Chronic fatigue syndrome

Chronic fatigue syndrome (CFS), also known as “myalgic encephalomyelitis,” is a multisystem disease characterized by severe fatigue, cognitive dysfunction, unrefreshing sleep, orthostatic intolerance, and post-exertional malaise. The etiology of CFS is not completely understood but possible factors include genetic predisposition, prior infections, and immune abnormalities to the immune system. Diagnosis is based on clinical examination (i.e., IOM diagnostic criteria for CFS) and exclusion of other causes (e.g., glucose measurement to rule out diabetes mellitus). Since there is no curative treatment, management focuses on alleviating symptoms (e.g., improving quality of sleep). In most cases, symptoms improve with treatment but complete resolution of symptoms is rare.

• Reported prevalence: 0.2–0.4% population ^[1][2]
• Sex: ♀ > ♂ ^[1]

Epidemiological data refers to the US, unless otherwise specified.

The etiology of CFS is not completely understood. Factors possibly involved include the following:

• Genetic predisposition: The prevalence of certain gene polymorphisms (SNPs) in individuals with CFS suggest a genetic component. ^[3][4]
• Prior infections: EBV, HHV-6, parvovirus B19, SARS-CoV-2 ^[5][6][7][8]
• Immune abnormalities
  • ↓ Function of NK cells ^[9]
  • Presence of autoantibodies directed at the nervous system (e.g., autoantibodies against nuclear/membrane structures, autoantibodies against neurotransmitter receptors) ^[10][11][12]
  • ↑ Activated CD8⁺ T cells levels ^[13]
  • ↑ Cytokine levels ^[14]

• Most common symptoms:
  • Unexplained fatigue that is not relieved by rest
  • Post-exertional malaise (e.g., muscle/joint pain, headache)
  • Unrefreshing sleep (i.e., daytime hypersomnolence and nighttime insomnia)
  • Cognitive impairment (e.g., impaired short term memory, decreased attention span)
  • Orthostatic intolerance (e.g., dizziness, nausea, vomiting)
  • Psychiatric symptoms (e.g., anxiety, depression)
• Symptoms are typically exacerbated by excessive physical activity or stress (e.g., infection).
• Physical examination is typically normal.

2015 IOM diagnostic criteria for CFS ^[2]

• Presence of all three of the following symptoms:
  • New-onset (not life-long) and often profound fatigue that
    • Is not alleviated by rest.
    • Is not the result of excessive exertion.
    • Substantially impairs academic, professional, leisure, or social function for > 6 months
  • Post-exertional malaise
  • Unrefreshing sleep
• Presence of at least one of the following two symptoms:
  • Cognitive impairment
  • Orthostatic intolerance
• Diagnosis should be reassessed if symptoms are not moderate to severe at least 50% of the time.

Rule out other causes

See also “Differential diagnoses” below.

• CBC with differential count (to rule out, e.g., anemia or leukemia)
• Glucose, electrolytes (to rule out, e.g., diabetes mellitus)
• Renal function tests (to rule out e.g., adrenal abnormalities), liver function tests (to rule out e.g., hepatitis C)
• TSH (to rule out hypothyroidism or hyperthyroidism)
• Creatine kinase (to rule out e.g., idiopathic inflammatory myopathies)
• Sleep study (to rule out e.g., obstructive sleep apnea)

• General: chronic fatigue (fatigue without post-exertional malaise, unrefreshing sleep, and cognitive impairment)
• Rheumatological disorders
  • Fibromyalgia
  • Polymyalgia rheumatica
  • Polymyositis
  • Systemic lupus erythematosus
  • Rheumatoid arthritis
  • Sjogren syndrome
• Endocrine disorders
  • Diabetes mellitus
  • Adrenal abnormalities (e.g., Addison disease, adrenal insufficiency, Cushing disease),
  • Thyroid abnormalities (i.e., hypothyroidism and hyperthyroidism)
• Neurological disorders
  • Multiple sclerosis
  • Dementia, pseudodementia
  • Vitamin B₁₂ deficiency
  • Myasthenia gravis, Ehlers-Danlos syndrome
• Respiratory disorders
  • Obstructive sleep apnea
  • Chronic obstructive pulmonary disease
  • Sarcoidosis
• Gastrointestinal disorders
  • Inflammatory bowel disease
  • Celiac disease
• Hematological disorders: anemia
• Oncological disorders: malignancies
• Infectious disorders
  • HIV/AIDS
  • Chronic hepatitis B or C
  • Tuberculosis
• Psychiatric disorders
  • Major depressive disorder, bipolar disorder
  • Eating disorder
  • Schizophrenia
  • Somatoform disorders
  • Substance abuse
• Other: orthostatic hypotension

The differential diagnoses listed here are not exhaustive.

Since there is no curative treatment, management focuses on alleviating symptoms.

• Improve sleep hygiene for better quality of sleep. ^[15]
• NSAIDs if pain is present
• Low-dose tricyclic antidepressants (e.g., amitriptyline) ^[16]
  • If nocturnal awakenings persist despite improved sleep hygiene
  • Can also be used for pain management
• Fludrocortisone or atenolol for dizziness
• Individualized exercise ^[17]

In most patients, symptoms improve with treatment but complete resolution of symptoms is rare (∼ 2% of cases). ^[18]