arrhythmia causes haemodynamic disturbance; however, its implications depend more on the type of arrhythmia, so that ventricular tachycardias have a poorer prognosis than supraventricular tachychardias.
INVESTIGATIVE TECHNIQUES The principal method of analysis of arrhythmia is the 12-lead ECG. The correct interpretation of the ECG may depend on comparison with previously acquired recordings.
24-hour ECG (Holter monitor) Recorders can monitor two channels of an ECG in ambulant patients over a continuous 24-hour period (Fig. 12.27). Some rhythm disturbances may occur very infrequently and require alternative equipment. Event recorders can be applied by the patient during symptoms and record a few seconds of ECG in a solid-state memory. This can subsequently be replayed or transmitted by telephone to a central station, where a doctor can advise on the nature of the event. For those patients who receive no warning of impending rhythm disturbance, there are newer implantable automatic solid-state recorders (ILR, implantable loop recorders) that sample the ECG over long periods but only memorize significant events, or events triggered by the patient.
but not the ventricular, activity; this is most commonly encountered in complete heart block (p. 503 and Fig. 12.31). Sinus arrhythmia is the quickening of the heart rate that occurs cyclically with each inspiration. It is most marked in individuals (often young) with high vagal tone.
12
EGTOPIC OR EXTRASYSTOLIC BEATS These are defined as beats that arise outside the normal heart pacemaker. They may be generated in the atria, the AV node, the bundle of His or the ventricles. They may also arise as 'escape' beats in sinus bradycardia.
Atrial ectopics FIG. 12.27 24-hour continuous ambulatory ECG monitoring At 19.20 hours the sinus rhythm is interrupted by ventricular ectopic beats and a short run of ventricular tachycardia. O
Exercise EGG The exercise test has a role in managing certain patients with arrhythmia. Those with recurrent ventricular tachycardia, or Wolff-Parkinson-White syndrome, may undergo exercise testing to check the efficacy of their drug treatment. However, not all these patients have exerciseinduced arrhythmia and may instead require more sophisticated electrophysiological (EP) studies.
Intracardiac electrophysiological testing The techniques of cardiac catheterization enable localized intracardiac ECGs to be recorded, using catheters similar to pacing catheters but with electrodes mounted distally. The activity of the atria, AV node, bundle of His and ventricles can be recorded independently. By combining recording with artificial stimulation from intracardiac pacemakers, a detailed analysis of intracardiac conduction can be made. This has proved useful in studying patients with tachycardia, in whom the abnormal rhythm may be induced and its origin (ventricular or supraventricular) confirmed. The site, number and potential danger from accessory AV bypass tracts (e.g. in Wolff-Parkinson-White syndrome) can be mapped and the tracts ablated. The effectiveness of drug regimens and the potential for using antitachycardia pacemakers are also tested using EP studies.
NORMAL SINUS RHYTHM Each ventricular (QRS) complex is preceded by a P wave with a normal P-wave axis (i.e. from the sinus node, P-wave axis = 0° to +90°) and normal PR interval (0.11-0.20s). In some circumstances sinus rhythm may control the atrial,
Atrial ectopics or atrial premature beats (Fig. 12.28A) are usually preceded by a P wave of different shape, different PR interval and, frequently, a different axis to the sinus P wave. The following QRS complex is normal. Atrial ectopics are common even in normal hearts, although, like all extrasystoles, they may be felt as uncomfortable fluttering, palpitation or 'skipped beats' in the chest. Stimulants, such as alcohol or caffeine-containing drinks and cigarettes, may be precipitants.
Junctional ectopics Junctional ectopics may arise from the AV node or proximal bundle of His, although this differentiation cannot normally be made, hence the less specific term 'Junctional' rather than the older 'nodal beat'. Atrial activation occurs retrogradely, so that the P wave is positive in aVR and negative in II, III and aVF. The delay between ectopic activation and ventricular activity depends on its site of origin and will vary the timing of the P wave. This can precede, be buried in, or follow the QRS complex, which has a configuration identical to that in sinus rhythm.
Ventricular ectopics Ventricular ectopic (VE) beats, by definition, are not preceded by a P wave and have a broad QRS configuration (Fig. 12.28B). There is no prognostic significance attached to whether the ectopic beat has a left or right bundle branch block pattern. However, when frequent or multiform VEs are found in association with underlying coronary heart disease or cardiomyopathy, there is an increased risk of sudden death. Control of VEs with drugs may improve symptoms, but may not improve the prognosis; the severity of the underlying heart disease is probably a more important influence on survival. In addition, the drugs used to suppress VEs may themselves precipitate serious ventricular arrhythmias.
Clinical features Ectopic beats, whether from atria or ventricles, are commonly found in normal individuals and generally not per-
501
FIG. 12.28 ECGs showing ectopic beats fAl An atrial ectopic beat, demonstrated by the varying shape of the P wave. B Coupled ventricular ectopics (bigeminy).
ceived by the patient. In some patients the frequency of ectopics is increased and they may produce the feelings of a 'missed beat' or even atypical chest pain (see p. 467). Ectopics are frequently more obvious to the patient at rest, presumably owing to the relative bradycardia allowing an ectopic focus to activate. Suppression with exercise that increases the heart rate is common and a good prognostic sign. Explanation of the cause of the symptom and avoidance of certain common precipitants of ectopics, such as alcohol, caffeine and cigarette smoke, may be all that is needed to treat the patient. Some patients improve when given (3blockers (e.g. metoprolol 25-100mg b.d., sotalol 20-80mg b.d. or bisoprolol 2.5-5.0mg o.d.)
BRADYCARDIA AND HEART BLOCK Bradycardia Defined as a heart rate less than 60bpm, bradycardia may be due to vagal tone in athletes or, more commonly, be an unwanted effect of -adrenoreceptor-blocking drugs. It generally requires no treatment, unless severe and producing symptoms. In an emergency (e.g. severe bradycardia complicating a myocardial infarction), it responds to atropine (600 g i.v. repeated to a maximum of 2.4 mg in 2 hours). If persistent, a temporary artificial pacemaker should be implanted. Chronic bradycardia may be a manifestation of the sick sinus syndrome (p. 516) and may benefit from permanent pacemaker implantation.
Sinus node block and sinus arrest Both sinus node block and sinus arrest are associated with a pause in the normal train of sinus rhythm, leading to a delay in the appearance of the P wave. In sinus node block the resultant pause between P waves is approximately double the preceding sinus (P-P) interval. The essential pacemaker rate remains constant but a normal discharge does not occur. In sinus arrest the pause is not a Fig. 12.14
502
FIG. 12.29 ECG showing first-degree heart block Note prolonged PR interval (0.28s).
multiple of the sinus interval, implying a transient change in pacemaker automaticity which has led to the loss of the P wave. Chronotropic incompetence is a poorly defined condition affecting some patients whereby they are unable to increase their heart rate in response to exercise. Their maximum heart rate may reach only 75-80% of the agepredicted maximum (220/age). Atrial rate-responsive pacemakers are indicated in this relatively uncommon condition. Many cardiac drugs may produce sinus node dysfunction, particularly those used as antiarrhythmics. (3Adrenoceptor blockers, the calcium antagonists verapamil and diltiazem, as well as amiodarone, propafenone and flecainide, are all potential causes. Occasionally cimetidine, lithium and phenytoin may interfere with sinus node function. Although idiopathic degeneration of the sinus node, particularly with ageing, may be the commonest cause apart from these drugs, hypertension, myocardial ischaemia and rarer conditions such as sarcoid may account for sinus node dysfunction.
First-degree heart block In first-degree heart block (Fig. 12.29) the PR interval is prolonged (>0.20s). This may occur in otherwise normal patients and is caused by delayed propagation within the AV node. A modestly prolonged PR interval may also accompany vagally induced bradycardia. However, long PR intervals in the presence of a normal or fast heart rate imply an intrinsic defect in the AV node. This is generally benign. The development of first-degree heart block in the context of infective endocarditis usually means aortic root abscess formation. Similarly, widespread conducting tissue disease is suggested by the combination of firstdegree block, left axis deviation and bundle branch block. Symptomatic patients may require a pacemaker. Firstdegree block may also occur following myocardial infarction (p. 562).
Second-degree heart block Second-degree heart block (Fig. 12.30) is defined as intermittent failure to conduct an impulse from the atria to the ventricles, and may be temporary or permanent. It occurs in two major forms. The Wenckebach phenomenon or Mobitz type I block The Mobitz type I block (Wenckebach phenomenon)
12
FIG. 12.30 ECGs showing second-degree heart block S3 Mobitz type I showing progressive lengthening of the PR interval until the P wave is not conducted to the ventricles (arrow). B Mobitz type II. Four sinus beats are followed by cessation of conduction following the P wave (arrowed).
produces successively increasing PR intervals until a P wave is not conducted; the cycle then repeats itself. There are usually 3-5 beats in a cycle. This block occurs within the AV node and is probably relatively benign. It may complicate acute inferior myocardial infarction and generally does not require specific treatment. It may also be seen in patients with generalized conducting tissue disease, and as part of the sick sinus syndrome (p. 516).
FIG. 12.31 Three rhythm strips demonstrating complete heart block A Atrioventricular dissociation with a relatively rapid ventricular rate and narrow QRS complex (with acute inferior infarction). B A slow idioventricular rate with broad QRS complexes, [c] The unusual combination of complete heart block and atrial fibrillation (no P waves).
Mobitz type II block In the Mobitz type II block an unheralded failure to conduct a P wave occurs. The site of the block is below the AV node in the proximal bundle of His. This condition has a tendency to progress unpredictably to complete block, which may cause Stokes-Adams attacks or even death. This conduction disturbance is much less common than type I block, and because of its implications usually requires treatment with an artificial pacemaker.
may be within the AV node, when the escape ventricular rhythm will be within the lower regions of the node or bundle of His, giving narrow, normal configuration QRS complexes and heart rates of about 40bpm. Complete heart block may also occur at the level of the bundle of His, so that ventricular or distal bundle pacemakers control the heart rate, producing a much slower pulse (about 30bpm) and wide bundle branch block QRS complexes. O
Other special forms of second-degree block During atrial tachycardia (e.g. atrial flutter) there may often be conduction of alternate beats to the ventricles in a ratio of 2 P waves to 1 QRS complex. When a tachycardia is present this block constitutes the normal physiological function of the AV node, and the block can often be increased further (to 3:1 or 4:1 or more) by manoeuvres that stimulate vagal activity, such as carotid sinus massage. In the absence of an atrial tachycardia, established 2:1 conduction represents a form of second-degree block. Highgrade block is present when the ratio of P waves to QRS is 3:1 or greater. In either case, artificial permanent pacemaker implantation is the treatment of choice when the arrhythmia persists.
Clinical features
Complete or third-degree heart block In complete or third-degree block (Fig. 12.31) the atrial impulses fail to be conducted to the ventricles. The block
Symptoms First-degree heart block is asymptomatic, as are many cases of second-degree block, but patients may be aware of the dropped beat and the stronger post-pause beat in Mobitz types I and II. In complete heart block the most dramatic symptoms are related to recurrent asystole or the ventricular arrhythmias that complicate severe bradycardia. However, complete heart block may present without symptoms, despite a marked bradycardia; with heart failure secondary to a low cardiac output; and in the elderly as a confusional state secondary to poor cerebral perfusion and multiple syncopal episodes. Stokes-Adams attack Stokes-Adams attacks can be caused by transient asystole or a transient burst of tachycardia. They are usually unheralded and the patient may first be aware of lying on the ground or falling. Recovery is usually rapid and complete.
503
Skin pallor may be followed by flushing. If the anoxia lasts more than a few seconds a convulsion may occur and, on occasion, incontinence. Incomplete attacks are common, presenting with transient giddiness (without true vertigo) or near fainting (presyncope). Attacks are sporadic and random. There may be months to years between symptoms in some patients with intermittent block, so that 24-hour ambulatory ECG recordings may have to be made repeatedly for the diagnosis to be made. Occasionally, treatment with a pacemaker is warranted on the basis of the history alone, although intracardiac electrophysiological studies may help in these patients. Signs There are few clinical signs in heart block. The first heart sound is quiet in first-degree block, and intermittent dropped beats will be felt at the pulse in second-degree block. In complete heart block a slow pulse and intermittent cannon waves will be seen in the JVP, caused by occasional simultaneous contraction of the atria and ventricles. The large stroke volume and collapsing pulse with a systolic murmur may mimic aortic valve disease.
Management In congenital complete heart block there is a surprising degree of tolerance to the slow heart rate, which may show modest rate responsiveness with exercise. Nevertheless, adults with this condition may risk sudden death, and permanent pacemaker implantation is warranted. In acute inferior myocardial infarction complete heart block is due to transient ischaemia of the SA and AV nodes, and may not need a temporary pacemaker unless symptoms of heart failure occur (p. 562). In extensive anterior myocardial infarction complete heart block is related to extensive muscle damage and carries a poor prognosis. Drug treatment of complete heart block with isoprenaline slow-release capsules is now hardly ever justified, and permanent pacemakers should be offered to virtually all patients. Like sinus node disease, idiopathic fibrotic degeneration of the AV node is the most frequent cause of heart block. It may be precipitated after ischaemic damage or secondary to calcific degenerative aortic or mitral valve disease. Aortic valve surgery and congenital heart defect repairs may cause heart block, acutely or after delays of months to years. O
THE PERMANENT ARTIFICIAL PACEMAKER The basic pacemaker consists of a small battery container which can be implanted under the skin and connected by O MCQ12.7
504
an insulated electrode to the heart. Small electrical impulses can be transmitted through the electrode to stimulate the heart to contract. Since 1960 there has been a great increase in their use, and 1 million people worldwide now live with an implanted pacemaker. The initial sole indication for pacing was the treatment of chronic complete heart block, but now a major indication is the treatment of the sick sinus syndrome (p. 516). More recently, units able to treat tachycardias and administer internal DC cardioversion have been developed. Pacemakers that respond to the patient's activity by changing the pacing rate are now in common use. Early pacemakers were fixed rate. Modern pacemakers, however, are almost exclusively demand (or standby) units, providing a pulse only when the heart rate falls below certain predetermined limits, and have battery lives of 8-15 years. They may offer considerable adjustment and analysis via transcutaneous telemetry. The complexity of cardiac pacemakers has increased for a number of reasons: • To increase battery life by reducing unnecessary pacing and by reducing output to the lowest safe limit; • To allow fine control of the pacing heart rate and, with dual-chamber devices, to restore the atrial contribution to filling, which may be very important to individuals with impaired ventricular function or valve disease; • To detect when the patient needs an increase in heart rate (e.g. with exercise); • To detect tachycardias and abort them by programmed bursts of pacing (antitachycardia). A letter coding system, used internationally, describes the type of pacemaker used. In some pacemakers a facility allows the interval between the last natural beat and the paced beat to be longer than the pacing interval. Thus, only when a pause corresponding to a very low heart rate is exceeded will the pacemaker step in and gradually accelerate to its programmed paced rate. This stops the pacemaker inserting beats for trivial slowing of the heart (e.g. during sleep).
Dual-chamber pacemakers Dual-chamber pacemakers have been developed to achieve a more physiological situation than is possible with ventricular pacing alone. These require the implantation of electrodes in the right atrium and right ventricle. They use more complex, and therefore more expensive, generators. In addition, the capacity to 'fine-tune' the multiplicity of programmable functions to each individual patient requires both time and the availability of skilled pacemaker technicians or doctors in pacing clinics. Nevertheless, these units are justified in certain groups: • Patients with AV block but normal SA activity, in whom a true physiological situation can be achieved, with normal rate increase with activity, and maintained AV sequential contraction. This is usually reserved for young or active elderly patients.
• Patients with poor ventricular function or valve disease, where the atrial contribution to filling is of prime importance. • Patients with the 'pacemaker syndrome': a small number of patients develop severe symptomatic hypotension with pacing of the right ventricle alone. • Patients with carotid sinus sensitivity. Dual-chamber pacemakers should be avoided in patients with unstable SA activity or atrial fibrillation.
Dual-ventricular pacemakers It has been recognized that improvements in cardiac output and hence patients' symptoms may be gained by pacing the left ventricle in some individuals with conduction disturbance (LBBB). Electrodes are placed in a branch of the great cardiac vein via the coronary sinus in conjunction with the usual leads in RA and RV. The pacemaker thus provides synchronized LV and RV contraction, with claimed benefits in patient exercise capacity.
Pacemaker implantation and complications Permanent pacemakers are almost always inserted by a cardiologist using local anaesthesia and full surgical sterile technique. Like temporary pacemakers (p. 562), the pacing electrode is passed down a central vein (usually the cephalic or subclavian) to the right heart. The electrode and generator box are then buried subcutaneously, above the pectoralis major on the high anterior chest wall. Complications of implantation are similar to those of temporary pacemakers. Infection is rare, but when it occurs it requires major revision of the entire system and accounts for considerable morbidity and a small mortality. Lead displacement and fracture are very rare with modem pacing systems. Specific pacemaker malfunction is now very rare. With current telemetry the pacemaker (and lead) function can be assessed transcutaneously, so that premature battery failure can be predicted, problems with lead impedance
TABLE 12.9 Pacemaker description Letter position Function Pacemaker types
1
2
3
4
Chamber paced A = atrium V = ventricle D = dual A+V
Chamber sensed A V D
Response to sensing
Rate responsiveness
T = triggered I = inhibited D
R = Rate responsive
An entry of '0' in one position denotes the absence of that function, e.g. VOO would be an 'old-fashioned' ventricular pacemaker with no sensing and hence no response to sensing - the old fixed-rate pacemaker.
(electrical resistance), current leak and failure to sense can often be diagnosed, and the unit reprogrammed to compensate for problems until replacement is required. Failure to sense the patient's electrical activity and intermittent failure to capture may sometimes cause problems. Dualchamber pacemakers, although potentially much closer to normal physiology, carry their own problems, the most serious being the capacity to generate pacemaker-induced arrhythmia. Fortunately, these problems are rare. Interference with pacemaker function by external sources of high magnetic and electromagnetic fields is less of a problem than might be expected; few problems arise in the normal environment of most patients. However, magnetic resonance imaging is contraindicated, and cautery during surgery has to be performed with care, avoiding placing the ground electrode near the generator and altering the unit to a fixed-rate mode.
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THE TACHYCARDIAS Tachycardia is defined as a heart rate above 100 bpm, and is divided according to the origin of the pacemaker impulse. A classification is given in Table 12.10 and a guide to the use of antiarrhythmic agents in Table 12.11. A decision tree to aid in diagnosis is shown in Figure 12.32.
Mechanisms of production of tachycardias Three basic mechanisms have been established: abnormalities of automaticity; early after-depolarizations with triggered activity; and abnormal impulse conduction or re-entry. Abnormalities of automaticity Under normal circumstances only SA and AV node cells display automaticity. Abnormal automaticity may be displayed by diseased atrial and ventricular muscle. Stretch, alkalosis, temperature increases and hypoxia all increase the rate of repolarization and reduce the resting membrane potential (Vm), thereby accentuating the tendency to abnormal automaticity. Cardioactive drugs also influence heart rate and rhythm via these mechanisms. Therapeutic doses of some antiarrhythmics achieve their beneficial effects by decreasing the rate of depolarization (Table 12.11). Toxic doses may cause atrial and ventricular tachyarrhythmia by increasing the diastolic depolarization slope and lowering Vm. Early after-depolarizations ana triggered activity Following an action potential there may be a further spontaneous depolarization, which can occur early during repolarization or late. Single 'after-depolarizations' can precipitate further spontaneous beats, to produce a rapid cycle of spontaneous activity. Factors that encourage their occurrence include hypoxia, hypercapnia, high circulating
505
CASE STUDY 12.2 AN EPISODE OF COLLAPSE A 78-year-old woman presented to casualty having collapsed in the street whilst walking to a restaurant. The collapse was witnessed by her niece. They were walking at a good pace along a normal pavement on the flat. The patient was talking when she became silent and then slumped to the ground without warning. She struck her forehead on the pavement causing a small graze. She looked very pale at this moment but recovered within seconds. She was not incontinent and had no limb twitching. On recovery she was distressed but completely orientated. They attended casualty where she was found to be well orientated with no significant injuries. Physical examination was normal. She was normotensive and had a regular heart rate of 86 beats per minute with occasional pauses noted at the radial pulse. An ECG confirmed sinus rhythm, the PR interval was 334 msec and the QRS complexes were narrow and normal. During the 12-lead ECG, a 1.8 second pause in heart rhythm was detected. This appeared to be sinus arrest and the patient was not aware of this pause. During history taking she admitted that for the previous 2 weeks she had had waves of 'panic' attacks. These consisted of short-lived episodes when she felt very uncomfortable and was aware of a rapid fluttering in her chest associated with feeling faint. She was clear that the fall precipitating this admission was not preceded by any fluttering in her chest. She had seen her GP for these 'panic attacks' and
he had ordered a 24-hour halter monitor ECG. That revealed a background of sinus rhythm with a long PR interval and occasional pauses up to 2.3 seconds. Several episodes of narrow-complex, irregular tachycardia of up to 150 beats per minute were noted during the 24 hours. One of these which lasted 4 minutes was associated with the patient's symptoms in the chest.
Question What is the diagnosis and how should this patient be managed? Discussion This very fit 78-year-old woman has had a single syncopal fall which had the characteristics of a Stokes-Adams attack. This did not appear to be preceded by symptomatic arrhythmia on this occasion. Her 24-hour ECG revealed that she has episodes of tachycardia which punctuate normal sinus rhythm which itself was interrupted by occasional pauses of up to 2.3 seconds on this 24-hour recording. Her baseline ECG confirmed sinus rhythm but revealed a very long PR interval with no other conduction abnormality. This patient has the tachycardia-bradycardia or 'tachy-brady' syndrome, otherwise known as sick sinus syndrome. As is often the case, it is occurring in an otherwise healthy person with no other predisposing illnesses. Management must include the control of the tachycardia as well as
catecholamines, non-specific muscle injury and stretch. There is evidence that this activity occurs frequently and is important in producing tachycardia, particularly in the long QT syndrome (p. 517) and with drugs of the VaughanWilliams classes IA and III (Table 12.11).
Abnormal impulse conduction and re-entry
506
A wave of depolarization may sometimes circle endlessly
prevention of further syncopal episodes. It can be assumed that her collapse leading to the casualty admission represented a prolonged pause with sino-atrial arrest. Even without such a presentation, the current resting ECG indicates that it would be difficult to give her prophylactic treatment against paroxysmal atrial fibrillation (AF) because of the very long PR interval and occasional pauses. The risk would be that standard treatment of AF, such as a -blocker such as sotalol, or a class one agent such as flecainide, or a class three agent such as amiodarone, may all exacerbate the pauses and lead to the development of more profound arrhythmia. This patient received a permanent pacemaker. A dual chamber system was used to maintain atrioventricular synchrony. It is a demand pacemaker which will be inhibited during normal sinus rhythm but provide synchronized atrial and ventricular pacing if it detects a pause of greater that 1 second's duration. In order to prevent further bouts of paroxysmal AF she has been successfully treated with sotalol 40 mg b.d. Modern dual pacemakers have algorithms which may also help with the prevention of paroxysmal AF that has been generated by bradycardia pauses and atrial ectopics. These are known as DDRP pacemakers and their use is increasing although it is not yet determined whether their use will be an advantage over standard dual chamber pacemakers combined with drug therapy in this clinical setting.
around a loop of cardiac tissue. The mechanism of re-entry is shown in Figure 12.33. The loops of myocardial tissue may be found as a combination of alterations in anatomy (congenital or acquired), and abnormal function of parts of the heart. The best-known is that due to the presence of anomalous pathways connecting the atria with ventricular myocardium. This is the basis of the pre-excitation syndromes, so called because of the tendency of the aberrant pathways to excite
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TABLE 12.10 Features and classification of tachycardias Clinical
ECG
Type Supraventricular Sinus Atrial Paroxysmal atrial tachycardia Atrial fibrillation Atrial flutter
Rate (bpm)
>100
120-250
>140
150
Response to carotid sinus pressure
Symptoms and signs
P waves
QRS complex
Normal Abnormal shape
Normal Regular and normal aberrant conduction produces broad QRS of RBBB or, less commonly, LBBB type. Broad QRS also if BBB already present Irregular Very regular QRS complexes
Transient minor slowing May terminate tachycardia
Palpitation Palpitation, dizziness, breathlessness, chest pain may occur Diuresis on cessation
Transient slowing Conduction may decrease from usual 2:1 to 4:1 or less
As above As above
Absent Flutter waves; sawtooth pattern in lead V1
Junctional AVNRT* AVRT**
180-240 180-240
None seen (buried in QRS) Inverted P waves after QRS; QP interval < PR
Normal and regular Normal and regular
None, or abrupt cessation None, or abrupt cessation
As above As above
Ventricular Ventricular tachycardia
150-250
Dissociated P waves diagnostic, but can be difficult to see None seen
Regular broad QRS > 120ms sometimes >140ms. QRS look similar in V-leads 'concordance' Loss of regular discernible QRS features
No response
May cause collapse; sometimes well tolerated
Inappropriate
Collapse with rapid loss of consciousness
Ventricular fibrillation Ventricular flutter
150-300
* AVNRT = AV nodal tachycardia **AVRT = AV re-entrant tachycardia
areas of adjacent ventricle and produce the delta wave on the ECG (Fig. 12.34); the clinical syndrome that results is the Wolff-Parkinson-White (WPW) syndrome (p. 516). Slow conduction in the anomalous pathways is the basis for the arrhythmia in WPW, whereas in ischaemia segments of diseased ventricular muscle with slow conduction or unidirectional block are the cause.
SUPRAVENTRICULAR TACHYCARDIAS Supraventricular tachycardias (SVT) arise in the atria or AV node. They are characteristically associated with narrow QRS complexes, but there are important exceptions: • When there is pre-existing bundle branch block - a situation impossible to diagnose with certainty unless there are ECGs available in normal sinus rhythm - before or after the arrhythmia; • When there is rate-dependent bundle branch block; • In the pre-excitation syndromes (although the delta waves often do not show during tachycardia, as the anterograde conduction may be normal), orthodromic tachycardia.
Clinical features Common symptoms of SVT are an unpleasant awareness of rapid heartbeats or palpitations in the chest. Associated cardiac disease may dominate the picture, causing the arrhythmias to lower cardiac output, producing complaints of breathlessness, dizziness, fatigue or chest pain. The tachycardia may precipitate acute LV failure. Patients who suffer paroxysmal SVT, particularly those with structurally normal hearts, may notice polyuria during, or after, the attack.
Diagnosis Differentiating between the many forms of SVT may occasionally be difficult. The ECG is the basic diagnostic tool, although aspects of the history and, occasionally, physical examination can give clues. Very fast heart rates may produce ST and T-wave changes on the ECG which persist for some hours after cessation of the arrhythmia.
Sinus tachycardia Sinus tachycardia is a persistent sinus rate over 100 bpm. It is regarded as pathological when inappropriate and
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TABLE 12.11 Guide to use of antiarrhythmic drugs VaughanWilliams classification
Electrophysiological action On action potential
Increased threshold for activation Slow rate of rise of action potential? (Inhibit fast sodium channel)
QRS and QT prolongation, especially quinidine
Disopyramide
Comment
Toxicity now limits use. Effective in VT, and may convert AF or A flutter to sinus rhythm
Gl disturbance Proarrhythmogenic Interacts with digoxin and numerous other drugs
Now rarely used in UK practice
Not used long term, owing to side-effects. Acute i.v. for ventricular and supraventricular arrhythmia Ventricular and supraventricular arrhythmia Prophylaxis in paroxysmal AF Ventricular arrhythmia during and after myocardial infarction Phenytoin useful for digoxin toxicity arrhythmia
Lupus syndrome Other autoimmune disorders Negative inotropy Anticholinergic side-effects
IB Lidocaine • (lignocaine) Mexiletine Phenytoin .
Inhibit fast sodium channel Shorten action potential
Usually none
1C Flecainide 1 Propafenone
Inhibit fast sodium channel Inhibit His-Purkinje network with QRS widening
QRS duration prolongation and QT lengthening
Mainly ventricular arrhythmia
Bradycardia
SVT Exercise-induced VT Rate control of AF, as adjunct to digoxin For i.v. use, ultra short acting
Transient i LV function
Pneumonitis, proarrhythmia, interference with thyroid function, photosensitivity Profound hypotension p-blocker side-effects
Class II: p-Adrenoreceptor blockers e.g. Propanolol Slow diastolic depolarization Atenolol
Esmolol Class III: Amiodarone
CNS side-effects
Apart from lidocaine (lignocaine) in the acute situation little use in UK
Major proarrhythmic potential with flecainide
Have largely taken over class 1 treatment
Hypotension, wheeze Negative inotropy Claudication worsens
Prolongs action potential
QT prolongation
Prolongs action potential Additional p-blocking effects Prolongs AP
QT prolongation QT prolongation
Extremely wide-spectrum against SVT, VT and VF For life-threatening arrhythmia i.v. for resistant VF SVT and VT
QT prolongation
Acute termination AF
Proarrhythmia
Class IV: Calcium antagonists e.g. Verapamil Inhibit slow calcium channel
None
SVT, except acute AF
Hypotension Profound AV nodal block
Unclassified Digoxin
Inhibits Na/K ATPase
None
Control of AF rate
Adenosine
AV nodal block
None
SVT. Differentiation of SVT andVT
Digoxin toxicity Proarrhythmic Transient block; angor animi
Bretylium tosylate Sotalol Ibutilide
chronic, e.g. with diseases such as thyrotoxicosis, or when secondary to heart failure. Under these circumstances treatment consists of control of the underlying disorder. A number of diseases of sinus node function produce a chronic sinus tachycardia, such as the dysautonomia of diabetes, cardiac infiltration with amyloid, and extrapyramidal disease of the Shy-Drager syndrome.
Atria I tachycardia 508
Toxic effects
On ECG
Class I: Membrane-stabilizing drugs IA Quinidine
Procainamide
Indications
In atrial tachycardia (Fig. 12.35) the ECG shows abnormal
Not in general use in UK
P waves at rates from 120 to 250 bpm. The mechanism of the arrhythmia is usually enhanced, or abnormal, automaticity in the SA node or other site in the atria. Causes include coronary heart disease, cardiomyopathy, rheumatic heart disease and the sick sinus syndrome. The normal AV node may not conduct at rates much greater than 200 bpm, so that very fast atrial rates may be associated with intermittent failure of contraction. This may lead to an atrial tachycardia with 2:1 conduction or higher degrees of block. Conduction through the AV node may be further impaired by disease or drugs such as digoxin. Indeed, one
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509
FIG. 12.33 Mechanism of re-entry tachycardias Q] Normal conduction. B An area of abnormal conduction affects one limb of the circuit. This interrupts the antegrade conduction (large grey arrow) but is able to conduct retrogradely some moments later (black dashed line). This combination allows re-entry of the impulse (black arrow) and a tachycardia ensues.
FIG. 12.35 ECG showing atrial tachycardia with 2:1 conduction Dots indicate position of P waves. (Atrial rate is 300/min.)
FIG. 12.34 ECG characteristics of the Wolff-Parkinson-White syndrome Note the short PR interval and pre-excitation of the ventricle, producing the slurred upstroke of the R wave (delta wave, arrowed in V4). O
of the manifestations of digoxin toxicity is atrial tachycardia (at a relatively slow rate) with block.
Management Withdrawal of digoxin is important if toxicity is suspected. Otherwise, measures to control ventricular rate include intravenous verapamil (slow bolus of 5mg repeated to a maximum of 10-20mg in 20min) when there has been no prior -blocker therapy, and intravenous digoxin when glycoside toxicity is not the cause. Patients who have received -blocker therapy should be given verapamil with great caution, for fear of precipitating severe bradycardia or high-grade AV block. Intravenous -blockade (e.g. atenolol 2.5 mg i.v. over 2-5 min, repeated 2-3 times over 30min; esmolol 500 g/kg for 1min then 50 g/kg/min for up to 10 min) may also terminate the tachycardia, as will DC cardioversion or atrial overdrive pacing.
Atrial fibrillation Atrial fibrillation (AF) is probably the most common arrhythmia, and in many patients may be permanent. It is characterized by a chaotic, rapid and low-amplitude wave-
Q Fig. 12.15
510
Fig. 12.16
FIG. 12.36 Rhythm strips showing atrial fibrillation and flutter H Atrial fibrillation. Note the irregular ventricular rate. B Atrial flutter with typical sawtooth P waves and a regular ventricular response (4:1). C Atrial flutter with a variable ventricular response. ©
form on the ECG (Fig. 12.36). The ventricular response is characteristically completely irregular in rhythm, and usually shows a narrow QRS complex unless there is preexisting disease or rate-dependent bundle branch block. Despite an atrial activity of 350-600 impulses/min, the AV node conducts only intermittently and randomly. The nodal rate is usually less than 200 impulses/min, or even less in the presence of AV nodal disease or drugs suppressing nodal activity (e.g. digoxin). An exception to the rule of irregular ventricular activity in AF is when it coexists with complete heart block, when a subnodal pacemaker provides a slow, regular ventricular complex (Fig. 12.31). The rhythm is believed to be caused by localized re-entry circuits within the atria, and is a frequent consequence of chronic atrial distension from any cause. The causes of AF are shown in Table 12.12. The most common underlying condition is probably hypertension. Some patients develop
TABLE 12.12 Causes of atrial fibrillation With structural heart disease • Rheumatic mitral valve disease • Hypertension • Cardiomyopathy Dilated Hypertrophic • Atrial septal defect • Coronary heart disease
Without structural heart disease Alcohol Thyrotoxicosis Acute pericarditis Constrictive pericarditis Pulmonary embolism Sick sinus syndrome Myocarditis Coronary heart disease
there is associated rheumatic mitral valve disease, especially mitral stenosis. Stroke due to embolism is nearly five times more common in patients with AF than in those in sinus rhythm, and this relative risk rises to 17-fold if there is associated mitral valve disease.
12
Clinical features Clinically, the symptoms are determined by the rate of the arrhythmia and the underlying cardiac state, but they do not differ significantly from those of any SVT. The pulse is of variable rhythm and volume. Very early beats, especially with fast AF, may not produce sufficient stroke volume to produce a pulse at the wrist, producing an apex to radial pulse deficit in 'uncontrolled' AF. The venous pulse shows only a single waveform, corresponding to ventricular systole (the v wave).
RECENT ADVANCES ATRIAL DEFIBRILLATOR
Patients with intractable and poorly tolerated paroxysmal atrial fibrillation, especially those with left ventricular dysfunction, are being considered for nonpharmacological interventional therapy. These may include AV nodal ablation followed by dual-chamber pacemaker insertion, or operative procedures (e.g. 'maze or corridor' operation) to restore sinus rhythm while preserving atrial transport. An alternative currently being explored is the insertion of an implantable atrial defibrillator, similar to the implantable ventricular cardioverter/defibrillator. This device detects atrial fibrillation with satisfactory sensitivity and specificity. With improvements in electrode design, and by keeping the shock duration short and energy low (<1.5 J), intraatrial shocks are reasonably well tolerated by patients. The risk of proarrhythmia (inducing ventricular tachyarrhythmias) in humans has yet to be evaluated and kept below 1% per year (as in acceptable antiarrhythmic drug therapy). The final hurdle is cost, as these devices are significantly more expensive than permanent pacemakers.
the rhythm for no discernible reason and are said to be suffering lone atrial fibrillation; they appear to have a normal prognosis. For other patients the immediate consequence of the arrhythmia and its long-term prognosis are determined by the underlying condition. AF may be paroxysmal or permanent. Even when structural heart disease is absent paroxysms of AF can sometimes be symptomatically disabling, and although drug therapy to control the ventricular rate during an attack is reasonably effective, there may be considerable difficulty in providing adequate prophylactic therapy. The loss of a mechanical atrial systole can be very important in patients with severe heart disease, and in some is sufficient to precipitate heart failure. The loss of atrial contraction predisposes to stasis of blood in the atria and atrial appendages. Thrombi form, which pose the threat of systemic embolization. This tendency is accentuated where
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The aim of treatment is control of the ventricular rate, both at rest and during exercise. In individuals with paroxysmal AF, prevention of recurrences is attempted. Consideration should be given to converting all patients to sinus rhythm, unless there are grounds to believe that successful cardioversion is highly unlikely or reversion to AF almost inevitable. Patients falling into the latter category might be those with long-standing mitral valve disease and hugely dilated atria, or those discovered to have been in the rhythm for many years. The risk from cardioversion lies in the possibility of systemic embolization from the previously fibrillating left atrium. The risk of having intra-atrial clot due to AF rises rapidly with the time that the patient is exposed to the rhythm, so that cardioversion in anything other than emergency situations should be deferred in those who have been in AF for more than 48 hours without adequate anticoagulation. Acute AF Severely haemo dynamically compromised patient. Central line cannulation is needed for the infusion of amiodarone: 5mg/kg diluted in 250 mL of 5% dextrose and infused over 20-30 minutes. Significant electrolyte disturbances are excluded or treated and oxygenation maximized by treating pulmonary oedema, if present (p. 492). Arrangements are made to undertake DC cardioversion under a general anaesthetic. The initial slow bolus of amiodarone should be followed by an infusion of 1200 mg over the succeeding 24 hours, even if DC cardioversion is successful. Anticoagulation is not an issue in these patients. An alternative and older protocol is to use intravenous digitalization prior to DC cardioversion, since degeneration to ventricular fibrillation is unlikely in the absence of digoxin toxicity. Digoxin is given as 500 g in l00 mL 5% dextrose infused over 30 minutes. This may be repeated with a second dose of 500 g infused over 1 hour, or ouabain for much faster digitalization: Img in 100 mL 5% dextrose over 1 hour. In a compromised patient, negative inotropic agents such as verapamil, flecainide and -blockers should be avoided.
511
Haemodynamically stable patient with AF > 130bpm. The aim is to control ventricular rate to achieve a resting AF rate of 90bpm or less, and produce a 'chemical cardioversion' within 48 hours. If this conversion is not achieved the patient is discharged on maintenance drugs designed to control the ventricular rate, and anticoagulants prior to elective DC cardioversion. Oral digoxin is used to initiate ventricular rate control: digoxin 15 g/kg divided into three doses over first 24 hours. The maintenance dose of digoxin is established with reference to the level of this drug in the blood (see p. 518). In patients with good left ventricular function improved control of the heart rate may be achieved by using oral verapamil 40-80 mg 8-hourly. Caution should be exercised with combinations of digoxin and verapamil, because verapamil increases the plasma levels of digoxin. In the absence of structural heart disease or ischaemia, flecainide by i.v. bolus (slow injection of 2mg/kg up to 150 mg) is gaining popularity. Anticoagulation. All patients should be anticoagulated with heparin unless there are specific contraindications, such as very recent surgery. Heparin is given as a bolus of 5000U followed by 24000-48000U/24h adjusted according to the clotting times, aiming for a 2.5-3.0-fold increase over control clotting times. If cardioversion is not achieved the patient should be converted to oral anticoagulation with warfarin (aiming for an INR = 3.0) with a view to elective cardioversion after 3-6 weeks' adequate anticoagulation. Chemical cardioversion. This means using drugs to achieve what is usually undertaken with DC shock. It may be achieved with oral amiodarone or intravenous flecainide. The regimens are: a. Amiodarone 200 mg oral t.d.s. for 1 week, 200 mg b.d. for the second week, maintenance 100-200 mg daily. (NB: It is necessary to reduce the digoxin and warfarin doses if they are used concurrently.) Amiodarone is effective but may take several days to restore sinus rhythm. It may be combined with digitalization, but there is an interaction between these drugs, so digoxin doses should be reduced and plasma levels checked. b. Flecainide: 2mg/kg i.v. slow bolus over 10 minutes minimum. Maintenance with oral flecainide 50 mg 12hourly, increasing to a maximum 300mg/day. A recent report suggests that oral loading with 300 mg flecainide, followed by standard maintenance regimens, is as effective as i.v. treatment. In patients with good ventricular function (3-blockade with esmolol, the ultra-short-acting agent, has been successfully used (see p. 518 for treatment regimen). Maintaining sinus rhythm. If cardioversion is immediately successful, the patient with very recent-onset AF in
Fig.
512
12.16
an otherwise normal heart does not require anticoagulation. Digoxin is not continued, and if there has been an obvious precipitating event to the AF, such as excess alcohol, the appropriate advice is given and no preventative drugs are prescribed. If the AF, albeit of recent onset, was poorly tolerated, owing, for instance, to the coexistence of ventricular hypertrophy and poor LV compliance, treatment designed to prevent further attacks is advisable (see below under Paroxysmal AF). Patients who required anticoagulation or were electively cardioverted after some weeks in AF should continue to receive anticoagulants for up to 3 months, as well as prophylactic antiarrhythmic treatment continued for that time. If they remain in sinus rhythm and do not have severe cardiac abnormalities as the substrate for the rhythm, all antiarrhythmics may be discontinued at the 3-month review. Patients with severe cardiac abnormalities, or those in whom AF was poorly tolerated, should probably continue treatment in the long term. Chronic sustained AF Treatment aims to reduce the resting ventricular rate to about 90 bpm, with a modest increase on exertion. Digoxin alone, although effectively controlling the resting heart rate, is insufficient to control the response to exercise in a large proportion of patients. A combination of digoxin with verapamil (or digoxin with a -blocker) is superior to digoxin alone in these circumstances. Anticoagulation with warfarin reduces the risk of emboli and is essential when rheumatic valve disease is present, or if the heart (particularly the left atrium) is enlarged. It is indicated in patients with a previous history of systemic emboli, and where the cause of AF is thyrotoxicosis. Paroxysmal AF can be disabling. Commonly used prophylactic treatments are shown in Table 12.13. Digoxin is less effective at preventing attacks. The symptoms may be
SUMMARY 5 Digoxin points
Rapid loading
I.V.
Oral
500 g diluted over 30 min Second 500 g over 60 min
15|ig/kg in 3 divided doses in 24 h
Slow loading
125-250 g oral b.d. for 1 week
Maintenance
62.5-375 g o.d. (therapeutic range 1.0-2.6 mmol/L)
Reduce all dosages in: • elderly patients • renal impairment (by 30-70%, according to GFR) • combination with verapamil • combination with quinidine • combination with amiodarone
12
TABLE 12.13 Drug treatment of paroxysmal atria I fibrillation Amiodarone • Loading dose - 200 mg t.d.s. (to a total of 1.2-1.6 g) Maintenance dose -100-400 mg/day Flecainide • Upto150mgb.d. Propafenone • Up to 900 mg/day in divided doses Disopyramide • 250-800 mg/day in divided doses • Must be used with digoxin • Valuable in bradycardia-dependent AF
helped by verapamil, which lowers the peak heart rate during a paroxysm of AF. Ablation of the AV node and pacemaker implantation are used in intractable cases; this does, however, render the patient pacemaker dependent. Atrial flutter Atrial flutter is an arrhythmia caused by multiple re-entry circuits producing atrial contraction at 300 ± 50 bpm. Conduction block at the AV node (most commonly 2:1) is almost always present, producing a regular pulse of 150 bpm. This pulse rate should always lead to the clinical suspicion of atrial flutter. Vagal slowing of AV conduction produced by carotid sinus massage will temporarily increase the degree of AV block, and the sudden halving or more of the ventricular rate can easily be detected at the bedside. On the ECG monitor, P waves previously concealed within T waves become visible as a sawtooth pattern, thus establishing the diagnosis (Fig. 12.36C). O Physical examination may show flutter waves in the neck. The causes of atrial flutter are the same as those of AF (Table 12.12), but flutter is rarely permanent. Drugs are less effective in flutter compared with fibrillation, and DC cardioversion is the therapy of choice. Energies of 25-50 J are frequently sufficient to achieve successful cardioversion to sinus rhythm. Intravenous verapamil will successfully convert many patients to sinus rhythm, as will pacing the atria at or below the tachycardia rate (underdrive pacing), or rapidly for a few minutes (overdrive pacing). Chaotic atrial tachycardia and wandering atrial pacemaker Chaotic atrial tachycardia is characterized by multiple wave shapes and PR intervals. It is quite common in elderly patients, whereas in younger patients it is usually associated with severe respiratory disorders. It requires no specific intervention, except for control of any associated illness and withdrawal of digoxin if this has previously been prescribed. Conversely, a sustained rhythm may be slowed by digoxin or verapamil.
FIG. 12.37 AV nodal re-entry tachycardia Note rapid narrow QRS complex tachycardia (rate 185 bpm).
The wandering atrial pacemaker is a slower arrhythmia often associated with variations in vagal tone, allowing various subsidiary atrial pacemakers to become established. It requires no special treatment.
JUNGTIONAL TACHYCARDIAS AV nodal and AV re-entry tachycardia or paroxysmal supraventricular tachycardia The mechanism involved in these tachycardias is re-entry through a functionally distinct area of the AV node or tissues surrounding it. They are common, particularly in (young) patients with structurally normal hearts. There is a 1:1 relationship between atrial and ventricular activity. P waves generally cannot be identified; if they can be seen, they will be buried within the QRS or immediately follow it (Fig. 12.37). The onset is abrupt, usually precipitated by an atrial extrasystole, and an equally abrupt cessation is the rule, although the latter may not be appreciated by the patient as a sinus tachycardia may follow the arrhythmia. The usual rates are about 180-240 bpm, with narrow QRS complexes, except if there is pre-existing or rate-dependent bundle branch block. If manoeuvres or drugs induce a lower degree of conduction than 1:1, AVNRT is excluded and a paroxysmal atrial tachycardia or flutter is the more likely diagnosis. Management Treatment may not be necessary if the attacks are transient and infrequent. Several vagotonic manoeuvres may be helpful (Table 12.14), all of which can be taught to the patient who suffers paroxysmal attacks. Failing these simple approaches, drug therapy is usually successful. Intravenous adenosine is the drug of choice, although intravenous injections of verapamil, -blocker, disopyramide and amiodarone adenosine may also prove useful. Atrial and
513
TABLE 12,14 Simple procedures to terminate paroxysmal SVT
!
• Carotid sinus massage. If effective, the rhythm is abruptly stopped; occasionally only moderate slowing occurs • Cold water splash on face (to mimic the diving reflex). This may be effective, but is often difficult to administer • Performance of Valsalva's manoeuvre (often effective) • Swallowing cold drinks • Inducing vomiting (a few patients discover this themselves)
ventricular pacing may also be used, the former following a similar procedure to that used to convert atrial flutter. A more elegant approach is to interrupt the re-entry circuit with critically timed ventricular or atrial ectopic impulses using chronically implanted antitachycardia pacemakers. Long-term prevention can often be achieved with (3blockers, amiodarone, flecainide and propafenone. Transcatheter ablation of accessory pathways or the AV node can be undertaken. These latter techniques need a prior definitive intracardiac electrophysiological study (p. 501), but with the advent of radiofrequency catheter ablation are the treatment of choice in significantly symptomatic patients.
TABLE 12.15 Differentiation of VT from SVT with aberration or bundle branch block (BBB) Feature
Value in differentiation
Broad QRS complex (>120ms)
Very broad (>160ms) - almost always VT Broader than 140ms favours VT, but may be due to pre-existing BBB
Bizarre QRS morphology, similar in V1-V6 and not resembling any BBB pattern - concordance
Characteristic of VT when present
Independent P-wave activity
Diagnostic of VT, when found
Fusion beat with QRS between sinus and tachycardia morphology
Diagnostic of VT, when found
Variability of rate from 10 to 20ms; except for fusion/capture beats
Not good
Hypotension, shock and collapse
No value
When V-A conduction occurs with 2:1 block
When ventricular rate is shown to be greater than atrial, the rhythm is VT
Non-paroxysmal AV nodal or functional tachycardia Non-paroxysmal AV nodal tachycardia is a narrowcomplex tachycardia associated with inverted P waves in II, III and aVF. Characteristically, it is caused by ischaemia and digoxin toxicity, although junctional rhythms may be precipitated by most forms of heart disease; the mechanism is enhanced automaticity. Because the atria and ventricles are stimulated virtually simultaneously, the P waves may precede the QRS complexes with a short PR interval. Alternatively, they may be buried within the QRS complex or follow after it. The onset of the tachycardia is gradual and the established rates, between 60 and 130bpm, considerably slower than the paroxysmal forms of tachycardia. Therapy is along the same lines as for AV nodal and reentry tachycardias, although lignocaine may also be useful. Withdrawal of digoxin may be all that is required when toxicity is implicated.
BROAD-COMPLEX TACHYCARDIAS The hallmark of ventricular rhythm is the broad QRS complex. Ventricular fibrillation and flutter do not cause diagnostic difficulties, but ventricular tachycardia (VT) is often wrongly diagnosed as SVT with rate-related aberra-
FIG. 12.38 Ventricular tachycardia (monomorphic) A rapid, broad QRS complex tachycardia illustrating the similarity of appearance in complexes from V1 to V6 (concordance). O
tion, or with pre-existing bundle branch block. There is often a reluctance to diagnose VT, particularly on the part of less experienced physicians, probably because the implications for the patient are so much worse than for SVT. Guidelines for their differentiation are given in Table 12.15. In the context of acute infarction, or when there is severe underlying myocardial disease, the observation of a broad-complex tachycardia should always be assumed to be ventricular in origin until proved otherwise.
Ventricular tachycardia Q Fig. 12.17
514
VT (Fig. 12.38) is defined as the appearance of three or more ventricular ectopic beats in a sequence. When sustained, the rate is between 150 and 250 bpm and regular.
Unsustained VT can be seen in people with normal hearts, but organic heart disease is suspected if the rhythm is sustained or produces symptoms. Causes are coronary heart disease, cardiomyopathy or myocarditis. VT carries the risk of sudden death, usually due to degeneration of the rhythm to ventricular fibrillation (VF). Even with the guidelines to diagnosis given in Table 12.15, VT can in some circumstances be difficult to diagnose, and prolonged examination of the ECG or the use of an oesophageal ECG lead may be necessary. In about half of patients the sinus node continues to fire independently, so that atrial P waves dissociated from ventricular activity can sometimes be observed, if not buried within the QRS complex. O In a few patients, retrograde activation of the atria occurs; this may be recognized by finding inverted P waves. In paroxysmal VT (150-250bpm) the onset is abrupt, usually following a critically timed ectopic beat. A slower form of VT, accelerated idioventricular rhythm (rate 60130bpm), occurs as an enhanced automatic rhythm during periods of suppressed sinoatrial activity. It is usually seen in acute infarction and its prognosis - unlike that of paroxysmal VT - is generally good. Management Acute In the presence of acute haemodynamic disturbance or acute myocardial infarction, immediate DC cardioversion with a synchronized shock is the treatment of choice; this is followed by an intravenous lidocaine (lignocaine) bolus dose of 100 mg (or 1 mg/kg), followed by an infusion, starting at 4 mg/min for 30 min, reducing to 2 mg/min for 2 hours and continued at 1 mg/min thereafter, for approximately 24 hours. This approach is generally successful, particularly in acute infarction, when there is rarely any indication to continue to chronic oral antiarrhythmic therapy. In resistant or recurrent cases an alternative therapy is amiodarone. Mexiletine, flecainide or bretylium may be required in certain instances, although the acute use of many different antiarrhythmic drugs should be avoided. The serum potassium must be maintained at or above 4.5mmol, and acidosis and hypoxaemia reversed. Chronic Episodic or paroxysmal VT complicating organic heart disease (e.g. hypertrophic cardiomyopathy, chronic coronary heart disease and cardiomyopathy) requires prophylactic therapy. In choosing the drug, information on its
SUMMARY 6 Treatment of tachycardia where doubt persists as to SVT or VT
EQ
• DC cardioversion if haemodynamics are compromised. • Do not use verapamil. • Try i.v. adenosine (0.05-0.25 mg/kg) - it will terminate an SVT but will not affect VT or haemodynamics. • Try i.v. lidocaine (lignocaine) (1 mg/kg bolus) - it may terminate VT.
efficacy in the individual patient should be taken into account. The response to exercise testing and monitoring the effectiveness of therapy with Holter 24-hour ECG recordings is helpful. In those patients in whom VT is inducible by exercise, -blocking drugs may be useful; sotalol, with its class III effects (Table 12.11), may be the rational first choice. Patients with poor ventricular function are probably most at risk from VT. The choice of drug for these patients is very limited, owing to the negative inotropy of most antiarrhythmic agents. Amiodarone or mexiletine are the most useful in these patients. A new form of therapy for those patients in whom drug therapy fails is the use of small implantable automatic defibrillators (AICD) which detect the arrhythmia (VT or VF) and, after an appropriate pause, deliver a DC shock. Surgery and catheter ablation Certain patients have an anatomical basis for their ventricular arrhythmia - either a ventricular aneurysm or a localized area of ischaemically injured myocardium. Treatment options now include excision of the aneurysm or electrically abnormal tissue by surgery, or ablation using catheters capable of delivering radiofrequency ultrasound.
Torsade de pointes ventricular tachycardia Torsade de pointes VT is an uncommon but important arrhythmia, characterized by a VT, often of modest rate but associated with an undulating QRS height owing to a slow but continual variation in the QRS axis (Fig. 12.39). Its importance is owing to its precipitation by antiarrhythmic drugs, particularly if electrolyte disturbances coexist.
