Show Summary Details
Page of

Chronic fatigue syndrome (postviral fatigue syndrome, neurasthenia, and myalgic encephalomyelitis) 

Chronic fatigue syndrome (postviral fatigue syndrome, neurasthenia, and myalgic encephalomyelitis)
Chronic fatigue syndrome (postviral fatigue syndrome, neurasthenia, and myalgic encephalomyelitis)

Michael Sharpe

Page of

PRINTED FROM OXFORD MEDICINE ONLINE ( © Oxford University Press, 2016. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Medicine Online for personal use (for details see Privacy Policy and Legal Notice).

Subscriber: null; date: 21 November 2019


Chronic fatigue syndrome (CFS) is also known as postviral fatigue syndrome, neurasthenia, and myalgic encephalomyelitis. All describe an idiopathic syndrome characterized by disabling fatigue and other symptoms occurring chronically and exacerbated by minimal exertion.

Aetiology and pathogenesis—it is likely that multiple factors operate to predispose, precipitate, and perpetuate CFS: (1) predisposing factors—some individuals may be predisposed to develop CFS by virtue of genetics, personality, or other vulnerability; (2) precipitating factors—the condition may be precipitated by factors such as infection or psychological stresses; (3) perpetuating factors—for practical management the most important factors are those that perpetuate the illness and consequently act as barriers to recovery, including modifiable psychological, biological, behavioural, and social factors. Studies have reported a variety of biological abnormalities: few have been confirmed, but the most robust are (1) altered brain function, and (2) reduced hypothalamic-pituitary-adrenal axis responsiveness, although it is not clear if these are primary or secondary to inactivity.

Clinical context—important obstacles to recovery in many cases include (1) the psychological factors of fear and misconception about symptoms; (2) emotional distress; and (3) coping by becoming inactive or adopting a pattern of fluctuating levels of activity. The boundary with depression, anxiety, and other functional syndromes such as fibromyalgia is unclear.

Management and prognosis—this requires that the doctor excludes treatable conditions that may cause fatigue, demonstrates acceptance of the reality of the symptoms, addresses misconceptions about them, and refers for rehabilitative behavioural treatments when these are available and acceptable to the patient. There is no proven drug therapy and the prognosis without treatment is poor.

Acknowledgement: I am grateful to Simon Wessely, Peter White, and David Wilks for comments on this chapter.


Fatigue is an imprecise term with many meanings. In clinical medicine the symptom of fatigue implies a subjective feeling of lack of energy and endurance. While fatigue after exertion is a normal phenomenon, it is abnormal when it is disproportionate to exertion, persistent, and associated with impaired function. A variety of names have been given to this condition when it is unexplained by another diagnosis: chronic fatigue syndrome (CFS), postviral fatigue syndrome (PVFS), neurasthenia, and myalgic encephalomyelitis (ME). CFS is one of the most disputed illnesses in current medical practice, with strong differences of opinion about aetiology and treatment. Even the name is disputed and the unsatisfactory compromise term CFS/ME increasingly used.

Historical perspective

Illness characterized by chronic fatigue but without a clear pathological basis has a long history. In the 19th century it attracted a diagnosis of ‘neurasthenia’, but by the early 20th century this term fell into disuse. It is probable that patients continued to present to doctors with similar symptoms but received other diagnoses such as depression, brucellosis, and Epstein–Barr virus infection. As well as sporadic cases there have been occasional reports of apparent epidemics over the last 50 years, with one that occurred among staff at the Royal Free Hospital, London, United Kingdom in 1955 giving rise to the term myalgic encephalomyelitis (ME). By 1988 it had become increasingly accepted that most cases of chronic disabling fatigue were not caused by an infection or inflammation of the brain and the purely descriptive term chronic fatigue syndrome (CFS) was introduced. At the beginning of the 21st century the cause and treatment of this syndrome remain controversial.


There is no established pathology or cause for CFS, but a number of biological, psychological, and social factors have been identified that may play a role in the onset and perpetuation of illness. It is unlikely that all cases have the same cause.

Biological factors

A range of factors have been proposed but none established.


Twin studies suggest that CFS is moderately heritable. Preliminary studies suggesting the involvement of specific genes require replication.


