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Executive Summary – Aug. 23, 2016 (Update)

Diagnosis and Treatment of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome


July 2016 Update: Additional subgroup analyses found reduced strength of evidence when distinguishing studies of CBT from other counseling therapies and excluding studies using the Oxford case definition from previous pooled analysis. Further information can be found in an addendum to the full report.

Table of Contents

This systematic review was commissioned by the Office of Disease Prevention at the National Institutes of Health (NIH), sponsored by the NIH Office of Research on Women’s Health, and cosponsored by the Trans-NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Research Working Group to inform the NIH 2014 Pathways to Prevention Workshop, an evidence-based methodology workshop. The purpose of the workshop is to develop a research agenda. Accordingly, this review evaluates and summarizes research on methods for diagnosis of ME/CFS and the benefits and harms of treatments, and identifies gaps and limitations of current studies and needs for future research in these areas.


ME/CFS is a condition characterized by chronic and disabling fatigue, as well as various additional manifestations, including neurological and cognitive changes, motor impairment, pain, sleep disturbance, and altered immune and autonomic responses.1-4 Experts consider postexertional malaise and impairment of memory or concentration as critical components.5-7 Consistent with the NIH Workshop, this review uses the combined term ME/CFS to describe the condition.

The etiology of ME/CFS is not known, and there is uncertainty whether the condition reflects a single pathologically discrete syndrome, whether ME and CFS are subsets of the same illness, and whether ME/CFS is a nonspecific condition shared by other disease entities. Numerous studies have attempted to identify risk factors for developing ME/CFS, but none are definitive.

The diagnosis of ME/CFS relies on the use of clinical criteria to distinguish it from other conditions that may also present with fatigue. There are currently eight published case definitions with clinical criteria.1-3,8-12 All include persistent fatigue not attributable to a known underlying medical condition, as well as additional clinical signs and symptoms. Depending on the case definition, prevalence rates of ME/CFS in the United States range from 0.3 percent to 2.5 percent.13-15 Currently, no medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ME/CFS, but several have been used "off label." In practice, there are wide variations in the clinical management of patients, and many patients receive a multifaceted approach to treatment.

Scope of Review

This review includes studies of adults with symptoms related to ME/CFS. Outcomes from treatment trials include improved function, fatigue, quality of life, and involvement in daily activities. Included studies were conducted in clinical settings relevant to health care practices in the United States. Scientists from the NIH and Agency for Healthcare Research and Quality (AHRQ) and a panel of experts and patients worked with the systematic review investigators to consider the context and studies related to the Key Questions that guided the review. These are—

Key Question 1

What methods are available to clinicians to diagnose ME/CFS, and what conditions are required to be ruled out or excluded before assigning a diagnosis of ME/CFS?

  1. What are the accuracy and concordance of methods used to diagnose ME/CFS?
  2. How does the use of these methods vary by patient subgroups?
  3. What harms are associated with diagnosing ME/CFS?
Key Question 2
  1. What are the benefits of therapeutic interventions for patients with ME/CFS, and how do they vary by patient subgroups?
  2. What are the harms of therapeutic interventions for patients with ME/CFS, and how do they vary by patient subgroups?
  3. What are the characteristics of responders and nonresponders to interventions?


This systematic review follows established methods of AHRQ's Effective Health Care Program.16 A research librarian conducted electronic database searches identifying articles published between 1988 and September 2014. Searches were supplemented by references identified from additional sources, including suggestions from panel members and reviewers of the draft report. Criteria for including studies were developed based on relevance to the Key Questions. Two investigators independently reviewed all potential articles for eligibility, and discrepancies were resolved through discussion and consensus, with a third investigator making the final decision as needed. Only English-language articles were included.

For questions regarding diagnostic methods, studies were included that compared case definitions (e.g., Fukuda/Centers for Disease Control and Prevention [CDC], Canadian, International), and provided measures of agreement, or tested the ability of the method to identify ME/CFS patients using one of the case definitions as a reference standard. Studies of potential harms from diagnosis were also included, such as psychological harms, labeling, risk from diagnostic tests, and misdiagnosis.

For questions regarding treatment, studies were included that enrolled patients diagnosed with ME, CFS, or both by fulfilling criteria from at least one case definition. Randomized controlled trials of at least 12 weeks in duration that compared medications, complementary and alternative medicine approaches, counseling and behavior therapies, and exercise therapies with no treatment or other types of treatment were included. For completeness, additional trials of medications that were designed for shorter durations of treatment were separately summarized. Treatment outcomes included improved function, fatigue, quality of life, and involvement in daily activities. Studies of the results of laboratory tests or studies focusing on individual symptoms were not included.

Two investigators extracted data from each included study, and independently rated the quality of the methods of each study based on predefined criteria. Results of some of the treatment trials were statistically combined using meta-analysis. The overall strength of evidence was assessed for each Key Question and outcome in accordance with established methods. Experts in ME/CFS, individuals representing interest groups, and the expert and patient members of the panel were invited to review the draft report. The draft report was also posted for public comment during September and October 2014.



Thirty-six observational studies of methods to diagnose ME/CFS were included. Most studies enrolled predominantly female patients, had small sample sizes, and were conducted in the United States and Western Europe.

Key Question 1: What methods are available to clinicians to diagnose ME/CFS, and what conditions are required to be ruled out or excluded before assigning a diagnosis of ME/CFS?

