Chronic fatigue syndrome
|Chronic fatigue syndrome|
|Synonyms||Myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), systemic exertion intolerance disease (SEID), others:20|
|Specialty||Neurology, rheumatology, psychiatry|
|Symptoms||Long-term fatigue, worsening of symptoms with activity|
|Diagnostic method||Based on symptoms|
|Treatment||Cognitive behavioral therapy, gradual increase in activity|
|Frequency||7–3,000 per 100,000 adults|
Chronic fatigue syndrome (CFS), also referred to as myalgic encephalomyelitis (ME), is a medical condition characterized by long-term fatigue and other symptoms that limit a person's ability to carry out ordinary daily activities. Quality of life of persons with CFS can be compromised.
Biological, genetic, infectious, and psychological mechanisms have been proposed, but the cause is not understood. The fatigue of CFS is not due to ongoing exertion, is not much relieved by rest, and is not due to any other medical condition. Diagnosis is based on a person's signs and symptoms.
There is no cure. No medications or procedures have been approved in the United States. Evidence suggests that cognitive behavioral therapy and a gradual increase in activity suited to individual capacity can be beneficial in some cases. In a systematic review of exercise therapy, no evidence of serious adverse effects was found; however data was insufficient to form a conclusion. Tentative evidence supports the use of the medication rintatolimod. This evidence, however, has been deemed insufficient for FDA approval for this use in the United States.
Estimates of the number of persons with the condition vary from 7 to 3,000 per 100,000 adults. About 836,000 to 2.5 million Americans, and 250,000 people in the UK have CFS. Fatigue is a common symptom in many illnesses, but the high level of fatigue in CFS is comparatively rare. CFS occurs more often in women than in men, and is less common among children and adolescents. There is agreement that CFS has a negative effect on health, happiness and productivity but there is also controversy over many aspects of the disorder. Physicians, researchers and patient advocates promote different names and diagnostic criteria, while evidence for proposed causes and treatments is often contradictory or of low quality.
- 1 Signs and symptoms
- 2 Cause
- 3 Pathophysiology
- 4 Diagnosis
- 5 Management
- 6 Prognosis
- 7 Epidemiology
- 8 History
- 9 Society and culture
- 10 Research
- 11 See also
- 12 References
- 13 External links
Signs and symptoms
The most commonly used diagnostic criteria and definition of CFS for research and clinical purposes were published by the United States Centers for Disease Control and Prevention (CDC). The CDC recommends the following three criteria be fulfilled:
- A new onset (not lifelong) of severe fatigue for six consecutive months or greater duration which is unrelated to exertion, is not substantially relieved by rest, and is not a result of other medical conditions.
- The fatigue causes a significant reduction of previous activity levels.
- Four or more of the following symptoms that concurrently last six months or longer:
- impaired memory or concentration
- post-exertional malaise, where physical or mental exertions bring on "extreme, prolonged exhaustion and sickness"
- unrefreshing sleep
- muscle pain (myalgia)
- pain in multiple joints (arthralgia)
- headaches of a new kind or greater severity
- sore throat, frequent or recurring
- tender lymph nodes (cervical or axillary)
Other common symptoms include:
- brain fog (feeling like one is in a mental fog)
- difficulty maintaining an upright position, dizziness, balance problems or fainting
- allergies or sensitivities to foods, odors, chemicals, medications, or noise
- irritable bowel syndrome-like symptoms such as bloating, stomach pain, constipation, diarrhoea and nausea
- chills and night sweats
- visual disturbances (sensitivity to light, blurring, eye pain)
- depression or mood problems (irritability, mood swings, anxiety, panic attacks)
The CDC proposes that persons with symptoms resembling those of CFS consult a physician to rule out several treatable illnesses: Lyme disease, "sleep disorders, major depressive disorder, alcohol/substance abuse, diabetes, hypothyroidism, mononucleosis (mono), lupus, multiple sclerosis (MS), chronic hepatitis and various malignancies." Medications can also cause side effects that mimic symptoms of CFS. Central sensitization, or increased sensitivity to sensory stimuli such as pain have been observed in CFS. Sensitivity to pain increases post-exertionally, which is opposite to the normal pattern.
Gradual onset has been found to be most common, although large numbers of people self-report that onset was sudden.:158 Studies suggest that critical life events, severe physical stressors, and perceived life difficulties may precipitate CFS.
Despite a common diagnosis, the functional capacity of individuals with CFS varies greatly. Some persons with CFS lead relatively normal lives; others are totally bed-ridden and unable to care for themselves. For the majority of persons with CFS, work, school, and family activities are significantly reduced for extended periods of time. The severity of symptoms and disability is the same in both genders, and many experience strongly disabling chronic pain. Persons report critical reductions in levels of physical activity. Also, a reduction in the complexity of activity has been observed. Reported impairment is comparable to other fatiguing medical conditions including late-stage AIDS, lupus, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), and end-stage renal disease. CFS affects a person's functional status and well-being more than major medical conditions such as multiple sclerosis, congestive heart failure, or type II diabetes mellitus.
Often, there are courses of remission and relapse of symptoms, which make the illness difficult to manage. Persons who feel better for a period may overextend their activities, and the result can be a worsening of their symptoms with a relapse of the illness.
Employment rates vary with over half unable to work and nearly two-thirds limited in their work because of their illness. More than half were on disability benefits or temporary sick leave, and less than a fifth worked full-time.
CFS patients demonstrate significantly decreased scores on the SF-36 quality of life questionnaire, especially in the sub scales on vitality, physical functioning, general health, physical role, social functioning, while maintaining "role emotional", and mental health. Loss of economic production due to CFS is estimated at between $9 and $37 billion, and healthcare costs are estimated at between $9 and $14 billion in the US alone.
Cognitive symptoms are mainly from deficits in attention, memory, and reaction time. The deficits are in the range of 0.5 to 1.0 standard deviations below expected values, and are likely to affect day-to-day activities. Simple and complex information processing speed, and functions entailing working memory over long time periods were moderately to extensively impaired. These deficits are generally consistent with those reported by patients. Perceptual abilities, motor speed, language, reasoning, and intelligence did not appear to be significantly altered. There is an increased frequency of neuropsychiatric and neuropsychological symptoms in persons with CFS.
The cause of CFS is unknown. Genetic, physiological and psychological factors are thought to work together to precipitate and perpetuate the condition. It may begin as a flu-like illness with a sudden onset, or it may occur gradually. Because of this, various infectious causes have been proposed; however, there is insufficient evidence to support such causation. Infections proposed include mononucleosis, chlamydia, HHV-6, and lyme disease.
All ethnic groups and income levels are susceptible to the illness. The CDC states that CFS is "at least as common" in African Americans and Hispanics as Caucasians. A 2009 meta-analysis, however, showed that compared with the White American majority, African Americans and Native Americans have a higher risk of CFS, though it acknowledged that studies and data were limited. More women than men get CFS — between 60 and 85% of cases are women; however, there is some indication that the prevalence among men is underreported. The illness is reported to occur more frequently in persons between the ages of 40 and 59. CFS is less prevalent among children and adolescents than among adults.
Psychological stress, childhood trauma, perfectionist personalities, old age, lower middle education, low physical fitness, preexisting psychological illness, and allergies may be risk factors for developing chronic fatigue. This has led some to believe that stress-related visceral responses underlie CFS. Pre-existing depressive and anxiety disorders, as well as high expectation of parents and family history were predisposing factors identified in another review.
People with CFS and their relatives tend to attribute their illness to physical causes (such as a virus or pollution) rather than to psychological causes. Such attributions do not seem a risk factor for the development of CFS, but probably are associated with increased symptoms and worse outcomes over time.
Tentative evidence suggests a relationship between autonomic nervous system dysfunction and diseases such as CFS, fibromyalgia, irritable bowel syndrome, and interstitial cystitis. However, it is unknown if this relationship is causative. Reviews of CFS literature have found autonomic abnormalities such as decreased sleep efficiency, increased sleep latency, decreased slow wave sleep, and abnormal heart rate response to tilt table tests suggesting a role of the autonomic nervous system in CFS. However, these results were limited by inconsistency. Some neuroimaging studies have observed prefrontal and brainstem hypometabolism; however, studies have been limited by sample size. Decreased frontal grey matter, and decreased white matter in the brain stem have been observed, as well as decreased global cerebral metabolism; however, these findings have been contradictory.
