|
Home | Issues | eMJA shop | My account | Classifieds | Contact | More... | Topics | Search |
→ Previous article in this issue
→ View contents list for 6 May issue of the MJA
→ View the 1997 draft of these guidelines (now superseded)
→ More Clinical Guidelines published by the MJA
→ Download a pdf version of this article
→ More articles on General medicine
Clinical Practice Guidelines
Dr Robert Loblay, PhD, FRACP, Immunologist, Department of Medicine, University of Sydney (Convenor); Royal Australasian College of Physicians.
Associate Professor Graeme Stewart, PhD, FRACP, Immunologist, Westmead Hospital (Co-convenor); Royal Australasian College of Physicians; Former member, Ministerial CFS Review Committee.
Dr James Bertouch, MD, FRACP, Rheumatologist, Prince of Wales Hospital, Sydney; nominated by Australian Rheumatology Association.
Associate Professor Peter Cistulli, PhD, FRACP, Respiratory Physician, Department of Respiratory Medicine & Sleep Disorders Centre, St George Hospital; nominated by the Australasian Sleep Association.
Dr Paul Darveniza, MD, FRACP, Neurologist, St Vincent's Hospital Sydney; nominated by the Australian Association of Neurologists.
Mr Craig Ellis, BA, BSW(Hons), Member, ME/CFS Society of Victoria; nominated as a Consumers' Health Forum of Australia Inc. representative.
Professor Paul Gatenby, FRACP, FRCPA, Immunologist, The Canberra Hospital; nominated by the Australian Rheumatology Association.
Dr David Gillis, FRACP, FRCPA, Immunologist, Institute of Medical and Veterinary Science, Adelaide; nominated by the Australasian Society of Clinical Immunology and Allergy.
Professor Ian Hickie, MD, FRANZCP, Psychiatrist, Department of Community Psychiatry, University of New South Wales; nominated by the Royal Australian and New Zealand College of Psychiatrists.
Associate Professor Andrew Lloyd, MD, FRACP, Infectious Diseases Physician, School of Medical Sciences, University of New South Wales; nominated by the Australasian Society for Infectious Diseases.
Dr Bryce Phillips, MB BS, General Practitioner, Melbourne; former member, Ministerial CFS Review Committee.
Professor Wai-On Phoon, FRACP, FAFOM(Hon), Occupational Medicine Physician, Centre for Occupational and Environmental Health, University of Sydney; nominated by the Australasian Faculty of Occupational Medicine.
Dr Katherine Rowe, MD, FRACP, Paediatrician, Royal Children's Hospital (Melbourne); nominated by the Paediatrics & Child Health Division, Royal Australasian College of Physicians.
Dr Ian Steven, MD, FRACGP, General Practitioner; nominated by the Royal Australian College of General Practitioners.
Professor Denis Wakefield, MD, FRACP, Immunologist, School of Medical Sciences, University of New South Wales; nominated by the Royal College of Pathologists of Australia.
Dr David O Watson, MB BS, FRACP, Consultant Physician, St John of God Health Care WA; former Chairman, Ministerial CFS Review Committee; nominated by the Royal Australasian College of Physicians.
These guidelines are primarily aimed at assisting general practitioners, but they are also relevant to specialist physicians and other healthcare professionals involved in managing people with fatigue states, including physiotherapists, occupational therapists, psychologists and social workers. They are based on information available at the date of publication, and are intended to provide a general guide to best practice. However, it should be emphasised that evidence-based clinical practice involves not only use of the best available research evidence, but also exercise of the practitioner's clinical judgement, taking account of individual patient preferences.
In 1990, the Royal Australasian College of Physicians (RACP) published a brief position paper on the investigation and management of chronic fatigue syndrome (CFS) in the RACP magazine, Fellowship Affairs. In 1993, as a result of perceived variations in clinical practice, the then Commonwealth Minister for Health (Senator Graham Richardson) established a CFS Review Committee (comprising Dr David Watson [general physician], Dr Bryce Phillips [general practitioner] and Associate Professor Graeme Stewart [clinical immunologist]) to make recommendations on "diagnostic and management regimens that the medical profession would regard as appropriate for sufferers of CFS". The Review Committee approached the RACP for an up-to-date position, and the College passed the request to the Australasian Society of Clinical Immunology and Allergy (ASCIA). In 1994, a fully revised discussion paper prepared by ASCIA1 was circulated to all specialist physicians in Fellowship Affairs, together with a questionnaire, and the paper and survey results were subsequently made available to the Ministerial Review Committee.
In 1995, as a result of the Review Committee's recommendations, the Commonwealth Department of Health funded the Royal Australian College of General Practitioners to conduct a survey of general practitioners' opinions and practices in relation to CFS. The Ministerial Review Committee also recommended the production of consensus guidelines for distribution to all medical practitioners in Australia. Fortuitously, in October 1995, the National Health and Medical Research Council (NHMRC) published Guidelines for the development and implementation of clinical practice guidelines,2 which provided an ideal framework for this purpose. Consequently, in 1996, a multidisciplinary Working Group (including a Consumer Health Forum representative) was established under the auspices of the RACP to develop and disseminate evidence-based guidelines, following the procedures recommended by the NHMRC. The Commonwealth Department of Health and Family Services provided funding.
A: Quality-of-evidence ratings
I: Consistent evidence obtained from more than two independent, randomised and controlled studies or from two independent, population-based epidemiological studies. Studies included here are characterised by sufficient statistical power, rigorous methods and inclusion of representative patient samples. Alternatively, a meta-analysis of smaller, well-characterised studies may support key findings.
II: Consistent evidence from two randomised controlled studies from independent centres, a single multicentre randomised controlled study or a population-based epidemiological study. Data included here have sufficient statistical power, rigorous methods and the inclusion of representative patient samples.
III-1: Consistent evidence obtained from two or more well-designed and controlled studies performed by a single research group.
III-2: Consistent evidence obtained from more than one study, but where such studies have methodological constraints, such as limited statistical power, or the inclusion of patient samples which may be non-representative.
III-3: Evidence obtained from a single case-control study or a selected cohort study.
III-4: Conflicting evidence obtained from two or more well-designed and controlled studies.
IV: Consensus opinions of respected authorities, based on clinical experience and/or descriptive reports.
The Working Group conducted an extensive review of the relevant scientific literature on prolonged fatigue, chronic fatigue and CFS, and the evidence was rated according to a modification of the schema recommended by the NHMRC. In addition, the Ministerial Review Committee report and a variety of other local and international public domain documents were examined.