Eight case definitions that include clinical criteria have been developed to identify patients with ME/CFS and are used by clinicians to distinguish ME/CFS from other conditions that also present with fatigue (Table A).1-3,8-12 Although most case definitions require that other conditions be excluded prior to assigning a diagnosis of ME/CFS, no studies compared strategies for ruling out alternative diagnoses. The Oxford (Sharpe, 1991) case definition incorporates the smallest number of symptoms (new onset of fatigue with impairment of physical and mental function), suggesting less specificity for ME/CFS.12

Table A. Case definitions
Symptoms London ME8 Canadian ME/CFS1 Revised
Canadian ME/CFS10
International ME2 CDC – CFS, Holmes9 Oxford CFS12 CDC – CFS, Fukuda3 CDC – CFS, Reeves11
CDC = Centers for Disease Control and Prevention; CFS = chronic fatigue syndrome; ME = myalgic encephalomyelitis.
General physical X X X   X X X X
X X X X X   X X
  X X X X   X X
Other system involvement       X        
Key Question 1a: What are the accuracy and concordance of methods used to diagnose ME/CFS?

Diagnostic methods were evaluated in eight descriptive studies comparing case definitions, although the accuracy of each method could not be determined because there is no established reference standard. Patients diagnosed using clinical criteria for ME or ME/CFS had more severe symptoms or impairment than those diagnosed using criteria for CFS alone. The Oxford CFS (Sharpe, 1991) and the London ME (Dowsett, 1994) case definitions were not compared in studies, leaving uncertainty as to their comparability.5,14,18-22

Three studies that compared CFS patients diagnosed using the CDC (Holmes, 1988, or Fukuda, 1994) case definitions versus patients with other diseases identified differences in reported symptoms using various self-reported symptom scales.18,23,24 These results suggest that some scales could be reasonable candidates for further evaluation as diagnostic tests (Fatigue Impact Scale, Chalder Fatigue Scale, Hospital Anxiety and Depression scale, and certain subscales or combinations of the 36-Item Short Form survey [SF-36] with the Zung Depression Scale). However, these measures have not yet been evaluated for this purpose. No studies evaluated whether diagnostic methods could adequately identify clinical subgroups of patients.

Eleven studies evaluated other types of methods to diagnose ME/CFS, but results were inconclusive. These included studies using self-reported symptom scales (the artificial neural network test, the Schedule of Fatigue and Anergia for CFS scale, subscales of the SF-36, and other scales) and various serum biomarkers.25-36 The artificial neural network test was able to differentiate ME/CFS patients from healthy controls; however, no studies evaluated this method or other methods using an adequate sample size and spectrum of patients. No studies demonstrated an accurate and reliable method for identifying patients or subgroups of patients with ME/CFS in comparison with other patients, with diagnostic uncertainty as to whether they have ME/CFS or another condition in which fatigue is a prominent symptom.

Key Question 1b: How does the use of these methods vary by patient subgroups?

Three studies described how methods for diagnosis may differ for patient subgroups.17,33,34 One study reported that older patients were more impaired, but it did not consider how symptom evaluation might vary with age. Two studies found that results of cardiopulmonary exercise tests were different for ME/CFS patients and healthy controls, and that certain subscales of the SF-36 were associated with slow recovery after exercise. No studies evaluated differences in the performance of case definitions among patients with specific sets of symptoms (autonomic/neuroendocrine, neurological/neurocognitive, immunological/infectious).

Key Question 1c: What harms are associated with diagnosing ME/CFS?

Fourteen studies evaluated harms of the diagnostic process or diagnosis of ME/CFS, including the perceived harms (or benefits) of receiving a diagnosis of ME/CFS, as well as missed/alternative diagnoses.13,37-49 Five studies found that patients with CFS feel stigmatized by their diagnosis in terms of financial stability, work opportunities, perceived judgments on their characters, social isolation, and interactions with the health care system.38,39,41-43 Two studies indicated that medical trainees and mental health practitioners make judgments about a patient’s condition based on the name it carries (ME, CFS, or other) and what treatment is being given.37,44 A substantial burden of misdiagnosis was found in the ME/CFS population.13,37,40,45,46,48


Thirty-five randomized trials of the benefits and harms of treatments for ME/CFS were included. Most had fair- or poor-quality research methods, enrolled predominantly female patients from ME/CFS specialty clinics based on the CDC (Fukuda, 1994) or Oxford (Sharpe, 1991) case definitions, had small sample sizes, and were conducted in the United States and Western Europe.

Key Question 2 a and b: What are the (a) benefits and (b) harms of therapeutic interventions for patients with ME/CFS, and how do they vary by patient subgroups?

Nine trials compared medical treatment of ME/CFS with placebo, although none of these medications have been approved by FDA for this indication.50-58 Results are summarized in Table B. Studies primarily included patients meeting CDC case definitions for ME/CFS (Fukuda, 1994, and/or Holmes, 1988), which identify less debilitated patients than those meeting ME case definitions. The immune modulator rintatolimod improved some measures of exercise performance compared with placebo in two trials (low strength of evidence), while trials of galantamine, hydrocortisone, immunoglobulin G, valganciclovir, isoprinosine, and fluoxetine were inconclusive (insufficient evidence). Additional trials with durations less than 12 weeks indicated no differences between placebo and acyclovir59 and improved scores for physical health and function with rituximab,60 although both trials enrolled 30 or fewer participants and the clinical implications of these results are not clear.