Immunological abnormalities are frequently observed in those with CFS. Decreased NK cell activity is found in CFS patients and correlates with severity of symptoms. CFS patients have an abnormal response to exercise, including increased production of complement products, increased oxidative stress combined with decreased antioxidant response, and increased Interleukin 10, and TLR4, some of which correlates with symptom severity. Increased levels of cytokines have been proposed to account for the decreased ATP production and increased lactate during exercise; however, the elevations of cytokine levels are inconsistent in specific cytokine, albeit frequently found. A hypothesized mechanism for inflammation in CFS proposes that inflammation inhibits serotonin synthesis through the Trycat pathway. Similarities have been drawn between cancer and CFS with regard to abnormal intracellular immunological signaling. Abnormalities observed include hyperactivity of Ribonuclease L, a protein activated by IFN, and hyperactivity of NF-κB.
Evidence points to abnormalities in the hypothalamic-pituitary-adrenal axis (HPA axis) in some, but not all, persons with CFS, which may include slightly low cortisol levels, a decrease in the variation of cortisol levels throughout the day, decreased responsiveness of the HPA axis, and a high serotonergic state, which can be considered to be a "HPA axis phenotype" that is also present in some other conditions, including PTSD and some autoimmune conditions. It is unclear whether or not the HPA axis plays a primary role as a cause of CFS, or has a secondary role in worsening or perpetuating symptoms later in the course of the illness. In most healthy adults, the cortisol awakening response shows an increase in cortisol levels averaging 50% in the first half-hour after waking. In people with CFS, it appears this increase is significantly less, but methods of measuring cortisol levels vary, so this is not certain. Factors leading to reduced cortisol levels include low activity levels, depression and early-life stress.
Autoimmunity has been proposed to be a factor in CFS; however, the only relevant finding is a subset of patients with increased B Cell activity and autoantibodies, possibly as a result of decreased NK cell regulation or viral mimicry.
There are no characteristic laboratory abnormalities to diagnose CFS; testing is used to rule out other conditions which could be responsible for the symptoms. When symptoms are attributable to certain other conditions, the diagnosis of CFS is excluded. As such, a diagnosis of CFS/ME is generally one of exclusion (of alternative diagnoses).
Notable definitions include:
- Centers for Disease Control and Prevention (CDC) definition (1994), the most widely used clinical and research description of CFS, is also called the Fukuda definition and is a revision of the Holmes or CDC 1988 scoring system. The 1994 criteria require the presence of four or more symptoms beyond fatigue, while the 1988 criteria require six to eight.
- The ME/CFS 2003 Canadian Clinical working definition states: "A patient with ME/CFS will meet the criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction, and pain; have two or more neurological/cognitive manifestations and one or more symptoms from two of the categories of autonomic, neuroendocrine, and immune manifestations; and the illness persists for at least 6 months".
Clinical practice guidelines are generally based on case descriptions, with the aim of improving diagnosis, management and treatment. An example is the CFS/ME guideline for the National Health Services in England and Wales, produced in 2007 by the National Institute for Health and Clinical Excellence (NICE).
Certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of CFS can be given. Hypothyroidism, anemia, coeliac disease (that can occur without gastrointestinal symptoms), diabetes and certain psychiatric disorders are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms. Other diseases, listed by the Centers for Disease Control and Prevention, include infectious diseases (such as Epstein–Barr virus, influenza, HIV infection, tuberculosis, Lyme disease), neuroendocrine diseases (such as thyroiditis, Addison's disease, adrenal insufficiency, Cushing's disease), hematologic diseases (such as occult malignancy, lymphoma), rheumatologic diseases (such as fibromyalgia, polymyalgia rheumatica, Sjögren's syndrome, giant-cell arteritis, polymyositis, dermatomyositis), psychiatric diseases (such as bipolar disorder, schizophrenia, delusional disorders, dementia, anorexia/bulimia nervosa), neuropsychologic diseases (such as obstructive sleep apnea, parkinsonism, multiple sclerosis), and others (such as nasal obstruction from allergies, sinusitis, anatomic obstruction, autoimmune diseases, some chronic illness, alcohol or substance abuse, pharmacologic side effects, heavy metal exposure and toxicity, marked body weight fluctuation).
Persons with fibromyalgia (FM, or fibromyalgia syndrome, FMS), like those with CFS, have muscle pain, severe fatigue and sleep disturbances. The presence of allodynia (abnormal pain responses to mild stimulation) and of extensive tender points in specific locations differentiates FM from CFS, although the two diseases often co-occur.
Depressive symptoms, if seen in CFS, may be differentially diagnosed from primary depression by the absence of anhedonia, decreased motivation, and guilt; and the presence of somatic symptoms such as sore throat, swollen lymph nodes, and exercise intolerance with post exertional exacerbation of symptoms.
There is no certain pharmacological treatment or cure for CFS although various drugs have been or are being investigated. A 2014 report prepared by the Agency for Healthcare Research and Quality stated that there are wide variations in patient management, that many receive a multifaceted approach to treatment, and that no medications have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of ME/CFS, although several have been used off label. The report concluded that although counseling and graded exercise therapy (GET) have shown some benefits, these interventions have not been studied fully enough to recommend them for all persons affected. The report expressed concern that GET appears to be associated with worsening symptoms in some.
The United States Centres for Disease Control and Prevention (CDC) has a guide for the management of CFS, and the United Kingdom's National Institute for Health and Clinical Excellence(NICE) has a guideline for the delivery of NHS care to persons with CFS.
The CDC states that while there is no cure a number of methods might improve symptoms. The NICE guideline is directed toward clinicians, and specifies the need for shared decision-making between the patient and healthcare professionals, with acknowledgement of the reality and impact of the condition and the symptoms. The NICE guideline covers illness management aspects of diet, sleep and sleep disorders, rest, relaxation, and pacing. Referral to specialist care for cognitive behavioural therapy, graded exercise therapy and activity management programmes are recommended to be offered as a choice to patients with mild or moderate CFS. In 2017 NICE announced it is to update its guidance for CFS.
Cognitive behavioral therapy
A 2014 National Institutes of Health report concluded that while counseling and behavior therapies could produce benefits for patients, they may not yield improvement in quality of life, and because of this limitation such therapies should not be considered as a primary treatment, but rather should be used only as one component of a broader approach. This same report stated that although counseling approaches have shown benefit in some measures of fatigue, function and overall improvement, these approaches have been inadequately studied in subgroups of the wider CFS patient population. Further concern was expressed that reporting of negative effects experienced by patients receiving counseling and behavior therapies had been poor. A report by the Institute of Medicine published in 2015 states that it is unclear whether CBT helps to improve cognitive impairments experienced by patients.:265
A 2008 Cochrane Review concluded that CBT did reduce the symptom of fatigue, but noted that the benefits of CBT may diminish after the therapy is completed, and that due to study limitations "the significance of these findings should be interpreted with caution". A 2014 systematic review reported that there was only limited evidence that patients increased levels of physical activity after receiving CBT. The authors concluded that, as this finding is contrary to the cognitive behavioural model of CFS, patients receiving CBT were adapting to the illness rather than recovering from it.
Patient organisations have long criticised the use of CBT as a treatment for CFS. In 2012 the ME Association (MEA) commenced an extensive opinion survey of patients who had received a CBT treatment in the UK. Based on the finding of this survey, in 2015 the MEA concluded that CBT in its current form should not be recommended as a primary intervention for people with CFS In a letter published online in the Lancet in 2016, Dr Charles Shepherd, medical advisor to the MEA, expressed the view that the contention between patients and researchers lay in "a flawed model of causation that takes no account of the heterogeneity of both clinical presentations and disease pathways that come under the umbrella diagnosis of ME/CFS".
A 2014 National Institutes of Health report concluded that while exercise therapy of the type known as graded exercise therapy (GET), could produce benefits, it may not yield improvement in quality of life and that because of this limitation, GET should not be considered as a primary treatment, but instead be used only as one component of a broader approach. The report also noted that a focus on exercise programs had discouraged patient participation in other types of physical activity, due to concerns of precipitating increased symptoms. A July 2016 addendum to this report recommended that the Oxford criteria not be used when studying ME/CFS. If studies based on the Oxford criteria were excluded, there would be insufficient evidence of the effectiveness of GET on any outcome.
A 2016 Cochrane review stated that exercise therapy could contribute to alleviation of some symptoms of CFS, especially fatigue. The Cochrane review also noted that research was inconclusive as to which, if any, type of exercise therapy was superior, and concluded that no evidence had been found suggesting that exercise therapy worsened outcomes. A 2015 review article determined that serious adverse effects, or harms, from exercise therapy were poorly reported in most studies, and determined there was insufficient evidence for a conclusion.