Submissions were invited from interested practitioners, consumers and patient support groups. Eighty submissions were received from people with CFS, carers, concerned individuals and CFS Societies. The Consumer Health Forum representative produced two documents: A compilation of submissions made by people with chronic fatigue syndrome and others to the Royal Australasian College of Physicians for the investigation of chronic fatigue and management of chronic fatigue syndrome clinical practice guidelines,3 and A CFS health consumer perspective.4 Quotations for the perspective boxes in these guidelines were drawn from these documents.
The working group prepared draft guidelines that were widely circulated in early 1998. Comments were sought from relevant specialist societies, Royal Colleges, the National Health and Medical Research Council, patient support groups, complementary practitioner associations, and interested individual practitioners and consumers. The draft was also made available on the MJA website <http://www.mja.com.au/public/guides/cfs/cfs1.html>.
The draft guidelines attracted widespread comment both as a result of the initial public consultation and over the four years that they remained available on the MJA website. They were subsequently extensively revised and updated, and underwent a limited second round of public consultation. This final version of the guidelines is the result of revisions carried out in the light of comments received.
The evidence contained within published studies was evaluated according to the process outlined in the NHMRC Guidelines for the development and implementation of clinical practice guidelines (see Box A).2 The quality-of-evidence ratings were modified to provide an integrated system for evaluating diagnostic, epidemiological and pathophysiological studies, as well as treatment trials.
Studies were rated primarily according to the rigour of the research methods used. However, since the interpretation of individual studies is often constrained by selection and other biases, replication across different studies performed in independent research centres was considered a key factor in assessing the reliability of evidence. When the available evidence from several well-conducted studies on a particular topic was conflicting, the quality-of-evidence ranking indicated this uncertainty (Level III-4).
Level IV evidence represents consensus opinions of experts, including working group members, based on clinical experience and limited scientific data. Although such statements may inform current practice, they should be interpreted cautiously, as they may undergo future modification in the light of new evidence.
"To study the phenomena of disease without books is to sail an uncharted sea, while to study books without patients is not to go to sea at all."5
Fatigue can be defined as a pervasive sense of tiredness or lack of energy that is not related exclusively to exertion. It is a common complaint in the community and is usually transitory. If fatigue is prolonged beyond six months, is disabling, and is accompanied by other characteristic constitutional and neuropsychiatric symptoms, then a diagnosis of chronic fatigue syndrome (CFS) should be considered.
"CFS" is a descriptive term used to define a recognisable pattern of symptoms that cannot be attributed to any alternative condition. The symptoms are currently believed to be the result of disturbed brain function, but the underlying pathophysiology is not known. Therefore, CFS cannot be defined as a specific "disease" entity at present. Indeed, there is growing evidence that the disorder is heterogeneous, and it will probably prove to have no single or simple aetiology.
It is important for practitioners to appreciate the distinction between disease, illness and disability.
Diseases are defined and categorised according to our contemporary understanding of causal mechanisms and pathophysiology. As new knowledge emerges, disease definitions and terminology change. Illness, by contrast, is the subjective experience of suffering and, as such, can only be defined by reference to the sick person. Disability is the functional impairment - physical, psychological and social - caused by disease and illness.
Even though an underlying disease process cannot presently be defined in patients with CFS, the suffering and disability caused by the illness can be very considerable - in many cases comparable to that seen in multiple sclerosis and rheumatoid arthritis. It is therefore important that doctors acknowledge the reality and seriousness of the suffering and disability experienced by people with CFS. Our goal as physicians is not only to identify and treat disease, but also to help relieve suffering and disability, whatever the cause.
CFS is diagnosed on clinical grounds. It relies on the presence of characteristic symptoms (see Box B), and the exclusion of alternative medical and psychiatric diagnoses. In individual patients, the symptoms of CFS may overlap with other common syndromes such as fibromyalgia and irritable-bowel syndrome, and the primary diagnosis will depend on which symptoms are the most dominant and disabling. People with CFS often have concurrent depression, and this need not exclude the diagnosis.
As similar symptoms can also occur in a range of other disorders (eg, thyroid disease, anaemia, major depression), the first priority in clinical assessment is to exclude alternative explanations. This can be achieved by careful history-taking, physical examination and a restricted set of laboratory investigations.
B: Diagnostic criteria for chronic fatigue syndrome6
1. Fatigue
Clinically evaluated, unexplained, persistent or relapsing fatigue persistent for six months or more, that:
is of new or definite onset;
is not the result of ongoing exertion;
is not substantially alleviated by rest;
results in substantial reduction in previous levels of occupational, educational, social or personal activities;
and
2. Other symptoms
Four or more of the following symptoms that are concurrent, persistent for six months or more and which did not predate the fatigue:
Impaired short term memory or concentration
Sore throat
Tender cervical or axillary lymph nodes
Muscle pain
Multi-joint pain without arthritis
Headaches of a new type, pattern, or severity
Unrefreshing sleep
Post-exertional malaise lasting more than 24 hours
It is important to take careful note of the character of the fatigue. In people with CFS, fatigue is typically exacerbated by relatively minor physical or mental activity, and is associated with a protracted recovery period lasting hours or days. The fatigue should be differentiated specifically from weakness (neuromuscular disease), dyspnoea and effort intolerance (cardiac or respiratory disease), somnolence (primary sleep disorders), and loss of motivation and pleasure (major depression).
Additional clues which could point to alternative diagnoses include unexplained weight loss (occult infection, malignancy, thyrotoxicosis, Crohn's disease); dry skin and cold intolerance (hypothyroidism); snoring and daytime sleepiness (sleep apnoea); risk factors for transmission of blood-borne infections (HIV, hepatitis C); prior episodes of depression or anxiety (vulnerability to psychiatric disorder); arthralgia or rash (connective tissue disease); and prescribed or illicit drug misuse. A history of altered bowel habit may indicate an underlying gastrointestinal infection (eg, giardiasis), coeliac disease, thyroid disease, or inflammatory bowel disease.
Characteristically, there are no abnormal physical findings in people with CFS. The physical examination and mental state examination are therefore primarily directed towards excluding other disorders. A careful assessment for neurological deficits or signs of anaemia, cardiac failure, respiratory disease, hidden infection, connective tissue disease or tumour should be conducted. The presence of persistent fever, lymphadenopathy, or enlargement of the liver or spleen are not features of CFS and always warrant further investigation.