Harms of medications included suppression of adrenal glucocorticoid responsiveness, increased appetite, weight gain, and difficulty sleeping with hydrocortisone; flulike syndrome, chills, vasodilation, dyspnea, and dry skin with rintatolimod; headaches with immunoglobulin G; discontinuation of treatment with fluoxetine; and nephrotoxicity with acyclovir.

Table B. Trials of medications
Treatment Number of Trials (Participants) Results (Treatment vs. Placebo)*
*Statistically significant differences between treatment and placebo groups.
Trial less than 12 weeks in duration.
Galantamine (acetyl-cholinesterase inhibitor) 1 (423) No differences. (Insufficient evidence)
Hydrocortisone (corticosteroid) 1 (68) No differences. (Insufficient evidence)
Hydrocortisone + fludrocortisone (corticosteroid) 1 (80) No differences. (Insufficient evidence)
Immunoglobulin G (antibody) 1 (28) Better scores on social functioning scale for placebo group; no difference on physical functioning scale. (Insufficient evidence)
Rintatolimod (immune modulator) 2 (324)
  • Improved exercise duration, exercise work, and cardiopulmonary exercise tolerance. (Low strength of evidence)
  • Increased activities of daily living. (Insufficient evidence)
Valganciclovir (antiviral agent) 1 (30) Decreased fatigue scores; no differences in overall function. (Insufficient evidence)
Isoprinosine (immune modulator) 1 (15) No differences. (Insufficient evidence)
Fluoxetine (selective serotonin reuptake inhibitor) 1 (68) No differences. (Insufficient evidence)
Acyclovir (antiviral) 1 (30) No differences. (Insufficient evidence)
Rituximab (monoclonal antibody) 1 (27) Improved physical health and function scores, but not other outcomes. (Insufficient evidence)

Seven trials compared complementary and alternative medicine approaches versus usual care, placebo, or alternative therapies (Table C) in ME/CFS patients diagnosed by the Oxford (Sharpe, 1991) or CDC (Fukuda, 1994) case definitions.61-67 Therapies included dietary supplements, distant healing, homeopathy, melatonin, and phototherapy. None reported statistically significant clinical differences between treatment and control groups (insufficient evidence). Harms were not reported in the studies.

Table C. Trials of complementary and alternative medicine therapies
Treatment Number of Trials (Participants) Results (Treatment vs. Control)*
*Statistically significant differences between treatment and control groups.
Acclydine vs. placebo 1 (57) No differences. (Insufficient evidence)
Acetyl-L-carnitine vs. propionyl-L-carnitine vs. combination 1 (89)

No differences. (Insufficient evidence)

Pollen extract vs. placebo 1 (22) No differences. (Insufficient evidence)
Low sugar/low yeast diet vs. healthy eating 1 (39) No differences. (Insufficient evidence)
Distant healing vs. no treatment 1 (409) No differences. (Insufficient evidence)
Homeopathy vs. placebo 1 (89) Improved general fatigue scores, not considered clinically significant. (Insufficient evidence)
Melatonin or Phototherapy vs placebo 1 (30) No differences. (Insufficient evidence)

Fourteen trials compared counseling or behavioral therapy versus usual care, no treatment, or other types of counseling or behavioral therapy (Table D) in ME/CFS patients diagnosed primarily by the Oxford (Sharpe, 1991) or CDC (Fukuda, 1994) case definitions.68-89 Results were mixed for most outcomes, but when considering all studies comparing any type of counseling with a control, counseling improved fatigue (7 of 11 trials showed positive effect), measures of functioning (4 of 11 trials showed positive effect; 2 of 11 showed mixed results on different measures), quality of life (2 of 4 trials showed positive effect), and global improvement (2 of 2 trials showed positive effect). Treatment effectiveness may not be generalizable to all patients because no study used a case definition that selected for more disabled patients (i.e., case definition for ME). When reported, harms of counseling and behavioral therapies were less with counseling compared with usual care, support, or adaptive pacing.

Table D. Trials of counseling or behavioral therapy
Treatment Number of Trials (Participants) Results (Treatment vs. Control)*
*Statistically significant differences between treatment and control groups.
CI = confidence interval.
Counseling and behavioral therapy vs. no treatment, support, relaxation, or adaptive pacing 13 (1,648)
  • Higher function scores; weighted mean difference, 7.73 (95% CI, 3.58 to 11.87; 8 trials). (Low strength of evidence)
  • Improved fatigue in 7 trials; no differences in 4 trials. (Low strength of evidence)
  • Improved quality of life in 2 trials; no differences in 2 trials. (Low strength of evidence)
  • More hours worked per week (mean 36 vs. 24; p<0.04) in 1 trial; no differences in 1 trial. (Low strength of evidence)
  • Improvement on work and social adjustment scales in 2 trials. (Low strength of evidence)
  • Better global improvement in 2 trials. (Moderate strength of evidence)
Face-to-face vs. telephone cognitive behavioral therapy 1 (43) Better clinical global improvement with face-to-face therapy; no differences in overall function. (Insufficient evidence)

Six trials evaluated exercise therapies, including graded exercise therapy (GET), qigong, and home orthostatic training, compared with no treatment or several other types of therapies in ME/CFS patients diagnosed primarily by the Oxford (Sharpe, 1991) or CDC (Fukuda, 1994) case definitions (Table E).57,89-93 GET improved measures of fatigue, function, and clinical global impression of change compared with controls. Treatment effectiveness may not be generalizable to all patients because no study used a case definition that selected for more disabled patients (i.e., case definition for ME). Harms were not well reported, although in one trial patients receiving GET reported more adverse events compared with those receiving cognitive behavior therapy (CBT), adaptive pacing, or usual care; one trial reported more withdrawals of patients receiving GET, one trial had a high percentage of patients refusing repeat exercise testing, and several other trials reported more withdrawals of patients receiving GET, all compared with controls.

