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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

  • Hyperthyroidism and hypothyroidism

  • Heart failure (HF)

  • Infection (eg, endocarditis, tuberculosis, hepatitis, Lyme disease, HIV, mononucleosis)

  • Chronic obstructive pulmonary disease (COPD)

  • Interstitial lung disease

  • End-stage kidney disease

  • Sleep apnea

  • Anemia

  • Autoimmune disease

  • Multiple sclerosis

  • Irritable bowel syndrome

  • Parkinson disease, multiple sclerosis

  • Cerebrovascular accident

  • Cancer

  • Medications (eg, β-blockers, sedatives)


Laboratory Tests

  • Obtain

    • Complete blood count

    • Erythrocyte sedimentation rate

    • Serum electrolytes

    • Serum glucose

    • Blood urea nitrogen

    • Serum creatinine

    • Serum calcium

    • Liver biochemical tests

    • 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



  • 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

    • HF

    • COPD

    • Arthritis

    • Cancer

  • Treatment of chronic fatigue syndrome involves a comprehensive multidisciplinary intervention

    • Optimal medical management of coexisting disorders, eg, depression

    • Cognitive-behavioral therapy

    • Graded exercise program

    • Therapeutic care (a complementary medicine modality that uses acupressure) reduces fatigue in some patients with breast cancer receiving chemotherapy


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