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Clinical descriptions of chronic fatigue syndrome

The clinical descriptions of chronic fatigue syndrome (CFS) vary. Different agencies and scientific bodies have produced different guidelines to define the condition, with some overlap of symptoms between descriptions. Aspects of the condition are controversial, with disagreements over etiology, pathophysiology, treatment and naming between medical practitioners, researchers, patients and advocacy groups. Subgroup analysis suggests that, depending on the applied definition, the CFS population may represent a variety of conditions rather than a single disease entity.



CDC 1994 criteriaEdit

The most widely used diagnostic criteria for CFS[1] are the 1994 research guidelines proposed by the "International Chronic Fatigue Syndrome Study Group", led by the Centers for Disease Control and Prevention.[2][3] These criteria are sometimes called the "Fukuda definition" after the first author (Keiji Fukuda) of the publication. The 1994 CDC criteria specify the following conditions must be met:

Primary symptoms

Clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is:

  • of new or definite onset (has not been lifelong);
  • is not the result of ongoing exertion;
  • is not substantially alleviated by rest; and
  • results in substantial reduction in previous levels of occupational, educational, social, or personal activities.
Additional requirements

The concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue:

  1. self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities;
  2. sore throat;
  3. tender cervical or axillary lymph nodes;
  4. muscle pain;
  5. multi-joint pain without joint swelling or redness;
  6. headaches of a new type, pattern, or severity;
  7. unrefreshing sleep;
  8. post-exertional malaise lasting more than 24 hours.
Final requirement

All other known causes of chronic fatigue must have been ruled out, specifically clinical depression, side effects of medication, eating disorders and substance abuse.

The clinical evaluation should include:

  1. A thorough history that covers medical and psychosocial circumstances at the onset of fatigue; depression or other psychiatric disorders; episodes of medically unexplained symptoms; alcohol or other substance abuse; and current use of prescription and over-the-counter medications and food supplements;
  2. A mental status examination to identify abnormalities in mood, intellectual function, memory, and personality. Particular attention should be directed toward current symptoms of depression or anxiety, self-destructive thoughts, and observable signs such as psychomotor retardation. Evidence of a psychiatric or neurologic disorder requires that an appropriate psychiatric, psychological, or neurologic evaluation be done;
  3. A thorough physical examination;
  4. A minimum battery of laboratory screening tests, including complete blood count with leukocyte differential; erythrocyte sedimentation rate; serum levels of alanine aminotransferase, total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose, blood urea nitrogen, electrolytes, and creatinine; determination of thyroid-stimulating hormone; and urinalysis.

Other diagnostic tests have no recognized value unless indicated on an individual basis to confirm or exclude a differential diagnosis, such as multiple sclerosis.

CDC 1988 criteriaEdit

The initial chronic fatigue syndrome definition was published in 1988. It is also called the "Holmes definition", after the manuscript's first author.[4] Unlike the 1994 CDC criteria, the Holmes criteria exclude patients with psychiatric diagnoses and require the presence of eight secondary symptoms, not just four.

Oxford 1991 criteriaEdit

The Oxford criteria was published in 1991[5] and include both CFS of unknown etiology and a subtype of CFS called post-infectious fatigue syndrome (PIFS), which "either follows an infection or is associated with a current infection." Important differences are that the presence of mental fatigue is necessary to fulfill the criteria and symptoms are accepted that may suggest a psychiatric disorder.[1]

Canadian 2003 criteriaEdit

A clinical case definition for ME/CFS was initiated by Health Canada and published by an international group of researchers in 2003.[6] Diagnosis requires "two or more neurological/cognitive manifestations" and one or more symptoms from at least two of the categories of autonomic, neuroendocrine and immune manifestations, in addition to multiple major criteria of fatigue, post exertional malaise and/or fatigue, chronic pain and sleep dysfunction. The definition is also referred to as the Canadian consensus criteria.[7]