Patients presenting with CFS often give a history suggestive of acute infection at the outset, hence the term ‘postviral fatigue syndrome’. A number of viruses including retroviruses have been reported as causes but to date none have an established aetiological role. Prospective studies confirm that fatigue states lasting several months can follow infections such as Epstein–Barr virus and Q fever. However, the available evidence does not support the hypothesis that chronic occult infection is commonly a cause of CFS.

Immune dysfunction

Minor immune abnormalities, most commonly mild activation, have been detected in some patients with CFS. Cytokines can cause fatigue, but no consistent immune abnormality or casual link of these with symptoms has been established. The role of immune factors in CFS remains of interest but is still unclear.

Dysfunction of the central nervous system

There is evidence for abnormalities in neuroendocrine tests of serotonergic function and in functional neuroimaging. However, abnormalities in similar domains have been found in patients with depression and anxiety disorders, hence the specificity and clinical utility of such tests remains to be established.

Endocrine dysfunction

Some of the most robust biological findings in CFS relate to the hypothalamic-pituitary-adrenal axis. The main finding has been under-responsiveness of the axis, but it remains unclear whether this is cause or consequence of CFS. Replacement therapy with low-dose hydrocortisone has been reported to produce short-term symptomatic relief. However, the balance of risks and benefits of this treatment is not yet established.


Some patients with chronic fatigue syndrome are profoundly inactive. This may lead to muscle wasting, changes in the cardiovascular response to exertion, and postural hypotension. The consequent intolerance of activity may perpetuate the illness by leading to symptoms that are interpreted as worsening of illness and further avoidance.

Idiopathic postural hypotension (neurally mediated hypotension)

A tendency to postural hypotension has been reported in some patients with CFS, particularly young women. The aetiological and treatment implications of this observation remain unclear.

Sleep disorder

Various sleep abnormalities have been reported as associated with CFS. They include both specific sleep disorders, such as restless legs syndrome, and nonspecific abnormalities, such as fragmentation of sleep. These may contribute to daytime fatigue in at least some cases.

Psychological and behavioural factors

There is evidence that these may perpetuate chronic fatigue syndrome.


Many patients describe major life stresses preceding illness onset, and it has therefore been suggested that at least some cases of CFS may be stress related.

Emotional disorder

Many patients seen in hospital clinics who meet criteria for CFS also meet criteria for depressive and anxiety disorders. Fatigue is a symptom of depression and anxiety. In many but not all cases CFS may be confounded with these emotional disorders, which remain the main differential diagnosis.

Fears and beliefs about symptoms

Patients often have misconceptions about the nature of their illness that may perpetuate it, including beliefs that activity that exacerbates symptoms is harmful and that CFS is an untreatable neurological disease.

Coping behaviour

A number of coping behaviours may be associated with poorer outcome. These may result from the beliefs described above and include excessive avoidance of physical activities (leading to chronic disability), the repeated seeking of (ineffective) medical care, and a failure to address psychological and social problems (such as stressful employment).

Social and iatrogenic factors

Information about CFS or ME—whether from doctors, patient groups, or the media—that leads patients to see their illness as mysterious, with a hopeless prognosis, and best treated by rest, is likely to inhibit efforts toward rehabilitation.



One-quarter of people complain of persistent fatigue, but population studies in the United Kingdom and United States of America suggest that only about 0.5% could be regarded as having CFS, most of whom are aged between 20 and 40, with a predominance of women. The syndrome is also seen in children and adolescents, but less commonly.


Epidemics of a chronic fatigue-like syndrome have been described from various parts of the globe. This observation is compatible with, but does not establish, an infective cause. It remains unclear whether these were true epidemics and also whether the clinical picture reported is similar to that of cases of sporadic CFS.


As the cause is unknown there is no specific primary prevention. Secondary prevention is important as it is likely that good early management and avoidance of iatrogenesis will reduce the risk of chronicity.

Clinical features

CFS is defined by symptoms alone.


