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Chronic Fatigue Syndrome
Anthony Valdini, MD, MS, FACP, FAAFP
image BASICS
  • A condition characterized by profound mental and physical exhaustion, with at least 6 months presence of multiple systemic and neuropsychiatric symptoms, and at least four of eight associated conditions are required per CDC definition:
    • Impaired memory
    • Sore throat
    • Tender lymph nodes
    • Persistent muscle or joint pain
    • New headaches
    • Nonrefreshing sleep
    • Postexertional malaise >24 hours
  • Must have a new or definite onset (not lifelong)
  • Fatigue is not relieved by rest and results in >50% reduction in previous activities (occupational, educational, social, and personal). Other potential medical causes must be ruled out (1).
  • Exclusions: See “History.”
  • Predominant age: 20 to 50 years
  • Predominant sex: male < female
  • All socioeconomic groups
  • Associations between ethnicity and incidence have been reported. Higher rates found in ethnic minorities (Native Americans and African Americans) compared with white populations based on population studies. Service-based studies (tertiary care) have reported higher rates among whites or no association between incidence and ethnicity (2).
Estimates vary widely and depend on case definition and population studied, but a reasonable estimate using a strict case definition is 100 cases per 100,000 population. Community-based studies have reported prevalence rates of 0.23 and 0.42%.
  • Unknown and likely multifactorial
    • Possible interaction between genetic predisposition, environmental factors, an initiating stressor, and perpetuating factors
  • A recent theory attributes possible neuroendocrine immunologic and biochemical effects in CFS to dysbiosis of the gut microbiome.
  • Physiologic or environmental stressor could be precipitant.
  • Many patients with chronic fatigue recall significant stressors (e.g., major medical procedure, loss of a loved one, loss of employment) in months before symptoms began.
  • Systems hypothesized to contribute to altered physiology include the following:
    • Neuroendocrine (e.g., diminished cortisol response to increased corticotropin concentrations)
    • Immune (e.g., increased C-reactive protein and &bgr;-2 microglobulin)
    • Neuromuscular (e.g., dysfunction of oxidative metabolism)
    • Autonomic (Orthostatic hypotension is reported in a proportion of chronic fatigue syndrome [CFS] sufferers.)
    • Serotonergic (e.g., hyperserotonergic mechanisms or upregulation of serotonin receptors)
Higher concordance among monozygotic twins compared with dizygotic twins
Possible predisposing factors include the following: (3)
  • Personality characteristics (neuroticism and introversion)
  • Lifestyle
    • Childhood inactivity or overactivity
    • Inactivity in adulthood after infectious mononucleosis
    • Familial predisposition
    • Comorbid mood disorders of depression and anxiety
  • Long-standing medical conditions in childhood
  • Childhood trauma (emotional, physical, sexual abuse) (4)
  • Prolonged idiopathic chronic fatigue
  • Postinfectious fatigue and CFS have followed: mononucleosis, Ross River virus, Coxiella burnetii, herpes zoster, Q fever, and Guardia lamblia
  • Because of concern for a possible “as yet undiscovered” infectious etiology, CFS patients were excluded from donating blood by the American Red Cross in 2010.
Common comorbidities include the following:
  • Fibromyalgia (more common in women)
  • Irritable bowel syndrome
  • Gynecologic conditions (pelvic pain, endometriosis) and GYN surgeries (hysterectomy, oophorectomy) (5)
  • Anxiety disorders
  • Major depression
  • Posttraumatic stress disorder (including physical and/or past sexual abuse)
  • Domestic violence
  • Attention deficit hyperactivity disorder (ADHD)
  • Postural orthostatic tachycardia syndrome (POTS)
  • Sleep disorders, including OSA
  • Reduced left ventricular size and mass
  • Discrete onset
  • Profound mental and physical exhaustion
  • At least 6 months presence of multiple systemic and neuropsychiatric symptoms
  • Significantly interferes with daily activities/work
  • At least four of eight associated conditions per CDC definition:
    • Impaired memory, sore throat, tender lymph nodes, persistent muscle or joint pain, new headaches, nonrefreshing sleep, postexertional malaise
  • Exclusion criteria
    • <2 years after recovery of substance/alcohol abuse
    • Any past or current dx of anorexia nervosa or bulimia, dementia, schizophrenia, or bipolar disease
    • BMI ≥40
    • Malignancy
    • Previously diagnosed medical condition, unresolved clinically (e.g., hepatitis B or C)
Complete physical exam to rule out other medical causes for symptoms. Note: Tender adenopathy is one of the defining criteria.