Management Acquired forms are treated by withdrawal of the offending agent and correction of electrolyte abnormalities. In
FIG. 12.39 Rhythm strip illustrating torsade de pointes, a broad-complex ventricular tachycardia Note the fluctuation in size of the complexes.
515
OTHER ARRHYTHMIC SYNDROMES Sick sinus syndrome
FIG. 12.40 Rhythm strip showing ventricular fibrillation
less stable situations an infusion of isoprenaline, or increasing the heart rate with a temporary pacemaker, is the appropriate remedy. Congenital syndromes can be caused by abnormalities in sympathetic supply to the heart. These are best treated with (3-blocking agents.
Ventricular fibrillation and ventricular flutter VF is characterized by rapid, irregular and uncoordinated electrical activity in the ventricles, probably due to re-entry circuits within localized areas of myocardium. The ECG shows more or less coarse, irregular waveforms, without discernible P, QRS or T waves (Fig. 12.40). In ventricular flutter the entire tracing appears as a rough sawtooth with a rate of 160-250 bpm, without normal QRS morphology. If either rhythm occurs effective contraction and cardiac output cease, leading to unconsciousness within seconds. These rhythms do not usually revert spontaneously and are often precipitated by an ectopic beat or runs of VT, particularly when they complicate acute myocardial infarction. VF is probably the arrhythmia responsible for most cases of sudden death in the community (p. 561). In the context of acute myocardial infarction, when VF occurs early, within 24-48 hours of onset of the illness (primary VF), and is successfully treated, the prognosis for the patient is not adversely affected. However, VF occurring late in the course of acute infarction (secondary VF) often follows extensive muscle damage and carries a grave prognosis. Management Witnessed collapse due to VF (usually seen only in coronary care units) requires immediate action; a precordial chest thump (p. 519) may convert up to 15% of cases without the need for electrical defibrillation. In all other circumstances basic cardiopulmonary resuscitation should begin until the treatment of choice is available, namely defibrillation by the application of an external DC shock (p. 519). Correction of acidosis, hypoxaemia and electrolyte imbalance improves the likelihood of conversion to a stable rhythm. Drug treatment and long-term prophylactic therapy are the same as for VT. Primary VF does not generally require subsequent prophylactic therapy. O O MCQ12.8
516
O
MCQ12.9
The sick sinus syndrome (SSS) is a relatively common condition, characterized by episodic arrhythmias combining episodes of profound bradycardia and heart block with episodes of tachycardia (it is sometimes called the tachycardia-bradycardia syndrome). The bradycardias may be paroxysmal or sustained sinus bradycardia, episodes of sinus arrest, or SA block producing long pauses in pulse rate and pauses after atrial ectopics. Immediately following a tachycardia there may be a prolonged pause or very slow sinus rhythm sufficient to cause dizziness or a Stokes-Adams attack. The tachycardias are mostly supraventricular, with AF, flutter, chaotic atrial rhythm and atrial tachycardia being the most common, although VT (especially torsades de pointes) is occasionally seen, as is chronic AF with a slow ventricular rate. The pathology is probably degeneration and fibrosis in the sinus node and conducting tissues. The AV node is often involved in the degenerative process. Ischaemic heart disease and amyloid infiltration of the heart may be the cause in some patients, and SSS has also been associated with many other pathologies, from cardiomyopathy to Friedreich's ataxia. Drugs such as digoxin, (3adrenoreceptor blockers or quinidine may mimic SSS. Apart from discomfort and Stokes-Adams episodes, the condition carries a risk of systemic embolization and is the cause of episodic heart failure. Sick sinus syndrome is often unmasked when drugs are given to treat tachycardia, and profound bradycardia or heart block is produced, necessitating the implantation of a pacemaker. Management and prognosis Treatment is with a combination of antiarrhythmic drugs and pacemaker implantation. The prognosis is generally good, but mainly dependent on any underlying condition.
Wolff-Parkinson-White syndrome The ECG abnormality of short PR interval (<0.12s) with abnormal QRS widening due to delta wave (Fig. 12.34) is relatively common. The clinical syndrome, WolffParkinson-White (WPW) syndrome, with paroxysmal tachycardias is much less common, although the precise incidence of arrhythmia in individuals with the ECG abnormality is not clearly established. The syndrome generally occurs in an otherwise normal heart, although it may complicate Ebstein's anomaly (p. 538) or mitral valve prolapse (p. 525). The abnormality is due to an accessory pathway between the atrium and ventricle allowing a reentry or reciprocating tachycardia to develop (p. 506). The tachycardia produces narrow QRS complexes without the delta wave, because conduction is anterograde through the AV node. Thus, the diagnosis of WPW may not be made until an ECG in sinus rhythm is obtained. There is an
increased incidence of AF. In a small proportion of patients who have a short refractory period in the accessory pathway AF may conduct very rapidly (1:1) to the ventricles; this may degenerate to VF and is the usual cause of sudden death in these patients. Investigation and management Electrophysiological studies establish the site, number and refractory period of the accessory pathway(s). Treatment may include antiarrhythmic drugs, but often requires ablation of localized accessory bundles during electrophysiological (EP) testing. Digoxin and verapamil should be avoided, as they can increase accessory pathway conduction. Lown-Ganong-Levine syndrome
Patients with Lown-Ganong-Levine syndrome (LGL) have short bypass tracts that connect the atria to various portions of the proximal bundle of His or distal AV node. The ECG manifestation is of a short PR interval (<0.12s) without pre-excitation (no delta waves). Such patients are subject to paroxysmal tachycardias, but are less commonly threatened by rapidly conducted AF. Treatment is the same as for WPW syndrome.
Long QT syndrome Several congenital disorders are described which are characterized by a long (>0.45 s) QT interval. They are caused by increased action potential duration and predispose to ventricular tachycardia, and are associated with sudden death, exceeding 60% at 15 years in untreated symptomatic patients. The Romano-Ward syndrome is autosomal dominant and more common than the autosomal recessive disorder Jowell-Lang-Nielsen syndrome. The nuclear basis for these disorders has been characterized and mutations on the genes coding four cardiac action potential ion channels have been identified: LQT1, LQT2,LQT3 and SCN5A. The clinical course of long QT syndromes is influenced by the associated mutations, so that one group (LQT1 patients) is susceptible to physical and emotional stresses as triggers for VT, and LQT3 patients are more at risk during sleep. Treatment has reduced mortality to 3-4% within 10 years of the first symptom. The mainstay of treatment consists of -blockers, cardiac sympathetic denervation, and the use of pacemakers whenever there is bradycardia or pause-induced syncope. Gene-specific therapies remain an exciting prospect for the future.
SYNOPSIS OF DRUG TREATMENT OF ARRHYTHMIAS A decision tree for the diagnosis of tachycardias is shown in Figure 12.32. Summaries of the treatment of, and drug doses used in, arrhythmias are given in Tables 12.11,12.16 and 12.17. O
12
TABLE 12.16 Emergency drug treatment of common arrhythmias Arrhythmia
First-line therapy
Second-line therapy
Atrial fibrillation
i.v. flecainide bolus plus infusion. DC cardioversion if BP low DC cardioversion (50-1 00 J)
3-Blockers Verapamil DC cardioversion Verapamil Vagotonic manoeuvres Atrial pacing DC cardioversion Digoxin (if not digoxin toxicity) 3-Blocker Disopyramide Flecainide Amiodarone DC cardioversion DC cardioversion
Atrial flutter Atrial tachycardia and junctional tachycardia SVT and AVNRT or AVRT type
Vagotonic manoeuvres Adenosine Verapamil Vagotonic manoeuvres Adenosine Verapamil
SVT in WPW with
Adenosine
narrow QRS SVT in WPW with broad (delta wave) QRS VT and VF
Bradycardia Complete heart block
Amiodarone Flecainide Adenosine DC cardioversion Lidocaine (lignocaine)
DC cardioversion Bretylium Amiodarone Flecainide Mexiletine
Atropine Isoprenaline Pacemaker Isoprenaline
RESUSCITATION
Within 20 seconds of cardiac inactivity the victim falls unconscious, breathing soon ceases and the pupils dilate. Sudden death affects about 50000 people a year in the UK. Half of these are not previously known to have coronary artery disease. About 60% of deaths due to myocardial infarction occur within an hour of the first symptom (see Fig. 12.62), the majority occurring outside hospitals. The commonest rhythm disturbance (over 60% of cases) is VF. Cardiopulmonary resuscitation (CPR) may involve: • Basic life support, requiring training but no special equipment; • Advanced life support, which requires equipment and specialized skills. Many cities in the UK and other industrialized countries are involved in training the public in basic life support skills, and provide specialized ambulances with very rapid response times and facilities for advanced life support and DC cardioversion. Examples are Belfast and Brighton in the UK, and Seattle in the USA. With such basic life support available about 20% of victims may reach hospi-
517
TABLE 12.17 Doses and methods of administration of drugs commonly used in acute arrhythmia Drug
First dose
Method
Maintenance
Side-effects
Amiodarone
2-5mg/kg
i.v. slow bolus
Usually required 600-1 200 mg/day i.v. infusion
iBP Need central venous access
Atropine
0.6-1. 2 mg
i.v. bolus
Not used
Anticholinergic side-effects
p-Blockers Atenolol Metoprolol
5-10 mg 5-1 5 mg
i.v. bolus i.v. bolus
50-1 00 mg oral/day 1 00-400 mg oral/day
4 Heart rate;
Very short acting
Esmolol
500ng/kg
i.v. bolus 1 min
50u.g/kg/minfor4min
Bretylium
5-10mg/kg
i.v. rapid in emergency
Optional 1-2mg/min (i.v. infusion)
Digoxin
0.5 mg
i.v. slow bolus
Optional 0.75-1 .Omg for first 24 h, then 0.25 mg/day (oral)
Flecainide
1-2mg/kg
i.v. bolus over 10-30 min
Optional 0.15-0.25mg/kg/h (i.v. infusion)
Isoprenaline
50 g
i.v. rapid in emergency
Optional 0.02-0.1 8 g/kg/min
Lidocaine (lignocaine)
100mg
i.v. bolus
Essential 4mg/min reducing to 2mg/min for 24 h (i.v. infusion)
Verapamil
5mg, repeat with 10mg after 10 min
i.v. slow bolus
Optional 0.005 mg/kg/min for 1h (i.v.) or 80-1 20 mg/8-hourly (oral)
Adenosine
0.05-0.25 mg/kg (3-1 8 mg)
i.v. bolus (fast)
Not usual
tal and 11% live to be discharged. These numbers are halved when basic life support is not available. Survival is worse in older patients, and when arrest occurs at home or in the street. In hospital, when cardiac arrest due to VF occurs within 4 hours of symptoms and is successfully treated, 80% of patients are alive 3 years later.
BP; bronchospasm
BP; nausea Toxicity: lower dose in renal impairment and in elderly BP; cardiac failure Heart rate CNS toxicity
BP;
Transient
heart rate; AV block
BP; chest pain; angor animi
TABLE 12.18 Basic cardiac arrest procedures A Assessment Patient unconscious or asleep? Call for help if unconscious. Is airway clear? Clear it, pull chin up. B Breathing
BASIC LIFE SUPPORT
518
The basic cardiac arrest procedures are given in Table 12.18. Initial assessment is rapidly followed by establishing a clear, open airway. This is done by head tilt with chin lift and jaw thrust. In the absence of airway obstruction, rescue breathing begins with the mouth-to-mouth technique. Recommendations vary, but in the UK, four quick breaths are advocated. In the USA, two slow breaths (1-1.5s each) have been suggested, in order to diminish the likelihood of gastric distension with air, and subsequent vomiting (risking inhalation of vomit into the unprotected airway). Protective masks and airway equipment should be provided for personnel most often exposed (ambulance and paramedical staff), even though the risk of infection (such as from hepatitis B or HIV) is likely to be very small. Bag and mask techniques are taught to nursing and
If patient is breathing: turn to recovery position. If patient is not breathing, but is choking: Heimlich manoeuvre. If patient is not breathing, but is not choking: start mouth-to-mouth resuscitation. Call for assistance. C Circulation If no pulse: start external cardiac massage call for assistance continue ventilation
medical staff, but are frequently more difficult to use and less effective in inexperienced hands than is mouth-tomouth ventilation. Closed cardiac compression follows at a rate of 60-80 compressions/min. Training in the technique is essential. Midsternal compression is carried out with the heel of one hand to depress the sternum by 2-4 cm. The patient should
be on a rigid, flat surface with the resuscitator kneeling alongside. The arms are kept straight and compression is produced primarily by body-weight movement. Closed chest compression achieves a cardiac output by virtue of cyclical changes in intrathoracic pressure, rather than by squeezing the heart. A single-handed resuscitator should provide 15 chest compressions for every 2 mouth-to-mouth breaths. If two people are available, the ratio should be 5:1. CPR must be continuous, and pauses to reassess the situation or allow for advanced life-support techniques should not be greater than 10 seconds. The first response to a witnessed arrest should be a forceful precordial thump. This may be sufficient to convert VF or VT to a more stable rhythm by localized myocardial depolarization, or even to initiate a rhythm in cases of acute asystole.
ADVANCED LIFE SUPPORT Advanced life support (summarized in Fig. 12.41) consists of defibrillation with DC shock, endotracheal intubation, and the use of drugs and pacemakers.
DC defibrillation In VF, the earlier DC shock is given, the more successful the outcome. When defibrillators are immediately avail-
able, such as in coronary care units, the first procedure following the precordial thump should be defibrillation at 200 J. This will be sufficient to revert 85% of cases to a more stable rhythm. In 10% of patients a further 200 J shock is required and is successful. If these approaches are unsuccessful, life support must be begun immediately. Outside coronary care units, basic life support must be begun and interrupted only when the defibrillator is ready to produce the first shock of 200 J. If no monitor is available, major pulses are checked and, if absent after 3s, 15 chest compressions are given with the appropriate mouth-to-mouth breaths. A second shock follows the same pattern of events and, if VF persists, intravenous lidocaine (lignocaine) (100 mg i.v. bolus) is given before the third shock at 400 J. Adrenaline may be given before the fourth shock at the highest energy and, if an acidosis is demonstrated by arterial gases, bicarbonate (Immol/kg) is given before the fifth high-energy shock (Fig. 12.41). The technique of DC shock administration can be taught to nursing and paramedical personnel. Early defibrillation administered out of hospital by ambulance crews has been shown to improve survival from VF. Defibrillation paddles are placed on the chest with firm pressure, one under the right clavicle and one just lateral to the usual cardiac apex. Skin impedance is reduced with conducting gel or pads, and the administrator of the shock ensures that no-one is touching the patient before the shock is delivered. Complications are remarkably few, although very high-energy shocks or many repeated shocks carry the risk of some myocardial damage.
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Endotracheal intubation If there is no recovery after a few minutes of basic life support, endotracheal intubation is necessary. This is a skilled technique which can be mastered by medical and paramedical staff alike, but which requires frequent practice. After the cardiac arrest it may be necessary to continue ventilation, via a mechanical ventilator, of seriously ill patients, those with a damaged ribcage from cardiac massage and those who sustain cerebral damage.
Drugs in advanced life support The number of drugs of proven benefit is small, despite the large number available to treat ventricular arrhythmia.
FIG. 12.41 Flow diagram of resuscitation procedures
(Based on recommendations of the UK Resuscitation Council.)
• Adrenaline (epinephrine) is the inotropic and chronotropic agent of choice. It is given intravenously in a dose of Img (ImL of 1/1000) or 2mg via the endotracheal tube. • Lidocaine (lignocaine) is given after VF and during attempts to treat VF. A bolus of Img/kg (or 100 mg) is followed by an infusion (4mg/min, reducing to 2mg/min over 24 hours). A second half-dose bolus can be given 10-20 minutes after the first. • Sodium bicarbonate. Bicarbonate infusion is only used in established acidosis, which is a relatively late event.
519
An average dose is Immol/kg of 4.2% sodium bicarbonate solution. • Calcium chloride is useful in specific circumstances, such as resuscitation after cardiopulmonary bypass and in calcium antagonist overdose. The usual dose is 10 mL of 10% calcium chloride. • Other drugs. The treatment of resistant VF or ventricular tachyarrhythmias may require the use of one or other of the alternative drugs available (p. 517). None, however, has a proven role as 'standard' therapy in CPR, and their indications have to be determined individually at the time of the resuscitation attempt.
RESUSCITATION FROM CHOKING Collapse due to acute airway obstruction is often caused by a lump of food. In the UK it is still recommended that active coughing with gravity drainage be encouraged while the subject is still conscious. This is supplemented by back blows and, finally, the abdominal thrusts known as the Heimlich manoeuvre. The latter depends upon gripping the subject from behind and, with clenched fist, producing a rapid, powerful upward thrust in the upper abdomen. This produces a rapid airflow, which may be sufficient to dislodge the obstruction.
Special techniques Cardiac pacing Cardiac pacing can be used to treat bradycardia, heart block and, sometimes, asystole. Asystole, unless it has been caused by drugs, rarely responds to cardiac pacing. Intra-aortic balloon counterpulsation Highly specialized techniques such as intra-aortic balloon counterpulsation have a limited role in specialized centres, where they can be used to support the circulation until a definitive procedure can be performed. Intracardiac injection Intracardiac injection has been used to administer calcium or adrenaline during cardiac arrest with asystole. Central venous cannulation delivers drugs to the heart with much less hazard.
When to stop Rigid rules cannot be given, but guidelines are possible. Resuscitation is almost never successful in patients who have a cardiac arrest complicating another serious illness, such as pneumonia or malignancy. It is important, therefore, that the staff likely to be first to witness a collapse should have had clear guidance concerning the desirability of resuscitation in individual patients. In general, the outlook for a useful neurological recovery is poor if the arrest occurred out of hospital and was not witnessed, or if more than 4 minutes passed without even basic life support being attempted. If no spontaneous respiration or cardiac output is achieved after 30 minutes of adequate advanced life support, then further attempts at resuscitation are questionable. The state of the pupils, whether widely dilated and reacting or not, is unreliable with respect to outcome. Age should not be used as the sole determinant of policy on resuscitation. O
O MCQ 12.10 520
VALVULAR DISEASE OF THE HEART AETIOLOGY AND NATURAL HISTORY In western countries, rheumatic heart disease was, until recently, the commonest cause of valve disease, and in most developing countries this is still the case. Various forms of degenerative valvular disease are increasingly being seen, some based on congenital abnormalities of the valve, others apparently arising de novo in middle age or later. For both rheumatic and congenital heart disease, it is often difficult to predict the progression of what initially may seem a trivial lesion of no consequence, to one that may be life-threatening 30 or more years later. What dictates progression of the valve lesion? Mechanical forces must be involved; pressure and shear forces on the valve probably make it thicken and even calcify. The tolerance of the myocardium and the advent of myocardial disease add to the difficulty in prognosis.
THE EFFECTS OF STENOSIS AND REGURGITATION Heart valve disease can occur either because of a narrowing of the valve (stenosis), causing obstruction to blood flow through the valve, or when the valve leaks, when the lesion is termed regurgitant, incompetent or insufficient. A combined or mixed lesion is common.
Valve stenosis Mild degrees of stenosis may produce an audible murmur and also a risk of endocarditis, but place an insignificant physiological burden on the heart. For significant symptoms to result, stenosis has to progress until the valve is narrowed to less than 30% of its normal area. Flow through the valve is maintained at close to normal levels by a compensatory increase in pressure in the chamber of the heart upstream of the stenotic valve. This chamber therefore hypertrophies.
TABLE 12.19 Relationship between valve area, blood velocity and pressure gradient Area (cm2)
Condition of valve Stenosis alone Normal Mild stenosis Severe stenosis Stenosis and regurgitation Normal area, no regurgitation Normal area, 50% regurgitation Mild stenosis, 50% regurgitation Mild stenosis, 66% regurgitation
Velocity (m/s)
Pressure gradient (mmHg)
3
1
4
1.5 0.6
2
16 100
5
3
1
4
3
2
1.5
4
16 64
1.5
6
144
2
The Bernoulli equation (P = 4V ), relating blood flow velocity (V) to pressure gradient (P) across a valve, shows the effects of regurgitation on the pressure gradient if the forward stroke volume is maintained. The figures are chosen for simplicity. With 50% regurgitation, the forward stroke volume and (theoretically) the flow velocity doubles; with 66% regurgitation, they increase threefold. In practice, the flow time also increases.
The severity of the stenosis is quantified by the pressure drop across the valve. In a normal valve this drop is not measurable by conventional techniques. However, in severe aortic stenosis the left ventricular pressure may rise to as much as 200 mmHg more than the aortic pressure, and the valve area may be less than 25% of normal. In mitral stenosis the left atrial pressure cannot rise above 40 mmHg because the pulmonary capillaries are unable to withstand a higher pressure. Thus, the mitral valve gradient is usually much less than the aortic valve gradient in significant stenosis, and the residual valve area accordingly greater. It follows that there are three ways of assessing the severity of a valve stenosis: • The pressure gradient across the valve. This indicates the additional work required to push blood through the valve. However, this is flow dependent (no flow, no gradient); if there is heart failure, with low flow, the valve gradient is smaller. • The valve area. Formerly, this could only be calculated from cardiac catheterization data, but direct measurement is now possible from ultrasound. There is, however, controversy over the accuracy of the measurements, because of the beam spread and lateral resolution of the ultrasound. • The peak blood velocity across the valve. Measured by Doppler ultrasound, this bears a very simple relationship to the pressure gradient (Table 12.19).
Valvular regurgitation Normal human valves are highly efficient. The aortic valve closes as the flow decelerates, and is fully closed with about 97% efficiency. However, severe mitral or aortic valve
regurgitation can be associated with up to 80% regurgitation (efficiency 20%). The forward flow then has to be five times greater than normal to allow for this leakage, and the chamber supplying the blood dilates accordingly. In aortic regurgitation the left ventricle enlarges; in mitral regurgitation the left atrium and left ventricle both enlarge greatly. Acute regurgitation (such as mitral valve chordal rupture, or aortic regurgitation from acute endocarditis) is badly tolerated, as the left ventricle and left atrium have not had time to increase in volume. The rapid increase in left ventricular diastolic pressure or left atrial pressure has severe consequences for left ventricular perfusion and pulmonary capillary pressure.
12
Combined valve lesions The combined effect of even mild stenosis with regurgitation is potentially catastrophic. Because the forward flow with as little as 50% regurgitation is twice normal, even a 50% stenosis becomes highly significant. This is shown in Table 12.19, where it can be seen that, with a combined lesion, the regurgitation greatly potentiates the effect of the stenosis. This is particularly true of the mitral valve, where pressures need to rise much less before producing symptoms.
MITRAL STENOSIS Aetiology Although a rare congenital form exists, mitral stenosis is almost always a consequence of rheumatic heart disease, and is the commonest valvular manifestation of the disease. The two valve cusps become adherent along their commissures, producing progressive stenosis with a 'fish mouth' orifice. Initially the cusps remain fairly pliable, but become increasingly rigid with time and eventually calcify. The increasing degree of stenosis produces a rise in left atrial pressure and left atrial dilatation. The raised pulmonary venous pressure can induce pulmonary oedema and lead to progressive pulmonary hypertension, with secondary incompetence of the tricuspid valve. Clinical features Mitral stenosis, which is commoner in women, may remain asymptomatic for many years with little limitation of exercise tolerance. However, an additional load on the heart, such as pregnancy, exertion, emotional stress or intercurrent chest infection (which is more common in patients with mitral valve disease because of the pulmonary vascular congestion), may produce the first symptoms of left heart failure. The onset of fast AF in middle age is a common presentation, often leading to left heart failure, and thrombus formation with the risk of embolism. Right heart failure eventually develops as a consequence of pulmonary hypertension.
521
The typical facial appearance of a patient with mitral valve disease - ruddy complexion, with red or vaguely cyanosed cheeks (mitral fades] - is now more commonly encountered in severe non-rheumatic causes of heart failure. Symptoms Of left heart failure The symptoms of left heart failure (p. 488) are shortness of breath on exertion, orthopnoea, paroxysmal nocturnal dyspnoea, pulmonary oedema, and haemoptysis of fresh blood occurring from rupture of a congested bronchial or pulmonary vein (uncommon with other causes of left heart failure). Haemoptysis may also be due to pulmonary infarction, which is more common in mitral valve disease. Due to atrial fibrillation The raised left atrial pressure may lead to AF, sometimes paroxysmal at first, but then sustained. The loss of atrial contraction and the shortened diastolic filling period can change an asymptomatic patient into one severely disabled by breathlessness, and may convert a quiescent stenosis into a life-threatening condition. Systemic embolism. Thrombus can form in the enlarged left atrium and give rise to systemic emboli. A hemiplegia may occur and embolism to other sites is frequent. The patient in sinus rhythm is also at risk from embolism, but to a lesser extent. The greatest risk is in the patient who, having been in AF, reverts to sinus rhythm, as the return of coordinated atrial contraction can dislodge clot. Due to a raised left atrial pressure Long-standing raised left atrial pressure often leads to constriction of pulmonary arterioles and thickening of the capillary basement membranes. There is increased resistance to flow through the lungs, and hence pulmonary hypertension. Right ventricular hypertrophy compensates for the increased load on the right ventricle. When pulmonary hypertension is severe, right ventricular failure follows, usually (but not always) associated with left heart failure. Right ventricular dilatation may lead to tricuspid regurgitation, with its attendant symptoms and signs (p. 531). Less frequently, tricuspid valve disease (regurgitation more frequently than stenosis) occurs through direct involvement in rheumatic fever. Massive enlargement of the left atrium can lead to hoarseness from pressure on the recurrent laryngeal nerve, dysphagia from oesophageal compression, and bronchiectasis from distortion of the left main bronchus.
522
Signs The main signs of mitral stenosis are listed in Summary box 7. Pure mitral stenosis in sinus rhythm without pulmonary hypertension is relatively uncommon. The signs are then purely auscultatory, as cardiac output is maintained and there is no significant right ventricular hypertrophy. The auscultatory signs are:
• An opening snap (OS, Fig. 12.42B) best heard halfway between the apex and the left sternal edge. It occurs close to the aortic second sound in severe stenosis, but is more separated from it in mild stenosis. • A rumbling diastolic murmur. This commences with the opening snap and fades rapidly in mild stenosis, but is full length and runs into the presystolic murmur in severe stenosis. • The presystolic murmur coincides with atrial systolic flow through the valve. It is of the same character as the mid-diastolic murmur and is sometimes heard when the latter cannot be heard. It is absent in AF. • A loud first heart sound. In the mobile stenotic valve the cusps are still fully open as systole starts, and so they close with a louder sound than normal. This is an unreliable sign. Later signs are AF and pulmonary hypertension. These patients also have signs of a low cardiac output, mitral fades, small stroke volume with small-volume pulse, a raised JVP, right ventricular hypertrophy, and a middiastolic murmur following the opening snap. When the cardiac output is very low the mitral murmur may be virtually inaudible, especially if the patient is in heart failure - so-called silent mitral stenosis.
Investigation In sinus rhythm the ECG may show P mitrale (Fig. 12.12, p. 477). Severe pulmonary hypertension may produce right ventricular hypertrophy or 'strain', but this aspect of the ECG is often unhelpful.
SUMMARY 7 Symptoms and signs of mitral stenosis Symptoms Of left heart failure
Shortness of breath, orthopnoea, paroxysmal nocturnal dyspnoea, haemoptysis
Of atrial fibrillation
Palpitations and syncope (at onset) May precipitate left heart failure Systemic embolism to CNS, limbs, gut and kidneys
Of pulmonary hypertension
Weight loss and cachexia Right heart failure
Signs Uncomplicated (auscultatory only)
Opening snap Mid-diastolic murmur Presystolic murmur
With atrial fibrillation
Irregular pulse
With pulmonary hypertension
Parasternal lift (RVH) Loud P2 Tapping apex (loud S1)
If very severe
Mitral facies Cardiac cachexia
12
FIG. 12.42 Features of mitral stenosis A Chest X-ray showing cardiomegaly with gross left atrial enlargement. B Diagrammatic illustration of the pressures in left atrium (blue) and left ventricle (black), showing a diastolic pressure gradient (shaded light blue). The timing of an opening snap (OS) and diastolic murmur is shown. S1 and S2 = first and second heart sounds.C Typical M mode. The mitral valve (arrowed) movement is abnormal (compare with Fig. 12.18). D 2D echocardiographic appearance in mitral stenosis. Thickened mitral valve (MV), dilated left atrium (LA) and the LV cavity (LV) are shown.
Chest X-ray. The chest X-ray may show enlargement of the left atrium (Fig. 12.42A), redistribution of flow to the upper zones, left heart failure and enlargement of the right side of the heart if there is coincident pulmonary hypertension. A penetrated lateral X-ray will show a calcified valve in most patients over the age of 50. Echocardiography. The echocardiogram shows thickening of the cusps (Fig. 12.42D), which are fused together so that the posterior cusp moves anteriorly in diastole with the anterior cusp. The severity of the stenosis is assessed by the rate of ventricular filling and direct assessment of the valve area from 2D echo. The echo is extremely useful for examining the size of the left atrium and hence the risk of thrombus formation and embolism. Occasionally, clot can be demonstrated in the left atrium with 2D echo, but is more reliably shown by transoesophageal echo. Doppler ultrasound demonstrates the blood velocity and, by calculation, can give a fair approximation of the pressure gradient across the valve non-invasively. It can also detect mitral regurgitation. Middle-aged adults in the developed countries will almost always be investigated by cardiac catheterization, mainly coronary angiography, prior to consideration for surgery.
Management
who does not require any treatment, with an eventual decision on anticoagulation; • Medical management of the symptomatic patient with a decision on surgery; • Surgical management of the patient with more severe disease.
Medical In the asymptomatic patient in sinus rhythm no treatment is necessary, but the patient should be advised about prophylaxis against infective endocarditis (p. 578) and carefully assessed during pregnancy (p. 582). The onset of AF may lead to the development of symptoms. Even asymptomatic patients in sinus rhythm with moderate stenosis are at risk from thromboembolism from the left atrium, so the relative risks of anticoagulation have to be weighed against the benefits in each case. The indications for anticoagulation in mitral stenosis are listed in Table 12.20. In the symptomatic patient the aim of medical management should be to control the symptoms of left heart failure with diuretics. In AF the ventricular rate should be controlled with digoxin, either alone or in combination with (or substituted by) a -blocker or verapamil (p. 511). The risk of thromboembolic episodes should be reduced by anticoagulation.
Management of mitral stenosis consists of three phases: • Monitoring the asymptomatic patient with mild disease
523
TABLE 12.20 Indications for anticoagulation in mitral stenosis • • • • •
Aetiology
Moderate or severe stenosis Enlarged left atrium Atrial fibrillation - paroxysmal or sustained Sinus rhythm with recurrent palpitations Any symptoms suggestive of arterial embolism
The percentage of valves coming to surgery which are rheumatic is now below 50% in many series. Regurgitation can result from:
Surgical Closed and balloon mitral valvotomy Closed surgical mitral valvotomy is an extremely effective operation, which has been performed successfully even during the second trimester of pregnancy without much hazard to mother or fetus. The operation uses a mechanical dilator to tear the fused commissures. It is introduced via a left thoracotomy, through the apex of the left ventricle. The surgeon also amputates the atrial appendage, thereby removing the source of most systemic emboli. Cardiopulmonary bypass is not required. In recent years the need for this operation has diminished considerably with the development of catheter-based techniques, where a balloon is passed via the femoral vein and across the atrial septum. It is positioned across the mitral orifice and inflated to the appropriate size until the stenosis is relieved. O The balloon technique requires only 1-2 days' hospitalization and avoids the need for a thoracotomy scar, but leaves behind the atrial appendage. The results obtained are comparable to those of the previous surgical series. Symptomatic improvements can be expected to last 4-12 years and sometimes much longer before repeat valvotomy or, more commonly, valve replacement is required. Open valvotomy Open valvotomy through a midline sternal incision, with the patient on cardiac bypass, is necessary if there is doubt about the applicability of valvotomy. It allows direct inspection of the valve and, should regurgitation result from splitting the valve, it can be replaced or even repaired. Valve replacement is essential if there is significant regurgitation or if the valve is heavily calcified. Prognosis
Mitral valvotomy can dramatically improve the symptoms of the patient with mitral stenosis. With time, however, the valve tends to become more rigid and calcify, becoming restenotic even if there is no fusion of the commissures. Often, a degree of regurgitation develops and, occasionally, other valves affected by rheumatic heart disease start to cause problems. OO O Fig. 12.18
524
GMCQ10.11
MITRAL REGURGITATION
Case 12.2
• Dilatation of the valve ring • Damage, retraction or perforation of the valve cusps • Damage to the subvalvular apparatus (chordae, papillary muscle, or the ventricular muscle to which the papillary muscles attach). Non-rheumatic causes of mitral regurgitation are: • Heart failure. Dilatation of the left ventricle will produce 'functional mitral regurgitation' owing to dilatation of the valve ring and a shift in the attachments of the chordae tendinae. This may disappear as the ventricle shrinks with treatment, but may become a permanent feature. • Myocardial infarction. Papillary muscle dysfunction can arise as a result of inferior myocardial infarction, producing a characteristic type of mitral regurgitation which is usually not severe. In contrast, infarction complicated by rupture of the papillary muscle produces catastrophic regurgitation, and is usually fatal unless repaired urgently. • Degenerative changes. These are often seen in mitral valves at surgery. The pathogenesis is not fully understood, as degenerative changes can occur in rheumatic valves or others known to be mildly incompetent for a long period. Rupture of the smaller chordae tendinae can occur slowly and progressively, causing increasing mitral regurgitation. Acute chordal rupture of a major trunk causes sudden severe mitral regurgitation. Other causes In mitral valve prolapse there is prolapse of a mitral valve cusp late in systole, often from a degree of 'redundancy' in the length of the chordae tendinae. It may be a feature of Marfan's syndrome and osteogenesis imperfecta. Elderly patients often develop a minor degree of mitral regurgitation from calcification of the valve ring. This produces a characteristic wheezy systolic murmur. Endocarditis may make even a trivial degree of regurgitation more severe, and acute endocarditis can rapidly destroy a normal valve. There is a degree of mitral regurgitation in most cases of hypertrophic obstructive cardiomyopathy (p. 571). Congenital forms of mitral regurgitation include cleft cusps in AV canal defects and endocardial cushion defects in association with ostium primum atrial septal defects (p. 540). Sharp (stabbing) and blunt (steering-wheel injury) trauma to the precordium, acromegaly and Libman-Sacks endocarditis in systemic lupus erythematosus (SLE) are other rare causes.
IB
Clinical features Symptoms and pathophysiology Chronic The symptoms of chronic mitral regurgitation are essentially the same as those of mitral stenosis, but severe pulmonary hypertension is less common with pure mitral regurgitation. The slowly progressive regurgitation is accommodated by a gradual increase in size of the left ventricle, which ejects the blood into a slowly enlarging and compliant left atrium and pulmonary venous vasculature. Up to 80% of the left ventricular stroke volume may be regurgitant in severe cases, and the left ventricular stroke volume can exceed 250 mL. Symptoms in chronic mitral regurgitation usually develop when the left ventricle begins to suffer deterioration and end-diastolic pressure rises. Usually, systolic function and ejection fraction are well maintained, because the left ventricle is ejecting largely into a low impedance outflow. The symptoms of left heart failure, AF and pulmonary hypertension are the same as for mitral stenosis (p. 522). Acute In acute mitral regurgitation, e.g. complicating acute MI or due to rupture of chordae tendinae, a small left ventricle is regurgitating into a small uncompliant left atrium. This produces a very high pressure pulse or v wave in the left atrium, which may reach 60 mmHg. Left atrial pressure rapidly exceeds that needed to produce pulmonary oedema. The low forward output may precipitate tachycardia, which makes the regurgitation worse. Acute mitral regurgitation thus usually presents with severe pulmonary oedema. Signs Uncomplicated pure mitral regurgitation, if trivial, has only auscultatory signs (Fig. 12.43). However, if the regurgitation is more severe, the left ventricular volume load becomes clinically evident by a hyperactive left ventricle with displacement of the cardiac apex down and laterally. Enlargement of the left atrium in systole may be felt as a parasternal heave. In severe regurgitation the pulse may become small and rather jerky from a shortened ejection time. Severe regurgitation is evident on auscultation by the presence of a third heart sound and short mid-diastolic murmur, produced by the greatly enhanced forward flow through the mitral valve during diastole. The pansystolic murmur of rheumatic mitral regurgitation, or other types of regurgitation with a central jet, is best heard at the apex of the heart and may be louder with the patient tipped to the left. Other types of mitral regurgitation - including the late systolic murmur of the floppy valve syndrome - may be best heard at the left sternal edge, and are often not pansystolic in character. Differential diagnosis from trivial aortic stenosis and ventricular septal defect can therefore be difficult, and requires non-
FIG. 12.43 Features of mitral regurgitation A Illustrates diversion of blood into the left atrium. B Shows the pressures in the left ventricle and left atrium in both mild and severe cases and the accompanying murmurs. PSM = pansystolic murmur; MDM = mid-diastolic murmur. C M-mode echocardiogram through the left ventricle (LV) in a case of severe mitral regurgitation due to valvular disease. The ventricle is dilated and hyperkinetic. D M-mode echocardiogram at the same level in a patient with mitral regurgitation due to poor LV function. The LV is dilated and hypokinetic. IVS = interventricular septum; PW = posterior wall.
invasive tests such as echocardiography and Doppler ultrasound, or even cardiac catheterization.
Mitral valve prolapse Mitral valve prolapse (also known as floppy mitral valve, or Barlow's syndrome) varies in severity from a trivial abnormality picked up on echocardiography, which has little or no consequence to the patient, to severe mitral regurgitation and heart failure. In its mild form there are single or multiple systolic clicks in the mitral area, which may be associated with a late systolic murmur of mild mitral regurgitation. There may be a tendency to supraven-
525
Investigation of mitral regurgitation The ECG is of little value in indicating the severity of the regurgitation. There may be P mitrale and left ventricular hypertrophy, but very severe regurgitation can exist in the presence of an almost normal ECG. Chest X-ray may show enlargement of the left ventricle as well as the left atrium. There may be evidence of raised pulmonary venous pressure. M-mode echocardiography is useful in demonstrating the volume load on the left ventricle and the size of the left atrium. The important distinction of mitral regurgitation due to an abnormal valve from that secondary to poor LV function may be revealed (Fig. 12.44). This has important management implications, perhaps emphasizing a surgical approach for the former and medical antifailure treatment for the latter. The technique will in most cases be able to show a rheumatic thickened mitral valve, mitral valve prolapse or flail cusp. Doppler ultrasound demonstrates mitral regurgitation and distinguishes it from aortic stenosis or a ventricular septal defect. Cardiac catheterization gives a direct measurement of the left ventricular filling pressure and left atrial pressure. Angiography shows the severity of the leak and often its mechanism; it also allows associated coronary disease to be defined. FIG. 12.44 Features of aortic stenosis A Pressures in the left ventricle (black) and aorta (blue) showing a systolic pressure gradient due to aortic stenosis. The ejection systolic murmur is illustrated. B 2D echocardiogram showing severe aortic valve (AV) thickening. Ao = aorta; LV = left ventricle; LA = left atrium; RV = right ventricle. DC] Position of probe and direction of Doppler beam. D Continuous-wave Doppler record showing highvelocity signals. Peak = 4.5 m/s (dottled line), predicting a gradient of 82mmHg.
tricular arrhythmia and atypical chest pain and associated mild skeletal abnormalities, commonly a straight back (loss of thoracic kyphosis). The underlying abnormality consists of redundancy in the chordae tendinae, allowing posterior prolapse of one or other mitral cusp in late systole. More severe degeneration of the subvalvular apparatus is seen in certain patients, particularly those with Marfan's syndrome (Ch. 3, p. 71), although severely floppy mitral valves may occur without obvious cause. Isolated mitral regurgitation, even if severe, can be tolerated for long periods if its development is gradual. A number of patients with the mild 'click-murmur' syndrome suffer significant complications, such as systemic embolization, arrhythmia and endocarditis. Treatment of severe regurgitation is surgical.
O MCQ12.12
526
Management Trivial regurgitation is very well tolerated and requires only endocarditis prophylaxis (p. 578). Moderately severe mitral regurgitation can be well tolerated for years, but the patient may slowly come to accept a diminishing exercise tolerance. The timing of valve replacement can be difficult. Worsening left ventricular function is an indication, as the procedure carries more risk when left ventricular function is poor. Severe regurgitation and acute regurgitation merit early valve replacement. Repair of regurgitant valves is increasingly advocated in anatomically suitable cases. O
MITRAL REGURGITATION WITH STENOSIS The combination of mitral regurgitation with stenosis is almost invariably a result of rheumatic heart disease, but occasionally arises in other conditions, such as LibmanSacks endocarditis in SLE. Mixed mitral valve disease presents later than pure stenosis, and is very common after mitral valvotomy. The physical signs are shown in Figures 12.42 and 12.43. AF is more likely than with pure stenosis. Even a mild degree of regurgitation makes the effective degree of mitral stenosis much greater (p. 521). The predominant lesion can be difficult to assess in the presence of hypertension or aortic valve disease, which will also produce left ventricular hypertrophy. A pansystolic murmur alone may arise from coincident tricuspid regurgitation with pure
mitral stenosis. The degree of mitral regurgitation can vary with the heart rate and the degree of left ventricular dilatation. What may appear to be severe regurgitation when the patient is in heart failure may settle considerably as the patient improves. Management is as for mitral stenosis alone (p. 523). Assessment of the mitral valve with Doppler ultrasound shows that minor degrees of mitral regurgitation are extremely common, even when these cannot be detected clinically.
AORTIC STENOSIS Aetiology Outflow obstruction to the left ventricle can be at the valve itself (valvular), above it (supravalvular) or below (subvalvular). About 1% of cases of 'aortic stenosis' are supraor subvalvular. Supravalvular stenosis is a congenital form of atresia of the ascending aorta, and is associated with a characteristic 'elfin' facies. Subvalvular stenosis is either a congenital ring lesion (which is amenable to surgery) or a variable muscular obstruction produced by hypertrophic obstructive cardiomyopathy (p. 571). Valvular aortic stenosis can result from: • Congenital aortic stenosis, presenting in childhood, the valve having one, two or three cusps; • Bicuspid aortic valve presenting in adulthood. About 1% of the population are born with two, instead of three, cusps. About one-third of these develop calcific aortic stenosis, one-third mixed aortic valve disease, and one-third have no significant valvular abnormality. The valve itself seems to be mechanically unsatisfactory and suffers mechanical stresses, which lead to progressive damage; • Rheumatic heart disease. This involves the aortic valve in about 50% of cases of rheumatic valvular disease, most frequently producing aortic regurgitation, often a mixed lesion but sometimes pure stenosis; • Senile aortic calcification. Although calcification of the valve ring is commonly benign, it can invade the cusps and produce a calcified tricuspid valve as it renders the cusps immobile. This aetiology is more common over the age of 70. The valve cusps are not fused. Pathophysiology
Clinical features
12
Aortic stenosis may remain asymptomatic until it is very severe, and is then life-threatening. The symptoms are: • Left heart failure. Shortness of breath on exertion may precede paroxysmal nocturnal dyspnoea and orthopnoea, or the patient may present with acute pulmonary oedema. • Angina. The thickened myocardium is perfused by a lower than normal perfusion gradient owing to low aortic diastolic pressure and a high left ventricular enddiastolic pressure. For these reasons, angina can occur without any coronary narrowing, although coronary artery disease often coexists in older patients. • Syncope on exertion. This is a sinister symptom which indicates a fixed cardiac output and presages sudden death. The mechanisms may be: skeletal muscle vasodilatation causing a drop in blood pressure; a rise in ventricular pressure producing reflex bradycardia and vasodilatation; myocardial ischaemia triggering ventricular arrhythmia. • Sudden death, probably resulting from myocardial ischaemia and ventricular irritability, leading to a fatal arrhythmia. This may be provoked by exertion. • Right heart failure. Rarely the presentation is right heart failure supervening on left. • Emboli from a heavily calcified valve. These are usually fairly small and cause small strokes or visual disturbances.
The signs of pure aortic stenosis are shown in Figure 12.44. Although the systolic ejection murmur suggests the possible diagnosis, the most important physical sign is the slowrising poor volume pulse, best felt at the carotid, where a systolic thrill may also be evident. The heart is not enlarged unless the patient has been in failure, but the left ventricular apex beat is powerful and 'pressure loaded'. Differential diagnosis from a 'flow murmur' is based on the slow-rising pulse, the presence of left ventricular hypertrophy and the absence of the aortic component of the second heart sound. The loudness of the murmur is a poor index of severity and the murmur may even be absent in heart failure. In congenital aortic stenosis there may be an ejection click as the valve cusps tent as they tension.
Outflow obstruction to the left ventricle leads to: • Concentric left ventricular hypertrophy • Compensatory enlargement of the coronary arterial circulation as the metabolic demands of the hypertrophied left ventricle increase; • A relatively fixed cardiac output. A resting pressure gradient of l00mmHg would have to become 400mmHg for the flow velocity through the valve to double. The heart is incapable of generating such a pressure, and is therefore near its limit at rest.
investigation Electrocardiography A normal ECG virtually rules out significant aortic stenosis, except in congenital disease when the trace may remain remarkably normal despite a large gradient. A number of ECG changes are seen in aortic stenosis: • Left ventricular hypertrophy. Often widening of QRS and T wave changes of 'strain' predominate over voltage
527
SUMMARY 8 Symptoms of aortic stenosis • • • • •
Left heart failure - dyspnoea, orthopnoea, pulmonary oedema Angina Exertional syncope or near syncope Small cerebral emboli Right heart failure
change. T-wave inversion over LV leads may be the only feature. Loss of anterior R waves may occur. • Left axis deviation and, eventually, left bundle branch block may occur either from severe hypertrophy or invasion of the conduction system by calcium from the valve. • Left atrial hypertrophy or 'P mitrale\ A large negative component to the P wave in VI indicates raised left ventricular filling pressure. • Complete heart block.
Medical Treatment of heart failure follows conventional lines (p. 494). Vasodilator agents are contraindicated, as a reduction in systemic resistance can lead to a severe drop in blood pressure, and syncope.
AORTIC REGURGITATION
Chest X-ray The chest X-ray can be normal but may show a poststenotic dilatation of the ascending aorta, prominence of the left ventricle and a calcined aortic valve on lateral chest X-ray. The latter in a patient under 55 suggests tight stenosis; above this age the valve may calcify even with an insignificant gradient. Significant enlargement of the left ventricle occurs with heart failure or coincident aortic regurgitation.
Aetiology
M-mode echocardiography M-mode echocardiography can display thickening and calcification of the valve cusps, but is less useful in congenital stenosis. The compensatory hypertrophy of the left ventricular wall is well shown. 2D echocardiography may give a good view of the aortic valve orifice.
Dilatation of the valve ring occurs classically in syphilitic aortic regurgitation, but can also occur with hypertension and aortic dissection; less common causes include cystic medial necrosis in Marfan's syndrome, and osteogenesis imperfecta. Damage to the valve cusps is a feature of rheumatic aortic regurgitation, infective endocarditis, and less common conditions such as Libman-Sacks endocarditis, mucopolysaccharidoses and pseudoxanthoma elasticum. The seronegative arthritides, ankylosing spondylitis, Reiter's disease and psoriatic arthritis can be associated with an aortitis and cusp damage, leading to aortic regurgitation. Rarely, rheumatoid arthritis is associated with a nodular cusp damage leading to aortic regurgitation. Bicuspid aortic valve (found in 1% of the population) can lead to predominant aortic regurgitation (p. 527). There are other congenital forms of aortic regurgitation, e.g. that associated with a supracristal ventricular septal defect.
Doppler ultrasound Doppler ultrasound measures the jet velocity and predicts the valve gradient. A high blood velocity (>4m/s) indicates a surgically significant gradient, but as jet velocities can be underestimated, a low jet velocity record is a less reliable finding. Cardiac catheterization Measurement of the valve gradient by cardiac catheterization is not essential if the diagnosis is well established. Catheterization is usually indicated where there is doubt about the site or degree of stenosis, a not-infrequent occurrence in older patients, who may be poor ultrasound subjects. It also allows analysis of ventricular function. Coronary angiography is now considered essential prior to operation in all but the very elderly.
Management
528
tomy in children may gain sufficient time for them to reach a reasonable size before having aortic valve replacement. For adults, valve replacement is the only treatment. If the ventricle has already been badly damaged the results are less good, but in the patient with a normal ventricle the left ventricular hypertrophy regresses fairly rapidly. Lesser degrees of stenosis need serial follow-up, as the stenosis may become more significant with time at a rate averaging about 8mmHg/yr, although this may be very variable.
Surgical Tight aortic stenosis has such a poor prognosis that surgery should be offered to all patients. Valvuloplasty or valvo-
The aortic valve cusps normally overlap on closure to the extent of about 25% of the cusp area. Aortic regurgitation can arise from: • Dilatation of the valve ring so that the cusps no longer meet adequately to prevent leakage • Damage to the cusps themselves • In some diseases, a combination of these factors.
Clinical features Symptoms and pathophysiology Aortic regurgitation can be well tolerated for years if it develops slowly. Up to 80% regurgitation can be found in severe chronic aortic regurgitation, but acute regurgitation (such as follows aortic dissection or acute infective endocarditis) is poorly tolerated. The severity of the regurgitation is normally indicated
12
by a low diastolic blood pressure and wide pulse pressure. These may appear more 'normal' in heart failure as the stroke volume falls and the end-diastolic pressure of the left ventricle rises. As aortic regurgitation progresses, the increasing leakage requires a larger and larger forward flow. This is usually achieved not by a tachycardia but by the left ventricular end-diastolic size increasing with an increased stroke volume. Initially, the ejection fraction of the left ventricle is well maintained and exercise tolerance is excellent. However, after an unpredictable time there is a steady or sudden deterioration in left ventricular function, usually with a great increase in heart size and the development of symptoms of left ventricular failure. Eventually, right heart failure follows, with the development of pulmonary hypertension. The development of heart failure indicates serious dilatation of the left ventricle and the need for urgent consideration of valve surgery. Heart failure in aortic regurgitation is associated with rapidly worsening left ventricular function, which may never recover even with valve replacement. Angina can develop because the dilated left ventricle has increased oxygen requirements (as in congestive cardiomyopathy), but is usually associated with coronary artery disease. AF occurs in about 15% of cases, usually those with long-standing failure. Physical signs The physical signs of aortic regurgitation (Fig. 12.45) are related to the large stroke volume, the peripheral vasodilatation and the compensatory increase in size of the left ventricle. The pulse may be collapsing or bisferiens (p. 471), or feel normal if there is heart failure. The blood pressure indicates the large pulse pressure and low diastolic pressure. If the diastolic pressure is well maintained in the presence of severe aortic regurgitation, coincident hypertension should be suspected. The left ventricle is very active, and in severe cases the apex beat is displaced. The increased forward flow is often accompanied by a systolic flow murmur, which, of itself, does not indicate coincident stenosis. The early diastolic murmur is notoriously difficult to hear. The murmur is best heard with the diaphragm of the stethoscope, with the patient sitting forward having breathed out. It may be best heard at the left sternal edge, nearer the apex or in the aortic area, depending on the direction of the jet. Typically, valve ring dilatation regurgitation is better heard in the third right interspace rather than the third left. An Austin Flint murmur may be associated with aortic regurgitation. This is an apical diastolic murmur, similar to that of mitral stenosis, arising from the anterior cusp of the mitral valve, which vibrates in the jet of aortic regurgitation. Because aortic regurgitation may be both difficult to hear and is a frequent lesion in infective endocarditis, a patient with a fever and steadily widening pulse pressure is regarded as having aortic regurgitation and endocarditis until proved otherwise.
FIG. 12.45 Features of aortic regurgitation [A] Pressures in the aorta (blue) and left ventricle (black) are illustrated with the accompanying murmurs (3 = third sound). B Direction of regurgitant flow (arrow) and orientation of M-mode and Doppler beams (dotted lines), C Continuous-wave Doppler signal showing a regurgitant jet throughout diastole with a maximal velocity of 4m/s (upwards signal). The small downward signal excludes aortic stenosis. D M-mode echocardiogram showing flutter of the anterior mitral valve leaf (arrowed), which may close prematurely in severe aortic regurgitation, causing an early first heart sound.
Investigation ECG shows left ventricular hypertrophy of the diastolic overload type, in that, initially at least, voltage changes with prominent Q waves over the lateral leads predominate over T-wave changes. Later, the T waves invert. Chest X-ray shows increasing size of the left ventricle and often some dilatation of the proximal aorta. Generalized cardiac enlargement may follow and, eventually, changes of raised pulmonary venous pressure. Echocardiography. M mode shows the dilated left ventricle and its wall thickness. Calculation can be made of the stroke volume and ejection fraction, which are useful for following progress. In many cases vibration of the anterior cusp of the mitral valve or the septum can be seen, confirming the diagnosis. Doppler ultrasound will confirm the diagnosis but cannot quantify the lesion. Cardiac catheterization is necessary to examine left ventricular function, the severity of the aortic regurgitation and its anatomy, as well as looking for other pathology, such as mitral regurgitation and coronary artery disease.
