Chronic fatigue syndrome (CFS) is the common name for a group of significantly debilitating medical conditions characterized by persistent fatigue and other specific symptoms that lasts for a minimum of six months in adults (and 3 months in children or adolescents). The fatigue is not due to exertion, not significantly relieved by rest, and is not caused by other medical conditions. CFS may also be referred to as myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), or by several other terms. Biological, genetic, infectious and psychological mechanisms have been proposed, but the etiology of CFS is not understood and it may have multiple causes.
Symptoms of CFS include malaise after exertion; unrefreshing sleep, widespread muscle and joint pain, sore throat, headaches of a type not previously experienced, cognitive difficulties, chronic and severe mental and physical exhaustion, and other characteristic symptoms in a previously healthy and active person. Additional symptoms may be reported, including muscle weakness, increased sensitivity to light, sounds and smells, orthostatic intolerance, digestive disturbances, depression, painful and often slightly swollen lymph nodes, cardiac and respiratory problems. It is unclear if these symptoms represent co-morbid conditions or if they are produced by an underlying etiology of CFS. CFS symptoms vary in number, type, and severity from person to person. Quality of life of persons with CFS can be extremely compromised.
Fatigue is a common symptom in many illnesses, but CFS is comparatively rare. Estimates of prevalence vary from 7 to 3,000 cases of CFS for every 100,000 adults; national health organizations have estimated more than one million Americans and approximately a quarter of a million people in the UK have CFS. CFS occurs more often in women than men, and is less prevalent among children and adolescents.
Although there is agreement that CFS poses genuine threats to health, happiness and productivity, various physicians' groups, researchers and patient advocates promote differing nomenclatures, diagnostic criteria, etiologic hypotheses and treatments, resulting in controversy about many aspects of the disorder. The name "chronic fatigue syndrome" is controversial; many patients and advocacy groups, as well as some experts, believe the name trivializes the medical condition and they promote a name change.
The Oxford criteria (1991) include CFS of unknown etiology and a subtype called post-infectious fatigue syndrome (PIFS). Important differences are that the presence of mental fatigue is necessary to fulfill the criteria and symptoms are accepted that may suggest a psychiatric disorder.
The 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 will persist for at least 6 months]".
The different case definitions used to research the illness may influence the types of patients selected for studies, and research also suggests subtypes of patients exist within the heterogeneous illness.
Chronic fatigue syndrome is the most commonly used designation, but widespread approval of a name is lacking. Different authorities on the illness view CFS as a central nervous system, metabolic, infectious or post-infectious, cardiovascular, immune system or psychiatric disorder, and different symptom profiles may be caused by various disorders.
Over time and in different countries, many names have been associated with the condition(s). Aside from CFS, some other names used include Akureyri disease, benign myalgic encephalomyelitis, chronic fatigue immune dysfunction syndrome, chronic infectious mononucleosis, epidemic myalgic encephalomyelitis, epidemic neuromyasthenia, Iceland disease, myalgic encephalomyelitis, myalgic encephalitis, myalgic encephalopathy, post-viral fatigue syndrome, raphe nucleus encephalopathy, Royal Free disease, Tapanui flu, and yuppie flu (the last considered pejorative). Many patients would prefer a different name such as "myalgic encephalomyelitis", believing the name "chronic fatigue syndrome" trivializes the condition, prevents it from being seen as a serious health problem, and discourages research.
A 2001 review referenced myalgic encephalomyelitis symptoms in a 1959 article by Acheson, stating ME could be a distinct syndrome from CFS, but in literature the two terms are generally seen as synonymous. A 1999 review explained that the Royal Colleges of Physicians, Psychiatrists, and General Practitioners in 1996 advocated the use of chronic fatigue syndrome instead of myalgic encephalomyelitis or ME, which was in wide use in the United Kingdom, "because there is, so far, no recognized pathology in muscles and in the central nervous system as is implied by the term ME." An editorial noted that the 1996 report received some acceptance, but also criticism from those advocating the use of different naming conventions, suggesting the report was biased, dominated by psychiatrists, and that dissenting voices were excluded. In 2002, a Lancet commentary noted the recent report by the "Working Group on CFS/ME" used the compromise name CFS/ME stating, "The fact that both names for the illness were used symbolises respect for different viewpoints whilst acknowledging the continuing lack of consensus on a universally acceptable name."