Table E. Trials of exercise therapy
Treatment Number of Trials (Participants) Results (Treatment vs. Control)*
* Statistically significant differences between treatment and control groups.
CI = confidence interval.
Graded exercise therapy vs. no treatment, flexibility/relaxation therapy, or adaptive pacing 4 (619)
  • Better overall function scores; weighted mean difference, 10.29 (95% CI, 6.71 to 13.86; 3 trials). (Moderate strength of evidence)
  • Decreased fatigue in 3 trials; no differences in 1 trial. (Low strength of evidence)
  • More working 1 year after treatment (66% vs. 39%). (Insufficient evidence)
  • Improved scores on work and social adjustment scales compared with adaptive pacing and no treatment. (Low strength of evidence)
  • Better global improvement; changes in clinical global improvement, 1.26 (95% CI, 1.26 to 1.89; 3 trials). (Moderate strength of evidence)
Qigong exercise vs. no qigong exercise 1 (52) Better physical function and fatigue scores. (Insufficient evidence)
Home orthostatic training vs. sham home orthostatic training 1 (36) No differences. (Insufficient evidence)

Four trials compared either head-to-head interventions or combinations of two interventions (Table F). GET and CBT led to similar improvement in measures of function but mixed results on other outcomes.57,73,74,76,79,89 When reported, harms of CBT were less than those with GET. GET improved fatigue and function compared with fluoxetine, which was ineffective.

Table F. Head-to-head and comparison trials
Treatment Number of Trials (Participants) Results*
* Statistically significant differences between treatment and control groups.
Cognitive behavioral therapy vs. cognitive therapy vs. anaerobic therapy 1 (114) Improved function with cognitive behavioral therapy or cognitive therapy vs. anaerobic therapy. (Insufficient evidence)
Graded exercise therapy ± fluoxetine vs. fluoxetine ± placebo 1 (136)
  • Improved functional work capacity with exercise alone or combined with fluoxetine.
  • Improved fatigue with exercise alone or combined with fluoxetine. (Insufficient evidence)
Cognitive behavioral therapy vs. graded exercise therapy 1 (314) No differences. (Insufficient evidence)
Cognitive behavioral therapy + graded exercise therapy vs. usual care 1 (115) No differences. (Insufficient evidence)
Key Question 2c: What are the characteristics of responders and nonresponders to interventions?

Four trials described characteristics of patients more likely to respond to therapies for ME/CFS. Younger patients with less impairment and less focus on their symptoms who were adherent to therapy (e.g., readings, sleep diaries, activity goals, relaxation) were more likely to improve on some measures of fatigue and/or function.68,74,87,92 Avoiding overexercising and underexercising (i.e., staying within one’s energy envelope) was also beneficial. This evidence is insufficient, however, because these results have not been duplicated and their applicability to other patients is not known.


Eight case definitions for ME/CFS exist, and several diagnostic methods have been studied. Case definitions with criteria for ME and ME/CFS that require symptoms of postexertional malaise, neurological impairment, and autonomic dysfunction identify patients with more impairment, lower functioning, and more severe symptoms than case definitions with criteria for CFS alone. However, none of the case definitions or other diagnostic methods have been adequately tested to determine how well they differentiate patients with ME/CFS from patients with other conditions. No studies evaluated how diagnostic tests vary by patient subgroups or how to rule out related conditions before making an ME/CFS diagnosis. Studies indicated that an ME/CFS diagnosis is associated with perceived stigma, financial instability, difficulty in social interactions and relationships, and a greater chance of receiving a psychiatric diagnosis. One study identified feelings of legitimacy upon receiving the diagnosis of ME/CFS.

Thirty-five trials of treatments included medication, complementary and alternative medicine approaches, counseling or behavioral therapy, and exercise therapy. Two trials of rintatolimod showed improvement in some measures of performance, while one trial showed improvement in fatigue, activities of daily living, and reduced use of other medications for relief of ME/CFS symptoms. Single trials enrolling only 30 participants reported improved measures of fatigue with valganciclovir and improved physical health and function scores with rituximab. The benefits of pollen extract, homeopathy, and L-carnitine preparations remain uncertain, because improvement was found in some but not other measures of the same outcome and between group comparisons were not evaluated. When all counseling and behavioral therapy trials were combined, measures of fatigue and global improvement were significantly improved, although results were not consistent across all trials. GET improved measures of function, global improvement, and to a lesser degree, fatigue. Although harms were not well reported across trials, GET was associated with a higher number of reported adverse events in some trials. For all other treatments, effects are uncertain because important outcomes were not measured, the study methods were inadequate, or too few participants were enrolled to provide useful estimates. Most treatments were evaluated in only a single trial and were conducted in referral settings. Participants' baseline function and severity of symptoms were not usually reported, and it is not clear how well the results of the trials apply to clinical practice.


