Benign Myalgic EncephalomyelitisME InternationalMyalgic EncephalomyelitisME International

Chronic fatigue syndrome

Page 1 (of 4)

Clinical practice guidelines - 2002

Produced by a Working Group convened under the auspices of the Royal Australasian College of Physicians
This supplement to the MJA was funded by a grant from the Commonwealth Department of Health and Ageing.

MJA 6 May 2002 176 (9 Suppl): S17-S55

Membership of the Working Group

Preface

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.

Background

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 ASCIA 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, 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.


Guideline development

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, and A CFS health consumer perspective. 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.

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.

Literature review and evidence ratings

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). 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.

Clinical Overview


"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."



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.

What is CFS?

"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.

Diagnosis

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 syndrome
  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:
    1. Impaired short term memory or concentration
    2. Sore throat
    3. Tender cervical or axillary lymph nodes
    4. Muscle pain
    5. Multi-joint pain without arthritis
    6. Headaches of a new type, pattern, or severity
    7. Unrefreshing sleep
    8. Post-exertional malaise lasting more than 24 hours


Clinical history

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.

Examination

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).

Investigation

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.

Specialist referral

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).

Management

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.

Understanding the illness

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.

Physical activity

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.

Sleep

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:

  1. 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;
  2. judicious use of sedative-hypnotic medication to achieve sleep;
  3. use of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) for relief of musculoskeletal pain;
  4. avoiding (preferably) daytime naps or keeping them under 30 minutes;
  5. 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.

Symptomatic drug treatment

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.

Psychological and social support

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 CFS
CFS = chronic fatigue syndrome; HACC = home and community care.


Special considerations in children and adolescents

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.


1: What is chronic fatigue syndrome?
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.

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.


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 disability[20,21] and significant social or economic cost.

Diagnostic criteria

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 CFS[6] 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]

"Disease" or "illness"?

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]

What other terms are commonly used for CFS?

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]

How common is CFS?

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
StudyPFCFCFS
Buchwald et al, 1987, USA 51 -21%-
Kroenke et al, 1988, USA 723.8%--
David et al, 1990, UK 810.5%-0.16%
Cathebras et al, 1992, Canada 913.6%5.7%-
Bates 1993, USA 52-27%0.3%-1.3%
Katerndahl 1993, USA 106.9%>--

McDonald et al, 1993, UK 53

-112%2.5%
Walker et al, 1993, USA116.7%--
Pawlikowska et al, 1994, UK 15-18.3%-
Buchwald et al, 1995, USA 39-19%0.1%-0.3%
Hickie et al 1996, Australia 1325%-0.3%-1.3%
Wessely et al 1997, UK 54-11.3%0.5%-2.6%

Who is at risk of CFS?

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 practice[66] 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]

Does CFS overlap with other illnesses?

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 fibromyalgia[99] 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-10[108]) 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-IV[107]). 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 CFS[16,33] 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).