Signs and symptoms
The majority of CFS cases start suddenly, usually accompanied by a "flu-like illness" while a significant proportion of cases begin within several months of severe adverse stress. An Australian prospective study found that after infection by viral and non-viral pathogens, a sub-set of individuals met the criteria for CFS, with the researchers concluding that "post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to CFS". However, accurate prevalence and exact roles of infection and stress in the development of CFS are currently unknown.
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 last six months or longer:
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.
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 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.
Many people do not fully recover from CFS even with treatment.Cognitive behavioural therapy (CBT) and graded exercise therapy (GET) have shown moderate effectiveness for many people in multiple randomized controlled trials. As many of the CBT and GET studies required visits to a clinic, those severely affected may not have been included. Two large surveys of patients indicated that pacing is a helpful intervention, or is considered useful by 82-96% of participants. Medication plays a minor role in management. No intervention has been proven effective in restoring the ability to work.
Cognitive behavioral therapy
Cognitive behavioral therapy, a form of psychological therapy often used to treat chronically ill patients, is a moderately effective treatment for CFS that can be useful to "manage activity levels, stress, and symptoms." CBT tries to help patients understand their individual symptoms and beliefs and develop strategies to improve day-to-day functioning whatever the cause of the symptoms. CBT is also thought to help patients by removing unhelpful illness beliefs which may perpetuate the illness.
A Cochrane Review meta-analysis of 15 randomized, controlled cognitive behavioral therapy trials with 1043 participants concluded that CBT was an effective treatment to reduce the symptom of fatigue. Four reviewed studies showed that CBT resulted in a clinical response for 40% of participants vs 26% of those treated with "usual care". Similarly, in three studies CBT worked better than other types of psychological therapies (48% vs 27%). The effects may diminish after a course of therapy is completed; the reviewers write that "the evidence base at follow-up is limited to a small group of studies with inconsistent findings" and encourage further studies. A 2007 meta-analysis of 5 CBT randomized controlled trials of chronic fatigue and chronic fatigue syndrome reported 33-73% of the patients improved to the point of no longer being clinically fatigued. A 2010 meta-analysis of trials that measured physical activity before and after CBT showed that although CBT effectively reduced fatigue, activity levels were not affected by CBT and changes in physical activity were not related to changes in fatigue. They conclude that the effect of CBT on fatigue is not mediated by a change in physical activity.
CBT has been criticised by patients' organisations because of negative reports from some of their members that have indicated that CBT can make people worse, a common result across multiple patient surveys. Some dispute the evidence base behind CBT as well as graded exercise therapy (below), and conclude that it would be unethical to use these modalities.
Graded exercise therapy
Graded exercise therapy is a form of physical therapy. A meta-analysis published in 2004 of five randomized trials found that patients who received exercise therapy were less fatigued after 12 weeks than the control participants, and the authors cautiously conclude that GET shows promise as a treatment. However, after 6 months the benefit became non-significant compared to the control group who did not receive GET, and functional work capacity was not significantly improved after therapy. A systematic review published in 2006 included the same five RCTs, noting that "no severely affected patients were included in the studies of GET". Surveys conducted on behalf of patient organizations find adverse effects to be very common.
To avoid detrimental effects from GET, care must be taken to avoid the exacerbation of symptoms while catering the program to individual capabilities and the fluctuating nature of symptoms.
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. Some programmes combine symptom and time-contingent approaches. A trial of one such programme reported limited benefits. A larger, randomised controlled trial found that pacing had statistically better results than relaxation/flexibility therapy. A 2009 survey of 828 Norwegian CFS patients found that pacing was evaluated as useful by 96% of the participants.