The behavioural signs of psychiatric disorder should also be sought, including psychomotor slowing (major depression), physiological arousal (anxiety states and panic disorder) and cognitive deficits (delirium or dementia).
There are currently no validated laboratory tests to confirm the diagnosis of CFS, assess its severity or monitor progress. Hence, the purpose of laboratory investigation is to help exclude other disorders.
Recommended screening investigations are:
full blood count and erythrocyte sedimentation rate;
serum electrolyte, calcium and creatinine levels;
biochemical liver function tests;
thyroid function tests (TSH); and
urinalysis for blood, protein and glucose.
Additional investigations should be ordered only if the history or examination plausibly suggests other diagnoses (eg, autoimmune connective tissue disease, coeliac disease), or if abnormalities are found in the screening investigations. Routine analysis of immune function (lymphocyte subsets, immunoglobulin levels), infectious disease serology, or environmental toxins are not recommended.
Unvalidated diagnostic tests should only be performed in the context of an appropriately designed and ethically approved clinical trial.
In most cases, a general practitioner should be able to diagnose CFS. However, if, after a careful history, examination and screening investigations, the diagnosis remains uncertain, the opinion of a specialist physician, adolescent physician or paediatrician should be sought. Referral to a psychiatrist may also be useful for people with profound or prolonged depression or anxiety states. Specialist referral may also help in formulating an appropriate management plan (see below).
In the early stages reassurance and supportive care is generally all that is required, as most prolonged fatigue states will resolve spontaneously. In people with established CFS, providing a definite diagnosis, along with general information about the illness and its natural history, are important starting points for good clinical care.
A definitive diagnosis also serves to validate the patient's experience of illness and suffering. Doctors who display empathy, acceptance of their patient's suffering, a non-judgemental style and a commitment to continued care are likely to establish a beneficial therapeutic relationship. Conversely, doctors who reject or trivialise the patient's illness experience are likely to promote feelings of alienation and to perpetuate ill health.
In managing people with CFS it is important to:
develop an individualised management plan for physical and social rehabilitation;
discourage excessive rest and minimise social isolation;
maintain regular contact;
evaluate the basis of any new symptom or deterioration in function; and
provide support for the person and his or her family, including access to social security, educational assistance and disability services where appropriate.
To date, no pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore primarily directed at relief of symptoms (eg, headache, muscle pain) and minimising impediments to recovery (loss of functional capacity, disruption of the sleep-wake cycle, intercurrent depression and social isolation). Additional elements of good clinical management are the development of a clear and mutual understanding of the nature of the illness; a sensible approach to physical and mental activity; and realistic expectations about long-term outcome possibilities.
Helping people with CFS understand the nature of their illness is an important element of good clinical management. For example, some people harbour fears that an occult infection, environmental pollutants or electromagnetic fields may be causing irreversible neurological or immunological damage. Others may have been led to believe that any physical activity at all could be harmful. Unwarranted concerns of this kind may lead to maladaptive attitudes and behaviours that may increase disability and retard recovery.
Doctors should also avoid simplistic attributions of CFS to "chronic infection", "immune dysfunction", "malingering", or "mere depression". Instead, it should be recognised that the illness is likely to be multifactorial in origin. A broad perspective that encompasses medical, psychological, and social aspects is more appropriate.
In general, people with CFS should be encouraged to undertake physical and intellectual tasks, starting at a level that is tolerated without significant exacerbation of symptoms. This should initially be in divided sessions of relatively short duration. As exercise tolerance improves, duration and intensity of activity can be gradually increased. Graded exercise programs have been shown to be beneficial for some people with CFS, and can improve functional status.
It is important to discuss with the patient the vicious circle whereby initial avoidance of physical activity may lead to longer-term avoidance of all activity. In the early stages of the illness, many people with CFS put off chores or social engagements until they feel better, then push themselves excessively on "good days" to make up for lost time. The subsequent worsening of symptoms and delayed recovery can establish a cyclic pattern of illness and disability.
An individualised management program should be carefully negotiated between the patient and doctor, with particular attention to:
starting at a level of activity that can be achieved without exacerbation of symptoms - abrupt resumption of strenuous activity after prolonged periods of inactivity should be discouraged;
undertaking activity on a regular basis, with sessions of limited duration; and
planning for regular reviews to achieve feasible increases in activity over a realistic time-frame (eg, several months).
In formulating a management plan, it is important to be aware that in many people with CFS the degree of fatigue can fluctuate unpredictably from day to day and week to week. Flexibility in the level of physical and mental activity undertaken to allow for such fluctuations ("pacing") should be explicitly discussed.
Unrefreshing sleep is extremely common in people with CFS. Patients usually report a longer time to fall asleep, an increased time in bed awake, and a broken and restless sleep pattern. A shift from regular night-time sleep to daytime naps and a late-night to late-morning sleep cycle is sometimes noted. It is known that chronic disruption of the normal sleep pattern can induce symptoms in healthy volunteers, including fatigue, musculoskeletal pains, irritability and impairment of concentration.
The general goals of sleep management are to establish a regular, unbroken, night-time sleep pattern and to improve perceptions of the quality of sleep. Although direct evidence of benefit in CFS is currently lacking, the following strategies may be helpful:
establishing a regular bed-time routine - going to bed when "sleepy" rather than "tired"; putting the light out immediately rather than reading or watching television in bed; and "anchoring" the sleep routine by setting the alarm to the same rising time every day;
judicious use of sedative-hypnotic medication to achieve sleep;
use of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) for relief of musculoskeletal pain;
avoiding (preferably) daytime naps or keeping them under 30 minutes;
gentle exercise during the day (within the limits of the individual's functional capacity).
Where appropriate, the advice of a specialist sleep physician should be sought, either to exclude a primary sleep disorder or to manage the sleep disturbance. Sleep hygiene strategies can also be incorporated into a "cognitive behaviour" therapy program (see Chapter 3). Clinical experience suggests that sleep interventions in people with CFS may reduce symptoms and improve functional capacity, although direct evidence for this is lacking.
No medication has yet been shown to provide long term remission or "cure" in people with CFS. However, there is a place for symptomatic treatment for relief of specific symptoms if they are sufficiently distressing. As such treatments for CFS are empirical, each patient should be monitored carefully to ensure that the symptomatic benefits outweigh any side effects.
Many people with CFS report an increased susceptibility to drug side effects, and it is advisable to begin with small doses when introducing new agents.