529
SUMMARY 9 Clinical features of aortic regurgitation Symptoms Left heart failure: breathlessness Myocardial ischaemia, angina Atrial fibrillation (less frequently) Physical signs Large stroke volume with vasodilatation Collapsing pulse Wide pulse pressure Head nodding, capillary pulsation Enlarged left ventricle with dynamic displaced apex Auscultatory High-pitched early diastolic murmur Forward flow systolic murmur Premature first heart sound (in severe cases) Austin Flint murmur
Management Surgery Those in heart failure have been left too late to obtain the maximum benefit from surgery, as a dilated 'myopathic' heart never returns to normal and is associated with a high risk of sudden death. The currently used criteria for surgery are based on echocardiographic dimensions; others are now being developed based on the use of isotope left ventricular angiography. A fall in the ejection fraction of the left ventricle on exercise has been suggested as a criterion for surgery, as the ejection fraction is normally well maintained or even increases. Acute aortic regurgitation requires very close attention and urgent valve replacement at the first sign of heart failure. Delay can result in catastrophic heart failure and death, as the degree of regurgitation and size of the heart rapidly increase.
Medical Medical management of chronic regurgitation consists of treatment of heart failure and control of other problems, such as arrhythmias and endocarditis prophylaxis (p. 578). There is some evidence that using vasodilators such as nifedipine can delay the need for valve replacement when begun in moderate regurgitation. O
Investigation and management Assessment of combined lesions has been greatly helped by Doppler ultrasound and echocardiography. The gradient measured by Doppler ultrasound may appear much greater than the pull-back pressure gradient measured at cardiac catheterization. Surgery for combined lesions is based on the same criteria as for single lesions. Onset of symptoms means that there is severe left ventricular hypertrophy and probably fibrosis, with consequent poor left ventricular function. Surgery is therefore ideally timed to anticipate symptoms and allow the left ventricular hypertrophy to regress. A gradient of over 50mmHg, the development of a left ventricular strain pattern on ECG, left ventricular dilatation and any evidence of heart failure are all considered indications for aortic valve replacement.
COMBINED MITRAL AND AORTIC VALVE DISEASE Over 50% of patients with rheumatic mitral valve disease will eventually develop evidence of aortic valve disease, most commonly aortic regurgitation, but sometimes stenosis as well. The presence of disease in both valves makes assessment of the severity of the individual lesions more difficult. Mitral valve disease in particular tends to reduce cardiac output and stroke volume, which may make the physical signs of aortic valve disease, such as the carotid pulse, far less evident. Aortic regurgitation and mitral regurgitation both cause a volume load on the left ventricle, so the contribution of each lesion to this is difficult to assess. The auscultatory signs may also be far more difficult to elicit, particularly if the patient is in heart failure.
MIXED AORTIC VALVE DISEASE
Investigation and management
About one-third of patients with aortic valve disease have a combined lesion with significant regurgitation and stenosis. As previously described, regurgitation makes a great difference to the valve gradient (p. 521, Table 12.19), and a stenotic valve with a gradient of 16mmHg in systole would have a gradient of over 60mmHg if twice the flow
The presence of aortic valve disease should be suspected in every patient with rheumatic mitral valve disease, particularly if they have ECG evidence of left ventricular hypertrophy, or a slightly sustained carotid pulse. Fortunately, echocardiography and, in particular, Doppler ultrasound enable the valves to be individually examined for evidence of stenosis and regurgitation. This is far more accurate than inspection of the valves at surgery. If a patient is being considered for mitral valve replacement in the presence of aortic valve disease, it is unwise for the surgeon to leave anything but trivial aortic valve disease.
O MCQ 12.13 530
were accommodated, because of 50% regurgitation. The physical signs of the combined lesion are distinctive, with a large-volume sustained or bisferiens pulse, a markedly hypertrophied left ventricle which is both pressure and volume loaded, and both systolic ejection and early diastolic murmurs. The second sound is single. A combined lesion cannot be caused by syphilis or other pathologies that primarily dilate the aortic root.
12 FIG. 12.46 Features of tricuspid regurgitation fAl Illustration of regurgitant flow and direction of Doppler beam (dotted line). PA = pulmonary artery; SVC and IVC = superior and inferior vena cava. Q] and [C] Continuous-wave Doppler signals, both showing tricuspid regurgitation (downwards signal). In B there is severe (organic) regurgitation with normal pulmonary artery pressure and increased tricuspid forward flow. In C there is pulmonary hypertension with a high-velocity regurgitant jet through the tricuspid valve.
What may seem a trivial degree of aortic regurgitation or stenosis at presentation may become clinically important with replacement of the mitral valve.
TRICUSPID REGURGITATION Tricuspid regurgitation most commonly arises as a result of dilatation of the valve ring secondary to right heart failure with pulmonary hypertension. Less common causes are actual rheumatic involvement of the tricuspid valve leaflets producing 'organic tricuspid disease', and rightsided endocarditis, which is rare in anyone other than intravenous drug addicts. Floppy tricuspid valve may be associated with floppy mitral valve, and some congenital heart disease is associated with tricuspid regurgitation either as a primary phenomenon or secondary to right heart enlargement (e.g. atrial septal defect). Endomyocardial fibrosis, a disease occurring in the tropics, especially Africa, causes mitral and tricuspid regurgitation. Doppler ultrasound has shown that a right-sided cardiac enlargement in rheumatic heart disease is almost invariably associated with a regurgitant jet through the tricuspid valve, very often in the absence of any physical signs. Similarly, it may be the cause of an 'innocent systolic murmur'.
Clinical features Pathophysiology and symptoms The leakage of a small percentage of the right ventricular stroke volume is easily accommodated by the right atrium. As the volume of regurgitation increases, there is increasing enlargement of the right atrium and right ventricle, and the movement of the interventricular septum becomes dominated by the right ventricle and so 'paradoxical'. The large systolic pressure pulse in the right atrium leads to
stagnation and, eventually, reversal of blood flow in the great veins; the liver becomes distended and pulsatile (Fig. 12.46). The high hepatic venous pressure leads to cardiac cirrhosis, and this may occasionally lead to secondary portal hypertension and splenomegaly. The poor venous return, high venous pressures and poor hepatic function are associated, in most patients, with a degree of cardiac cachexia, poor wound healing and difficulties with haemostasis. Tricuspid regurgitation due to disease of the valve is much better tolerated, as the regurgitation is at a much lower pressure than when it is secondary to pulmonary hypertension. The principal symptoms are those of right heart failure, with low cardiac output, fatigue, oedema and pain from hepatic congestion which may arise on exercise - so-called 'hepatic angina', i.e. epigastric or right-sided subcostal pain arising on exercise and gradually (more gradually than 'true' angina) disappearing with cessation of exercise. Signs The patient may have AF and is often slightly jaundiced. In moderate to severe cases there is a highly pulsatile jugular vein with a large v wave and rapid y descent. The height of the v wave peak may be as much as 15cm above the sternal angle, and in these circumstances the jugular vein is palpably pulsatile and can be confused with an arterial pulse. The right ventricle is very active and gives rise to a right parasternal impulse. A pansystolic murmur is heard at the left sternal edge, or even at the cardiac apex, which may be formed by the right ventricle under these circumstances. The murmur is often lower in pitch than a mitral murmur. There can be a right ventricular third heart sound. Abdominal examination reveals a pulsatile liver, which is often visible but is best felt bimanually.
531
Investigation ECG may be unhelpful and is usually dominated by other factors associated with the underlying cardiac disease. Chest X-ray shows right-sided cardiac enlargement, and there may be a fullness in the region of the distended superior vena cava. O Echocardiography shows an enlarged right ventricle with paradoxical movement of the interventricular septum suggesting 'volume load' of the right ventricle. The tricuspid valve leaflets are more easily seen with an enlarged right heart. Doppler ultrasound will confirm a regurgitant jet through the tricuspid valve. The jet velocity will give an indication of the gradient across the valve, and hence the right ventricular pressure and the severity of the pulmonary hypertension (if any).
Management As tricuspid regurgitation is often secondary to pulmonary hypertension, the treatment is frequently that of the underlying cause. Bed rest and diuretics will be effective in many cases, with the murmur and pulsatile jugular veins disappearing. Intravenous diuretics may be required, as the oral drugs may be poorly absorbed. Organic tricuspid valve disease may require surgical treatment by replacement or annuloplasty at the same time as other cardiac surgery.
TRICUSPID STENOSIS Tricuspid stenosis is a very uncommon manifestation of rheumatic heart disease. It mimics mitral stenosis, but produces right heart failure rather than left. It almost always complicates rheumatic involvement of the mitral and aortic valves, and should be suspected if there is a high venous pressure with a slow y descent in the JVP. The diastolic murmur is reputedly enhanced on inspiration and is best heard at the left sternal edge. There can be a tricuspid opening snap, and often coincident tricuspid regurgitation.
Investigation and management The diagnosis can be confirmed by echocardiography, which will show the thickened cusps. Doppler ultrasound can be used to measure the jet velocity and thus calculate the diastolic gradient. Cardiac catheterization with a double-lumen catheter is needed to measure the rather small valve gradient. Treatment is by valve replacement.
O Fig. 12.19
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PULMONARY REGURGITATION Pulmonary regurgitation is usually caused by dilatation of the pulmonary valve ring in pulmonary hypertension. It may also follow pulmonary valvotomy or valvuloplasty. In severe cases the right ventricle is hyperactive from volume loading, and the murmur is difficult to distinguish from that of aortic regurgitation, being an early diastolic murmur at the left sternal edge starting immediately after the pulmonary component of the second sound. It may have a slightly lower pitch and be more obvious on inspiration, but the two can easily be confused. The Graham Steel murmur of pulmonary regurgitation in mitral valve disease is far more frequently due to aortic regurgitation than was formerly believed. Pulmonary regurgitation is usually well tolerated but can be one reason why the heart remains enlarged after surgical correction of Fallot's tetralogy.
PULMONARY STENOSIS Pulmonary stenosis is the second most common form of congenital heart disease in adults; it is commoner in women. Mild cases, with gradients of less than SOmmHg, are common. Stenosis may occur at valvular or subvalvular level, or even in the pulmonary arteries. There is a raised pressure in the right ventricle and, in severe cases, reduced lung blood flow and poor effort tolerance.
Clinical features Most cases are asymptomatic. With gradients of over SOmmHg, the most common symptom is dyspnoea on exertion. In very severe stenosis symptoms of exertional syncope and angina become prominent, similar to those associated with aortic stenosis. In children and young adults, pulmonary stenosis may present with severe right heart failure. The physical signs are of a small volume pulse, a large a wave in the JVP, a right ventricular substernal heave and a harsh systolic murmur in the pulmonary area. The latter appears very long and drowns the heart sounds in severe cases of infundibular stenosis, but can be a short ejection murmur in mild cases. The timing of pulmonary valve closure, which is delayed in severe cases, is a useful indication of severity.
Investigation and management ECG shows right ventricular hypertrophy. The chest X-ray shows oligaemic lung fields; a large poststenotic dilatation with dilatation of the pulmonary conus is common in valvular, but not infundibular, stenosis. The right ventricle is not significantly enlarged unless it has failed. Doppler ultrasound assesses the valve gradient. Echocardiography will show the hypertrophy of the right ventricle and the site of the obstruction.
Surgical valvotomy has been largely replaced as a treatment for pulmonary stenosis by balloon valvuloplasty (see below).
SURGICAL MANAGEMENT OF ACQUIRED HEART VALVE DISEASE The choices in surgical management of heart valve disease have recently become more complex, with closed valvotomy, open valvotomy and balloon valvuloplasty all being possible approaches.
Cardiac bypass In the technique of cardiac bypass the circulation is arrested and there is extracorporeal circulation from a roller pump and external oxygenator. The brain is perfused at relatively low pressure, and the oxygenator and perfusion system introduce microemboli into the arterial circulation. There is therefore a morbidity associated with prolonged cardiac bypass. Most of the morbidity seems to be reversible (e.g. intellectual impairment) but patients with cerebrovascular disease, such as carotid stenosis, are at particularly high risk from cerebral infarction.
Balloon valvuloplasty In balloon valvuloplasty a balloon catheter is inserted through the valve orifice and then dilated to split open the valve. The aortic valve can be dilated in children, and balloon valvuloplasty has been especially successful for pulmonary and mitral stenosis. If torrential regurgitation is produced during mitral valvuloplasty, valve replacement is essential.
Valve repair and replacement Plastic surgical repair to a damaged valve uses pericardial or other tissue to repair defects in the valve cusps, or suturing of the valve ring to a prosthetic former to correct a grossly dilated valve ring. The latter is commonly performed in severe tricuspid regurgitation. The procedures are time-consuming and technically demanding and have had a history of variable results. Prosthetic and biological valves The type of valve used for replacement depends very often on local preference and expertise. Mechanical valves require permanent oral anticoagulation with warfarin. Biological valves do not, but are prone to early failure and calcification. The original prosthetic Starr-Edwards valve essentially a ball in a cage - was built for durability, but early models formed thrombus on the struts and were also rather noisy. Numerous attempts have been made to improve on this, but many have developed mechanical problems and the Starr valve remains the most durable prosthesis currently available. In order to avoid the anticoagulation essential with
mechanical valves, various attempts have been made to use biological ones. Fresh human homografts have been used very successfully in the aorta, but availability has been a problem. The most widely used biological valves are xenografts. Porcine or bovine tissue is usually mounted on a ring or stent; such valves have the advantage of not requiring long-term anticoagulation, nor do they produce the loud prosthetic clicks of mechanical valves. Their disadvantages are that they have an unpredictable lifespan and can calcify and become stenosed very rapidly in young patients. However, most of them last at least 5 years. They may be considered in women of childbearing age who wish to have a family without the teratogenic risks of anticoagulation. Such patients must be prepared to face the subsequent reoperation for valve replacement when the biological valve fails. Under current UK legislation a heavy-goods or publicservice vehicle licence holder cannot drive if he or she is on anticoagulants, and so these patients may have to opt for biological valves if they wish to maintain their occupation.
12
FURTHER READING ON VALVULAR DISEASE Guidelines on the investigation and management of valvular heart disease July 1996 Prendergast B, Banning A P, Hall R J C on behalf of a working group of the British Cardiac Society and the Royal College of Physicians, London
CONGENITAL HEART DISEASE
Incidence and aetiology Congenital heart abnormalities are present in about 8-12 per 1000 live births (excluding bicuspid aortic valve and floppy mitral valve). The simpler abnormalities are commonest, with ventricular septal defect (VSD) accounting for 25-30% of cases and patent ductus arteriosus 10% (Table 12.21). Pulmonary stenosis, atrial septal defect (ASD), coarctation of the aorta, aortic stenosis and tetralogy of Fallot together account for another 35% of cases. Of the complex lesions, transposition of the arteries, AV septal defects and the hypoplastic left heart syndrome are the most frequently seen. The fetal circulation is shown in Figure 12.47. Only a minority of these patients (10-15%) would survive to adolescence and adulthood without the help of cardiac surgery and interventional cardiology. Over the last 15-20 years babies have survived who would previously have died, so that cardiologists and physicians are now more likely to see adult patients with medically or surgically corrected lesions than to diagnose a congenital defect for the first time in adult life. The relative frequency of different lesions at different ages depends on the compatibility of the lesion with longevity. ASD, for example, can present in the patient's
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TABLE 12.21 Relative frequency of types of congenital heart disease Congenital defect
Frequency (%)
Live births Atrial septal defect Pulmonary stenosis Tetralogy of Fallot Ventricular septal defect Eisenmenger syndrome Patent ductus arteriosus Coarctation of the aorta Other
30 25 10 9 7 7 5 7
Stillbirths Ventricular septal defect Univentricular heart (with tricuspid and mitral atresia) Atrial septal defect Coarctation of the aorta Complete transposition Atrioventricular septal defects Hypoplastic left heart Tetralogy of Fallot Other
35 13 10 9 9 9 6 3
TABLE 12.22 Causes of congenital heart disease Causes
Defect
Rubella
Patent ductus, atrial septal defect, pulmonary stenosis
Drugs Alcohol
Ebstein's anomaly Tricuspid atresia
Thalidomide
Multiple defects
Inherited disease Connective tissue disorders Marfan's Ehlers-Danlos Inborn metabolic errors Mucopolysaccharidoses Homocystinuria Pompe's disease Chromosomal abnormalities Down's syndrome Trisomy 13 and 18
6
Turner's syndrome Other inherited syndromes Di George's Friedreich's ataxia Holt-Oram Kartagener's Tuberous sclerosis
FIG. 12.47 Diagram of the fetal circulation SVC and IVC = superior and inferior vena cava.
OMCQ 12.14 534
Ventricular septal defect
Lithium
Aortic dilatation and incompetence; mitral incompetence Mitral regurgitation; arterial dilatation Valve disease, cardiomyopathy Aortic and pulmonary dilatation Glycogen deposition in myocardium Atrial and ventricular septal defect; Fallot's tetralogy; endocardial cushion defect Ventricular septal defect; right ventricular anomalies; pulmonary stenosis Coarctation of aorta, bicuspid aortic valve; pulmonary stenosis Fallot's tetralogy; aortic arch anomalies Cardiomyopathy Atrial septal defect Dextrocardia Cardiomyopathy
70s, but congenital aortic stenosis or Coarctation of the aorta presents much earlier, either to the physician or as a cause of sudden death. As the cohort of patients with surgically palliated or corrected hearts reaches maturity, so special issues arise involving counselling, the advisability of pregnancy, the likelihood of inheritance in the next generation, and the timing of heart or heart-lung transplantation in the disabled or deteriorating patient. The commonest forms of congenital heart disease seen after birth are shown in Table 12.21. Spontaneously aborted fetuses have a much higher incidence of severe congenital heart disease than do normal-term infants. Congenital heart defects may occur as part of more complex syndromes; there are often associated minor thoracic abnormalities. Most cases of congenital heart disease remain unexplained. Some causes are listed in Table 12.22. Most lesions develop in the first trimester of pregnancy, many at about the 7th week. Many involve 'mistakes' in the complex
IB FIG. 12.48 Diagrammatic representation of blood flow in the systemic and pulmonary circulation A Normal. B Left-to-right shunt. El Right-to-left shunt; the pulmonary blood flow is reduced as a result of development of high resistance. RH = right heart; LH = left heart.
embryological processes of flexing, twisting and formation of septa and the formation and closure of foramina (Fig. 12.48). The formation of a patent ductus arteriosus (more correctly a persistent ductus arteriosus) and coarctation of the aorta appear to be due to physiological mechanisms that go wrong after birth.
CHROMOSOMAL ABNORMALITIES Chromosomal abnormalities can be accompanied by congenital heart disease. Down's syndrome (mongolism or trisomy 21, see Ch. 3, p. 66) is associated with endocardial cushion or AV canal defects (ASD mitral and tricuspid regurgitation), but VSDs and pulmonary stenosis also have an increased incidence. Turner's syndrome (XO) - characterized by stunted growth, web neck, female sexual stunting and cubitus valgus - has a greatly increased incidence of coarctation of the aorta and pulmonary stenosis. Maternal viral illnesses Viral infection in early pregnancy, typically rubella, appears to be the cause of some congenital heart defects. Rubella produces a characteristic association of defects, including deafness, cataract, and often persistent ductus arteriosus, although other lesions may occur. Although rubella is the best-documented viral agent, mumps and influenza epidemics have been shown to increase the risk of congenital defects if the mother has the illness early in pregnancy. Other agents, e.g. cytomegalovirus, herpes simplex and coxsackie virus, have also been implicated. About 5% of cases of congenital heart disease can be explained by viral illness. Maternal illness and drug effects Maternal illness, especially SLE, may predispose to congenital AV block. Drugs taken by the mother can be teratogenic, and drugs now associated with congenital heart disease include alcohol, lithium, amphetamines, phenytoin, oestrogen/progesterone and trimethadione. Counselling, pregnancy and contraception A mother who has congenital heart disease herself, or who has one affected child, can usually be counselled that sub-
sequent pregnancy carries a low risk (1-5%) of congenital heart disease. Concordance rates for identical twins are between 15 and 20%, and for non-identical twins between 3 and 5%, suggesting environmental as well as genetic factor(s) in the development of congenital heart disease. In families with affected first-degree relatives the risk to the fetus increases to 50% when there are three affected relatives. When both spouses have congenital heart disease the risk may be up to 15%. In all these instances professional help from clinical geneticists is invaluable. Fetal echocardiography can be used to screen high-risk pregnancies. Mendelian dominant inheritance is seen in Marfan's syndrome and some families with hypertrophic cardiomyopathy; both conditions present in adulthood. Pregnancy in cyanotic congenital heart disease carries a high risk of complications and accelerated deterioration, and frequently ends in spontaneous abortion. At particular risk are women with haemoglobin above 17g/dL and those with pulmonary hypertension or the Eisenmenger reaction (p. 536). Patients with lesser degrees of cyanosis and polycythaemia may occasionally be brought through successful pregnancies by a combination of rest and prevention of thrombosis, infection or prolonged labour. Sterilization is usually recommended for high-risk (Eisenmenger) women. Even this relatively minor surgical procedure can be dangerous, but is less so than pregnancy. High-oestrogen-containing contraceptive pills increase an already high risk of thrombosis and embolization; it is not clear if the low-oestrogen pills are any safer in this group of women. The potential associated infective risk prevents the use of intrauterine devices. Vasectomy for the male partner and barrier methods are alternatives, but are too unreliable. O
ACQUIRED COMPLICATIONS OF CONGENITAL HEART DISEASE Apart from the simplest conditions of ASD, PDA and VSD, where early surgical correction is associated with few long-term consequences, many operated and unoperated patients develop complications. Pulmonary vascular disease, myocardial failure, arrhythmia, systemic embolization, endocarditis and degeneration of prosthetic valves
535
and conduits are some of the complex problems posed by the survivors of congenital heart defects. Their optimal management calls upon many skills within cardiology and other disciplines. In the future long-term management of this group of patients is likely to be concentrated in a few centralized units containing all the expertise required and a large enough cohort of patients to further define treatment strategies - the so-called GUCHD units (grown-up congenital heart disease).
CYANOTIC CONGENITAL HE ART DISEASE Central cyanosis occurs with an arterial oxygen saturation of <85%. Milder degrees of cyanosis may not be evident at rest but are readily precipitated by mild exertion at the bedside. A degree of shunting through the ductus arteriosus occurs for several hours, or even days, after birth, and this may persist. More commonly, right-to-left shunting occurs through persisting embryonic defects or through the foramen ovale (Fig. 12.48). The persistence of central cyanosis after birth, or its later onset, depends on a left-toright communication and on the resistance to outflow from the right heart being higher than that of the left. High resistance to outflow of the right heart is usually caused by congenital pulmonary stenosis (valvular or muscular) or by acquired pulmonary hypertension due to constriction of the pulmonary resistance vessels. Acquired pulmonary hypertension occurs with high flow through the lungs, so a left-to-right shunt can eventually reverse and become right-to-left, with cyanosis (the Eisenmenger reaction). Cyanotic heart disease produces a characteristic appearance, with central cyanosis (which may vary with activity), clubbing, impaired growth and intellectual development (if severe) and marked polycythaemia after the first year of life. Complications of the right-to-left shunt include cerebral abscess and paradoxical emboli, in which embolism from clot in peripheral veins gains access to the systemic circulation through the shunt. The severe polycythaemia can lead to thrombosis and infarction. Polycythaemia is proportional to the degree of desaturation. Regular venesection may be needed to maintain haemoglobin levels of 16-18 g/dL. Pulmonary hypertension can be complicated by recurrent haemoptysis.
FALLOT'S TETRALOGY Pallet's tetralogy is the commonest form of cyanotic con-
Case 12.3 536
genital heart disease seen after the age of 1 year. The four main features of this abnormality (see Fig. 12.49) are: • A ventricular septal defect (through which the shunting occurs); • Pulmonary stenosis, which may be muscular or valvular, and acts as the obstruction that leads to the right-to-left flow; • An overriding aorta. The aorta is positioned above the VSD; • Right ventricular hypertrophy, due to the pressure and volume load to which the RV is subjected. Incomplete forms of the condition exist in which not all the features are present and the child may be acyanotic - 'pink tetralogy'.
Clinical features The child may be deeply cyanosed at rest and is subject to cyanotic and exertional syncopal episodes which appear to be related to changes in the degree of shunting. The physical signs are cyanosis, clubbing, right ventricular hypertrophy, a harsh systolic murmur at the upper left sternal edge (often with a thrill) and a single second heart sound. Children with tetralogy characteristically learn to squat, which increases systemic vascular resistance and so diminishes R-L shunting.
Investigation The characteristic features of Pallet's tetralogy on investigation are illustrated in Figure 12.49. Chest X-ray shows a characteristic cardiac silhouette of severe right ventricular hypertrophy which lifts the cardiac apex (coeur en sabot) and oligaemic lung fields. ECG shows right ventricular hypertrophy. Echocardiography shows the overriding aorta and VSD and, with Doppler, can demonstrate the pulmonary stenosis, the right ventricular pressure and, sometimes, the flow through the VSD. Cardiac catheterization can be used to measure the pressures and show the severity of the outflow tract obstruction.
Surgical treatment Total surgical correction is now often attempted at an early age, but palliative operations to increase the lung blood flow were common in the past and are sometimes required now to encourage growth of the pulmonary vasculature, prior to complete intracardiac repair. The palliative shunts included the Blalock-Taussig anastomosis (subclavian to pulmonary artery) and aortic to pulmonary shunts, the Waterston and Potts shunts.
Prognosis and clinical features after surgery Without correction, less than 5% survive to adult life; 90% survive with surgery. In future, adult patients will have had
LESS COMMON FORMS OF GYANOTIC CONGENITAL HEART DISEASE
12
Some of the less common forms of cyanotic congenital heart disease are important causes of neonatal and infant death; however, they can be diagnosed accurately with modern imaging techniques and treated surgically. Even in neonates, cardiac transplantation and heart-lung transplantation may make some formerly inoperable conditions amenable to surgery.
Transposition of the great arteries
FIG. 12.49 Features of Pallet's tetralogy A Diagram of abnormality. VSD = ventricular septal defect; PA = pulmonary artery; B = aorta. B Physical signs. C Chest X-ray showing right ventricular hypertrophy, typical 'coeur en sabot'. D EGG showing right atrial and ventricular hypertrophy and right axis deviation.
a total repair at an earlier age, probably without prior palliative surgery. Late mortality, 10-15 years after repair, is low, at 2-7%, and mainly comprises arrhythmia, including complete heart block. The vast majority of patients have normal exercise capacity and those that do not often have residual ventricular septal defects or pulmonary hypertension. These patients virtually all have a crescendodecrescendo murmur. Many have a decrescendo murmur of pulmonary incompetence; signs of a residual VSD are somewhat less common. The chest X-ray can be normal, but often shows cardiomegaly, and right bundle branch block on the ECG is almost always seen. After palliative surgery the radial pulse may be absent or weak on the side of the shunt and arterial collaterals may develop. The shunt may produce a continuous murmur. O
Complete transposition In this uncommon abnormality the atria and ventricles are in normal relationship to each other but the great arteries arise from the wrong ventricles (transposed). The pulmonary and systemic circulations are therefore operating in parallel rather than in series, which is incompatible with life unless there is some communication between the two circuits. About half the neonates have an intact ventricular septum, and death ensues as the patent ductus arteriosus closes naturally. Survival is dramatically improved by a catheter method of producing an ASD (Rashkind procedure). The other half of the group have large VSDs allowing bidirectional shunting and mixing of the bloodstream; 20% have a single ventricle, usually the right, now classified as double-outlet right ventricle (DORV). Double-outlet left ventricle (DOLV) is very rare. The natural history of this group is very variable, with some individuals surviving to adulthood. Children who survive thanks to the Rashkind procedure have few physical signs but remain cyanosed. Corrective surgery The 'Mustard' procedure produces an intra-atrial repair using a pericardial baffle to redirect flow in the atria to the appropriate ventricle. Results have been excellent, with a return to normal saturations, although arrhythmias may be a problem in later life. Concern over the ability of the right ventricle to function in later life has led to the development of an arterial switch operation and the Rastelli procedure, where a valved conduit connects the right ventricle to the pulmonary artery. It is not yet clear whether these two demanding operations will improve on the results achieved with intra-atrial repairs. Mustard baffles may develop stenoses or leaks in later life, requiring careful evaluation by echocardiography and catheterization. Relief of baffle obstruction may be required and achieved percutaneously using balloon dilatation techniques.
Congenitally corrected transposition Here the great arteries are transposed but blood flows
537
correctly, as the left and right ventricles are inverted. Thus, blood flows from the right atrium through a bicuspid mitral valve into a morphological left ventricle and into the pulmonary artery. From the left atrium a tricuspid valve leads to the right ventricle and the aortic valve. Survival without surgery is common and the clinical features are dominated by associated abnormalities and problems (these include VSD, single ventricle - DORV or DOLV - and pulmonary stenosis or pulmonary vascular disease).
Abnormalities of venous return The systemic veins may drain into the left atrium, producing cyanosis with exercise. Both situations are rare on their own and are associated with other serious congenital defects. Total anomalous pulmonary venous drainage (TAPVD) into the right atrium or left innominate vein is associated with right-to-left shunting across an ASD or patent foramen ovale. The physical features are those of an ASD with central cyanosis. Operations to reroute the veins and close the ASD produce excellent long-term results, although adults are susceptible to atrial arrhythmia.
Tricuspid atresia Unoperated adults with this condition do exist, although survival through childhood is unusual without surgical intervention. Blood flows from the right atrium to the left, through the mitral valve into the left ventricle and via a VSD to a not uncommonly stenosed right ventricular outflow tract. The clinical signs are dominated by pulmonary stenosis and VSD murmurs. Cyanosis is variable and depends on the size of the VSD and degree of pulmonary stenosis. Surgical correction is by a BlalockTaussig shunt or connection of the right atrium to the right ventricle, more commonly by Fontan's procedure, where the right atrium is connected to the pulmonary artery.
Ebstein's anomaly of the tricuspid valve This condition is often acyanotic. The septal and posterior leaflets of the tricuspid valve are attached to the right ventricular wall so that a large part of the right ventricle becomes atrialized. The right ventricle is small, but the right atrium becomes enormous. There is often some tricuspid regurgitation, and occasionally the abnormal valve obstructs filling, or even emptying, of the right ventricle. There is a high incidence of patent foramen ovale or ASD, and supraventricular arrhythmias are very common. The condition often presents in adult life. It may remain asymptomatic for years and present with an abnormal chest X-
Fig. 12.20
538
ray or ECG. The patient may, on the other hand, present with right heart failure, dyspnoea on exertion and, sometimes, mild cyanosis and clubbing. Clinically, the heart is large and inactive. There is often a murmur of tricuspid regurgitation and a cV wave in the neck. ECG shows small voltages, right atrial hypertrophy and right bundle branch block. A Wolff-Parkinson-White configuration (p. 516) is common. Chest X-ray shows a globular or flask-shaped heart with a prominent convex right atrial border. Echocardiogram and cardiac catheterization findings are characteristic. Cardiomegaly alone is not an indication for surgical treatment, as arrhythmia and heart failure respond well to conventional medical therapy.
ACYANOTIC CONGENITAL HEART DISEASE Conditions where blood is shunted from left to right may initially be without cyanosis but, if undetected, high flows through the pulmonary vascular bed will eventually lead to a reversal of the blood flow and cyanosis - the Eisenmenger reaction. Thus some acyanotic lesions may later produce cyanosis.
ATRIAL SEPTAL DEFECT ASDs can be of three types - secundum, primum or sinus venosus defect (Fig. 12.50). In adult cardiology they occur in the above order of decreasing frequency. The foramen ovale only acts as an ASD if right-sided pressures exceed left, e.g. in pulmonary embolism. ASD constitutes 10% of congenital heart disease.
Pathogenesis Blood flows from the left to the right atrium, and thence to the right ventricle and lungs. Because the lungs have a low impedance to flow, shunting is considerable. The patient has a limited exercise capacity, as maximal systemic cardiac output cannot be achieved on exercise. The right ventricle hypertrophies and the lung blood flow is increased, which seems to increase the likelihood of pulmonary infections. Symptoms are usually not prominent until middle age and include dyspnoea, fatigue (low exercise cardiac output) and, quite frequently, palpitations caused by atrial arrhythmias. Heart failure, when it occurs, is usually both right and left sided, as any rise in atrial pressure on one side of the septum will shunt the blood to the other side. After middle age the pulmonary vascular resistance may rise, with the development of massive pulmonary arteries (visible on chest X-ray) and, occasionally, reversal of the shunt.
Secundum a trial septal defect Clinical features Secundum ASD (Fig. 12.50A) is usually uncomplicated. The physical signs are the result of right ventricular hypertrophy and increased flow through the right side of the heart; this causes pulmonary and tricuspid flow murmurs and delayed closure of the pulmonary valve. The associated signs are wide, fixed splitting of the second sound and pulmonary systolic murmur; a tricuspid diastolic murmur is usually heard if shunting is significant (Fig. 12.51). Investigation and management Chest X-ray (Fig. 12.51) shows enlargement of the heart, prominent pulmonary arteries, pulmonary plethora and,
usually, a small aortic knuckle. ECG shows right bundle branch block in most cases, with right axis deviation. Echocardiography shows dilated RV with a 'volume load' of the RV. O The shunt can be demonstrated by contrast injection or with colour Doppler. Transoesophageal echocardiography can best delineate the types of ASD, and also the pulmonary venous drainage in relation to the ASD. An occasional finding associated with ostium secundum ASD is mitral stenosis (Lutembacher's syndrome). Cardiac catheterization can demonstrate the size of the shunt. Blood samples taken in the different cardiac chambers show a step-up in oxygen content of the blood occurring at the lower right atrium. The shunt size can be calculated from the oxygen content of the pulmonary artery blood and left-sided samples. Angiography to delin-
ED
FIG. 12.50 Sites of atrial septal defect A Ostium secundum. B Ostium primum (or atrioventricular canal defect). The septal leaflet of the mitral valve is often involved, allowing a communication between the left ventricle (LV) and both atria. C Sinus venosus defect, where the abnormality involves anomalous pulmonary venous drainage. SVC and IVC = superior and inferior vena cava. PV = pulmonary vein.
FIG. 12.51 Features of atrial septal defect A Chest X-ray showing enlarged pulmonary arteries, pulmonary plethora and relatively small aortic knuckle. B ECG showing a vertical axis (normal) and partial right bundle branch block, [c] Phonocardiogram demonstrating wide splitting of second heart sound. D M-mode echocardiogram at the ventricular level shows a volume-overload RV with paradoxical movement of the interventricular septum (IVS) which is out of phase with the posterior wall (PW) of the left ventricle.
539
eate ASD is no longer necessary because transoesophageal echocardiography and MRI are superior imaging techniques for this. Surgical closure is usually advised if the defect is associated with a shunt that gives a pulmonary flow greater than 1.5 times systemic flow even in adults, unless pulmonary vascular resistance and pressure have become so high as to cause a right-to-left shunt (Eisenmenger syndrome) and the patient turns cyanotic. In recent years a number of devices have been developed that allow the closure of ASD by percutaneous catheter-based occluders. For suitably placed and sized ASD these techniques may soon become the closure method of choice.
Primum atrial septal defect This is a much less common form, accounting for 10% of ASDs, but is relatively common in Down's syndrome. Clinical features, investigation and treatment The clinical features are similar to those of secundum ASD, but may be dominated by an associated mitral regurgitation, and the ECG usually shows a left axis deviation. A left ventricular angiogram shows the defect. Surgical correction is more complex than for a secundum defect, and may involve mitral valve repair or replacement.
Sinus venosus defect This is usually a high right atrial defect near the junction with the SVC. It is often associated with anomalous pulmonary venous drainage into the right atrium. O
VENTRICULAR SEPTAL DEFECT VSDs may occur as isolated lesions or be associated with other congenital defects of the heart. They are relatively common (Table 12.21) and have an equal sex incidence. About 50% close spontaneously during childhood. They may occur as muscular, membranous, infundibular or posterior (AV) defects and may be multiple. There is considerable shunting of blood from left to right unless a rise in pulmonary outflow resistance occurs owing to vascular disease caused by the high pulmonary flow. In extreme cases the flow reverses, causing cyanosis and the Eisenmenger syndrome. Small ventricular septal defects Small VSDs are common and are asymptomatic. There is
540
O MCQ 12.15
Fig. 12.21
Q MCQ 12.17
Case 12.4
MCQ 12.16
a loud systolic murmur with a thrill at the left sternal edge (maladie de Roger}, with no associated cardiomegaly and minimal, if any, changes of pulmonary plethora on chest X-ray. The ECG is usually normal. Differential diagnosis is from mitral regurgitation and is simply accomplished with Doppler ultrasound. The only complication of a small VSD is the risk of endocarditis, and antibiotic prophylaxis is essential. Although the surgical mortality and morbidity for closure of small defects are low, surgery is not usually necessary. Moderate and large ventricular septal defects With larger VSDs, systemic cardiac output is limited on exercise and can produce symptoms of fatigue and dyspnoea. As they are both volume loaded, both ventricles enlarge with displacement of the cardiac apex. The pansystolic murmur and thrill typical of maladie de Roger may be softer in these patients, as the jet velocity of the VSD and the pressure gradient between the ventricles becomes smaller the larger the defect. As pulmonary hypertension becomes prominent, the murmur may almost disappear as the pressures in the two ventricles balance. Investigation and management The features of VSDs on investigation are illustrated in Figure 12.52. ECG shows biventricular hypertrophy, and there is increasing right ventricular hypertrophy with pulmonary hypertension. Chest X-ray shows pulmonary plethora and cardiomegaly with both right and left ventricular hypertrophy. As pulmonary hypertension develops, the central pulmonary arteries increase in size and the peripheral vessels become pruned. 0 Echocardiography and Doppler ultrasound can show the location of the VSD, and can be used to calculate right ventricular pressure. Magnetic resonance scanning can demonstrate the defect and measure the shunt. Surgical closure is advised unless pulmonary artery pressure has risen too high. ©
COARCTATION OF THE AORTA Coarctation of the aorta is a narrowing, or even complete interruption, of the aorta distal to the aortic arch, with blood flow to the lower body augmented by flow carried through collateral vessels. Coarctation represents about 5% of adult congenital heart disease, and is seen in males three times as frequently as in females. The condition leads to upper body hypertension and an increased risk of aortic dissection. There is often a bicuspid aortic valve, which can become stenotic (or is congenitally stenosed). Other congenital defects are sometimes associated. There is also an associated risk of subarachnoid haemorrhage from berry aneurysm of the circle of Willis. These are presumed to be an associated congenital anomaly. The coarctation is nearly always at the aortic isthmus distal to the left subclavian artery, but can, rarely, occur
upper half being the left subclavian artery and the lower half the poststenotic dilatation of the aorta. Rib-notching is seen in most adults with coarctation, and is caused by the collateral arteries. Visualization of the coarctation is sometimes possible using 2D echocardiography, and the jet can often be located with Doppler ultrasound. The investigation of choice nowadays is MRI, which can also be used in serial scans to detect any sign of recurrence after surgery. Angiography of the aorta is not always needed, but cardiac catheterization is often performed to look for associated lesions and to confirm the length of the narrow segment.
12
Management and prognosis
FIG. 12.52 Features of ventricular septal defect A The characteristic systolic murmur associated with a widely split second heart sound with a premature aortic second sound (A2) and maintained mobility of P2 with respiration (dashed line on inspiration). B Doppler ultrasound showing highvelocity jet (6m/s). C and D 2D echocardiogram showing the septal defect (VSD).
Significant coarctation should always be corrected in children, either surgically or by balloon catheter. In adults, surgical correction is the definitive treatment, although it carries higher morbidity and mortality owing to the established hypertension, which often still requires treatment even after successful correction. The associated aortic valve lesions may progress and subarachnoid haemorrhage may occur. Endocarditis prophylaxis is necessary in uncorrected coarctation. OO
PERSISTENT DUCTUS ARTERIOSUS proximal to it. It may be due to ductal tissue in the wall of the aorta, leading to progressive stenosis of the aorta, as in ductal closure. The degree of stenosis becomes comparatively more severe as the child grows. The coarctation is followed by a poststenotic dilatation in most cases; however, if there is complete interruption of the aorta there may be some atresia of the descending aorta.
Clinical features Presenting complaints include left ventricular failure, subarachnoid haemorrhage and aortic dissection; however, most cases should be identified in childhood. The coarctation itself may become the site of an endocarditis, as may the bicuspid valve. The physical signs are hypertension, a large-volume pulse in the arms and carotids, and weak, delayed femoral pulses. Occasionally, the left subclavian is involved in the coarctation, producing weak left arm pulses. There is often palpable left ventricular hypertrophy, a systolic murmur over the precordium and in the back, and palpable collateral arteries running over the medial aspects of the scapulae.
Investigation Diagnosis is confirmed by Doppler ultrasound, demonstrating a lower systolic blood pressure in the ankles than in the brachial artery. The chest X-ray often shows the characteristic '3' sign over the aortic knuckle, with the
Persistent ductus arteriosus (PDA) is a congenital abnormality caused by failure of the ductus arteriosus to close and form the ligamentum arteriosum. The result is a shunt of blood from the aorta into the pulmonary circulation. The shunt is from the aorta just distal to the left subclavian artery, and so an increased flow occurs through the left heart and pulmonary circulation but not the right heart. The ductus arteriosus remains patent for a variable time after birth, and failure to close can be associated with congenital abnormalities other than PDA. The isolated lesion is usually diagnosed in childhood from the presence of a continuous or 'machinery murmur' at the upper left sternal edge.
Clinical features Overload of the left heart can lead to heart failure in older patients. The increased lung blood flow in infants can present with the consequences of increased pulmonary vascular resistance: extremely rarely, reversal of the flow through the ductus, with cyanotic blood passing to the distal aorta, occurs, producing clubbing of the toes but not the fingers. Rarely, the ductus may be the site of endocarditis.
Investigation and management Diagnosis is based on the physical findings of the characteristic murmur, a collapsing pulse and a chest X-ray which
541
usually shows a prominent pulmonary conus and increased lung blood flow. Echocardiography and Doppler ultrasound are extremely useful in demonstrating both the lesion and the volume load on the left ventricle. Cardiac catheterization with aortography is not usually necessary in uncomplicated cases, but it may be useful in differentiating the much less common aortopulmonary window, which requires much more complex surgery. Simple cases require ligation and transection of the PDA.
identification of anatomical lesions in the coronary arteries provides information about the feasibility of interventional procedures (bypass surgery or angioplasty), but it is the significance of the physiological effects of stenoses (e.g. angina, dyspnoea, arrhythmias, ECG changes or other investigational manifestations) which provides the indication whether the lesion(s) should be operated upon.
THE CORONARY CIRCULATION Flow in normal and abnormal coronary arteries
COR TRIATRIATUM In cor triatriatum the left atrium is divided by a diaphragm above the mitral valve, which gives rise to obstruction to pulmonary venous return to the left heart. There is a variable-size orifice (or none at all) which is easily opened surgically. The condition is thus eminently treatable.
DEXTROCARDIA Dextrocardia - in which there is a mirror image of the normal heart - is usually quite benign if associated with situs inversus (stomach bubble also on the right); however, it may be associated with other congenital abnormalities and can be confused with dextroversion, in which the heart is rotated rather than being a mirror image.
FURTHER READING ON ACYANOTIC CONGENITAL HEART DISEASE
Flow through the coronary arteries is regulated, with mean flow maintained through wide changes in mean arterial pressure (see Fig. 12.54). However, coronary vascular resistance is greatly affected by extrinsic compression during cardiac muscle contraction. Compression of the intramyocardial vessels during systole means that flow occurs in diastole (Fig. 12.53). This is particularly marked for the left coronary artery. Myocardial vessels are innervated and respond to neural, humoral and local metabolites. The heart has little capacity for anaerobic metabolism and cannot tolerate an oxygen debt. It is therefore dependent on increased perfusion to cope with an increased oxygen demand. Myocardial oxygen extraction is not increased with increasing demand, which must be met by increased coronary flow due to coronary vasodilatation. The coronary vascular resistance will fall to 20-25% of its basal state in response to maximal demand during exercise. This ability to lower the resistance to flow explains why it is possible to maintain normal flow at rest even when there is an 80% reduction in the diameter of a large coronary artery. The relationship between changes in perfusion pres-
Perloff J K 1995 Surgical closure of atrial septal defect in adults. N Engl J Med 333: 513-514
CORONARY HEART DISEASE (CHD) Coronary heart disease (CHD) refers to the consequences of coronary artery disease. Atheromatous disease outweighs all other causes, but coronary arteritis and embolism can cause ischaemia. CHD can still occur in the absence of demonstrable coronary angiographic stenosis, owing either to dynamic coronary artery spasm resulting in Prinzmetal angina, or to microvascular abnormalities too small to be detected by contrast angiography. Conceptually it is important to distinguish the anatomy of coronary artery disease from the physiology of the effects of the coronary stenoses on the myocardium. The QMCQ12.18
542
FIG. 12.53 Coronary arterial flow [A! Aortic pressure. IITI Flow in the left and right coronary arteries. Note the abrupt fall in left coronary flow with the onset of systole.
12 FIG. 12.55 Anatomy of the coronary circulation LAD = left anterior descending, LCx = left circumflex (dotted line represents position of LCx at the back of the heart), RCA = right coronary artery. Section across heart (A-A) shows the approximate distribution of blood supply.
FIG. 12.54 Effect of mean coronary arterial pressure on flow Coronary blood flow (blue line) is maintained constant despite variations in perfusion pressure. At perfusion levels below 60 mmHg coronary blood flow falls because the limit of coronary vasodilation is reached. A maximally vasodilated coronary artery has a linear pressure-flow relationship, as shown (light blue line). Stenoses of varying severity will alter the pressure-flow relationship of the dilated artery as shown by the grey and black straight lines. At rest an individual might have an artery flow at point A (a perfusion pressure approximately 100 mmHg); with exercise the demand rises (dashed line) and flow increases to point B, within the capacity of a normal vessel to dilate. If the individual's coronary artery had a moderate stenosis, only point C could have been reached, which is less than the flow required, so ischaemia (angina) is produced. A critical stenosis may interfere with the delivery of the necessary resting flow (D) so ischaemia at rest ensues.
sure and resistances of coronary arteries and flow is shown in Figure 12.54.
Coronary anatomy The anatomy of the coronary circulation is shown in Figure 12.55. Three major coronary arteries provide the heart with its blood supply. Major anatomical variations are rare. The main stems of the left coronary artery (LCA) and right coronary artery (RCA) arise from the aorta at the sinuses of Valsalva. The main stem of the LCA is a relatively short vessel. It divides into the left anterior descending artery (LAD) - which is responsible for the blood supply to the major part of the left ventricle and the interventricular septum - and the circumflex artery (Cx, usually the smaller branch of the left main stem), which supplies the posterior and variable amounts of the inferior walls of the left ventricle. The RCA supplies the right ventricle and inferior left ventricle. In some individuals variable amounts of the left ventricular apex, septum and posterior wall may be supplied by the RCA. This artery usually (60% of cases) provides the SA and AV nodes with their blood supply. The myocardium has a very rich capillary network, which appears to be regulated by precapillary resistance
vessels. In addition, there is the potential for a network of collateral vessels connecting coronary arterial networks to each other. When developed, these collaterals become important in coronary artery disease. O
ATHEROMA OF THE CORONARY ARTERIES The commonest cause of changes in the luminal diameter of the epicardial coronary arteries is the presence of atheromatous plaques (Fig. 12.56). The lesions may encircle an artery or be eccentric; they may be discrete and localized, or involve the greater length of the vessel. The eccentricity of some plaques may be important when vasospasm is the cause of angina; the normal arterial wall opposite the plaque maintains its ability to contract, producing a very marked reduction in cross-sectional area even if the smooth muscle contraction is modest in degree and the atheromatous plaque small. Acute changes in the plaques may account for unstable angina, myocardial infarction and sudden death. A fissure develops, breaching the thin endothelium that covers a lipid-rich plaque. The subsequent process is shown in Figure 12.56. These events appear to account for many of the more acute forms of coronary disease, and have renewed interest in the role of thrombosis in acute cardiac ischaemia. This has led to the successful use of fibrinolytic agents and aspirin in the treatment of infarction (p. 559). Under some circumstances atheromatous plaques may regress. This has been achieved by drugs that lower LDL cholesterol and triglyceride and increase HDL cholesterol.
Clinical features Symptoms The cardinal symptom is angina pectoris. This is a chest discomfort precipitated by exertion and relieved by rest. It is often described as a pressing or constricting feeling and, less often, as a pain. It remains remarkably constant within each individual, even though its precipitants may vary significantly from day to day. The patient may hold a clenched fist in front of the sternum to indicate the squeezing nature
543
A. Normal
B. Atheromatous plaque
C. Plaque dissection and acute expansion
FIG. 12.56 Progression of atheromatous lesion A and B Normal endothelium and structure of atheromatous plaque. C Acute expansion of the lesion occurs when the endothelial cells rupture, allowing haemorrhage into the plaque and platelet aggregation on the endothelial surface.
Crescendo angina and unstable angina Both crescendo and unstable angina may represent states of preinfarction. In crescendo angina a history of increasingly frequent attacks of angina with ever-diminishing levels of exertion is obtained. Unstable angina includes situations where episodes of pain are frequent, may occur without obvious cause and at rest, and where acute infarction has been excluded. Decubitus angina is angina occurring at rest in bed.
Signs There are few physical findings in uncomplicated CHD. An underlying cause, such as aortic stenosis, may give characteristic signs. There may be evidence of hypertension or hyperlipidaemia. Cardiac dilatation, hypertrophy and failure are all late features and are non-specific. Some individuals undoubtedly have significant ischaemic episodes without symptoms. This may be discovered by routine ECG, when pathological Q waves may be found with no history of any antecedent chest pains. Investigations of patients with ambulatory recorders have also shown some individuals to have changes in the ST segments usually associated with ischaemia, despite a total lack of symptoms. Even patients with known angina may have episodes of ST segment change which appear to be clinically silent. Patients with known coronary disease who have silent ischaemia fare worse than those without this finding.
Differential diagnosis of angina
Acute coronary syndromes The above is a description of typical stable atheromatous Fig. 12.22
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coronary artery disease. Several other anginal syndromes occur which are common and account for many hospital admissions and much morbidity.
of the pain, and may describe radiating discomfort in the arm (left more often than right), the jaw or even a choking sensation in the throat. Dyspnoea frequently accompanies angina. There is usually rapid relief of the symptom with sublingual, or spray, glyceryl trinitrate. The pain of myocardial infarction may be similar, but generally begins at rest, does not respond so well to nitrates, lasts longer than 20 minutes, and is often associated with feelings of impending death, nausea, sweating and collapse. Unfortunately, in many patients with CHD the first manifestation of the disease may be sudden death. Prevention of atheroma is necessary to reduce this, although out-of-hospital resuscitation may improve the survival of the few fortunate enough to collapse within reach of a person competent in basic life support.
Vasospastic angina Some degree of arterial spasm is probably present in most episodes of angina, but spasm occurring in an otherwise normal coronary artery has also been observed. It can be severe enough to cause infarction, but is very rare. In Prinzmetal's syndrome rest pain is frequent and is associated with acute ST segment elevation, which resolves to normal with cessation of pain. This condition is rare and almost certainly involves coronary vasospasm.
Valve disease. Angina is a common symptom in aortic stenosis (p. 527) and aortic regurgitation (p. 529), particularly when the valve lesions are severe or acute. In cases of aortic regurgitation due to syphilis, chest pains may be caused by severe aortic reflux, but coronary ostial stenosis may also occur. In hypertrophic cardiomyopathy, hypertrophy may lead to angina. Aortic dissection and pulmonary embolism. These are discussed on pages 599 and 675. Pericarditis. Chest pain may be severe with acute pericarditis and is exacerbated by movement, deep respiration or coughing. It is often relieved by sitting forward and by non-steroidal anti-inflammatory drugs (NSAIDs). The clinical sign of pericardial friction rub may come and go. Oesophageal spasm. The pain of oesophageal spasm may be severe and, because it occurs at rest and can be associated with T-wave changes on the ECG, it may cause con-
siderable confusion and be diagnosed as unstable angina in some patients. Hiatus hernia with oesophagitis can cause chest pain. This can be demonstrated by infusions of mild acidic mixtures into the oesophagus of affected individuals. Radiological and endoscopic methods will demonstrate the abnormalities. CHD may coexist in the same individual. Acute cholecystitis and peptic ulceration can produce severe pains in the lower chest and xiphisternal areas, and may infrequently be mistaken for acute myocardial infarction. Non-specific T-wave changes on the ECG have been observed during these acute illnesses. Da Costa's syndrome (also known by several other names, e.g. neurocirculatory asthenia) has a long history and is characterized by sharp transient chest pains, which occur with relaxation, may disappear with exertion, and are associated with easy fatigue. Mitral valve prolapse. Atypical (for CHD) chest pains may occur in patients with mitral valve prolapse of mild degree. Hyperventilation. Patients who hyperventilate may produce symptoms indistinguishable from those of angina, and may have an abnormal resting and exercise ECG to accompany their symptoms. So-called syndrome X is characterized by typical angina in association with radiologically normal coronary arteries but a positive exercise test. It may be due to microvascular disease. Tietze's syndrome may cause diagnostic confusion until the painful costal cartilage is palpated.