The principal symptom is chronic mental and physical fatigue, tiredness, or exhaustion that is exacerbated by activity. Patients often report being able to perform activities for brief periods, but subsequently experiencing severe fatigue for hours or days thereafter. Other commonly associated symptoms include impaired memory and concentration, muscular and joint pain, unrefreshing sleep, dizziness and breathlessness, headache, tender lymph glands, and sore throat.

Patients often describe day-to-day fluctuations, irrespective of activity. Periods of almost complete recovery may be followed by relapse, often sufficiently severe to make normal daily activity impossible. Depression and anxiety are common, and some patients suffer panic attacks.

Patients and their relatives may hold strong beliefs about the nature and aetiology of their illness (see section on Aetiology), and it is important to take these into account when discussing treatment.

Physical signs

Physical examination is typically unremarkable. Complaints of fever and lymphadenopathy are not confirmed on examination. The presence of definite physical signs (such as objectively measured fever) should not be ascribed to the syndrome and alternative diagnoses should be sought.

Differential diagnosis

Almost any disease may present with fatigue. The differential diagnosis of idiopathic CFS is correspondingly large (Table The nature of the fatigue may offer useful clues:

  • Muscular diseases should be considered if the patient has objective weakness, no psychological symptoms, and a family history.

  • Prominent sleepiness suggests a sleep disorder, e.g. prominent snoring and morning headaches in the obese patient raise the possibility of obstructive sleep apnoea.

  • Depression is suggested by fatigue that is worse in the morning and accompanied by loss of motivation, interest, and pleasure. Other symptoms of depression may include sadness, loss of appetite and weight, and feelings of pessimism and failure.

  • Anxiety is also associated with fatigue and may give rise to many of the somatic symptoms of chronic fatigue syndrome such as muscle pain, impaired concentration, and poor sleep. Severe episodic anxiety (panic) may be described as episodic severe symptoms followed by hours of fatigue.

  • Somatization disorder is suggested by a lifelong pattern of many physical symptoms referable to multiple bodily systems, with a history of unproductive investigation and unsuccessful treatments.

Table Conditions to be considered in the differential diagnosis of chronic fatigue syndrome

Nature of symptoms

Possible condition


Occult malignancy

Autoimmune disease

Endocrine disease

Cardiac, respiratory, or renal failure


Malabsorption including coeliac disease


Disseminated sclerosis

Myasthenia gravis

Parkinson’s disease

Early dementia

Cerebrovascular disease

Infectious disease

Chronic active hepatitis (B or C)

Lyme borreliosis



Respiratory disease

Nocturnal asthma

Obstructive sleep apnoea

Chronic toxicity



Heavy metals



Major depressive disorder


Anxiety and panic disorder

Somatization disorder

Clinical investigation

There are no specific diagnostic tests and no characteristic abnormalities on laboratory investigations that are conducted purely to exclude other diseases. All patients should have a full blood count, erythrocyte sedimentation rate or C-reactive protein, basic biochemistry screen, creatine kinase, random blood glucose, urine analysis, thyroid function, and (possibly) serological screening tests for autoimmune inflammatory disorders (antinuclear antibody test). Further investigation depends on the clinical findings and differential diagnoses under consideration.

Criteria for diagnosis

The current international consensus definition reported by Fukuda and colleagues is shown in Table Guidelines on its application have been published by Reeves and colleagues in 2003.

Table International consensus definition of chronic fatigue syndrome

1. Complaint of fatigue

Of new onset

Not relieved by rest

Duration at least 6 months

2. At least four of the following additional symptoms

Subjective memory impairment

Sore throat

Tender lymph nodes

Muscle pain–Joint pain


Unrefreshing sleep

Post-exertional malaise lasting >24 h

3. Impairment of functioning

4. Other conditions that might explain fatigue excluded

Fukuda K et al. (1994). Chronic fatigue syndrome: a comprehensive approach to its definition and management. Annals of Internal Medicine 121, 953–9.