Although depression is a common symptom in people with CFS, the disorder as a whole cannot be regarded simply as a "somatised" variant of a depressive illness. Overall, clinical trials of antidepressant drugs show no consistent pattern of improvement. However, judicious use of particular agents may provide symptomatic improvement in subjective energy (moclobemide), sleep disturbance (amitryptyline, nefazodone), muscle and joint pain (amitryptyline), and depressed mood (sertraline, paroxetine, nefazodone). A reasonable approach is to consider undertaking an "N = 1" therapeutic trial of a selected drug based on this broad pattern of effects on brain function. Given that these drug therapies are increasingly varied and complex, there is an important role for the specialist physician or psychiatrist to guide the choice of drugs and their monitoring.
In people with the overlapping syndrome of fibromyalgia, the use of symptomatic treatments such as analgesics and NSAIDs, in combination with tricyclic agents, can be effective in reducing pain and improving sleep.
As with other chronic illnesses, managing people with CFS requires consideration of the psychological and social impacts of the illness.
People with CFS may be unable to continue full-time work, so financial difficulties may rapidly develop. Similarly, CFS frequently disrupts high school or university studies. Successful return to work or school after a prolonged illness with CFS often requires a rehabilitation program incorporating medical treatments, psychological support and occupational therapy. Doctors may need to coordinate the help of other healthcare and educational professionals to implement this.
The impact of the illness on the person's family should also be considered. In some circumstances it may be useful for people with CFS to bring their spouse or partner to a consultation, both to help them better understand the illness and to discuss their difficulties in coping. Parents of children and adolescents with CFS should be seen regularly, and may require additional support and counselling.
Doctors should be prepared to act as advocates for their patients in negotiations with employers, educational institutions and social welfare organisations. For instance, part-time work or school alternatives may need to be arranged, or disability allowances may need to be sought.
Joining a patient support group may be valuable for some people. CFS societies can offer individual and group support, education, and advice about access to social welfare agencies (Box C). Individuals may also benefit from the opportunity to exchange information on how to cope with the many practical day-to-day difficulties that arise for those living with this debilitating condition. However, the quality of advice given can vary and it is therefore useful for the doctor to have ongoing knowledge of the activities and attitudes of local support groups.
C: Support and resources for people with CFS14
CFS = chronic fatigue syndrome; HACC = home and community care.
Children and adolescents are in a dynamic developmental state, and issues such as self-concept, autonomy, body image, socialisation, sexuality and academic goals are of central importance. Early intervention in those with persistent fatigue is therefore especially important. For this reason, many experts believe that in children and adolescents a diagnosis of CFS should be considered when unexplained fatigue persists for three months, rather than the six months stipulated in the adult case definition.
The family practitioner or paediatrician should seek the cooperation of the parents and other carers in devising a supportive rehabilitation plan. Information should be provided to young people, their family and teachers to help them gain an appropriate understanding of the illness, and in some cases visiting the school and talking to classmates might be helpful. Although there is considerable variation, prognosis in children and adolescents is better than in adults, with recovery likely to occur within two to four years.
An individualised plan should be developed over the week for:
maintenance of peer contact and relationships with friends;
academic and recreational activity; and
physical activity, rest periods and sleep.
Adjustments to schooling may involve limiting the number of subjects taken, or the number of days per week at school (particularly if travel to and from school is causing exhaustion). Occasionally, a mixture of distance education and school attendance for one or more subjects allows both social contact and maintenance of academic progress. Those in Years 11 and 12 who are hoping to qualify for university entrance may need to apply for special consideration, and consider a 12-month extension.
Appropriate psychosocial support throughout the illness is particularly important. Prolonged absence from school may lead to anxiety about falling behind with classwork, and young people may become frustrated and depressed by their inability to participate in sporting and social activities. These issues should be discussed explicitly.
Psychiatric labelling is generally unhelpful. In most cases, there is little evidence that the disorder is "psychosomatic", and inappropriate speculation about "school phobia" may be damaging and counterproductive. Early correction of such misunderstandings leads to fewer difficulties in the long-term.
Those at the more severe end of the disability spectrum may require a more intensive, multidisciplinary approach to rehabilitation and psychosocial support. Where there are obvious behavioural problems or major disturbances in family functioning, the assistance of a child psychologist or psychiatrist may be of value.
Epidemiology
Prolonged fatigue is common in primary care, with a prevalence of 10%-25% (Level I).
The prevalence of CFS in the community is 0.2%-0.7% (Level III-2), and 0.5%-2.5% in primary care (Level I).
CFS predominantly affects young adults (Level I).
CFS occurs in individuals from all socioeconomic groups (Level I).
For an explanation of the rating of levels of evidence, see page S21.
Natural history
Most fatigue syndromes are of short duration and resolve spontaneously (Level II).
People with CFS for more than five years tend to remain symptomatic, although function may improve slowly over time (Level II).
People meeting diagnostic criteria for CFS rarely develop another medical condition that explains their symptoms, but are at increased risk of developing psychological disorders (Level II).
Concurrent psychological disorder, somatic symptoms, high levels of fatigue and a low sense of control over symptoms are associated with poorer outcomes (Level II).
A supportive doctor-patient relationship is an important component of managing people with CFS (Level III-3).
For an explanation of the rating of levels of evidence, see page S21.
Prolonged and disabling fatigue is present in 10%-25% of patients presenting to general practitioners.7-13 Fatigue syndromes lie along a continuum of severity,8,14-16 from ubiquitous transient and mild states to the more severe and prolonged fatigue disorders, including CFS.17-19 As with many other problems in clinical medicine (such as blood pressure and body weight), the challenge is to identify the point at which the problem becomes clinically significant. In relation to fatigue states, it is important to focus on those in whom the disorder is associated with ongoing disability20,21 and significant social or economic cost.22
In 1988, the United States Centers for Disease Control proposed the term "chronic fatigue syndrome" to describe a clinical condition defined by a cluster of constitutional and neuropsychiatric symptoms occurring in a distinctive pattern.23 Current diagnostic criteria (see Box B) describe CFS as a syndrome of physical and mental fatigue, usually of acute onset, which is markedly exacerbated by physical activity. Other common symptoms include headaches, myalgia, arthralgia, and post-exertional malaise; cognitive difficulties, with impaired memory and concentration; unrefreshing sleep; and mood changes.16,24-27 The diagnostic criteria also require that the person must have been ill for more than six months and that the symptom complex is associated with substantial disability.