The main limitation of this review is the lack of studies to address important questions, particularly regarding methods of diagnosis. Available studies generally enrolled small numbers of participants, and many treatment trials were too small to detect significant differences between groups. Most treatment trials did not describe their methods in sufficient detail to assess their quality. Studies used a variety of methods to measure outcomes, limiting comparisons across studies. While this review focused on outcomes that patients can experience, such as fatigue, a review of other types of outcomes such as postexertional malaise would provide additional evidence.

Future Research

  • Case definitions: Consensus about which case definition is appropriate to use as the gold standard will further advance the study of diagnostic methods for ME/CFS. In the absence of consensus, future studies aimed at clarifying the diagnosis of ME/CFS should consider reporting how well a diagnostic test compares with more than one of the case definitions. Future research should retire the use of the Oxford (Sharpe, 1991) case definition given that it is a high risk of including patients who may have an alternate fatiguing illness, or whose illness resolves spontatneously with time. A national longitudinal registry of patients with a diagnosis of ME/CFS would allow for comparison of diagnostic criteria between patients and clarification of diagnoses over time. This strategy could also identify a well-characterized population for use in both diagnostic and treatment trials.
  • Diagnosis instruments: Future studies evaluating the capability of diagnostic methods for ME/CFS should include a broad range of patients with conditions that require clinical distinction from ME/CFS, such as fibromyalgia and depression. Additionally, studies should report how well a particular method distinguishes ME/CFS from other conditions using standard performance measures, such as concordance, sensitivity, and specificity.
  • Treatment trials: Definitive treatment trials require larger numbers of participants based on appropriate power calculations for primary outcomes to determine efficacy, and more rigorous adherence to methodological standards such as blinding of outcome assessors, intention-to-treat analysis, and strategies to minimize patients lost to followup. Future trials should enroll more men, more racial and ethnic minorities, and broader age ranges. Given the fluctuating nature of ME/CFS, followup periods greater than 1 year would help determine effectiveness and harms over time.
  • The development of a set of core outcome measures, including patient-centered outcomes, such as quality of life, employment, and time spent in activity, would help guide research and facilitate future analyses. Trial registries and collaborations would help consolidate and standardize data. Reporting more information about concomitant treatments and adherence to treatment would improve the applicability of study findings. Similarly, stratification of results by patient characteristics, such as age, sex, race, and intermediate outcomes, would help determine the applicability of different treatments for specific patients and situations. Studies should report findings according to important features of ME/CFS, such as postexertional malaise, neurocognitive status, and autonomic function, to identify subgroups that may respond differently to specific treatments. Studies also need to report harms more completely to help identify patients negatively affected by certain treatments.
  • Given the devastating impact that this condition has had on patients and families, researchers planning and developing trials should consider involving the patient and/or advocate voice so that future research is relevant and meaningful to those affected by ME/CFS.


