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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

  • 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)

  • Fatigue is often attributable to

    • Overexertion

    • Poor physical conditioning

    • Sleep disturbance

    • Obesity

    • Undernutrition

    • Emotional problems

  • One study found that atopy (especially numerous atopic syndromes) is associated with chronic fatigue syndrome

  • The lifetime prevalence of significant fatigue (present for at least 2 weeks) is about 25%

  • Neuropsychological and neuroendocrine studies reveal abnormalities in most patients but no consistent patterns

Clinical Findings

Symptoms and Signs

  • Screen for psychiatric disorders

  • Evaluation and classification of unexplained chronic fatigue involves

    • History and physical examination

    • Mental status examination (abnormalities require appropriate psychiatric, psychological, or neurologic examination)

    • Screening laboratory tests (see below)

  • Fatigue is classified as chronic fatigue syndrome if criteria for severity of fatigue are met and four or more of the following symptoms are concurrently present for 6 months or longer

    • Impaired memory or concentration

    • Sore throat

    • Tender cervical or axillary lymph nodes

    • Muscle pain

    • Multijoint pain

    • New headaches

    • Unrefreshing sleep

    • Postexertion malaise

  • Fatigue is classified as idiopathic chronic fatigue if criteria for fatigue severity or the above symptoms are not met

Differential Diagnosis

  • Hypothyroidism

  • Anemia

  • Depression

  • Obstructive sleep apnea or insufficient sleep

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

  • Diabetes mellitus

  • Heart failure

  • Chronic obstructive pulmonary disease

  • Chronic kidney disease

  • Parkinson disease

  • Cerebrovascular accident

  • Cancer

  • Alcohol use disorder

  • Hypercalcemia

  • Drugs, eg, sedatives, β-blockers

  • Somatoform disorder (somatization)

  • Fibromyalgia

  • Mononucleosis

  • Autoimmune disease

  • Multiple sclerosis


Laboratory Tests

  • Obtain

    • Complete blood count

    • Erythrocyte sedimentation rate

    • Serum electrolytes

    • Serum glucose

    • Blood urea nitrogen

    • Serum creatinine

    • Serum calcium

    • Liver biochemical and thyroid function tests

    • Antinuclear antibody

    • Urinalysis

    • Tuberculin skin test

  • Consider, as indicated

    • Serum cortisol

    • Rheumatoid factor

    • Immunoglobulin levels

    • Lyme serology in endemic areas

    • HIV antibody test


  • A recent longitudinal MRI study of patients with chronic fatigue syndrome showed no abnormal patterns in rate and extent of

    • Brain atrophy

    • Ventricle volume

    • White matter lesions

    • Cerebral blood flow

    • Aqueductal cerebrospinal fluid flow



  • Treat affective or anxiety disorder only if present

  • Treat postural hypotension with fludrocortisone, 0.1 mg orally daily, and increased dietary sodium

  • Psychostimulants, such as methylphenidate, have shown inconsistent results in treatment of cancer-related fatigue

Therapeutic Procedures

  • Resistance training and aerobic exercise lessens fatigue in a number of chronic conditions, including


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