Delineating CFS as a clinical syndrome has facilitated descriptive clinical research to test the validity of the concept, epidemiological studies to document prevalence and to formulate aetiological hypotheses, laboratory studies to test hypotheses about underlying pathophysiology, and research into a range of treatment strategies.28,29 Although a variety of research definitions have been proposed,6,23,24,27,30-33 the current international consensus criteria for CFS6 have gained wide acceptance in the scientific literature.34,35 In routine clinical practice, a diagnosis of CFS may be appropriate even though the requirement of four out of eight additional symptoms is not formally met (see Box B). Such patients (with "idiopathic chronic fatigue"6) can have comparable levels of disability,27 and may also benefit from the assessment and intervention strategies described in these guidelines.
In primary care, up to two-thirds of people presenting with persistent fatigue have some other identifiable medical or psychiatric disorder that accounts for the symptom,36-41 and careful assessment to exclude these is essential before making a diagnosis of CFS.6
Syndromal diagnoses like CFS have a long history of use in clinical medicine.42 In the absence of a clear understanding of the underlying pathophysiology, CFS is best regarded as an "illness" - a subjective state that can only be defined by reference to the sick individual - rather than a "disease".43-45 "Disability" arises when illness interferes with the individual's ability to function normally. People with CFS are clearly ill, and are often significantly disabled, even though an underlying disease process has not yet been identified.46
In the United Kingdom the earlier term "myalgic encephalomyelitis" ("ME")47 is still in use, and in the United States the term "chronic fatigue and immune dysfunction syndrome" (CFIDS) is in widespread popular use. Both names inappropriately suggest that the cause or mechanism of illness is understood (inflammation of the brain, spinal cord and muscles; or immune deficiency). Most research groups prefer the term "CFS", as it leaves open the question of aetiology and pathogenesis.6,23
Neurasthenia (literally meaning "nervous exhaustion") is a diagnosis included in the International classification of diseases (ICD-10) to describe a syndrome of mental and physical fatigue of at least three months' duration. The term has a long tradition of use in psychiatric classification,48 but the extent of its overlap with CFS, and with common psychological disorders such as anxiety and depression, remains to be determined.49 Although patients are rarely labelled as having neurasthenia in Australia, the UK or the US, the diagnostic term is widely used in Europe and elsewhere. Neurasthenia has a prevalence of 5.4% (range, 2%-10%) in primary care settings worldwide.50
The reported prevalence estimates of CFS differ as a consequence of variations in sampling methods, survey instruments and diagnostic criteria, particularly with regard to duration of illness and the extent to which alternative medical and psychiatric diagnoses were excluded (Box 1.1). Early attempts to record the community prevalence suggested a range of 0.002% to 0.04%.30,55,56 These figures appear to be substantial underestimates as a consequence of limitations in sampling or diagnostic protocols.
The true prevalence of CFS can only be determined in large-scale community studies employing adequate case detection and characterisation techniques. In the US and UK, four studies have provided a more realistic estimate of 0.2% to 0.7% (that is, 200-700 cases per 100 000 people).39,40,57,58 In Japan, the community prevalence has been reported to be 1.5%.59
In primary care settings, estimates of the prevalence of CFS are between 0.5% and 2.5%, depending on the intensity of medical, psychiatric and laboratory evaluation (Box 1.1). Preliminary estimates of the incidence of new cases per year of prolonged fatigue or chronic fatigue in primary care are 3%-5%,40,60,61 whereas the incidence of CFS is about 0.4%.40
1.1: The prevalence of fatigue states
Prevalence of prolonged fatigue (PF), chronic fatigue (CF) and chronic fatigue syndrome (CFS) in primary care
|
Study |
PF |
CF |
CFS | ||||||||
|
| |||||||||||
|
Buchwald et al, 1987, USA51 |
- |
21% |
- | ||||||||
|
Kroenke et al, 1988, USA7 |
23.8% |
- |
- | ||||||||
|
David et al, 1990, UK8 |
10.5% |
- |
0.16% | ||||||||
|
Cathebras et al, 1992, Canada9 |
13.6% |
5.7% |
- | ||||||||
|
Bates 1993, USA52 |
- |
27% |
0.3%-1.3% | ||||||||
|
Katerndahl 1993, USA10 |
6.9% |
- |
- | ||||||||
|
McDonald et al, 1993, UK53 |
- |
112% |
2.5% | ||||||||
|
Walker et al, 1993, USA11 |
6.7% |
- |
- | ||||||||
|
Pawlikowska et al, 1994, UK15 |
- |
18.3% |
- | ||||||||
|
Buchwald et al, 1995, USA39 |
- |
19% |
0.1%-0.3% | ||||||||
|
Hickie et al 1996, Australia13 |
25% |
- |
0.3%-1.3% | ||||||||
|
Wessely et al 1997, UK54 |
- |
11.3% |
0.5%-2.6% | ||||||||
|
| |||||||||||
CFS predominantly affects young adults, with a peak age of onset between 20 and 40 years.30,40,57,62 In samples of patients from treatment centres, CFS appears to be more common in women (typically in a ratio of 2-3:130), but this may be because women attend all levels of medical care more frequently than men.63 CFS does not preferentially affect individuals from upper socioeconomic groups (contrary to the notion of "yuppie flu").30 Rather, some studies suggest that fatigue syndromes may be more common in people from more socially disadvantaged groups.13,40,62,64 One study has suggested that nurses have a high rate of CFS, indicating that specific occupations may be at risk.65
It is unlikely that common, non-specific viral illnesses trigger the onset of CFS, but specific infections, such as mononucleosis, quite commonly do so. A large controlled study in general practice66 found that people presenting with minor symptomatic infections were no more likely to report chronic fatigue subsequently than those presenting for other reasons. By contrast, a prospective cohort study following individuals with serologically confirmed Epstein-Barr virus infection documented the development of a chronic fatigue state that was independent of psychiatric diagnoses.67 In the Australian context it appears that infections such as Q fever and Ross River virus infection may also trigger CFS.68-71
Fatigue is a central feature of many clinical syndromes (see Box 1.2), including CFS, fibromyalgia, irritable bowel syndrome, major depression, anxiety and somatoform disorders.72-82 These syndromes also share other, non-specific symptoms, including musculoskeletal pain, sleep disturbance, neurocognitive impairment and mood changes.83 Fibromyalgia, in particular, is a closely related syndrome, differing mainly in its relative emphasis on musculoskeletal pain rather than fatigue.73,84-89
1.2: Overlapping diagnoses
Prolonged fatigue states are found in fibromyalgia, irritable bowel syndrome, anxiety and depression, as well as in chronic fatigue syndrome
The number of non-specific medical symptoms reported by people with CFS is strongly correlated with the presence of psychological symptoms.16,90 Up to two-thirds of adults with CFS have either prior or concurrent major depression,36,40,60,74,91-98 as do people with fibromyalgia99 and irritable-bowel syndrome.100,101 By comparison, the lifetime rate of comparable depressive disorders in the general community is 15%-25%.102-106 The high rate of comorbidity is not surprising, as current diagnostic criteria for both CFS and major depression (DSM-IV;107 ICD-10108) include fatigue, sleep disturbance and cognitive impairment, and the presence of mood changes is no longer an exclusion criterion for the diagnosis of CFS.
Perhaps the most difficult diagnostic uncertainty between CFS and psychological illness is in relation to "somatoform" disorders (DSM-IV107). In these disorders, people present with medically inexplicable physical symptoms that are hypothesised to be the result of underlying psychological processes. As the causes of CFS are "unexplained", there is an obvious overlap between the diagnostic criteria for the somatoform disorders and CFS.16,90,109-112
A recent international multicentre study attempted to stratify patients diagnosed with CFS in tertiary referral centres, without prior clinical assumptions.113 The results suggested heterogeneity, with variation between centres, but it was not possible to determine whether the hypothesised subgroups (with "classical CFS" versus "multiple somatic" symptoms) lie on a continuum or represent truly distinct aetiological categories. Nor was it clear whether somatic symptoms were the result of a constitutional vulnerability or were secondary to chronic illness. It was concluded that, although stratification was likely to be important in future research, the basis for allocating subcategories remains controversial.
Whether it will ever be possible to neatly separate a "core condition" of CFS16,33 from other "functional somatic syndromes"114 or to successfully delineate aetiological subcategories of CFS patients remains unclear.18,83 Whatever the case, however, in everyday clinical practice "somatisation" and "somatoform" are unhelpful diagnostic labels which are best avoided in patients with CFS (see Chapter 5).
Though not considered a "cause" of CFS, some patients with chronic fatigue report food intolerances that can exacerbate symptoms.115,116 If food intolerance is suspected on clinical grounds, dietary investigation under the supervision of an appropriately qualified physician and dietitian may be warranted.
Some studies have suggested an overlap between CFS and multiple chemical sensitivity (MCS)82,87,117-124 Gulf War syndrome124,125-128 and "sick building" syndrome.129 The existence of these as valid diagnostic or ontological entities is highly contentious82,130-138 and their consideration is beyond the scope of these clinical practice guidelines.
1.3: Evaluation of the evidence for infections as factors in the pathophysiology of CFS
Non-specific infections
Raised titres of IgG antibodies directed against common viruses (eg, herpesviruses, enteroviruses) are common, but are of no pathophysiological or diagnostic significance51,173,184 (Level I).
Common, non-specific infections (eg, upper respiratory tract infections) are not likely to trigger CFS66 (Level II).
Epstein-Barr virus
Infectious mononucleosis can trigger CFS67,185-188 (Level I).
Reactivation of EBV is not more prevalent in CFS94,190-192 (Level II).
Enteroviruses
Earlier reports of enteroviral RNA particles in the muscles have not been confirmed by more comprehensive studies192-200 (Level I).
Retroviruses
Human herpesvirus-6
There is conflicting evidence for reactivation of HHV-6 replication176,184,191,209-216 (Level III-4).
Ross River virus
Borna disease virus
There is conflicting evidence of Borna disease virus infection in patients with CFS184,218-222 (Level III-4).
Non-viral infections (Q fever, Lyme disease, Mycoplasma)
Retrospective studies suggest CFS may follow adequately treated Q fever or Lyme disease68,69,223-228 (Level IV).
The existence of Lyme disease in Australia has not been confirmed229 (Level III-3).
An increased prevalence of colonisation by non-pathogenic mycoplasmal commensal species has been detected by polymerase chain reaction in the blood of a proportion of patients with CFS230-232 (Level III-2).
Comment: Many studies that have suggested a link between infections and CFS have relied upon the detection of antibodies against the viral or other agent as an indirect means of implicating the organism in the pathophysiology of CFS. These studies have suggested that "high" titres of IgG antibodies directed against viruses such as EBV, HHV-6 or enteroviruses reflect chronic, active viral infection. However, case-control studies indicate that such "elevated" antibody titres are also found in healthy individuals many years after the original infection. Those studies which have sought direct evidence of chronic viral replication have not found an increased prevalence of viral isolation in people with CFS.
1.4: Evaluation of the evidence for immunological factors in the pathophysiology of CFS
General
Despite numerous studies there is no consensus on the pattern and prevalence of immunological disturbance in people with CFS165,233 (Level III-4).
Preliminary evidence of an HLA association234 has not been confirmed235 (Level III-4).
Lymphocytes
Reduced lymphocyte proliferation and natural killer cell cytotoxicity are common, but findings are non-specific94,149,198,236-252 (Level I).
Despite numerous studies there is no consensus on the pattern and prevalence of changes in peripheral blood lymphocyte subpopulations or activation status149,198,240-242,246,247,249,253-259 (Level III-4).
Immunoglobulins
There is conflicting evidence for reduced serum immunoglobulin G (IgG) and IgG subclass levels239,260-264 (Level III-4).
Atopy
Delayed type hypersensitivity skin responses
Cytokines
Numerous studies using different methods have yielded conflicting evidence for increased serum levels of cytokines or cytokine production94,198,237,276-292 (Level III-4).
Antiviral immunity
Alterations in the 2-5A synthetase/ribonuclease (RNase L) antiviral pathway have been described in a significant proportion of patients with CFS293-295 (Level II).
Autoimmune/inflammatory conditions
There is conflicting evidence of a role for autoantibodies296-299 (Level III-4).
Sicca symptoms are common and a subset of people with CFS meet clinical but not laboratory criteria for Sjögren's syndrome26,300-302 (Level II).
An increased prevalence of elevated serum angiotensin-converting enzyme levels has been reported in patients with CFS303 (Level III-3).
Comment: Numerous studies have sought evidence for a disturbance in immunity in people with CFS, but no consensus has emerged. The divergent results are likely to have arisen from variations in methodology, as well as inadequate attention to important confounding variables such as the effects of sleep disturbance, diurnal variation, medication, mood (and others) on laboratory measures of immunity.
