Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem condition characterized by severe fatigue that is not relieved by rest, postexertional malaise, and unrefreshing sleep. The cause is not completely understood, but possible factors include genetic predisposition, history of infections, and immune abnormalities. The diagnosis is based on clinical features and confirmed using diagnostic criteria. Other causes of fatigue and malaise should be excluded based on clinical evaluation and/or diagnostic testing. There is currently no curative treatment. Management is focused on alleviating symptoms (e.g., improving quality of sleep), educating patients on energy management, and providing supportive care. In most patients, symptoms improve with management, but complete resolution is rare.

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

Epidemiological data refers to the US, unless otherwise specified.

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

• Genetic predisposition: The prevalence of certain gene polymorphisms (SNPs) in individuals with ME/CFS suggests a genetic component. [3][4]
• Viral infections, e.g.: 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]

• The clinical presentation of ME/CFS is variable; the most common features include: [15]
  • New-onset, unexplained severe fatigue that is not relieved by rest
  • Myalgia and/or arthralgia
  • Headaches
  • Flu-like symptoms
  • Postexertional malaise (highly specific feature): Symptoms are triggered or exacerbated 12–48 hours after a period of physical activity or stress.
  • Sleep disturbances (e.g., unrefreshing sleep, hypersomnolence, and/or insomnia)
  • Cognitive impairment (e.g., short-term memory impairment, decreased attention span, brain fog)
  • Symptoms of orthostatic intolerance (e.g., dizziness, nausea, vomiting)
  • Sensory hypersensitivity
  • Symptoms of comorbid conditions (e.g., anxiety, depressed mood, diffuse musculoskeletal pain)
• Physical examination is typically normal. [15]

Clinical features of ME/CFS are typically exacerbated by physical activity or stress. [15]

Approach [15][16]

• Perform a detailed clinical evaluation of fatigue.
• Consider other causes of fatigue and malaise.
• There are no specific diagnostic studies to confirm ME/CFS.
• Obtain diagnostic studies for malaise and fatigue to rule out alternative causes based on clinical suspicion.
  • Initial studies include CBC, BMP, TFTs, and LFTs.
  • Advanced studies may be considered by specialists.
• Confirm the diagnosis using the diagnostic criteria for ME/CFS.
• Reassess the diagnosis if symptoms are not moderate to severe at least 50% of the time.

A thorough clinical evaluation is crucial, as other potentially treatable causes of fatigue and malaise may manifest similarly to ME/CFS. [15][16]

2015 Institute of Medicine diagnostic criteria for CFS [2][17]

• All of the following:
  • Profound fatigue
    • New onset (not lifelong)
    • Not alleviated by rest
    • Not due to excessive exertion
    • Substantially impairs academic, professional, leisure, and/or social function for > 6 months
  • Postexertional malaise
  • Unrefreshing sleep
• AND ≥ 1 of the following:
  • Cognitive impairment
  • Orthostatic intolerance (e.g., postural orthostatic tachycardia syndrome or postural hypotension)

Approx. 50% of patients with postacute COVID-19 syndrome meet the diagnostic criteria for ME/CFS. [15]

• 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.

General principles [15]

• There is currently no curative treatment.
• Therapy focuses on symptom management and supportive care to maximize quality of life.
• Educate patients on self-management strategies.
• Identify and treat comorbid conditions (e.g., fibromyalgia, mood disorders, irritable bowel syndrome).
• Consider referral to a specialist ME/CFS clinic for patients with severe or complex features. [15]

Approach to exercise should be carefully planned based on the patient's symptoms and energy limits to avoid postexertional malaise and sustained functional deterioration. [15][16]

Patient education [15][16]

• Self-management strategies (e.g., activity pacing)
  • Goal: to balance periods of activity and rest to avoid postexertional malaise and reduce the risk of deterioration
  • Patient instructions
    • Determine an individual activity baseline (i.e., physical, cognitive, emotional, and social) that minimizes symptoms.
    • Avoid exceeding the activity baseline.
    • Schedule rest periods throughout the day (e.g., before challenging activities).
    • Consider using activity diaries and/or tracking devices (e.g., mobile heart-rate monitor) to monitor activity and symptoms.
• Response to symptom deterioration: Instruct patients to decrease energy expenditure until symptoms return to baseline.
• Lifestyle changes, e.g.:
  • Sleep hygiene
  • Healthy balanced diet
  • Adequate fluid intake

Symptom deterioration is often triggered by infections and/or exertion and can occur despite good energy management.

Symptom management and supportive care [15]

Provide individualized care and consider specialist referral for patients with complex or severe features.

• Fatigue: See “Management of malaise and fatigue.”
• Sleep disorders: Consider pharmacotherapy for insomnia (e.g., melatonin, doxepin, suvorexant).
• Sensory hypersensitivity: Recommend exposure reduction (e.g., noise-canceling headphones, tinted glasses).
• Cognitive impairment
  • Perform a cognitive assessment and consider referral to neurology.
  • Refer for occupational therapy.
• Orthostatic intolerance
  • Refer for cardiovascular evaluation (e.g., tilt table test).
  • See “Nonpharmacological management of noncardiac syncope” and “Medications for noncardiac syncope” for more information.
• Pain management
  • Arthralgia or myalgia: Consider oral analgesics (e.g., acetaminophen, NSAIDs), SSRIs, or pregabalin.
  • Neuropathic pain: Consider adjuvant analgesics (e.g., pregabalin, tricyclic antidepressants).
• Dizziness or vertigo
  • Perform a clinical evaluation for vertigo and consider vestibular rehabilitation therapy.
  • See also “Persistent postural-perceptual dizziness.”

Intolerance to pharmacological treatment is common in patients with ME/CFS. [15]

• Long-term prognosis of ME/CFS is variable.
• In most patients, symptoms improve with management, but complete resolution of symptoms is rare. [16]