As with CBT, patient organisations have long criticised the use of exercise therapy, most notably GET, as a treatment for CFS. In 2012 the MEA commenced an extensive opinion survey of patients who had received GET. Based on the findings of this survey, in 2015 the MEA concluded that GET in its current delivered form should not be recommended as a primary intervention for persons with CFS.
Pacing is an energy management strategy based on the observation that symptoms of the illness tend to increase following minimal exertion. There are two forms: symptom-contingent pacing, where the decision to stop (and rest or change an activity) is determined by an awareness of an exacerbation of symptoms; and time-contingent pacing, which is determined by a set schedule of activities which a patient estimates he or she is able to complete without triggering post-exertional malaise (PEM).Thus the principle behind pacing for CFS is to avoid over-exertion and an exacerbation of symptoms. It is not aimed at treating the illness as a whole. Those whose illness appears stable may gradually increase activity and exercise levels, but, according to the principle of pacing, must rest if it becomes clear that they have exceeded their limits.
Patients with CFS benefit from a well-balanced diet and eating regularly (eating little and often), including slow-release starchy foods in meals and snacks. Although elimination diets are not generally recommended, many people experience relief of CFS symptoms with these diets, including gastrointestinal complaints. To avoid the risk of malnutrition, they should be supervised by a dietitian.
Antidepressants are mostly ineffective in treating CFS. Antiviral and immunological therapies have provided some benefit, but are limited by their side effects. Alternative treatments, such as carnitine and essential fatty acids, show promising results.
Steroid replacement therapy is not effective.
There is some preliminary evidence that the immunomodulatory medication rintatolimod improves exercise capacity, as well as cognitive function and quality of life, based on two trials. The US FDA has repeatedly denied commercial approval, citing numerous deficiencies in both trials, and concluding that the available evidence is insufficient to demonstrate its safety or efficacy in CFS.
A systematic review described improvement and occupational outcomes of people with CFS found that "the median full recovery rate was 5% (range 0–31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8–63%). Return to work at follow-up ranged from 8 to 30% in the three studies that considered this outcome." .... "In five studies, a worsening of symptoms during the period of follow-up was reported in between 5 and 20% of patients." A good outcome was associated with less fatigue severity at baseline. Other factors were occasionally, but not consistently, related to outcome, including age at onset (5 of 16 studies), and attributing illness to a psychological cause and/or having a sense of control over symptoms (4 of 16 studies). Another review found that children have a better prognosis than adults, with 54–94% having recovered by follow-up compared to less than 10% of adults returning to pre-illness levels of functioning.
A 2003 review reported between 7 and 3,000 cases of CFS for every 100,000 adults. Ranjith reviewed the epidemiological literature on CFS and suggested that the wide variance of the prevalence estimates may be due to the different definitions of CFS in use, the settings in which patients were selected, and the methodology used to exclude study participants with possible alternative diagnoses. The Centers for Disease Control states a 2015 report estimates 836,000 to 2.5 million Americans have CFS but most remain undiagnosed. Approximately 250,000 people in the UK are affected with the illness according to the UK Department of Health archives.
From 1934 onwards, outbreaks of a previously unknown illness began to be recorded by doctors. Initially considered to be occurrences of poliomyelitis, the illness was subsequently referred to as "epidemic neuromyasthenia". In the 1950s, the term "benign myalgic encephalomyelitis" was used in relation to a comparable outbreak at the Royal Free Hospital in London. The descriptions of each outbreak were varied, but included symptoms of malaise, tender lymph nodes, sore throat, pain, and signs of encephalomyelitis. The cause of the condition was not identified, although it appeared to be infectious, and the term "benign myalgic encephalomyelitis" was chosen to reflect the lack of mortality, the severe muscular pains, evidence of damage to the nervous system, and to the presumed inflammatory nature of the disorder. The syndrome appeared in sporadic as well as epidemic cases and in 1969, benign myalgic encephalomyelitis appeared as an entry to the International Classification of Diseases under Diseases of the nervous system.
The authors of a review of 15 outbreaks of benign myalgic encephalomyelitis, carried out in 1970, concluded that these were psychosocial phenomena caused by either mass hysteria on the part of the patients or altered medical perception of the community. These conclusions were based on the higher prevalence of the disease in females in whom there was a lack of physical signs. On that basis, the authors recommended that the disease should be renamed "myalgia nervosa". Despite strong refutation by Dr. Melvin Ramsay, the proposed psychological cause created great controversy, and convinced health professionals that this was a plausible explanation for the condition.
The continued work of Ramsay demonstrated that, although the disease rarely resulted in mortality, it was often severely disabling.:28–29 Because of this, Ramsay proposed that the prefix "benign" be dropped. In 1986, Ramsay published the first diagnostic criteria for ME, in which the condition was characterized by:
- a form of muscle fatiguability in which, even after minimal physical effort, 3 or more days elapse before full muscle power is restored;
- extraordinary variability or fluctuation of symptoms, even in the course of one day;
- an alarming chronicity.
Chronic fatigue syndrome
In the mid-1980s, two large outbreaks of an illness which resembled mononucleosis drew national attention in the United States. Located in Nevada and New York, the outbreaks involved an illness which was characterized by "chronic or recurrent debilitating fatigue, and various combinations of other symptoms, including a sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias". An initial link to the Epstein-Barr virus saw the illness acquire the name "chronic Epstein-Barr virus syndrome".:29
The United States Centers for Disease Control and Prevention convened a working group tasked with reaching a consensus on the clinical features of the illness. Meeting in 1987, the working group concluded that CFS was not new, and that the many different names given to it previously reflected widely differing concepts of the illness's cause and epidemiology. The CDC working group chose "chronic fatigue syndrome" as a more neutral and inclusive name for the illness, but noted that "myalgic encephalomyelitis" was widely accepted in other parts of the world. The first definition of CFS was published in 1988, and although the cause of the illness remained unknown, there were several attempts to update this definition, most notably in 1994. In 2006, the CDC commenced a national program to educate the American public and health care professionals about CFS.
Other medical terms
A range of both theorised and confirmed medical entities and naming conventions have appeared historically in the medical literature dealing with ME and CFS, these include:
- Epidemic neuromyasthenia: a term used for outbreaks with symptoms resembling poliomyelitis.
- Iceland disease and Akureyri disease: synonymous terms used for an outbreak of fatigue symptoms in Iceland.
- Low natural killer syndrome, a term, used mainly in Japan, reflecting research showing diminished in-vitro activity of natural killer cells (NKs) isolated from patients.
- Neurasthenia has been proposed as an historical diagnosis that occupied a similar medical and cultural space to CFS.
- Royal Free disease: named after the historically significant outbreak in 1955 at the Royal Free Hospital used as an informal synonym for "benign myalgic encephalomyelitis".
- Tapanui Flu: a term commonly used in New Zealand, deriving from the name of a town where numerous people suffered from the syndrome.
Society and culture
Many names have been proposed for the illness, currently, the most commonly used are "chronic fatigue syndrome", "myalgic encephalomyelitis", and the umbrella term "ME/CFS". Reaching consensus on a name is challenging because the cause and pathology remain unknown.:29–30
The term "chronic fatigue syndrome" has been criticized by patients as being both stigmatizing and trivializing, and which in turn prevents the illness from being seen as a serious health problem that deserves appropriate research. While many patients prefer "myalgic encephalomyelitis", which they believe better reflects the medical nature of the illness, there is resistance amongst clinicians toward the use of myalgic encephalomyelitis on the grounds that the inflammation of the central nervous system (myelitis) implied by the term has not been demonstrated.
A 2015 report from the Institute of Medicine proposes the illness be renamed "systemic exertion intolerance disease" and suggests new diagnostic criteria for it. Many patients, clinicians, and researchers believe lengthy, disproportionate exhaustion after physical or mental exertion is a core symptom (also known as post-exertional malaise).
Reynolds et al. (2004) estimated that the illness caused about $20,000 per person with CFS in lost productivity which totals to $9.1 billion per year in the United States. This is comparable to other chronic illnesses that extract some of the biggest medical and socioeconomic costs. A 2008 study calculated that the total annual cost burden of ME/CFS to society in the US was extensive, and could approach $24.0 billion.
May 12 is designated as ME/CFS and Fibromyalgia International Awareness Day. The day is observed so that stakeholders have an occasion to improve the knowledge of "the public, policymakers, and healthcare professionals about the symptoms, diagnosis, and treatment of ME/CFS, as well as the need for a better understanding of this complex illness."
Some in the medical community do not recognize CFS as a real condition, nor is there agreement on its prevalence. There has been much disagreement over proposed causes, diagnosis, and treatment of the illness. This uncertainty can significantly affect doctor-patient relations. A 2006 survey of GPs in southwest England found that despite more than two thirds of them accepting CFS/ME as a recognizable clinical entity, nearly half did not feel confident with making the diagnosis and/or treating the disease. Three other key factors that were significantly, positively associated with GPs' attitudes were knowing someone socially with CFS/ME, being male and seeing more patients with the condition in the last year.