Other treatments of CFS have been proposed but their effectiveness has not been confirmed. Medications thought to have promise in alleviating symptoms include antidepressant and immunomodulatory agents. The evidence for antidepressants is mixed, and their use remains controversial. Many CFS patients are sensitive to medications, particularly sedatives, and some patients report chemical and food sensitivities. CFS patients have a low placebo response, especially to psychological-psychiatric interventions, perhaps due to patient expectations.
A systematic review of 14 studies that 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, a sense of control over symptoms and not attributing illness to a physical cause. 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 premorbid levels of functioning.
A 2003 review states that studies have 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 reports that more than 1 million Americans have CFS and approximately 80% of the cases are undiagnosed. Approximately 250,000 people in the UK are affected with the illness according to the National Health Service.
All ethnic and racial groups appear susceptible to the illness, and lower income groups are slightly more likely to develop CFS. A 2009 meta-analysis showed that compared with the White American majority, African Americans and Native Americans have a significantly higher risk of CFS. 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 people between the ages of 40 and 59. CFS is less prevalent among children and adolescents than adults. Blood relatives of people who have CFS appear to be more predisposed. There is no direct evidence that CFS is contagious.
A systematic review in 2008 included eleven primary studies that had assessed various demographic, medical, psychological, social and environmental factors to predict the development of CFS, and found many had reported significant associations to CFS. The reviewers concluded that the lack of generalizability and replication between studies meant that "none of the identified factors appear suitable for the timely identification of patients at risk of developing CFS/ME within clinical practice."
Certain medical conditions can cause chronic fatigue and must be ruled out before a diagnosis of CFS can be given. Hypothyroidism, anemia, diabetes and certain psychiatric disorders are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms.
People 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, though the two diseases often co-occur. Fatigue and muscle pain occurs frequently in the initial phase of various hereditary muscle disorders and in several autoimmune, endocrine and metabolic syndromes; and are frequently labelled as CFS or fibromyalgia in the absence of obvious biochemical/metabolic abnormalities and neurological symptoms.
A 2006 review found that there was a lack of literature to establish the discriminant validity of undifferentiated somatoform disorder from CFS. The author stated that there is a need for proponents of chronic fatigue syndrome to distinguish it from undifferentiated somatoform disorder. The author also mentioned that the experience of fatigue as exclusively physical and not mental is captured by the definition of somatoform disorder but not CFS. Hysterical diagnoses are not merely diagnoses of exclusion but require criteria to be met on the positive grounds of both primary and secondary gain.
Depressive symptoms, if seen in CFS, may be differentially diagnosed from primary depression due to 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 postexertional exacerbation of symptoms.
Many CFS patients will also have, or appear to have, other medical problems or related diagnoses. Co-morbid fibromyalgia is common. Fibromyalgia occurs in a large percentage of CFS patients between onset and the second year, and some researchers suggest fibromyalgia and CFS are related. As previously mentioned, many CFS sufferers also experience symptoms of irritable bowel syndrome, temporomandibular joint pain, headache including migraines, and other forms of myalgia. Though CFS patients have significantly higher rates of current mood disorders than the general population, feeling anxious or depressed is a commonplace reaction to the losses caused by any chronic physical illness which can in some cases become a comorbid situational depression. Compared with the non-fatigued population, male CFS patients are more likely to experience chronic pelvic pain syndrome (CP/CPPS), and female CFS patients are also more likely to experience chronic pelvic pain. CFS is significantly more common in women with endometriosis compared with women in the general USA population.
In 1934, an outbreak then referred to as atypical poliomyelitis (at the time it was considered a form of polio) occurred at the Los Angeles County Hospital. It strongly resembled what is now called chronic fatigue syndrome and affected a large number of nurses and doctors. In 1955 at the Royal Free Hospital in London, another outbreak occurred that also affected mostly the hospital staff. Also resembling CFS, it was called both Royal Free disease and benign myalgic encephalomyelitis and formed the basis of descriptions by Acheson, Ramsay, and others. In 1969, benign myalgic encephalomyelitis was first classified into the International Classification of Diseases under Diseases of the nervous system.