An important difference is that the Canadian definition excludes patients with symptoms of mental illness.[1] It was updated in 2010 to provide greater specification to the original. Functional impairment must be below defined thresholds in two of the three designated subscales of the Short Form 36 Health Survey i.e. Vitality, Social Functioning, and Role-Physical. Criterion symptoms which predate fatigue onset can now be counted towards diagnosis, and individuals "who do not meet the fatigue criterion may still obtain a Clinical ME/CFS diagnosis if they meet the other five criteria".[8]

London criteriaEdit

The London criteria were designed for research purposes and used by AFME in all the studies funded by them until the mid 90s. An incomplete version edited by Nick Anderson (CEO of AFME) was published in a 1994 report. These revised criteria require exercise-induced fatigue; memory and concentration impairment, normally accompanied by other neurological or psychological symptoms; and variability of symptoms, often brought on by mental or physical activity.[9] In light of the advances in understanding of ME and CFS, the criteria for ME as described by Ramsay and others were updated in 2009.[10][unreliable source] These have been cited in articles and are currently being evaluated, for example, in studies to ascertain differences between patients selected using different case definitions.[11]

2011 'international consensus criteria' for MEEdit

Developed by a group of 26 individuals from 13 countries and consisting of clinicians, researchers, teaching faculty and an independent patient advocate. Based on the 2003 "Canadian" definition by Carruthers et al., chronic fatigue is no longer required and the six-month waiting period before diagnosis has been dropped. The main symptom is "post-exertional neuroimmune exhaustion" (PENE) i.e. low stamina, rapid fatigability, symptom exacerbation, and variable onset with prolonged recovery; which is also accompanied by symptoms from neurological, immune/gastro-intestinal/genitourinary, and energy metabolism/transport impairment categories, and at least a 50% reduction in activity which is described as "mild".[12]

National guidelinesEdit

National guidelines, based upon some or all of the above diagnostic criteria, have been produced by several national bodies, for example in Australia in 2002[13] and in the United Kingdom in 2007.

The National Institute for Health and Clinical Excellence (NICE) in England and Wales published a multidisciplinary clinical practice guideline in 2007 in which the following criteria are employed:[14]

  • fatigue that is new, persistent and/or recurrent, not explained by other conditions and has resulted in a substantial reduction in activity level characterised by post-exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days) and
  • one or more of the following list of symptoms: difficulty with sleeping, muscle and/or joint pain at multiple sites without evidence of inflammation, headaches, painful lymph nodes that are not pathologically enlarged, sore throat, cognitive dysfunction, worsening of symptoms by physical or mental exertion, general malaise, dizziness and/or nausea and palpitations with no identifiable heart problem.

The diagnosis should be reconsidered if none of the following symptoms remain: post-exertional fatigue or malaise, cognitive difficulties, sleep disturbance, chronic pain.[14]

The guideline requires fatigue to have been present for 4 months in an adult or 3 months in a child. It expects a diagnosis in a child to be made by a pediatrician. The guideline states that a referral to a CFS/ME specialist should be offered immediately to the severely ill.[14]


There is no generally accepted diagnostic test to reliably diagnose or exclude chronic fatigue syndrome.

The 1994 CDC criteria states diagnostic tests should be directed to confirm or exclude other causes for fatigue and other symptoms. Further tests may be individually necessary to identify underlying or contributing conditions that require treatment. The use of tests for diagnosing chronic fatigue syndrome should only be done in the context of protocol-based research. The following routine tests are recommended:[3]

The 2007 NICE guideline includes, in addition to panel recommended by the CDC, tests for C-reactive protein (a marker of inflammation), creatine kinase (a muscle-related enzyme), plasma viscosity (optional if ESR done) and serology for celiac disease. Ferritin determination may be performed in children and young people, and in adults only if other tests suggest iron deficiency. The guideline recommends clinical judgment in decisions to perform other tests in addition to the standard set. Testing for infections (e.g. Lyme disease, viral hepatitis, HIV, mononucleosis, toxoplasmosis or cytomegalovirus) is only recommended if the patient gives a specific history for this. The NICE guideline discourages routine performance of the head-up tilt test, auditory brainstem response and electrodermal conductivity for the purpose of diagnosis.[14]