  1. Carruthers BM, Jain AK, de Meirleir KL, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndr. 2003;11(1):7-115.
  2. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270(4): 327-38. PMID: 21777306.
  3. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953-9. PMID: 7978722.
  4. Friedberg F, Bateman L, Bested AC, et al. ME/CFS: A Primer for Clinical Practitioners. Chicago: International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis; 2014.
  5. Jason LA, Brown A, Evans M, et al. Contrasting chronic fatigue syndrome versus myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue. 2013;1(3):168-86. PMID: 23914329.
  6. Davenport TE, Stevens SR, VanNess MJ, et al. Conceptual model for physical therapist management of chronic fatigue syndrome/myalgic encephalomyelitis. Phys Ther. 2010;90(4): 602-14. PMID: 20185614.
  7. Carruthers BM, van de Sande MI, De Meirleir K, et al. Myalgic Encephalomyelitis – Adult&Paediatric: International Consensus Primer for Medical Practitioners; 2012.
  8. Dowsett E, Goudsmit E, Macintyre A, et al. Report From the National Task Force on Chronic Fatigue Syndrome (CFS), Post Viral Fatigue Syndrome (PVFS), Myalgic Encephalomyelitis (ME). Westcare; 1994.
  9. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108(3):387-9. PMID: 2829679.
  10. Jason L, Evans M, Porter N, et al. The development of a revised Canadian myalgic encephalomyelitis chronic fatigue syndrome case definition. Am J Biochem Biotechnol. 2010;6(2):120-35.
  11. Reeves WC, Wagner D, Nisenbaum R, et al. Chronic fatigue syndrome—a clinically empirical approach to its definition and study. BMC Med. 2005;3:19. PMID: 16356178.
  12. Sharpe MC, Archard LC, Banatvala JE, et al. A report—chronic fatigue syndrome: guidelines for research. J R Soc Med. 1991;84(2):118-21. PMID: 1999813.
  13. Reyes M, Nisenbaum R, Hoaglin DC, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003;163(13):1530-6. PMID: 12860574.
  14. Jason LA, Brown A, Clyne E, et al. Contrasting case definitions for chronic fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis. Eval Health Prof. 2012;35(3):280-304. PMID: 22158691.
  15. Reeves WC, Jones JF, Maloney E, et al. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007;5:5. PMID: 17559660.
  16. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Rockville (MD): Agency for Healthcare Research and Quality. January 2014. Chapters available at
  17. Lewis I, Pairman J, Spickett G, et al. Is chronic fatigue syndrome in older patients a different disease? — a clinical cohort study. Eur J Clin Invest. 2013;43(3):302-8. PMID: 23397955.
  18. Aslakson E, Vollmer-Conna U, White PD. The validity of an empirical delineation of heterogeneity in chronic unexplained fatigue. Pharmacogenomics. 2006;7(3):365-73. PMID: 16610947.
  19. Brown AA, Jason LA, Evans MA, et al. Contrasting case definitions: the ME International Consensus Criteria vs. the Fukuda et al. CFS criteria. N Am J Psychol. 2013;15(1):103-20. PMID: 25364305.
  20. Jason LA, Sunnquist M, Brown A, et al. Are Myalgic Encephalomyelitis and chronic fatigue syndrome different illnesses? A preliminary analysis. J Health Psychol. 2014. Epub ahead of print. PMID: 24510231.
  21. Jason LA, Torres-Harding SR, Taylor RR, et al. A comparison of the 1988 and 1994 diagnostic criteria for chronic fatigue syndrome. J Clin Psychol Med Settings. 2001;8(4):337-43.
  22. Van Hoof E, De Meirleir K. Chronic fatigue syndrome and myalgic encephalomyletis: are both conditions on the same continuum? N Am J Psychol. 2005;7(2):189-204.
  23. Katon WJ, Buchwald DS, Simon GE, et al. Psychiatric illness in patients with chronic fatigue and those with rheumatoid arthritis. J Gen Intern Med. 1991;6(4):277-85. PMID: 1890495.
  24. Komaroff AL, Fagioli LR, Doolittle TH, et al. Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. Am J Med. 1996;101(3):281-90. PMID: 8873490.
  25. Tiev KP, Demettre E, Ercolano P, et al. RNase L levels in peripheral blood mononuclear cells: 37-kilodalton/83-kilodalton isoform ratio is a potential test for chronic fatigue syndrome. Clin Diagn Lab Immunol. 2003;10(2):315-6. PMID: 12626460.
  26. Linder R, Dinser R, Wagner M, et al. Generation of classification criteria for chronic fatigue syndrome using an artificial neural network and traditional criteria set. In Vivo. 2002;16(1):37-43. PMID: 11980359.
  27. Hadzi-Pavlovic D, Hickie IB, Wilson AJ, et al. Screening for prolonged fatigue syndromes: validation of the SOFA scale. Soc Psychiatry Psychiatr Epidemiol. 2000;35(10):471-9. PMID: 11127722.
  28. Jason LA, Evans M, Brown A, et al. Sensitivity and specificity of the CDC empirical chronic fatigue syndrome case definition. Psychology. 2010;1(1):9-16. PMID: 23685416.
  29. Jason L, Brown M, Evans M, et al. Measuring substantial reductions in functioning in patients with chronic fatigue syndrome. Disabil Rehabil. 2011;33(7):589-98. PMID: 20617920.
  30. Gaab J, Engert V, Heitz V, et al. Associations between neuroendocrine responses to the Insulin Tolerance Test and patient characteristics in chronic fatigue syndrome. J Psychosom Res. 2004;56(4):419-24. PMID: 15094026.
  31. Gaab J, Huster D, Peisen R, et al. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med. 2002;64(2):311-8. PMID: 11914448.
  32. Gaab J, Rohleder N, Heitz V, et al. Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology. 2005;30(2):188-98. PMID: 15471616.
  33. Davenport TE, Stevens SR, Baroni K, et al. Reliability and validity of Short Form 36 Version 2 to measure health perceptions in a sub-group of individuals with fatigue. Disabil Rehabil. 2011;33(25-26):2596-604. PMID: 21682669.
