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A. Scope of Problem

  1. Chronic fatigue is a very common problem in primary practice
  2. 4-5% of all office visits
  3. In top 10 presentations to office
  4. Up to 80% are due to emotional / psychiatric causes
  5. Only ~5% patients with chronic fatigue meet criteria for Chronic Fatigue Syndrome

B. Common Causes of Fatigue

  1. Psychiatric
    1. Depression
    2. Chronic Anxiety
    3. Personality Disorder - Somatization
    4. Lifelong history of bodily complaints
  2. Sleep disorders - with or without psychiatric disease
  3. Medications
    1. Benzodiazapines and other hypnotics
    2. Anti-histamines
    3. Anti-cholinergics
    4. Tricyclic antidepressants
    5. Centrally acting antihypertensives - clonidine, propranolol, methyldopa
  4. Endocrine Disorders
    1. Hypothyroidism
    2. Apathetic Hyperthyroidism - often with atrial fibrillation in the elderly
    3. Addison's Disease
    4. Panhypopituitarism
    5. Diabetes mellitus
    6. Hypercalcemia (hyperparathyroidism)
    7. Iron deficiency (without or with anemia) [3]
  5. Hematologic
    1. Anemia - usually requires hematocrit <26% for symptoms of fatigue
    2. Leukemia
    3. Lymphoma
  6. Serious Chronic Disease
    1. Chronic obstructive pulmonary disease
    2. CHF
    3. Uremia
    4. Liver Failure
  7. Chronic Infection
    1. Endocarditis
    2. Hepatitis
    3. Tuberculosis
    4. Lyme Disease
    5. HIV / AIDS
    6. Acute Mononucleosis
    7. Acute CMV infection
  8. Chronic Inflammatory Disease
    1. SLE
    2. Rheumatoid Arthritis
    3. Systemic Sclerosis
    4. Vasculitis: ANCA+ and ANCA- vasculidites
  9. Neoplasm / Cancer [17]
  10. Chronic Fatigue Syndrome Definition [2]
    1. Abrupt onset of chronic fatigue >6 months (patient without prior history of fatigue)
    2. Rule out other causes (no consistent viral associations)
    3. Fatigue causes >50% decline in daily activities
    4. Low grade fever, myalgias, lymphadenopathy, sore throat, depression, cognitive deficits, reduced sleep
    5. May be related to neurally mediated hypotension [4]

C. History and Physical

  1. Must take careful history and do very complete physical
    1. Helps rule out medical (non-psychiatric) causes
    2. Strongly encourages patients
  2. Physical Exam Comments
    1. Skin, Nodes, and joint examinations must be included
    2. Mental Status exam (recommend Mini-Mental) must be included
  3. Patient should keep a log of symptoms, including fever curve

D. Laboratory Evaluation

  1. Consider the tests below as situation suggests
  2. Standard: CBC and differential, ESR (concern if > ~50mm/hr), electrolytes, thyroid function
  3. Secondary: HIV Test, liver function tests, calcium and albumin levels
  4. Antinuclear antibody (ANA) and Rheumatoid Factor (RF) are sometimes helpful
  5. The following tests should only be ordered if clinically indicated:
    1. Titers of EBV, CMV, and Human Herpesvirus 6 (HHV-6)
    2. Toxoplasmosis
    3. Lyme Titers
  6. EBNA (Epstein-Barr Virus Nuclear Antigen) Antibodies
    1. Found in many patients
    2. Unclear significance
  7. Tilt Table Examination may be useful in evaluating for chronic fatigue syndrome [4]
  8. Ferritin levels <50µg/L associated with fatigue even in absence of anemia [3]

E. Chronic Fatigue Syndrome (CFS) [2,5]

  1. Symptoms
    1. Acute onset
    2. Post-exercise fatigue
    3. Generalized headache
    4. Neuropsychiatric: depression / anxiety
    5. Fever, sore throat, and painful lymph nodes uncommon
    6. Muscle Weakness with myalgias and/or arthralgias
    7. Difficulty sleeping
    8. Adding anorexia and nausea may improve classification
  2. Major Criteria for Diagnosis
    1. Decreased activity >50% for >6 months
    2. Difficulty Concentrating
    3. Headache
  3. Immunological Hypothesis [5,6]
    1. Many patients with CFS have activated CD8+ T lymphocytes (CD8+ numbers normal)
    2. CD8+ T cells are believed to have anti-viral cytolytic activity
    3. Chronic viral infection and immune activation may lead to cytokine release
    4. Antiviral cytokines, especially interferons, lead to symptoms found in CFS
    5. Interferon activated 2-5A Synthetases and ribonuclease L are present in most CFS
    6. A unique 37K form of 2-5A binding protein is overexpressed in ~70% of CFS
    7. Normal 2-5A binding proteins are 80K (and some 40K)
    8. The novel 37K protein is not found in normal persons, depression or fibromyalgia
    9. Association with reactivation of Epstein-Barr Virus (EBV) is controversial
    10. However, no immunological modulations have provided significant clinical benefit [17]
  4. Laboratory Findings
    1. Increased Antibodies (Abs) to a variety of viral proteins
    2. No specific viral etiology has been identified, however
    3. Total Serum immunoglobulins (Ig) and Ig Production reduced
    4. Interleukin 2 and Interferon gamma Levels reduced
    5. CD4 : CD8 Ratios elevated
    6. Serum ACE levels increased
    7. Autonomic Nervous system Dysfunction
  5. Tilt Table Examination [4,9]
    1. 25-90% of patients with chronic fatigue syndrome may have abnormal tilt table tests
    2. Nearly 30% of asymptomatic control patients will have abnormal tilt table tests
    3. This test is used to document neurally mediated hypotension (autonomic dysfunction)
    4. Parasympathetic and sympathetic autonomic dysfunction have been documented in CFS [4]
    5. Autonomic dysfunction occurred within 4 weeks of viral infection in nearly 50% [9]
    6. In randomized trial of fludrocortisone versus placebo for CFS with positive tilt table examination, no difference between groups [15]