From the patient perspective, one 1997 study found that 77% of individuals with CFS reported negative experiences with health care providers. In a more recent metaanalysis of qualitative studies, a major theme identified in patient discourses was that they felt severely ill, yet blamed and dismissed. Another recent study of themes in patient newsgroup postings noted key themes relating to denial of social recognition of suffering and feelings of being accused of "simply faking it". Another theme that emerged strongly was that achieving diagnosis and acknowledgement requires tremendous amounts of "hard work" by patients.
Based on concern following 2009 claims of a link, subsequently shown to be unfounded, between CFS and a retrovirus, in 2010 a variety of national blood banks adopted measures to discourage or prohibit individuals diagnosed with CFS from donating blood. Organizations adopting these or similar measures included the Canadian Blood Services, the New Zealand Blood Service, the Australian Red Cross Blood Service and the American Association of Blood Banks, In November 2010, the UK National Blood Service introduced a permanent deferral of donation from ME/CFS patients based on the potential harm to those patients that may result from their giving blood. Donation policy in the UK now states, "CFS is generally diagnosed by excluding other conditions and may follow an infection that may or may not have been viral and which may be carried by the affected individual."
There has been much contention over the cause, pathophysiology, nomenclature, and diagnostic criteria of chronic fatigue syndrome. Historically, many professionals within the medical community were unfamiliar with CFS, or did not recognize it as a real condition; nor was there agreement on its prevalence or seriousness. Controversies still exist about whether funding should be directed towards biomedical or psychological/psychosocial research.
In 2009, the journal Science published a study that identified the XMRV retrovirus in a population of people with CFS. Other studies failed to reproduce this finding, and in 2011, the editor of Science formally retracted its XMRV paper while the Proceedings of the National Academy of Sciences similarly retracted a 2010 paper which had appeared to support the finding of a connection between XMRV and CFS.
Media treatment of CFS has often been controversial; in November 1990, the magazine Newsweek ran a cover story on CFS which, although supportive of an organic cause of the illness, also featured the term Yuppie Flu. Reflecting a stereotype that CFS mainly affected yuppies, the implication was that CFS was a form of burnout. Use of the term Yuppie flu is considered offensive both by patients and clinicians.
In November 2006, an unofficial inquiry by an ad hoc group of parliamentarians in the United Kingdom, set up and chaired by former MP, Dr Ian Gibson, called the Group on Scientific Research into ME, was addressed by a government minister claiming that few good biomedical research proposals have been submitted to the Medical Research Council (MRC) in contrast to those for psychosocial research. They were also told by other scientists of proposals that have been rejected, with claims of bias against biomedical research.
The MRC confirmed to the Group that, from April 2003 to November 2006, it has turned down 10 biomedical applications relating to CFS/ME and funded five applications relating to CFS/ME, mostly in the psychiatric/psychosocial domain.
In 2008, the MRC set up an expert group to consider how the MRC might encourage new high-quality research into CFS/ME and partnerships between researchers already working on CFS/ME and those in associated areas. It currently lists CFS/ME with a highlight notice, inviting researchers to develop high-quality research proposals for funding. In February 2010, the All-Party Parliamentary Group on ME (APPG on ME) produced a legacy paper, which welcomed the recent MRC initiative, but felt that there has been far too much emphasis in the past on psychological research, with insufficient attention to biomedical research, and that it is vital that further biomedical research be undertaken to help discover a cause and more effective forms of management for this disease.
On 29 October 2015 the National Institutes of Health declared its intent to increase research on ME/CFS. The NIH Clinical Center will study individuals with ME/CFS, and the National Institute of Neurological Disorders and Stroke (NINDS) will lead the Trans-NIH ME/CFS Research Working Group as part of a multi-institute research effort.
The different case definitions used to research the illness influence the types of patients selected for studies, and research also suggests subtypes of patients may exist within a heterogeneous population. In one of the definitions, symptoms are accepted that may suggest a psychiatric disorder, while others specifically exclude primary psychiatric disorders. The lack of a single, unifying case definition was criticized in the Institute of Medicine's 2015 report for "creating an unclear picture of the symptoms and signs of the disorder" and "complicating comparisons of the results".:72
- Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of, Medicine (10 February 2015). "Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness.". PMID 25695122.
- Guideline 53: Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy). London: National Institute for Health and Clinical Excellence. 2007. ISBN 1-84629-453-3.
- "Treatment | Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)". www.cdc.gov. 30 May 2017. Retrieved 12 July 2017.
- "Chronic Fatigue Syndrome Causes". Centers for Disease Control and Prevention. October 15, 2010. Retrieved 2012-12-20.
- Smith ME, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, Fu R, Nelson HD (2015). "Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop". Ann. Intern. Med. (Systematic review). 162 (12): 841–50. PMID 26075755. doi:10.7326/M15-0114.
- Larun, Lillebeth; Brurberg, Kjetil; Odgaard-Jensen, Jan; Price, Jonathan R (February 2016). "Exercise therapy for chronic fatigue syndrome". Cochrane Database Syst Rev. doi:10.1002/14651858.CD003200.pub4. Retrieved 26 November 2016.
- Afari N, Buchwald D; Buchwald (2003). "Chronic fatigue syndrome: a review". Am J Psychiatry. 160 (2): 221–36. PMID 12562565. doi:10.1176/appi.ajp.160.2.221.
- Ranjith G (2005). "Epidemiology of chronic fatigue syndrome". Occup Med (Lond). 55 (1): 13–29. PMID 15699086. doi:10.1093/occmed/kqi012.
- Evengård B, Schacterle RS, Komaroff AL; Schacterle; Komaroff (Nov 1999). "Chronic fatigue syndrome: new insights and old ignorance". Journal of Internal Medicine. 246 (5): 455–469. PMID 10583715. doi:10.1046/j.1365-2796.1999.00513.x. Retrieved 2009-10-21.
- Anderson JS, Ferrans CE; Ferrans (June 1997). "The quality of life of persons with chronic fatigue syndrome". J Nerv Ment Dis. 185 (6): 359–67. PMID 9205421. doi:10.1097/00005053-199706000-00001.
- "Chronic Fatigue Syndrome: Case Definition". CDC. 2006-05-03. Retrieved 2009-01-22.
- "ME/CFS, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Advancing the Research; Background; Pathways to Prevention (P2P) Workshop". prevention.nih.gov. 12 August 2016. Retrieved 3 August 2017.
- Research, Center for Drug Evaluation and. "News & Events - Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome (ME and CFS): Questions and Answers". www.fda.gov. Retrieved 2017-01-18.
- "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome". Centers for Disease Control and Prevention. July 3, 2017. Retrieved July 28, 2017.
- "Annex 1: Epidemiology of CFS/ME". UK Department of Health. 2012-01-06. Archived from the original on 2012-01-06. Retrieved July 28, 2017.
- Gallagher AM, Thomas JM, Hamilton WT, White PD; Thomas; Hamilton; White (2004). "Incidence of fatigue symptoms and diagnoses presenting in UK primary care from 1990 to 2001". J R Soc Med. 97 (12): 571–5. PMC . PMID 15574853. doi:10.1258/jrsm.97.12.571.
- "Chronic Fatigue Syndrome Who's at risk?". Centers for Disease Control and Prevention. February 14, 2013. Retrieved 2013-09-25.
- Ottati, Victor C. (2002). The social psychology of politics. New York: Kluwer Academic/Plenum. pp. 159–160. ISBN 0-306-46723-2. Retrieved 2009-08-11.
- Price JR, Mitchell E, Tidy E, Hunot V; Mitchell; Tidy; Hunot (2008). Price, Jonathan R, ed. "Cognitive behaviour therapy for chronic fatigue syndrome in adults". Cochrane Database Syst Rev (3): CD001027. PMID 18646067. doi:10.1002/14651858.CD001027.pub2.
- "CDC - Chronic Fatigue Syndrome (CFS) - Diagnosis". Cdc.gov. Retrieved 2012-07-22.
- "Chronic Fatigue Syndrome (CFS), Symptoms". Centers for Disease Control and Prevention. 2012-05-14. Retrieved 2012-09-23.
- "CDC, Chronic Fatigue Syndrome (CFS), Making a Diagnosis" (PDF). Cdc.gov. Retrieved 2011-01-28.
