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chronic fatigue syndrome; myalgic encephalomyelitis; neurasthenia; systemic exertion intolerance disease (CFS)

A controversial illness that shares symptoms with major depression, fibromyalgia & somatoform disorders. Also known as: nervous exhaustion, Icelandic disease, atypical poliomyelitis, chronic mononucleosis. Etiology: 1) unknown 2) suspected or hypothesized etiologies a) infection - Epstein-Barr virus (EBV) infection - enterovirus - retrovirus - human retrovirus XMRV is found in 67-87% of patients with chronic fatigue syndrome versus 3-4% of healthy controls [4,5] - retrovirus XMRV findings disputed [6] - other agents b) trauma c) immune dysfunction - cellular - decreased number of natural killer (NK) cells - NK cell dysfunction - reduced lymphocyte proliferation - increased production of gamma interferon - increase or decrease in CD8 cells - humoral - autoantibodies - partial hypogammaglobulinemia - decreased IgG subclasses - polyclonal activation of B cells - circulating immune complexes - other immunologic factors - allergies - cytokine abnormalities d) neurochemical disturbances e) comorbidities common (also see differential diagnosis) [18] - sleep disorders - irritable bowel syndrome - fibromyalgia - depression - anxiety Epidemiology: 1) > 80% female 2) average age is late 30's 3) > 95% are white Pathology: - mild hypocortisolism caused by central underproduction of corticotropin-releasing factor (CRF) [3] Genetics: - overexpression of WASF3 disrupts mitochondrial respiration & may mediate exercise intolerance in chronic fatigue syndrome [23] Clinical manifestations: 1) major criteria a) persistent or relapsing fatigue - onset may be abrupt or gradual [18] - abrupt onset, within hours or days - gradual onset may occur over months of years [18] - frequently follows viral-like syndrome or trauma - reduces daily activity by > 50% - persists for more than 6 months b) exclusion of other chronic conditions - malignancy - autoimmune disease - chronic psychiatric disorders - may have non-psychiatric depression, somatization, anxiety disorder &/or panic disorder - chronic inflammatory disease & rheumatic disease - may have fibromyalgia, check for trigger points - chronic infectious state - exclude inadequately treated Lyme disease - adverse pharmaceutical effects & substance abuse - endocrinopathy - severe obesity 2) minor criteria a) signs - low-grade fever - non-exudative pharyngitis - palpable or tender cervical or axillary lymph nodes b) symptoms - generalized muscle weakness - chills - sore throat - myalgias - post-exertional malaise & prolonged fatigue after physical activity which had been well tolerated in the past - migratory arthritis without erythema or swelling - neuropsychological complaints - sleep disturbances, unrefreshing sleep - generalized headache - acute (hours) or subacute (days) development of symptoms 3) other (also see diagnostic criteria) - atopy (allergies) is common - orthostatic intolerance, cognitive impairment, & pain are common [18] - substantial impairment in both physical & mental function occur at some point [18] - fever, lymphadenopathy & muscle atrophy are not features Diagnostic criteria: - diagnosis requires both 2 major criteria plus 8 minor criteria. - impaired day-to-day function accompanied by fatigur - malaise following physical, cognitive, or emotional exertion - unrefreshing sleep - plus either orthostatic intolerance or cognitive impairment - symptoms must be present for 6 months - at least half the time, symptom intensity must be moderate to severe [10,22] Laboratory: 1) no specific laboratory tests to confirm chronic fatigue syndrome - avoid unnecessary testing [1] 2) exclusion testing a) recommended [1] (no evidence base provided) - complete blood count with differential - thyroid function tests - serum glucose b) other as indicated by history & physical - serum electrolytes - urinalysis - erythrocyte sedimentation rate (ESR) - antinuclear antibody (ANA) - rheumatoid factor - 24 hour urinary free cortisol may confirm mild hypocortisolism [3] - cosyntropin stimulation test - serum immunoglobulin levels - HIV1 testing - serology for Lyme disease 3) Epstein-Barr virus titers of little utility 4) non-specific findings a) atypical lymphocytes b) relative lymphocytosis c) mild elevation of liver function tests Special laboratory: as indicated by history & physical 1) skin-testing may be positive for many seasonal & environmental antigens 2) PPD 3) sleep study 4) electrical impedance assay - passed through mononuclear white blood cells (incubated in plasma) before & after osmotic stress [20] - impedance rises precipitously following osmotic stress in patients with chronic fatigue syndrome Differential diagnosis: 1) depression 2) anxiety 3) fibromyalgia 4) somatoform disorder 5) chronic viral disease - chronic viral hepatitis 6) malignancy 7) rhinitis 8) endocrine disorders a) hypothyroidism b) Addison's disease c) Cushing's disease d) diabetes mellitus 9) chronic inflammatory state a) sarcoidosis b) multiple sclerosis 10) rheumatologic diseases a) Sjogren's syndrome b) polymyalgia rheumatica c) polymyositis 11) chronic psychiatric disease a) major depression b) bipolar disorder c) schizophrenia 12) sleep disorder Complications: - depression - increased risk for suicide (0.1%)* [12] * lower than that for affective disorders, personality disorders, or alcoholism [12] Management: 1) individually tailored program required [1] a) no therapy is beneficial for all patients b) no FDA-approved medications c) regular follow-up to monitor symptoms 2) cognitive behavioral therapy of benefit [1,9] - internet-based cognitive-behavioral therapy effective in treating teenagers [7] - benefit modest & weak [17] 3) graded exercise program of benefit [1,9] - benefit modest & weak [17] 4) sleep hygiene [1] 5) treatment of underlying atopy (allergies) if present 6) mental health evaluation (rule out other diagnoses) 7) antidepressants may be of some benefit - benefit tends to occur at low doses - no pharmaceutical agent FDA-approved for treatment of chronic fatigue syndrome [1] 8) of no benefit - anakinra of no benefit in reducing fatigue in women with chronic fatigue syndrome [16] - rituximab of no benefit [12] 9) experimental therapy a) acyclovir (Zovirax) b) immunoglobulin c) magnesium sulfate d) Ampligen (low benefit to risk ratio) e) essential fatty acid f) 5 hydroxytryptophan 10) patient education a) support groups b) progressive exercise program c) nutritional guidance d) emphasis on control of symptoms rather than cure