Investigation The aim of investigations is to confirm that the clinical history is due to significant coronary artery disease, to determine at how much risk of infarction or progression the patient may be, and whether any remediable risk factors may be present. Once coronary artery disease has been confirmed using non-invasive tests, an assessment of ventricular function may be necessary and, finally, coronary angiography performed if surgery or angioplasty are being considered. (Investigation of myocardial infarction is considered on pp. 556-558.)
ECG The resting ECG may be normal, even when coronary disease is severe. Signs of ischaemia characteristically involve the ST segments, with depression in the leads corresponding to the myocardial territory involved (Fig. 12.57). The associated T waves may be flattened or biphasic. These ECG signs are not specific, however: they may be found in some normal individuals and may be produced by hyperventilation or a change in posture. Exercise test The exercise test has been described on page 480. Exercise will induce ischaemia with coronary stenoses of 70% or more (Fig. 12.57). If a population of asymptomatic indi-
12 FIG. 12.57 Exercise ECG showing typical and severe down-sloping ST segment depression
viduals is subjected to an exercise test there will be an incidence of false positive tests up to 20%. The predictive capacity of the exercise test depends on the prevalence of the disease in the population (Bayes' theorem). Therefore, exercise tests should be avoided in patients with a low pretest probability of having coronary heart disease, as there are likely to be more false than true positive results. The exercise ECG has several uses: • To detect CHD in patients with suspicious symptoms, especially those with an intermediate probability of disease; • To identify patients at high risk of further infarction or death early after myocardial infarction; • To assess functional capacity and adequacy of treatment. Although changes in the ST segment are the most characteristic features of a positive exercise test (Fig. 12.57), O the development of angina and the workload performed up to the development of symptoms or ECG change also aid interpretation. A normal blood pressure response consists of a rise in systolic pressure by at least 20mmHg. Diastolic pressure falls with exercise, but is so difficult to measure under these circumstances that it is not routinely taken. The gravest prognostic indicator in exercise testing is a failure of systolic pressure to rise, or even a fall. The appearance of multiple ventricular ectopic beats is also associated with severe disease. Radionuclide studies Radionuclide techniques (p. 485) are complementary to the other non-invasive methods used in assessing CHD. Information on ventricular wall motion abnormalities (MUGA scan) and regional perfusion (201T1 scan) can be obtained. Echocardiography and Doppler ultrasound Echocardiography (p. 483) may be useful to assess ventricular function and wall motion abnormalities, as well as excluding non-coronary causes of ischaemia, such as aortic stenosis or hypertrophic cardiomyopathy. Ambulatory ECG (Holter) monitoring Ambulatory ECG monitoring (p. 500) is generally used to detect arrhythmias, but may also detect episodes of ST segment change during normal activities. Some of these episodes may not be accompanied by symptoms of angina
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(silent ischaemia). In the patient with known coronary disease, frequent episodes of silent ischaemia are associated with a high risk of infarction. In the patient with few or no symptoms the implications of this finding are not at all clear. The role of routine 24-hour ECG recording for ST segment analysis in CHD is not established, as it remains to be proven that the information gained is any more useful than that from the exercise test. Left ventricular and coronary angiography The aim of these investigations is to establish the functional state of the left ventricle, to exclude valve lesions that might account for the symptoms (such as occult aortic stenosis), and to obtain detailed pictures of the coronary arteries. O A global left ventricular ejection fraction (EF) of 50-70% is normal, and end-diastolic pressure is usually below 12mmHg. Subjective assessment is often sufficient to describe left ventricular wall motion abnormalities without recourse to the numerical estimation of EF. The coronary arteries are selectively intubated and cineangiograms taken in several projections. A 50% reduction in the diameter of an artery is generally considered to be a clinically significant stenosis. Cardiac catheterization provides unambiguous information on the location of coronary artery stenoses. However, the clinical significance of stenoses is sometimes difficult to judge; the exercise test and thallium scan may provide complementary information. Cardiac catheterization is indicated in all patients in whom coronary angioplasty or coronary bypass surgery is being contemplated. In some patients with troublesome symptoms and a low likelihood of CHD this examination is performed to finally exclude the possibility of coronary artery disease. This group may comprise between 10 and 20% of all patients undergoing cardiac catheterization. The invasive nature of catheterization is necessarily associated with a morbidity (<1.0%) and mortality (<0.1%). This means that angiography cannot assume the role of a screening test for coronary disease.
MANAGEMENT OF CHRONIC STABLE ANGINA Once the diagnosis is established, treatment should be aimed at restoring a normal exercise capacity. Investigations should establish the individual's risk, and contributory risk factors be reduced as far as possible. A flow diagram of the management of angina is shown in Figure 12.58.
General measures All patients should be advised to stop smoking, achieve O Fig. 12.10
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FIG. 12.58 Flow diagram of management of angina PTCA = percutaneous transarterial coronary angioplasty.
their ideal weight and have raised blood pressure controlled. Lipid measurements should be made. Those with total cholesterol >5.2mmol/L, HDL/LDL <20%, triglyceride >2.0mmol/L should be given an appropriate diet (Ch. 5, p. 136) until repeat estimations are within the recommended ranges. First-degree relatives of young patients with CHD should have their lipid levels measured. The patients with angina of effort, a normal resting ECG and chest X-ray, and whose symptoms are well controlled on simple treatment can probably be managed adequately without further investigation. The prognosis in CHD is dependent on the severity of the stenoses, the number of coronary arteries involved and on left ventricular function. This information can only be obtained accurately at cardiac catheterization, which should be offered to patients below 40 years of age, whose risk is highest. The risk of death is approximately 4% per year in other patients, but increases to between 7 and 9% if there are associated abnormalities in the resting ECG. Thus, although a resting ECG may be sufficient investigation for many patients, further determination of the risk to the individual is obtained by non-invasive tests, especially the exercise test and myocardial perfusion scanning with Tl201 (p. 486).
12
TABLE 12.23 Drugs commonly used in the treatment of angina Drug
Route
Dose
Frequency
Nitrates Glyceryl trinitrate (GTN) Tablets Spray Buccal Patches
Sublinguai Oral Buccal Skin
0.3-0.6 mg 0.4mg/spray 1-1 Omg 5-10 mg
PRN and prophylaxis PRN and prophylaxis PRN and prophylaxis Daily (omit for 8-12 hours)
Isosorbide dinitrate (ISDN)
Oral (some sustained release)
10-80mg
4-8-hourly
Isosorbide mononitrate
Oral (some SR)
10-1 20 mg
6-24-hourly
Parenteral preparations GTN ISDN
i.v. i.v.
0.6-1 2 mg/h 1-12mg/h
Infusion Infusion
fi-Blockers. Many alternatives, including: Atenolol (fa selective) Bisoprolol Propranolol (non-selective)
Oral Oral Oral
50-200 mg 5-1 Omg 30-360 mg/day
Daily Daily 6-hourly
Calcium antagonists Nifedipine Long-acting Diltiazem Modified release Verapamil Slow release
Oral Oral Oral Oral Oral Oral
10-20mg 30-90 mg 60-120 mg 90-240mg 40-120 mg 90-240 mg
8-hourly (12-24-hourly for sustained release) Daily 8-hourly (12-24-hourly for sustained release) 12 hourly-daily 8-hourly (12-24-hourly for sustained release form) Daily
New agents Nicorandil (ATP-sensitive K+ channel opener) Trimetazidine
Oral Oral
10-20mg Not available in UK
12-hourly
Catheterization may then be required for those with a positive test at low workloads, those with large reversible Tl201 perfusion scan defects, and those in whom medical treatment is not being successful.
Drug treatment The drugs commonly used in the treatment of angina are listed in Table 12.23.
Aspirin Although not a symptomatic treatment, all patients should be given 75-150 mg of aspirin per day as an antithrombotic agent. Nitrates Therapy begins with sublingual tablets or aerosol spray nitrates. These are used to treat an anginal episode and can be successfully used in prophylaxis by patients with predictable symptoms. The aerosol spray has the advantage of a long storage life compared to glyceryl trinitrate (GTN) tablets, which deteriorate rapidly in their container once
opened. The onset of action is very rapid (within 1-2 min) and its duration can be up to 20 minutes. With all nitrates troublesome headache can prevent their use in certain susceptible individuals, although this side-effect usually stops after a few days of treatment. Longer-acting nitrate preparations include glyceryl trinitrate given via the skin, using sustained-release plasters or patches. Isosorbide dinitrate is absorbed from the gut and metabolized by the liver to the active mononitrate. The duration of action is longer than short-acting nitrates, but 4-8-hourly doses are needed to maintain blood levels. Mononitrates are absorbed in the gut and do not require hepatic conversion; thus, some variability in effectiveness due to liver metabolism is avoided. Their duration of action is longer, so one or two daily doses are adequate. An idiosyncratic reaction to GTN (and also other nitrates) is syncopal attacks. Clinically, this has to be distinguished from syncope secondary to angina, which is suggestive of an arrhythmia, whereas nitrate-induced syncope is associated with bradycardia and hypotension (a vasovagal type of reaction).
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RECENT ADVANCES IN ISCHAEMIC PRECONDITIONING There is good experimental evidence that heart muscle is able to adapt to conditions of ischaemia, so that short bursts of ischaemia (in the order of 2-5 minutes, singly or repeated over a short period) will render the myocardium resistant to a much longer period of lack of blood supply. In laboratory conditions 30-60 minutes of coronary occlusion will produce infarction of 40-60% of the muscle supplied by that coronary artery. Merely occluding the artery temporarily, for 2-3 minutes once or twice before the long occlusion, can reduce infarct size to just 10-20% of the muscle at risk. This phenomenon is called preconditioning, and is associated not only with reduced infarct size, but also with a dramatic reduction in reperfusion arrhythmia. These observations are being extended to human heart muscle suffering global ischaemia, as in cardiac surgery, or regional ischaemia, as in angina and PTCA. The mechanisms underlying preconditioning are being sought, but there is good evidence to suggest adenosine receptors and opening of ATP-sensitive potassium channels may be involved. This opens up the prospects of using drugs to mimic ischaemia-induced preconditioning.
Tolerance Tolerance to nitrates develops as sulphydryl (SH) groups on the vessel walls become oxidized by constant exposure; this prevents the production of nitric oxide and stimulation of guanilate cyclase, which is believed to be fundamental to the smooth muscle relaxation produced by these drugs. A nitrate-free period of 6 hours in every 24 is sufficient to allow recovery of SH groups when longer-acting preparations are used. The tendency for patients to develop a tolerance to longacting nitrates (tachyphylaxis) limits their usefulness. No controlled trials have demonstrated an improvement in mortality with stable angina or after myocardial infarction. Their primary use therefore remains as an effective symptomatic treatment of coronary heart disease.
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-Blocking drugs |3-Adrenoreceptor blockade has become established as a cornerstone in the treatment of angina. Although many -blocking drugs with varying pharmacological properties are available, there is no overwhelming evidence to suggest that one is any better than the others. Some patients find they are unpleasant owing to a 'sedative' action and an interference with exercise capacity. They are specifically contraindicated in patients with asthma, and relatively contraindicated in diabetes and in those with peripheral vascular disease, bradycardia or heart block. A number of patients may have been mislabelled as asthmatics in the past. A safe way of testing whether -blockade may be used in these patients is by infusing esmolol (50-
200 g/kg/min), because it has the shortest half-life and any detrimental effects may be reversed relatively rapidly. A cardioselective -blocker (selective for blockade of 1 receptors > p2) may then be used as maintenance treatment, e.g. bisoprolol (2.5-5mg o.d.). In angina, these drugs achieve their benefit by reducing myocardial oxygen demand consequent on a fall in heart rate, blood pressure and myocardial contractility. There is good evidence that -blockers improve prognosis after myocardial infarction. However, no prospective trial has extended this observation to the treatment of stable angina. Calcium antagonists Calcium antagonists are effective in angina, achieving their effect by smooth muscle relaxation in the coronary arteries and peripheral circulation, increasing myocardial supply and reducing myocardial work. The three types of calcium antagonist available for clinical use are the dihydropyridines (e.g. nifedipine, nicardipine, amlodipine, felodipine), diltiazem and verapamil. They vary in their pharmacological properties, and so their indications may be different. The mode of action varies with the type of drug, all of which inhibit cellular calcium entry but differ in their tissue specificity. The dihydropyridines act primarily by arteriolar vasodilatation with minimal effects on the SA node and the myocardium. They may cause a reflex tachycardia. The action of diltiazem is more marked on the SA and AV nodes, producing a mild bradycardia, but less negative inotropy than verapamil. It is advisable to avoid using a dihydropyridine as monotherapy in angina. These drugs are best used in combination with a |3-blocker. If a |3-blocker is contraindicated, or when monotherapy with a calcium antagonist is desirable, then the use of verapamil (40-120mg t.d.s., SR 240mg o.d. or b.d.) or diltiazem (SR 90-120 mg b.d.) is recommended. The negative inotropic and chronotropic effects of verapamil are useful in antianginal treatment in those without heart failure or heart block. In heart failure the least negatively inotropic calcium antagonists are to be used, such as nicardipine, felodipine or lacidipine. Calcium antagonists are a useful symptomatic treatment for angina, with added beneficial blood-pressure-lowering action. As with nitrates, there are no prospective trial data that suggest any effect of these drugs on prognosis. There are some data to suggest that patients with good LV function may do better on diltiazem or verapamil after transmural and non-Q-wave myocardial infarction.
Nicorandil Nicorandil is now accepted as another class of antianginal agent. It is the first potassium channel opener (KCO) that has been shown to be effective in the treatment of angina. It can be used in preference to some of the above drugs in coronary artery spasm, angina in asthmatics and diabetics, and in patients with heart failure or peripheral vascular disease. It is an arterial and venous vasodilator which combines the arteriolar vasodilation of ATP-sensitive
potassium channel opening with a nitrate-like venodilatory capacity. A major prospective trial on the drug in stable angina will report in 2001/2002. Other compounds Amiodarone was introduced as an antianginal preparation but its use is now limited to the treatment of serious arrhythmia. Perhexilene alters the metabolism of cardiac muscle from FFA to glucose, and can be effective in refractory angina. In certain identifiable genotypes, however, it can have serious side-effects, including hepatotoxicity and peripheral neuropathy. Trimetazidine is marketed in some parts of Europe. It has a poorly characterized mode of action. ACE inhibitors Although there has been a demonstrable mortality benefit when these drugs are used in patients following MI, particularly when LV function is impaired, there are no convincing data on their use in stable angina. Drug combinations in angina There is a progression in therapy before medical treatment can really be said to have failed. Most patients begin treatment with nitrates or KCO and a (3-blocker. A calcium antagonist is used if -blockers are contraindicated. Elderly patients may well be adequately controlled with nitrates and a reduction in activity, and many find that -blockers induce unpleasant lethargy. Younger patients may not wish to reduce their activity, and find the prophylactic action of -blockers or calcium antagonists a considerable advantage. Verapamil and diltiazem produce profound bradycardia or heart block when used with a (3blocker, so these combinations should be used cautiously. Patients with severe disease commonly require 'multiple therapy' to control their symptoms, but the benefits of these three- or four-drug combinations are dubious. Practical prescribing in angina Provided there is no contraindication to the use of the drugs in individual patients, the schema of drug therapy shown in Figure 12.59 may be adopted: • It is generally wise to start antianginal medication by selecting the shortest-acting drugs and small doses several times a day, and build up the doses gradually if clinically indicated and in the absence of adverse reactions. In this way any unexpected adverse reaction will not be as prolonged or as severe as if larger doses and longer-acting versions had been used. Drug compliance is generally not problematic (as it can be in the treatment of hypertension). • The exception to the above rule occurs when treating coronary arterial spasm and arrhythmia secondary to myocardial ischaemia. In these conditions it is imperative to institute full therapeutic cover for the entire 24 hours using known effective doses, which can subsequently be reduced if side-effects supervene. • In vasospastic or Prinzmetal's angina the aim of treat-
ment is to prevent the powerful vasoconstriction: combination therapy using long-acting isosorbide mononitrate, dihydropyridine calcium antagonists and nicorandil may be required. p-Blockers may have to be added to counteract the reflex tachycardia and to reduce the intensity of angina by reducing oxygen demand during an attack. • In patients with other conditions concomitant with angina, drugs that precipitate angina (e.g. theophylline, digoxin, thyroxine) may have to be reduced or stopped, and an alternative therapy sought. In angina patients with heart failure and low blood pressure, or with hypertension, it may be necessary to replace their prescribed vasodilators (e.g. ACE inhibitors, a-blockers, hydralazine) with those possessing antianginal properties.
12
Coronary artery bypass graft surgery (CABG) Effective surgical treatment has had a profound effect on the management of CHD in the developed world. Coronary artery bypass grafting can now be performed with an overall operative mortality of under 1 %. Symptoms can be eradicated in 80-90% of patients and improved considerably in a further 5-10%; a few are no better or, indeed, are worse following surgery. It might therefore be asked why this form of therapy, which aims to 'revascularize' the heart, is not offered to all patients with angina. Several factors are responsible, including: • Finite morbidity from surgery • Deterioration of grafts • Survival advantage for surgical treatment has been proven for only moderate- and high-risk subgroups of patients • Benefit in symptoms has to outweigh the cost in wellbeing for up to 12 weeks postoperatively. Deterioration of grafts Saphenous vein bypass grafts have an appreciable rate of deterioration: more than 90% are patent immediately after surgery, but then occlude at a rate of approximately 2% of grafts per year between 5 and 10 years, and at 4% per year thereafter. About 60% of grafts are patent after 10 years. This implies that surgery is not a permanent cure, merely another method of symptom control in these patients. Improvements in early vein-patency rates have been achieved by the use of antithrombotic agents, such as aspirin. Even more significant has been the use of the internal mammary arteries (IMA) as grafts. This is more demanding technically, but has been shown to provide greater than 90% patency rates at 10 years. Unfortunately, complete cardiac revascularization is not often possible even when both IMA are used. Survival advantage Survival is improved by surgery in those with left main stem disease and those with three-vessel coronary disease and impaired left ventricular function (Table 12.24). It is
549
FIG. 12.59 Schema for medical antianginal therapy
very likely to improve survival in patients with severe angina, three-vessel coronary disease and normal ventricular function. The situation is less clear for patients with less marked symptoms and those with little in the way of symptoms but with a positive exercise test, although evidence is mounting that this group of patients also benefit from surgery. Surgery appears to be a more effective treatment for patients with continued symptoms not controlled by drugs. There is a diminution in fatal heart attacks, but probably not in non-fatal events. Randomized studies have failed to show any differences between medical and surgical treat-
O MCQ12.19
550
0 Fig. 12.23
Case 12.5
TABLE 12.24 Indications for coronary artery surgery in angina Indication
Comment
Left main stem stenosis Symptoms uncontrolled despite maximal medical treatment Impaired LV function especially with three-vessel coronary artery disease Proximal stenosis in left anterior descending coronary artery with positive exercise test at low workload
Proven survival benefit of surgery Improved survival with surgery in some subgroups of patients Improved survival with surgery Likely improved survival with surgery
ment in the numbers of patients who return to work, or in the amount of recreational activity they take up. However, the sociological measures may not reflect the changes in perceived quality of life in the two groups of patients.
TABLE 12.25 Indications for coronary angioplasty Indication
Comment
All indications for surgery (except left main stem stenosis) where coronary lesions suitable* Symptomatic single-vessel coronary disease
Single- and double-vessel PTCA. Low risk, high efficacy
Coronary disease where surgery impossible ('salvage PTCA') In AMI, especially if thrombolysis contraindicated
PTCA is as good and safe as surgery but patients face a higher incidence of recurrence A suitable approach in the very elderly or infirm Survival advantage over thrombolysis
* Suitable coronary lesions: proximal, discrete, not involving major branches, recent onset, non-calcified, circumferential lesions.
Thus, in general, patients are considered for coronary artery surgery if medical therapy fails to control their symptoms adequately, or if they fall into the above higherrisk groups. These broad guidelines conceal a large number of patients in a rather grey area, in whom individual assessments must be made. These might include young patients with severe stenoses causing highly positive exercise tests, in whom the consequences of occlusion might be a disabling infarction and in whom an internal mammary graft might be expected to be a highly successful treatment. Patients with extensive left ventricular aneurysm may often improve, in terms of heart failure control and anginal symptoms, with plication or resection of the aneurysmal area.
Changes in surgical technique A number of new, less invasive methods of coronary revascularization are currently in use. They share the aim of avoiding the requirement for cardiopulmonary bypass and its attendant complexity and morbidity. Their application is more limited than that of conventional CABG and the long-term advantages over CABG, or indeed angioplasty, have not yet been assessed by trial. O
Percutaneous transarterial coronary angioplasty (PTCA) (Table 12.25) © The indications for percutaneous transarterial coronary angioplasty (PTCA), first introduced in 1977, are similar to those that select for surgery. In most centres one or two stenoses are tackled by angioplasty, and patients with severe three-vessel coronary disease are generally considered for CABG. Patients with left main stem disease are also not considered for PTCA, unless surgery is impossible for technical reasons or because of coincidental disease. Intracoronary stents are now routinely deployed following balloon angioplasty. Debate continues regarding their optimal use, but the great improvement in immediate angiographic appearances, the virtual eradication of the
need for urgent CABG in emergencies, and the rapid reduction in the cost of stents has fuelled their adoption in advance of randomized trials.
IB
Restenosis Initial experience with PTCA revealed a >30% angiographic restenosis rate, with a need for further intervention in up to 25% of patients. The routine use of stents has halved these incidences, and in selected cases symptomatic restenosis rates may be less than 10% at 1 year. Patients with small arteries (<2.5mm diameter) and those with very large arteries (>4.0mm diameter) are best managed without stents, but they form less than 10% of the PTCA population. The determinants' recurrence are unknown, but most patients are given antithrombotic treatment with aspirin and newer antithrombotic agents, clopidogrel or ticlopidine. Some patients receive calcium antagonists and/or nitrates as treatment for vasospasm. Immediate complications such as vessel occlusion, myocardial infarction or the requirement for urgent surgery have diminished dramatically with the development and increased use of coronary stents. Overall, complications for elective PTCA now should approximate 1 %. O
Newer techniques Interventional cardiology is a rapidly evolving field. In
RECENT ADVANCES - INHIBITORS OF PLATELET AGGREG/VTORY RECEPTORS Despite the availability of aspirin, heparin, warfarin and fibrinolytic agents (streptokinase, tPA, urokinase), the treatment of certain conditions such as unstable angina and the result of angioplasty of acute ischaemic syndromes are still unsatisfactory because of unpredictable tendencies to thrombus formation and acute occlusion. Indeed, it has been suggested that intracoronary infusion of fibrinolytic agents can, paradoxically, hasten thrombus formation. There is therefore a need to find more effective agents that will prevent intravascular thrombus formation without causing significant bleeding complications. Platelet IIB/IIIA receptors are necessary to form a meshwork of interlinked platelets, which is an essential process to induce new thrombus formation. Inhibitors of this receptor prevent this and have shown promising results in the treatment of unstable angina and in reducing the incidence of acute occlusions peri- and postangioplasty. Three types of such inhibitors are being tested: monoclonal antibody against the receptor, peptide inhibitors, and chemical non-antibody and nonpeptide inhibitors. The relative efficacies of these agents in the treatment of diverse manifestations of the acute ischaemic syndrome have yet to be elucidated.
551
farction. Symptomatic treatment alone is associated with a mortality of about 12-15%, with a further 12% of patients suffering full transmural myocardial infarction within 12 months. An enormous amount of effort has gone into establishing the most appropriate protocols to manage these patients, particularly as many of the options are technically sophisticated or demand the use of very expensive new drugs.
FIG. 12.60 Technique of coronary angioplasty A The guide catheter is introduced into the coronary ostium. B A steerable guide wire is advanced across the lesion. C The balloon catheter is advanced from the guiding catheter over the guide wire and positioned so that the balloon straddles the narrowing. D Balloon inflation splits and compresses the atheromatous plaque. E After deflation, the balloon is removed and the arterial wall shows irregularity at the site of the narrowing. F A balloon-mounted stent is deployed G The stent remains in situ to be re-endothelialized within weeks.
order to extend the principles of PTCA to more demanding lesions, various devices have been developed. These include laser-assisted PTCA (mostly for occlusions on calcified lesions), atherectomy devices, devices to remove thrombos, and catheters capable of delivering drugs or radiation therapy directly to the lesion. Their precise roles continue to be defined.
ACUTE CORONARY SYNDROMES(ACS)
552
These syndromes, which include the clinical diagnoses of unstable angina, non-Q-wave myocardial infarction and rest angina, share much of the pathophysiology of acute myocardial infarction. Rupture of the fibrous cap over an atheromatous plaque, intracoronary thrombus formation and myocardial ischaemia are common to all. Numerically, the acute coronary syndromes now account for more hospital admissions than acute myocardial in-
Management The diagnosis relies on the clinical history of crescendo angina (p. 544) or rest pain, which is not associated with ST segment elevation on the ECG or with significant cardiac enzyme elevation (CK or CKMB). The patient should be admitted into a coronary care unit where bed rest is imposed. Light sedation can be helpful. Medical therapy includes oxygen, aspirin (150-200mg orally) and heparin with i.v. nitrate. Close monitoring of blood pressure is required during nitrate infusion, and the systolic pressure should not be reduced by more than 20%. p-Blockers and calcium antagonists may be added when symptoms persist despite increased doses of i.v. nitrate. Use of thrombolytics in unstable angina does not improve the prognosis and may even worsen outcome. Opiates should be used if pain is persistent. Heparin and aspirin are well established in the treatment of ACS. Low molecular weight heparin has the advantage of ease of use (subcutaneous injection rather than i.v. infusion), more predictable effects on clotting parameters and probably better outcomes in ACS than with conventional i.v. unfractionated heparin. It is, however, more expensive, although increased drug cost may be mitigated by savings in overall patient care (no i.v. pump, fewer laboratory tests, etc.). Recently, more powerful antiplatelet agents, including the oral agents ticlodipine and clopidogrel and the parenteral platelet glycoprotein Ilb/IIIa receptor inhibitors, have been used in ACS. The former can be used when there is aspirin intolerance or allergy. Several trials of IIb/IIIa receptor antagonists have shown that these parenterally given drugs can reduce the combined complications of death and myocardial infarction. They are very expensive and will initially be used in the highest-risk subgroup of patients, as well as those undergoing urgent angioplasty. The timing of cardiac catheterization and angioplasty in ACS is hotly debated. In the USA and some countries in Europe early investigation and PTCA is the norm. In countries such as the UK, with less well-developed cardiac intervention facilities, fewer patients are investigated, and in those that are, the tests are performed later, sometimes electively in the post-discharge recovery period. Long-term outcomes appear comparable whichever strategy is used.
Risk stratification in ACS (Table 12.26) Straightforward clinical features can be used to identify patients at high risk of death or myocardial infarction from
12
CASE STUDY 12.3 INCREASING CHEST PAIN A previously well man of 68 years came to the emergency department with a history of increasingly severe chest pains. The pains were central and radiated to the angle of the jaw. Although he had initially noticed milder pains precipitated by activity and emotion, for the previous 2 nights he had been woken from sleep with increasingly severe episodes of the same discomfort. The last bout of pain had been about 8 hours previously and had lasted altogether for 40-45 minutes. It was not associated with sweating, nausea or other sensations. The pain had woken him from sleep. Initially he thought it was indigestion, but its persistence, and lack of response to antacids, led him to seek advice. He had no significant past medical history but was having treatment with a statin for a hyperlipidaemia detected by a routine screen by his GP. He was an ex-smoker, having given up 6 months prior to presentation, and he had a strong positive family history of ischaemic heart disease with three first-degree relatives suffering myocardial infarction before the age of 60. In the emergency department his initial ECG was normal, but half an hour later he began to suffer chest pains and a further ECG revealed flattening of the T wave in lead AVL and 1.5mm horizontal ST segment depression in leads V4, V5 and V6. He was given sublingual glyceryl trinitrate (GTN), the pain resolved and ECG returned to normal after 10 minutes.
Question How might the diagnosis of an acute coronary syndrome be confirmed and how should the patient be subsequently managed?
Discussion Acute coronary syndromes rely upon a classical history related to myocardial ischaemia in the absence of transmural infarction. Infarction should be excluded by the absence of evidence from the ECG (ST elevation and subsequent development of Q waves and T-wave changes). In addition, to diagnose acute myocardial infarction a 2-3 fold elevation in creatine kinase enzyme and its isoform CK-MB should be demonstrated. The characteristics of the chest pain in infarction also suggest the diagnosis in that the pains tend to be more prolonged than in an acute coronary syndrome, not responsive to GTN and often associated with other symptoms such as nausea, sweating and breathlessness. Acute coronary syndrome is often therefore a diagnosis of exclusion. In this case the association of ST segment depression with pain is a highly important prognostic factor. Additional important prognostic features include the presence of an elevated myocardial specific enzyme in the blood, either troponin T or troponin I. Elevations of these enzymes during acute coronary syndrome presentation is associated with a much higher incidence of
ACS. Continuation of chest pain despite adequate treatment, the presence of ST depression with chest pain, or the development of T-wave changes identify a high-risk group. An early indicator is the detection of elevations in the cardiac-specific troponins T or I. These patients will generally benefit from cardiac catheterization with a view to revascularization, usually
complications. Indeed patients with angina-type pains in whom the troponins are negative 6-8 hours after the symptom have a very low risk of subsequent events and can usually be discharged safely from hospital for further outpatient evaluation. This patient is in a high-risk subgroup which requires stabilization. Mainstays of treatment include intravenous nitrate therapy plus heparinization using low molecular weight heparin. Beta-blockers are used and help to control the pain. The smooth-muscle potassium channel activator nicorandil causes arterial dilatation and may also improve the immediate situation. There is discussion as to whether all patients with acute coronary syndromes in the higher risk groups should automatically be offered invasive investigation with cardiac catheterization and angiography. This is the most common approach in Europe, the USA and Australia. Cardiac catheterization and angiography are essential if patients have further episodes of pain with or without ECG change despite pharmacological therapy. A case can be made for delaying angiography in those patients whose symptoms disappear on the initial treatment. If patients require cardiac catheterization, additional treatment with drug inhibitors of platelet aggregation (by binding to the Ilb/IIIa cell surface receptor), such as clopidogrel or ticlopidine, further improves their prognosis and decreases the risks of acute . angiography and angioplasty treatment.
by PTCA. Angioplasty and stent treatment is further improved, in terms of both immediate and long-term outcome, if these patients are given bolus plus infusions of Ilb/IIIa receptor inhibitors immediately before or during the coronary intervention. Those patients - often the majority - without ECG changes on troponin elevation (Fig. 12.61) may safely be
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RECENT ADVANCES IN LASER
TRANSMYOCARDIAL REVASCULARIZATION
FIG. 12.61 Cardiac specific troponin I levels to predict risk of mortality in patients with acute coronary syndromes
TABLE 12.26 Risk stratification in ACS, The presence of just one feature may be sufficient to classify a patient who is clinically at high risk of death or Ml from ACS. Feature
Low risk
High risk
ST depression 3=1 mm with pain 8 hr troponin T or troponin I
Absent
Present
Negative
Failure to control episodes of chest pain T-wave changes Haemodynamic disturbance with pain Conventional risk attributes in acute Ml/ischaemia, e.g. old age, poor LV Previous Ml
Absent
Positive - the higher the enzyme, the higher the risk Present
Absent Absent
Present Present
Absent
Present
discharged early for conventional outpatient investigation by exercise testing or Tl201 scanning, and management similar to that for those with stable angina. The diagnostic work-up should include identification of other conditions that may exacerbate angina, such as anaemia, hypertension, thyrotoxicosis, severe anxiety and cocaine abuse.
FURTHER READING ON CORONARY HEART DISEASE 554
Braunwald E 1998 Unstable angina: an etiologic approach to management. Circulation 98: 2219-2222.
One of the prerequisites of coronary artery bypass surgery or angioplasty is that the coronary arterial stenoses should occur proximally in epicardial coronary arteries. If the stenoses occur distally, especially if the distal intramyocardial vessels are affected, neither of these two procedures will produce much benefit. Certain medical conditions, such as diabetes mellitus, predispose to such distal disease. Hitherto, the only option has been cardiac transplantation, for either severe cardiac failure or intractable angina. Recently, laser transmyocardial revascularization has been developed as a potential alternative. During open chest surgery, thin rays of powerful laser beams are directed from the epicardial surface towards the left ventricular chamber in a myocardial region that has been shown to be viable, and either ischaemic or hibernating. Through a process which has not yet been elucidated, the epicardial portion of these artificial channels spontaneously seals up, leaving intramyocardial channels communicating with the ventricular chamber, and effectively forming new coronary vessels. Preliminary studies suggest that perfusion and oxygenation of these myocardial regions can be restored towards normal, and that symptoms and functional status can be significantly improved in selected patients. The effects on ventricular function need investigation. Clinical studies are currently in progress, and the applicability of this technique in practice will depend on the results.
Shepherd J, Cobbe S M, Ford I et al. 1995 Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 333:1301-1307. The Bypass Angioplasty Revascularisation Investigation (BARI) Investigators. 1996 Comparison of coronary bypass surgery with angioplasty in patients with multi-vessel disease. N Engl J Med 335: 217-225. Yusuf S, Zucker D, Peduzzi P et al. 1994 Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 344: 563-510.
MYOCARDIAL INFARCTION In the UK about 200000 people suffer a myocardial infarction each year. Half die from the infarction, and, of these, half do so before they reach hospital (Fig. 12.62). Most of this group suffer an arrhythmia, and death occurs instantaneously or within 1 hour of the first symptom. Clearly, these deaths will only be avoided by measures that prevent the development of coronary disease, although
TABLE 12.27 Mortality from acute myocardial infarction Class
Definition
1
Uncomplicated, without clinical signs of LV failure Generally asymptomatic, but manifesting a ventricular third sound, basal crackles or raised venous pressure Clinical evidence of pulmonary oedema Cardiogenic shock indicated by a systolic BP below 90 mmHg and at least one of: oliguria (<20mL/h), low skin temperature, or mental confusion
II
III IV FIG. 12.62 Mortality following onset of acute myocardial infarction A high proportion of patients die of ventricular fibrillation within 1 hour of onset.
prehospital and community resuscitation schemes can make an impact. Hospital admissions for infarction total 70-80000 per year in the UK, with an overall in-hospital mortality around 10%, plus a 10% mortality in the first year. The acute mortality varies with the type of infarct, from 3-6% for the patient with an uncomplicated infarction injuring only a limited amount of myocardium, to 50-80% with massive myocardial necrosis and shock (Table 12.27). The amount of muscle damaged determines both early and late outcomes from infarction. The advent of coronary care units (CCU) has led to a reduction in acute mortality, which has fallen from over 20% in 1966-67 to under 10% in the 1980s.
Admissions (%)
Mortality
33
6
38
17
10
38
19
81
12
(%)
Data from: Killip and Kimball 1969 American Journal of Cardiology 20: 457-467.
buccal nitrates. Associated symptoms are sweating, nausea, vomiting, breathlessness and collapse. Like angina, the pain may radiate to the arms, throat and jaw. Many patients believe they are suffering from indigestion and consume antacids. With the advent of thrombolytic therapy, it has become even more important to be aware of possible differential diagnoses in the patient with acute chest pain (p. 544).
Examination DIAGNOSIS OF MYOCARDIAL INFARCTION The clinical syndrome is less precise than the pathological definition, but a working diagnosis includes two of the following: • A typical history • The evolution of characteristic ECG change ending with Q-wave formation • A significant elevation and subsequent fall in creatine phosphokinase, preferably the MB isoenzyme fraction, aspartate transaminase, hydroxybutyrate dehydrogenase, or cardiac troponin-T.
CLINICAL FEATURES History A squeezing or tight, chest or epigastric pain, with its onset at rest, is reported by 80% of patients, a large proportion (40%) of whom may have an antecedent history of angina. The pain lasts longer than angina - typically more than 20 minutes - and is resistant to treatment with sublingual or
There are no specific features that accompany myocardial infarction. During the acute phase patients vary a great deal in their appearance, and the physical signs are largely those associated with pain and fear and are initially dominated by autonomic nervous activity. With acute anterior infarction there is a tendency for sympathetic activity to predominate, with a tachycardia, cool pale periphery and a normal, or even slightly raised, blood pressure in the early minutes. This contrasts with acute inferior infarction, which is commonly associated with massive vagal discharge, producing a cold sweaty periphery, bradycardia, hypotension, nausea and vomiting. The blood pressure tends to fall to lower than normal for the patient within a few hours of infarction, but some may have a hypertensive reaction. The venous pressure is generally normal in the early stages unless there has been extensive right ventricular involvement, which may occur with an inferior or posterior infarction. In left ventricular infarction, heart failure may develop and the pulmonary venous pressure will rise, signifying severe myocardial damage. Auscultation commonly reveals a fourth heart sound and a third sound over the apex in those patients in incipient left ventricular failure. The left ventricular impulse may be anterior and dyskinetic when a large
555
segment of left ventricular wall is moving paradoxically; this is particularly marked later in those individuals who develop an aneurysm. Orthopnoea and basal crackles are present in patients developing pulmonary oedema. A pyrexia develops within 12 hours in patients who suffer significant myocardial injury; it may persist for up to a week and is associated with a polymorphonuclear leukocytosis. Pericardial friction rubs are occasionally encountered soon after infarction, and signify a large loss of myocardium extending to the epicardium. This finding is distinct from the pericarditis and pneumonitis of Dressler's syndrome, which is a rare complication occurring during the first 6 weeks after a myocardial infarction and which has an immunological basis (p. 566). Other physical signs in myocardial infarction are due to the mechanical complications of the condition and are discussed individually below.
INVESTIGATION ECG changes in acute infarction The ECG changes of acute infarction may take some hours to develop, and occasionally are completely absent. Treatment of acute infarction must often begin before there is any objective evidence confirming the diagnosis (a rise in plasma enzyme levels also takes some hours to occur). 57 segment elevation The most characteristic feature of infarction on the ECG is the development of ST segment elevation, with a convex upward pattern in the leads facing the area of ventricle infarcted. The diastolic isoelectric line is depressed, so accentuating the ST elevation that follows it (Fig. 12.63). Reciprocal ST depression is often seen in leads opposite the infarction; this is usually indicative of severe multiplevessel coronary disease, but may on occasion represent a purely electrical phenomenon. ST elevation (the current of injury] is produced by ischaemia, and can occur in the absence of infarcted tissue. Thus, such ST changes can be associated with anginal pain due to coronary vasopasm (Prinzmetal's angina), and resolve rapidly and completely when spasm is relieved and ischaemia reversed. ST elevation during acute infarction lasts for some days but may persist longer. If it is still present some weeks after infarction, left ventricular aneurysm or extensive dyskinesia is likely.
556
T-wave inversion The terminal portion of the T wave begins to invert within hours of infarction and produces symmetrical inversion after a few days (Fig. 12.63). This appearance persists for weeks or months, and is occasionally a permanent feature of the ECG. In some patients at the very earliest stage of infarction the only ECG change may be in the T waves, which become very prominent, peaked and symmetrical.
FIG. 12.63 Evolution of ECG change in an acute inferior infarction Initially there is marked ST segment elevation in II, III, aVF, and reciprocal depression in V2-V4. At 12 hours a Q wave is developing in II, III and aVF, and the ST segment has returned to the baseline. At 48 hours the Q wave has deepened and broadened and there is T-wave inversion.
This appearance is sometimes called the hyper acute pattern of infarction. Symmetrical T inversion alone, without Qwave formation, may indicate a limited infarction in some patients (see non-Q-wave infarction, below) and this has important implications for their management. Q-wave formation Q waves are often the latest change to be seen on ECG. They are often permanent and are sometimes considered the definitive ECG change of infarction. They must have a depth of at least 25% of the succeeding R-wave height (or greater than 3mV) and last longer than 40ms (one small square at 25mm/s). They may appear within 24 hours of infarction and are associated with loss in R-wave height of the corresponding leads. Alternative patterns Ideally, ECG proof of infarction should include successive traces showing the presence and resolution of ST segment elevation. T-wave inversion and pathological Q-wave formation (Fig. 12.63). Often such a classic progression is missing, and the diagnosis may rest on a slightly deeper than normal Q wave in V4, loss of R-wave height or the absence of the small q waves of initial septal depolarization in I, aVL, V5 and V6; this may occur in septal infarc-
12
tion, but is also produced by incomplete left bundle branch block. In the presence of bundle branch block the ECG changes due to infarction may be difficult to detect or absent. With right bundle branch block septal depolarization occurs normally. Changes in ST segments and T waves may appear, but the ECG diagnosis of infarction often cannot be made with certainty. Bundle branch block patterns may precede infarction or be a consequence of it.
Localization of infarction from the ECG Although myocardial infarction can be endocardial, epicardial, or involve the whole thickness of the ventricular wall, these distinctions cannot reliably be made by ECG. Localization to an approximate region of the left ventricle is possible, however. The precordial leads give most information in this respect. If they have been correctly positioned, leads VI and V2 face the right ventricle, although an extra lead (V4R, at the level of V4 on the right of the sternum below VI) is better; V3 faces the interventricular septum; V4 the anterior and lateral borders; and V6 the posterolateral wall of the left ventricle (this is because the apex faces backwards).
FIG. 12.64 ECG of acute anterior infarction ST segment elevation in V1-V6 and Q waves in V2-V4.
Inferior infarction In inferior infarction, changes are seen in leads III, aVF and II, with reciprocal change in I, aVL and the anterior leads. Inferolateral infarction extends to involve lead V6. The right coronary and its posterior descending branch account for most of these cases (Fig. 12.63). Anterior infarction Anterior infarction is extensive when leads V2 to V6 are involved with changes in I, aVL and II. There may be reciprocal changes in the inferior leads II and aVF. Anterior infarction implies involvement of the LAD coronary artery. Infarction may be anteroseptal when the ECG changes are limited to leads V3 and V2. Anterolateral infarction may present with changes in I, aVL and V5, with some involvement in V4 and V6 (Fig. 12.64). Posterior infarction The true posterior infarction is usually caused by occlusion in the circumflex coronary artery, and its hallmark on the ECG is a tall R wave in VI (Fig. 12.65). There is often associated ST depression in leads V2 and V3, with subsequent peaking of T waves in Vl-3. Non-Q-wave and subendocardial infarction Non-Q-wave infarction is a rather imprecise term used to identify patients who have the hallmarks of MI without full ECG change or enzyme rise. Non-Q-wave MI is now more correctly considered with acute coronary syndromes.
Laboratory tests Infarction causes the release of intracellular enzymes into
FIG. 12.65 ECG of acute posterior infarction Inferior ST elevation (in II, III, aVF) and a tall R wave in V1 (mirror of the Q wave) are shown.
the circulation. These may be used to estimate the size of the infarction. Classically, creatine phosphokinase (CK) has been used to detect muscle damage and specificity for cardiac muscle injury improved by assays of a more cardiac-specific isoenzyme (CK-MB). CPK and CPK-MB rise within hours of infarction, and fall within 24-48 hours. The absolute peak of CPK or CPK-MB gives a crude estimate of the size of infarction. Lactate dehydrogenase (or its more cardiac-specific isoenzyme LDH1 is assayed as hydroxybutyrate dehydrogenase (HBD); it appears in blood within 12-24 hours after infarction and may remain elevated for some days (see Table 12.28). Elevations of the contractile protein components, troponin I (cTnl) and troponin T (cTnT) are now taking the place of LDH (HBD) enzymes. Bedside quantitative troponin testing is now widely available and is particularly
557
TABLE 12.28 Biochemical markers of myocardial infarction Marker
Range of time to initial elevation in h
Mean time to peak (h)
CK-MB
3-12
24
cTnl
3-12
24
cTnT
3-12
12h-»2days
LDH
10
24-48
Myoglobin
1-4
6-7
Adapted from Taegtmeyer H Biochemistry of acute myocardial infarction. In: Francis GS, Alpert JS eds Coronary Care. Boston: Little, Brown & Co 1995: 45
useful for stratification in ACS. In patients presenting late, or where CK enzyme analysis is equivocal, the tendency for cTnl and cTnT to persist for days after the event can be diagnostically helpful. Myoglobin is highly specific and appears early, giving promise as a tool for more rapid identification of patients likely to benefit from thrombolytic treatment. A raised polymorphonuclear leukocyte count and an elevated erythrocyte sedimentation rate (ESR) are non-specific accompaniments of acute infarction. A very high ESR in the early stages of infarction raises the possibility of infarction being secondary to a giant cell arteritis or immunological disease such as polyarteritis nodosa.
Imaging techniques Radionuclide studies may be used to measure ventricular function (MUGA scan, p. 487) or document areas of potentially reversible ischaemia (201T1 scan, p. 486). The echocardiogram can be used to assess ventricular function and localize areas of infarction and dyskinesia.
can be produced by the sudden increase in right ventricular work associated with an acute massive pulmonary embolism. Syncope is often the first manifestation of the embolism, which is associated with marked dyspnoea, tachypnoea and cyanosis. Acute pericarditis (p. 586) produces chest pain, often accompanied by a fever and a friction rub.
MANAGEMENT OF ACUTE INFARCTION The aims of management are pain relief, infarct limitation, and the treatment of arrhythmic and mechanical complications. Management is subsequently directed to defining the relatively small proportion of patients at a greater than normal risk in the postinfarction period, and to rehabilitation and secondary prevention.
Analgesia and oxygen Fear and pain exacerbate some of the ill effects of sympathetic hyperactivity. Analgesia and sedation is achieved with opiates, preferably diamorphine (2.5-5.Omg i.v.) or morphine sulphate (4-8mg i.m.). These drugs combine sedation with an advantageous vasodilatory action, which improves haemodynamics. Respiratory depression is rare in the setting of acute infarction. The relief of pain itself may help raise blood pressure and reduce the heart rate. Associated nausea is treated using metoclopramide (10 mg i.v.) or prochlorperazine (12.5-25mg i.m.). An inhaled mixture of nitrous oxide and oxygen (Entonox) provides pain relief prior to arrival in hospital. Oxygen by mask is frequently given to patients with acute infarction to counteract the hypoxaemic effects of pulmonary oedema. However, many patients are not hypoxaemic, and in such cases oxygen delivery to the tissues will not be improved by this treatment.
Acute (3-adrenoreceptor blockade DIFFERENTIAL DIAGNOSIS Acute chest pain syndromes can pose diagnostic difficulties in acute myocardial infarction (p. 544), particularly as there are no specific physical signs in acute infarction and the diagnostic tests may be normal in the initial hours of the attack. With the advent of thrombolysis and acute p-adrenoreceptor blockade used early in the management of acute infarction, diagnostic accuracy has become even more important. The symptoms of aortic dissection (p. 599) may be very similar. Pain indistinguishable from acute cardiac ischaemia
Acute intravenous (3-blockade can be given safely to many acute infarction patients. Large-scale trials have shown a small rate of reduction in early deaths caused by reinfarction and cardiac rupture. An additional effect is a reduction in pain. Acute intravenous -blockade would have to be given to 200 patients to prevent one death, one reinfarction and one cardiac arrest. Chronic therapy after infarction saves two lives for every 100 patients treated for 1 year.
Limitation of infarct size Six hours is the time limit within which it is possible that measures to restore blood supply will salvage ischaemic muscle. If collateral channels are poor, this time limit may be considerably less.
MCQ 12.20
558
Thrombolysis In approximately 80% of patients a myocardial infarction
is caused by thrombotic occlusion of a vessel, usually superimposed on an atherosclerotic plaque. Despite the first use of thrombolytic agents in myocardial infarction as early as 1958, their adoption as one of the mainstays of treatment followed the publication of two giant trials using streptokinase. A single injection of 1.5 x 106 units i.v. over 1 hour within 12 hours of the first symptom reduced mortality by 18%. More than 200000 patients have now been randomized in therapeutic trials with thrombolytic agents. The most widely used agents remain streptokinase and the recombinant tissue plasminogen activator rtPA. Haemorrhagic complications occur, though sufficiently rarely as not to interfere with the overall beneficial effect of therapy. Patients with clotting disorders, a previous history of stroke or peptic ulceration, and those with severe hypertension or any injuries are excluded from this treatment. It is important to exclude aortic dissection, as fibrinolytic treatment can prove catastrophic. Other relative contraindications are a known hypersensitivity to the drug, recent streptococcal infection, survivors from cardiac arrest who have had cardiac massage, and those with heart block who may need a temporary pacemaker. Streptokinase should not be administered within 2 years of a previous treatment. Benefit from thrombolysis is increased if it is given within 6 hours (and preferably 3 hours) of the first symptom. This has led to newer fibrinolytic agents that can be administered at the site of the presenting symptoms, by either the ambulance crew or the GP. Aspirin and heparin Aspirin alone reduces mortality by 25%, and with streptokinase gives a combined reduction of 45%. Continuous infusion of heparin after thrombolysis and after coronary angioplasty is routine in many centres. Patients with large infarctions suffer fewer systemic emboli from ventricular clot if treated with heparin. Bleeding complications and stroke are slightly more common. Heparin treatment is potentially more important after the shorter-acting rtPA, when it should be given for 48 hours. Warfarin treatment is limited to those in AF, or where a large LV thrombus is shown. Angioplasty and surgery Early revascularization during acute infarction may be the revascularization method of choice, but the cost of providing a 24-hour service for these complex, labourintensive techniques is considerable. Individual cases will continue to be so treated in centres where angioplasty or surgical suites are closely linked to the acute admission wards.
Nitrates and calcium antagonist drugs Nitrates by intravenous infusion (2-10 mg/h for isosorbide, 1-12 mg/h for GTN) are frequently used in the acute phase of infarction, where persistent pain is a problem; their use
is associated with a modest reduction in mortality. They have the advantage of causing reduction in preload and afterload, which may relieve left heart failure (see p. 493). Hypotension can be a problem, particularly in patients who are dependent on a high right heart filling pressure to maintain stroke volume, such as those with right ventricular infarction. Cutaneous therapy is best reserved for the less acute stages of infarction, when converting patients from intravenous infusion to maintenance therapy. Calcium antagonist drugs are effective in improving ischaemic cardiac pain, but their use has not been associated with any improvement in infarction mortality. Calcium antagonists, particularly the rate-slowing agents diltiazem and verapamil, can be used when there are contraindications to -blockade. O
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ACE inhibitors Given within a few days of infarction there is an early benefit, which has now been proved to persist for many years (>4) post MI. These drugs should not be given while patients are hypotensive, particularly during the acute stages of myocardial infarction. Benefit from ACE inhibitors is probably not adequately explained purely by their vasodilatory and antihypertensive effects.
HMG-CoA reductase inhibitors - the statins More than 70% of myocardial infarction survivors in the UK have a total cholesterol >5 mmol/L. There is now convincing evidence that the majority will benefit from being treated with a statin.
Bed rest, mobilization and rehabilitation Bed rest during the acute phase of infarction is aimed at minimizing harmful cardiac remodelling processes. However, prolonged bed rest is unnecessary and can cause complications of its own (such as deep vein thrombosis, pulmonary embolism, deconditioning and bedsores). Prophylactic subcutaneous heparin (12 500 U b.d.) may be indicated if prolonged bed rest is necessary. Mobilization can begin within 24 hours in uncomplicated infarction. Patients can generally be discharged on the 10th day, having demonstrated their ability to walk and manage a flight of stairs before returning home. Mobilization should be slowed if there is a return of chest discomfort, a heart rate below 50bpm or above 120 bpm, the return of ischaemic ST elevation on the ECG, or an increase of more than 15mmHg in systolic pressure with gentle ambulation. Acute myocardial infarction is quite a distressing experience. Patients should be counselled individually and many of them appreciate a clear explanation of the condition and prognosis in simple layman's terms. Advice on risk factors (e.g. stopping smoking) can be initiated at this stage.
559
TABLE 12.29 Thrombolytic agents in myocardial infarction Feature
t-PA
Streptokinase
Anistreplase (APSAC)
Reteplase
Plasma clearance time (min) Fibrin specificity Piasminogen binding Antigen icity Risk of hypotension Method of administration
4-8
15-25
50-90
>20
Minimal Indirect Yes Yes i.v. infusion (1 h)
Minimal Indirect Yes Yes Bolus
High Direct No No Bolus
Licensing
Moderate Direct No No Bolus + i.v. infusion Licensed
Licensed
Licensed
Expense
High
Low
Moderate
Unlicensed in UK ??
