Chronic Fatigue Syndrome (CFS) 

Updated: Aug 29, 2018
Author: Jefferson R Roberts, MD; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Chronic fatigue syndrome (CFS) is a disorder characterized by unexplained profound fatigue that is worsened by exertion. The fatigue is accompanied by cognitive dysfunction and impairment of daily functioning that persists for more than 6 months.

CFS was originally termed myalgic encephalomyelitis (ME) because British clinicians noted a skeletal muscle component manifesting as chronic fatigue and an encephalitic component manifesting as cognitive difficulties. However, this term is inappropriate because of a lack of encephalomyelitis in laboratory and imaging studies, and myalgia is not a core symptom of the disease.[1]

In 2015, the Institute of Medicine (IOM) proposed that the condition be renamed systemic exertion intolerance disease (SEID) to better reflect the condition's hallmark defining symptom, postexertional malaise.[2]

​The cause of CFS is unknown, and there are no direct tests to diagnose CFS. If the source of the fatigue can be explained, the patient probably does not have CFS. The diagnosis is one of exclusion that meets the clinical criteria below.

Diagnostic criteria

A diagnosis of CFS requires the following three symptoms:[1]

  • A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest
  • Postexertional malaise
  • Unrefreshing sleep

At least one of the following must also be present:

  • Cognitive impairment
  • Orthostatic intolerance

Pathophysiology

CFS is a biological illness, not a psychologic disorder. The exact pathogenesis is unknown. Numerous mechanisms and molecules have been implicated that lead to abnormalities in immune dysfunction, hormonal regulation, metabolism and response to oxidative stress to include impaired natural killer cell function and/or T-cell function, elevated cytokines, and autoantibodies (rheumatic factor, antithyroid antibodies, antigliadin, anti–smooth muscle antibodies, and cold agglutinins).[3, 4] Infections have been suspected; however, no causal role has been established.

Etiology

Many viruses have been studied as potential causes of CFS; however, no definitive causal relation has been determined. Historically, human herpesvirus type 6, enterovirus, rubella virus, Candida albicans, bornavirus, Mycoplasma, Chlamydia pneumoniae, retroviruses, coxsackie B virus, cytomegalovirus, and xenotropic murine leukemia virus-related virus have been studied and have not been found to cause CFS.[5, 6, 7, 8, 9, 10, 11, 12] Some people infected with Epstein-Barr virus, Ross River virus, Coxiella burnetii, or Giardia have developed criteria for CFS, but not all individuals with CFS have had these infections.[3]

Environmental factors have also been suspected as a trigger for CFS; however, no specific factors have been identified.

Epidemiology

CFS affects 836,000 to 2.5 million Americans.[1] An estimated 84%-91% of individuals with the condition have not been diagnosed; therefore, the true prevalence is unknown. Overall, CFS is more common in females than in males and occurs most commonly in young to middle-aged adults.[13] The average age of onset is 33 years, although cases have been reported in patients younger than 10 years and older than 70 years. Patients with CFS experience loss of productivity and high medical costs that contribute to a total economic burden of $17-24 billion annually.[1]

Prognosis

CFS has no cure, its symptoms can persist for years, and its clinical course is punctuated by remissions and relapses. One prospective study suggests that approximately 50% of patients with CFS can return to part-time or full-time work.[14] Longer duration of illness, severe fatigue, comorbid depression, and anxiety are factors associated with a poorer prognosis.[15] Good outcomes are associated with less fatigue severity at baseline, a sense of control over symptoms, and no attribution of the illness to a physical cause.[16] Despite the considerable burden of morbidity associated with CFS, there is no evidence of an increased risk of mortality.

Patient Education

For patient education resources, see the Back, Ribs, Neck, and Head Center, as well as Chronic Fatigue Syndrome, Fibromyalgia, and Fatigue.

 

Presentation

History

Patients with CFS typically report experiencing postexertional fatigue and feeling excessively tired after relatively normal tasks that they did for years before CFS without any particular problem. Patients also report fatigue even after prolonged periods of rest or sleep. At least one quarter of patients with CFS are bed- or house-bound at some point in their illness. Patients with CFS often report a history of antecedent flulike infection that precipitated the prolonged state of fatigue and followed the initial illness.

Patients with CFS typically report problems with short-term memory but not with long-term memory. They may also report verbal dyslexia that manifests as the inability to find or say a particular word during normal speech. This typically disturbs patients with CFS and may interfere with their occupation.

The five main symptoms of CFS are summarized as follows:[1]

  • Reduction or impairment in ability to carry out normal daily activities, accompanied by profound fatigue
  • Postexertional malaise (worsening of symptoms after physical, cognitive, or emotional effort)
  • Unrefreshing sleep
  • Cognitive impairment
  • Orthostatic intolerance (symptoms that worsen when a person stands upright and improve when the person lies back down)

Physical Examination

Physical examination often reveals no abnormalities. Some patients may have positive orthostatic vital signs.