- Nijs, Jo; Meeus, Mira; Van Oosterwijck, Jessica; Ickmans, Kelly; Moorkens, Greta; Hans, Guy; De Clerck, Luc S. (1 February 2012). "In the mind or in the brain? Scientific evidence for central sensitisation in chronic fatigue syndrome". European Journal of Clinical Investigation. 42 (2): 203–212. ISSN 1365-2362. PMID 21793823. doi:10.1111/j.1365-2362.2011.02575.x.
- Wyller VB (2007). "The chronic fatigue syndrome--an update". Acta Neurologica Scandinavica. Supplementum. 187: 7–14. PMID 17419822. doi:10.1111/j.1600-0404.2007.00840.x.
- Vanness JM, Snell CR, Strayer DR, Dempsey L, Stevens SR; Snell; Strayer; Dempsey l; Stevens (2003). "Subclassifying chronic fatigue syndrome through exercise testing". Med Sci Sports Exerc. 35 (6): 908–13. PMID 12783037. doi:10.1249/01.MSS.0000069510.58763.E8.
- Ross SD, Estok RP, Frame D, Stone LR, Ludensky V, Levine CB; Estok; Frame; Stone; Ludensky; Levine (2004). "Disability and chronic fatigue syndrome: a focus on function". Arch Intern Med. 164 (10): 1098–107. PMID 15159267. doi:10.1001/archinte.164.10.1098.
- Ho-Yen DO, McNamara I; McNamara (1991). "General practitioners' experience of the chronic fatigue syndrome". Br J Gen Pract. 41 (349): 324–6. PMC . PMID 1777276.
- Meeus M, Nijs J, Meirleir KD; Nijs; Meirleir (2007). "Chronic musculoskeletal pain in patients with the chronic fatigue syndrome: A systematic review". Eur J Pain. 11 (4): 377–386. PMID 16843021. doi:10.1016/j.ejpain.2006.06.005.
- McCully KK, Sisto SA, Natelson BH; Sisto; Natelson (1996). "Use of exercise for treatment of chronic fatigue syndrome". Sports Med. 21 (1): 35–48. PMID 8771284. doi:10.2165/00007256-199621010-00004.
- Burton C, Knoop H, Popovic N, Sharpe M, Bleijenberg G; Knoop; Popovic; Sharpe; Bleijenberg (June 2009). "Reduced complexity of activity patterns in patients with Chronic Fatigue Syndrome: a case control study". Biopsychosoc Med. 3 (1): 7. PMC . PMID 19490619. doi:10.1186/1751-0759-3-7.
- Solomon L, Nisenbaum R, Reyes M, Papanicolaou DA, Reeves WC; Nisenbaum; Reyes; Papanicolaou; Reeves (2003). "Functional status of persons with chronic fatigue syndrome in the Wichita, Kansas, population". Health Qual Life Outcomes. 1 (1): 48–58. PMC . PMID 14577835. doi:10.1186/1477-7525-1-48.
- Mark, Loveless, MD, congressional testimony of, May 12, 1995, as reported in Hillary Johnson. (1996). Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic. Crown Publishers, New York. ISBN 0-517-70353-X. pp.364-365
- Komaroff AL, Fagioli LR, Doolittle TH, Gandek B, Gleit MA, Guerriero RT, Kornish RJ, Ware NC, Ware JE, Bates DW; Fagioli; Doolittle; Gandek; Gleit; Guerriero; Kornish Rj; Ware; Ware Jr; Bates (September 1996). "Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups". Am. J. Med. 101 (3): 281–90. PMID 8873490. doi:10.1016/S0002-9343(96)00174-X.
- Unger; Linn; Brimmer; Lap; Komaroff; Nath; Laird; Isklander (December 30, 2016). "CDC Grand Rounds: Chronic Fatigue Syndrome — Advancing Research and Clinical Education" (PDF). US Department of Health and Human Services/Centers for Disease Control and Prevention. 65 (50): 51.
- Cockshell SJ, Mathias JL; Mathias (January 2010). "Cognitive functioning in chronic fatigue syndrome: a meta-analysis". Psychol Med. 40 (8): 1–15. PMID 20047703. doi:10.1017/S0033291709992054.
- Christley, Yvonne; Duffy, Tim; Everall, Ian Paul; Martin, Colin R. (1 April 2013). "The neuropsychiatric and neuropsychological features of chronic fatigue syndrome: revisiting the enigma". Current Psychiatry Reports. 15 (4): 353. ISSN 1535-1645. PMID 23440559. doi:10.1007/s11920-013-0353-8.
- Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press (US). pp. 159–162. ISBN 9780309316897. PMID 25695122.
- Natelson BH, Lange G (2002). "A status report on chronic fatigue syndrome". Environ. Health Perspect. 110 Suppl 4 (Suppl 4): 673–7. PMC . PMID 12194905. doi:10.1289/ehp.02110s4673.
- "Chronic Fatigue Syndrome Who's at risk?". U.S. Centers for Disease Control and Prevention. March 10, 2006. Retrieved 2016-05-04.
- Dinos, S; Khoshaba, B; Ashby, D; White, PD; Nazroo, J; Wessely, S; Bhui, KS (2009). "A systematic review of chronic fatigue, its syndromes and ethnicity: prevalence, severity, co-morbidity and coping". International Journal of Epidemiology. 38 (6): 1554–70. PMID 19349479. doi:10.1093/ije/dyp147.
- "Chronic Fatigue Syndrome Basic Facts". Centers for Disease Control and Prevention. May 9, 2006. Retrieved 2008-02-07.
- Walsh CM, Zainal NZ, Middleton SJ, Paykel ES; Zainal; Middleton; Paykel (2001). "A family history study of chronic fatigue syndrome". Psychiatr Genet. 11 (3): 123–8. PMID 11702053. doi:10.1097/00041444-200109000-00003.
- Van Houdenhove, Boudewijn; Kempke, Stefan; Luyten, Patrick (1 June 2010). "Psychiatric aspects of chronic fatigue syndrome and fibromyalgia". Current Psychiatry Reports. 12 (3): 208–214. PMID 20425282. doi:10.1007/s11920-010-0105-y.
- Hempel, S.; Chambers, D.; Bagnall, A.-M.; Forbes, C. (1 July 2008). "Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies". Psychological Medicine. 38 (7): 915–926. PMID 17892624. doi:10.1017/S0033291707001602.
- Lievesley, Kate; Rimes, Katharine A.; Chalder, Trudie (1 April 2014). "A review of the predisposing, precipitating and perpetuating factors in Chronic Fatigue Syndrome in children and adolescents". Clinical Psychology Review. 34 (3): 233–248. ISSN 1873-7811. PMID 24632047. doi:10.1016/j.cpr.2014.02.002.
- Cho HJ, Hotopf M, Wessely S (2005). "The placebo response in the treatment of chronic fatigue syndrome: A systematic review and meta-analysis". Psychosom Med. 67 (2): 301–13. PMID 15784798. doi:10.1097/01.psy.0000156969.76986.e0. Retrieved 2008-12-12.
- Martinez-Martinez, Laura-Aline; Mora, Tania; Vargas; Fuentes-Iniestra; Martinez-Lavın (April 2014). "Sympathetic Nervous System Dysfunction in Fibromyalgia, Chronic Fatigue Syndrome, Irritable Bowel Syndrome, and Interstitial Cystitis". Journal of clinical rheumatology:. 20 (3): 146–150. PMID 24662556. doi:10.1097/RHU.0000000000000089.
- Jackson,, Melinda; Bruck, Dorothy (5 December 2012). "Sleep Abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Review". J Clin Sleep Med. 8 (6): 719–728. doi:10.5664/jcsm.2276.
- Tanaka, Masaaki; Tajima, Seiki; Mizuno, Kei; Ishii, Akira; Konishi, Yukuo; Miike, Teruhisa; Watanabe, Yasuyoshi (2015). "Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder". The Journal of Physiological Sciences. 65 (6): 483–498. PMC . PMID 26420687. doi:10.1007/s12576-015-0399-y.
- Van Cauwenbergh, Deborah; Nijs, Jo; Kos, Daphne; Van Weijnen, Laura; Struyf, Filip; Meeus, Mira (1 May 2014). "Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review". European Journal of Clinical Investigation. 44 (5): 516–526. doi:10.1111/eci.12256.
- Ortega, Francisco; Zorzanelli, Rafaela (1 April 2011). "Neuroimaging and the case of chronic fatigue syndrome". Ciência & Saúde Coletiva. 16 (4): 2123–2132. ISSN 1413-8123. doi:10.1590/S1413-81232011000400012.