TABLE 12130 Contraindications to thrombolytic therapy
TABLE 12.31 Benefits of treatment during and after acute myocardial infarction
Major contraindications Any previous history of haemorrhagic stroke History of stroke, dementia or CNS damage within 1 year Head trauma or brain surgery within 6 months Known intracranial neoplasm Suspected aortic dissection Internal bleeding within 6 weeks Active bleeding or known bleeding disorder Major surgery, trauma or bleeding within 6 weeks Traumatic cardiopulmonary resuscitation
[ACUTE Ml] Deaths prevented/1000 patients treated Treatment i.v. p-Blocker
Relative contraindications Oral anticoagulant therapy Acute pancreatitis Pregnancy or within 1 week postpartum Active peptic ulceration Transient ischaemic attack within 6 months Dementia Infective endocarditis Active cavitating pulmonary tuberculosis Advanced liver disease Intracardiac thrombi Uncontrolled hypertension (SBP >180mmHg, DBP >110mmHg) Puncture of non-compressible blood vessel within 2 weeks Previous Streptokinase therapy (for repeat treatment with SK)
FURTHER READING ON MYOCARDIAL INFARCTION
560
Ball S G (ed) 1995 Myocardial infarction: from trials to practice. Petersfield: Wrightson Biomedical, p. 194 Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology 1996. Acute myocardial infarction: prehospital and in-hospital management. Eur Heart J. 17: 43-63
7
Oral -blocker Aspirin
[POST Ml] Major event prevented (including death and Ml) per 1000 patients treated
21 deaths 21 reinfarction 24
7 deaths 9 reinfarction 3 strokes
Streptokinase and aspirin
52
ACE inhibitor HMG-CoA reductase inhibitor
Smoking cessation
5-8 -
? 7 deaths 11 CABG/PTCA 12 Ml 3CVA 4 heart failures 15 deaths 46 reinfarction
(Adapted from British Cardiac Society ACCSAP Commentary)
•
COMPLICATIONS OF MYOCARDIAL INFARCTION ARRHYTHMIAS Arrhythmias are a common complication of myocardial infarction.
Tachycardias Sinus tachycardia Sinus tachycardia (heart rate greater than 100 bpm) is associated with a poor prognosis if it persists despite control of pain, anxiety and cardiac failure. -Blockers will reduce its incidence but cannot be given to patients with severe impairment of ventricular function or hypotension. Ventricular fibrillation VF is a lethal arrhythmia which can complicate acute myocardial infarction from the moment of coronary occlusion. It is the cause of most cases of sudden death due to CHD. Its peak incidence is in the first few hours of the attack, when it is termed primary VF and, if successfully dealt with in an otherwise uncomplicated infarction, has a good prognosis. Secondary VF occurs several days or weeks after infarction, usually in patients who have suffered extensive muscle damage and heart failure. Its prognosis is then very poor. Treatment is by DC defibrillation; the earlier it is used, the more likely is a successful outcome. The procedure itself is described fully on page 519. Lidocaine (lignocaine) is also given after successful defibrillation to prevent further episodes. Limitations on the use of lidocaine (lignocaine) include its narrow therapeutic margin, central nervous system side-effects being the most common. Doses have to be reduced in the elderly and in those with poor hepatic function. The use of lidocaine (lignocaine) to prevent VF is controversial. Many episodes of VF are preceded by multiple or frequent ventricular ectopic beats, or early ectopics falling on the vulnerable period of the ECG - the R on T phenomenon. Warning arrhythmias give frequent false positive and false negative associations and their treatment does not reduce the incidence of VF. Ventricular ectopic beats At an early stage (6-72 hours) in an acute myocardial infarction, frequent ventricular ectopic (VE) beats (>10VE/h) are seen in 70% of patients. Ectopy then diminishes, so that only 10% of patients have frequent VEs at the time of discharge. Frequent VEs at the time of discharge from hospital carries an increased (two- to threefold) risk of death in the first year. This association appears to be independent of ventricular function. Although drugs to effectively inhibit ectopic activity are available, controlled trials have not shown any benefit and, indeed, some worsening survival associated with treatment of frequent or complex VE. Treatment of frequent VEs is indicated if their occurrence causes symptoms due to an effective bradycardia or diminished output. Ventricular tachycardia Haemodynamic disturbance and degeneration to VF is common with sustained VT in acute infarction. DC shock therapy is indicated in almost all cases, to be followed by intravenous or oral therapy (p. 515). Lidocaine (ligno-
caine) is usually used in the acute situation, followed by other Vaughan-Williams class I drugs and amiodarone. Although drug therapy may suppress the arrhythmia the effect on survival is less certain. Patients with non-sustained VT should probably be monitored carefully, and receive a predischarge exercise test and oral antiarrhythmic therapy for the first few weeks after infarction. The risk of death is increased if VT is present at discharge.
12
Accelerated idioventricular rhythm Occasionally a ventricular rhythm at a rate of 60-90 bpm can arise. It generally has broad complexes, but they may be narrow if the origin is high in the bundle of His. This rhythm rarely requires specific treatment, but may be an indication of profound sinus and AV nodal suppression, which may respond to atropine (0.6-1.2mg). Investigation and adjunctive therapy Patients suffering from VF or early ventricular arrhythmia may be treated conventionally. Those with late or secondary arrhythmia deserve very careful inpatient assessment, including angiography. Revascularization by CABG or PTCA may be necessary. Increasingly, patients who remain at risk of sudden death post MI will be offered treatment with an implantable cardioverter defibrillator (AICD), especially if an arrhythmic tendency persists after adequate revascularization. Supraventricular tachycardia Atrial fibrillation (AF) is the commonest supraventricular tachycardia seen in acute infarction, atrial flutter being relatively uncommon. Tachycardias causing severe haemodynamic disturbance are usually best dealt with by DC cardioversion. In atrial flutter this is generally the treatment of choice, as low energies are often required to convert to sinus rhythm. In AF, digoxin is given by oral loading (p. 511) (0.5-1.0mg a.d.) followed by 0.125-0.25 mg o.d. Control of AF rate may require the concurrent administration of another drug (p. 511). -Blockers are often used, and verapamil or diltiazem are also effective. Paroxysmal atrial tachycardia may complicate acute infarction; if hypotension is severe, DC cardioversion is the therapy of first choice. Intravenous adenosine or verapamil is effective in terminating many of these episodes, and intravenous -blockade (atenolol 5mg or metoprolol 515 mg) may be an alternative. If the first-choice drug fails to produce a satisfactory slowing of the rhythm or conversion to sinus rhythm, it is best to use DC cardioversion to avoid additive negative inotropic effects of antiarrhythmic drugs. An alternative therapy for atrial flutter and atrial tachycardia is overdrive pacing; this has the advantage of avoiding negatively inotropic drugs but requires a temporary transvenous pacemaker placed in the right atrium.
Bradycardia Bradycardia is often transient and requires no treatment.
561
When it produces symptoms or impairs the haemodynamics, treatment with a pacemaker or drugs is required. Sinus fyradycardia Up to 80% of patients with acute inferior infarction develop a heart rate less than 60bpm in the very early stages of the condition. This usually responds to atropine (0.5-1.Omg i.v.), but if symptomatic bradycardia persists a temporary pacemaker is required.
Heart block First-degree heart block The lengthening of the PR interval may be seen during the evolution of an infarction, particularly inferior infarction. When pre-existing it requires no action. However, lengthening PR intervals deserve observation, as this implies interference with AV node function, and progression to higher grades of block may occur. Second-degree heart block Both Mobitz types I and II (p. 502) require very careful observation. Progression to complete heart block and sudden death is uncommon with inferior infarction, where Mobitz type I is a frequent, though transient, complication (about 15% of cases). In anterior infarction with extensive involvement of the interventricular septum, Mobitz type II block may be seen and carries a poor prognosis (80% mortality) which owes more to the associated large mass of muscle loss than to the conduction disturbance itself. Temporary pacemakers should be used in all cases where second-degree block produces symptoms (e.g. syncope) or haemodynamic disturbance, or when antiarrhythmic drugs are to be given. A permanent pacemaker should be considered for survivors of anterior infarction with persistent block. Third-degree or complete heart block Complete heart block is a common complication of inferior infarction (about 10% of cases), when treatment is along the same lines as for second-degree block. It needs no specific treatment if well tolerated, but temporary cardiac pacing should be employed if heart failure, or rates less than 50bpm, occurs. In anterior infarction, complete block (incidence approximately 5% of cases) may occur suddenly or be preceded by bifascicular block (see below). It generally occurs in large infarctions involving the septal tissue where the conducting tissue is concentrated, and always requires treatment with a permanent pacemaker. This may not always improve survival but management is considerably eased. Complete heart block rarely persists, but if it does persist beyond 7-14 days after infarction a permanent pacemaker is required.
562
Bifascicular and trifascicular heart block Interruption of conduction through the right bundle and
either fascicle of the left bundle constitutes bifascicular block. When the anterior fascicle is involved (left anterior hemiblock, LAH) the QRS axis is greater than -30° with small r waves in II, III and aVF and absent initial q waves in V5 and V6. Posterior fascicular block (left posterior hemiblock, LPH) produces a rightward axis shift (greater than +100°) with an S wave in I and Q in III. Trifascicular block is any combination of bifascicular block associated with a long PR interval. The association of right bundle branch block with LPH in anterior infarction indicates considerable ischaemic damage, and its appearance is an indication for prophylactic use of a temporary pacemaker, as progression to complete block may be sudden. Right bundle branch block with left anterior hemiblock does not carry such a poor prognosis, and is a slightly less powerful indication for pacing.
Temporary transvenous cardiac pacemakers The indications for implanting a pacemaker in acute infarction are summarized in Table 12.32. There are various methods by which pacing can be achieved, but in general transvenous routes are the most stable and can be maintained for the few days that are required. The methods require the insertion of a bipolar electrode into the right ventricular apex, usually under radiological control. Pacing thresholds of under 1 V at 2 ms pulse width duration should be established, as the threshold tends to rise after implantation. To achieve this, it may be necessary to try various positions in the right ventricular apex. The pacemaker is an external box which is always set in the demand mode; this ensures the patient's ventricular activity is sensed and pacing only begun when the intrinsic heart rate falls below a preset rate (usually between 70 and 90bpm). A stable position of the temporary electrode is confirmed by establishing pacing at an output of 1 V, and ensuring ventricular capture is not lost during maximal inspiration, coughing or sniffing. There should be sufficient slack in the electrode to accommodate these movements of the thorax without displacing the tip of the electrode. Once the electrode position is finalized it is secured to the skin under a sterile dressing. Except in an emergency, it is rarely justified to manipulate a temporary pacemaker after it has been inserted for some time, as sterility cannot be assured. If displacement has occurred, a replacement pacemaker will be required. Threshold measurements should be checked daily, or more frequently if the patient is pacemaker dependent. The pacemaker settings are adjusted to provide a voltage output of at least three to four times threshold. A threshold of over 2 V is an indication to replace the electrode. Atrial and dual-chamber pacing Although pacing via a ventricular electrode is sufficient in most instances, there are circumstances where atrial or dual-chamber pacing is required. The former can be used to treat atrial flutter or bradycardia-dependent rhythms
TABLE 12.32 Indications for temporary pacemaker in acute myocardial infarction (Ml) A. Indicated regardless of Ml site Symptomatic and drug-resistant bradycardia due to:
B. Indicated in anterior Ml All indications in A
C. Not indicated First-degree heart block alone
sinus bradycardia, sinus arrest, SA block
RBBB + LPHB
Asymptomatic Mobitz type I
second-degree heart block
RBBB + LAHB
Asymptomatic bradycardia or junctional rhythm
third-degree heart block
Trifascicular block:
Sick sinus syndrome with bradycardia-tachycardia Drug-resistant tachycardia DC shock-resistant tachycardia Ventricular standstill Alternating LBBB with RBBB
long PR + LBBB long PR, RBBB + LPHB or LAHB Second-degree heart block, especially if Mobitz type II
12
LAHB ' LBBB RBBB
in isolation
LPHB .
LAHB = left anterior hemiblock; RAHB = right anterior hemiblock; LPHB = left posterior hemiblock; LBBB = left bundle branch block; RBBB = right bundle branch block
when AV nodal conduction is intact. Electrode positioning is more difficult and stability can be a problem. In dual-chamber or physiological pacing, sequential pacing of first the atria, followed, after a suitable pause, by the ventricles, offers a near physiological system maintaining the atrial contribution to cardiac filling. This can be very important in severe ventricular impairment, right ventricular infarction, or when there is associated valvular disease, such as aortic stenosis. The technique requires suitable dual-chamber pacemakers and the expertise to implant atrial as well as ventricular electrodes; availability is thus likely to be limited to specialized cardiac centres.
CARDIAC FAILURE Dyspnoea, basal crepitations and the radiographic signs associated with pulmonary oedema (p. 492) are frequently encountered in the early stages of infarction.
Management Prompt treatment with intravenous loop diuretics (furosemide (frusemide) 20-40 mg or bumetanide 1-2 mg) has been the mainstay of treatment. Larger initial doses are often given, but are rarely necessary and may produce hypotension, worsening the patient's overall condition. Diamorphine 2.5-5.0 mg i.v. is also helpful, and oxygen, given by a close-fitting, low dead-space mask (e.g. MC mask at 4L/min) is indicated. The preferred treatment is now with vasodilatation using intravenous nitrates, reducing preload. Patients with low blood pressure and heart failure are best managed using arterial and indirect left atrial pressure measurement. The latter is obtained with a Swan-Ganz catheter placed in a pulmonary arterial branch (see below). The aim of treatment should be to decrease the indirect left atrial pressure (or pulmonary capillary wedge pressure) to less than 20mmHg, while maintaining systolic blood pressure above lOOmmHg and diastolic
pressure over 60mmHg. Nitrates with inotropes (dobutamine ± dopamine) may be better than diuretics in these difficult cases. A week after infarction, introduction of ACE inhibitors has been shown to improve prognosis.
CARDIOGENIC SHOCK Cardiogenic shock in myocardial infarction is defined as hypotension with a systolic pressure under lOOmmHg; it is invariably accompanied by ventricular failure, peripheral vasoconstriction and oliguria (<20mL/h of urine), and usually arterial hypoxaemia, mental confusion and metabolic acidosis (Table 12.33). Remediable causes, such as uncontrolled pain, arrhythmia or excesses of negatively inotropic or vasodilating drugs (e.g. p-adrenoreceptor blockers or calcium antagonists and diamorphine) should be excluded and treated specifically. Shock is caused by damage affecting 30-40% of ventricular muscle mass and, if untreated, carries an 80-100% acute mortality. Treatment is by early revascularization, especially by PTCA. It may reduce early mortality to 50-60% at 1 month.
RIGHT VENTRICULAR INFARCTION Right ventricular infarction may produce cardiogenic shock, as defined above, but carries a very much better prognosis. The findings are a lower than expected indirect left atrial pressure and a relatively high right atrial pressure. The ECG shows changes of inferior or posterior infarction, and lead V4R may reveal the infarction clearly. Treatment consists of maintenance of a high right-sided filling pressure, which may have been inadvertently lowered by diuretics given to treat the seemingly high venous pressure. The cardiac output and systemic pressure may respond to infusion with colloid. Inotropes and diuretics may thus be avoided altogether in these patients.
563
TABLE 12.33 Cardiogenic shock in myocardial infarction Features (in increasing order of severity) • hypotension (SBP<100 mmHg) • thready impalpable peripheral pulses • pale and cool hands/feet/nose ± peripheral cyanosis • oliguria/anuria • sweat! ness • mental obtundation Exclude shock due to: • absolute/relative hypovolaemia (especially in the presence of RV infarction) • drugs (especially diamorphine, morphine, nitrates, p-blockers) • vasovagal reaction (tends to be bradycardiac) • heart block/bradyarrhythmia • tachyarrhythmia • tamponade • other causes (septicaemia, anaphylaxis) Investigations • echocardiography (essential) • haemodynamic monitoring - thermodilution Swan-Ganz catheter ± arterial cannula
Management Pressure monitoring, including indirect left atrial pressure, systemic arterial pressure and a facility for measuring cardiac output, are the minimum requirements for managing patients with shock. Therapy consists of oxygen,
RECENT ADVANCES p-BLOCKADE FOR HEART FAILURE
564
Following studies showing that angiotensin-converting enzyme inhibitors (ACEIs) can prolong the survival of patients with heart failure, a recent study has shown that carvedilol, a vasodilating (3-adrenergic blocker, used in addition to ACEIs, can further improve survival. This result has produced a major shift in our ideas of managing heart failure, away from that of using positive inotropic and chronotropic agents to enhance cardiac performance to that of using a negative inotropic and heart slowing agent instead. The exact mechanisms of why ACEIs and -blockers produce beneficial effects whereas oral positive inotropic agents (such as milrinone, enoximone, flosequinan) worsen mortality is unknown, but one simple likely explanation is that activation of the sympathetic and renin-angiotensin-aldosterone systems commonly seen in heart failure leads to increased loss of cardiac myocytes, which is further accelerated by positive inotropic agents, and can be substantially diminished by using ACEIs and P-blockers.
inotropic agents, diuretics and, very rarely, mechanical support of respiration by ventilation and of the circulation with intra-aortic balloon counterpulsation (see below). Inotropic agents are required to maintain the systolic pressure to perfuse the tissues, but are arrhythmogenic and may increase oxygen requirements. Diuretics are used to relieve pulmonary oedema, but adequate ventricular filling pressures must be maintained or else cardiac output falls. The inotropic agents of choice are dopamine, dobutamine and phosphodiesterase inhibitors (milrinone, enoximone and amrinone). Dopamine Dopamine has three important actions, which appear at increasing dose ranges. Low-dose dopamine infusion (0.5-2.5 jig/kg/min) primarily produces renal and mesenteric vessel dilatation, and is frequently used at this dose
RECENT ADVANCES IN VENTRICULAR ASSIST DEVICES AND ARTIFICIAL HEARTS With improvements in the treatment of various cardiac diseases (notably myocardial infarction and lifethreatening arrhythmia), the incidence of heart failure rises steadily. The demand for cardiac transplantation cannot be met because of a severe shortage of donor hearts. Alternatives are being explored. Transplanting genetically engineered immunologically compatible animal hearts may become feasible, but there are ethical problems raised by the antivivisection lobby and the theoretical fear of trans-species transmission of unknown viral or prion infections. Technological advances have made the development of a reliable artificial heart a distinct possibility in the next few decades. The first problem was infection, especially at the points of insertion of tubes through the skin. The development of a new battery system, which can be charged across the intact skin, has made possible the implantation of the entire device inside the body. The second major problem is compatibility with blood, which advances in material science have largely overcome. Other problems, such as avoidance of haemolysis, size of device, fracture, bleeding and thrombus formation, have to be surmounted. The comparison of today's pacemaker technology with that of 50 years ago provides optimism that artificial hearts may become a medical reality in this century. In the meantime, those patients who suffer severe transient reversible myocardial hypofunction (for example due to myocardial stunning) may require mechanical support of the circulation to 'rest' the myocardium and allow it to recover. The use of ventricular (usually left ventricular, but occasionally biventricular) assist devices to support the circulation for a short period allows the patient to buy time until myocardial function is restored.
12
CASE STUDY 12.4 CHEST PAIN AND PULMONARY OEDEMA A 67-year-old diabetic man with no previously known cardiac history was transferred as an emergency to the cardiology unit. He had presented a few hours earlier to his local emergency department with a 3-day history of chest pain and was noted to have an ECG consistent with an extensive antero-septal infarction. There were widespread Q waves visible in leads V2-V6, and there were virtually no R waves in the anterior chest leads. 3 mm of ST segment elevation was visible from V2-V4. They were unable to give him thrombolysis due to hypotension; his blood pressure on arrival was 70/40. His chest X-ray showed gross pulmonary oedema, and his oxygen saturation on air was low and could only be barely maintained with a high volume oxygen mask. On arrival to the cardiac unit, he was noted to be tachycardic with a blood pressure of 60/40 and barely conscious. Oxygen saturation was 88% with signs of gross pulmonary oedema. He had an indwelling urinary catheter and a documented urine flow of 50 mL of urine over the previous 3 hours. The ECG was as described by the referring hospital. Arterial blood gases confirmed hypoxaemia with an acidosis giving a pH of 7.14 and a base excess of 13.
Question How should this patient with cardiogenic shock due to recent cardiac infarction be managed? Discussion This man presents the picture of cardiogenic shock due to myocardial infarction. This carries a greater than 80% acute mortality. Firstly he requires resuscitation and stabilization. His gas exchange is poor, he has pulmonary oedema and is exhausted by the effort of breathing. He was therefore intubated as an emergency and ventilated. Unfortunately, the act of intubation led to a further fall in systemic pressure. Although pharmacological support of pressure could have been instituted with dobutamine by intravenous infusion, it was decided to support the circulation by inserting an intraarterial aortic balloon pump. He was transferred to the cardiac catheterization laboratory, where the pump was inserted percutaneously from the right femoral artery. One-toone ventricular assistance was set up with an immediate improvement in mean arterial pressure from 40 to 60 mmHg. Signs of ischaemia on the ECG improved as did blood gases and acidosis.
as a renal protector during times of systemic hypotension. Medium-dose dopamine infusion (5.0-lOug/kg/min) has a direct myocardial inotropic action, and at high doses (>10[ig/kg/min) the drug produces peripheral vasoconstriction (a-adrenoreceptor mediated), thereby raising systemic pressure at the cost of vasoconstriction in tissue beds, including renal. The drug must be infused through a large central vein, and at medium to high infusion rates may precipitate cardiac arrhythmias. Dobutamine Dobutamine is a synthetic dopamine analogue which directly stimulates (3i receptors; unlike dopamine, it does not release noradrenaline (norepinephrine) and so is less affected by the reduction in cardiac stores of this hormone in chronic heart failure. Dobutamine can be used via a
The patient proceeded immediately to angiography which revealed a proximal occlusion on the left descending coronary artery but normal circumflex and right coronary. An infusion of a Ilb/IIIa antagonist was begun and the occlusion re-opened by balloon angioplasty with a subsequent stent insertion. The angioplasty was uncomplicated apart from a short burst of ventricular tachycardia soon after reperfusion. This did not require treatment. He was transferred back to intensive care and was able to be extubated the next day. Cardiogenic shock is an extremely severe complication of myocardial infarction with a very high mortality. It appears likely that mortality is reduced to 40-50% by revascularization using emergency angioplasty. In these circumstances intra-aortic balloon counter-pulsation is the treatment of choice to support the circulation without the complications of additional pharmacological therapy. The patient recovered and was able to be discharged from hospital. He had some residual impairment of ventricular function and subsequent treatment was along the lines of secondary management of a myocardial infarction.
peripheral vein and the dose is usually between 2.5 and 40|ig/kg/min. Its action is primarily inotropic, and hence improves cardiac output while at the same time reducing ventricular filling pressures. Combination therapy Dopamine in low dose to promote renal bed vasodilatation and dobutamine in doses to achieve an improved cardiac output are often used in combination in cardiogenic shock; lower doses of each can thus be used. Filling pressures (measured via a Swan-Ganz catheter) are titrated against systemic pressure and the drug dosages adjusted every 10 minutes to achieve an optimal cardiac output and sufficient perfusion pressure to maintain renal, cerebral and myocardial function while avoiding excessive heart rates and pulmonary oedema. Ideally, therefore, the
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dose of dobutamine is adjusted every 10 minutes until the cardiac output reaches a plateau. Dopamine is adjusted to achieve a reasonable urinary output (>60mL/h); this may require support with intermittent bolus doses of loop diuretics. Left atrial pressure is maintained between 15 and 20mmHg (below the threshold to produce pulmonary oedema and above the level that begins to impair cardiac output). The right atrial pressure is maintained high enough to support the cardiac output and left atrial pressure. The heart rate is kept between 100 and 120 bpm and systolic blood pressure between 110 and 120mmHg, with a diastolic pressure near SOmmHg. The patient should be comfortable in this state, with near normal arterial oxygen saturation and no acidosis. Mechanical support Mechanical support of the circulation can be achieved using intra-aortic balloon pump counterpulsation. Mechanical ventilation of patients in cardiogenic shock is justified if they are to be offered more definitive therapy. Coronary angioplasty improves the outlook in these patients. The technique involves passing a balloon catheter into the descending aorta, by percutaneous techniques allied to cardiac catheterization. The balloon is then inflated with helium and deflated, triggered to the ECG. This produces an enhanced aortic diastolic pressure.
ACUTE VENTRICULAR SEPTAL RUPTURE AND RUPTURED PAPILLARY MUSCLE Acute ventricular septal rupture and ruptured papillary muscle are uncommon and very severe complications of acute myocardial infarction. They tend to occur 2-10 days after the acute event and produce sudden deterioration, with acute heart failure, shock, and the development of a new systolic murmur. It may be impossible to differentiate the two conditions clinically, although echocardiography and Doppler ultrasound can do so in most cases. Treatment is early surgery in both instances, although mortality remains high. There may be an advantage to allow tissues to 'heal' before closure of a VSD, but unfortunately most patients will succumb before sufficient time elapses. There are some conspicuous successes with early surgery and, when possible, circulatory support prior to operation may be life-saving.
cally by the sudden onset of severe pain followed rapidly by cardiovascular collapse. Resuscitation from this event is unusual; the clinical picture is of electromechanical dissociation (EMD), where an ECG rhythm is present but no output ensues.
VENTRICULAR ANEURYSM Ventricular aneurysm is a late complication of myocardial infarction in 10-15% of patients. True aneurysms cause thinning and paradoxical motion of portions of the ventricular wall. Recurrent arrhythmia, refractory heart failure, embolization and rupture are the complications of true aneurysms, which are manifest clinically by paradoxical precordial pulsation, persistent ST elevation on the ECG and an abnormal LV border contour on the chest Xray. False aneurysms are limited cardiac ruptures whose structure has become organized and stabilized; the main complications include those of true aneurysms as well as a greater tendency for late and fatal rupture. Surgery is the treatment of choice for all false aneurysms and symptomatic true aneurysms. Antiarrhythmic therapy may be necessary and anticoagulation for true aneurysms is wise, as 60-70% of them contain thrombus.
DRESSLER'S OR POSTMYOCARDIAL INFARCTION SYNDROME Dressler's syndrome is an immunological syndrome of pleuropericarditis which may occur in 1-4% of patients, 2-12 weeks after infarction (or open heart surgery). Antibodies directed against the sarcolemma and subsarcolemma of myocytes may be found. The clinical syndrome is similar to acute pericarditis (p. 586), with pain, fever, leukocytosis, a high ESR and a 'pericarditic' ECG in 50% of cases. It must be differentiated from extension of myocardial infarction, pulmonary embolism or pneumonia. Treatment usually consists of NSAIDs, although steroids may be required for severe and recurrent episodes. The prognosis is good.
PROGNOSIS AFTER MYOCARDIAL INFARCTION
CARDIAC RUPTURE
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Cardiac rupture is a much commoner cause of sudden death in hospital than has previously been recognized (10-20% of in-hospital deaths). It typically occurs several days after the acute infarction and appears to be commoner in men, in those with higher blood pressures, and in those who suffer anterior infarction. Acute -blockade protects from this complication, which is manifested clini-
After a myocardial infarction the prognosis of the patient is dependent on the success of treatment of the complications described above, the likelihood of recurrence or extension of the infarct, and the extent of eventual impairment of cardiac function. Despite modern advances in medicine, some 40% of myocardial infarction victims die without reaching the hospital. In the prethrombolytic era the introduction of coronary care units resulted in an
approximate halving of hospital mortality rates from about 30% to about 15%, and the predominant cause of death changed from fatal arrhythmias to heart failure. After surviving an acute myocardial infarction, the prognosis is dependent on: 1. The extent of ventricular impairment 2. The propensity to life-threatening arrhythmia 3. The possibility of further infarction. The extent of left ventricular dysfunction is dependent on: • The state of left ventricular function prior to the infarction • The size and nature of the infarction • The subsequent repair and remodelling processes • The amount of viable myocardium still in jeopardy from ischaemia (inadequate blood supply and cardiac myocytes functioning in energy deficit), stunning (reasonable blood supply but myocyte contraction impaired) or hibernation (reduced blood supply but myocytes downregulated so as not to be in energy deficit). Thus, patients with diminished starting numbers of cardiac myocytes (due to either previous myocardial infarctions or old age - secondary to natural attrition of myocytes, which averages about 35% from the age of 18 to 90 years, or previous cardiomyopathy) or pre-existing ventricular dysfunction from any cause (e.g. valvular or hypertensive heart disease) would not tolerate the same myocardial infarction as well as those with normal or athletic hearts. Obviously, patients incurring a larger myocardial infarction are likely to have a worse prognosis than those with a smaller infarction. The repair processes post infarction may be impaired (e.g. by concomitant therapy with corticosteroids or NSAIDs), leading to a greater likelihood of infarct expansion and ventricular aneurysm formation, resulting in a ventricle that functions less well than one with normal scar tissue formation. The most important long-term prognostic indicator is left ventricular dysfunction. The clinical diagnosis of heart failure is a good indicator of dysfunction; patients with heart failure post infarction have 2-4 times greater mortality rates than those without. The simplest measurements of dysfunction are left ventricular ejection fraction or endsystolic volume, the depression of which has been found to correlate with mortality. These patients deserve a more aggressive approach to treatment, in terms of risk factor reduction, ACE inhibition and, if indicated, revascularization (see below). The presence of arrhythmias at rest or during exertion is an adverse prognostic indicator after myocardial infarction. Arrhythmias can be identified by Holter monitoring, exercise tests or direct electrophysiological studies. Frequent ventricular ectopics or inducible ventricular tachycardia are predictive of sudden death. Late potentials in averaged ECGs and reduced heart variability are also predictive of life-threatening arrhythmias. High-grade AV
block and bundle branch block resulting from myocardial infaction are associated with a poor outcome. Residual myocardial ischaemia, as manifested by postinfarction angina or positive exercise tests, is an important predictor of reinfarction and mortality. High-grade stenosis or occlusion of the infarcted related artery supplying a large portion of the left ventricle is an independent prognostic indicator. Much prognostic information can be obtained from clinical data and non-invasive investigations (e.g. ECG, chest X-ray, exercise tests, echocardiography) and, if indicated by these, more sophisticated or invasive investigations may then be performed. It is important to point out that, although various parameters may be predictive of prognosis, this does not imply that therapeutic attempts to improve these parameters necessarily lead to benefits to patients or improved outcome. A rational approach to management is required.
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FURTHER READING ON PROGNOSIS AFTER MYOCARDIAL INFARCTION Emanuelsson H, Karlson B W, Herlitz J 1994 Characteristics and prognosis of patients with acute myocardial infarction in relation to occurrence of congestive heart failure. Eur Heart J 15: 761-768. Gaudron P, Eiles C, Kugler I, Ertl G 1993 Progressive left ventricular dysfunction and remodelling after myocardial infarction. Potential mechanisms and early predictors. Circulation 87: 755-763. Stevenson R, Ranjadayalan K, Wilkinson P, Roberts R, Timmis A D 1993 Short and long term prognosis of acute myocardial infarction since introduction of thrombolysis. Br Med J 307: 349-353.
MANAGEMENT OF MYOCARDIAL INFARCTION SURVIVORS The objectives of management post infarction are to initiate or continue the management of ongoing complications described above, and to minimize the chances of further myocardial infarction, either as infarct extension or as infarction in a new territory. The ideal treatment for the latter is to produce a regression of all coronary artery stenoses, but this remains unattainable. Current techniques of revascularization (coronary bypass surgery or angioplasty) are not without risk and should therefore be reserved for those with most to gain in terms of symptomatic relief and/or prognosis. Assiduous attention to risk factor management is required as part of the rehabilitation programme.
Investigations after myocardial infarction The objective of investigation is: • To select high-risk patients for therapy which has been shown to reduce mortality, reinfarction or heart failure
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• To establish the cause (s) of symptoms • To exclude patients who will derive little or no benefit from therapy, or are likely to be harmed by therapy • To assess functional capacity and prognosis. To this end many patients would benefit from a formal predischarge or follow-up stress test (e.g. exercise ECGs, exercise/stress radionuclide myocardial perfusion scan) and an assessment of left ventricular function (using either echocardiography or radionuclide ventriculography). (A cautionary note: interpretation of exercise ECGs after infarction requires skill, as false positive results are not infrequently found.) The incidence of subsequent coronary events is low in those who have a good exercise capacity without positive test results. Coronary angiography may be considered in those with stress-induced angina or evidence of myocardial ischaemia, especially in patients with impaired left ventricles. Patients with postinfarction angina, especially after non-Q-wave myocardial infarction, even without positive exercise ECGs, should be considered for coronary angiography.
Drug therapy A simple principle recommended when introducing drug therapy in the coronary care unit is that any cardioactive agent is preferably introduced using small frequent doses of the shortest-acting drugs to avoid major or prolonged adverse reactions, and the doses increased subsequently or changed to longer-acting versions. The exceptions to this rule are the treatment of life-threatening arrhythmias or prevention of coronary artery spasm or acute occlusion, when known full effective doses that will cover the entire 24 hours of the day should be introduced, and the doses reduced or changed to alternatives if side-effects become intolerable. p-Blockers The most successful agents in secondary prevention of further coronary events following myocardial infarction are the (3-blocking drugs. Despite differences in the pharmacology of different agents, it is likely that this effect is common to the whole class of drugs, the only exceptions being those with high intrinsic sympathomimetic activity, such as oxprenolol. Sudden death and reinfarction appear to be successfully prevented. Data from all the randomized trials suggest a 10-25% reduction in mortality. Most events occur within the first 6-12 weeks of infarction. Treatment with (3-blockers is therefore recommended for at least 3 months, and in high-risk individuals for a year. Patients at very low risk of reinfarction or death may not require this form of treatment.
Case 12.6
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ACE inhibitors In clinical trials involving some 105 postinfarction survivors, ACE inhibitors have been shown to reduce mortality significantly by 5-27%, the greater reduction being in patients with clinical heart failure or demonstrable left ventricular dysfunction after infarction. Although mortality reduction is demonstrable when ACE inhibitors are given to unselected patients post infarct, the overall statistical extension of life achieved thereby amounts to only a few days. Hence this approach may not be considered cost-effective. Initiating ACE inhibitors too early following an acute infarction was associated with no benefit, and in some patients it may be harmful. In patients who benefit most from ACE inhibition (i.e. those with heart failure) it is advisable to delay introduction until the haemodynamic status becomes stable. ACE inhibitors are contraindicated in cardiogenic shock or preshock, and in unstable angina vasodilators with antianginal properties should preferentially be used. The initiating dose should be small to avoid protracted hypotension in unexpected cases, and the dose increased stepwise to a maintenance dose of, for example, ramipril 5mg b.d., lisinopril 10 mg o.d. or trandolapril 4mg o.d. Treatment may need to be continued indefinitely in patients with continuing heart failure requiring chronic diuretic therapy, and in whom there is demonstrable left ventricular systolic impairment, provided the ACE inhibitor is tolerated. Those who have intolerable sideeffects may be considered for angiotensin II receptor inhibition (e.g. with losartan), although whether this drug possesses the same beneficial effects as ACE inhibitors requires further studies. Those with transient failure after infarction may need ACE inhibition for about 6 months when the cardiac remodelling processes have stabilized. Antithrombotics Aspirin is a safe antithrombotic. It is economical and well tolerated in the absence of peptic ulcer disease. Its role after infarction is not well established and the precise dosage is contentious. A very small dose of 75 mg dissolved in lOOmL of water every day, or even alternate days, may have advantages over larger doses, as the desired antiplatelet activity is then achieved without the unwanted inhibition of endothelial wall prostacyclin activity. Other antiplatelet drugs, e.g. sulfinpyrazone and dipyridamole, have no demonstrated advantage over aspirin alone. Ticlopidine and clopidogrel may be used in patients who are intolerant of or allergic to aspirin. Anticoagulants Anticoagulation with warfarin following myocardial infarction has been a topic for controversy for many years. Although a small benefit in survival is apparent, particularly for a small subgroup of compliant elderly patients, there are considerable problems associated with its safe usage over many years. Where warfarin has been com-
pared with aspirin, the benefits are equivalent and sideeffects are equally common, although different. However, aspirin therapy requires much less supervision and hence is preferable for patients and physicians alike. Patients with extensive anterior infarction, with demonstrable intraventricular clot (shown by echocardiography), can have the risk of further emboli reduced by warfarin anticoagulation. The risks of emboli are highest in the first few weeks, hence treatment may only be required for 3-4 months. Lipid-lowering agents As in treatment of any condition, there needs to be a weighing of benefits versus risks. Lipid-lowering agents are no exception in possessing unwanted effects, such that, although they are capable of reducing cardiovascular mortality and morbidity, there was a fear that they might increase non-cardiac deaths. Low-cholesterol and low-fat dieting is much safer, and all infarct survivors should be strongly encouraged to adhere to this recommendation. If the serum cholesterol levels are still elevated (above 5.5mmol/L) despite strict dieting, an HMG-CoA reductase such as simvastatin or pravastatin (10-40 mg o.d.) may be introduced. These drugs have been shown to improve longterm (about 6 years) survival as primary or secondary prevention in subjects with elevated cholesterol, although their effect beyond 10 years is unknown.
Cardiac rehabilitation Rehabilitation is a process whereby patients are helped realistically to regain their physical, mental, social, vocational and employment potential in their community. It is an intrinsic component of the clinical management of cardiac disease. In a climate of limited resources, the patients to be targeted are those with the highest potential for health gain. After myocardial infarction, patients with the highest risks (such as those with heart failure, arrhythmia, angina and hypertension) and those in employment prior to infarction are the ones who should be preferentially entered into rehabilitation programmes. In many centres there has been a tendency to select for rehabilitation those who are already in excellent prognostic categories, and the potential for gain is small. Results of rehabilitation studies suggest a benefit in survival with the additional decrease in other coronary events. The phases of rehabilitation are: 1. Week 1 post infarction, either in hospital or at home (if the patient is not admitted) 2. For a few weeks during convalescence 3. The active outpatient hospital-supervised period - up to 6 months 4. Community and long-term follow-up. Hospital-based rehabilitation programmes usually encompass phases 1, 2 and 3, whereas phase 4 takes place in
the primary care setting, health clubs or cardiac patient support groups. The components of rehabilitation include counselling, psychosocial care, risk factor management, education, exercise training, relaxation therapy and vocational assessment. One purpose of counselling is to explain the medical diagnosis, the results of investigations, the pros and cons of intervention, and the prognosis and implications in sympathetic, positive but realistic terms which patients can understand. Another main objective is to encourage behavioural change rather than simply to provide emotional support. Persistent anxiety and depression occur in about 25% of patients and relatives, and these usually respond to correction of misconceptions and addressing their main concerns. Patients who undergo exercise rehabilitation attain their optimal functional state more rapidly, have fewer visits to their doctors and are more likely to return to work. Formal exercise testing is essential to determine the correct individualized exercise prescription. It can also be used to monitor progress. Patients with a negative exercise test at a good workload have an excellent prognosis, and this information is of great psychological benefit. The type of exercise most beneficial for cardiovascular fitness is aerobic isotonic exercise (e.g. brisk walking, cycling, swimming or jogging). The amount and duration of exercise training that is required to produce benefit is 20 minutes of exercise at 75-80% of the maximal heart rate achieved on exercise testing, 2-3 days per week. Training effects may be seen after 6-12 weeks of this degree of effort. Ventricular function and, possibly, myocardial perfusion improve with prolonged exercise training. Most centres encourage the continued use of -blockers throughout exercise programmes. O
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FURTHER READING ON MANAGEMENT OF MYQCARDIAL INFARCTION SURVIVORS Betteridge D J, Dodson P M, Durrington P N et al 1993 Management of hyperlipidaemia: guidelines of the British Hyperlipidaemia Association. Postgrad Med J 69: 359-369. Cleland J G F 1995 Clinical perspective. ACE inhibitors for myocardial infarction: how should they be used? Eur Heart J 16: 153-159. Scandinavian Simvastatin Survival Study Group 1994 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383-1389. Shepherd J, Cobbe S M, Ford I et al 1995 West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333:1301-1307. Smith G D, Song F, Sheldon T A 1993 Cholesterol lowering and mortality: importance of considering initial level of risk. Br Med J 306:1367-1373. Tan L B, Ball S G 1994 ACE inhibition after myocardial infarction. London: Science Press, pp. 1-78. Thompson B R, Bowman G S, Kitson A L, de Bono D P, Hopkins A 1996 Cardiac rehabilitation in the United Kingdom: guidelines and audit standards. Heart 75: 89-93.
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TABLE 12,34 Causes of myocarditis Cause
Example
Viral
Coxsackie B, but a wide range of enteroviruses, echoviruses, adenoviruses, polio, influenza Chlamydia and coxiella (Q fever) Infants and immune-compromised adults T. cmzi (Chagas1 disease of S. America) Often toxin-mediated, e.g. diphtheria Radiation, severe hypothermia Emetine, carbon monoxide
Rickettsiae Toxoplasma Trypanosomiasis Bacteria Physical Drugs and poisons
DISEASES OF HEART MUSCLE
MYOCARDITIS The causes of myocarditis are shown in Table 12.34. In the Western world the commonest causes are viral, of which the most important are Coxsackie B and echovirus infections. Toxoplasmosis affects the myocardium in the neonate. Trypanosoma cruzi is the major cause of infective heart muscle disease in South America and is discussed on pages 354-355. Acute viral myocarditis may complicate many severe viral infections and has been described with almost all common viral diseases. Clinically important myocarditis is uncommon, but ECG changes, possibly due to myocarditis, are more frequent.
Clinical features A febrile illness followed by acute unexplained heart failure, cardiac arrhythmias and chest pain are the main presenting features of myocarditis. Chest pain usually results from a myopericarditis. An arrhythmia, such as frequent ventricular ectopic beats, is probably the most frequent manifestation of a mild attack of myocarditis, and is often seen after any viral infection. The physical signs may include gallop rhythm and heart failure with cardiac enlargement.
Diagnosis and investigation Diagnosis is made on the basis of the history and an ECG, which may show a variety of arrhythmias, conduction defects, and myocardial injury with ST and T-wave abnormalities. An echocardiogram is helpful in diagnosis and
Fig.
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12.24
shows reduced ventricular contractility. Endomyocardial biopsy is occasionally necessary to make the diagnosis. This technique is used to obtain a small piece of myocardium for histological examination. In acute myocarditis there is a marked lymphocytic and inflammatory cell infiltrate. Necrosis of myocytes is seen and, often, interstitial fibrosis. Later in the disease the histological appearances become less marked and merge into those of congestive (dilated) cardiomyopathy (see below).
Management Strict rest is advised until symptoms and signs and ECG abnormalities have resolved. Strenuous exercise is prohibited during this period. Cardiac arrhythmias are treated. Anticoagulants should be considered, as intraventricular clots are common. Although most patients make an apparently full recovery, about 15% have a poor prognosis with continuing evidence of cardiac enlargement and, in some cases, of progressive heart failure. These patients may only be saved by cardiac transplantation. It seems likely that some patients will progress to a dilated cardiomyopathy. Immunosuppressive therapy may be helpful in the more severe cases when they present in the early phases of myocarditis, preferably with histological confirmation of the diagnosis.
CARDIOMYOPATHIES Cardiomyopathy is the term used to describe heart muscle disease, and is usually only used when hypertension and coronary artery disease have been excluded. Cardiomyopathy is more frequent in people of African origin - not only in Africa and the Caribbean, but also in the UK. The reasons for this are still unknown. Cardiomyopathies are now classified into three main groups, shown in Table 12.35.
Dilated cardiomyopathy Dilated cardiomyopathies (DCM, also called congestive cardiomyopathy - COCM) comprise half or more of patients diagnosed with cardiomyopathy. The aetiology is usually not identifiable, because an identical clinical histological and pathological picture can arise after damage to the heart from many causes, including toxins (such as cobalt), drugs (such as adriamycin), or following an attack of acute myocarditis. Chronic alcoholism is associated with DCM, and, as alcohol has a direct suppressant effect on the heart, it is thought to be an aetiological agent in many cases. Other causes are given in Table 12.35. Clinical features Presymptomatic DCM may be present for several years without coming to the notice of a doctor unless there is a routine chest X-ray. At this stage there may be some
12
TABLE 1245 Types of cardiomyopathy' Type
Features
Causes
Dilated cardiomyopathy (DCM)
Large cavity, poor contraction. AV valve regurgitation. Low ejection fraction
Hypertrophic (obstructive) cardiomyopathy (HCM or HOCM) Restrictive cardiomyopathy
Idiopathic ventricular wall thickening, often asymmetric. Small cavity. High ejection fraction Thick-walled ventricle or fibrosed endocardium restricts filling, but systolic function (ejection fraction) maintained. Much less common
High percentage unknown (idiopathic) Following myocarditis of any cause Alcohol, cobalt, adriamycin, daunorubicin Systemic illness: amyloid; sarcoid; haemochromatosis Usually familial, may be sporadic, Similar picture may arise in the elderly, secondary to hypertension/aortic stenosis Endomyocardial fibrosis and Lb'ffler's endocarditis Amyloid; sarcoid; haemochromatosis
*Some patients may have features of more than one type of cardiomyopathy, e.g. dilated and restrictive, and individual diseases, such as haemochromatosis, may commonly have features of both.
diminution in maximum effort tolerance, but unless the subject concerned is an athlete, this usually goes unnoticed or is ascribed to normal ageing. Later on, symptoms are dominated by heart failure in severe cases, with both left- and right-sided failure being eventually intractable. AF and thromboembolism are frequent complications and 10% of patients have recurrent chest pain or angina on effort, despite normal coronary arteries. The clinical picture is of a dilated heart that contracts very poorly, with a markedly reduced ejection fraction and a high filling pressure. Physical examination usually reveals cardiomegaly, with a gallop rhythm. Both mitral and tricuspid regurgitation are common when the patient presents in heart failure, and are secondary to the ventricular dilatation. Investigation Chest X-ray reveals the cardiomegaly, which often involves all the chambers of the heart. O The ECG is non-specific and may show features of ventricular hypertrophy, Q waves and widespread T-wave inversion. Echocardiography can be used to exclude a pericardial effusion and haemodynamically significant valve disease. The distinction between cardiomyopathy with mitral regurgitation and heart failure due to valvular disease is important and can be made by echocardiography, which shows vigorous LV contraction when the valvular disease is primary. Management and prognosis When these patients present with heart failure the prognosis is poor, with a 50% mortality in the following 2 years. Treatable causes of heart failure, such as valve disease, must be excluded, and endomyocardial biopsy may be necessary in the young patient to exclude an active myocarditis. Heart failure is treated conventionally (p. 493). Anticoagulation is advised if a high risk of thromboembolism exists.
Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is characterized by marked left ventricular wall thickening and a small left ventricular cavity. Usually, the wall thickening is asymmetric and predominantly affects the interventricular septum; this is known as asymmetrical septal hypertrophy (ASH). The hypertrophy can lead to left ventricular outflow obstruction with abnormal systolic anterior motion (SAM) of the mitral valve; when this occurs, there is almost always a variable degree of mitral regurgitation. The condition is then known as hypertrophic obstructive cardiomyopathy (HOCM). Similar processes can occur, but less frequently, on the right side of the heart, and sometimes both sides of the heart are involved. Aetiology and pathology There is a familial incidence of HCM. It is inherited as an
RECENT ADVANCES IN GENETICS OF HYPERTROPHIC CARDIOMYOPATHY CARDIOMYOPATHY
OF
Hypertrophic cardiomyopathy is a phenotypically and genetically heterogeneous disorder linked to at least four different loci on chromosomes 1, 11, 14 and 15. Three of the disease genes have been identified, encoding for proteins of cardiac |3-myosin heavy chain ([3MHC), cardiac troponin-T and a-tropomyosin. Other loci and genes remain to be identified. In each of these genes, different mutations have been identified which are statistically associated with different disease manifestations and severity. In clinical practice, the identification of these genes and mutations may aid earlier diagnosis and provide prognostic information, complementing information from clinical assessments. However, the implications of these on the treatment and counselling of patients have yet to be evaluated.
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autosomal dominant, but sporadic examples account for most cases. The condition may be mild and show only on echocardiographic examination. Some cases have associated 'triggers' for left ventricular hypertrophy, such as hypertension or aortic valve disease, but there is usually no obvious cause. On microscopy the muscle fibres are thickened and appear to be arranged haphazardly. The appearances are not specific. One theory suggests that the geometrical arrangement of the fibres is such that they pull antagonistically during systole, and that this results in myofibrillar hypertrophy and disruption. A number of genetic mutations have been identified in families with HCM. Statistically, some mutations are associated with a very high risk of premature arrhythmic deaths, but others are associated with a more benign course. When confirmed, these findings will have fundamental implications for managing the disease and for the screening of affected families. Clinical features Syncope and palpitations from a variety of arrhythmias are common and sudden death may occur. Angina can develop without coronary artery disease. The thickened myocardium can produce an inflow obstruction and lead to heart failure from a raised filling pressure. In later stages there is an enlarged heart and a risk of systemic embolism. The physical signs depend on whether there is outflow obstruction. In its absence there may only be third or fourth heart sounds and a rather muscular feel to the left ventricular impulse. In the presence of outflow obstruction, systolic ejection is shortened, there is a jerky carotid pulse (compared with a sustained and weak pulse in aortic stenosis) and the apex beat has a characteristic presystolic lift. Outflow obstruction produces a harsh late systolic murmur, which may be masked by a pansystolic murmur of coincidental mitral regurgitation. The ejection murmur becomes louder on forced expiration or with the Valsalva manoeuvre (creating a positive intrathoracic pressure), or an inhalation of amylnitrite or administration of an arterial vasodilator or positive inotropic agent (e.g. isoprenaline). It becomes diminished on deep inspiration or with Mueller's manoeuvre (creating a negative intrathoracic pressure), or the administration of an arterial vasoconstrictor, owing to the diminution of the ventriculoarterial pressure gradient. The presence of exertional angina, exertional syncope and a systolic murmur with left ventricular hypertrophy can easily lead to a mistaken diagnosis of aortic stenosis. Although the physical signs differ from those of true aortic stenosis, echocardiography has proved invaluable in establishing the correct diagnosis.
Q MCQ 12.21
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A significant number of sporadic cases are discovered at autopsy in young people, not infrequently when they have collapsed during physical activity or sport. Investigation Chest X-ray is often unremarkable in the absence of heart failure. The ECG is non-specific, showing left ventricular hypertrophy and, occasionally, Q waves. Echocardiography demonstrates the left ventricular wall thickening, particularly ASH, and, with obstruction, shows SAM of the mitral valve (see above). Two-dimensional echocardiography shows that the septal hypertrophy can be a localized bulge, and also the high ejection fraction. Careful echocardiographic examination is required not to miss isolated apical hypertrophic cardiomyopathy. Doppler ultrasound will demonstrate the mitral regurgitation, as well as the highvelocity jet in late systole that develops in the outflow tract of the left ventricle in the presence of obstruction. Cardiac catheterization and angiography are necessary to confirm normal coronary arteries, to judge the degree of mitral regurgitation and to measure the apex-to-base pressure gradient in the left ventricle. Manoc/emenf Sudden death is a continuing hazard even with antiarrhythmic therapy, and various agents are used to control symptoms of palpitations without apparently preventing sudden death. (3-Blockers can abolish outflow obstruction, and may help in the management of heart failure. Calcium antagonists, such as verapamil, have been used to reduce ventricular hypertrophy, with variable results. Both types of drug slow the heart rate and aid diastolic function. Surgical intervention has been used quite extensively, with mitral valve replacement and outflow tract myomectomy being used to abolish outflow tract obstruction. There is a high surgical mortality and, unless the myomectomy is radical, outflow tract obstruction can recur. The role of surgery therefore remains controversial. More recently, therapeutic embolization of septal branches of the left anterior descending artery has been shown to reduce outflow obstruction, leading to clinical improvement. Screening of siblings of those affected reveals a high incidence of mild degrees of asymptomatic asymmetrical hypertrophy. Investigation and monitoring of these subjects may eventually enable the mortality and morbidity of this condition to be reduced, but may also cause great anxiety in an asymptomatic individual.
Restrictive cardiomyopathies O There is a small subgroup of heart muscle disorders characterized by a very high filling pressure to the ventricles resulting from rigidity of the walls owing to infiltration with abnormal tissue. Reasonable systolic function is usually maintained. Clinically, such restrictive cardiomyopathies present with very similar features to constrictive pericarditis, with evidence of severe heart failure and a relatively small heart.
Cardiac amyloid Cardiac amyloid is the commonest cause of death in primary amyloidosis (Ch. 23, p. 1263). The gastrointestinal tract and tongue are often also involved, as are the nerves and skin. Presentation is either with heart failure secondary to poor systolic function (like a DCM), or with severe right heart failure secondary to a restrictive pattern. There may be evidence of tricuspid and mitral regurgitation with a loud gallop rhythm, and echocardiography shows thickening of the ventricular walls with a small left ventricular cavity. Characteristically, the ventricular walls, infiltrated by amyloid, have a very bright echo appearance, and there may be conduction abnormalities which may require a pacemaker. The diagnosis may be confirmed by rectal or gingival biopsy or, sometimes, by cardiac biopsy. There is no specific treatment for these patients, who fortunately present late in life. Haemochromatosis and transfusion haemosiderosis Overload of the body with iron can damage the heart. Haemochromatosis is a genetic disease in which iron overload occurs (see Ch. 16, p. 868). Transfusion haemosiderosis is caused by repeated blood transfusion (usually more than 100 units) for chronic anaemias, such as thalassaemia, and results in similar tissue loading with iron. The iron damages the liver, heart, gonads and pancreas, causing hepatomegaly, heart failure, gonadal dysfunction and diabetes. There is a characteristic dusky skin pigmentation. Cardiac manifestations are found in the majority of patients. Cardiac involvement does not necessarily parallel other organ involvement, although cardiac failure is always associated with high levels of iron in the heart. There is usually myocardial thickening and dilatation, and so the patient presents with features of both a dilated and a restrictive cardiomyopathy. The diagnosis is based on demonstration of excessive iron in the body, with the serum ferritin being particularly high. Cardiac findings are of heart failure and arrhythmias both supraventricular and ventricular - with disorders of conduction. There may be a low-voltage ECG. The main aim of management should be to reduce body iron levels by chelation or, in the case of haemochromatosis, by repeated venesection.
