Chronic fatigue syndrome.html
 
| ca | de | en | es | fr | it | nl | no | pl | pt | ru | ro | fi | sv | tr | vo |


 

Chronic fatigue syndrome
Classification and external resources
ICD-10 G93.3
ICD-9 780.71
DiseasesDB 1645
MedlinePlus 001244
eMedicine med/3392  ped/2795
MeSH D015673

Chronic fatigue syndrome (CFS) is the most common name1 given to a poorly understood, variably debilitating disorder or disorders of uncertain causation.

Symptoms of CFS include widespread muscle and joint pain, cognitive difficulties, chronic, often severe mental and physical exhaustion and other characteristic symptoms in a previously healthy and active person. Fatigue is a common symptom in many illnesses, but CFS is a multi-systemic disease and is relatively rare by comparison.2 Diagnosis requires a number of features, the most common being severe mental and physical exhaustion which is "unrelieved by rest," is worsened by exertion, and is present for at least six months. All diagnostic criteria require that the symptoms must not be caused by other medical conditions. CFS patients may report additional symptoms,3 including muscle weakness, cognitive dysfunction, hypersensitivity, orthostatic intolerance, digestive disturbances, depression, poor immune response, and cardiac and respiratory problems. It is unclear if these symptoms represent co-morbid conditions or are produced by an underlying etiology of CFS.4 Full resolution occurs in only 5-10% of cases.5

CFS is thought to have an incidence of 4 adults per 1,000 in the United States.6 For unknown reasons, CFS occurs more often in women than men, and in people in their 40s and 50s.78 The illness is estimated to be less prevalent among children and adolescents,5 but studies are contradictory as to the degree.citation needed There is no medical test which is widely accepted to be diagnostic of CFS. It remains a diagnosis of exclusion based largely on patient history and symptomatic criteria, although a number of tests can aid diagnosis.9

Whereas there is agreement on the genuine threat to health, happiness, and productivity posed by CFS, various physicians groups, researchers, and patient activists promote different nomenclature, diagnostic criteria, etiologic hypotheses, and treatments, resulting in controversy about many aspects of the disorder. The name CFS itself is controversial, as advocacy groups as well as some experts feel it trivializes the illness and have supported efforts to change it. Many alternative names for chronic fatigue syndrome exist.

Contents

Signs and symptoms

Onset

The majority of CFS cases start suddenly,10 usually accompanied by a "flu-like illness"4 which is more likely to occur in winter,1112 while a significant proportion of cases begin within several months of severe adverse stress.131410 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".15 The accurate prevalence and exact roles of infection and stress in the development of CFS however are currently unknown.

Symptoms

The United States Centers for Disease Control (CDC) has established a definition of CFS16 that is the most commonly used in research and clinical applications.3 According to the CDC, CFS involves:

1. Fatigue, unexplained, persisting (lasting six months or longer), "not due to ongoing exertion," and not substantially reduced by rest. The person must have experienced a significant reduction in activity levels.
2. Four or more of the following symptoms:
  • 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)

When symptoms can be due to other conditions, the diagnosis of CFS is excluded. The CDC specifically refers to several problems with symptoms resembling those of CFS: "mononucleosis, Lyme disease, lupus, multiple sclerosis, fibromyalgia, primary sleep disorders, severe obesity and major depressive disorders. Medications can also cause side effects that mimic the symptoms of CFS."16

Activity levels

Patients report critical reductions in levels of physical activity17 and are as impaired as persons whose fatigue can be explained by another medical or a psychiatric condition.18 According to the CDC, studies show that the degree of disability or functional impairment in CFS patients is comparable to that caused by well-known, severe medical conditions, such as multiple sclerosis, late-stage AIDS, lupus, rheumatoid arthritis, heart disease, end-stage renal disease, chronic obstructive pulmonary disease (COPD), and the effects of chemotherapy.1920 The severity of symptoms and disability is the same in both genders,21 and chronic pain is strongly disabling in CFS patients,22 but despite a common diagnosis the functional capacity of CFS patients varies greatly.23 While some patients are able to lead a relatively normal life, others are totally bed-bound and unable to care for themselves. A systematic review found that in a synthesis of studies, 42% of patients were employed, 54% were unemployed, 64% reported CFS-related work limitations, 55% were on disability benefits or temporary sick leave, and 19% worked full-time.9

Research

The lack of any established test to detect this disorder, or evaluate the patient response to any treatment, challenges all researchers and prevents objective research results that conforms to typical medical standards. Many of the active researchers were the original attending physicians at outbreaks: Paul Cheney MD and Daniel Petersen MD and David Sheffield Bell MD. The Chronic Fatigue Syndrome Advisory Committee have included several US experts including Nancy Klimas MD, Lucinda Bateman MD, Christopher Snell PhD, Morris Papernik MD.