  34. Davenport TE, Stevens SR, Baroni K, et al. Diagnostic accuracy of symptoms characterising chronic fatigue syndrome. Disabil Rehabil. 2011;33(19-20):1768-75. PMID: 21208154.
  35. Brown AA, Evans MA, Jason LA. Examining the energy envelope and associated symptom patterns in chronic fatigue syndrome: does coping matter? Chronic Illn. 2013;9(4):302-11. PMID: 23585632.
  36. Watson SP, Ruskin AS, Simonis V, et al. Identifying defining aspects of chronic fatigue syndrome via unsupervised machine learning and feature selection. Int J Machine Learning Computing. 2014;4(2):133-8.
  37. Jason LA, Taylor RR. Measuring attributions about chronic fatigue syndrome. J Chronic Fatigue Syndr. 2001;8(3-4):31-40.
  38. Asbring P, Narvanen A-L. Women's experiences of stigma in relation to chronic fatigue syndrome and fibromyalgia. Qual Health Res. 2002;12(2):148-60. PMID: 11837367.
  39. Assefi NP, Coy TV, Uslan D, et al. Financial, occupational, and personal consequences of disability in patients with chronic fatigue syndrome and fibromyalgia compared to other fatiguing conditions. J Rheumatol. 2003;30(4):804-8. PMID: 12672203.
  40. Deale A, Wessely S. Diagnosis of psychiatric disorder in clinical evaluation of chronic fatigue syndrome. J R Soc Med. 2000;93(6):310-2. PMID: 10911826.
  41. Dickson A, Knussen C, Flowers P. Stigma and the delegitimation experience: an interpretative phenomenological analysis of people living with chronic fatigue syndrome. Psychol Health. 2007;22(7):851-67.
  42. Green J, Romei J, Natelson BH. Stigma and chronic fatigue syndrome. J Chronic Fatigue Syndr. 1999;5(2): 63-95.
  43. Guise J, McVittie C, McKinlay A. A discourse analytic study of ME/CFS (Chronic Fatigue Syndrome) sufferers' experiences of interactions with doctors. J Health Psychol. 2010;15(3):426-35. PMID: 20348363.
  44. Jason LA, Taylor RR, Stepanek Z, et al. Attitudes regarding chronic fatigue syndrome: the importance of a name. J Health Psychol. 2001;6(1):61-71. PMID: 22049238.
  45. Brimmer DJ, Maloney E, Devlin R, et al. A pilot registry of unexplained fatiguing illnesses and chronic fatigue syndrome. BMC Res Notes. 2013;6: 309. PMID: 23915640.
  46. Devasahayam A, Lawn T, Murphy M, et al. Alternative diagnoses to chronic fatigue syndrome in referrals to a specialist service: service evaluation survey. JRSM Short Rep. 2012;3(1):4. PMID: 22299071.
  47. Lawn T, Kumar P, Knight B, et al. Psychiatric misdiagnoses in patients with chronic fatigue syndrome. JRSM Short Rep. 2010;1(4):28. PMID: 21103120.
  48. Newton JL, Mabillard H, Scott A, et al. The Newcastle NHS Chronic Fatigue Syndrome Service: not all fatigue is the same. J R Coll Physicians Edinb. 2010;40(4):304-7. PMID: 21132135.
  49. Woodward RV, Broom DH, Legge DG. Diagnosis in chronic illness: disabling or enabling—the case of chronic fatigue syndrome. J R Soc Med. 1995;88(6):325-9. PMID: 7629762.
  50. Blacker CVR, Greenwood DT, Wesnes KA, et al. Effect of galantamine hydrobromide in chronic fatigue syndrome: a randomized controlled trial. JAMA. 2004;292(10):1195-204. PMID: 15353532.
  51. Blockmans D, Persoons P, Van Houdenhove B, et al. Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study. Am J Med. 2003;114(9):736-41. PMID: 12829200.
  52. McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998;280(12):1061-6. PMID: 9757853.
  53. Montoya JG, Kogelnik AM, Bhangoo M, et al. Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome. J Med Virol. 2013;85(12):2101-9. PMID: 23959519.
  54. Peterson PK, Shepard J, Macres M, et al. A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Am J Med. 1990;89(5):554-60. PMID: 2239975.
  55. Strayer DR, Carter WA, Brodsky I, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I) midline dot poly(C12U), in chronic fatigue syndrome. Clin Infect Dis. 1994;18(Suppl 1):S88-S95. PMID: 8148460.
  56. Strayer DR, Carter WA, Stouch BC, et al. A double-blind, placebo-controlled, randomized, clinical trial of the TLR-3 agonist rintatolimod in severe cases of chronic fatigue syndrome. PLoS One. 2012;7(3):e31334. PMID: 22431963.
  57. Wearden AJ, Morriss RK, Mullis R, et al. Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome.[Erratum appears in Br J Psychiatry 1998 Jul;173:89]. Br J Psychiatry. 1998;172:485-90. PMID: 9828987.
  58. Diaz-Mitoma F, Turgonyi E, Kumar A, et al. Clinical improvement in chronic fatigue syndrome is associated with enhanced natural killer cell-mediated cytotoxicity: The results of a pilot study with Isoprinosine. J Chronic Fatigue Syndr. 2003;11(2):71-93.
  59. Straus SE, Dale JK, Tobi M, et al. Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial. N Engl J Med. 1988;319(26):1692-8. PMID: 2849717.
  60. Fluge O, Bruland O, Risa K, et al. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study. PLoS One. 2011;6(10): e26358. PMID: 22039471.
  61. Hobday RA, Thomas S, O'Donovan A, et al. Dietary intervention in chronic fatigue syndrome. J Hum Nutr Diet. 2008;21(2):141-9. PMID: 18339054.
  62. Öckerman PA. Antioxidant treatment of chronic fatigue syndrome. Clin Pract Alternat Med. 2000;1(2): 88-91.
  63. The GKH, Bleijenberg G, van der Meer JWM. The effect of acclydine in chronic fatigue syndrome: a randomized controlled trial. PLoS Clin Trials. 2007;2(5):e19. PMID: 17525791.
  64. Vermeulen RCW, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004;66(2):276-82. PMID: 15039515.
  65. Walach H, Bosch H, Lewith G, et al. Effectiveness of distant healing for patients with chronic fatigue syndrome: a randomised controlled partially blinded trial (EUHEALS). Psychother Psychosom. 2008;77(3):158-66. PMID: 18277062.