The name chronic fatigue syndrome was used in the medical literature in 1987 to describe a condition resembling "chronic active Epstein-Barr virus (EBV) infection" but which presented no evidence of EBV as its cause. The initial case definition of CFS was published in 1988, "Chronic fatigue syndrome: a working case definition", (the Holmes definition), and displaced the name chronic Epstein-Barr virus syndrome. This research case definition was published after US Centers for Disease Control and Prevention epidemiologists examined patients at the Lake Tahoe outbreak. In 2006, the CDC commenced a national program to educate the American public and health care professionals about CFS.
A 2009 study published in the journal Science reported an association between a retrovirus xenotropic murine leukemia virus-related virus (XMRV) and CFS. The editors of Science subsequently attached an "Editorial Expression of Concern" to the report to the effect that the validity of the study "is now seriously in question". and in September 2011, the authors published a "Partial Retraction" of their 2009 findings, this was followed by a full retraction by the magazine’s Editor in Chief after the authors failed to agree on a full retraction statement. Also in September 2011, the Blood XMRV Scientific Research Working Group published a report which concluded "that currently available XMRV/P-MLV assays, including the assays employed by the three participating laboratories that previously reported positive results on samples from CFS patients and controls (2, 4), cannot reproducibly detect direct virus markers (RNA, DNA, or culture) or specific antibodies in blood samples from subjects previously characterized as XMRV/P-MLV positive (all but one with a diagnosis of CFS) or healthy blood donors." In December 2011, the Proceedings of the National Academy of Sciences published a similar retraction for an August 2010 paper.
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 support for 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.
Society and culture
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.
A study found that CFS patients report a heavy psychosocial burden. A survey by the Tymes Trust reported that children with CFS often state that they struggle for recognition of their needs or they feel bullied by medical and educational professionals.
A study found that CFS patients in support groups reported no change in negative interactions compared to an improvement in negative interactions reported by those treated with Cognitive Behavioural Therapy. Patients with greater amounts of negative interactions received worse social support on average than disease-free cancer patients or healthy controls which, in turn, led to greater fatigue severity and functional impairment than CBT-treated patients.
May 12 is designated as International Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Awareness Day (ME/CFS). 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. The context of contested causation may affect the lives of the individuals diagnosed with CFS, affecting the patient-doctor relationship, the doctor's confidence in their ability to diagnose and treat, ability to share issues and control in diagnosis with the patient, and raise problematic issues of reparation, compensation, and blame. Disagreements over how the condition is dealt with by health-care systems have resulted in an expensive and prolonged conflict for all involved.
A major divide exists over whether funding for research and treatment should focus on physiological, psychological, or psychosocial aspects of CFS. This division is especially great between patient groups and psychological and psychosocial treatment advocates in Great Britain. In 2011, it was reported by the BBC that this conflict had involved personal vilification and allegations of professional misconduct to professional societies and universities of researchers who were investigating possible psychiatric connections. One of these researchers, Simon Wessely, reported personal death threats. Virologist Myra McClure stated she was subjected to horrible abuse from extremists after publishing a paper indicating that early studies suggesting a link between CFS and the XMRV virus were flawed. As a result, she decided not to pursue any further research into CFS. Pediatrician Esther Crawley changed her phone number and talked to the police. Wellcome Trust's Mark Walport indicated good research is needed to understand the illness, but it would be tragic if serious researchers are dissuaded from working on it. He further stated, "But why would any scientist work on it if they know that all they're going to receive is a torrent of abuse?" The ME Association's Charles Shepherd stated the abuse of researchers was unacceptable, but also that patients are angry and frustrated by a lack of UK government funding into bio-medical research for the illness that is instead going to psychological research.
There has been much contention over the etiology, pathophysiology, nomenclature, and diagnostic criteria of chronic fatigue syndrome. Controversies still exist over funding for research and treatment of physiological versus psychological and psychosocial aspects of the illness. 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. Contrasting viewpoints among CFS experts became apparent in 1993, when psychiatrists David and Wessely contested the WHO classification of CFS under diseases of the nervous system, arguing that it was a form of neurasthenia to be classified as a psychiatric condition.
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