Chronic Fatigue Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care



  • A condition characterized by profound mental and physical exhaustion, with at least 6 months presence of multiple systemic and neuropsychiatric symptoms. At least 4 of 8 associated conditions are required per Centers for Disease Control and Prevention (CDC) definition:
    • Impaired memory
    • Sore throat
    • Tender lymph nodes
    • Persistent muscle or joint pain
    • New headaches
    • Unrefreshing sleep
    • Postexertion malaise
  • Must have a new or definite onset (not lifelong). Fatigue is not relieved by rest and results in >50% reduction in previous activities (occupational, educational, social, and personal). Other potential medical causes must be ruled out.


  • Predominant age: 20–50 years
  • Predominant sex: Male < Female
  • All socioeconomic groups
  • Because of cultural differences in presentation, doctors in less developed countries may not recognize the syndrome, making an accurate prevalence difficult to determine (1).
  • Various associations between ethnicity and incidence have been reported. Higher rates found in ethnic minorities (Native Americans, Latinos, and African Americans) compared to white populations, based on population studies. Service-based studies (tertiary care) have reported higher rates among whites, or no association between incidence and ethnicity (2).


Available studies have focused on prevalence of the disorder.


Estimates vary widely and depend upon case definition and population studied, but a reasonable estimate using a strict case definition is 100 cases per 100,000 population. Community-based studies have reported prevalence rates of 0.23% and 0.42%.

Risk Factors

Possible predisposing factors include (3,4):

  • Personality characteristics (neuroticism and introversion)
  • Lifestyle:
    • Childhood inactivity or overactivity
    • Inactivity in adulthood after infectious mononucleosis
    • Familial predisposition
    • Comorbid mood disorders of depression and anxiety
  • Long-standing medical conditions in childhood
  • Childhood trauma (emotional, physical, sexual abuse)


  • Higher concordance has been reported among monozygotic twins compared with dizygotic twins.
  • Gender may be a significant predictor


  • Unknown and likely multifactorial:
    • Possible interaction between genetic predisposition, environmental factors, an initiating stressor, and perpetuating factors
  • Physiologic or environmental stressor could be precipitant.
  • Many patients with chronic fatigue recall significant stressors (e.g., major medical procedure, loss of a loved one, loss of employment) in months before symptoms began.
  • Systems hypothesized to contribute to physiology include:
    • Neuroendocrine (e.g., diminished cortisol response to increased corticotropin concentrations)
    • Immune (e.g., increased C-reactive protein and beta-2 microglobulin) (5)
    • Neuromuscular (e.g., dysfunction of oxidative metabolism) (5)
  • Serotonergic (e.g., hyperserotonergic mechanisms or upregulation of serotonin receptors).

Commonly Associated Conditions

  • Common comorbidities include:
    • Fibromyalgia
    • Irritable bowel syndrome
    • Temporomandibular joint disorder
    • Anxiety disorders
    • Major depression
    • Post-traumatic stress disorder (including physical and/or sexual past abuse)
    • Domestic violence
  • Exclusions:
    • Patients are excluded from chronic fatigue syndrome (CFS) definition until 2 years after resolution of substance/alcohol abuse and 5 years after resolution of anorexia nervosa or bulimia.

Major depressive disorder, Posttraumatic stress disorder, HIV, familial predisposition, physical exhaustion, tender lymph nodes, neuroticism, mood disorders, neuropsychiatric symptoms,



See “Description” for CFS historical features.

Physical Exam

Complete physical examination to rule out other medical causes for symptoms. Note: Tender adenopathy is one of the defining criteria.