Text Books

The principle text books are compliations of prior medical journal articles. They include:

Mechanism

Main article: Pathophysiology of chronic fatigue syndrome

The mechanisms and pathogenesis of chronic fatigue syndrome are unknown,5 but are the subjects of many research studies, including physiological and epidemiological studies. The Centers for Disease Control and Prevention maintains a list of experts studies on mechanisms. Hypotheses being researched include viral infection,bacterial infections, hypothalamic-pituitary-adrenal axis abnormalities (though it is unclear if this is a cause, or consequence, of CFS), immune dysfunction as well as mental and psychosocial factors causing or contributing towards CFS;24 though some individuals with CFS firmly reject any psychological involvement and believe strongly that their condition has a physical cause.25 Other hypotheses include oxidative stress and genetic predisposition.26

Exposure to chemicals, infectious agents, stress, and other insults in early life have been suggested as a component of later-life CFS.27 Another hypothesis is that a virus or another infectious agent might provoke an abnormal immune response in some people becomes a chronic, rather than an acute response.28 Abnormal expressions have also been documented for 88 human genes in CFS patients; the genes were associated with blood diseases and functioning, the immune system, cancer, cell death and infection.29 Abnormal biological responses to exercise have also been detected, relating to oxidative stress3031 and immune function.32

The central nervous system is important in CFS. Research has been reported on a "Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis (HPA axis)" in CFS.33 Genetic factors may be the basis for some of these changes. A 2008 study of gene polymorphisms indicates genetic predisposition possibly resulting in enhanced activity of serotonin.34 Another report says that low cortisol levels can be responsible: "hypocortisolaemia might sensitize the hypothalamic-pituitary-adrenal axis to development of persistent central fatigue after stress."35 Some researchers conclude that the involvement of the nervous and immune systems involvements are intertwined.36

Psychological factors

The success of certain treatments suggests CFS may be perpetuated when patients fixate on a physical cause of illness, their symptoms and when exercise is avoided. Lack of support or reinforcement of illness behavior from social networks can also delay recovery,37 as can conflict with doctors who insist on psychological causes over a patient's objections. High scores of neuroticism and introversion on psychological tests have also been associated with a predisposition to developing CFS.38

Classification

Main article: Clinical descriptions of chronic fatigue syndrome

There are no medical tests or physical signs to diagnose CFS,5 so testing is used to rule out other potential causes for symptoms.39 The most widely used3 clinical and research description of CFS is the CDC definition published in 1994 (details given above).39 The 1994 CDC definition, also called the Fukuda definition after the first author on the report, was based on the Holmes or CDC 1988 scoring system.40 The 1994 criteria require the presence of only four symptoms beyond fatigue, where the 1988 criteria require six to eight.41

Other notable definitions include

  • The Oxford criteria (1991)42
  • The 2003 Canadian case definition for ME/CFS43 was developed "in an attempt to exclude psychiatric cases."38 This definition requires presence of symptoms from at least one category of autonomic, neuroendocrine, or immune symptoms. Doctors with the National Health Service in the UK are discouraged from using this case definition, since requiring the presence of these signs could exclude patients,41 and the criteria "have not been evaluated for research purposes."44

Using different case definitions may influence the types of patients selected.45 Some authors suggest that subtypes of patients may exist.46 Clinical practice guidelines, with the aim of improving diagnosis, management, and treatment, are generally based on case descriptions. Guidelines are usually produced at national or international levels by medical associations or governmental bodies after evidence is examined and usually include summarized consensus statements. An example of a CFS guideline for the National Health Service in England and Wales, produced in 2007 by the National Institute for Health and Clinical Excellence (NICE).41

Treatment

Main article: Chronic fatigue syndrome treatment

Many patients do not fully recover from CFS, even with treatment.47 Suggested treatments for CFS include diets, physiotherapy, supplements, anti-depressants, pain killers, pacing or energy management, graded exercise/activity and complementary and alternative medicine. Some management strategies are suggested to reduce the consequences of having CFS, including cognitive behavioral therapy and graded exercise therapy (GET).4838495051

Cognitive behavioral therapy

A treatment for CFS currently deemed as both evidence-based and moderately efficacious is cognitive behavioral therapy (CBT), a form of psychological therapy.52 Since the cause or causes of CFS are unknown, CBT tries to help patients understand their individual symptoms and beliefs and develop strategies to improve day-to-day functioning.53 CFS researcher Vincent Deary believes the CBT model of medically unexplained symptoms (MUS) has value as a heuristic for the generation of symptoms for conditions like CFS.54