- Jasona, Leonard A.; Zinn, Marcie L.; Zinn, Mark A. (2 February 2017). "Myalgic Encephalomyelitis: Symptoms and Biomarkers". Current Neuropharmacology. 13 (5): 701–734. ISSN 1570-159X. PMC . PMID 26411464. doi:10.2174/1570159X13666150928105725.
- Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J (2014). "Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review" (PDF). Exerc Immunol Rev. 20: 94–116. PMID 24974723. Retrieved 2015-06-19.
- Armstrong, Christopher W.; McGregor, Neil R.; Butt, Henry L.; Gooley, Paul R. (1 January 2014). "Metabolism in chronic fatigue syndrome". Advances in Clinical Chemistry. 66: 121–172. PMID 25344988.
- Morris, Gerwyn; Anderson, George; Galecki, Piotr; Berk, Michael; Maes, Michael (8 March 2013). "A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior". BMC Medicine. 11: 64. PMC . PMID 23497361. doi:10.1186/1741-7015-11-64.
- Syndrome, Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue; Populations, Board on the Health of Select; Medicine, Institute of. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. National Academies Press. pp. 148–151. ISBN 9780309316897.
- Griffith, James; Zarrouf, Fahd (2008). "A Systematic Review of Chronic Fatigue Syndrome: Don't Assume It's Depression". Prim Care Companion Journal of Clinical Psychiatry. 10 (2): 120–128. PMC . PMID 18458765. doi:10.4088/pcc.v10n0206.
- Anderson, George; Maes, Michael; Berk, Michael (1 June 2012). "Biological underpinnings of the commonalities in depression, somatization, and Chronic Fatigue Syndrome". Medical Hypotheses. 78 (6): 752–756. PMID 22445460. doi:10.1016/j.mehy.2012.02.023.
- Meeus, Mira; Mistiaen, Wilhelm; Lambrecht, Luc; Nijs, Jo (1 November 2009). "Immunological Similarities between Cancer and Chronic Fatigue Syndrome: The Common Link to Fatigue?". Anticancer Research. 29 (11): 4717–4726.
- Silverman, Marni N.; Heim, Christine M.; Nater, Urs M.; Marques, Andrea H.; Sternberg, Esther M. (11 December 2016). "Neuroendocrine and Immune Contributors to Fatigue". PM & R : the journal of injury, function, and rehabilitation. 2 (5): 338–346. PMC . PMID 20656615. doi:10.1016/j.pmrj.2010.04.008.
- Morris, Gerwyn; Anderson, George; Maes, Michael (20 October 2016). "Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways". Molecular Neurobiology: 1–14. doi:10.1007/s12035-016-0170-2.
- Cho HJ, Skowera A, Cleare A, Wessely S (2006). "Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology". Current Opinion in Psychiatry. 19 (1): 67–73. PMID 16612182. doi:10.1097/01.yco.0000194370.40062.b0.
- Papadopoulos, Andrew S.; Cleare, Anthony J. (27 September 2011). "Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome". Nature Reviews Endocrinology. 8 (1): 22–32. PMID 21946893. doi:10.1038/nrendo.2011.153.
- Tak LM, Cleare AJ, Ormel J, Manoharan A, Kok IC, Wessely S, Rosmalen JG (May 2011). "Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders.". Biol Psychol. 87 (2): 183–94. PMID 21315796. doi:10.1016/j.biopsycho.2011.02.002.
- Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ (2007). "Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome." (PDF). Neuropsychobiology. 55 (2): 112–20. PMID 17596739. doi:10.1159/000104468.
- Powell, Daniel JH; Liossi, Christina; Moss-Morris, Rona; Schlotz, Wolff (1 November 2013). "Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome". Psychoneuroendocrinology. 38 (11): 2405–2422. PMID 23916911. doi:10.1016/j.psyneuen.2013.07.004.
- Morris, Gerwyn; Berk, Michael; Galecki, Piotr; Maes, Michael (1 April 2014). "The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs)". Molecular Neurobiology. 49 (2): 741–756. PMID 24068616. doi:10.1007/s12035-013-8553-0.
- Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER; Lloyd; Vernon; Klimas; Jason; Bleijenberg; Evengard; White; Nisenbaum; Unger; International Chronic Fatigue Syndrome Study Group (2003). "Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution". BMC Health Serv Res. 3 (1): 25. PMC . PMID 14702202. doi:10.1186/1472-6963-3-25.
- Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A; Straus; Hickie; Sharpe; Dobbins; Komaroff (15 Dec 1994). "The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group". Ann Intern Med. 121 (12): 953–9. PMID 7978722. doi:10.7326/0003-4819-121-12-199412150-00009.
- Bansal, Amolak S (2016-07-19). "Investigating unexplained fatigue in general practice with a particular focus on CFS/ME". BMC Family Practice. 17 (81). PMC . PMID 27436349. doi:10.1186/s12875-016-0493-0.
- Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S; Kaplan; Gantz; Komaroff; Schonberger; Straus; Jones; Dubois; Cunningham-Rundles; Pahwa (1988). "Chronic fatigue syndrome: a working case definition". Ann Intern Med. 108 (3): 387–9. PMID 2829679. doi:10.7326/0003-4819-108-3-387.
- Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, et al. (2003). "Myalgic encephalomyalitis/chronic fatigue syndrome: Clinical working definition, diagnostic and treatment protocols" (PDF). Journal of Chronic Fatigue Syndrome. 11 (1): 7–97. doi:10.1300/J092v11n01_02. Archived from the original (PDF) on 2010-09-18.
- Craig T, Kakumanu S; Kakumanu (Mar 2002). "Chronic fatigue syndrome: evaluation and treatment". Am Fam Physician. 65 (6): 1083–90. PMID 11925084.
- Logan AC, Wong C (Oct 2001). "Chronic fatigue syndrome: oxidative stress and dietary modifications" (PDF). Altern Med Rev. 6 (5): 450–9. PMID 11703165.
Finally, recent evidence suggests celiac disease can present with neurological symptoms in the absence of gastrointestinal symptoms; therefore, celiac disease should be included in the differential diagnosis of CFS.
- Bradley LA, McKendree-Smith NL, Alarcón GS; McKendree-Smith; Alarcón (2000). "Pain complaints in patients with fibromyalgia versus chronic fatigue syndrome". Curr Rev Pain. 4 (2): 148–57. PMID 10998728. doi:10.1007/s11916-000-0050-2.
- Smith, Beth; Nelson, HD; Haney, E (December 2014). Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. (Evidence Reports/Technology Assessments, No. 219 ed.). Agency for Healthcare Research and Quality (US). Retrieved 22 January 2016.
- Smith, Beth; Nelson, HD; Haney, E; et al. (December 2014). Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Evidence Reports/Technology Assessments, No. 219 ed.). Agency for Healthcare Research and Quality (US). Retrieved 22 January 2016.
- London: National Institute for Health and Clinical Excellence (2007). Guideline 53: Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy). ISBN 1846294533. Retrieved 22 January 2016.
- Guideline 53: Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy). London: National Institute for Health and Clinical Excellence. 2017.
- Green, Carmen R.; Cowan, Penney; Elk, Ronit; O'Neil, Kathleen M.; Rasmussen, Angela L. (16 June 2015). "Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome". Annals of Internal Medicine. 162 (12): 860. doi:10.7326/M15-0338. Retrieved 20 January 2016.
- Adamowicz JL, Caikauskaite I, Friedberg F; Caikauskaite; Friedberg (Nov 2014). "Defining recovery in chronic fatigue syndrome: a critical review". Qual Life Res. 23 (9): 2407–16. PMID 24791749. doi:10.1007/s11136-014-0705-9.
- Clark C, Buchwald D, MacIntyre A, Sharpe M, Wessely S; Buchwald; MacIntyre; Sharpe; Wessely (January 2002). "Chronic fatigue syndrome: a step towards agreement". Lancet. 359 (9301): 97–8. PMID 11809249. doi:10.1016/S0140-6736(02)07336-1.
- The ME Association. "No decisions about me without me" (PDF). ME Association. The ME Association. Retrieved 20 January 2016.
- Shepherd, Charles (18 January 2016). "Patient reaction to the PACE trial". The Lancet Psychiatry. 3: e7–e8. doi:10.1016/S2215-0366(15)00546-5. Retrieved 20 January 2016.
- Agency for Healthcare Research and Quality, US Dept of Health and Human Services. "July 2016 Addendum, Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome".
- Goudsmit EM, Nijs J, Jason LA, Wallman KE; Nijs; Jason; Wallman (19 December 2011). "Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document". Disability and Rehabilitation. 34 (13): 1140–7. PMID 22181560. doi:10.3109/09638288.2011.635746.
