Chronic Fatigue Syndrome (Myalgic Encephalomyelitis) 

Updated: Sep 07, 2020
Author: Jefferson R Roberts, MD; Chief Editor: Michael Stuart Bronze, MD 

Overview

Practice Essentials

Chronic fatigue syndrome (CFS) (also called myalgic encephalomyelitis [ME]), 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 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).[1, 2]  Infections have been suspected; however, no causal role has been established.[3]

Patients with CFS present to the emergency department with a complex list of symptoms, including orthostatic intolerance, fatigue, postexertional malaise (PEM), and diarrhea.[4]

CFS affects 836,000 to 2.5 million Americans.[5]  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.[6]  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.[5]

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 considered inaccurate by some experts because there is a lack of encephalomyelitis in laboratory and imaging studies, and myalgia is not a core symptom of the disease.[5]

The National Academy of Medicine (formerly The Institute of Medicine) proposed that the condition be called systemic exertion intolerance disease (SEID) to better reflect the condition's hallmark defining symptom, postexertional malaise.[7]

​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

According to the National Academy of Medicine, diagnosis of CFS (ME) requires the presence of the following 3 symptoms for more than 6 months, and the intensity of the symptoms should be moderate or severe for at least 50% of the time[5] :

  • Fatigue: A noticeable decrease or impairment in the ability of a patient to engage in activities that they enjoyed before the onset of the illness, with this impairment continuing for more than 6 months and associated with new-onset severe fatigue, unrelated to exertion, and not relieved by rest.
  • Post-exertional malaise (PEM): Patients experience worsening symptoms and function after exposure to physical or cognitive stressors that were previously well tolerated.
  • Unrefreshing sleep: Patients feel that tired after a night's sleep.

Criterion fulfillment for diagnosis requires all 3 of the symptoms above, along with one of the symptoms below[5, 8] :

  • Cognitive impairment - Problems with the thought or executive function, worsened by exertion, effort, or stress or time pressure.
  • Orthostatic intolerance - Worsening of symptoms upon assuming and maintaining an upright posture. Symptoms are improved,, although not necessarily eliminated, by lying back down or elevating the feet.

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.[9, 10, 11, 12, 13, 14, 15, 16]  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.[1]  Other studies have observed alterations in the functioning of natural killer (NK) cells and a decreased response of T cells to certain specific antigens.[8, 3, 17]

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

Testing

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 may include the following:

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

According to a systematic review by  by Shan et al, consistent observation of sluggish functional MRI (fMRI) signal response suggests abnormal neurovascular coupling in CFS.[18]  Almutairi et al, in another systematic review, found that fMRI studies demonstrated both increases and decreases in activation patterns in patients with CFS but noted that this may have been related to task demand. They also noted that fMRI signal cannot differentiate between neural excitation and inhibition or function-specific neural processing.[19]

Treatment

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.[20, 21]  However, the surveillance report from the National Institute for Health and Care Excellence (NICE) recommends against CBT.[22]  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.[23]

Exercise is not a cure for CFS. A 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.[24]

The PACE trial found that graded exercise therapy (GET) effectively improved measures of fatigue and physical functioning.[20]  However, updates from the NICE guideline surveillance report recommend against GET.[20, 21, 22, 23]

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.[25]  Longer duration of illness, severe fatigue, comorbid depression, and anxiety are factors associated with a poorer prognosis.[26]  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.[27]  Despite the considerable burden of morbidity associated with CFS, there is no evidence of an increased risk of mortality.

 

Presentation

History

Patients with chronic fatigue syndrome (myalgic encephalomyelitis) 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 National Academy of Medicine notes 5 main symptoms of CFS[5] :

  • 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

 

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.[28] 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).[29] 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