Diagnostic Tests & Interpretation

No single diagnostic test available


Standard laboratory tests are recommended to rule out other causes for symptoms (6):

  • Chemistry panel
  • Complete blood count (CBC)
  • Urinalysis
  • Thyroid-stimulating hormone (TSH)
  • Erythrocyte sedimentation rate (ESR) or C-reactive protein
  • Liver function
  • Screen for drugs of abuse
  • Age-/gender-appropriate cancer screening
  • Additional studies, if clinical findings are suggestive (6):
    • Antinuclear antibodies (if +ESR)
    • Rheumatoid factor (if +ESR)
    • Creatine kinase
    • Tuberculin skin test
    • Serum cortisol
    • Human immunodeficiency virus (HIV)
    • Lyme serology
    • Gluten sensitivity (IgA tissue transglutaminase)

Follow-Up & Special Considerations

  • Assessment for comorbid psychiatric disorders.
  • Assessment for personality and psychosocial factors and maladaptive coping styles.
  • In patients with sleep disturbance, polysomnography may reveal a treatable comorbid disease.


No applicable imaging tests available

Differential Diagnosis

  • Insomnia: Primary (no clear etiology) vs. secondary (due to anxiety, depression, environmental factors, poor sleep hygiene, etc.)
  • Idiopathic chronic fatigue (i.e., fatigue of unknown cause for >6 months without meeting criteria for CFS)
  • Morbid obesity, body mass index (BMI) >40
  • Malignancy
  • Autoimmune disease
  • Localized infection (e.g., occult abscess)
  • Chronic or subacute bacterial disease (e.g., endocarditis)
  • Lyme disease
  • Fungal disease (e.g., histoplasmosis, coccidioidomycosis)
  • Parasitic disease (e.g., amebiasis, giardiasis, helminth infestation)
  • HIV-related disease
  • Psychiatric disorders:
    • Major depression
    • Somatization disorder
  • Chronic inflammatory disease (sarcoidosis, Wegener granulomatosis)
  • Known chronic viral disease (HIV)
  • Neuromuscular disease (multiple sclerosis, myasthenia gravis)
  • Endocrine disorder (hypothyroidism, Addison disease, Cushing’s syndrome, diabetes mellitus)
  • Iatrogenic (e.g., medication side effects)
  • Toxic agent exposure
  • Other known or defined systemic disease (chronic pulmonary, cardiac, hepatic, renal, or hematologic disease)
  • Pregnancy until 3 months post-partum
  • Physiologic fatigue (inadequate or disrupted sleep, menopause)
  • Weakness and sleepiness can indicate a different etiology.



  • No established pharmacologic treatment recommendations
  • Studies have been conducted with antidepressants, immunoglobulins, hydrocortisone, and modafinil. None have shown clear benefit (6).
  • If insomnia present, use of non-addicting sleep aids (hydroxyzine, trazodone, doxepin, etc.) may improve outcomes.

Additional Treatment

General Measures

  • Two treatments have been shown effective, often used in combination (7,8,9):
    • Individual cognitive behavioral therapy (CBT): Challenge fatigue-related cognition. Plan social and occupational rehabilitation.
    • Graded exercise therapy (GET): Track amount of exercise patient can do without exacerbating symptoms and gradually increase the intensity and duration. Both involve a carefully planned balance between activity and rest.
  • Patients learn how to gradually increase activity in a way that will not exacerbate their illness. Vigorous exercise can trigger relapse, perhaps related to immune dysregulation; therefore, activity plan must be carefully monitored (8).
  • Improves functional capacity and diminishes sense of fatigue (9).
  • GET is more effective when delivered with educational interventions, explaining symptoms, and encouragement with telephone reminders (9).
  • The duration of illness does not predict treatment outcome, so this approach can be applied to patients with chronic symptoms.

Issues for Referral

  • Psychiatrist to assess for comorbid disorders if screening indicates need
  • Rehabilitative medicine

Complementary and Alternative Medicine

Support's development and hosting
  • Although complementary and alternative medicines have been suggested, data are insufficient to recommend their use.
  • Social support groups have not proven to be effective.

Ongoing Care

Follow-Up Recommendations

  • Gradual increase in physical exercise with scheduled rest periods.
  • Avoid extended periods of rest.