1.5: Evaluation of the evidence for disturbance of central nervous system function as a factor in the pathophysiology of CFS
Impaired hypothalamic-pituitary-adrenal (HPA) axis activation has been shown304-323 (Level III-2).
There is conflicting evidence for reduced levels of insulin-like growth factors (IGFs)324-327 (Level III-4).
Disturbances of sleep maintenance (eg, frequent awakenings) are prevalent81,328-331 (Level III-2).
There is conflicting evidence of disturbed circadian rhythm332,333 (Level III-4).
Sleep disruption or circadian rhythm disturbance may perpetuate musculoskeletal symptoms77,334,335 (Level III-3).
Sympathetic nervous system function
Altered blood pressure responses to postural change, consistent with neurally mediated hypotension, have been shown336-345 (Level III-2).
There is conflicting evidence for reduced sympathetic nervous system markers340,346-348 (Level III-4).
There is conflicting evidence for increased sensitivity of serotonin and dopamine receptors to antagonists305-307,349 (Level III-4).
There is conflicting evidence for an increased prevalence of white matter abnormalities on magnetic resonance imaging176,350-363 (Level III-4).
Regional cerebral blood flow studies (eg, single photon emission computed tomography [SPECT]) have produced conflicting results176,350-361,364-366 (Level III-4).
Gait and motor abnormalities have been described367,368 (Level III-2).
Attention, concentration and other measures of cognitive function are impaired361,369-383 (Level I). Interpretation of findings is uncertain.384
There is conflicting evidence for impaired visual and auditory
memory361,369-378
(Level III-4).
Psychological/psychiatric factors
Changes in biological markers (eg, HPA axis function, immunity, sleep architecture) in patients with major depression are different from those in patients with CFS81,245,307 (Level III-2).
There is conflicting evidence of a role for personality factors.385-390 There were no differences in perfectionism, attitudes towards mental illness, defensiveness, social desirability or measures of neuroticism when patients with CFS were compared with a control group with rheumatoid arthritis391 (Level III-4).
Increased measures of suggestibility have been reported392 (Level III-3).
Childhood sexual or physical abuse were not found to be risk factors for development of CFS393 (Level III-3).
In a retrospective study, patients with CFS were more likely than controls to have experienced critical life events, infections and high fatigue levels during the three months before onset of CFS394 (Level III-3).
There is conflicting evidence of rates of premorbid psychiatric disorders (depression, anxiety, somatisation disorder) in patients with CFS91-99,395 (Level III-4).
Comment: Several lines of evidence suggest that a disturbance of central nervous system function is present in people with CFS. This disturbance is reversible and, as yet, poorly characterised. The pattern of alteration seen in people with CFS in these studies contrasts with that seen in people with major depression, suggesting different pathophysiological processes in these two syndromes.
1.6: Evaluation of the evidence for other factors proposed to contribute to the pathophysiology of CFS
Genetic factors
Studies in twins suggest a genetic vulnerability to idiopathic chronic fatigue and possibly CFS396,397 (Level III-2).
Neuromuscular disorder
Muscle strength, endurance and recovery are normal179,398-402 (Level I).
Conflicting evidence for a disturbance in mitochondrial function403,404 (Level III-4).
The hypothesis that CFS is the result of channelopathy is not supported by empirical data405,406 (Level IV).
Cardiac abnormality
Metabolic disturbance
Urinary excretion of protein metabolites may be altered410-412 (Level III-2).
Serum acylcarnitine deficiency has been reported413 (Level III-3).
Differences in total body potassium levels between patients with CFS and control patients have been reported414 (Level III-3).
Poisoning
Levels of chlorinated hydrocarbons may be increased415,416 (Level III-3).
Chronic exposure to industrial solvents, insecticides or pesticides may cause an illness resembling CFS417-419 (Level IV).
Silicone breast implants may be associated with a syndrome resembling CFS75,84,118,420-423 (Level IV).
Ciguatera poisoning may precipitate a syndrome resembling CFS424, (Level IV).
Comment: Apart from the strong evidence indicating that the muscle is not the site of pathophysiological disturbance giving rise to fatigue in people with CFS, these studies provide only very limited preliminary evidence of other possible factors linked to CFS.
In the early stages of an illness characterised by prolonged fatigue, spontaneous recovery is common.139 After infectious mononucleosis 41% of patients reported prominent fatigue during the acute illness, of whom 71% had prolonged fatigue one month later, 43% at two months, and 9% at six months.67
By contrast, full recovery in patients with established CFS is less common. In prospective studies, rates of self-reported improvement vary from 11%-64%,140-143 and worsening at 12-18 months was reported in 15%-20%.140,143 A US population surveillance study estimated a cumulative five-year recovery rate of 31%.144
The long-term outcome of CFS has been evaluated mostly in people treated within tertiary referral settings.140,145-150 Such patient samples are biased towards chronic illness and limited patterns of recovery.60,91,139 Patient reports drawn from self-help group populations show similar biases with respect to functional impairment.146 In an Australian study conducted in a specialist setting,150 65 of 103 patients (63%) who had had symptoms for about five years reported abatement of symptoms and improvement in functional capacity over the next three years, but complete recovery was uncommon (6%). During follow-up, patients were very unlikely to develop other medical disorders (2%), but a significant number did develop other psychological disorders (19%), notably major depression and anxiety. Similar outcomes were confirmed in several other retrospective studies from tertiary referral centres.
Factors associated with poorer outcomes include illness duration, subjective cognitive impairment and somatic symptoms,143-151 as well as high levels of fatigue or functional impairment and a low sense of control over symptoms.140 Outcome has not been found to be associated with sex or life stress events,146-152 or with laboratory parameters, such as viral antibody titres and immunological measures (including T-cell-subset measurements).153
At the more severe end of the clinical spectrum, although improvement over time can occur, the prognosis for recovery is poor.154,155 Patients who have had CFS for more than 10 years are more disabled than those with shorter-duration illness, and have significantly more severe symptoms (particularly cognitive impairment) and more frequent symptoms of fibromyalgia.156
Among 2075 people followed up in 19 published studies of the outcome of prolonged fatigue and CFS, there was one death by suicide and two unrelated deaths.139 These studies included mean follow-up periods ranging from six months to four years, suggesting that suicide rates and overall mortality are not increased in people with CFS.
In studies of children and adolescents with CFS the outcome is significantly better than in adults. Two studies evaluating chronic fatigue in children reported that 77%-94% recovered or their condition improved.157,158 The average duration of illness is 2-4 years [see Chapter 4].159-163
Phenomena associated with CFS
CFS does not typically follow common, non-specific viral illnesses (Level II).
Specific infections such as infectious mononucleosis can trigger CFS (Level I).
There is currently no convincing evidence that retroviruses cause CFS (Level I).
Immunological alterations are common in people with CFS (Level III-4), but are of uncertain pathophysiological significance.
Neuroendocrine changes indicating hypothalamic-pituitary-axis disturbance are common in people with CFS (Level III-4), but are of uncertain pathophysiological significance.
Sleep disturbance is very common in people with CFS (Level I), but is of uncertain pathophysiological significance.
Neurocognitive performance in people with CFS is impaired (Level I).
Neuromuscular performance in people with CFS is normal, implicating the central nervous system as the likely site of pathophysiological disturbance (Level I).
For an explanation of the rating of levels of evidence, see page S21.
The pathophysiological basis of CFS is unclear. The leading hypotheses put forward over the past decade are summarised in Boxes 1.3 to 1.7 and include:
a unique pattern of infection with a recognised or novel pathogen;164
altered central nervous system (CNS) function resulting from an abnormal immune response against a common antigen;16,165,166
a neuropsychiatric disorder with clinical and neurobiological aspects suggesting a link to depressive disorders;169 and
a psychologically determined response to infection or other stimuli occurring in "vulnerable" individuals.110,170-172
Other hypotheses exist but have not been scientifically evaluated. The probable heterogeneity within patient groups labelled as having CFS18,28,82,83,113 makes it highly likely that there are multiple contributing factors in the disorder.
The financial impact of CFS on those affected and on the community has been evaluated.22 A conservative Australian estimate of the direct costs (those incurred in diagnosis and management) was $1936 per case per annum (in 1988/89 dollars). After inclusion of indirect costs (from lost productivity associated with the disorder) the aggregate annual cost of CFS was $9436 per case (1988/89 dollars). In 2000/01 dollars, this represents a direct cost of $2764 per case and an annual aggregate cost of $13 471 to the community. Based on a conservative assumption of a community prevalence of CFS of 0.2% (200 cases per 100 000 population), this implies an annual cost to the Australian community of $525 million.
Diagnosis
Clinical diagnosis
A diagnosis of CFS is made on clinical grounds (Level IV).
Diagnosis relies on the presence of characteristic symptoms and exclusion of alternative medical and psychiatric disorders (Level IV).
The physical examination in people with CFS is normal (Level I).
People with CFS commonly have concurrent depression (Level I), which does not necessarily represent an alternative primary diagnosis.
CFS frequently overlaps with other common syndromes such as fibromyalgia and irritable bowel syndrome (Level III-2).
Laboratory investigation
There is no validated diagnostic test for CFS (Level I).
The purpose of laboratory investigation is to exclude other conditions that may cause fatigue (Level IV).
For most patients the following investigations are sufficient: blood count and ESR, serum levels of electrolytes (including calcium and phosphate), standard biochemical tests of liver and kidney function, thyroid function tests (TSH) and urinalysis for protein, blood and glucose (Level I).
Symptoms or signs that are not typical of CFS (eg, fever, weight loss, enlargement of liver, spleen or lymph nodes) should be investigated separately, as indicated clinically (Level IV).
Specialist referral
An experienced general practitioner should be able to make a diagnosis of CFS in most patients. Specialist medical or psychiatric referral is only required if the diagnosis remains in doubt (Level IV).
For an explanation of the rating of levels of evidence, see page S21.
Patients who complain of persisting "fatigue" or "tiredness" may be describing any one of a diverse range of clinical phenomena, ranging from muscle weakness to dyspnoea or depressed mood. The initial task is to clarify the nature of the "fatigue". Fatigue, like pain, is intrinsically a brain-mediated sensation. As with pain, most people report that the fatigue is experienced as a peripheral phenomenon, apparently occurring in musculoskeletal regions. When questioned closely, most people with CFS report that they also experience "mental fatigue", typically precipitated by complex neuropsychological tasks.74,426
To differentiate the various causes of mental and physical fatigue, doctors should focus on the description of the complaint (Box 2.1). Fatigue in people with CFS is typically exacerbated by physical tasks previously achieved with ease, and recovery from periods of worsened fatigue can take hours or even days. Pathological fatigue can be differentiated from:
somnolence (or "sleepiness"), as it is not relieved by sleep;
neuromuscular weakness, as people with CFS can generate muscle strength and endurance when circumstances demand;24,400,427 and
the lack of motivation and loss of pleasure from usual daily activities that characterise depressive illness.
2.1: What can a person with "fatigue" or "tiredness" be describing?
In most instances the symptoms of chronic fatigue syndrome can be distinguished from the closely related phenomena of somnolence, muscle weakness, neuromuscular fatigability, depressed mood or anhedonia.
|
Person describes: |
Interpretation | ||||||||||
|
| |||||||||||
|
→ Muscle weakness (eg, myopathy; polymyositis) | ||||||||||
|
→ Neuromuscular fatigability (eg, myasthenia gravis) | ||||||||||
|
→ Central fatigue (eg, multiple sclerosis) | ||||||||||
|
→ Anhedonia (eg, major depression) | ||||||||||
|
→ Somnolence (eg, sleep apnoea, narcolepsy) | ||||||||||
|
→ Dyspnoea → Weakness (eg, airflow limitation; cardiac failure; anaemia) | ||||||||||
|
→ Inflammation (eg, systemic lupus erythematosus) → Infection (eg, influenza) | ||||||||||
CFS is distinguished from similar fatigue-related illnesses not only by carefully characterising the fatigue itself, but also by evaluating associated symptoms and signs. People with CFS also report:
unrefreshing sleep;
myalgia:
arthralgia;
loss of concentration;
memory impairment;
irritable mood, and
postexertional malaise (may be delayed).
Any of these associated features may be exacerbated by minor physical activity.
Although these symptoms are common in people with CFS, they are not specific and may occur in a range of other medical and neuropsychiatric disorders. In adults presenting for medical assessment with fatigue states the most common alternative diagnosis to consider is major depression.25,36,39,40,66,74,92-94,96,97 Other commonly detected disorders (Box 2.3) are sleep apnoea, hypothyroidism, anaemia, coeliac disease, chronic hepatitis, panic disorder, generalised anxiety, and somatoform disorders.16,27<