General management

The doctor should listen to the patient’s story and ask about his or her own understanding of the illness. It is usually also worth seeing the partner or relevant family members. It is important to address misunderstandings about the nature of the illness, and especially to make clear that it is not progressive or life-threatening (see below). A positive explanation of CFS as a ‘dysfunction of the central nervous system’, emphasizing potential reversibility, is often helpful. The adverse physiological and psychological effects of prolonged bed rest should be explained, and the patient encouraged to avoid extremes of both inactivity and exertion. An initial hospital appointment that achieves all the above usually requires at least 45 min. An evidence-based self-help book may be recommended (such as Chronic fatigue syndrome (CSF/ME): the facts; see Further reading).

Drug therapy

There is no drug therapy of proven efficacy. A trial of an antidepressant drug may be considered if there is evidence of depression. It is advisable to choose a nonsedating type and to start with a low dose, which may reduce anxiety, improve the quality of sleep, and reduce pain, but it is important to give a recommended dose if there is evidence that the patient has a depressive disorder.

Rehabilitation, graded activity, and cognitive behavioural therapy (CBT)

The rehabilitative behavioural treatments of slowly graded activity or exercise programmes and CBT have been found to be more effective than conventional management in systematic reviews of randomized trials. They are currently the mainstay of management, but they are not effective in all patients and require both careful explanation and therapists skilled in their delivery to patients with CFS.

It is particularly important that patients do not interpret referral for a behavioural treatment as the doctor implying that their illness is imaginary. It can be explained that the most likely cause of fatigue in CFS is changes in brain and neuroendocrine function and that these can be reversed by these therapies. General physical rehabilitation services may be useful for patients with chronic severe disability.

Other treatments

Many other treatments have been proposed, but none has been adequately evaluated. Many unproved and often unscientific therapies are offered, some at considerable expense to the patient, hence patients should be cautioned about the potential risks of pursuing unproven treatments unless they are part of a clinical trial.


The prognosis for functional recovery is relatively good for patients seen in general practice. It is poorer for those severe enough to be referred to hospital clinics. A long history, multiple symptoms, and entrenched belief that the illness is irreversible predict a particularly poor prognosis. Rehabilitative treatments can improve the patient’s ability to function. There is no mortality associated with CFS other than suicide, which may reflect unrecognized depressive illness and the physical consequences of severe and prolonged disability.

Other issues

CFS can be associated with severe chronic disability and occupational impairment, with severe economic implications for patient, employer, and insurer. The ambiguous status of CFS as an accepted disease makes disputes in these areas especially difficult to resolve.

Areas of controversy

Almost all aspects of chronic fatigue syndrome are controversial. Most controversy has centred on whether it is most appropriately regarded as a medical or a psychiatric syndrome. This debate should be seen in the context of the stigma associated with psychiatric illness but often prevents patients receiving potentially effective treatment.

Likely future developments

Although there is likely to be increased acceptance of CFS as a ‘real’ illness, it is also likely that aetiologically subgroups will be identified. The most likely area for increased understanding will come from studies of altered brain function. It is possible that pharmacological agents with antifatigue action will be identified, but it is more likely that there will be increasing evidence for and provision of rehabilitative behavioural treatments.

Further reading

Campling F, Sharpe M (2008). Chronic fatigue syndrome (CFS/ME): the facts 2nd edition. Oxford University Press, Oxford.Find this resource:

    Chambers D, et al. (2006). Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. J R Soc Med, 99, 506–20.Find this resource:

    Fukuda K, et al. (1994). The chronic fatigue syndrome: a comprehensive approach to its definition and management. International Chronic Fatigue Syndrome Study Group. Ann Intern Med, 121, 953–9.Find this resource:

    Henningsen P, Zipfel S, Herzog W (2007). Management of functional somatic syndromes. Lancet, 369, 946–55.Find this resource:

    Prins JB, van der Meer JW, Bleijenberg G (2006). Chronic fatigue syndrome. Lancet, 367, 346–55.Find this resource:

    National Institute for Health and Clinical Excellence. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy); diagnosis and management. Clinical guidelines CG53.

    Reeves WC, et al. (2003). Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res, 3, 25.Find this resource:

    Wessely S, Nimnuan C, Sharpe M (1999). Functional somatic syndromes: one or many? Lancet, 354, 936–9.Find this resource:

    Wessely S, Sharpe M, Hotopf M (1998). Chronic fatigue and its syndromes. Oxford University Press, Oxford.Find this resource: