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For further information, see CMDT Part 2-10: Fatigue & Chronic Fatigue Syndrome

Key Features

Essentials of Diagnosis

  • Inquire about

    • Weight loss

    • Fever

    • Sleep-disordered breathing

    • Medications; substance use

General Considerations


  • As an isolated symptom, accounts for 1–3% of visits to generalists

  • Lifetime prevalence is about 25%

  • Fatigue or lassitude and the closely related complaints of weakness, tiredness, and lethargy are often attributed to

    • Overexertion

    • Poor physical conditioning

    • Sleep disturbance

    • Obesity

    • Undernutrition

    • Emotional problems

  • Fatigue of unknown cause or related to psychiatric illness exceeds that due to physical illness, injury, alcohol, or medications

Chronic fatigue syndrome

  • Diagnosis lacks a gold standard

  • Compared with persons who do not have chronic fatigue, persons with chronic fatigue syndrome

    • Report a greater frequency of childhood trauma and psychopathology

    • Demonstrate higher levels of emotional instability and self-reported stress

  • Neuropsychological and neuroendocrine studies reveal abnormalities in most patients but no consistent pattern; for example, one study found neuroinflammation in the brain of patients with chronic fatigue syndrome that correlated with severity of neuropsychological symptoms

  • Older patients demonstrate a greater disease impact than younger patients

Clinical Findings

Symptoms and Signs


  • Clinically relevant fatigue is composed of three major components

    • Generalized weakness (difficulty in initiating activities)

    • Easy fatigability (difficulty in completing activities)

    • Mental fatigue (difficulty with concentration and memory)

  • Important diseases that can cause fatigue include

    • Hyperthyroidism and hypothyroidism

    • Heart failure

    • Infections (endocarditis, hepatitis)

    • Chronic obstructive pulmonary disease

    • Sleep apnea

    • Anemia

    • Autoimmune disorders

    • Multiple sclerosis

    • Irritable bowel syndrome

    • Parkinson disease

    • Cerebrovascular accident

    • Cancer

  • Other causes

    • Alcohol use disorder

    • Vitamin C deficiency (scurvy)

    • Side effects from medications (eg, sedatives and beta-blockers)

    • Psychological conditions (eg, insomnia, depression, anxiety, panic attacks, dysthmia, and somatic symptom disorder)

  • Mononucleosis and sinusitis are common outpatient infectious causes

  • Although frequently associated with Lyme disease, severe fatigue as a long-term sequela is rare

Chronic fatigue syndrome

  • Also called systemic exertion intolerance disease (SEID)

  • Diagnosis of SEID requires the presence of all three of the following:

    • Substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue that is

      • Often profound

      • New or definite onset (not lifelong)

      • Not the result of ongoing excessive exertion

      • Not substantially alleviated by rest

    • Postexertional malaise

    • Unrefreshing sleep

  • In addition, the patient must have at least one of the following:

    • Cognitive impairment

    • Orthostatic intolerance (lightheadedness, dizziness, and headache that worsen with upright posture and improve with recumbency)

Differential Diagnosis

  • Depression

  • Insufficient sleep

  • Infection, eg, tuberculosis, hepatitis, endocarditis, HIV, Lyme disease

  • Diabetes mellitus

  • Heart failure

  • Chronic obstructive pulmonary disease

  • Chronic kidney disease


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