Cardiac carcinoid In the carcinoid syndrome, where a carcinoid tumour (usually ileal) has metastasized widely, over 50% of patients have cardiac involvement, consisting of endocardial plaques of fibrous tissue. This is almost always on the right side of the heart and involves the tricuspid and pulmonary valves, the vena cava and the coronary sinus, producing distortion and valvular stenosis. Serotonin and kinin peptides produced by the tumour are normally inactivated in the liver and lung; thus the left side of the heart is protected. Clinically, the patient has the systemic manifestations of
carcinoid syndrome: flushing, diarrhoea and, sometimes, bronchoconstriction. In addition, there are symptoms and signs of right heart failure, often with pulmonary stenosis and tricuspid regurgitation. The circulating vasodilators may also produce a hyperkinetic circulation with highoutput heart failure.
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Sarcoidosis Between 20% and 30% of autopsied cases of generalized sarcoid show cardiac involvement, although clinical manifestations are present in only about 5% of patients. Presentation may be with a cardiomyopathic picture of either the dilated or the restrictive type, although it can also present with conduction abnormalities, heart block and sudden death. Heart block in a young patient may be the first manifestation of sarcoid. Diagnosis and management In the presence of the classic pulmonary findings diagnosis does not require myocardial biopsy, but where there is doubt a biopsy can be extremely helpful. Isotope and magnetic resonance imaging may show infiltration. Treatment is on the whole unsatisfactory. Pacing may reduce the risk of sudden death in patients with conduction system damage, and large doses of corticosteroids are usually advocated in an attempt to prevent progressive myocardial infiltration. Endomyocardial fibrosis Endomyocardial fibrosis is relatively common in regions of Africa, particularly Nigeria and Uganda, where it accounts for more than 20% of cardiac deaths. It is also found in other tropical areas and, occasionally, in Europeans who have been resident in endemic areas. Pathologically, there is gross fibrous thickening of the endocardium of one or both ventricles, usually associated with severe AV valve regurgitation. It commonly presents in young people of both sexes, often from low-income groups. Clinical features The clinical presentation of endomyocardial fibrosis depends on whether one or both ventricles are involved. The disease may be heralded by fever, but usually presents with severe heart failure and sometimes arrhythmias. The heart is not usually markedly enlarged, although pericardial effusion is not uncommon. Clinical signs of valvular regurgitation and heart failure predominate. Systemic and pulmonary emboli may complicate the clinical course. Echocardiography, particularly 2D scanning, may demonstrate the thickened endocardium, which can obliterate parts of the ventricular cavity. Intraventricular clot may also be shown. Surgical excision of the thickened endocardium, with tricuspid and mitral valve replacement, has given some encouraging results in a disease that appears to have, for most, a relentless progression. Endocardial fibroelastosis Endocardial fibroelastosis is a condition of infancy, in
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which there is gross thickening of the endocardium, with subsequent heart failure. It may present as a primary condition or follow aortic stenosis, other left-sided heart conditions or cardiac surgery in which endocardial perfusion may have been at risk. Loffler's endocarditis Loffler's endocarditis - a syndrome of prolonged eosinophilia with associated localized or widespread eosinophilic infiltrates - involves the heart in over 90% of cases. The hypereosinophilic syndrome is most commonly idiopathic, but may occur with eosinophilic leukaemia or secondarily with Hodgkin's disease, polyarteritis nodosa, tumours and parasitic infestation. The clinical picture is of a severe progressive cardiomyopathy with a restrictive picture, often with systemic embolism, in a patient with a wasting disease and marked eosinophilia. The disease process starts as an eosinophilic myocarditis, and progresses with the formation of multiple endocardial thrombi. In the third stage there is fibrosis and a hyaline membrane forms over the endocardium. The disease thus has some similarities to endomyocardial fibrosis. The clinical course of the disease can be from a few months to 12 years.
This usually occurs in someone with a pre-existing severe disease. Over the last two decades the clinical spectrum of infective endocarditis has changed greatly. This is owing to the gradual decline in the numbers of patients with rheumatic heart disease, an increase in the number of patients who have had cardiac surgery, invasive investigation being used in elderly patients, and the epidemic of intravenous drug abuse. Nowadays, infective endocarditis occurs quite frequently in elderly patients with degenerative disease of the heart valves and in whom there is no evidence of either rheumatic or congenital heart disease. Furthermore, infective endocarditis is not easily divided into the subacute and acute forms. There are a wide range of infective agents of different virulence, and the same organism, such as Staphylococcus aureus, can behave quite differently on different occasions, depending on the patient's host defences and the particular strain of organism. The intravenous drug abuser may develop infective endocarditis with a variety of unusual organisms, sometimes on apparently normal valves and quite commonly on the tricuspid valve. Bacteria are not the only causes of infective endocarditis. Fungal and rickettsial infections, as well as viral infective endocarditis, can occur. For these reasons, the more general term infective endocarditis is preferred to the earlier classification.
INFECTIVE ENDOCARDITIS
Pathogenesis Infective endocarditis is a multisystem disease caused by infection of the heart valves or adjacent endocardium. It is characterized by prolonged fever, weight loss, embolic phenomena and renal failure.
Classification Until recently, it was usual to divide the disease into two groups: • Subacute bacterial endocarditis • Acute bacterial endocarditis.
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Subacute bacterial endocarditis (SEE) affects relatively young patients with an identifiable pre-existing cardiac abnormality, usually rheumatic valvular heart disease or a congenital abnormality of the heart associated with a jet lesion. The heart valves become infected with an organism of normally low virulence which slowly forms vegetations on the damaged valve and produces progressive valvular regurgitation. This is accompanied by intracardiac abscesses, embolic episodes and a slow, wasting fever, often associated with evidence of formation of immune complexes, leading to glomerulonephritis. Acute bacterial endocarditis occurs in immunocompromised patients or those suffering from a staphylococcal septicaemia. Apparently normal mitral or aortic valves are rapidly destroyed in the course of 24-48 hours, resulting in torrential regurgitation and death from heart failure.
Pre-existing cardiac lesions Endocarditis usually develops in congenitally abnormal or rheumatic hearts in which there is a 'jet' lesion. The altered flow of blood allows bacteria to impact directly on the endocardial surface. Previous damage to the endothelium (e.g. as a result of rheumatic heart disease) facilitates colonization by bacteria present in the bloodstream, which stick to the endocardial lesion and multiply. A chronic lesion, such as one produced by a jet of blood impinging on the endocardium, remains susceptible. However, transient lesions, such as those produced by passing a cardiac catheter or cannula through the heart valves for as little as 15 minutes, heal rapidly and, as a result, rarely become infected. Bacteraemia Transient bacteraemia is common with trauma to the mouth and teeth; the organism most commonly present, Streptococcus viridans, is also very likely to stick to an endocardial lesion and colonize it. Gram-negative bacilli, which can be grown from the blood in Gram-negative infections and at the time of urogenital manipulation and surgery, are less likely to cause endocarditis and stick less readily to endocardial lesions. In practice, any surgical procedure involving manipulation of any organ or part of the body not normally bacteria-free should be regarded as a potential cause of bacteraemia.
Infective endocarditis may occur following a chest or urinary infection or septicaemia. It can also occur following a variety of operative and investigative procedures, but the risk of these procedures producing a bacteraemia is variable. Minor medical procedures that may provoke bacteraemia include the following: • Dental extraction and manipulation. Transient bacteraemia with streptococci and some enterococci lasts from 15 minutes to several hours. Chewing can cause bacteraemia even in edentulous individuals. • Oropharynx. Tonsillectomy, rigid bronchoscopy, orotracheal intubation and nasopharyngeal suction. • Gastrointestinal tract. Barium enema, sigmoidoscopy and colonoscopy. • Urogenital tract. Urinary catheterization, prostatectomy and prostatic massage have all been found to produce a bacteraemia, but normal vaginal parturition does so only occasionally. • Intravenous cannulae. These are a potential source of bacteraemia and should not be used unnecessarily in patients at risk. Growth of the vegetation The vegetation grows as a concretion of bacteria and the reaction of the blood to their presence. The bacteria become covered in platelets and layers of fibrin. The exuberance of the vegetation depends on the organism. Fungal infections with Candida produce large vegetations which can even occlude the orifice of prosthetic valves. Other organisms may provoke so little reaction that the vegetations are too small to be demonstrated by echocardiography (which has a maximum resolution of a few millimetres). Infection can perforate the valve cusps and track into the adjacent myocardium and valve ring, causing abscesses and a variety of complications, depending on the site. These include fistula formation, bundle branch block, complete heart block, infective pericarditis and papillary muscle and chordal rupture. Embolism and immune complex manifestations Embolism of fragments of infective vegetation can produce embolic abscesses in the spleen, kidneys, brain and elsewhere, with 'mycotic' aneurysm of the arterial wall which may result in rupture and sudden haemorrhage. Embolic episodes result in cerebral and peripheral ischaemic attacks, transient haematuria, splenic infarcts and coronary occlusion. Long-standing infection leads to the formation of immune complexes, which may themselves complicate the presentation and course of the disease. These complexes are probably responsible for the glomerulonephritis that may accompany infective endocarditis, and for the skin lesions. Valve involvement The frequency of involvement of the four cardiac valves
is in direct relationship to the mechanical loading on the valves, i.e. mitral, aortic, tricuspid and pulmonary, in descending order of frequency. This is related to the much higher jet velocities usually found on the left side of the heart, although the very low incidence of involvement of the pulmonary valve in pulmonary stenosis remains unexplained. Untreated infective endocarditis of the aortic valve may lead rapidly to infection of the mitral valve, as the regurgitant jet of blood through the aortic valve most commonly strikes the anterior cusp of the mitral valve. Tricuspid valve endocarditis leads to a picture of recurrent lung 'pneumonitis' of a patchy nature caused by embolism of vegetation and organisms into the lung.
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Infecting organisms Streptococci About 50% of cases of infective endocarditis are caused by cx-haemolytic streptococci from the mouth and oropharynx, formerly classified as Strep, viridans but now subdivided into many organisms, e.g. Strep, mitior and Strep, sanguis. These organisms are most likely to reach the bloodstream after dental extraction or manipulation, bronchoscopy, and tonsillectomy and adenoidectomy. The enterococci of group D streptococci have become more frequent causes and can be found in the gastrointestinal tract, genitourinary tract and periodontal tissue. Accurate identification is sometimes difficult, and the prognosis is worse than for Strep, viridans infection. Strep, bovis, a non-enterococcal organism from group D, is an increasingly common finding in infective endocarditis, and the disease in these cases is very similar to that caused by Strep, viridans. Strep, pneumoniae is a less common agent but still causes some cases of acute infective endocarditis; the infection may be complicated by meningitis. Anaerobic streptococci, organisms that are initially difficult to grow, are found increasingly frequently but necessitate anaerobic cultures. The discovery of Strep, faecalis should lead to investigation of the gut, as colonic carcinoma may be an underlying cause. Staphylococci A staphylococcal septicaemia with Staph. aureus often involves the heart valves; if several positive cultures are obtained, a prolonged course of antistaphylococcal therapy is indicated even without definite evidence of cardiac pathology. Acute endocarditis can damage apparently normal valves very quickly. The same organism can produce a subacute picture. It is a frequent finding in intravenous drug abusers and diabetics with endocarditis. Staph. epidermidis (albus} may be grown as a contaminant of blood cultures, but repeated positive cultures are significant as it is a common cause of infective endocarditis, both in patients with prosthetic valves and in intravenous drug abusers. It is occasionally found in patients with indwelling subcutaneous intravenous lines. Many
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months may pass between the introduction of the infection and the presentation with endocarditis. Other organisms Neisseria gonorrhoeae and Gram-negative bacilli are relatively uncommon causes of infective endocarditis, but Pseudomonas is becoming more frequent. Q fever endocarditis is uncommon and is diagnosed by finding a rising titre of antibodies in the blood. Fungal endocarditis occurs with prosthetic valves and in patients who have had prolonged periods of antibiotics or corticosteroids, or who are intravenous drug abusers.
Clinical features The clinical features of infective endocarditis can be divided into several categories. Features of chronic infection The features of chronic infection include a remittent pyrexia, myalgia, arthralgia and general fatigue. These symptoms are accompanied by anaemia, anorexia and weight loss. Splenomegaly may be present but is usually not marked. Splenic infarction can lead to pain and a friction rub over the spleen. A splenic abscess can delay resolution of the fever. In long-standing cases cachexia and mild finger-clubbing may occur. Cardiac manifestations Heart murmurs are present in over 85% of cases but may easily be missed, especially in the presence of heart failure. Early diastolic murmurs are notoriously difficult to hear, and a wide pulse pressure is often the first clue that aortic regurgitation is present. Changing heart murmurs are uncommon but, when present, are very suggestive of the diagnosis. Cardiac arrhythmias and conduction abnormalities may follow the spread of infection from the valve ring to form myocardial abscesses. Heart failure can be a presenting symptom. Its presence signifies a poor prognosis and is an indication for early surgery. Sudden heart failure can occur with rupture of a valve cusp or chordae tendinae, or sinus of Valsalva aneurysm. Systemic embolism Embolism is a prominent feature of infective endocarditis and the presentation may be with a cerebrovascular event (e.g. a dense hemiplegia), an ischaemic limb, mesenteric embolus or haematuria from renal infarction. Over 50% of cases exhibit embolic phenomena: fungal endocarditis with large friable vegetations is notorious for producing large emboli. Right-sided endocarditis usually presents with recurrent patchy consolidation (pneumonitis).
Fig.
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12.25
Fig.
12.26
SUMMARY 10 Clinical features of infective endocarditis Infection
Fever, anorexia, weight loss, splenomegaly, cachexia, clubbing. Also arthralgia, bone pain
Cardiac
(History of cardiac murmur, bacteraemic procedure) New heart murmur, increasing valvular regurgitation, conduction disorders
Systemic embolism (about 50%) Arterial Pulmonary
Immunological Renal Skin
CVA, mesenteric, renal Infective emboli cause abscesses and arterial rupture. Recurrent pneumonitis Glomerulonephritis leading to renal failure Nails - splinter haemorrhages Conjunctival and buccal mucous membranes - petechiae Finger and toe tips - Osier nodes Thenar and hypothenar eminences - Osier nodes and Janeway lesions Retina - Roth spots and boatshaped haemorrhages
Immunological phenomena Renal A diffuse glomerulonephritis is present in many patients and is due to the deposition of immune complexes. The renal disease is shown by proteinuria and microscopic haematuria. In untreated endocarditis the blood urea begins to rise, but renal failure develops in less than 10% of cases. Even when advanced, renal failure recovers with adequate treatment of the infective endocarditis. Skin and mucous membranes Typical skin manifestations of infective endocarditis were much more common in the pre-antibiotic era, but are now seen in only 20^0% of cases. Thorough examination of the patient's skin, the mucosae of the oropharynx, conjunctivae and retinae should be repeated during the course of the disease, to check for new lesions. Petechial haemorrhages. Examination of the soft palate, pharynx, conjunctivae, hands, feet and anterior body wall may reveal petechial haemorrhages, often with a pale centre. Subungual or 'splinter haemorrhages' are usually seen as a faint dark line away from the nail margin in the fingers and, occasionally, the toes. O They may also be seen in patients who are debilitated for other reasons, or after trauma. When present, they occur in 'bursts' and indicate disease activity.
Osier nodes are painful, nodular, red to purple lesions that usually form on the fingertips 0 but can also occur on the backs of the toes, soles of the feet, the thenar and hypothenar eminences and, occasionally, elsewhere. Formerly common, they are now seen in less than a fifth of cases. The lesions can last a few hours to a few days. Janeway lesions are painless, 1-4 mm erythematous macules which are most common on the thenar and hypothenar eminences and the soles of the feet, and which blanch on pressure. Retinal lesions. The Roth spot is a 'cottonwool exudate' consisting of a perivascular collection of lymphocytes. It is not specific to infective endocarditis. Boat-shaped haemorrhages with a pale centre and white spots have also been described. All of these retinal and cutaneous lesions have been ascribed to 'septic emboli', but are now thought to be immunological manifestations of the disease.
Diagnosis Infective endocarditis is a possible diagnosis in any patient with a fever and a heart murmur, and is established by taking blood cultures. A patient with a heart murmur may have an intercurrent viral infection or some other cause for fever. Where the source of the fever is not clear, it is essential to take blood cultures before starting antibiotics, should they be considered necessary. This is especially important when a patient at risk of endocarditis develops a fever following a procedure that has not been covered with antibiotic prophylaxis. Any febrile patient who has had open heart surgery (other than coronary bypass grafting) should be considered at risk from infective endocarditis, even if no murmur is evident. In the elderly patient, endocarditis can exist without significant fever. Other signs of chronic infection, such as unexplained anaemia and high ESR in a patient with a heart murmur, should arouse suspicion and lead to blood cultures being taken. Echocardiography is an essental investigation in any patient with suspected endocarditis. It will demonstrate vegetations greater than 1 mm and document valvular and ventricular function. Blood cultures Blood cultures should be taken on six to eight occasions over the first 48 hours. It is not necessary to wait for peaks of fever. Anaerobic cultures should be taken and, although a higher percentage of positive cultures has been claimed for arterial blood culture, venous sampling is usually sufficient. Close liaison with the laboratory is essential so that any organism that grows is kept in subcultures and not discarded. Appropriate culture techniques can then be instituted for poorly growing organisms. Where the clinical evidence of the disease is overwhelming, especially if there is evidence of deteriorating valve function, antibiotic therapy may be started as soon as four to six cultures have been taken and before positive
cultures are reported by the laboratory. There is, however, an inevitable risk that this may interfere with identification of the organism if the initial cultures are negative. Where infective endocarditis is a high probability, and particularly if Strep, viridans is grown from blood culture, a dental opinion on possible septic foci in the mouth should be obtained. It is then possible to time any dental extraction or other dental work to follow by 1 hour or so the initiation of antibiotic therapy. This then removes the possibility of septic foci in the mouth harbouring antibiotic-resistant organisms which can then superinfect the heart after the initial organisms have been eradicated.
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Culture-negative endocarditis In 20% of cases no organisms are grown, despite many other features of the disease being present. This may occur because the patient has been treated with an antibiotic (which may render cultures negative for days or weeks after stopping treatment), because the organism involved is present in very small numbers, or because it is difficult to culture. Even in average cases of endocarditis there may be only 100 organisms per mL of blood and, particularly in long-standing cases with renal failure, the patient's antibodies may render the blood almost sterile, despite the presence of organisms in large vegetations. Repeated blood culture samples of l0mL should be inoculated into 100 mL of culture broth and incubated aerobically and anaerobically. The organisms may require special nutrients and may not grow for several days, or, in a few cases, for several weeks. If repeated cultures are negative, or the patient's condition is deteriorating, it may be necessary to embark on treatment without positive cultures. This course of action must only be followed after close consultation with a microbiologist, who may suggest unusual sampling techniques (occasionally bone marrow or urine is positive when blood is not), and after blood has been taken for fungal and rickettsial antibodies.
Management Successful treatment of infective endocarditis should involve close cooperation between physician and microbiologist. In uncomplicated cases 4-6 weeks of bactericidal antibiotic therapy is required, with serum levels of antibiotic sufficient to penetrate the vegetations and abscesses and eradicate the organism. Bacteriostatic antibiotics and bacteriostatic levels of bactericidal antibiotics are not suf-
SUMMARY 11 Features suggestive of infective endocarditis • • • • •
Fever Evidence of chronic infection A heart murmur suggestive of a jet lesion Positive blood culture on more than one occasion Presence of vegetations on echocardiography
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ficient, even with the host's natural defences, to eradicate the organism. Antibiotic therapy Although oral antibiotic therapy can be used for sensitive Strep, viridans infection, the intravenous route is preferred for initiating therapy and while awaiting 'back titrations'. For intravenous therapy a central venous catheter may overcome the problems of superficial venous cannulae. All cannulae must be inserted under strict aseptic conditions and kept scrupulously clean to prevent the risk of superinfection with fungi. They should be changed at least every third day. After culture and identification of the organism, its antibiotic sensitivity must be urgently assessed. The bacteriology laboratory assists by monitoring the patient's blood levels of antibiotic and titrating to determine what serum dilutions are bactericidal to the organism in culture. A level of 1 in 8 is considered satisfactory. It is essential that the antibiotic regimen for an acute septicaemic endocarditis include antistaphylococcal antibiotics. Where a subacute infection is being treated it is usual to use wide-spectrum antibiotics, such as gentamicin and ampicillin. The response to treatment is then monitored and the treatment changed or continued, depending on whether it appears to be controlling the infection. Culturenegative endocarditis, particularly with large vegetations or other indication of severe valvular involvement, may be an additional criterion for early surgical intervention, particularly if potentially hazardous antibiotics are being used. Monitoring treatment Successful antibiotic treatment ideally results in disappearance of the fever within a few days, a fall in the ESR, a rise in the haemoglobin and an increase in the patient's weight and wellbeing. Measurement of C-reactive protein may give a more reliable guide to response than the ESR. Evidence of microemboli, such as fresh splinter haemorrhages and microscopic haematuria, take longer to go, and large vegetations take several weeks to regress. Occasionally, the fever and high ESR do not settle, although repeated blood cultures remain negative. If other causes for persistent fever (e.g. splenic abscess or superinfection) are eliminated, then the fever may be antibiotic induced and disappear with cessation of antibiotic treatment. Surgery Severe valve failure and uncontrolled infection may require emergency valve replacement. If the patient presents with heart failure early surgery is essential, as even with rapid successful antibiotic treatment of endocarditis, damaged valves shrink and fibrose with progressive increase in the degree of valve regurgitation, and the heart
MCQ 12.22
578
Case 12.7
failure may become irreversible. Prosthetic valve endocarditis almost invariably requires valve replacement for the infection to be eliminated. A few days of antibiotic therapy prior to surgery reduces the risk of valve dehiscence from sewing the new valve into an infected valve ring, and reduces the risk of prosthetic valve endocarditis. A heavily infected valve with large vegetations may be electively replaced where there is risk of major embolism, or where the patient cannot be given effective bactericidal therapy. Tricuspid valve endocarditis with large vegetations can be treated by excision of the tricuspid valve without replacement, while the course of antibiotics is given. The prosthetic valve can then be sewn into a sterile ring. Apart from valve replacement, surgical closure of intracardiac fistulas, such as aortic-to-right-atrial shunts, and limited thoracotomy for epicardial pacing for heart block are occasionally required. Prophylaxis The recommended regimens for endocarditis prophylaxis vary slightly, but all are based on the use of a bactericidal antibiotic to cover a procedure likely to produce bacteraemia. If a general anaesthetic is involved, the antibiotic is given intravenously or intramuscularly. If no general anaesthetic is involved, oral preparations are given if possible. Regimens are shown in Table 12.36. A safe general rule is that prophylaxis should be given for all dental work where the teeth are manipulated, all pelvic, colonic and bladder instrumentation, and surgery. Normal parturition does not need routine cover unless the bladder is catheterized or forceps used. OO
SYPHILITIC ENDOCARDITIS Pathogenesis Syphilis is now much less common as a cause of heart disease. Cardiac involvement is a manifestation of the tertiary stage of the disease, which often follows a prolonged quiescent period. An endarteritis obliterans of the vasa vasorum of the aorta weakens the media, which undergoes a slow necrosis and causes thickening and scar formation in the intima. The changes are irregular, and complicated by fibrosis and calcification. Dilatation of the aorta occurs and can be localized, giving a fusiform or saccular aneurysm; it often also involves the valve ring, causing progressive, and often severe, aortic regurgitation. There may be damage to the aortic valve cusps leading to retraction, but never stenosis. Intimal scarring of the aorta can lead to coronary ostial stenosis. The changes do not always lead to overt heart disease. There is a higher percentage of cases of aortic regurgitation and aortic aneurysms in manual labourers with aortitis, than in sedentary men and women with necropsy evidence of aortitis. Thus, it may be that physical activity produces additional loads on the aorta, which induce these changes.
TABLE 12.36 Endocarditis prophylaxis Procedure
Recommendation
1. Dental procedure under local anaesthetic 2. Dental procedure under general anaesthetic 3. High risk - Refer to hospital • Patients with prosthetic valves • Patients allegic to penicillin or who have had penicillin more than once in the previous month • Patients who have had a previous attack of endocarditis 4. Surgery - upper respiratory tract
A
5. Surgery - genitourinary 6. Obstetrics and gynaecological patients 7. Gastrointestinal procedures
Penicillin allergy-B or C D or E or F
G
Pencillinallegy-H H
G
Penicillin allergy-H As 1 and 2 above Any postoperative antibiotic may have to be given intramuscularly or intravenously if swallowing painful Sterile urine, as 1 and 2 Infected urine - prophylaxis should also cover pathogens involved Cover only for patients with prosthetic valves - D or H Cover only for patients with prosthetic valves - D or H
A: Oral amoxicillin 3 g single dose taken under supervision 1 hour before procedure 1 Children under 10- /2dose Children under 5 - V2 dose
B: Oral erythromycin 1.5g under supervision 1-2 hours before procedure Children under 10- 1/2 dose Children under 5 - 1/4 dose
C: Oral clindamycin 600 mg single dose taken under supervision 1 hour before procedure Children under 10 - 6mg/kg body weight single dose taken under supervision 1 hour before procedure
D: Intramuscular amoxicillin 1g in 2.5 ml 1% lidocaine hydrochloride just before induction plus 0.5 by mouth 6 hours later Children under 10 -1/2 dose
E: Oral amoxicillin 3g dose 4 hours before anaesthesia followed by a further 3g by mouth as soon as possible after operation Children under 10- 1/2 dose Children under 5 - Y4 dose
F: Oral amoxicillin and probenecid Amoxicillin 3 g together with probenecid 1 g 4 hours before operation
G: Intravenous amoxicillin and gentamicin 1 g amoxicillin plus 120mg gentamicin intravenously just before induction, then 0.5 g amoxicillin orally 5 hours later Children under 10 - amoxicillin Ys dose, gentamicin 2mg/kg body weight
H: Intravenous vancomycin 1 g slow infusion over 1 hour before procedure followed by gentamicin 120mg intravenously just before induction Children under 10 - vancomycin 20mg/kg, gentamicin 2mg/kg
Clinical features The patient is usually a man (there is a 3:1 sex ratio for uncomplicated aortitis, but this rises to 10:1 for aortic aneurysm) in late middle age.
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Aortic regurgitation The presentation may be with pure aortic regurgitation with evidence (best shown echocardiographically) of a dilated aortic valve ring, and serological proof of previous Treponema pallidum infection. If untreated, the regurgitation tends to be progressive and severe; indeed, the classic 19th century physical signs described for aortic regurgitation are almost all based on patients with severe symphilitic aortic regurgitation (waterhammer pulse, head rocking etc.). With a dilated aortic root, the early diastolic murmur is louder in the third right interspace than the third left interspace. If there is coronary ostial stenosis severe angina is usually present, often leading to status anginosus (continuous pain), heart failure and death, unless there is early surgical intervention. Aortic aneurysm Aortic aneurysm is much less common than regurgitation. It usually occurs in the ascending aorta or arch rather than the descending aorta, where aneurysms are much more likely to be arteriosclerotic. The clinical features depend on the position of the aneurysm. Classically, the ascending aortic aneurysm produces signs of aortic regurgitation, the arch aneurysm symptoms such as dysphagia, cough, pain and dyspnoea, and the descending aneurysm pain from erosion of the spine. Diagnosis and investigation Serological proof of previous spirochaetal infection is usually followed by CSF examination because of the close association with neurosyphilis. Positive serology cannot be taken as proof of syphilitic infection in patients with yaws scars, who often have persistent positive serology even after treatment. However, the combination of aortic dilatation and positive serology would be taken as confirmatory. Arteriosclerotic aneurysms, cystic medial necrosis of the aorta and aortic dissection are now common differential diagnoses. Aortic regurgitation is investigated with particular emphasis on excluding coronary ostial stenosis. Aortic aneurysm is now often investigated by CT scanning. There is often laminated clot in the aneurysm, and classically, in aortitis there is calcium seen in the ascending aorta. The treatment of syphilis is described on page 461. The Herxheimer reaction is particularly dangerous in aortic regurgitation with coronary ostial stenosis. The regurgitation may progress after effective penicillin treatment, owing to further fibrosis. Surgical treatment is as for other causes of aortic regurgitation or aortic aneurysm, after effective chemotherapy.
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FURTHER READING ON INFECTIVE ENDOCARDITIS Dajani A S, Bisno A L, Chung K J et al 1991 Prevention of bacterial endocarditis: A statement for health professionals from the committee on rheumatic fever, endocarditis, and kawasaki disease of the council on cardiovascular disease in the young, the American Heart Association. Circulation 83:1174-1178. Endocarditis Working Party of the British Society for Antimicrobial Chemotherapy 1990 Antibiotic prophylaxis of infective endocarditis. Lancet 335: 88-89.
NON-INFECTIVE ENDOCARDITIS RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE Rheumatic heart disease is now uncommon in western Europe and North America, but is an important historical cause of what was once the bulk of valvular heart disease. It is still important in the developing world as a disease of childhood and a major cause of heart disease. Its decline in western countries started before the widespread use of antibiotics, and probably reflects increased standards of nutrition and hygiene and, possibly, a decline in the virulence and prevalence of Lancefield group A haemolytic streptococci. Rheumatic fever and chorea are the exclusive causes of chronic rheumatic heart disease, in which there is interstitial muscle fibrosis as well as the heart valve disease. However, some 50% of patients with chronic rheumatic heart disease give no history of either condition. Rheumatic fever develops in about 3% of young people exposed to an epidemic strain of (3-haemolytic Lancefield group A streptococcus. These patients usually have pharyngitis, but may have scarlet fever. After an apparent recovery they develop fever, sweats, skin rashes, arthritis and, sometimes, cardiac involvement from what appears to be an autoimmune disease starting 2-4 weeks after the initial sore throat and lasting 6-8 weeks, but occasionally as long as 26 weeks. Some patients give no definite history of an antecedent sore throat. Following the attack of rheumatic fever, some 70% of patients will eventually have evidence of rheumatic valvular heart disease, although the time interval can be as long as 50 years. On the other hand, the valve disease may become manifest during the attack of rheumatic fever, especially where regurgitation develops. Rheumatic fever may be recurrent, and the chances of valve disease increase with the number of attacks.
Pathology
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Although rheumatic fever follows a streptococcal infection, no bacteria are found in the lesions; however, they may still be present in the pharynx. There is an acute inflammatory reaction, with oedema in the affected tissues,
and then granulomatous lesions develop in the myocardium (Aschoff nodules). Oedema of the valve cusps is followed by verrucous fibrin deposits developing along the lines of apposition of the valve cusps, which eventually adhere at the commissures. In the acute illness there is an acute non-bacterial synovitis in the joints, and granulomata may develop subcutaneously on extensor surfaces of the limbs and over the Achilles tendons (rheumatic nodules). There is usually a high antistreptolysin O titre, and other antistreptococcal titres may also be high. It is thought that cross-reactivity between the streptococcal antigens and host tissue antigens leads to an autoimmune inflammatory process.
Clinical features and diagnosis The diagnosis of rheumatic fever depends on criteria proposed by Duckett-Jones (Table 12.37); two major criteria, or one major and two minor criteria, establish a high probability for the diagnosis. The patient is almost always between the ages of 3 and 30 years (usually 5-15); drenching sweats and a prolonged feverish illness occur, with extremely painful arthritis that moves from joint to joint (usually involving large joints such as the knee and elbow), which become hot, red, swollen and extremely painful for a few days and then recover fully. The flitting arthritis is characteristic, as is the classic skin rash, erythema marginatum. Subcutaneous nodules may develop after several weeks, usually over the elbows. Carditis may be pericarditis, myocarditis or, more importantly for the eventual appearance of valve disease, endocarditis. All may occur at once as pancarditis. The pericarditis is similar to any acute pericarditis (p. 586), with precordial pain, ECG changes (raised ST segments) and often an increase in cardiac silhouette on chest X-ray. Myocarditis is manifest by a tachycardia disproportionate for the degree of pyrexia, gallop rhythm and heart failure; there are also ECG changes, such as prolonged PR interval or greater degrees of AV block and T-wave flattening or inversion, and raised serum creatine phosphokinase AV. Death occasionally occurs from myocarditis. TABLE 12.37 Criteria for the diagnosis of rheumatic fever Major criteria
Minor criteria
• • • • •
• • • • •
Polyarthritis Carditis Subcutaneous nodules Chorea Erythema marginatum
Fever Arthralgia Prolonged PR interval on ECG Raised ESR Raised white blood count or C-reactive protein • Preceding p-haemolytic streptococcus infection • Previous rheumatic fever or inactive heart disease
Endocarditis is indicated by transient or changing murmurs. The classic murmur, which is specific for the condition, is the Carey Coombs murmur; this is a short rumbling diastolic murmur indicating mitral valvulitis. Sydenham's chorea Sydenham's chorea (St Vitus' dance) is usually a separate disease entity but, like rheumatic fever, appears to be related to recent p-haemolytic streptococcal infection and an autoimmune process; occasionally it accompanies the rheumatic fever, although it may follow some weeks later. It is characterized by sudden, jerky, purposeless movements of the face and limbs, such that the child is thought to be clumsy and grimacing. Pure chorea, even when unaccompanied by other evidence of rheumatic fever, is followed by a high incidence of rheumatic valve disease, indistinguishable from that following conventional rheumatic fever.
Investigation Laboratory investigations show a raised ESR, C-reactive protein and antistreptolysin O titre. Blood cultures are negative. Throat swab may be positive for p-haemolytic streptococcus, if the preceding pharyngitis has not been treated with antibiotic.
Differential diagnosis As there is no absolute diagnostic test it is extremely common to find patients who have been diagnosed as having rheumatic fever on weak evidence, such as a childhood fever with a few aches and pains and the presence of a systolic murmur. In one study some 50% of patients with mild congenital heart disease claimed to have had rheumatic fever, suggesting that a child with a heart murmur alone is very likely to be diagnosed as having rheumatic fever during the course of a febrile illness.
Management Aspirin is traditionally used to control the arthritis and fever; it is used in maximum doses. Where the patient is extremely ill, corticosteroids are commonly used, but there is no evidence that these reduce the incidence of endocarditis or subsequent development of rheumatic valvular disease. Prophylaxis Anyone who has had acute rheumatic fever is at risk of recurrence and is usually maintained on phenoxymethylpenicillin (250 mg orally daily, or an i.m. depot preparation of benzathine penicillin) or, if allergic to penicillin, oral sulphonamide, either until the age of 21 or for 5 years after the last attack of rheumatic fever, whichever comes later.
LIBMAN-SACKS ENDOCARDITIS
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SLE (p. 1172) may lead to heart failure from hypertension and a myopathic process affecting the left ventricle. Involvement of the heart valves by a verrucous endocarditis is described as involving a significant proportion of postmortem specimens; however, valve disease is a clinical problem in only a few long-standing cases of SLE. The warty outgrowths occur at, and away from, the free edges of the valve cusps and over the mural endocardium. They involve the mitral valve in particular, and may lead to thickening of the chordae and subvalvular apparatus. Mitral regurgitation and aortic regurgitation are said to be the commonest lesions, but mixed valve lesions occur. Aortic stenosis has also been described in SLE. LibmanSacks endocarditis may become the site of infective endocarditis and, if haemodynamically important, is treated by prosthetic valve replacement.
RHEUMATOID ARTHRITIS A small percentage of patients with very active rheumatoid arthritis develop mitral and aortic valve disease, with exuberant nodular granulomatous lesions on the valve cusps and at other sites throughout the body. These lesions only occasionally cause significant valve disease, but very occasionally may cause significant stenosis or regurgitation in a patient who has very exuberant and severe rheumatoid arthritis.
REITER'S DISEASE AND ANKYLOSING SPONDYLITIS Reiter's disease and ankylosing spondylitis (p. 1148) can produce a degree of aortitis and aortic root dilatation and cusp retraction similar to that seen in syphilitic aortitis. There may be associated conduction abnormalities as well as aortic regurgitation, and occasionally these patients require aortic valve replacement and cardiac pacemakers.
CARDIAC TUMOURS Cardiac tumours (Table 12.38) are rare. They can present a variety of clinical features and mimic many other cardiac and systemic diseases. Benign tumours comprise 75% of primary cardiac tumours.
MYXOMAS The origin of myxomas is controversial. They appear as a gelatinous pedunculated mass, usually arising from the
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TABLE 12.38 Most frequent cardiac tumours Tumour
Frequency (%)
Prognosis
Myxoma Lipoma Papillary fibroelastoma Rhabdomyoma Angiosarcoma Rhabdomyosarcoma Other (including secondary)
30 10 10 8.5 9 6 26.5
Benign Benign Benign Benign Malignant Malignant -
Syncope and sudden death are also recorded, and recurrent emboli can lead to severe pulmonary hypertension and a paradoxical embolization to the left side through a patent foramen ovale. Constitutional symptoms are as common as on the left. Physical signs are more frequent than on the left side, with systolic and diastolic murmurs being audible in over 80%, and endocardial friction rub audible in 20%. Myxomas may arise in the ventricles, but these are less common. As with atrial myxomas, they are likely to embolize and cause obstruction.
Investigation fossa ovalis in the atria; 75% occur on the left, but occasionally the tumour invades both atria. About 75% are found in women. There is a slight familial tendency, and current theory suggests that myxomas arise from embryonic cells in the septum. Clinical presentation is in late middle age, when they reach sufficient size. The clinical features are haemodynamic obstruction, embolization and constitutional symptoms.
Left atrial myxoma In left atrial myxoma the large gelatinous mass obstructs the mitral valve and simulates mitral stenosis, producing left heart failure. A ball-valve mechanism can produce recurrent pulmonary oedema or syncope, which can lead to sudden death. Pulmonary hypertension with subsequent right heart failure mimics mitral valve disease. In one-third of patients there are systemic emboli, the brain being the most frequent site. Systemic symptoms are found in 90% of patients and mimic those of a collagen disease or infective endocarditis, with fever, anorexia, weight loss, myalgia, arthritis, Raynaud's phenomenon, petechiae and fingerclubbing. These features are thought to result from immunological reactions to necrosing tumour. Physical signs can mimic those of mitral stenosis, with a diastolic murmur in about 20% of patients. More common is a systolic murmur of mitral regurgitation and, classically, there is a 'tumour plop' instead of the opening snap of mitral stenosis. However, the tumour can be silent or give only intermittent ausculatory findings.
Right atrial myxoma Right atrial myxomas are less common than those on the left side; they can cause severe right heart failure, with oedema, hepatomegaly, ascites and pleural effusion.
Q Fig. 12.27
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Echocardiography has revolutionized the diagnosis of myxoma. Q The tumour can often be visualized popping backwards and forwards through the valve orifice. However, it can be missed, and a study from several windows may be needed to show small tumours and, particularly, right atrial myxomas. If satisfactory echo pictures are available there is now nothing to be gained from cardiac catheterization, which runs the risk of dislodging tumour and causing systemic emboli. Laboratory tests are frequently abnormal, especially in patients with systemic symptoms. Haemoglobin is low (with normochromic normocytic film), but may occasionally be high with right atrial myxoma, severe pulmonary hypertension and right-to-left shunting through a patent foramen ovale. A neutrophil leukocytosis occurs. The ESR is often raised, with an increase in plasma gammaglobulins.
Management Surgical excision of the tumour is essential but carries some risk of tumour embolization and recurrence, both from the site of excision, if incomplete, and from other sites in the heart. The tumour is therefore excised with its atrial attachment, and the atrial septum then patched. Many surgeons now inspect all four cardiac chambers, because of the high incidence of local recurrence and the occasional multiple tumour. Atrial myxomas are relatively easily treated and should be suspected wherever there is unexplained systemic embolism, particularly if there are features of a 'collagen disease', if a case of 'infective endocarditis' is persistently culture negative, and if features of mitral valve disease are accompanied by syncopal episodes. Right atrial myxoma should be suspected in unexplained right heart failure and recurrent pulmonary emboli.
CARDIAC DISEASE AND PREGNANCY Pregnancy places a sustained load on the heart which increases throughout the pregnancy and then peaks with labour. There is a considerable increase in cardiac output (30-50%), blood volume (40-50%) and extracellular
volume (about 7L), with an increase in heart rate of about lObpm and a slight fall in mean blood pressure. The circulation of the pregnant woman is as if she were vasodilated, with warm peripheries and an increase of up to 30% in resting oxygen uptake. The increase in cardiac output is accomplished by an increase in heart rate, stroke volume and ejection fraction. Venous pressure in the upper body increases marginally, if at all, whereas there can be an increase in lower body venous pressure when supine or standing, due in part to pressure of the gravid uterus on the inferior vena cava. This pressure increase, and the increase of up to 8.5 L in total body water, often leads to oedema of the ankles. The increase in plasma volume occurs earlier than a compensatory increase in total red blood cell volume, so that an apparent anaemia ensues.
Diagnosis Pregnancy makes the diagnosis of heart disease more difficult. The pregnancy may produce symptoms of fatigue, shortness of breath, ankle oedema and syncope. Physical examination may reveal flow murmurs, a mammary souffle, venous hum, a third heart sound, a raised a wave in the jugular venous pulse, displacement of the cardiac apex (by the elevated diaphragm) and basal rales (which clear on coughing) for the same reason, all of which may be taken to indicate heart disease. The above confounding symptoms and signs are unfortunate because of the increased risk posed by heart disease to both the mother and the fetus. Another reason for establishing whether heart disease is present, even if it appears to be asymptomatic, is the small risk of puerperal endocarditis. The murmur of pregnancy (Still's murmur} is a low-pitched, often vibratory murmur heard at the left sternal edge but usually loudest in the pulmonary area. It is extremely common, midsystolic and unaccompanied by any other signs of heart disease. High-pitched systolic murmurs, and all diastolic murmurs, indicate heart disease. The use of echocardiography and Doppler ultrasound will often be of great value in these cases. Chest X-ray is relatively contraindicated. If essential, the fetus can be shielded. The risk to the fetus late in pregnancy is much smaller than first thought. The ECG is usually normal but the axis may shift to the left, with T-wave inversion in lead 3, a small Q wave, and sometimes even ST and T-wave inversion in the limb and precordial leads; these ECG changes revert to normal at the end of pregnancy and recur in later pregnancies.
Management If the pregnant mother is known to have heart disease and is in functional class 3 or worse of the New York Heart Association classification (p. 468, Table 12.1), it is hazardous for the pregnancy to continue. Certain types of heart disease, e.g. coarctation of the aorta, severe hyper-
tension, severe aortic or mitral stenosis or cardiomyopathy, present particular hazards. Cyanotic congenital heart disease poses great risk to the mother if pulmonary hypertension is severe. Spontaneous abortion is frequent. Surgery during pregnancy may offer a solution to the mother who is anxious to continue with the pregnancy; closed mitral valvotomy, or open valvotomy and valve replacement under cardiac bypass, have been performed with a low maternal mortality and acceptable fetal risk. If valvular disease or a jet lesion (VSD etc.) is diagnosed, appropriate antibiotic cover is given at the time of labour, particularly if instrumentation (e.g. urinary catheterization) is used at the time of delivery.
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Anticoagulants A particular problem may be the need for anticoagulants. Discontinuation of anticoagulants is dangerous for a mother with a prosthetic heart valve, and possibly also for one who has had a pulmonary embolus. Warfarin is avoided during the first trimester, because of an increased risk of fetal abnormality. For a planned pregnancy, heparin can be given during the first trimester. Warfarin is then given until heparin is used to cover delivery by caesarean section.
Peripartum cardiomyopathy Pregnancy and labour may make occult heart disease manifest. Occasionally, catastrophic heart failure supervenes and appears to be associated with a progressive cardiomyopathy.
Hypertension Hypertension in pregnancy and pre-eclamptic toxaemia and eclampsia are discussed on page 592.
SECONDARY HEART DISEASE A wide variety of pathological conditions may also increase cardiac output and produce heart failure. These include thyrotoxicosis, anaemia, cor pulmonale, beriberi, arteriovenous fistulas, generalized Paget's disease of bone and exfoliative dermatitis.
Thyrotoxicosis Thyrotoxicosis dramatically increases metabolic rate, but the thyroid hormones also have a stimulant effect on the autonomic nervous system and the heart itself. There is usually a sinus tachycardia which is indicative of the severity of the disease, but in 15% of cases thyrotoxicosis triggers a supraventricular arrhythmia, most frequently AF. Pulse pressure and blood pressure rise slightly and the heart contracts more vigorously in thyrotoxicosis.
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Anaemia Severe anaemia makes a twofold demand on the heart. In order to supply the oxygen requirements of the body, the heart has to increase cardiac output, despite itself being perfused with anaemic blood. Mild anaemia is of marginal importance, but life-threatening anaemia may lead to cardiac dilatation and severe heart failure, with pathological changes in the myocardium of 'fatty heart'. As the myocardium extracts virtually all the oxygen from the blood in the coronary circulation, autoregulation of flow demands a dramatic increase in coronary flow to compensate for the extra myocardial work of severe anaemia. This cannot be accommodated if there is coronary disease of any severity, and continuous angina and heart failure may result.
TABLE 12.39 Inherited connective tissue diseases and the heart Condition
Cardiac condition
General features
Cutis laxa
Peripheral pulmonary stenosis Mitral regurgitation Arterial rupture Aortic dilatation, dissection, aortic and mitral regurgitation
General skin laxity, disrupted elastic fibres Hypermobile joints Hyperelastic skin Gracile habitus, arachnodactyly, lens subluxation, sternal abnormalities Fragile bones, blue sclera
Ehlers-Danlos Marfan's
Osteogenesis imperfecta Pseudoxanthoma elasticum
Aortic regurgitation Peripheral and coronary artery disease
Beriberi Beriberi is uncommon outside Asia, but minor forms may occur in some alcoholics and food faddists. Severe thiamine deficiency (classically due to subsistence on polished rice) results in autonomic and other nervous system damage, with profound vasodilatation and a high cardiac output. In its fulminant form the patient may die from pulmonary oedema within 48 hours of the onset of symptoms. Response to conventional heart failure therapy without thiamine is poor. Thiamine is given as soon as the diagnosis is suspected, and should be given to alcoholics in heart failure and in all cases of resistant heart failure where the nutritional background of the patient is doubtful.
Arteriovenous fistulas, Paget's disease of bone, exfoliative dermatitis If they are severe enough, arteriovenous fistulas, Paget's disease of bone and exfoliative dermatitis may all cause a considerable reduction in peripheral resistance leading to a large increase in resting cardiac output. The patient has a bounding pulse and hyperkinetic circulation, often with a third heart sound and systolic murmur. Heart failure may supervene if the heart is already damaged or if the stress is severe enough. Treatment of the condition will alleviate the strain on the heart.
Inborn errors of metabolism and connective tissue disorders Heart disease may complicate or be part of many other medical conditions (Tables 12.39-12.42). Marfan's syndrome is discussed in Chapter 3, page 71. (see also p. 601). O Aortic dissection is a frequent and lifethreatening complication.
Degeneration of elastin fibres leading to yellow pseudoxanthomas of skin, retinal angioid streaks, hypertension
TABLE 12.40 Inborn errors of metabolism and the heart Condition
Cardiac condition
Pompe's disease
Glycogen storage disease involving the heart muscle Aortic and pulmonary artery dilatation Multivalvular disease, coronary artery disease and cardiomyopathy
Homocystinuria Mucopolysaccharidoses: Hurler's and Hunter's syndromes (mental deficiency) Morquio's disease
Aortic regurgitation
TABLE 12.41 Chromosomal abnormalities and the heart Chromosomal defect
Cardiac abnormality
Trisomy 21 (Down's syndrome)
Endocardial cushion defects, ASD, VSD, pulmonary stenosis VSD, double-outlet right ventricle VSD, persistent ductus arteriosus, pulmonary stenosis VSD Coarctation Persistent ductus arteriosus
Trisomy 13 Trisomy 18 Cri du chat (short arm deletion 5) XO (Turner's syndrome) XXXY and XXXXX
ASD = atrial septal defect; VSD = ventricular septal defect
Athlete's heart O Fig. 12.28 584
Exercise training induces changes in the heart muscle similar to those in skeletal muscle. Power athletes who perform mostly isometric exercises (weight lifting, wrestling, tug-of-war) develop ventricular hypertrophy. The left ven-
TABLE 12.42 Skeletal syndromes and the heart Syndrome
Cardiac abnormality
Skeletal syndrome
Ellis van Creveld
Single atrium or ASD
TAR
ASD or tetralogy of Fallot ASD (and others)
Chondrodystrophic dwarfism Absent radius, thrombocytopenia Upper limb deformity, hypoplasia of clavicles Polydactyly, obesity
Holt-Dram Laurence-MoonBiedl-Bardet Noonan Tuberous sclerosis Leopard Cockayne Progeria Apert
Variable Pulmonary valve dysplasia Cardiomyopathy Pulmonary stenosis Accelerated atherosclerosis Accelerated atherosclerosis VSD
Pectus excavatum Bone lesions Broad fades, ribs abnormal Cachectic dwarfism Skeletal hypoplasia Craniosynostosis, syndactyly
ASD = atrial septal defect; VSD = ventricular septal defect; TAR = thrombocytopenia-absent radius syndrome
tricle has to generate high pressures to overcome increased impedance to flow during the isometric exercises. Continuous measurement of pressure indicates that the mean arterial pressure rises above 160mmHg during maximal isometric deadlifts. Remodelling of the heart occurs so that high intraventricular pressures can be generated. This objective can be achieved through augmented tension development in each myofibril, but as (without altering its constitution) each myofibril has a performance maximum, this limits the contractile reserve available during times of haemodynamic stress. An alternative mechanism is to increase the number of in-parallel myofibrils, which would increase wall thickness. Greater wall tension and intraventricular pressure can then be generated with each myofibril developing the same tension as before. The appearance of the LV that is induced by pressure overload is essentially that of increased wall thickness, commonly referred to as concentric hypertrophy, similar to the appearance in patients with chronic hypertension or aortic stenosis. Endurance athletes who perform mostly isotonic exercises (long-distance running, swimming, cross-country skiing, aerobics) develop dilatation of the ventricles. Remodelling of the heart occurs to ensure that large stroke volumes can be delivered. As each sarcomere has a maximum shortening distance, the stroke volume is increased by increasing the number of in-series sarcomeres. However, according to LaPlace's law, the resulting ventricular distension would result in greater wall tension being required to generate the same intraventricular pressure. Some increase in in-parallel myofibrils and hence wall thickening is therefore also necessary. The appearance of
the left ventricle induced by volume overload is chamber dilatation and eccentric hypertrophy, similar to that found in patients with 'high-output states' such as Paget's disease, beriberi and anaemia, or those with valvular regurgitation. In elite athletes, because of the marked ventricular dilatation, the cardiothoracic ratio on chest X-ray may exceed 0.5. Owing to the large stroke volumes, their heart rates at rest and during equivalent exercise workloads are significantly lower than those of normal sedentary subjects. Their peak exercise heart rates are not diminished and, combined with the enormous stroke volumes, their peak cardiac outputs are markedly augmented (up to 35L/min). They therefore have superior oxygen delivery, exercise capacity and performance. In certain types of endurance training, such as cycling, rowing and canoeing, the exercise contains not only isotonic but also resistance components. In these situations the observed hypertrophy is characteristically a combination of concentric and eccentric. It is important to note that the above remodelling processes are adaptive mechanisms to maintain or enhance the pumping capability of the heart in response to the physiological demands imposed upon it. Although the ventricular appearances of hypertrophy and dilatation are similar to those in pathological states of aortic stenosis or regurgitation, these changes observed in athletes should not be regarded as abnormal but as supranormal, as they are physiological and beneficial. If they need treatment, say for hypertension, drugs (e.g. (3-blockers, verapamil) that would impede these adaptive changes should be avoided. Diagnosis and management Clinically, apart from bradycardia, other commonly found features of athletes are sinus arrhythmia, benign systolic murmur usually due to pulmonary flow murmur, and occasional third or fourth heart sounds. The ECG may indicate left and/or right ventricular hypertrophy. A common abnormality is atrial or ventricular arrhythmia, but most of these do not cause symptoms. Confirmation that these are benign may be achieved by demonstrating the complete disappearance of the arrhythmia during exercise. Because of the high vagal tone some athletes are prone to develop heart block, which may require pacemaker insertion. Echocardiography indicates the types and extent of hypertrophy or dilatation. The left ventricular ejection fraction is invariably normal. To determine whether an athlete has supranormal cardiac function a cardiopulmonary exercise test can be performed. Achieving a supranormal maximal oxygen consumption is an indirect indication of superior cardiac reserve. If in doubt, direct measurement of cardiac reserve can be made noninvasively by measuring the cardiac output and blood pressure during maximal exercise. Athletes are also susceptible to cardiac disease. Detection may not be straightforward, because the same extent of damage (e.g. myocarditis) occurring in a normal subject
12
585
would have resulted in obvious cardiac dysfunction or failure, but its occurrence in an elite athlete may be masked because the baseline cardiac performance may be so enhanced that the eventual cardiac function falls within the normal range. Symptomatically, however, the athletic subject would complain that exercise capacity is significantly reduced. Certain heart diseases are lethal when combined with vigorous or competitive sport. Subjects with hypertrophic cardiomyopathy, aortic stenosis, Marfan's syndrome involving the aorta and heart, and life-threatening arrhythmias should be dissuaded from taking part in such sport. Patients with suspected or confirmed viral myocarditis should be persuaded to stop training, because viral replication rates are enhanced with continued exercise, and the resultant damage to the myocardium may be worse than detraining. Apart from this, there is the potential danger of triggering serious arrhythmia during myocarditis, which may result in sudden death.
Sternal depression and straight back syndrome Abnormalities of the shape of the thorax are a common cause of systolic murmurs; they may also give rise to musculoskeletal chest pains, an abnormal X-ray appearance of the heart and, in severe cases, ECG changes. Sternal depression and an abnormally vertical dorsal spine (straight back syndrome) both allow very little room for the heart in the anterior-posterior axis; this is well shown on the lateral chest X-ray. There is often a systolic murmur arising from the distorted great vessels; respiratory function may be impaired because of restricted chest wall expansion on inspiration, giving rise to a poor effort tolerance; and there may be associated mitral valve prolapse as a congenital anomaly. The ECG commonly shows right bundle branch block, and there may be anterior T-wave inversion in the V leads in the most severe cases. Assessment includes careful clinical examination to exclude primary cardiac pathology, and echocardiography and Doppler ultrasound where doubt exists as to whether there is more than a 'flow murmur'. Mild forms of this condition are commonly seen in pregnancy, when the patients are referred because of the murmur. Reassurance often helps the chest pains, which usually have a musculoskeletal basis and become worse when the possibility of heart disease is raised. Simple back exercises may also help.
PERICARDIAL DISEASE
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The pericardium is a fibrous bag that supports and invests the heart. Like the pleura, it may be the site of inflammation, neoplastic infiltration and calcification, and may also be the site of fluid collection with or without inflammation.
TABLE 12,43 Causes of pericardial disease Infections Viral, e.g. Coxsackie, influenza Bacterial: pyogenic and tuberculosis Fungal Metabolic Uraemia Hypothyroidism Neoplastic Carcinoma of the bronchus Lymphomas Myocardial infarction
Autoimmune Collagen disease, rheumatoid arthritis, SLE Postpericardiotomy and postinfarction (Dressler's) syndromes Serum sickness and drug reactions Idiopathic (benign recurrent viral) relapsing pericarditis Rheumatic fever Haemopericardium Cardiac rupture Aortic dissection Trauma and surgery
Radiotherapy
Aetiology The causes of pericardial disease are shown in Table 12.43. All of these conditions can produce the clinical features of pericarditis with effusion. Heart failure can also cause a pericardial effusion, but these are small asymptomatic effusions, often discovered at routine echocardiography. Acute viral pericarditis The commonest viral causes are Coxsackie virus A or B, varicella, herpes simplex, influenza virus and echovirus (type 8). Frequently, a definite viral cause cannot be established. Typically, it occurs in young adults 1 or 2 weeks after an upper respiratory infection. The patient then develops fever, pericardial pain and malaise which may persist for a few weeks. Unfortunately, recurrences occur in about 25% of cases, possibly from an autoimmune mechanism. Tamponade is unusual. Acute pyogenic pericarditis Acute pyogenic pericarditis can follow pneumonia or a septicaemia and is treated with the appropriate antibiotics and repeated drainage, which may require surgical intervention. Staphylococcus and Haemophilus are the most common organisms involved. It may also occur in immunosuppressed patients and following cardiac surgery. Tuberculous pericarditis Tuberculous pericarditis may be asymptomatic until it presents as pericardial constriction (see below). It may present as a large pericardial effusion with enlargement of the cardiac silhouette on chest X-ray, or as a low-grade fever with weight loss, fatigue and features of pericarditis. Pericardial aspiration may reveal the organisms, but occasionally (as with pleural effusions) culture of the fluid or pericardial biopsy may be required before the diagnosis is established.
Malignant pericarditis Pericardial effusion fluid should always be sent for cytology, as malignancy may present with a pericardial effusion. The clinical features are similar to those of other types of pericarditis, but may be complicated by direct tumour extension into the pericardium, with a degree of constriction. Lung cancer is the commonest cause. Uraemic pericarditis Uraemic pericarditis develops with severe untreated uraemia and disappears with dialysis. It appears to be directly related to the blood urea level. Other types In most other types of pericarditis, such as in autoimmune disease, pericardial involvement is an incidental finding but may occasionally lead to constrictive pericarditis.
Clinical features The principal symptoms of pericarditis are pericardial pain, breathlessness (if the effusion becomes large enough) and, eventually, tamponade. There may be systemic symptoms related to infection, such as fever, rigors, weight loss and symptoms of the underlying cause (lung cancer, tuberculosis etc.). Pericardial pain Pericardial pain is a mediastinal pain that can be very similar to that of myocardial ischaemia, but differs in that it is more commonly referred to the shoulder and back and is often influenced by posture and mediastinal movements, such as coughing, sneezing and, particularly, swallowing. It is often relieved by leaning forward. The diagnosis may be difficult because of the occurrence of pericardial pain following myocardial infarction. There can also be a pleural element to the pain. Pericardial rub Pericardial rub - the main physical sign of pericarditis - is very variable and often absent. It is a rough scratching sound which seems nearer to the observer than the stethoscope headpiece. Typically, it has three components - systolic, diastolic and atrial-systolic. However, the atrialsystolic and diastolic components may not be present, and a purely systolic scratchy murmur may have other causes. The noise can sometimes be accentuated by leaning the patient forward or, if conditions allow, by putting them in the knee-elbow position. The sound conies and goes and does not necessarily disappear with the formation of an effusion; indeed, it may be found in up to 70% of patients with pericarditis and effusion. Pericardial effusion Pericardial effusion does not usually cause symptoms unless it is large, when there may be some breathlessness and, eventually, features of tamponade (see below). The
clinical signs of an effusion without tamponade (soft heart sounds, increased cardiac dullness etc.) are not as helpful as chest X-ray and ultrasound.
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Cardiac tamponade If the pericardial cavity fills with blood or pericardial fluid, the pericardial pressure may rise sufficiently to embarrass filling of the heart and lead to a form of cardiogenic shock (cardiac or pericardial tamponade), with very low cardiac output, cerebral confusion, and severe hypotension proceeding to death if the pericardium continues to fill. The pericardium is viscoelastic and can therefore stretch slowly to accept as much as 2 L of fluid over a period of time without the development of temponade, but much smaller amounts of fluid can be fatal if they accumulate quickly.
Aetiology Tamponade is usually caused by bleeding or effusion into the pericardial space. It can complicate aortic dissection and myocardial infarction with rupture into the pericardium. Bleeding can also follow surgery or trauma to the heart and mediastinum, and may follow perforation of the heart at cardiac catheterization, or injury after pericardial aspiration. Malignant disease is a common cause, but tamponade is an uncommon complication of other causes of pericardial effusion. Clinical features Severe hypotension with impalpable or very weak peripheral pulses may be present. Classically, careful palpation of the arterial pulses reveals pulsus paradoxus, in which the pulse pressure drops considerably on inspiration and the pulse may even become impalpable. The paradox is not that the pulse volume diminishes with inspiration (which happens normally to a small extent), but that the stroke volume of the left ventricle declines markedly while - paradoxically - the heart seems to be beating normally. The mechanism of pulsus paradoxus is related to the pericardial temponade dictating a small fixed volume to the heart. Normally, right ventricular filling is aided by inspiration but with tamponade (or pericardial constriction), this rightsided mechanism inhibits filling of the constricted left ventricle, whose stroke volume falls. The jugular venous pressure is usually markedly raised, may show a marked systolic drop (prominent x descent) and, sometimes, rises with inspiration (Kussmaul's sign). Chronic tamponade can mimic constriction, with hepatic enlargement and oedema. The heart sounds may be faint and there can be a pericardial rub.
Investigation of pericarditis The ECG changes of acute pericarditis are shown in Figure 12.66. The ST elevation remains concave upwards and is
587
FIG. 12.66 EGG of acute pericarditis illustrating widespread concave ST segment elevation
followed later by widespread T-wave inversion, probably indicating a degree of epicardial myocarditis. A large effusion can produce a diminution of ECG voltages; in extremely large effusions there can be 'electrical alternans', with the voltage being influenced by the heart swinging backwards and forwards in the effusion. Chest X-ray (if there is an effusion) shows increased cardiac silhouette, with a globular appearance to the heart but no evidence of raised pulmonary venous pressure. This appearance is not specific. Echocardiogram is the technique of choice in demonstrating a pericardial effusion, preferably with a 2D scan. A small effusion can be localized, and may be missed unless the operator is experienced. With a large effusion echocardiography will show the heart surrounded by a large bag of fluid, which is seen as an 'echo-free' space. Pericardial aspiration is described below. The fluid should be sent for bacteriological and cytological examination.
Pericardial pain often responds to anti-inflammatory agents. Infective pericarditis demands prompt diagnostic aspiration and identification of the infective agent, with appropriate chemotherapy. In viral pericarditis antiinflammatories alone are used, but where there is an autoimmune element, such as in postinfarction syndrome and recurrent 'viral' pericarditis, corticosteroids may help. A large effusion is drained as described below. If the patient suffers repeated attacks, a pericardial window can be made into the pleural space at operation.
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CONSTRICTIVE PERICARDITIS Constrictive pericarditis results from thickening and fibrosis of the pericardium with, in some cases, extensive calcification.
Management
O Case 12.8
Pericardial aspiration Pericardial aspiration can be both diagnostic and therapeutic. In an emergency, e.g. after a road traffic accident with trauma to the chest, if a patient is moribund with features suggesting tamponade (i.e. very high venous pressure), then aspiration from the apex of the heart with a needle of adequate length should not be delayed. Removal of even 50-100 mL of blood from the pericardium may reverse the state of shock. Elective aspiration is best performed in a coronary care unit with ECG, blood pressure and echo monitoring and a cardiac defibrillator available. After local analgesia of the chest wall, the pericardium is punctured either at the cardiac apex (which is free of major coronary vessels) or via a subxiphoid approach. The ECG monitor shows ventricular ectopics if the ventricles are touched. Using a metal needle connected to an ECG V lead, a current of injury (raised ST segment) is produced as soon as the myocardium is touched and, hopefully, before the ventricle is pierced. Ideally, a cannula, rather than a needle, is left in the pericardium, and aspiration or drainage follows. If the fluid looks like blood, pericardial blood from a haemopericardium can be distinguished from ventricular blood by the fact that it is defibrinated and will not clot. It also has a lower haemoglobin and haematocrit than venous blood, as it is almost always diluted with serous pericardial fluid. Diagnostic aspiration of a large effusion without subsequent drainage can lead to pericardial fluid draining into the pleural cavity. Drainage of a large effusion can take several hours, and recurrent effusion (e.g. in malignant disease) may require fenestration of the pericardium or insertion of a pericardioperitoneal drain by a cardiothoracic surgeon. O
Fig. 12.29
MCQ 12.23
Aetiology There may be an antecedent history of acute pericarditis or radiotherapy. Tuberculous pericarditis is now rare in western countries, but is the classic cause of calcific constrictive pericarditis.
Pathogenesis The heart is effectively encased in a rigid box, which eventually prevents it from filling. Haemodynamically, the diastolic pressures or filling pressures of the two sides of the heart become the same as the intrapericardial pressure; as this rises, the patient goes into bilateral heart failure, in which features of right-sided failure predominate.
Sometimes the constriction is selective, so that the left or the right side, inflow or even outflow, can be compromised most.
Clinical features Symptoms The major symptom is severe oedema, often with ascites, liver engorgement and progressive weight loss secondary to hepatic engorgement and low cardiac output. Patients with long-standing disease look cachectic, and with the liver enlargement and a degree of jaundice are easily thought to have carcinomatosis or cirrhosis of the liver. The absence of significant left-sided heart failure symptoms is characteristic. The patient can often lie flat without problems and does not have a history of paroxysmal nocturnal dyspnoea, but will always have a limited exercise tolerance and dyspnoea on exertion. Constriction may arise with no previous history of pericarditis. A previous history of pericarditis is a valuable clue to the diagnosis. Signs A very high venous pressure is invariable, as the enddiastolic pressure in both ventricles is about 25mmHg. The high venous pressure is interrupted by a rapid x and y descent or systolic collapse of the venous pressure. The pulse exhibits pulsus paradoxus, but this is not invariable and the presence of AF in about 30% of cases makes the sign difficult to elicit. The pulse will, in any case, be of small volume. The heart is not clinically enlarged and the rigid pericardium may impede palpation of the cardiac impulse. The heart sounds may be faint with a loud additional sound, the pericardial knock. This is a loud early third heart sound, resulting from the rapid filling of the ventricles being suddenly impeded by the rigid pericardium. Murmurs are uncommon.
Investigation The ECG is non-specific, showing low voltages and, usually, T-wave inversion; other changes may reflect epicardial myocardial damage resulting from pericardial impingement on the epicardial coronary arteries. Chest X-ray shows a normal-sized or slightly enlarged heart, often with an abnormal contour due to flattening of the atria. Calcification may be seen in the A-V groove on a lateral film. 0 Depending on the sites of constriction, there may be signs of left or right atrial hypertension. Pleural effusions are common. Screening of the heart reveals a typical 'diastolic shock', with lack of pulsatility of the atria. Echocardiography may demonstrate thickening of the pericardium. The ventricles fill rapidly in early diastole, but the differential diagnosis from restrictive cardiomyopathy is not easy. Cardiac catheterization would show elevation and equalization of diastolic pressures in all four chambers, with characteristic 'square root sign' of the early diastolic ventricular pressure waveform.
Management The only effective treatment is surgical decompression of the heart by removing enough of the pericardium to allow the heart to fill effectively. This means removing the adherent pericardium from around the great veins and atria, which are extremely thin-walled. Where the pericardium is adherent to the ventricles the coronary arteries are easily damaged, so considerable surgical skill and patience are required. ©
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SYSTEMIC BLOOD PRESSURE AND HYPERTENSION Cardiac performance and vascular resistance form part of an integrated system which controls arterial pressure and blood flow to the tissues. Despite our knowledge of many of the component mechanisms of pressure and flow control, many aspects remain unclear in both health and disease.
CONTROL OF BLOOD PRESSURE Neurosympathetic blood pressure control Activation of preganglionic sympathetic neurons to the heart produces an increased heart rate and increased strength of contraction. Vasomotor sympathetic outflow constricts vascular smooth muscle, producing arterial vasoconstriction. The supply to the veins is richer and more sensitive than to the arterial system. Increased vagal activity reduces the heart rate but, with the exception of the coronary and salivary gland vascular beds, there is no parasympathetic control of the blood vessels. Moment-to-moment reflex control of the circulation is via the arterial baroreceptors in the wall of the aorta and in the carotid arteries. The speed of this pressurecontrolling mechanism is illustrated by its important role in maintaining systemic pressure during abrupt changes in posture. Neurosympathetic influences on blood pressure and the circulation are rapid but tend to be transient; this is partly due to a tendency for the reflexes themselves to undergo accommodation, and partly because peripheral autoregulatory mechanisms may overcome neural constrictor effects.
Renin and angiotensin The renin-angiotensin-aldosterone system (Fig. 12.25) plays a major part in the control of blood pressure, regional blood flow and blood volume, via its control of sodium balance. Renin secretion from granules in the juxta-
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glomerular apparatus is stimulated by a fall in plasma volume, a drop in blood pressure and sodium depletion. The consequent rise in angiotensin II production and aldosterone secretion leads to sodium and water retention, and hence restoration of sodium balance and plasma volume. Under conditions of plasma volume reduction and sodium depletion (<50mmol Na+/day), angiotensin II contributes to the maintenance of blood pressure by both vasoconstriction and interaction with the sympathetic nervous system. In the kidney, angiotensin II has a preferential constrictor effect on efferent (postglomerular) arterioles, and thus maintains glomerular filtration pressure when the overall arterial pressure is diminished. The renin-angiotensin system plays a crucial role in the increased blood pressure seen with renal arterial constriction; the latter causes a rapid release of renin and angiotensin II and hence a rise in blood pressure. Angiotensin II causes changes in intrarenal flow patterns and stimulates aldosterone release. The combination of haemodynamic and direct effects on the renal tubules increases sodium reabsorption. An extrarenal local tissue renin-angiotensin system has been identified, and there is increasing evidence that abnormal function of this system may play a role in the pathogenesis of hypertension.
first sound (Kj) and diastolic pressure is usually within a few mmHg of sound muffling (K4). In many major trials of blood pressure treatment sound disappearance (K5) is used to define diastolic pressure. In some individuals K5 cannot be defined when peripheral vascular resistance is low, as sounds carry on to zero cuff pressure. The anauscultatory gap (K2-K3) is particularly prominent in the elderly; this is important, as mistaken identification of K3 as K] might lead to a serious underestimation of systolic pressure - by up to 15-20 mmHg in some cases. Its presence is accentuated by venous distension distal to the cuff. Accurate blood pressure measurement requires a cuff of adequate size: a small cuff will seriously overestimate pressures. The subject should be seated, with the manometer reservoir at the level of the sternal angle. The cuff bladder is arranged medially to overlap comfortably the medial aspect of the upper arm. Pressure in the cuff is inflated rapidly to 20-30 mmHg above that required to occlude the brachial or radial pulse. Pressure is then reduced slowly from the cuff while listening with a stethoscope over the previously located brachial pulse. The rate of pressure drop should not exceed 5 mmHg per second, and the line of sight should be such as to avoid parallax errors when reading the falling column of mercury.
Nitric oxide and endothelin
SYSTEMIC HYPERTENSION
More recent evidence suggests that nitric oxide (NO, previously known as endothelium-derived relaxant factor), endothelin, prostacyclin and other vasoactive factors that are locally produced by endothelial cells and vessel wall, play a role in the control of vascular tone and hence blood pressure. Suppression of NO production can result in hypertension, thus introducing the concept that blood pressure is controlled not only by vasoconstrictive neurohumoral factors, but also by paracrine vasodilators. Overproduction of NO, such as is seen in endotoxaemia, results in overvasodilatation leading to circulatory shock. Endothelin (first discovered in 1988), a peptide produced by endothelial cells and released abluminally towards the smooth muscle cells, is one of the most powerful vasoconstrictors. Its exact physiological role in the control of blood pressure is still unclear. Increased vascular synthesis and plasma concentrations of endothelin have been reported in hypertension, chronic renal failure and toxaemia of pregnancy. Hypertension has been reported to be due to a tumour overproducing endothelin. Endothelin receptor antagonists may have a role in the treatment of hypertension.
Definitions Blood pressure varies considerably, rising during exertion, and is subject to a circadian variation which may not be completely activity related. Ambient temperature and the degree of emotional or physical arousal will also affect systemic pressure levels. Systolic blood pressure rises with age
BLOOD PRESSURE MEASUREMENT
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Korotkoff defined the auscultatory features (Korotkoff sounds) over the brachial pulse as pressure was released from an inflatable cuff. Systolic pressure correlates with the
FIG. 12.67 Changes in blood pressure with age in three different communities: Londoners, urban Zulu and Kalahari Bushmen
therapy), it is very important to pay attention to other contributing risk factors as well.
Hypertension in special groups in the community
FIG. 12.68 Distribution of diastolic blood pressure in a western population (black line) Risk of death is shown by the blue line. The diastolic blood pressure levels are indicated at which treatment reduced mortality in two large trials (see text). VA = Veterans Administration; MRC = Medical Research Council.
in developed countries (Fig. 12.67). Within a community, blood pressure (systolic and diastolic) has a normal or Gaussian distribution, a factor that becomes very important when definitions of abnormalities of blood pressure are considered (Fig. 12.68). Insurance companies were among the first to note that a reduced lifespan was associated with recordings of elevated blood pressure. It was clear from their data that no cut-off pressure level could be identified at which no increased risk of premature death was present. Hypertension could therefore be defined as a blood pressure above a particular value, e.g. 160/90 mmHg. A more flexible definition - able to take into account new information derived from the results of therapeutic trials - might be preferable, for example 'the level of blood pressure above which investigation and treatment do more good than harm.' Figure 12.68 illustrates how successive treatment trials (the Veterans Administration in 1965, and the Medical Research Council in 1985) have lowered the blood pressure at which treatment has been shown to have benefits.
Risk stratification A small number of individuals have very high blood pressure and are at very high risk of complications of the disease and death. At lower levels the risk attributable to blood pressure is relatively less for the individual, but that low risk is shared by so many people that the associated complications and premature mortality pose a significant burden on the community. Blood pressure is not the only risk factor in these calculations. Because drug treatment of great numbers of the population tends to carry unwanted financial and medical consequences (owing to the requirement for lifelong
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There is a tendency to a high systolic blood pressure in old age and this carries with it the risks associated with hypertension at any age. Therapy is possible in older patients, and has been shown to reduce the risk of stroke and myocardial infarction. Urban black populations have a higher incidence of hypertension than their white neighbours. Both environmental and genetic factors are likely to be responsible. Hypertension is rare in some rural African communities but a very major problem in others. Stroke is the most common complication among black hypertensives, and myocardial infarction is relatively rare; the opposite is the case for white hypertensives. The effectiveness of treatment is similar among blacks and whites; however, there are minor differences in the response to certain drugs, with a slight resistance to the effects of B-adrenoreceptor blocking drugs being shown by black patients.
PRIMARY HYPERTENSION Borderline and labile hypertension About one-third of patients found to have an abnormal blood pressure at their first visit to the doctor will have lower blood pressure on subsequent visits. This borderline group may subsequently develop established hypertension. Some individuals appear to have wide swings in blood pressure, and have been called labile hypertensives. It seems likely that they do not form a pathologically distinct group, but manifest an accentuation of normal variability. As a group, they have a higher mortality than consistently normotensive individuals.
'White coat hypertension' Some patients have such a marked stress reaction when seeing a doctor (whether medical and whether wearing a white coat or not) that they raise their blood pressure to hypertensive levels. They appear calm externally and deny anxiety. This category of patients was first identified as a distinct subgroup on the introduction of ambulatory BP monitoring (see below). Whether patients with 'white coat hypertension' have a similar adverse prognosis as those with established chronic hypertension is unknown. There is a suggestion that some of them will eventually develop chronic hypertension later in life. These patients should be encouraged to undertake non-pharmacological methods of lowering blood pressure, such as avoiding obesity and increasing exercise. Some patients with essential hypertension may also have a component of 'white coat hypertension' superimposed.
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They are often given increasing numbers and doses of antihypertensive drugs. Repeated ambulatory blood pressure monitoring may be required to gauge their true response to treatment.
Because of arteriosclerotic changes in the major vessels of the elderly, the pulse pressure widens, with a greater rise in systolic than in diastolic pressure. Thus, isolated systolic hypertension may be observed. Even in isolation, systolic hypertension is associated with an excess risk of morbidity through stroke, myocardial infarction and congestive cardiac failure. Benefit of treatment in such cases is likely, and it is reasonable to aim for a systolic pressure reduction to <150mmHg.
not. This differentiation has no clinical or prognostic value as the conditions are identical, with an untreated mortality of about 80%. Patients may have a past history of hypertension, but in most this is the first manifestation of their disease. It is one of the few occasions when hypertension is associated with symptoms, which include visual disturbance, headache and breathlessness due to pulmonary oedema; with severe degrees of cerebral oedema blunting of consciousness, coma and epileptic seizures also occur. It is usually easy to treat and therapy is undoubtedly life-saving. Many factors have been implicated in the genesis of malignant hypertension. The rate of rise of pressure may be more important than absolute levels of hypertension and there may be associations with other factors that damage blood vessels, such as cigarette smoking.
Benign or essential hypertension
Hypertension in pregnancy
'Essential hypertension' is commonly used to mean idiopathic or primary hypertension. The majority of patients with hypertension (over 90%) have no known cause, and thus fall into the category of essential hypertension. This condition affects a vast proportion of the population - possibly as many as 20% of the middle-aged subjects in the UK, depending on the blood pressure levels adopted as the definition of hypertension. The diagnosis depends on an established elevated systemic pressure in the absence of changes in the ocular fundi and of proteinuria, and where no identifiable cause of pressure elevation has been demonstrated. Essential hypertension can affect any age group and can, when untreated, lead to many complications, including malignant and accelerated-phase hypertension.
During pregnancy cardiac output rises, but blood pressure normally falls owing to a decrease in vascular resistance. Obstetricians regard as abnormal a blood pressure greater than 140/90 (measured using Korotkoff 4 for diastolic pressure) in the first half of pregnancy, and by this criterion nearly one-quarter of the pregnant population will be hypertensive. About 2% will have a blood pressure greater than 160/105. Pre-eclampsia and eclampsia are placental syndromes which are limited to the duration of pregnancy, and of which elevated blood pressure is just one manifestation. Pre-eclampsia was previously defined as hypertension with proteinuria (>0.5 g/L per 24 hours) and oedema. However, the latter is a frequent finding in normal pregnancies and often absent in pre-eclampsia, so that it is no longer included as a diagnostic criterion. Proteinuria is a late manifestation of pre-eclamptic renal impairment. Impaired uric acid clearance, which occurs much earlier in the disease process, is more useful diagnostically. Evidence of disseminated intravascular coagulation occurs late in the disease. Eclampsia is defined as the development of convulsions in the above setting. The diagnosis of pre-eclampsia thus depends on the observations of an abnormal rise in blood pressure between the first and second halves of pregnancy of >30/20mmHg, associated with abnormal urate levels (>0.35 mmol/L at 32 weeks or >0.4mmol/L thereafter); proteinuria, impaired renal function and clotting disorders confirm the diagnosis, but occur very late in the disease. The consequences of pre-eclampsia are placental ischaemia and infarction and, in severe cases, maternal cerebral haemorrhage. Treatment is elective delivery, which confirms the diagnosis by effecting a rapid and complete cure. Medical management may reduce blood pressure but has not been shown to ameliorate other features of preeclampsia, which continue until delivery is effected. Pre-existing hypertension, low social class and the first pregnancy with a particular partner are risk factors for preeclampsia; interestingly, it appears to be less common in smokers.
Isolated systolic hypertension
Malignant and accelerated-phase hypertension Malignant or accelerated-phase hypertension is associated with vascular fibrinoid necrosis and loss of precapillary arteriolar autoregulation. The consequence is capillary vessel rupture and tissue necrosis through haemorrhage and ischaemia. The brunt of the damage is borne by renal, adrenal, cerebral, retinal, pancreatic and mesenteric vessels, for reasons that remain unclear. The clinical findings are elevated levels of blood pressure (which may be severe), associated with haemorrhages and exudates visible on the retina. Proteinuria due to similar vascular changes in the kidney is usual. Papilloedema (when present) O reflects cerebral oedema and was previously used to differentiate malignant hypertension, where it was present, from accelerated-phase hypertension, where it was
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Fig. 12.30
TABLE 12.44 Causes of secondary hypertension Type of cause Renal Parenchymal disease
Arterial disease
Endocrine disease Adrenal cortical overactivity Adrenal medullary overactivity Drug-induced
Congenital defects Miscellaneous
Examples Chronic renal failure of any cause Acute and chronic glomerulonephritis Polycystic disease Pyelonephritis Tumours, e.g. haemangiopericytoma; Wilms' tumour Diabetes Arteriosclerotic disease Fibromuscular dysplasia Embolism Polyarteritis nodosa Cushing's syndrome Conn's syndrome, adrenal hyperplasia Enzyme defects, e.g. congenital adrenal hyperplasia Phaeochromocytoma Contraceptive pill Liquorice-containing compounds Steroids Withdrawal of antihypertensives, esp. clonidine Cheese ingestion in patients taking monoamine oxidase inhibitors Sympathornimetic decongestant nasal sprays/appetite suppressants Coarctation of the aorta Porphyria (during acute attacks) Lead poisoning (during acute phase) Raised intracranial pressure
SECONDARY HYPERTENSION The causes of secondary hypertension are given in Table 12.44. As a general rule, the younger the patient with hypertension the greater is the likelihood that a cause will be found. In an adult hypertensive population less than 5% of patients will have a discernible cause. Although this proportion is small compared to those with essential hypertension, because many of the secondary causes are treatable by corrective surgery or specific therapy a high index of suspicion is required to avoid overlooking a treatable cause.
Renal disease The precise cause of high blood pressure in chronic renal failure is not clear. Adequate management of hypertension is important to prevent vascular complications due to hypertension and prevent further deterioration of renal function. There is no justification for surgical removal of
kidneys in unilateral renal disease, as medical treatment of hypertension is now likely to be more effective. Renal arterial stenosis activates the renin-angiotensin system, and restoration of the normal vascular supply may potentially cure the associated hypertension. Atheromatous disease is the commonest form of renovascular disease; it mainly affects middle-aged male smokers and is often part of a generalized degenerative disease of the arteries. Angioplasty may be useful, but the disease in smaller arteries limits the overall prognosis. In fibromuscular dysplasia (a disease of younger age groups), surgical reconstruction of renal arteries may be very effective. The importance of diagnosing renovascular hypertension has increased in recent years with the introduction of ACE inhibitors. These are to be avoided in renovascular hypertensives, as they can precipitate renal failure owing to the importance of angiotensin II in maintaining intrarenal haemodynamics in the underperfused kidney.
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Endocrine disease Hypertension, which may be severe, usually accompanies Cushing's syndrome (p. 932). Hypemldosteronism Overproduction of aldosterone may be due to single or multiple autonomous adrenal adenomas (Conn's syndrome) or bilateral micronodular hyperplasia of the zona glomerulosa. Clinical suspicion of primary hyperaldosteronism is raised when untreated hypertension is associated with hypokalaemia (K+ < 3.5mmol/L), alkalosis (HCCV > 30mmol/L), and a serum sodium which is high or at the upper limit of normality (Na+ > 145mmol/L). Investigation of primary hyperaldosteronism is aimed at differentiating adenomas from adrenal hyperplasia, as the former may be removed surgically. Radionucleotide adrenal scanning with labelled cholesterol, CT scanning and adrenal vein catheterization to measure the production of aldosterone offer the best methods of diagnosis. Explorative surgery may be necessary in some instances. Hyperplasia is treated successfully with antialdosterone drugs, such as spironolactone or amiloride.
Phaeochromocytomas Phaeochromocytomas are tumours, usually found in the adrenal, that secrete a mixture of catecholamines. They are responsible for clinical syndromes where hypertension may be episodic and alternate with episodes of postural hypotension. Paroxysms of hypertension are often associated with a constellation of symptoms, including headache, sweating, palpitations, feelings of apprehension and tremor. These symptoms are more sensitive in making the diagnosis than are most biochemical tests. The majority (90%) of the tumours are benign, and 10% arise outside the adrenals, most commonly at the bifurcation of the abdominal aorta. There are associated phaeochromocytomas in Sipple's syndrome (often a familial disorder with the combination of medullary carcinoma of thyroid and
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parathyroid adenoma) and in neurofibromatosis or von Recklinghausen's disease (p. 421). Investigation and management The diagnosis is confirmed by the detection of increased amounts of catecholamines and their breakdown products - normetadrenaline, metadrenaline and vanillylmandelic acid (VMA) - in urine or plasma. Localization of the tumour is by CT scanning and radionucleotide scans with MIBG (131I meta-iodobenzylguanidine). Treatment is surgical when possible, but can be hazardous owing to surges of catecholamine secretion during tumour manipulation. Preliminary treatment with a- and {3-blockade is essential, as are agents to raise blood pressure and prevent vascular collapse when the levels of these hormones fall rapidly as the tumour is removed.
Drug-induced hypertension Mineralocorticoid-induced hypertension with hypokalaemia and alkalosis accompanies the use of steroids, and may occur with carbenoxolone and excessive liquorice consumption. Hypertension induced by the contraceptive pill is generally mild and reversible on cessation of therapy, although this may take several months.
Coarctation of the aorta In coarctation of the aorta, children or young adults present with asymptomatic upper limb hypertension and are noted on physical examination to have characteristically late and low-volume femoral pulses compared with the radial pulses (radiofemoral delay). Hypertension may be difficult to treat medically and, if left until the patient is a teenager, is often only partially helped by surgical repair of the narrowed aortic segment. Those operated on late (after 20 years of age) frequently suffer the complications of uncontrolled hypertension, and about 12% may die in their 30s of cerebral haemorrhage or ruptured aortic aneurysm. Surgery is now recommended before the age of 6, but balloon angioplasty has recently been successfully used in this condition and may be used more frequently in the future if the initial good results are maintained. The hypertension of coarctation is not fully explained, but renal hypoperfusion, aortic baroreceptor activity and mechanical effects of aortic obstruction may all play a part. CLINICAL FEATURES OF HYPERTENSION
Until complications appear, essential hypertension has no symptoms and, by definition, no associated physical signs save the elevated blood pressure. Headaches (once widely
regarded as indicators of hypertension) are no more common in hypertension than in the general population, although very severe hypertension, associated with cerebral oedema, does produce headache. Breathlessness may be present, owing to elevated left ventricular and enddiastolic pressure and pulmonary venous congestion produced by left ventricular hypertrophy. Once the complications of essential hypertension are present, they are reflected in the symptoms and physical signs. Ventricular hypertrophy may lead to breathlessness, orthopnoea and frank cardiac failure; coronary disease to angina pectoris or myocardial infarction; cerebrovascular disease to stroke and dementia; and renal disease to all its associated symptoms. The presence of some symptoms (e.g. those associated with phaeochromocytoma) will suggest a secondary cause. Symptoms of renal impairment (e.g. nocturia and polyuria) may reflect the consequence of long-standing hypertension rather than its cause. Certain points in the examination of the hypertensive deserve emphasis, and require careful observation at diagnosis and during follow-up. Pulse Rate and rhythm. Atrial fibrillation is a late consequence of hypertension. A resting tachycardia might imply cardiac decompensation or a secondary cause, such as phaeochromocytoma or hyperthyroidism. Arterial wall. If thickened arteries are palpated in an under-50-year-old, aggressive treatment of blood pressure and other risk factors would be justifiable. Peripheral pulses. Radiofemoral delay is a sign of aortic coarctation, which may be a cause of hypertension in young patients. In older patients atherosclerotic disease may cause peripheral vascular bruits and absent distal pulses. Apex beat A displaced and thrusting apex beat indicates left ventricular hypertrophy (LVH) and therefore hypertension worthy of aggressive treatment. The absence of this sign does not exclude LVH. Abdomen Palpable kidneys might be found with polycystic renal disease. A systolic and diastolic abdominal or flank bruit raises the possibility of renal arterial stenosis. Optic fundus Haemorrhage, exudates and papilloedema (grades 3 and 4) are all signs of accelerated or malignant hypertension. Early signs of arterial wall thickening are narrowing of the arterial lumen (grade 1, which is difficult to identify) and arteriovenous nipping (grade 2). General aspects Other important general signs include:
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Fig. 12.31
• Signs of risk factors for vascular disease (xanthomata), which might tip the balance in favour of treatment because of the increase in vascular risk;
Signs suggesting Cushing's syndrome or neurofibromatosis (associated with phaeochromocytoma); Indications of congestive cardiac failure.
INVESTIGATION The aims of investigation are: • To establish the diagnosis • To identify a cause of the hypertension • To determine the presence and extent of complications from hypertension • To assess efficacy of treatment. The history and clinical examination provide clues as to which investigations are appropriate. Numerically, attempting to find an aetiology is far less rewarding, as only about 5% of all cases of hypertension have an identifiable cause. This proportion is higher in young adults, all of whom should be investigated accordingly.
Persistent proteinuria requires detailed testing of renal function (p. 1037). The discovery of haematuria should be followed by tests for inflammatory and neoplastic disease of the kidney. A 24-hour urine collection is required to quantify protein excretion; this may be helpful in hyperaldosteronism, Cushing's disease and phaeochromocytoma.
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Blood tests Routine haematological and biochemical tests are seldom rewarding. However, it is usual to obtain a full blood count and biochemical profile, which may occasionally provide useful information, for example: • An indication of renal function (urea and creatinine); • Electrolyte disturbances (low K+, raised HCO-3 and Na+) that might indicate hyperaldosteronism; • Other associated risk factors, such as hyperuricaemia or hyperlipidaemia; • Anaemia due to chronic renal disease, or polycythaemia secondary to renal disease.
ECG Ambulatory BP monitoring The difference between ambulatory BP (ABP) monitoring and clinic BP readings is similar to that between cinematography and snapshot photography. There are two ways of monitoring ambulatory BP: • With intra-arterial cannulation and direct pressure measurement • With indirect cuff manometry both of which record readings in a portable recorder which can subsequently be fed into a computer for display and analysis. The former method is now considered too invasive and is reserved for research purposes. Some patients with elevated blood pressure have 'white coat hypertension' (see above). The characteristic pattern is that they have significantly elevated blood pressure when the ambulatory BP monitor is first applied, and subsequent blood pressure readings at home or elsewhere show normal levels. A proportion of them show a further elevation of blood pressure as they make their way to hospital to return the equipment. Patients with essential hypertension possessing a 'white coat' component show elevated pressure at home, and further elevation during visits to hospital or clinic. The correlation between the effects of hypertension, such as left ventricular hypertrophy with isolated clinic BP reading, is much poorer than that with ABP. ABP provides information on diurnal variation in blood pressure. Blood pressure falls by about 20mmHg during sleep. The absence of nocturnal sleeptime falls in blood pressure is also associated with adverse prognosis. Urine testing Even though the yield of abnormal results by dipstick testing is not high, this simple test is essential in all cases.
An initial ECG may be helpful as a baseline for future changes, as well as in deciding whether to offer treatment. Features to be documented are signs of left atrial enlargement ('P mitrale', p. 477) and, with more severe levels of hypertension, evidence of LVH (Fig. 12.69) possibly associated with abnormalities in the ST segments and T waves that denote the 'strain' pattern. With effective blood pressure reduction these changes usually resolve. Chest X-ray The chest X-ray is helpful in establishing cardiac size and may reveal cardiac failure. 1 In most Caucasian patients it is normal, but cardiac enlargement is common in hypertensives of African descent. In young hypertensives, signs of a coarctation (p. 540) may be found.
FIG. 12.69 Typical ECG in severe hypertension showing left ventricular hypertrophy
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Ultrasound techniques The echocardiogram can determine the presence and extent of left ventricular hypertrophy. The presence of LV hypertrophy in a new patient without other causes for hypertrophy (e.g. athletism, aortic stenosis) is supportive of the diagnosis that the hypertension has been substantial and chronic. In epidemiological studies, left ventricular hypertrophy has been found to be an independent indicator of adverse prognosis. These patients benefit from more attentive management to achieve as normal a blood pressure level as possible. Abdominal ultrasound examination shows kidney size and ureteric anatomy and gives some information on the renal substance. Doppler study of the renal arteries can detect stenosis, the suspicion of which should lead to radionuclide renal scintigraphy to assess residual renal function, or to renal angiography. Renal artery stenosis is a contraindication for ACE inhibitor, renin inhibitor and angiotensin receptor antagonist therapy. Nuclear medicine techniques Nuclear medicine techniques are used to measure dynamic aspects of kidney and cardiac function. These specialized methods should be reserved for those in whom a specific problem has been identified. Renal angiography A renal arteriogram is the definitive test to determine renal artery stenosis. Angioplasty may be performed if the lesion is deemed suitable for intervention. Renal venous sampling may be performed to measure plasma renin activity, which provides complementary information about the extent and effects of arterial stenosis. Venous sampling may also be indicated to identify the locations of tumours producing vasoactive agents.
COMPLICATIONS OF HYPERTENSION
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The development of LVH in hypertension is an adaptive response, but the effects on diastolic function may give rise to pulmonary venous congestion and, with increasing hypertrophy, inner layers of myocardium become ischaemic. The associated acceleration of atheromatous coronary disease contributes to the progression to left ventricular dysfunction and cardiac failure. Atheroma deposition is accelerated by hypertension, and causes the most numerous of the complications of coronary artery disease; it also is responsible for most of the cases of stroke. Aortic dissection is a consequence of vessel wall degeneration and cystic medial necrosis. A pathologically distinct process affects smaller vessels, particularly of the renal and cerebral circulations; this consists of medial and intimal proliferation. Renal impairment may follow, although renal failure is usually a complication of the fibrinoid necrosis of the resistance
vessels, which characterizes malignant or acceleratedphase hypertension.
SUITABILITY FOR TREATMENT At the highest levels of blood pressure (diastolic greater than 115 mmHg) the risks to the individual patient are so high that treatment is mandatory. However, confirming that it is beneficial to treat patients with diastolic pressures between 90 and 114mmHg has been more difficult. The combined results of randomized trials suggest that treatment has decreased the odds of stroke significantly, by about 40%, but only managed to reduce the risk of heart attack by 10%. These large trials have provided no evidence to favour any one particular drug regimen over any other. Patients with diastolic blood pressures above 105 mmHg are recommended for treatment, particularly if they demonstrate any ventricular hypertrophy or renal impairment. For the 10-15% of the middle-aged population with diastolic pressures between 90 and 104 mmHg a more complex strategy is necessary. This is because halving the annual risk of a stroke, from 0.1 to 0.05% in an asymptomatic middle-aged man may not be worthwhile, particularly when set against the requirement for lifelong treatment. However, if the individual has already suffered a complication, such as a transient ischaemic attack, halving the annual stroke risk from 20 to 10% is a worthwhile goal. A strategy for patients with diastolic blood pressure between 90 and 104 mmHg should aim to identify those with the highest risk of complications. Treatment begins with measures to reduce associated risk factors, such as smoking, high blood lipids and obesity. Drug therapy of mild hypertension should therefore be reserved for those in whom all other measures have failed and those who carry the greatest risk of progression to severer forms of blood pressure or cardiovascular complications.
Systolic hypertension Although epidemiological studies have shown that systolic blood pressure is at least as good a predictor of subsequent complications as diastolic pressure, there is less information on the levels of systolic pressure that should be treated. In most cases, systolic and diastolic pressures follow each other closely. However, difficulties arise in elderly patients, where isolated systolic hypertension is more common. Precise guidelines are not available, but the fears that treatment might reduce cerebral blood flow and worsen cerebrovascular risks have not been borne out. Reduction of high systolic pressures (greater than 180 mmHg) might therefore be expected to accrue benefits by reducing the stroke rate, and this indeed has been the finding in the few studies of elderly hypertensive patients.
METHODS OF TREATMENT The importance of attention to associated risk factors, such as smoking and hyperlipidaemia, has already been emphasized, and is an important part of all treatment strategies. Blood pressure-lowering drugs may not be needed if other methods are successful.
Non-pharmacological methods Drug withdrawal. Withdrawal of drugs that may contribute to hypertension, e.g. NSAIDs, steroids and oestrogencontaining compounds such as the oral contraceptive pill, should be considered where possible. Patients with a high alcohol intake should be advised to abstain or reduce their intake. Dietary measures. For each kilogram loss of weight, blood pressure can be expected to fall by 2.5-3.0mmHg systolic and 1.5-2.3 mmHg diastolic. In general, salt restriction has not been found to be an effective treatment for hypertension at the levels of intake achievable with a tolerable western diet. However, high salt intakes can negate
the effectiveness of the thiazide diuretics used in treatment, so it is important to ensure patients moderate their intake. Relaxation. Teaching patients to relax - using formal programmes administered by non-medical personnel in general practices and continued at home by the patient has been shown to produce a modest sustained blood pressure reduction. Exercise. Aerobic exercise maintained for some 15-20 minutes will lower subsequent blood pressure readings by 5-10 mmHg for about 12 hours. Exercise may also improve associated cardiac risk factors, including obesity.
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Drug treatment of essential hypertension The principles of drug treatment for hypertension are theoretically simple. Therapy with a single drug given once a day is the ideal, but combination treatment is frequently necessary. A step-by-step approach is frequently used, starting with a first-line preparation alone, and then in combination with another, before third- and fourth-line drugs are used (Table 12.45).
TABLE 12.45 Indications for specific antihypertensive drugs and their common side-effects Indication
Advantages
Symptomatic side-effects
Other side-effects
First line or adjunct to p-blockers or Ca antagonists
Effective, cheap, usually once-daily treatment
Gout, impotence
Spironolactone Amiloride Loop
First line in Conn's or adrenal hyperplasia In renal disease
Potassium-sparing
Gastrointestinal upset
Powerful diuretics
Urinary urgency
Hypokalaemia Glucose intolerance Lipids Hyperkalaemia in renal impairment As for thiazides
B-Adrenoreceptor blockers
First line
Antianginal and antiarrhythmic
Asthma in some subjects, tiredness, claudication and cold hands/feet
? lipid effect LDL HDL
Calcium antagonists
First or second line
Antianginal and antiarrhythmic
Flushing, oedema, gastrointestinal upset
Heart block and negative inotropy with some examples
Angiotensin-convertingenzyme inhibitors
First line in renal disease First line in heart failure
Well tolerated and very powerful; useful in heart failure
Cough, postural hypotension
Profound hypotension Renal impairment in renovascular disease
Angiotension II receptor antagonists
Second or third line
As ACEI, but no cough
Dizziness
As ACEI, hepatic impairment
a-Adrenoreceptor antagonists
First or second line
Largely superseded by Ca antagonists and ACE inhibitors
Postural hypotension
-
Can be used alone effectively
Sedation, impotence
Haemolytic anaemia
Hydralazine
Second/third line Methyldopa in pregnancy Third line
Headache
SLE-type reactions
Diazoxide
Third line
Oedema
Glucose intolerance
Minoxidil Bethanidine/guanethidine
Third and fourth line Fourth line
Largely superseded by Ca antagonists and ACE inhibitors Largely superseded by Ca antagonists and ACE inhibitors Extremely powerful vasodilator Rarely indicated
Hirsutism, oedema Postural hypotension/impotence
Fluid retention Hypotensive infarction
Type of drug Diuretics Long-acting thiazides
Others Methyldopa/clonidine
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Diuretics The long-acting thiazide diuretics such as chlorothiazide and bendroflumethiazide (bendrofluazide) are effective, although symptomatic side-effects such as impotence and gout can occur. They are less powerful in renal failure, when loop diuretics such as frusemide and bumetanide have an advantage. Thiazide diuretics cause biochemical changes which have given concern about their long-term safety. In particular, mild hypokalaemia is common and may be associated with a risk of cardiac arrhythmias. Hyperuricaemia may produce symptomatic gout and, in conjunction with glucose intolerance and increases in cholesterol and triglyceride concentration, an overall worsening of the cardiovascular 'risk factor profile' is produced by these drugs. It is not at all clear whether these concerns are justified, although the lack of improvement in the incidence of myocardial infarction in the vast majority of hypertension treatment trials has been attributed in part to these unwanted biochemical effects of the thiazide diuretics. B-Adrenoreceptor blockers Chance clinical observations led to the recognition that the B-adrenoreceptor blockers are effective antihypertensives. These drugs are specifically contraindicated in obstructive airways disease, because of the production of asthma even by drugs with supposed cardiac selectivity. Other troublesome side-effects are related to the B-receptor blocking action, with bradycardia, tiredness, claudication and cold limbs being prominent. The demonstration of their protective effect following myocardial infarction, as well as their antiarrhythmic and antianginal actions, make B-blockers a rational choice when CHD complicates hypertension. They have to be used with great caution, if at all, in heart failure. Plasma lipids are altered with B-blockade, potentially worsening the cardiovascular risk. However, whether these alterations are deleterious in the long term has not been clarified. B-Blockers with diuretics have become established as the mainstays of the management of hypertension. There are many examples of these drugs. In the UK, atenolol, metoprolol, propranolol, bisoprolol and pindolol are commonly used examples. Calcium antagonists The antihypertensive effectiveness of calcium antagonists is related to the fall in peripheral vascular resistance that follows resistance vessel vasodilatation. Side-effects of nifedipine can be attributed to its vasodilator activity and include flushing, headache and oedema; in contrast, verapamil has more gastrointestinal side-effects and ought not to be combined with B-blockade because of its propensity 1
598
MCQ 12.24
to produce heart block and impair ventricular contractility. Diltiazem fills an intermediate position, with fewer peripheral effects and more cardiac effects than nifedipine, but fewer myocardial effects than verapamil. Although these drugs have not been subjected to close analysis in large trials, there is no doubt of their efficacy and popularity, even as a first-line therapy. Angiotensin-converting-enzyme inhibitors The ACE inhibitors were specifically manufactured to inhibit the renin-angiotensin system by blocking the conversion of angiotensin I to its active form, angiotensin II. These drugs are subjectively very well tolerated, and their associated efficacy, in all but the groups of patients with renal arterial stenoses, has led to their adoption as the first of the second-line treatments to be used in the more severe degrees of hypertension. Cough is a common (>10%) sideeffect of ACE inhibitors, but at higher doses severe neutropenia, rashes and taste disturbance have been seen with captopril. Their hypotensive effect may be severe in relatively hypovolaemic patients and in those with hyponatraemia (which might occur in those taking diuretics). ACE inhibitors will cause a deterioration in function or renal failure in renal arterial stenosis. Methyldopa In pregnancy methyldopa still maintains a place in the treatment of hypertension, but the associated CNS sideeffects have made it less popular now that less sedative preparations are available. Sympathetic ganglion blocking drugs In the past, the sympathetic ganglion blocking drugs (guanethidine and bethanidine) were important as early effective treatments, but their use is now limited by their troublesome postural hypotensive effects, lack of supine blood pressure control and the sexual dysfunction that they produce in men. Drug selection in therapy Despite decades of antihypertensive drug therapy, the only drugs that have been shown to improve prognosis are thiazide diuretics and B-blockers. In newly diagnosed hypertensive patients without contraindications, these drugs should be considered as first-line therapy. Newer agents have numerous claimed advantages, but whether these will translate into improved prognosis is uncertain. Their use may be more sensibly reserved for patients with contraindications for, or intolerance of, diuretic or B-blocker usage, unless they can provide specific advantages, as shown in the following conditions: • Patients with angina benefit from antihypertensive drugs which are also antianginal. • Diabetic patients with proteinuria may benefit more with ACE inhibitors as an antihypertensive agent. • Patients with systolic heart failure have a better
• •
•
•
prognosis with ACE inhibitor or vasodilating B-blocker therapy. Patients with significant left ventricular hypertrophy or diastolic ventricular failure may benefit more from ACE inhibition as antihypertensive therapy. Thiazide diuretics may worsen diabetic control and (3blockers may blunt the sensation of hypoglycaemia, and so these drugs should be reserved as second- or thirdline antihypertensive therapy in diabetics. Thiazide diuretics may result in hypokalaemia and/or hypomagnesaemia, which exacerbate or precipitate serious cardiac arrhythmia, and should be avoided in susceptible patients. In black hypertensives, (3-blockers and ACE inhibitors are less effective as monotherapy than diuretics and calcium antagonists.
Combination therapy Adequate control of hypertension with monotherapy should be sought before any combination therapy is considered. Once it has been established that monotherapy is inadequate, then combination therapy may be required. The choice of combinations is largely empirical in order to attain acceptable blood pressure levels, but, from published trials, p-blockers plus dihydropyridine calcium antagonists, ACE inhibitors plus diuretics or calcium antagonists appear to offer advantages, whereas [3-blockers plus ACE inhibitors or diuretics plus calcium antagonists appear less efficacious. Combination of a (5-blocker and verapamil should be avoided as the combination is very negatively dromotropic and inotropic. Both diuretics and ACE inhibitors are liable to alter electrolyte balance, and there is no standard formula to calculate combination dosage - there is no substitute but to monitor serum electrolytes serially.
Drug treatment of hypertension in pregnancy Pre-eclampsia The treatment of pre-eclampsia (p. 592) requires delivery of the fetus. Nevertheless, drugs may be needed to control the blood pressure before delivery can be achieved. Methyldopa (250-500 mg, 6-hourly by mouth) is used and, if necessary, can be given parenterally. It has the advantage of being effective and harmless to the fetus, although its sedative side-effects can confuse neurological assessment and its onset of action is slow (1 hour). Hydralazine, orally (<300mg daily), by intramuscular injection (1020 mg, 3-6-hourly) or by constant infusion (5-10mg/h) is a suitable alternative, although flushing, tachycardia and vomiting may be side-effects at the higher doses. Given intravenously, it has a rapid onset of action which can be maintained by a constant infusion. p-Adrenoreceptor blockers and calcium antagonists have been found to be effective in the acute situation, although experience with these drugs and follow-up of the delivered neonates has been shorter than for methyldopa and hydralazine. Diuret-
ics are used only when cardiac failure complicates the picture.