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 symptoms of fatigue. Comparing CBT with "usual care," four reviewed studies showed that CBT was more effective (40% vs 26%). 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.55 One follow-up study of a cohort of 96 patients suggested that CBT could facilitate full recovery in some patients, with 69% no longer meeting the CDC criteria for CFS.56

In a review in The Lancet, Dutch researchers state that while CBT is not necessarily a cure for CFS, in some studies it results in improvements in about 70% of patients. They stress that, with the current understanding of the biological nature of the brain, a psychological CFS model does not preclude neurobiological components.38 The authors of the Australian 2002 clinical practice guidelines state that speculation about psychogenesis based on the outcome of CBT trials is unwarranted.57

Whether or not CBT works for individual patients depends on many factors. A treatment can only work if patients agree to it, and the Cochrane review acknowledges the "understandable ambivalence" of individuals with CFS to treat physical symptoms with a psychological treatment.55 According to one source, characteristics that predict a lack of effectiveness for CBT include disability insurance, self-help group membership, an external locus of control, focusing on symptoms and a lack of physical activity.38 However, a US study published in late 2008 significantly counters this position, arguing that self-pacing by patients provides improved results.58

Graded exercise therapy

Over half of CFS patients studied experience improvements when using graded exercise therapy (GET), a form of physical therapy.38 Meta-analysis of multiple randomized, controlled trials of exercise therapy of patients diagnosed with CFS shows improvements in fatigue symptoms over controls.4859 Some patient organizations dispute the results of the exercise therapy trials.60

Other

Other treatments of CFS have been proposed but not much is known about how effective they are.38 Medications thought to have promise in alleviating stress-related disorders include antidepressant and immunomodulatory agents such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin.61 CFS patients are less susceptible to placebo effects than predicted, and have a low placebo response compared to patients with other diseases.25 Many CFS patients are sensitive to medications, particularly sedatives, and some patients report sensitivities to various foods or chemicals.62

Prognosis

Recovery

A systematic review of 14 studies of the outcome of untreated 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."63 According to the CDC, delays in diagnosis and treatment can reduce the chance of improvement.64

Deaths

CFS is unlikely to increase the risk of an early death. A systematic review of 14 studies of the outcome of CFS reported 8 deaths, but none were considered directly attributable to CFS,63 though British patient Sophia Mirza's death was directly attributed to her condition.65 To date there have been two studies directly addressing life expectancy in CFS. A preliminary study of CFS self-help group members reported a greater likelihood of death at a younger than average for cancer and suicide.66 A later study of a much larger group with a longer follow-up found that mortality rates of individuals with CFS did not differ from the general population of the United States.67

Epidemiology

Due to the multiple definition of CFS, estimates of its prevalence vary widely. Studies in the United States have previously found between 75 and 420 cases of CFS for every 100,000 adults. The CDC states that more than 1 million Americans have CFS and approximately 80% of the cases are undiagnosed.5 All ethnic and racial groups appear susceptible to the illness, and lower income groups are slightly more likely to develop CFS.8 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. Blood relatives of people who have CFS appear to be more predisposed.868 There is no evidence that CFS is contagious, though it is seen in members of the same family; this is believed to be a familial or genetic link but more research is required for a definite answer.69

Disease associations

Some diseases show a considerable overlap with CFS. Thyroid disorders, anemia, and diabetes are a few of the diseases that must be ruled out if the patient presents with appropriate symptoms.394170

People with fibromyalgia (FM, or fibromyalgia syndrome, FMS) have muscle pain and sleep disturbances. 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.citation needed Those with multiple chemical sensitivity (MCS) are sensitive to chemicals and have sleep disturbances. Many veterans with Gulf War syndrome (GWS) have symptoms almost identical to CFS.71 One study found several parallels when relating the symptoms of Post-polio syndrome with CFS, and postulates a possible common pathophysiology for the illnesses.72

Although post-Lyme syndrome and CFS share many features/symptoms, a study found that patients of the former experience more cognitive impairment and the patients of the latter experience more flu-like symptoms.73

One review (2006) 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.74 Hysterical diagnoses are not merely diagnoses of exclusion but require criteria to be met on the positive grounds of both primary and secondary gain.75 Primary depression can be excluded in the differential diagnosis due to the absence of anhedonia and la belle indifference, the variability (lability) of mood, and the presence of sensory phenomena and somatic signs such as ataxia, myclonus and most importantly, exercise intolerance with paresis, malaise and general deterioration.citation needed Feeling depressed is also a commonplace reaction to the losses caused by chronic illness76 which can in some cases become a comorbid situational depression.