  • Idiopathic chronic fatigue (i.e., fatigue of unknown cause for >6 months without meeting criteria for CFS)
  • Psychiatric disorders
    • Major depression
    • Somatization disorder
  • Physiologic fatigue (inadequate or disrupted sleep, menopause)
  • Pregnancy until 3 months postpartum
  • Insomnia: primary (no clear etiology) versus secondary (e.g., due to anxiety, depression, environmental factors, poor sleep hygiene)
  • Other known or defined systemic disease
  • Endocrine disorder (hypothyroidism, Addison disease, Cushing syndrome, diabetes mellitus)
  • Localized infection (e.g., occult abscess)
  • Chronic or subacute bacterial disease (e.g., endocarditis)
  • Lyme disease
  • Fungal disease (e.g., histoplasmosis, coccidioidomycosis)
  • Parasitic disease (e.g., amebiasis, giardiasis, helminth infestation)
  • HIV or related disease
  • Iatrogenic (e.g., medication side effects)
  • Toxic agent exposure
  • Obesity
  • Malignancy
  • Autoimmune disease
  • Chronic inflammatory disease (sarcoidosis, Wegener granulomatosis)
  • Neuromuscular disease (multiple sclerosis, myasthenia gravis)
No single diagnostic test available and finding an abnormal result is not always the same as discovering the cause of fatigue. Be prepared to renew the search for the cause if the problem is treated and the patient remains fatigued.
Initial Tests (lab, imaging)
  • Standard laboratory tests are recommended to rule out other causes for symptoms:
    • Chemistry panel
    • CBC
    • Urinalysis
    • Thyroid-stimulating hormone (TSH)
    • ESR or C-reactive protein
    • Liver function
    • Screen for drugs of abuse
    • Age/gender-appropriate cancer screening
  • Additional studies, if clinical findings are suggestive or patient at risk:
    • Antinuclear antibodies and rheumatoid factor (if elevated ESR)
    • Creatine kinase
    • Tuberculin skin test
    • Serum cortisol
    • HIV
    • Venereal Disease Research Laboratory or rapid plasma reagin
    • Lyme serology
    • IgA tissue transglutaminase
  • No applicable imaging tests available; however, EEG and/or MRI may be useful if patient has CNS symptoms; polysomnography, if patient is sleepy (4).
Follow-Up Tests & Special Considerations
  • Assess for comorbid psychiatric disorders.
  • Assess for personality and psychosocial factors and maladaptive coping styles.
  • P.197

  • In patients with sleep disturbance, polysomnography may reveal a treatable comorbid disease.
Focus on changes in lifestyle and insight, with a goal to avoid complicating treatments (e.g., addicting medications, invasive testing) or interventions that support secondary gain.
  • Individual CBT: Challenge fatigue-related cognition; plan social and occupational rehabilitation.
  • Graded exercise therapy (GET): Track amount of exercise patient can do without exacerbating symptoms and gradually increase intensity and duration. Both involve a careful balance between activity and rest (7)[A]. Fear of movement and avoidance of physical activity are common in CFS.
  • Patients learn how to gradually increase activity in a way that will not exacerbate their illness. Vigorous exercise can trigger relapse, perhaps related to immune dysregulation.
  • Improves functional capacity and diminishes sense of fatigue
  • GET is more effective with educational interventions using telephone reminders.
  • Duration of illness does not predict treatment outcome; aggressive combined care is indicated for all.
  • No established pharmacologic treatment recommendations
  • Studies have been conducted with antivirals, antidepressants, immunoglobulins, hydrocortisone, and modafinil. None has shown clear benefit.
  • Agomelatine, an antidepressant with agonist activity at melatonin receptors, is promising in early studies (8)[C].
  • If insomnia is present, use of nonaddicting sleep aids (hydroxyzine, trazodone, doxepin, etc.) may improve outcomes.