Diagnostic complications and suggested improvementsEdit

The National Institute for Health and Clinical Excellence (NICE) in England and Wales states that none of the existing case definitions are based on robust evidence, and no studies have confirmed any case definition to be superior to others.[15]

Some researchers say that subtypes of CFS may exist.[16][17]

Research with 200 patients with ME/CFS, as defined by the 2003 Canadian Consensus Criteria, which requires the hallmark symptom of postexertional malaise, was published December 22, 2016 in the Journal of Clinical Investigation, reporting a possible mechanism: "Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome".[18][19]

CDC 1994Edit

A 2003 international CFS study group for the CDC found ambiguities in the CDC 1994 CFS research case definition which contribute to inconsistent case identification.[20] Different self-reported causes of CFS are associated with significant differences in clinical measures and outcomes.[21]

An examination of the CDC 1994 criteria applied to several hundred patients found that the diagnosis could be strengthened by adding two new symptoms (anorexia and nausea) and eliminating three others (muscle weakness, joint pain, sleep disturbance).[22] Other suggested improvements to the diagnostic criteria include the use of severity ratings.[23]

CDC Empirical definition 2005Edit

A new "empirical definition" of the CDC 1994 criteria was published in 2005.[24] A 2009 evaluation of the 2005 empirical definition compared 27 patients with a prior diagnosis of CFS with 37 patients diagnosed with a Major Depressive Disorder. The researchers reported that "38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the new CDC definition."[25]

HHS/IOM New Criteria Study 2015Edit

On 15 August the US Department of Health and Human Services issued a notice of intent to award a contract to the Institutes of Medicine (now the National Academy of Medicine) for a Study on Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome with the purpose of : "recommending clinical diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)".[26] The award of contract was halted due concern over "potential sole source requisition" although subsequently joint funding was agreed between The Office on Women’s Health and the HHS.[27][28] The IOM commenced work on the project in the Autumn of 2013 with its first public hearing listed for 27 January 2014.[29]

The completed report recommends a name change to Systemic Exertion Intolerance Disease (SEID), a new diagnostic criteria, and some testing. It was published with a lengthy literature review, and various materials, all of which are available at the National Academies of Science website.[30]


  1. ^ a b c Wyller VB (2007). "The chronic fatigue syndrome--an update". Acta Neurologica Scandinavica. Supplementum. 187: 7–14. doi:10.1111/j.1600-0404.2007.00840.x. PMID 17419822.
  2. ^ "About CFS: What is Chronic Fatigue Syndrome?". National Institutes of Health. Archived from the original on 16 February 2013. Retrieved 27 June 2009.
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  13. ^ Australian Guidelines (2002)
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  18. ^
  19. ^ Fluge, Øystein; Mella, Olav; Bruland, Ove; Risa, Kristin; Dyrstad, Sissel E.; Alme, Kine; Rekeland, Ingrid G.; Sapkota, Dipak; Røsland, Gro V.; Fosså, Alexander; Ktoridou-Valen, Irini; Lunde, Sigrid; Sørland, Kari; Lien, Katarina; Herder, Ingrid; Thürmer, Hanne; Gotaas, Merete E.; Baranowska, Katarzyna A.; Bohnen, Louis M.L.J.; Schäfer, Christoph; McCann, Adrian; Sommerfelt, Kristian; Helgeland, Lars; Ueland, Per M.; Dahl, Olav; Tronstad, Karl J. (2016). "Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome". Jci Insight. 1 (21): e89376. doi:10.1172/jci.insight.89376. PMC 5161229. PMID 28018972.
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  24. ^ Reeves, William; Dieter Wagner; Rosane Nisenbaum; James Jones; Brian Gurbaxani; Laura Solomon; Dimitris Papanicolaou; Elizabeth Unger; Suzanne Vernon; Christine Heim (2005). "Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study". BMC Medicine. 3: 19. doi:10.1186/1741-7015-3-19. ISSN 1741-7015. PMC 1334212. PMID 16356178.
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  30. ^ "2015 ME/CFS SEID report". National Academies. 2015.