Patient Monitoring

Although no consensus exists, periodic re-evaluation is appropriate for support, relief of symptoms, and assessment for other possible causes of symptoms.


  • No diet has been shown to be effective for treatment of CFS.
  • A BMI of 40 has been associated with fatigue in general. Whether weight loss improves symptoms in such patients has yet to be tested.

Patient Education

  • Patient education is an important part of treatment of CFS, such as education on the benefits of cognitive therapies, lifestyle changes, and pharmacologic therapy directed at specific associated symptoms.
  • Chronic Fatigue and Immune Dysfunction Syndrome Association of America:
  • CDC Chronic Fatigue Syndrome:


  • Fluctuating course
  • Generally, improvement is slow, with a course of months to years.
  • An estimated 5% fully recover.


  • Depression
  • Unemployment. Although studies document improvement with treatment, fewer than 1/3 of patients in trials return to work (10).
  • Polypharmacy


1. Cho HJ, Menezes PR, Hotopf M et al. Comparative epidemiology of chronic fatigue syndrome in Brazilian and British primary care: prevalence and recognition. Br J Psychiatry. 2009;194:117–22.

2. Dinos S, Khoshaba B, Ashby D et al. A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping. Int J Epidemiol. 2009;38:1554–70.

3. Viner R, Hotopf M. Childhood predictors of self reported chronic fatigue syndrome/myalgic encephalomyelitis in adults: national birth cohort study. BMJ. 2004;329:941.

4. Heim C, Wagner D, Maloney E, et al. Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. Arch Gen Psychiatry. 2006;63:1258–66.

5. Fulle S, Pietrangelo T, Mancinelli R et al. Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis. J Muscle Res Cell Motil. 2007;28:355–62.

6. Baker R, Shaw EJ. Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): summary of NICE guidance. BMJ. 2007;335:446–8.

7. Margo KL, Margo GM. Two therapies lift mood in chronic fatigue syndrome. Current Psychiatry. 2006;5:91–100.

8. Nijs J, Paul L, Wallman K. Chronic fatigue syndrome: an approach combining self-management with graded exercise to avoid exacerbations. J Rehabil Med. 2008;40:241–7.

9. Price JR, Mitchell E, Tidy E, et al. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database Syst Rev. 2008:CD001027.

10. Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med-Oxford.2005;55:20–31.

Additional Reading

Adams D, Wu T, Yang X et al. Traditional Chinese medicinal herbs for the treatment of idiopathic chronic fatigue and chronic fatigue syndrome. Cochrane Database Syst Rev. 2009;CD006348.

12. Baker R, Shaw EJ et al. Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): summary of NICE guidance. BMJ. 2007;335:446–8.

13. Prins JB, van der Meer JW, Bleijenberg G et al. Chronic fatigue syndrome. Lancet. 2006;367:346–55.

14. Rimes KA, Chalder T et al. Treatments for chronic fatigue syndrome. Occup Med (Lond). 2005;55:32–9.

See Also (Topic, Algorithm, Electronic Media Element)

Algorithm: Fatigue



780.71 Chronic fatigue syndrome


52702003 Chronic fatigue syndrome (disorder)

Clinical Pearls

  • CFS and depression can be comorbid. However, to differentiate between the two, sore throat, tender lymph nodes, and post-exercise fatigue are much more characteristic of CFS.
  • Although a number randomized controlled trials on various pharmacologic agents (e.g., antidepressants, immune modulators) have been conducted, no single agent has been shown to be consistently effective.
  • About 70% of patients show improvement with cognitive behavioral therapy, compared to 55% with graded exercise therapy; in many cases, these two treatments can be undertaken in combination.
  • There are many more patients with idiopathic chronic fatigue than true CFS. To diagnose CFS, CDC criteria need to be met; standardized instruments (SF-36, Symptom Index) have been shown to be of use in the empirical diagnosis of CFS.

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