Food and environmental intolerances

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 syndrome[124,125-128] and "sick building" syndrome.[129] The existence of these as valid diagnostic or ontological entities is highly contentious[82,130-138] 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 significance[51,173,184] (Level I).
  • Common, non-specific infections (eg, upper respiratory tract infections) are not likely to trigger CFS[66] (Level II).
    Epstein-Barr virus
  • Infectious mononucleosis can trigger CFS[67,185-188] (Level I).
  • Reactivation of EBV is not more prevalent in CFS[94,190-192] (Level II).
    Enteroviruses
  • Earlier reports of enteroviral RNA particles in the muscles have not been confirmed by more comprehensive studies[192-200] (Level I).
    Retroviruses
  • There is strong evidence against a role for retroviruses in CFS[201-208] (Level I).
    Human herpesvirus-6
  • There is conflicting evidence for reactivation of HHV-6 replication[176,184,191,209-216] (Level III-4).
    Ross River virus
  • Retrospective studies suggest CFS may follow RRV infection[30,70,217] (Level III-2).
    Borna disease virus
  • There is conflicting evidence of Borna disease virus infection in patients with CFS[184,218-222] (Level III-4).
    Non-viral infections (Q fever, Lyme disease, Mycoplasma)
  • Retrospective studies suggest CFS may follow adequately treated Q fever or Lyme disease[68,69,223-228] (Level IV).
  • The existence of Lyme disease in Australia has not been confirmed[229] (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 CFS[230-232] (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 CFS[165,233] (Level III-4).
  • Preliminary evidence of an HLA association[234] has not been confirmed[235] (Level III-4).
    Lymphocytes
  • Reduced lymphocyte proliferation and natural killer cell cytotoxicity are common, but findings are non-specific[94,149,198,236-252] (Level I).
  • Despite numerous studies there is no consensus on the pattern and prevalence of changes in peripheral blood lymphocyte subpopulations or activation status[149,198,240-242,246,247,249,253-259] (Level III-4).
    Immunoglobulins
  • There is conflicting evidence for reduced serum immunoglobulin G (IgG) and IgG subclass levels[239,260-264] (Level III-4).
    Atopy
  • There is conflicting evidence for an increased prevalence of atopy[174,265-272] (Level III-4).
    Delayed type hypersensitivity skin responses
  • There is conflicting evidence for impaired DTH skin responses[24,198,239,245,273-275] (Level III-4).
    Cytokines
  • Numerous studies using different methods have yielded conflicting evidence for increased serum levels of cytokines or cytokine production[94,198,237,276-292] (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 CFS[293-295] (Level II).
    Autoimmune/inflammatory conditions
  • There is conflicting evidence of a role for autoantibodies[296-299] (Level III-4).
  • Sicca symptoms are common and a subset of people with CFS meet clinical but not laboratory criteria for Sjögren's syndrome[26,300-302] (Level II).
  • An increased prevalence of elevated serum angiotensin-converting enzyme levels has been reported in patients with CFS[303] (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
    Neuroendocrine function
  • Impaired hypothalamic-pituitary-adrenal (HPA) axis activation has been shown[304-323] (Level III-2).
  • There is conflicting evidence for reduced levels of insulin-like growth factors (IGFs)[324-327] (Level III-4).
    Sleep
  • Disturbances of sleep maintenance (eg, frequent awakenings) are prevalent[81,328-331] (Level III-2).
  • There is conflicting evidence of disturbed circadian rhythm[332,333] (Level III-4).
  • Sleep disruption or circadian rhythm disturbance may perpetuate musculoskeletal symptoms[]77,334,335] (Level III-3).
    Sympathetic nervous system function
  • Altered blood pressure responses to postural change, consistent with neurally mediated hypotension, have been shown[336-345] (Level III-2).
  • There is conflicting evidence for reduced sympathetic nervous system markers[340,346-348] (Level III-4).
    Neurotransmitter function
  • There is conflicting evidence for increased sensitivity of serotonin and dopamine receptors to antagonists[305-307,349] (Level III-4).
    Brain structure/function
  • There is conflicting evidence for an increased prevalence of white matter abnormalities on magnetic resonance imaging[176,350-363] (Level III-4).
  • Regional cerebral blood flow studies (eg, single photon emission computed tomography [SPECT]) have produced conflicting results[176,350-361,364-366] (Level III-4).
  • Gait and motor abnormalities have been described[367,368] (Level III-2).
    Cognitive performance
  • Attention, concentration and other measures of cognitive function are impaired[361,369-383] (Level I). Interpretation of findings is uncertain.[384]
  • There is conflicting evidence for impaired visual and auditory memory[361,369-378] (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 CFS[81,245,307] (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 arthritis[391] (Level III-4).
  • Increased measures of suggestibility have been reported[392] (Level III-3).
  • Childhood sexual or physical abuse were not found to be risk factors for development of CFS[393] (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 CFS[394] (Level III-3).
  • There is conflicting evidence of rates of premorbid psychiatric disorders (depression, anxiety, somatisation disorder) in patients with CFS[91-99,395] (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 CFS[396,397] (Level III-2).
    Neuromuscular disorder
  • Muscle strength, endurance and recovery are normal[179,398-402] (Level I).
  • Conflicting evidence for a disturbance in mitochondrial function[403,404] (Level III-4).
  • The hypothesis that CFS is the result of channelopathy is not supported by empirical data[405,406] (Level IV).
    Cardiac abnormality
  • Subtle abnormalities of cardiac function with exercise have been described[407-409] (Level III-2).
    Metabolic disturbance
  • Urinary excretion of protein metabolites may be altered[410-412] (Level III-2).
  • Serum acylcarnitine deficiency has been reported[413] (Level III-3).
  • Differences in total body potassium levels between patients with CFS and control patients have been reported[414] (Level III-3).
    Poisoning
  • Levels of chlorinated hydrocarbons may be increased[415,416] (Level III-3).
  • Chronic exposure to industrial solvents, insecticides or pesticides may cause an illness resembling CFS[417-419] (Level IV).
  • Silicone breast implants may be associated with a syndrome resembling CFS[75,84,118,420-423] (Level IV).
  • Ciguatera poisoning may precipitate a syndrome resembling CFS[424], (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.

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