Chronic Fatigue Syndrome (Myalgic Encephalomyelitis)

Updated: Sep 06, 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

Overview

What is chronic fatigue syndrome (CFS)?

What are the diagnostic criteria for chronic fatigue syndrome (CFS)?

What is the pathophysiology of chronic fatigue syndrome (CFS)?

What causes chronic fatigue syndrome (CFS)?

What is the prevalence of chronic fatigue syndrome (CFS)?

What is the prognosis of chronic fatigue syndrome (CFS)?

Presentation

Which clinical history findings are characteristic of chronic fatigue syndrome (CFS)?

What are the signs and symptoms of chronic fatigue syndrome (CFS)?

Which physical findings are characteristic of chronic fatigue syndrome (CFS)?

DDX

How is chronic fatigue syndrome (CFS) differentiated from other fatigue-producing disorders?

What are the differential diagnoses for Chronic Fatigue Syndrome (Myalgic Encephalomyelitis)?

Medications

What is the role of medications in the treatment of chronic fatigue syndrome (CFS)?

Author

Jefferson R Roberts, MD Chief of Rheumatology Service, Tripler Army Medical Center; Assistant Clinical Professor of Medicine, Uniformed Services University of the Health Sciences

Jefferson R Roberts, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Society for Simulation in Healthcare

Disclosure: Nothing to disclose.

Coauthor(s)

Mary L Lan, MD, MPH Resident Physician, Department of Medicine, Tripler Army Medical Center

Disclosure: Nothing to disclose.

Michael W Price, MD Chief, Medical Specialty Clinic #1, Tripler Army Medical Center; Instructor in Medicine, Uniformed Services University of the Health Sciences, F Edward Herbert School of Medicine

Michael W Price, MD is a member of the following medical societies: American Society of Tropical Medicine and Hygiene, Armed Forces Infectious Diseases Society, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Bryan D Carter, PhD Professor of Child Psychology in Psychiatry and Behavioral Sciences, Chief Psychologist in Division of Child and Adolescent Psychiatry, Director of Predoctoral Internship in Clinical Child/Pediatric Psychology, Director of Postdoctoral Fellowship Program in Pediatric Psychology, Director of Pediatric Consultation-Liaison Service to Kosair Children's Hospital, University of Louisville School of Medicine

Bryan D Carter, PhD is a member of the following medical societies: American Psychological Association

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Leonard R Krilov, MD Chief of Pediatric Infectious Diseases and International Adoption, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital

Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Medimmune Grant/research funds Cliinical trials; Medimmune Honoraria Speaking and teaching; Medimmune Consulting fee Consulting

Mark R Schleiss, MD American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Julian M Stewart, MD, PhD Associate Chairman of Pediatrics, Director, Center for Hypotension, Westchester Medical Center; Professor of Pediatrics and Physiology, New York Medical College

Julian M Stewart, MD, PhD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Robert W Tolan Jr, MD Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine

Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility

Disclosure: Novartis Honoraria Speaking and teaching

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Chronic Fatigue Syndrome (Myalgic Encephalomyelitis)

Overview

Practice Essentials

Diagnostic criteria

Etiology

Testing

Treatment

Prognosis

Presentation

History

Physical Examination

DDx

Diagnostic Considerations

Differential Diagnoses

Medication

Medication Summary

Questions & Answers

Contributor Information and Disclosures

References