- Chambers, Duncan; Bagnall, Anne-Marie; Hempel, Susanne; Forbes, Carol (4 December 2016). "Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review". Journal of the Royal Society of Medicine. 99 (10): 506–520. PMC . PMID 17021301. doi:10.1258/jrsm.99.10.506.
- Rimes, K. A. (1 January 2005). "Treatments for chronic fatigue syndrome" (PDF). Occupational Medicine. 55 (1): 32–39. PMID 15699088. doi:10.1093/occmed/kqi015.
- Papadopoulos, Andrew S.; Cleare, Anthony J. (27 September 2011). "Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome". Nature Reviews. Endocrinology. 8 (1): 22–32. PMID 21946893. doi:10.1038/nrendo.2011.153.
- Mitchell, William M (2016-06-02). "Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)". Expert Review of Clinical Pharmacology. 9 (6): 755–770. PMC . PMID 27045557. doi:10.1586/17512433.2016.1172960.
- Smith, M. E. Beth; Nelson, Heidi D.; Haney, Elizabeth; Pappas, Miranda; Daeges, Monica; Wasson, Ngoc; McDonagh, Marian (2014-12-01). Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Agency for Healthcare Research and Quality (US).
- Barclay, Laura (5 February 2013). "FDA Nixes Rintatolimod for Chronic Fatigue Syndrome". Medscape. Retrieved 18 January 2017.
- Cairns R, Hotopf M; Hotopf (2005). "A systematic review describing the prognosis of chronic fatigue syndrome". Occupational Medicine. 55 (1): 20–31. PMID 15699087. doi:10.1093/occmed/kqi013.
- Joyce J, Hotopf M, Wessely S; Hotopf; Wessely (1997). "The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review". QJM. 90 (3): 223–33. PMID 9093600. doi:10.1093/qjmed/90.3.223.
- Acheson ED (1959). "The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia". The American Journal of Medicine. 26 (4): 569–95. PMID 13637100. doi:10.1016/0002-9343(59)90280-3.
- Parish, JG (1978). "Early outbreaks of 'epidemic neuromyasthenia'". Postgraduate Medical Journal. 54: 711–717. PMC . PMID 370810. doi:10.1136/pgmj.54.637.711.
- Wojcik, W (2011). "Chronic fatigue syndrome: Labels, meanings and consequences". Journal of Psychosomatic Research. 70 (6): 500–504. PMID 21624573. doi:10.1016/j.jpsychores.2011.02.002.
- Lancet. Public health (1955). "Outbreak at the royal free". The Lancet. 266: 351–352. doi:10.1016/s0140-6736(55)92344-8.
- Price, JL (1961). "Myalgic encephalomyelitis". The Lancet. 1 (7180): 737–8. PMID 13737972. doi:10.1016/s0140-6736(61)92893-8.
- International Classification of Diseases. I. World Health Organization. 1969. pp. 158, (vol 2, pp. 173).
- McEvedy, CP; Beard, AW (January 1970). "Concept of benign myalgic encephalomyelitis.". British Medical Journal. 1: 11–5. PMC . PMID 5411596. doi:10.1136/bmj.1.5687.11.
- Speight, N (2013). "Myalgic encephalomyelitis/chronic fatigue syndrome: Review of history, clinical features, and controversies.". Saudi Journal of Medicine & Medical Sciences. 1 (1): 11–13. doi:10.4103/1658-631x.112905.
- Ramsay, AM (1988). "Myalgic encephalomyelitis, or what ?". Lancet. 2 (8602): 100–1. PMID 2898668. doi:10.1016/s0140-6736(88)90028-1.
- Ramsay, AM; Dowsett, EG; Dadswell, JV; Lyle, WH; Parish, JG (1977). "Icelandic disease (benign myalgic encephalomyelitis or royal free disease)". British Medical Journal. 1 (6072): 1350. PMC . PMID 861618. doi:10.1136/bmj.1.6072.1350-a.
- Ramsay AM. Myalgic encephalomyelitis and postviral fatigue states. Second Ed. 1988
- Straus, SE (1991). "History of chronic fatigue syndrome". Reviews of Infectious Diseases. 13 (Suppl. 1): S2–7. PMID 2020800. doi:10.1093/clinids/13.supplement_1.s2.
- "Press Briefing Transcripts". Centers for Disease Control and Prevention. November 3, 2006. Retrieved 2013-10-12.
- Shelokov A, Habel K, Verder E, Welsh W (August 1957). "Epidemic neuromyasthenia; an outbreak of poliomyelitislike illness in student nurses". The New England Journal of Medicine. 257 (8): 345–55. PMID 13464938. doi:10.1056/NEJM195708222570801.
- Blattner R (1956). "Benign myalgic encephalomyelitis (Akureyri disease, Iceland disease)". J. Pediatr. 49 (4): 504–6. PMID 13358047. doi:10.1016/S0022-3476(56)80241-2.
- edited by Straus, Stephen E. (1994). Chronic Fatigue Syndrome. New York, Basel, Hong Kong: Marcel Dekker Inc. p. 227. ISBN 0-8247-9187-8.
- Aoki T, Usuda Y, Miyakoshi H, Tamura K, Herberman RB (1987). "Low natural killer syndrome: clinical and immunologic features". Nat Immun Cell Growth Regul. 6 (3): 116–28. PMID 2442602.
- Wessely, S (1991). "History of postviral fatigue syndrome". British Medical Bulletin. 47 (4): 919–941. PMID 1794091.
- A. Melvin Ramsay (1986). Postviral Fatigue Syndrome. The saga of Royal Free disease. London: Gower. ISBN 0-906923-96-4.
- Simpson, LO (1984). "Myalgic encephalomyelitis". Journal of the Royal Society of Medicine. 84 (10): 633. PMC . PMID 1744860.
- Jason, LA; Richman, JA. "How science can stigmatize: The case of chronic fatigue syndrome". Journal of Chronic Fatigue Syndrome. 14 (4): 85–103. doi:10.1080/10573320802092146.
- Jason, LA; Holbert, C; Torres-Harding, S; Taylor, R (2004). "Stigma and the term chronic fatigue syndrome". Journal of Disability Policy Studies. 14 (4): 222–228. doi:10.1177/10442073040140040401.
- Royal Colleges of Physicians, Psychiatrists and General Practitioners (1996). Chronic fatigue syndrome; Report of a joint working group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners. London, UK: Royal College of Physicians of London. ISBN 1-86016-046-8.
- Chronic Fatigue Syndrome Gets a New Name By David Tuller February 10, 2015 11:01 am New York Times
- Reynolds KJ, Vernon SD, Bouchery E, Reeves WC; Vernon; Bouchery; Reeves (2004). "The economic impact of chronic fatigue syndrome". Cost effectiveness and resource allocation : C/E. 2 (1): 4. PMC . PMID 15210053. doi:10.1186/1478-7547-2-4.
- Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C; Corradi; Torres-Harding; Taylor; King (March 2005). "Chronic fatigue syndrome: the need for subtypes". Neuropsychol Rev. 15 (1): 29–58. PMID 15929497. doi:10.1007/s11065-005-3588-2.
- Avellaneda Fernández A, Pérez Martín A, Izquierdo Martínez M, Arruti Bustillo M, Barbado Hernández FJ, de la Cruz Labrado J, Díaz-Delgado Peñas R, Gutiérrez Rivas E, Palacín Delgado C, Rivera Redondo J, Ramón Giménez JR; Pérez Martín; Izquierdo Martínez; Arruti Bustillo; Barbado Hernández; de la Cruz Labrado J; Díaz-Delgado Peñas; Gutiérrez Rivas; Palacín Delgado; Rivera Redondo; Ramón Giménez (2009). "Chronic fatigue syndrome: aetiology, diagnosis and treatment". BMC Psychiatry. 9 Suppl 1: S1. PMC . PMID 19857242. doi:10.1186/1471-244X-9-S1-S1.
- Jason LA, Benton MC, Valentine L, Johnson A, Torres-Harding S; Benton; Valentine; Johnson; Torres-Harding (2008). "The Economic impact of ME/CFS: Individual and societal costs". Dyn Med. 7: 6. PMC . PMID 18397528. doi:10.1186/1476-5918-7-6.
- Broderick G, Craddock TJ; Craddock (2013). "Systems biology of complex symptom profiles: Capturing interactivity across behavior, brain and immune regulation". Brain, Behavior, and Immunity. 29: 1–8. PMC . PMID 23022717. doi:10.1016/j.bbi.2012.09.008.
- "ME/Chronic Fatigue Syndrome Awareness Day". Centers for Disease Control and Prevention. 2017-05-12. Retrieved July 12, 2017.