Related

depression fibromyalgia syndrome (fibromyositis, fibrositis) somatoform (psychosomatic) disorder; somatic symptom & related disorders (SSRD)

General

syndrome chronic mental disorder

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015. 2018, 2021.
  2. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996
  3. Journal Watch 21(10):83, 2001 Cleare AJ et al Urinary free cortisol in chronic fatigue syndrome. Am J Psychiatry 158:641, 2001 PMID: 11282703
  4. Lombardi VC et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009 Oct 8; http://dx.doi.org/10.1126/science.1179052 PMID: 19815723
  5. Lo S-C et al. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. Proc Natl Acad Sci U S A 2010 Aug 23 PMID: 20798047 http://dx.doi.org/10.1073/pnas.1006901107
  6. Journal Watch: June 1, 2011 Science Has Doubts About Its 2009 Study Linking Retrovirus with Chronic Fatigue - Knox K et al No Evidence of Murine-Like Gammaretroviruses in CFS Patients Previously Identified as XMRV-Infected http://www.sciencemag.org/content/early/2011/05/31/science.1204963.full.pdf - Paprotka T et al Recombinant Origin of the Retrovirus XMRV http://www.sciencemag.org/content/early/2011/05/31/science.1205292.full.pdf - Alberts B Editorial Expression of Concern http://www.sciencemag.org/content/early/2011/05/31/science.1208542.full.pdf
  7. Nijhof SL et al Effectiveness of internet-based cognitive behavioural treatment for adolescents with chronic fatigue syndrome (FITNET): a randomised controlled trial The Lancet, Early Online Publication, 1 March 2012 PMID: 22385683 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2812%2960025-7/fulltext - Bleijenberg G and Knoop H Chronic fatigue syndrome: where to PACE from here? The Lancet, Early Online Publication, 1 March 2012 PMID: 21334060 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960172-4/fulltext
  8. Holgate ST, Komaroff AL, Mangan D, Wessely S. Chronic fatigue syndrome: understanding a complex illness. Nat Rev Neurosci. 2011 Jul 27;12(9):539-44. doi: 10.1038/nrn3087. PMID: 21792218
  9. Reid S, Chalder T, Cleare A, Hotopf M, Wessely S. Chronic fatigue syndrome. Clin Evid (Online). 2011 May 26;2011 PMID: 21615974
  10. Institute of Medicine. Feb. 2015 Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Redefining an Illness. http://www.iom.edu/~/media/Files/Report%20Files/2015/MECFS/MECFS_ReportBrief.pdf - Ganiats TG Redefining the Chronic Fatigue Syndrome. Ann Intern Med. Published online 10 February 2015 PMID: 25668185 http://annals.org/article.aspx?articleid=2118972
  11. Komaroff AL Chronic Fatigue Syndrome: Biology, Diagnosis, and Management. Physician's First Watch, June 16, 2015 David G. Fairchild, MD, MPH, Editor-in-Chief Massachusetts Medical Society http://www.jwatch.org - Haney E et al Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162(12):834-840. PMID: 26075754 http://annals.org/article.aspx?articleid=2322800 - Smith ME, Haney E, McDonagh M et al Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015 Jun 16;162(12):841-50. doi: 10.7326/M15-0114. PMID: 26075755 - Komaroff AL Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Real Illness. Ann Intern Med. 2015;162(12):871-872. PMID: 26075760 http://annals.org/article.aspx?articleid=2322808 - Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011 Jul;31(3):325-37 PMID: 21964849