12
Chronic hypertension in pregnancy Because of its known lack of effects on the fetus, methyldopa is the drug of choice; hydralazine is the usual alternative, although (5-adrenoreceptor blockers are being used increasingly without undue hazard. Mothers who are known moderate hypertensives may be advised to cease treatment at the time of conception, although no teratogenicity has been associated with any of the commonly used antihypertensive drugs. O
Drug treatment of hypertensive emergencies Malignant or accelerated-phase hypertension This previously rapidly fatal condition is now managed by bed rest with admission to hospital and oral treatment. Parenteral treatment is avoided unless coma, fits or severe heart failure are present. Under these circumstances an effective treatment is an intravenous infusion of labetalol, starting at 25mg/h and increasing to 120mg/h, with additional diuretic treatment for pulmonary oedema. Intravenous nitrates are also effective in this situation. Hydralazine given intramuscularly has been a popular treatment, but the 20-minute delay in onset of action may lead to additional doses or drugs being given, resulting in hypotension some hours later. Methyldopa, even when given intravenously, is also too slow to be used effectively. For cases caused by phaeochromocytoma, phentolamine (2.5-10mg i.v. bolus or Img/min by i.v. infusion) produces a rapid pressure reduction by cc-adrenoreceptor blockade, but such a response is not limited to this disease. Oral treatment is optimal in most cases of malignant and accelerated hypertension, and any of the usual antihypertensive drugs can be used successfully. Recent observations show that sublingual nifedipine (10-20 mg) produces a smooth blood pressure reduction beginning within 10 minutes, although the reflex tachycardia it produces may require treatment with a (3-adrenoreceptor blocker. Additional diuretic treatment is often given. The degree and rapidity of blood pressure reduction are important. In chronic hypertensives, cerebral autoregulation is lost at mean blood pressures above ISOITS mmHg and below 90-120 mmHg. Treatment should reduce mean blood pressure to 100-120 mmHg and no lower. This should be achieved over a 12-36-hour period to allow time for the relatively slow process of reestablishing normal cerebral autoregulation. Aortic dissection Aortic dissection is an emergency requiring prompt reduction of mean blood pressure to 100-110 mmHg; this is usually achieved with an infusion of sodium nitroprusside, starting at 12.5mg/min and titrating the dose against
599
blood pressure every 2-3 min. Infusion should not continue beyond 24 hours, but the resulting thiocyanate accumulation can be diminished by concomitant use of hydroxycobalamine by injection. There may be an advantage in reducing the systolic rate of change in aortic pressure as well as mean pressure. This can be achieved with Padrenoreceptor blockade, so that labetalol infusion with its mixed, though predominantly p-receptor, effects has been advocated for use in dissection.
Hypertension in chronic renal failure A proportion of patients with chronic renal failure have hypertension; in these, blood pressure may be controlled by dietary sodium restriction and fluid removal at haemodialysis. Drug treatment is necessary in some cases, and the excretory metabolism must be taken into account when dosages are calculated. Treatment is generally similar to that in essential hypertension.
Hypertension in phaeochromocytoma Hypertensive crises in phaeochromocytoma can be treated conventionally, but it is important to avoid (3adrenoreceptor blockade before full a-adrenoreceptor blockade has been achieved, in order to avoid unopposed a effects exacerbating hypertension. Parenteral phentolamine can be used acutely, and longer-term control gained with phenoxybenzamine (10-30mgt.d.s.), with the later addition of small doses of a [3-blocker, such as propranolol (40mgt.d.s.). If a surgical cure cannot be effected, longterm treatment with oc-methyltyrosine can be used, although side-effects are often troublesome.
Adrenocortical hyperplasia and Conn's syndrome
VASCULAR DISEASE AORTIC ANEURYSM Most intrathoracic aortic aneurysms are asymptomatic unless they become large enough to produce pressure on a main bronchus, on the phrenic nerve or if they produce aortic regurgitation. They may rupture and result in sudden death. They are frequently diagnosed on chest X-ray. They are a common manifestation of collagen diseases such as Marfan's syndrome, and are a complication of atherosclerosis and hypertension.
ACUTE AORTIC DISSECTION Dissection occurs when there is haemorrhage into the wall of the aorta, causing the media to separate from the other layers (Fig. 12.70). Most dissections are seen in middleaged or elderly men with arteriosclerosis and hypertension. More than 50% of patients who present with dissection die within 24 hours. It is a particular complication of Marfan's syndrome, where cystic medial necrosis is common. In this disorder progressive aortic dilatation leads to aortic incompetence and dissection with a high mortality. Dissections can be classified clinically according to the part of the aorta that is affected. When the ascending aorta is involved, it is termed a type A dissection (De Bakey types I and II), whereas those where only the aorta beyond the left subclavian origin is involved are called type B dissections (De Bakey type III).
Clinical features The most prominent symptom is a very sudden onset
Surgical removal of the adenomas in Conn's syndrome may not always cure the electrolyte disturbances and hypertension. In these circumstances, as in idiopathic hyperplasia, treatment with amiloride (20-70 mg daily) or spironolactone (200-400 mg daily) is effective.
FURTHER READING ON SYSTEMIC BLOOD PRESSURE AND HYPERTENSION Guidelines Subcommittee 1993 Guidelines for the management of mild hypertension: memorandum from a World Health Organization/International Society of Hypertension meeting. J Hypertens 11: 905-918.
600
1
Figs 12.32-12.34
3
MCQ 12.25 4
2
Fig. 12.35
Fig. 20.36
FIG. 12.70 Sites of dissection in aortic aneurysm
of excruciating pain, often described as tearing in nature. Unlike infarction pain, the pain is often totally unheralded and at its worst initially, but may uncommonly develop to a pulsating discomfort that persists. The pain may radiate through to the back and, in type B dissection, to the left shoulder. Typical myocardial infarction pain may also coexist if the coronary arteries are involved by the dissection.
Diagnosis and investigation The diagnosis can be difficult, and its importance has considerably increased with the emphasis on early acute treatment of myocardial infarction with thrombolytic drugs. Clearly, these may have terrible consequences in dissection. The patient is frequently hypertensive or has a history of hypertension, which may or may not have been treated. Patients with Marfan's syndrome are usually easy to identify but form only a small proportion of cases. In about 10% of patients a difference in blood pressure (20mmHg or more) in the two arms may be found, and in some a prominent pulsation is visible at the root of the neck. Auscultation may reveal aortic regurgitation in type A dissection, which is typically more obvious at the right sternal edge. The ECG may be normal except in those cases with associated coronary artery involvement. In some individuals the chest X-ray provides the first clue to the diagnosis, with mediastinal widening, left-sided pleural effusions and expansion of the aortic knuckle border beyond a calcified rim of endothelium. 1 The diagnosis is confirmed at cardial catheterization by contrast aortography. Coronary angiography is also performed to allow surgical repair. CT is helpful and less invasive, often being performed prior to catheterization but rarely supplanting it totally. 2 MRI is rapidly replacing CT. Echocardiography by the standard methods may demonstrate a proximal ascending aortic dissection, but transoesophageal echocardiography is the only ultrasound method able to adequately demonstrate the descending thoracic aorta. Transoesophageal colour Doppler is particularly useful, as the flow patterns make the intimal tear more obvious.
Complications Complications of the dissection include occlusion of arterial branches, including the coronary arteries, head and neck vessels, and indeed all distal arterial branches. Stretching of the aortic annulus in type A dissection is responsible for aortic regurgitation, which may be severe and lead to left ventricular failure and shock. Progressive dilatation of the aorta may obstruct the airways or oesophagus. Finally, rupture of the aortic wall may occur, producing pericardial or pleural effusion and, occasionally, intrabronchial haemorrhage. This complication frequently, but not always, causes death.
Management Treatment is usually surgical for type A dissection and many cases of type B. However, acute management includes blood pressure reduction by parenteral treatment, preferably with drugs reducing the inotropic force of the heart, such as labetalol by infusion. Pain control and sedation are also very important in this very distressing condition, where the outlook is often very poor. 3 4
12
ARTERITIS Arteritis is an inflammatory process involving the artery wall. It can occur in vessels of various sizes. If these are small, the condition is called necrotizing vasculitis and is found in a large number of 'autoimmune' conditions (discussed in Chapter 22). Involvement of the large arteries is much less common and occurs principally in Kawasaki's disease, Takayasu's (or pulseless) disease and giant cell (or temporal) arteritis.
KAWASAKI'S DISEASE Kawasaki's disease is a disease of children described originally in Japan but now reported from other parts of the world. The aetiological agent is unknown, but as the disease occurs in cyclical epidemics an infective agent is suspected. It was originally called 'mucocutaneous lymph node syndrome' because of the prolonged fever, skin rash and marked cervical lymphadenopathy. Later it was realized that there is a high incidence of coronary artery aneurysms, occlusions and myocardial infarction which, because many of the patients are infants, were originally missed. Diagnosis of these lesions can often be made noninvasively by ECG and 2D echocardiography. Management is based on the use of antithrombotic agents and steroids, but aspirin alone has been found to result in a lower incidence of coronary artery complications than some other regimens.
TAKAYASU'S ARTERITIS
Takayasu's arteritis - a disease which predominantly affects oriental women - was first described by an ophthalmologist whose first case was a young woman with cataracts and unusual arteriovenous anastomoses around the optic papillae. It was later realized that similar ophthalmic findings were seen in patients with absent radial pulses, hence its alternative name, 'pulseless disease'. The disease can be classified into three types: • Type I involves the aortic arch and its branches, producing diminished or absent pulses over the upper body (so-called 'reversed coarctation').
601
• Type II involves the descending aorta, particularly the renal arteries and vessels supplying the abdominal viscera. • Type III is a combination of I and II. Takayasu's arteritis has also been implicated in the development of primary pulmonary hypertension. The aetiology is unknown but the disease commonly starts in teenage girls, with a sex ratio of 8:1.
Clinical features There is often a systemic illness, with fever, arthralgia and fatigue. There may be pain and tenderness over the affected arteries. This systemic phase passes and is followed by a latent period. Some time later these patients, and others who had no systemic prodrome, present with the typical features of weak or absent pulses, low or unrecordable upper body blood pressure, hypertension, heart failure and ocular damage. The hypertension is produced by an increased aortic impedance secondary to major vessel occlusion or narrowing, and also from renal artery stenoses causing renal hypertension. Bruits over affected vessels are common. Heart failure is usually secondary to hypertension, but coronary artery ostial stenoses can occur, causing angina; aortic regurgitation has also been described.
Management and prognosis The acute systemic illness is alleviated by corticosteroids, which may reduce the incidence of sequelae. Antiplatelet agents, such as aspirin and dipyridamole, and warfarin have been used to reduce the frequency of cerebral transient ischaemic attacks and possibly retard the progression of arterial lesions. Morbidity is chiefly from heart failure and cerebrovascular events. Surgical treatment of severe vascular stenoses may become necessary.
GIANT CELL (TEMPORAL) ARTERITIS
602
Although predominantly affecting the cranial arteries, giant cell arteritis can, like Takayasu's arteritis, involve the aorta and its proximal branches. The disease is described more fully in Chapter 22, page 1183. Where major vessel arteritis occurs, it may complicate the more common presentation with cranial arteritis and polymyalgia rheumatica, or may occur alone. Symptoms are similar to those of Takayasu's arteritis, including angina and exercise-related ischaemia of the upper and lower limbs. Aortic regurgitation, aneurysm and dissection can complicate giant cell arteritis of the aorta. As for the commoner forms of the disease, treatment is with corticosteroids.
PERIPHERAL VASCULAR DISEASE ARTERIAL DISEASE Thoracic outlet syndromes In the past, the thoracic outlet syndromes were thought to be due principally to arterial compression of the subclavian artery but it is now appreciated that many of the symptoms are caused by compression of the brachial plexus as well. This is from an anomalous fibrous band that stretches from a cervical rib to the first rib and, in doing so, compresses the neurovascular bundle. The patient has symptoms in the hand, which appear promptly when the arm is abducted to 90° and externally rotated. A bruit can then be found over the supraclavicular fossa. These features disappear when the arm is returned to a relaxed position. Aneurysm of, and embolism from, the subclavian artery is a comparatively rare complication of this condition, which can lead to digital gangrene.
Peripheral arterial disease and arteriosclerosis Arteriosclerotic arterial disease can be from atheroma, focal calcific sclerosis (Monckeberg's arteriosclerosis) or arteriosclerosis. Monckeberg's sclerosis leads to calcification of the media without narrowing of the vessels, but is often associated with arteriosclerosis and luminal narrowing. Most symptomatic disease is due to atheromatous plaque formation, with subsequent stenosis, occlusion or embolization of the vessel. Haemorrhage into an atheromatous plaque may precipitate a sudden vessel occlusion. Emboli may arise from atheromatous plaques (as occurs frequently from the carotid); however, major emboli are more frequently from the heart, in such conditions as mitral valve disease, left ventricular aneurysm, mural thrombus following myocardial infarction, left atrial myxoma, endocarditis, and from any enlarged heart, particularly if there is atrial fibrillation. The sites of predilection for the atheroma are not fully explained, and any one patient may have principally coronary, cerebrovascular or peripheral vascular symptoms, with risk factors very similar to another patient whose symptoms are quite different. Atheroma tends to develop in the abdominal aorta and at the origins of major branches. These may be sites of mechanical stress or low shear.
Intermittent claudication Ischaemia of the lower limbs is usually accompanied by effort-related cramp in the calves, thighs and buttocks, which disappears with rest. The site of claudication indicates the probable site of stenosis or occlusion - the higher
the claudication the higher the atheroma is likely to be found. The walking distance on the flat is usually remarkably repeatable. Claudication is often accompanied by profound weakness as well as cramp in the affected muscles, which have become acidotic from anaerobic exercise. The combination of hip and thigh claudication with impotence in males (the Leriche syndrome) is due to severe atheromatous occlusion of the lower end of the aorta. More severe ischaemia produces a continuous pain at rest, particularly in bed. The pain is most frequently in the toes or foot, with some paraesthesia. The foot is often hung over the edge of the bed and may be subject to ulceration and gangrene. In diabetics with peripheral neuropathy there may be no pain but only ulceration and gangrene. Diagnosis and investigation Peripheral vascular disease is assessed by a careful history and clinical examination for signs of ischaemia, absent pulses, audible bruits over the proximal arteries, poor skin nutrition, low skin temperature and loss of hair, and then by blood pressure measurement. This is usually done using Doppler ultrasound on the ankle arteries with a proximal cuff. The normal ankle systolic pressure is usually higher than brachial (by about 20%) and should be maintained after exercise. The ischaemic leg often has an ankle pressure of about 50% of brachial at rest, which becomes unrecordable after exercise when the blood is diverted to areas of vasodilatation elsewhere. The severity of the hypotension is related to the degree of arterial disease. Management Most patients with claudication benefit from medical measures such as weight reduction, complete cessation of smoking and an energetic training regime that increases the claudication distance. Vasodilators and viscosityreducing drugs have a limited role. Surgical intervention after angiography now includes angioplasty, as well as endarterectomy and bypass grafting. It is reserved for more severe cases.
Gangrene Sudden ischaemia of a limb (from trauma, arterial thrombosis or embolism) leads to pain, pallor, coldness, and then numbness of the limb distal to the occlusion. If perfusion is not restored, sensation is severely diminished in an hour; within 6 hours ischaemic contracture of the muscles has started. This is followed by subcutaneous haemorrhage and focal gangrene. Fixed staining of the skin indicates death of the underlying tissues. Persistent pain and numbness without loss of sensation indicate a collateral flow. Managemenf This is an emergency and treatment is surgical, by embolectomy, emergency bypass grafting or eventual amputation.
Embolectomy under local anaesthetic can often save a limb. Heparin is used to prevent further clotting, particularly if there is an obvious embolic source.
12
Buerger's disease Buerger's disease was previously thought to be a distinct disease, but is now considered to be an accelerated form of atheroma affecting young men of 20-40 years of age who smoke (or chew) tobacco heavily. It affects the small arteries of the hands and feet, with an intense inflammatory response, and often involves the veins as well. Hand and instep claudication may occur, with loss of ankle and wrist pulses and gangrene of the toes and fingers. There is often an associated Raynaud's phenomenon (see below) and a migratory nodular phlebitis. Cessation of smoking or chewing tobacco is imperative. Prognosis For patients with symptoms of limb ischaemia, the rate of limb loss is about 2% per year for non-diabetics and 7% per year for diabetics.
Raynaud's syndrome and phenomenon Raynaud's syndrome and phenomenon are vasospastic conditions affecting mainly the hands; they are often precipitated by cold and sometimes by motion, although random spontaneous attacks are common. Attacks are characterized by episodes of arteriolar spasm; these produce cold pale fingers and hands, progressing over minutes or hours to cyanosis and ending with a red flushing phase. When the condition is not associated with any underlying disorders it is termed Raynaud's syndrome, and skin changes are not seen. This is commoner in young women. Raynaud's phenomenon occurs secondary to underlying systemic conditions, the most common being scleroderma. Other collagen diseases may be associated with Raynaud's phenomenon, as may thoracic outlet compression, arteriosclerotic vascular disease, vibration trauma in pneumatic drill users, and serum protein abnormalities.
Mesenteric ischaemia Mesenteric (or small bowel) ischaemia is described in Chapter 15, page 795.
VENOUS DISEASE Varicose veins are the commonest vascular disorder affecting the legs, and venous thrombosis is a frequent complication of many medical and surgical conditions.
Varicose veins Varicose veins are dilated and tortuous veins that vary in size from large palpable bunches to mere discoloured superficial spider bursts on the skin. They arise either
603
through primary abnormalities in the venous wall leading to dilatation and incompetence of the valves, or secondarily after damage caused by previous thrombosis. In either case, factors that impede venous flow or increase venous pressure in the legs contribute to their development, as does the prolonged standing required in certain occupations. Many patients suffer no symptoms but the veins can be responsible for discomfort, usually described as heaviness or pulling. Oedema may occur and, in chronic severe disease, pigmentation of the skin, a disfiguring dermatitis, ulceration or, at its severest, gangrene may follow. These complications are more prominent in the areas subject to the highest venous pressures, where skin nutrition is consequently poorest, namely in the lower third of the leg, often more marked medially. Management Elastic stocking support, injection of sclerosants and surgical removal (or stripping) of the veins are used to treat the varicose veins. Relief of exacerbating factors, such as obesity, ascites and right heart failure, is also important. Ulcers often heal slowly, and must be kept clean and uninfected. Elevation of the limb aids healing.
Venous thrombosis Occlusion of veins by thrombus is very common. It leads to considerable morbidity and, when the deep veins of the leg and pelvis are involved, to the risk of serious illness or death through pulmonary embolism. Superficial venous thrombosis Superficial venous thrombosis causes pain and swelling over the affected vessel, which is often palpable as a tender cord or small nodule. Unless complicated by progression to deep vein thrombosis (DVT), superficial venous thromboses are essentially benign and require only symptomatic treatment. NSAIDs, such as indomethacin or aspirin, plus local applied heat, are of help. Deep venous thrombosis The incidence of DVT is low in physically active subjects. The predisposing factors are divided into: • Transient/reversible factors - surgery, trauma, bed rest, prolonged immobility (e.g. long-haul airflights), pregnancy; • Chronic factors - venous disease, hypercoagulability of blood, active or occult malignant disease, pelvic masses and marked obesity; • Idiopathic - with no known risk factors.
1
604
MCQ 13.1
The risk of recurrence of DVT is lower in patients with a reversible risk factor than in those with chronic risk factors or idiopathic DVT. The risk of pulmonary embolism (PE) is low in patients with DVT confined to the calf veins. It is the proximal DVT involving veins in the thigh and pelvis that are potential sources of large pulmonary emboli. DVT of the axillary or internal jugular veins is much less common and rarely gives rise to PE. Superior vena caval thrombosis can lead to PE, and a known precipitating factor is the presence of indwelling central venous catheters (e.g. for parenteral nutrition). Clinical features and diagnosis The diagnosis of DVT is often difficult. The main features are pain and swelling of the affected limb. The symptoms vary with the extent and type of vein involved and are often absent. Dorsiflexion of the foot may produce calf tenderness (Homan's sign) in the extended leg, but this sign is often not very helpful. The most useful diagnostic test is the venogram which, when technically adequate, will usually establish the presence and extent of any thrombus. Doppler ultrasound velocity profiles can be useful, although only for DVT affecting veins above the knee. The major conditions which may mimic DVT include muscle trauma, rupture of a popliteal (Baker's) cyst (which resembles calf vein DVT) and sciatic nerve irritation. Complications The most serious complication in DVT is PE (Ch. 13, p. 675). This is usually a complication of thrombus above the knee, but sometimes occurs with calf vein thrombosis. Other complications include vein wall and valve damage leading to long-term venous insufficiency. Management Treatment of DVT is by intravenous heparin bolus (5000 U) followed by a constant infusion (24000^8000 U/24h) sufficient to maintain a partial thromboplastin time two to three times normal. Oral anticoagulation with warfarin is then instituted, with the heparin being discontinued once a prothrombin ratio of 2.5-3.0 is achieved. Oral anticoagulation is continued for 6 weeks in patients with transient/reversible predisposing factors, and for 6 months in those with idiopathic DVT. It may need to be indefinite in patients with known active malignancy, other bedridden conditions, recurrent DVT or haematological hypercoagulable states (e.g. thrombophilia). Recurrent subacute pulmonary embolism leading to chronic pulmonary hypertension is associated with a poor prognosis, and may require insertion of an inferior vena caval filter; such patients also need indefinite anticoagulation. It has become clear that prophylactic treatment with relatively low doses of anticoagulants (heparin by subcutaneous or intramuscular injection: 5000 U 8-hourly or enoxaparin 20mgs.c. o.d.) can prevent DVT, and hence PE, in patients at risk, such as those on prolonged bed rest after major surgery.
13
FURTHER READING British Thoracic Society 2002 The burden of lung disease (www.brit-thoracic.org.uk)
Respiratory
STRUCTURE AND FUNCTION OF THE RESPIRATORY SYSTEM 1
Disease John Moxham and John F Costello
Structure and function of the respiratory system 605 Symptoms and signs of respiratory disease 611 Examination of the respiratory system 619 Imaging the thorax 623 Bronchoscopy and lung biopsy
Respiratory failure 670 Lung transplantation 674 Pulmonary hypertension 674 Pulmonary Ihromboembolism 675 Sarcoidosis 682 Connective tissue and related diseases and the lung 689
627
Vasculitides and the lung 690
Respiratory infections 631
Pulmonary arteriovenous malformations and shunts 691
Lung abscess 647 Bronchiectasis 648 Cystic fibrosis 649
Pulmonary fibrosis and diffuse interstitial lung disease 692
Asthma 651
The acute respiratory distress syndrome 697
Pulmonary eosinophilia 659
Lung tumours 700
Chronic bronchitis and emphysema 661
Pleural disease 710
Respiration during sleep 668
Respiration can be defined as those processes concerned with gas exchange between an organism and its environment. In humans respiration begins with the uptake of O2 and ends with the elimination of CO2. The adequacy of gas exchange by the lungs depends on four closely integrated processes:
Neuromuscular and skeletal disorders 718
Respiratory diseases are responsible for a large proportion of premature mortality and serious morbidity among the population, and at the same time for a large amount of minor illness. In England and Wales respiratory diseases (including lung cancer) account for approximately a quarter of all deaths. They are the second most common cause of death after cardiovascular disease. Much morbidity and many deaths are smoking related. Unfortunately, despite an overall decline in numbers smoking, the prevalence of smoking in young people in the UK is on the increase, as is that in many developing countries.
• • • •
Ventilation Diffusion of gases Pulmonary capillary blood flow The carriage of gases by the blood.
In addition, breathing is regulated in accordance with the constantly changing metabolic needs of the body by an intricate control system. The anatomical organization of the human lung is eminently suited to its role as an exchanger of O2 and CO2. A series of branching airways conducts air into and out of the alveolar spaces. Similarly, the pulmonary circulation delivers blood to, and drains blood from, the pulmonary capillaries. Ninety per cent of the alveolar surface (80m2 in an adult lung) is covered with capillaries, providing a thin but large film of blood for exposure to the gases in the alveolar spaces. The respiratory system has other functions besides gas exchange: • The upper airways filter and humidify inspired air. • It provides an elaborate defence mechanism that protects the body against inhaled pathogenic microorganisms and toxic chemicals. • The pulmonary blood vessels serve as a reservoir for the left side of the heart. • It provides O2 and substrates for its own metabolic needs. • The lung modifies the pharmacological properties of a variety of drugs.
Ventilation Ventilation is the cyclical movement of ambient air into and out of the lungs, and the distribution and mixing of that air within the lungs. This cycle is accomplished by contraction and relaxation of the respiratory muscles and the elastic recoil of the lungs. During normal quiet breathing, about two-thirds of the inspired gas reaches perfused alveoli; this fraction is known as alveolar ventilation (VA). The rest of the inspired gas fills the conducting airways and
605
alveoli that may not be well perfused, and is known as physiological dead space (VD) or 'wasted ventilation'. Therefore, total ventilation (usually in L/min) = VA + VD. The commonly measured static lung volumes are shown in Figure 13.1. The static volumes depend on the distensibility (i.e. compliance) of both the lung and chest wall, and also the capacity of the respiratory muscles, often impaired in neurological disorders, such as motor neuron disease. The distensibility or compliance of the lung is affected by the elastic recoil due to the connective tissue elements in the parenchyma and the surfactant that lines the alveolar surface. Thus the compliance of the lung is decreased in diffuse pulmonary fibrosis (tissue changes) and neonatal respiratory distress syndrome (reduced surfactant), and increased in emphysema because of the destruction of lung elastic connective tissue. Reduced compliance of the chest wall (which includes the thoracic cage and the abdominal
wall) can be caused by bony ankylosis (ankylosing spondylitis), pleural thickening, obesity and ascites.
Diffusion of gases The term 'diffusion' describes the passive movement of O2 and CO2 between alveolar gas and pulmonary capillary blood (Fig. 13.2). It depends on three major factors: • The matching of ventilation and blood flow • The diffusion of gas from the alveolus to the red blood cell • The availability of haemoglobin and the chemical reactions within the red blood cell. Although O2 is the physiological gas that is most likely to be affected by abnormalities of diffusion, the diffusion capacity of the lung is usually measured with a nonphysiological gas, carbon monoxide (TLCO, or transfer factor). If the haemoglobin concentration is normal, a decreased transfer factor means either a reduction in the
Total lung capacity (L)
Vital capacity (L)
Residual volume (L)
3.4-5.9 2.4-4.3
1.1-2.3 1.0-2.0
4.8 -7.9
2.7-5.3 2.0-4.0
1.4-2.6 1,1-2.2
4.5-7.6 3.4-6.0
2.4-4.7 1.9-3.6
1.7-2.7 1.3-2.4
4.3-7.3 3.3-5.8
Age 20 -39
Male Female
3.6-6.1
Age 40 - 59
Male Female Age 60+
Male Female
FIG. 13.1 The subdivisions of lung volume Functional residual capacity (FRC) is the resting expiratory level. (TLC = total lung capacity; TV = tidal volume; IC = inspiratory capacity; VC = vital capacity; RV = residual volume; IRV = inspiratory reserve volume; ERV = expiratory reserve volume.) Normal values are also shown.
1
606
MCQ13.2
FIG. 13.2 The terminal respiratory unit In the terminal respiratory unit A blood from the pulmonary artery is in close proximity to alveolar gas, facilitating gas exchange B and thus the uptake of 02 and the elimination of C02.
effective alveolar-capillary surface available for diffusion (thickening, loss of membrane, or inability to inflate part or all of the lung to expose it to inspired air, as in lobar collapse or respiratory muscle weakness) or obstruction or destruction of capillaries (decrease in capillary blood volume).
Carbon dioxide is transported in the blood as HCO3 in solution, or in combination with haemoglobin. The chemical reactions are reversed as blood flows through pulmonary capillaries, thus allowing CO2 to evolve into alveolar gas. Carbon dioxide forms carbonic acid in the blood by the reaction:
Pulmonary capillary blood flow The adequacy of pulmonary capillary blood flow depends upon the volume and distribution of right ventricular output. Because distribution is gravity dependent, in the upright position there is more blood flow to the bases than to the apices of the lung; in addition, local mechanisms exist to divert blood from poorly ventilated regions of the lung.
13
CO2 + H2O -> H2CO3 catalysed by carbonic anhydrase, and the carbonic acid then dissociates by the reaction: H2CO3 - H+ + HCO3Accordingly, a rise in arterial Pco2 tends to increase H+ and decrease pH; this mechanism is of fundamental importance in acid-base balance and the regulation of ventilation (p. 1114).
Carriage of gases by the blood Oxygen is transported in the blood mainly in combination with haemoglobin; a small amount is present in solution. The relationship between the percentage saturation of haemoglobin and the partial pressure (or tension) of O2 (Po2) in the blood is shown in Figure 13.3. The shape of the curve is important: blood is nearly fully saturated when the Po2 is greater than 8kPa (60mmHg), as it usually is in arterial blood; furthermore, when the prevailing Po2 is low, 5.3kPa (40mmHg), as it is in the tissues, haemoglobin readily gives up its O2, which is then available for metabolic activities. The position of the curve is not fixed, and shifts occur to the right (decreased affinity) and left (increased affinity) in many common clinical conditions. Shifts of the curve to the right, resulting from an increase in Pco2, H+ concentration, temperature and organic phosphates (particularly 2,3-diphosphoglycerate), are beneficial because they facilitate O2 transfer to the tissues and thus serve to maintain tissue oxygenation (see also p. 1203).
Control of ventilation The rhythmic pattern of breathing is driven by the spontaneous discharge of neurons located chiefly in the medulla. The activity of these cells is modulated by signals from the pons, hypothalamus and cortex, and from central chemoreceptors and receptors in the lung. Although the physiological mechanisms involved are largely unknown, there is a remarkable matching of metabolic activities and ventilation.
PATHOPHYSIOLOGY
1
It is convenient to consider generalized lung disorders under the following headings: • • • •
Airflow obstruction Restrictive lung disease Abnormalities of diffusion Abnormalities of pulmonary blood vessels.
These functional categories often overlap and, of course, do not account for localized abnormalities such as those caused by tumours, pneumonia or pulmonary infarction.
Airflow obstruction Airflow obstruction is common and occurs in acute and chronic asthma, chronic bronchitis, emphysema, cystic fibrosis and bronchiectasis. Small peripheral airways are obstructed in patients with obliterative bronchiolitis and fibrosis, and inflammation can be demonstrated in the small airways of young smokers. Localized obstruction can be due to tumours, adenopathy, inhaled material, tracheal damage and pressure from an enlarged thyroid gland. FIG. 13.3 Oxygen dissociation curve In normal subjects a large fall in arterial oxygen tension causes a small reduction in oxyhaemoglobin saturation (and oxygen carriage). In a hypoxic patient (for example, with a PaO2 of 6 kPa/45 mmHg) a small fall in oxygen tension causes marked further desaturation.
Determinants of bronchial calibre The total cross-sectional area of the tracheobronchial tree increases progressively as each generation of airways branches because the sum of diameters of the daughter branches exceeds that of the parent branch. Therefore,
607
resistance to airflow, which depends on cross-sectional area, is greatest in the large or central airways and least in the small or peripheral airways. Airway calibre is influenced by the tone of bronchial smooth muscle, which in turn is regulated by a variety of neurohumoral mechanisms. Normally, there is a small amount of resting tone because parasympathetic-bronchoconstrictor impulses predominate over sympathetic-bronchodilator impulses. In addition to bronchoconstriction, airway calibre may be decreased by mucosal oedema, muscle hyperplasia, bronchial secretions and loss of elastic recoil. Bronchial calibre will also be reduced by external compression or intraluminal tumour. Tests of airflow obstruction There are simple tests to assess the severity of airflow obstruction that can be performed at the bedside, in the doctor's surgery or in the laboratory. A simple handheld meter is used to measure the maximum or peak expiratory flow rate (PEFR). PEFR measurements are widely used to assess the severity of asthma (see Fig. 13.33) A portable spirometer can be used to measure the forced expiratory volume in 1 second (FEVi - Fig. 13.4A) and the vital capacity (VC). Normally the lung can be rapidly deflated during a maximal expiratory effort and the FEV1 is >75% of the maximum volume that can be expelled (VC), but with airways obstruction expiratory flow rates are reduced and the FEV1 becomes a smaller percentage of VC. Both tests depend on patient cooperation and effort, and predominantly reflect the function of relatively large airways. Additional useful information on the calibre of smaller airways can be obtained by recording flow against volume during a forced expiratory manoeuvre, producing a maximal expiratory flow-volume curve (Fig. 13.4B). Maximum expiratory flows (PEFR) are achieved from close to full inspiration (total lung capacity) and flow becomes progressively less as the lung volume falls. This is partly due to the narrowing of normal airways that occurs as the lungs get smaller. In patients with widespread airways obstruction (e.g. chronic bronchitis) the narrowing of bronchi means that at low lung volumes there is a marked increase in airways resistance and a fall in maximum flows. The flow-volume curve is therefore convex. Diffuse airways obstruction causes an increased volume of gas to be trapped in the lung at the end of expiration. Hyperinflation is therefore an important feature of airways obstruction, and can be demonstrated in the laboratory as an increase in residual volume (RV) and an increase in the ratio of RV to total lung capacity (Fig. 13.5). In all patients with airways obstruction, reversibility in response to an inhaled (32 agonist should be assessed. Rapid improvement after inhalation of bronchodilators is characteristic of asthma (see Fig. 13.34) and may occur to a lesser degree in some patients with chronic bronchitis, emphysema and bronchiectasis.
608
Upper airway obstruction This may be caused, for example, by tumours of the larynx
A
B FIG. 13.4
A Forced expiratory spirogram Starting from a full inspiration, the volume expired during a forced expiration (forced vital capacity, FVC) is reduced in both obstructive and restrictive pulmonary disease. However, the volume expired in 1 second (FEV1) is disproportionately reduced in patients with airways obstruction, but not in those with restriction. B Expiratory flow-volume curves In patients with airways obstruction expiratory flow is strikingly reduced as residual volume is approached. In restrictive disorders the shape of the flow-volume curve (although not the magnitude) is normal. (TLC = total lung capacity; RV = residual volume; PEFR = peak expiratory flow rate.)
or trachea, by post-tracheostomy strictures or by inhaled foreign bodies. Clinically, it can be difficult to distinguish upper airway obstruction from other causes of airflow limitation (although severe narrowing of the upper airway causes stridor). The flow-volume loop is diagnostically helpful (Fig. 13.6). In patients with asthma or chronic bronchitis expiratory flow is more reduced than inspiratory flow; when upper airway obstruction is present, inspiratory flow may also be equally reduced.
Restrictive lung disease Limitation of lung expansion can result from diseases of
IB
FIG. 13.5 The effect of obstructive and restrictive disorders on lung volumes Both obstruction and restriction reduce vital capacity (VC). With obstruction, residual volume (RV) and functional residual capacity (FRC) increase due to airway narrowing and closure during expiration, and the patient becomes 'hyperinflated'. With restrictive disorders total lung capacity (TLC) and FRC are reduced due to reduced compliance, or reduced respiratory muscle strength. (TV = tidal volume; IC = inspiratory capacity; ERV = expiratory reserve volume.)
FIG. 13.6 Flow-volume curves with airways obstruction With obstruction of the upper airway (e.g. tracheal tumour) maximal flow rates are reduced, resulting in the characteristic 'plateau' shape of the flow-volume curve. When breathing out from full inspiration (total lung capacity: TLC), peak expiratory flow rate (PEFR) is reduced. Typically PEFR is reduced to a greater extent than the forced expiratory volume during the first second (FEV1). (RV = residual volume.)
the bony ribcage, pleura or lung parenchyma, and of the respiratory muscles. A restrictive defect is therefore a feature of disorders as diverse as kyphoscoliosis, the pneumoconioses and polyneuritis. Pleural thickening or effusion also limits lung expansion. The most common causes of restrictive lung disease, however, are diffuse infiltrative processes within the lung, such as pulmonary fibrosis or extensive sarcoidosis, which reduce pulmonary compliance. Regardless of the underlying cause, pulmonary function tests show small lung volumes (Figs 13.4 and 13.5) and, often, a reduced transfer factor. Airways resistance is not increased and the ratio of FEV1 to vital capacity (VC) is not reduced.
increased blood volume and haemoglobin content of the lungs, as in left-to-right intracardiac shunts, polycythaemia, early left heart failure and pulmonary haemorrhage. The TLCO is raised in asthma, perhaps reflecting the widespread inflammation of the small airways. Transfer factor may be expressed as the carbon monoxide transfer coefficient (KCO), which is the TLCO per litre of alveolar volume. When lung volume is reduced (e.g. pneumonectomy) but the remaining lung is normal, TLCO is reduced but KCO is normal. When lung volume is small because of an inability to expand the lung (e.g. weakness, obesity) TLCO is low but KCO is normal or increased.
Abnormalities of diffusion
Abnormalities of pulmonary blood vessels
Abnormality of any of the parameters that determine diffusion will reduce TLCO (see p. 606). Tests of diffusing capacity are affected by the concentration of haemoglobin; thus TLCO is low in patients with anaemia and high in those with polycythaemia. When corrected for changes in haemoglobin concentration, decreased TLCO values are found most commonly in patients with destruction or obliteration of pulmonary capillaries and/or maldistribution of alveolar ventilation (emphysema, pulmonary vascular disease, interstitial infiltrative diseases). Increased TLCO values are not common but are found in patients with
The function of the pulmonary vascular system is to expose mixed venous blood to adequately ventilated alveoli (Fig. 13.2). Local vasoconstriction in response to hypoxia acts to divert blood flow from poorly ventilated to betterventilated regions. Conversely, if blood flow to part of the lung is compromised, ventilation of that region is reduced. Both these compensatory mechanisms tend to preserve the normal balance between blood flow and ventilation that is essential for efficient gas exchange. The most common disorder of the pulmonary circulation
609
is pulmonary embolism. Chronic obliterative disease of pulmonary arteries may cause severe dyspnoea on exertion but is difficult to diagnose at an early stage because physical examination, chest X-rays and spirometry show no abnormalities. In such disorders, gas transfer is reduced and hypoxaemia intensifies, or may only be apparent, on exercise.
Arterial blood gases and pH Arterial blood gases and pH are also discussed in Chapter 21. The prime function of the lung is to add O2 and remove CO2 from blood. Thus the ultimate test of the adequacy of ventilation, diffusion, pulmonary capillary blood flow and control of ventilation is measurement of Po2, Pco2 and pH of arterial, or arterialized earlobe, blood. 1 'Arterial Po2 Arterial oxygen tension (Pao2) is normally between 11.3 and 13.3 kPa (85 and lOOmmHg) in healthy adults breathing air, at rest and at sea level. The main causes of hypoxia are ventilation-perfusion (V/Q) abnormalities (e.g. pneumonia), hypoventilation (e.g. narcotics or sedatives), impaired diffusion (e.g. interstitial lung disease) and right-to-left shunts (e.g. pulmonary arteriovenous malformation). V/Q abnormalities are the most common cause; hypoventilation is characterized by hypercapnia, and impaired diffusion is rarely an important mechanism except on exercise. Breathing at altitude causes hypoxia (see Ch. 2, p. 49). Reduced delivery of oxygen to tissues, and therefore cellular hypoxia, occurs in severe anaemia, poor tissue perfusion, and (rarely) with respiratory chain enzyme abnormalities (e.g. mitochondrial myopathies, cyanide poisoning). Patients may have significant arterial hypoxaemia without symptoms. Central cyanosis only occurs when the saturation of arterial blood is less than 85%. Thus the clinical signs and symptoms of mild to moderate, but nevertheless important, arterial hypoxia are unreliable, and the diagnosis must be made by analysis of arterial blood gases. With chronic hypoxia patients develop secondary polycythaemia and pulmonary hypertension. Arterial Pco2 The arterial CO2 tension (Paco2) at rest is 4.6-6.0 kPa (35-45 mmHg). Regulation of arterial Pco2 is determined according to the equation: Arterial Pco2 =Kx
CO2 production Alveolar ventilation
Only two variables, CO2 production and alveolar ventilation, are involved. Deviation from normal values of arter-
1
610
MCQ 13.3
ial Pco2 can be viewed as a failure of alveolar ventilation to increase or decrease in accordance with metabolic changes. Hyperventilation, an increase in ventilation in excess of metabolic need so that arterial Pco2 decreases, occurs in patients with a variety of common lung diseases (asthma, pneumonia, pulmonary embolism), presumably from reflexes arising from the chest wall or within the diseased lung. Hyperventilation also results from stimulation of the central nervous system by drugs (aspirin), irritative lesions (cerebral tumours, infections) or anxiety. When Paco2 falls below about 20 mmHg there may be a sudden onset of dramatic symptoms such as paraesthesiae, blackouts and chest pain (owing to vasoconstriction and increased nervous irritability). Some patients hyperventilate and have symptoms due to hypocapnia, without any demonstrable cause. Symptoms are often misattributed by both the patient and the attending doctors to serious organic disease. Correct early recognition and reassurance are helpful. Inappropriate breathlessness may be a separate syndrome which is often, but not invariably, associated with excessive breathing and hypocapnia during exercise. The causes are obscure, but about one-third of such patients are depressed. There are few management strategies and response to treatment is poor. It should be stressed that, following the documentation of hyperventilation (i.e. hypocapnia), recognized disorders that cause excessive ventilation should be excluded before attributing the condition to a psychological cause. Hypoventilation can result from disorders that involve the airways (chronic bronchitis), lung parenchyma (advanced diffuse interstitial fibrosis), chest wall (kyphoscoliosis), respiratory muscles (myasthenia gravis) or central nervous system (sedative drugs). Commonly, in chronic diseases that can eventually lead to hypoventilation, hypercapnia first occurs during sleep. Primary causes of sleep-disordered breathing (e.g. obstructive sleep apnoea) can lead to profound hypoxia by night and eventually persistent hypercapnia by day. Like arterial hypoxia, mild to moderate changes in arterial Pco2 produce no or few signs and symptoms. Thus, analysis of arterial blood gases is required to determine the presence and severity of disturbances in Pco2.
Arterial pH The arterial pH (Fig. 13.7) at rest is 7.38. It can also be expressed as H+ content, and the normal value is 3545 nmol/L. The arterial pH value represents the net effects of both respiratory and non-respiratory factors that regulate Pco2 and HCO3 (and other buffers). When ventilation increases acutely, Pco2 decreases and pH increases; conversely, when ventilation decreases acutely, Pco2 increases and pH decreases. If the ventilatory changes persist, pH gradually returns towards normal values as the kidney makes appropriate adjustments in blood concentration of HCO3-. Thus the pH value depends on both the magnitude of the change in Pco2 and whether or not compensation has had time to occur.
TABLE 13.1 Indications for lung function testing
ED
Diagnostic To evaluate symptoms, signs and abnormal laboratory tests Screening 'at-risk' individuals (smokers, occupational exposure) Assessing preoperative risk Assessing prognosis Monitoring To evaluate the effects of treatment (e.g. bronchodilators, corticosteroids) To assess progress in chronic disease (COPD, pulmonary fibrosis, drug-induced lung disease) Measurement of disability Assessment as part of rehabilitation programmes Medicoiegal issues, insurance claims Epidemiological surveys (Adapted from Crapo, R. N Engl J Med, 1994, 331: 25-30).
FIG. 13.7 Acid-base diagram The relationship of arterial pH [H+], Pco2 and bicarbonate with disturbances of acid-base balance. For example, acute ventilatory failure leads to a raised arterial Pco2 and a reduction in pH; compensatory renal mechanisms then increase bicarbonate and restore pH to normal. (Modified from Flenley D C 1971 Another non-logarithmic acid-base diagram? Lancet 1961.)
Lung function testing (Table 13.1) Patterns of lung function abnormality are easily identified (Table 13.2). Airflow limitation without reversibility and with a normal TLCO is compatible with chronic obstructive bronchitis; if emphysema is present, however, TLCO and KCO will be reduced. A more than 15% improvement in FEY1 or peak flow after inhaled bronchodilator is suggestive of asthma. Restrictive lung disease due to pulmonary fibrosis will show low lung volumes with a normal or high FEV1/VC ratio and a reduced TLCO, whereas if the restriction is due to chest wall disease the TLCO may be normal or slightly reduced and the KCO raised.
lessness. Patients with lung disease stop exercising before achieving their maximum predicted heart rate and have levels of ventilation that are disproportionately high for a given oxygen uptake. Assessment of respiratory muscle strength is useful in patients with neuromuscular diseases and when evaluating selected patients with unexplained breathlessness (see p. 615). Vital capacity is a particularly useful simple test. Maximum inspiratory and expiratory mouth pressures can be measured using simple hand-held pressure meters. Specialist laboratories can undertake more complex techniques (e.g. phrenic nerve stimulation and diaphragm strength measurements). Overnight pulse oximetry and, in selected cases, polysomnography, is required to properly investigate sleep-disordered breathing (see pp. 668-670).
FURTHER READING ON STRUCTURE AND FUNCTION OF THE RESPIRATORY SYSTEM Hughes J M B, Pride N B 1999 Lung function tests. Philadelphia: WB Saunders.
Exercise testing
Simple tests can be of great clinical value in patients limited by lung disease. The 6- or 12-minute walking distance, in which the patient walks as far as he can during the time allowed, gives an indication of overall exercise capability. In some patients it may not be certain that lung function is impaired, and in such instances the monitoring of oxygen saturation, by finger probe, during treadmill or cycle ergometer exercise, is a sensitive technique for detecting minor abnormalities of oxygenation. Formal laboratory exercise testing - measuring oxygen uptake, CO2 production, heart rate and ventilation during progressive treadmill or cycle ergometer exercise - can be helpful, particularly in patients with unexplained breath-
SYMPTOMS AND SIGNS OF RESPIRATORY DISEASE The most important symptoms of respiratory disease are: Cough Sputum Haemoptysis Breathlessness Wheeze Chest pain.
611
TABLE 13.2 Patterns of abnormality in lung function tests Feature
Asthma
Chronic bronchitis
Emphysema
Pulmonary fibrosis
Chest wall abnormalities*
Airflow obstruction Reversibility Hyperinflation Reduction of lung volumes TLCO KCO Lung compliance
Yes Yes Yes No Normal or increased Normal or increased Normal
Yes Slight Yes No Normal Normal Normal
Yes Slight Yes No Reduced Reduced Increased
No No No Yes Reduced Reduced Reduced
No No No Yes Normal or reduced+ Normal or increased Normal or reduced
* e.g. kyphoscoliosis, muscle weakness. + (See p. 609)
Cough
612
Cough is initiated when irritant receptors in the mucous membrane of the respiratory tract are stimulated. Cough is by far the most common respiratory symptom, and is characteristic in heavy smokers. Frequently, cough is triggered by the presence of sputum in the respiratory tract, and is useful in helping to clear infection from the bronchial tree. A wide variety of inhaled irritants in addition to cigarette smoke (e.g. noxious gases or cold air) may stimulate coughing, and this is more likely if the airways are already irritable because of inflammation as a consequence of infection. Similarly, the irritant receptors in the bronchial tree may be stimulated by tumours, inhaled foreign bodies, allergens and the asthmatic response, pulmonary oedema and external compression by lymph nodes. In non-smokers the most frequent causes of chronic cough are asthma, sinus disease and oesophageal reflux. With neurological disease laryngeal function may be impaired or oesophageal motility abnormal (e.g. achalasia), and cough may be due to repeated aspiration. Drugs can cause cough, by damaging the lung (p. 696) or causing asthma (p. 651). A characteristic persistent dry cough can occur with ACE inhibitors. Cough after drinking can also indicate an oesophagobronchial fistula. In some patients cough is worse at night, particularly in asthma or pulmonary oedema. Prolonged coughing reduces venous return, causes a transient fall in cardiac output and cerebral oxygenation, and leads to cough syncope. Damage to the recurrent laryngeal nerve, commonly at the left hilum due to bronchial carcinoma, leads to vocal cord paralysis and an inability to produce a normal explosive cough, which becomes 'bovine'. A dry cough, sometimes following an upper respiratory tract infection and often persisting for weeks or months, for which no cause can be found, is a common clinical problem. It can present a formidable management difficulty, especially as patients' expectations of 'cure' are high (Table 13.3, Figure 13.8).
TABLE 13.3 Investigation of chronic cough Chest X-ray/HRCT Pulmonary function testing Sinus X-ray/CT Skin prick testing Blood/sputum eosinophils Sputum culture/AFB Oesophageal function - Barium swallow, pH, manometry, Speech therapist evaluation Bronchoscopy (when occult endobronchial lesion suspected) Common causes of refractory cough Asthma Chronic bronchitis/smoking Post viral URTI Gastro-oesophageal reflux Chronic sinusitis/post nasal drip Bronchiectasis Endobronchial - tumours foreign body exposure to irritants Parenchymal - pulmonary fibrosis sarcoidosis Cardiac - left ventricular failure Drugs-ACE inhibitors Inhaled irritants Neuromuscular disorders Psychogenic
Sputum In healthy subjects the bronchial tree produces approximately 100 mL of mucus each day; this is carried upwards by ciliary action and is then unconsciously swallowed. This
TABLE 13.4 Important causes of haemoptysis Pulmonary infections Bronchiectasis (particularly upper lobe bronchiectasis from past pulmonary tuberculosis) Lung abscess Pneumonia Tuberculosis Aspergilloma Pulmonary infarction Tumours Carcinoma Adenoma (Haemoptysis is unusual with pulmonary metastases) Pulmonary oedema Particularly due to mitral stenosis Pulmonary haemorrhage Goodpasture's syndrome Idiopathic pulmonary haemosiderosis Systemic lupus erythematosus Pulmonary vasculitis
Trauma Needle biopsy Transbronchial biopsy Pulmonary contusion Vascular abnormalities Arteriovenous malformation Hereditary haemorrhagic telangiectasia Bleeding disorders Usually severe thrombocytopenia from any cause Miscellaneous Pulmonary endometriosis (catamenial haemoptysis)
13
Disorders of the upper airways Epistaxis Tumours
FIG. 13.8 Algorithm for investigation of chronic cough
'escalator' is a normal part of the mechanism for clearing debris and pathogens from the bronchial tree. In disease processes causing the production of excess mucus, irritant receptors are stimulated and sputum is coughed up. Sputum is not described reliably by patients and it is always best to inspect it. Sputum may be clear, white or mucoid, as in chronic bronchitis, or purulent, in which case pus is mixed with mucus and the sputum is yellow or green. Sputum may contain blood, which may be bright red (e.g. pulmonary infarction), a rusty colour (acute pneumonia) or pink (pulmonary oedema due to left heart failure). In asthma the sputum may contain mucus plugs. Microscopically, sputum may contain bacteria, pus cells, eosinophils (as in asthma and pulmonary eosinophilia) or malignant cells. It is helpful to know the volume of sputum produced each day, and this can be particularly large: greater than 20 mL in bronchiectasis, cystic fibrosis, and lung abscess when there is a bronchopulmonary fistula. Clinical progress can be monitored by documentation of sputum volume. Occasionally patients with alveolar cell carcinoma produce very large volumes of clear watery sputum
(bronchorrhoea). Anaerobic infection results in foulsmelling sputum.
Haemoptysis Patients may have difficulty in being sure that blood has been coughed rather than vomited. Coughed blood may be from a lesion of the nose, nasopharynx and vocal cords. When infection causes haemoptysis, blood will be mixed with purulent sputum, whereas in non-infective causes (e.g. pulmonary infarction) there is usually frank blood and no sputum. In patients with chronic bronchitis it is common for the sputum to contain occasional specks of blood, but more substantial haemoptysis is unusual (Table 13.4). A cause for haemoptysis should be carefully sought in all cases, but a definite diagnosis is only achieved in 60-70%. Occasionally haemoptysis can be severe and lifethreatening. This occurs most frequently in cavitating tuberculosis and bronchial carcinoma. In those patients in whom no definite cause for haemoptysis is found, careful follow-up is necessary, with repeated chest X-rays. The importance of haemoptysis as the presenting feature of lung cancer must be emphasized. In particular, frank haemoptysis in a smoker, even in the presence of a normal plain chest X-ray, may be the earliest warning of a
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CASE STUDY: 13.1 PERSISTENT SEVERE HAEMOPTYSIS A 45-year-old Afro-Caribbean woman was admitted to hospital with persistent severe haemoptysis. She had originally attended the hospital 10 years previously with sharp central chest pain, bilateral hilar adenopathy, and enlargement of the mediastinal lymph nodes. At that time a lymph node biopsy, via a mediastinoscopy, demonstrated non-caseating granulomata, consistent with a diagnosis of sarcoidosis. Subsequently the patient developed bilateral pulmonary infiltrates and increasing breathlessness. She was treated with oral prednisolone, with substantial symptomatic improvement. Over the next few years, on varying doses of prednisolone, the adenopathy resolved but the interstitial lung disease persisted. The patient developed a moderately severe restrictive defect on lung function testing. She found the adverse effects of steroid therapy, particularly the weight gain and hirsutism, troublesome, and for a period of several years did not attend regularly for follow-up and took her steroid treatment intermittently. Eighteen months prior to her current admission she first experienced haemoptysis. At that time bronchoscopy showed blood throughout the bronchial tree, but probably originating from the left upper lobe bronchus. Chest X-rays and a CT scan showed extensive bilateral upper lobe fibrosis with spaces within the lung and cavity formation (Case Fig. 13.1.1).
Questions 1. Should the diagnosis of sarcoidosis be reconsidered? 2. What is the cause of the haemoptysis? 3. What would be the future management 01 this patient?
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CASE FIG. 13.1.1 [70 Chest X-ray showing bilateral upper zone volume loss, fibrosis and cavitation (best seen on the right). B CT scan There are large spaces in the upper zones of both lungs.
The original presentation is typical of sarcoidosis. It is not uncommon for patients with extensive intrathoracic lymphadenopathy to experience chest pain, often with a sharp quality. The histology of the lymph node makes the diagnosis virtually certain. Tuberculosis was possible and culture of the biopsy material was essential. In this pa