  • Psychiatrist to assist in managing comorbid disorders if needed
  • Rehabilitative medicine
  • Insufficient to recommend any complementary and alternative medicine option for all (9)
  • Social support groups have not proven to be effective.
  • Gradual increase in physical exercise with scheduled rest periods
  • Avoid extended periods of rest.
Patient Monitoring
Although no consensus exists, periodic reevaluation is appropriate for support, relief of symptoms, and assessment for other possible causes of symptoms.
  • No diet has been shown to be effective for treatment of CFS.
  • Whether weight loss improves symptoms in obese CFS patients has yet to be tested.
  • Patient education is an important part of treatment of CFS, such as education on the benefits of cognitive therapies, lifestyle changes, and pharmacologic therapy directed at specific-associated symptoms.
  • Chronic Fatigue and Immune Dysfunction Syndrome Association of America: http://solvecfs.org/
  • CDC, Chronic Fatigue Syndrome: http://www.cdc.gov/cfs/
  • Fluctuating course is common.
  • Generally, improvement is slow, with a course of months to years.
  • An estimated 5% fully recover.
  • Patients with poor social adjustment, a strong belief in an organic etiology, financial secondary gain, or age >50 years are less likely to improve (10).
1. Baker R, Shaw EJ. Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): summary of NICE guidance. BMJ. 2007;335(7617):446-448.
2. Dinos S, Khoshaba B, Ashby D, et al. A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping. Int J Epidemiol. 2009;38(6):1554-1570.
3. Lievesley K, Rimes KA, Chalder T. A review of the predisposing, precipitating and perpetuating factors in chronic fatigue syndrome in children and adolescents. Clin Psychol Rev. 2014;34(3): 233-248.
4. Duffy FH, McAnulty GB, McCreary MC, et al. EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients—a case control study. BMC Neurol. 2011;11:82.
5. Boneva RS, Maloney EM, Lin JM, et al. Gynecological history in chronic fatigue syndrome: a population-based case-control study. J Womens Health (Larchmt). 2011;20(1):21-28.
6. 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;377(9768):823-836.
7. Nijs J, Paul L, Wallman K. Chronic fatigue syndrome: an approach combining self-management with graded exercise to avoid exacerbations. J Rehabil Med. 2008;40(4):241-247.
8. Pardini M, Cordano C, Benassi F, et al. Agomelatine but not melatonin improves fatigue perception: a longitudinal proof-of-concept study. Eur Neuropsychopharmacol. 2014;24(6):939-944.
9. Adams D, Wu T, Yang X, et al. Traditional Chinese medicinal herbs for the treatment of idiopathic chronic fatigue and chronic fatigue syndrome. Cochrane Database Syst Rev. 2009;(4):CD006348.
10. Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005;55(1):20-31.
Additional Reading
  • Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011;270(4):327-328.
  • Centers for Disease Control and Prevention. Diagnosis and management of chronic fatigue syndrome, CDC course for clinicians. http://www.cdc.gov/cfs/education/diagnosis/course.html.
  • Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21(2):69-72.
  • Social Security Administration. Providing medical evidence to the social security administration for individuals with chronic fatigue syndrome fact sheet. https://www.socialsecurity.gov/disability/professionals/cfs-pub063.htm.
  • The IOM convened an expert panel at the request of several US government agencies. In the report submitted to HHS, they suggest changing name from CFS to “Systemic Exertion Intolerance Disease,” and redefining diagnostic criteria. http://www.ncbi.nlm.nih.gov/pubmed/25695122.
See Also
Algorithm: Fatigue
R53.82 Chronic fatigue, unspecified
Clinical Pearls
  • CFS and depression can be comorbid. However, to differentiate between the two, sore throat, tender lymph nodes, and postexercise fatigue are much more characteristic of CFS.
  • No universal pharmacologic agents (e.g., antidepressants, immune modulators) have been shown to be consistently effective.
  • ˜70% of patients show improvement with CBT, compared to 55% with GET; in many cases, these two treatments can be undertaken in combination.
  • There are many more patients with idiopathic chronic fatigue than true CFS. To diagnose CFS, CDC criteria need to be met; standardized instruments (SF-36, symptom index and Multidimensional Fatigue Inventory [MFI]) have been shown to be of use in the empirical diagnosis of CFS and may be helpful for following patients' progress.