  66. Weatherley-Jones E, Nicholl JP, Thomas KJ, et al. A randomised, controlled, triple-blind trial of the efficacy of homeopathic treatment for chronic fatigue syndrome. J Psychosom Res. 2004;56(2):189-97. PMID: 15016577.
  67. Williams G, Waterhouse J, Mugarza J, et al. Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy. Eur J Clin Invest. 2002;32(11):831-7. PMID: 12423324.
  68. Bazelmans E, Prins JB, Lulofs R, et al. Cognitive behaviour group therapy for chronic fatigue syndrome: a non-randomised waiting list controlled study. Psychother Psychosom. 2005;74(4):218-24. PMID: 15947511.
  69. Burgess M, Andiappan M, Chalder T. Cognitive behaviour therapy for chronic fatigue syndrome in adults: face to face versus telephone treatment: a randomized controlled trial. Behav Cogn Psychother. 2012;40(2):175-91. PMID: 21929831.
  70. Deale A, Chalder T, Marks I, et al. Cognitive behavior therapy for chronic fatigue syndrome: a randomized controlled trial. Am J Psychiatry. 1997;154(3):408-14. PMID: 9054791.
  71. Deale A, Husain K, Chalder T, et al. Long-term outcome of cognitive behavior therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J Psychiatry. 2001;158(12):2038-42. PMID: 11729022.
  72. Goudsmit EM, Ho-Yen DO, Dancey CP. Learning to cope with chronic illness. Efficacy of a multi-component treatment for people with chronic fatigue syndrome. Patient Educ Couns. 2009;77(2):231-6. PMID: 19576714.
  73. Hlavaty LE, Brown MM, Jason LA. The effect of homework compliance on treatment outcomes for participants with myalgic encephalomyelitis/chronic fatigue syndrome. Rehabil Psychol. 2011;56(3):212-8. PMID: 21767035.
  74. Jason L, Benton M, Torres-Harding S, et al. The impact of energy modulation on physical functioning and fatigue severity among patients with ME/CFS. Patient Educ Couns. 2009;77(2):237-41. PMID: 19356884.
  75. Jason LA, Roesner N, Porter N, et al. Provision of social support to individuals with chronic fatigue syndrome. J Clin Psychol. 2010;66(3):249-58. PMID: 19902489.
  76. Jason LA, Torres-Harding S, Friedberg F, et al. Non-pharmacologic interventions for CFS: a randomized trial. J Clin Psychol Med Settings. 2007;14(4):275-96.
  77. Knoop H, van der Meer JWM, Bleijenberg G. Guided self-instructions for people with chronic fatigue syndrome: randomised controlled trial. Br J Psychiatry. 2008;193(4):340-1. PMID: 18827302.
  78. Lopez C, Antoni M, Penedo F, et al. A pilot study of cognitive behavioral stress management effects on stress, quality of life, and symptoms in persons with chronic fatigue syndrome. J Psychosom Res. 2011;70(4):328-34. PMID: 21414452.
  79. Núñez M, Fernandez-Sola J, Núñez E, et al. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1year of follow-up. Clin Rheumatol. 2011;30(3):381-9. PMID: 21234629.
  80. O'Dowd H, Gladwell P, Rogers CA, et al. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technol Assess. 2006;10(37):iii-iv, ix-x, 1-121. PMID: 17014748.
  81. Sharpe M, Hawton K, Simkin S, et al. Cognitive behaviour therapy for the chronic fatigue syndrome: a randomized controlled trial. BMJ. 1996;312(7022):22-6. PMID: 8555852.
  82. Taylor RR. Quality of life and symptom severity for individuals with chronic fatigue syndrome: findings from a randomized clinical trial. Am J Occup Ther. 2004;58(1):35-43. PMID: 14763634.
  83. Tummers M, Knoop H, Bleijenberg G. Effectiveness of stepped care for chronic fatigue syndrome: a randomized noninferiority trial. J Consult Clin Psychol. 2010;78(5):724-31. PMID: 20873907.
  84. Tummers M, Knoop H, van Dam A, et al. Implementing a minimal intervention for chronic fatigue syndrome in a mental health centre: a randomized controlled trial. Psychol Med. 2012;42(10):2205-15. PMID: 22354999.
  85. Tummers M, Knoop H, van Dam A, et al. Moderators of the treatment response to guided self-instruction for chronic fatigue syndrome. J Psychosom Res. 2013;74(5):373-7. PMID: 23597323.
  86. Wearden AJ, Dowrick C, Chew-Graham C, et al. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ. 2010;340:c1777. PMID: 20418251.
  87. Wearden AJ, Dunn G, Dowrick C, et al. Depressive symptoms and pragmatic rehabilitation for chronic fatigue syndrome. Br J Psychiatry. 2012;201(3):227-32. PMID: 22844025.
  88. Wearden AJ, Emsley R. Mediators of the effects on fatigue of pragmatic rehabilitation for chronic fatigue syndrome. J Consult Clin Psychol. 2013;81(5):831-8. PMID: 23796316.
  89. 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):823-36. PMID: 21334061.
  90. Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ. 1997;314(7095):1647-52. PMID: 9180065.
  91. Ho RTH, Chan JSM, Wang C-W, et al. A randomized controlled trial of qigong exercise on fatigue symptoms, functioning, and telomerase activity in persons with chronic fatigue or chronic fatigue syndrome. Ann Behav Med. 2012;44(2):160-70. PMID: 22736201.
  92. Moss-Morris R, Sharon C, Tobin R, et al. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol. 2005;10(2):245-59. PMID: 15723894.
  93. Sutcliffe K, Gray J, Tan MP, et al. Home orthostatic training in chronic fatigue syndrome—a randomized, placebo-controlled feasibility study. Eur J Clin Invest. 2010;40(1):18-24. PMID: 19912315.


Smith MEB, Nelson HD, Haney E, Pappas M, Daeges M, Wasson N, McDonagh M. Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Evidence Report/Technology Assessment No. 219. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-I.) AHRQ Publication No. 15-E001-EF. Rockville, MD: Agency for Healthcare Research and Quality; December 2014.