F. Treatments

  1. Underlying medical conditions
  2. Treat Depression Aggressively
    1. Newer, less sedating agents preferred
    2. Prozac® (Fluoxetine) in younger patients (20mg po qam)
    3. Zoloft® (Sertraline) in older patients (50mg po qam)
    4. Psychiatric counseling strongly advised, with medical reassurance
  3. Restore Sleep Patterns
    1. Sedating anti-depressants (tricyclics usually preferred) may be useful
    2. Amitriptylline 25-100mg po qhs
    3. Nortriptylline 10-25mg po qhs less sedating
    4. Trazadone 50-100mg po qhs is usually most sedating with fewer side effects
    5. Non-benzodiazepine sedatives (zolpidem and others) are also effective
  4. Treatment for CFS [2,17]
    1. Graded exercise therapy and cognitive behavior therapy are most important modalities
    2. Cardiovascular deconditioning is prominant, so exercise is crucial part of therapy [9]
    3. Educating patients to encourage graded exercise program improves physical function [7]
    4. Cognitive behavior therapy for CFS is more effective than guided support [13]
    5. Pharmacologic therapy has generally been disappointing [14]
    6. Neurally mediated hypotension documented on tilt table testing may be involved [4]
    7. Treatment with ß-blocking agents and/or disopyramide may improve hypotension [4]
    8. Hydrocortisone 13mg/m2 qam and 3mg/m2 qpm provided mild improvements in symptoms and caused adrenal suppression [11]
    9. However, hydrocortisone 5-10mg qam (once daily low dose) showed significant improvements in >25% of patients without adrenal suppression [12]
    10. Fludrocortisone (Flurinef®) provided no benefit in CFS with neurally mediated hypotension [15]
    11. Combination hydrocortisone + fludrocortisone did not improve symptoms of CFS [16]
    12. Intravenous immunoglobulin (IVIg) showed no efficacy in CFS [10]
    13. Galantamine (Reminyl®), an acetylcholinesterase inhibitor, had no effect on CFS [8]

References

  1. Yennurajalingam S and Bruera E. 2007. JAMA. 297(3):295 abstract
  2. Prins JB, van der Meer JW, Bleijenberg G. 2005. 367(9507):346
  3. Verdon F, Burnand B, Fallab Stubi CL, et al. 2003. BMJ. 326:1124 abstract
  4. Goldstein DS, Robertson D, Esler M, et al. 2002. Ann Intern Med. 137(9):753 abstract
  5. Komaroff AL. 2000. Am J Med. 108(2):169 (editorial review) abstract
  6. De Meirleir K, Bisbal C, Campine I, et al. 2000. Am J Med. 108(2):99 abstract
  7. Powell P, Bentall RP, Nye FJ, Edwards RH. 2001. Brit J Med. 322:387 abstract
  8. Blacker CVR, Greenwood DT, Wesnes KA, et al. 2004. JAMA. 292(10):1195 abstract
  9. Freeman R and Komaroff AL. 1997. Am J Med. 102(4):357 abstract
  10. Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, et al. 1997. Am J Med. 103(1):38 abstract
  11. McKenzie R, O'Fallon A, Dale J, et al. 1998. JAMA. 280(12):1061 abstract
  12. Cleare AJ, Heap E, Malhi GS, et al. 1999. Lancet. 353(9151):455 abstract
  13. Prins JB, Bleijenberg G, Bazelmans E, et al. 2001. Lancet. 357(9259):841 abstract
  14. Whiting P, Bagnall AM, Sowden AJ, et al. 2001. JAMA. 286(11):1360 abstract
  15. Rowe PC, Calkins H, DeBusk K, et al. 2001. JAMA. 285(1):52 abstract
  16. Blockmans D, Persoons P, van Houdenhove B, et al. 2003. Am J Med. 114(9):736 abstract
  17. Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. 2003. Lancet. 362(9384):640 abstract