- Lee, Nancy. "Dr. Nancy Lee on International Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Day". U.S. Department of Health & Human Services. Archived from the original on 2012-07-08. Retrieved 2013-10-12.
- "'Torrent of abuse' hindering ME research". BBC. 2011-07-29. Retrieved 2011-07-31.
- Wallace PG, Sharpe M (October 1991). "Post-viral fatigue syndrome. Epidemiology: a critical review" (PDF). Br Med Bull. 47 (4): 942–951. PMID 1794092.
- Mounstephen A, Sharpe M; Sharpe (1997). "Chronic fatigue syndrome and occupational health". Occupational Medicine. 47 (4): 217–27. PMID 9231495. doi:10.1093/occmed/47.4.217.
- Hooge J (1992). "Chronic fatigue syndrome: cause, controversy and care". Br J Nurs. 1 (9): 440–1, 443, 445–6. PMID 1446147.
- Sharpe M (1996). "Chronic fatigue syndrome". Psychiatr. Clin. North Am. 19 (3): 549–73. PMID 8856816. doi:10.1016/S0193-953X(05)70305-1.
- Denz-Penhey H, Murdoch JC; Murdoch (1993). "General practitioners acceptance of the validity of chronic fatigue syndrome as a diagnosis". N. Z. Med. J. 106 (953): 122–4. PMID 8474729.
- Greenlee JE, Rose JW; Rose (2000). "Controversies in neurological infectious diseases". Semin Neurol. 20 (3): 375–86. PMID 11051301. doi:10.1055/s-2000-9429.
- Horton-Salway M (2007). "The ME Bandwagon and other labels: constructing the genuine case in talk about a controversial illness". Br J Soc Psychol. 46 (Pt 4): 895–914. PMID 17535450. doi:10.1348/014466607X173456.
- Bowen, J; Pheby, D; Charlett, A; McNulty, C (August 2005). "Chronic Fatigue Syndrome: a survey of GPs' attitudes and knowledge.". Family practice. 22 (4): 389–93. PMID 15805128. doi:10.1093/fampra/cmi019.
- Larun, L; Malterud, K (December 2007). "Identity and coping experiences in Chronic Fatigue Syndrome: a synthesis of qualitative studies.". Patient education and counseling. 69 (1–3): 20–8. PMID 17698311. doi:10.1016/j.pec.2007.06.008.
- Dumit J (2005-08-08). "Illnesses you have to fight to get: facts as forces in uncertain, emergent illnesses". Soc Sci Med. 62 (3): 577–90. PMID 16085344. doi:10.1016/j.socscimed.2005.06.018.
- Lombardi VC, Ruscetti FW, Das Gupta J, et al. (October 2009). "Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome". Science. 326 (5952): 585–9. Bibcode:2009Sci...326..585L. PMID 19815723. doi:10.1126/science.1179052. (Retracted, see doi:10.1126/science.334.6063.1636-a)
- "No blood from chronic fatigue donors: agency". CBC. 2010-04-07. Archived from the original on April 11, 2010. Retrieved 2010-06-25.
- Atkinson, K (2010-04-21). "Chronic Fatigue Set To Disqualify Blood Donors". Voxy.co.nz. Retrieved 2010-06-25.
- "Blood Service updates CFS donor policy". Australian Red Cross Blood Service. Archived from the original on October 14, 2013. Retrieved 2013-07-07.
- "Recommendation on Chronic Fatigue Syndrome and Blood Donation". American Association of Blood Banks. 2010-06-18. Archived from the original on June 25, 2010. Retrieved 2010-06-25.
- NHS Blood and Transplant (2010-11-05). "ME/CFS sufferers permanently deferred from giving blood". Retrieved 2011-10-09.
- NHS Blood and Transplant. "Chronic Fatigue Syndrome". Retrieved 2015-02-11.
- Hempel S, Chambers D, Bagnall AM, Forbes C (July 2008). "Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies". Psychol Med. 38 (7): 915–26. PMID 17892624. doi:10.1017/S0033291707001602.
- Tuller, David (2008-05-30). "Chronic Fatigue Syndrome No Longer Seen as 'Yuppie Flu'". The New York Times. Retrieved 2015-06-29.
- Jason LA, Richman JA, Friedberg F, Wagner L, Taylor R, Jordan KM; Richman; Friedberg; Wagner; Taylor; Jordan (1997). "Politics, science, and the emergence of a new disease. The case of chronic fatigue syndrome". Am Psychol. 52 (9): 973–83. PMID 9301342. doi:10.1037/0003-066X.52.9.973.
- Couper J (2000). "Chronic fatigue syndrome and Australian psychiatry: lessons from the UK experience". Aust N Z J Psychiatry. 34 (5): 762–9. PMID 11037362. doi:10.1046/j.1440-1614.2000.00810.x.
- Erlwein O; et al. (2010). Nixon, Douglas F, ed. "Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome". PLoS ONE. 5 (1): e8519. Bibcode:2010PLoSO...5.8519E. PMC . PMID 20066031. doi:10.1371/journal.pone.0008519.
- Harriet C T Groom, Virginie C Boucherit, Kerry Makinson, Edward Randal, Sarah Baptista, Suzanne Hagan, John W Gow, Frank M Mattes, Judith Breuer, Jonathan R Kerr, Jonathan P Stoye, Kate N Bishop (2010). "Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome". Retrovirology. 7 (1): 10. PMC . PMID 20156349. doi:10.1186/1742-4690-7-10.
- van Kuppeveld FJ, Jong AS, Lanke KH, et al. (2010). "Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort". BMJ. 340: c1018. PMC . PMID 20185493. doi:10.1136/bmj.c1018.
- Alberts B (December 2011). "Retraction". Science. 334 (6063): 1636. Bibcode:2011Sci...334.1636A. PMID 22194552. doi:10.1126/science.334.6063.1636-a.
- Lo SC, Pripuzova N, Li B, et al. (January 2012). "Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors". Proc. Natl. Acad. Sci. U.S.A. 109 (1): 346. Bibcode:2012PNAS..109..346.. PMC . PMID 22203980. doi:10.1073/pnas.1119641109.
- Cowley, Geoffrey, with Mary Hager and Nadine Joseph (1990-11-12). "Chronic Fatigue Syndrome". Newsweek: Cover Story.
- Frumkin H; Packard RM; Brown P; Berkelman RL (2004). Emerging illnesses and society: negotiating the public health agenda. Baltimore: Johns Hopkins University Press. pp. 156. ISBN 0-8018-7942-6.
- "Erythos.com" (PDF). Retrieved 2011-01-28.
- "Chronic Fatigue Syndrome/Myalgic Encephalomyelitis". MRC.ac.uk. Archived from the original on January 6, 2011. Retrieved 2011-01-28.
- "APPGME.org.uk" (PDF). Retrieved 2011-01-28.
- "IACFS/ME Statement on the PACE Trial: The Issue of Illness 'Reversal'", 24 February 2011, The International Association for Chronic Fatigue Syndrome/ME (IACFS/ME), "Archived copy". Archived from the original on 2011-07-18. Retrieved 2011-08-03.
- "PACE: 'surprising and disappointing'", 18 February 2011, Action for ME, http://www.afme.org.uk/news.asp?newsid=1047
- "ME Association press statement about the results of the PACE study", Tony Britton for the ME Association, 18 February 2011, http://www.meassociation.org.uk/?p=4607
- "Falling off the PACE", Kimberly McCleary, [undated (Retrieved 26 July 2011)], The CAA (CFIDS Association of America), "Archived copy" (PDF). Archived from the original (PDF) on 2011-06-25. Retrieved 2011-08-03.
- NIH takes action to bolster research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | National Institutes of Health (NIH)
- Whistler T, Unger ER, Nisenbaum R, Vernon SD; Unger; Nisenbaum; Vernon (December 2003). "Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome". J Transl Med. 1 (1): 10. PMC . PMID 14641939. doi:10.1186/1479-5876-1-10.
- Kennedy G, Abbot NC, Spence V, Underwood C, Belch JJ; Abbot; Spence; Underwood; Belch (February 2004). "The specificity of the CDC-1994 criteria for chronic fatigue syndrome: comparison of health status in three groups of patients who fulfill the criteria". Ann Epidemiol. 14 (2): 95–100. PMID 15018881. doi:10.1016/j.annepidem.2003.10.004.
- Aslakson E, Vollmer-Conna U, White PD; Vollmer-Conna; White (April 2006). "The validity of an empirical delineation of heterogeneity in chronic unexplained fatigue". Pharmacogenomics. 7 (3): 365–73. PMID 16610947. doi:10.2217/146224126.96.36.1995.