Many patients with or without CFS have small, moveable, painless lymph nodes that most commonly involve the neck, axillary region, or inguinal region. A single lymph node that is very large, tender, or immobile suggests a diagnosis other than CFS. Similarly, generalized adenopathy suggests a diagnosis other than CFS.

In the oropharynx, purple or crimson crescent discoloration of both anterior tonsillar pillars in the absence of pharyngitis is a frequent marker in patients with CFS. The cause of crimson crescents is unknown, but they are common in patients with CFS. Nonetheless, crimson crescents are not specific for CFS.

Trigger points, which suggest fibromyalgia, are absent in patients with CFS. Fibromyalgia and CFS rarely coexist in the same patient.

 

DDx

Diagnostic Considerations

CFS is a diagnosis of exclusion. The key diagnostic task is to differentiate it from other disorders that also have a fatigue component. CFS may be distinguished from other causes of fatigue based on the presence of cognitive dysfunction, which is absent in almost all other fatigue-producing disorders. Once a specific cause of fatigue has been diagnosed, CFS is excluded by definition.

It is especially important to rule out systemic disorders, particularly lymphoreticular malignancies, in patients who present with fatigue. Other diseases may be excluded based on the history, physical examination, or laboratory findings. In some cases, these other potential causes of fatigue must be reinvestigated several times.

Differential Diagnoses

 

Workup

Laboratory Studies

Laboratory findings are normal in CFS. Tests are used to assess for other underlying causes of fatigue, as follows:

  • Complete blood cell count
  • Chemistries including electrolytes, renal, and liver function tests
  • Thyroid function tests
  • C-reactive protein
  • Erythrocyte sedimentation rate
  • Creatine kinase
  • Cultures, viral titers, cerebrospinal fluid studies (upon high suspicion for infection)

Other Tests

Other tests may include the following:

  • Polysomnography
  • Electrocardiography (ECG)
  • Cardiopulmonary exercise test separated by 24 hours
  • Tilt-table testing

Imaging Studies

Brain Imaging

Computed tomography (CT) or magnetic resonance imaging (MRI) of the brain is useful for ruling out central nervous system (CNS) disorders in patients with otherwise unexplained CNS symptoms. Results of CT scanning and MRI may be normal in patients with CFS. Findings of CNS imaging studies are not specific for CFS and are thus used to rule out alternative explanations rather than to diagnose CFS.

 

Treatment

Approach Considerations

CFS has no cure. Treatment is largely supportive and focuses on symptom relief. Large randomized controlled trials such as the pacing, graded activity, and cognitive behavior therapy: a randomized evaluation (PACE) trial and Cochrane reviews have recommended cognitive behavioral therapy (CBT) as an effective method for treating CFS in adults.[17, 18] However, the surveillance report in 2017 from the National Institute for Health and Care Excellence (NICE) evidence reviews recommend against CBT.[19] The Centers for Disease Control and Prevention (CDC) and the Agency for Healthcare Research and Quality (AHRQ) both have removed CBT as a recommended treatment for CFS because of insufficient evidence.[20]

Diet

No restrictive or elimination diets have been proven to be beneficial.

Exercise Therapy

Exercise is not a cure for CFS. A 2017 Cochrane review evaluated exercise therapy for patients with CFS. The study found that patients felt less fatigued following exercise therapy and felt improved in terms of sleep, physical function, and general health. However, the authors could not conclude that exercise therapy improved the outcomes of pain, quality of life, anxiety, and/or depression.[21]

The PACE trial found that graded exercise therapy (GET) effectively improved measures of fatigue and physical functioning.[17] However, updates from the NICE guideline surveillance report in 2017 recommend against GET. The CDC and AHRQ both have removed GET as a recommended treatment.[20]

 

Medication

Medication Summary

No drugs have been FDA-approved for CFS treatment. Clinical trials have found that antiviral agents are ineffective in relieving the symptoms of CFS.[22] Various medications have been shown to be ineffective, including antibiotics, glucocorticoids, liver extract, chelating agents, intravenous (IV) vitamins, vitamin B-12, and IV or oral vitamin or mineral supplements. Antidepressants have no major role in the treatment of CFS.

A randomized placebo-controlled double-blind trial to evaluate the effect of cytokine inhibition with anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, was conducted and did not show any improvement in fatigue severity both in the short term (4 weeks) or the long term (6 months).[23] Future studies may evaluate inhibition of other cytokines such as IL-6, tumor necrosis factor, and/or interferons.

To date, no evidence-based interventions are available for the treatment of CFS.

 

Questions & Answers