  12. Roberts E et al. Mortality of people with chronic fatigue syndrome: A retrospective cohort study in England and Wales from the South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLaM BRC) Clinical Record Interactive Search (CRIS) Register. Lancet 2016 Feb 9 PMID: 26873808 Free Article
  13. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015 Feb. The National Academies Collection: Reports funded by National Institutes of Health. PMID: 25695122 Free Books & Documents, Free full text
  14. White PD, Goldsmith KA, Johnson AL et al Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. PMID: 21334061 Free PMC Article
  15. Yancey JR, Thomas SM. Chronic fatigue syndrome: diagnosis and treatment. Am Fam Physician. 2012 Oct 15;86(8):741-6. Review. PMID: 23062157 Free Article
  16. Roerink ME, Bredie SJ, Heijnen M et al Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial. Ann Intern Med. March 7, 2017. PMID: 28265678 http://annals.org/aim/article/2607809/cytokine-inhibition-patients-chronic-fatigue-syndrome-randomized-trial
  17. Wilshire CE, Kindlon T, Courtney R et al. Rethinking the treatment of chronic fatigue syndrome - A reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychol. 2018 Mar 22;6(1):6 PMID: 29562932 Free PMC Article https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-018-0218-3
  18. Tucker ME. CDC Launches New ME/CFS Guidance for Clinicians. Medscape Medical News. WebMD Inc. July 13, 2018 https://www.medscape.com/viewarticle/899316 - Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Centers for Disease Control and Prevention. Information for Healthcare Providers. Atlanta. July 12, 2018. https://www.cdc.gov/me-cfs/healthcare-providers/index.html
  19. Fluge O, Rekeland IG, Lien K et al. B-lymphocyte depletion in patients with myalgic encephalomyelitis/ chronic fatigue syndrome: A randomized, double-blind, placebo- controlled trial. Ann Intern Med 2019 Apr 2; PMID: 30934066 https://annals.org/aim/article-abstract/2729816/myalgic-encephalomyelitis-chronic-fatigue-syndrome-trial-fails-confirm-earlier-observations - Rowe PC. Myalgic encephalomyelitis/chronic fatigue syndrome: Trial fails to confirm earlier observations of rituximab's effectiveness. Ann Intern Med 2019 Apr 2 PMID: 30934063 https://annals.org/aim/article-abstract/2729816/myalgic-encephalomyelitis-chronic-fatigue-syndrome-trial-fails-confirm-earlier-observations
  20. Esfandyarpour R, Kashi A, Nemat-Gorgani M, Wilhelmy J, Davis RW. A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Proc Natl Acad Sci U S A 2019 May 21; 116:10250. PMID: 31036648 https://www.pnas.org/content/116/21/10250
  21. Komaroff AL. Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome. JAMA. Published online July 5, 2019. PMID: 31276153 https://jamanetwork.com/journals/jama/fullarticle/2737854
  22. Syrek R Trending Clinical Topic: Chronic Fatigue Syndrome Medscape September 3, 2021 https://reference.medscape.com/viewarticle/957514
  23. Wang Pt, Ma J, Kim YC et al WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U.S.A. 2023. 120(34):e2302738120 August 14. https://www.pnas.org/doi/10.1073/pnas.2302738120
  24. Chronic Fatigue Syndrome National Institute for Health and Clinical Excellence http://guidance.nice.org.uk/CG53/guidance/pdf/English - Centers for Disease Control and Prevention Chronic Fatigue Syndrome (CFS) http://www.cdc.gov/cfs/general/index.html