Co-morbidity

Many CFS patients will also have, or appear to have, other medical problems or related diagnoses. Co-morbid fibromyalgia is common, where only patients with fibromyalgia show abnormal pain responses.77 Fibromyalgia occurs in a large percentage of CFS patients between onset and the second year, and some researchers suggest fibromyalgia and CFS are related.78 Similarly, multiple chemical sensitivity (MCS) is reported by many CFS patients, and it is speculated that these similar conditions may be related by some underlying mechanism, such as elevated nitric oxide/peroxynitrite.79 As previously mentioned, many CFS sufferers also experience symptoms of irritable bowel syndrome, temporomandibular joint pain, headache including migraines, and other forms of myalgia. CFS patients have significantly higher rates of current mood disorders than the general population.80 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.81 CFS is significantly more common in women with endometriosis compared with women in the general USA population.82

History

Main article: History of chronic fatigue syndrome

In 1934 there was an outbreak of a condition then referred to as atypical poliomyelitis at the Los Angeles County Hospital. Strongly resembling what is now called chronic fatigue syndrome and affecting a large number of nurses and doctors, at the time it was considered a form of polio.83 In 1955 at the Royal Free Hospital in London, United Kingdom, 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 Achenson, Ramsay, and others.84 In 1969 benign myalgic encephalomyelitis was first classified into the International Classification of Diseases under Diseases of the nervous system.85

The name chronic fatigue syndrome was proposed in the 1988 article, "Chronic fatigue syndrome: a working case definition", (the Holmes definition), to replace 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.868740 involving Paul Cheney MD and Daniel Petersen MD, who subsequently became early researchers. In 2006 the CDC commenced a public awareness program.5

Society and culture

Social issues

Many patients report that a chronic fatigue syndrome diagnosis carries a considerable social stigma, and has frequently been viewed as malingering, hypochondriasis, phobia, "wanting attention" or "yuppie flu". As there is no medical test to diagnose CFS, it has been argued that it is easy to invent or feign CFS-like symptoms for financial, social, or emotional benefits.8889 CFS sufferers argue in turn that the perceived "benefits" are hardly as generous as some may believe, and that CFS patients would greatly prefer to be healthy and independent. The Australian 2002 clinical practice guidelines for CFS state that "In the absence of evidence of malingering, speculative judgements about unconscious motivation should be avoided; the psychoanalytic concept of 'secondary gain' has been misused in medicolegal settings and does not rest on a solid empirical base."57

A study found that CFS patients endure a heavy psychosocial burden.90 2,338 respondents of a survey by a UK patient organization highlights that those with the worst symptoms often receive the least support from health and social services.91 A study found that CFS patients receive worse social support than disease-free cancer patients or healthy controls, which may perpetuate fatigue severity and functional impairment in CFS.37 A survey by the Thymes Trust found that children with CFS often state that they struggle for recognition of their needs and/or they feel bullied by medical and educational professionals.92 The ambiguity of the status of CFS as a medical condition may cause higher perceived stigma.93 A study suggests that while there are no gender differences in CFS symptoms, men and women have different perceptions of their illness and are treated differently by the medical profession.94 Anxiety and depression often result from the emotional, social and financial crises caused by CFS; analysis of the deaths of individuals with CFS found that suicide is one of the three most prevalent causes, and the mean age of suicide is much younger than that of the remainder of the population.66

Doctor-patient relations

Some in the medical community did not at first recognize CFS as a real condition, nor was there agreement on its prevalence.9596 There has been much disagreement over proposed causes, diagnosis, and treatment of the illness.979899100101 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.102 The etiology is unknown and a major divide exists over whether funding for research and treatment should focus on physiological, psychological or psychosocial aspects of CFS. The division is especially great between patient groups and psychological and psychosocial treatment advocates in Great Britain.101 Sufferers describe the struggle for healthcare and legitimacy due to bureaucratic denial of the condition because of its lack of a known etiology. Disagreements over how the condition is dealt with by health care systems has resulted in an expensive and prolonged conflict for all involved.10396

Naming

Main article: Alternative names for chronic fatigue syndrome

Selecting a name for CFS has been challenging, since consensus is lacking within the clinical, research, and patient communities regarding its defining features and causes. Different authorities on the illness view CFS as a central nervous system, metabolic, infectious or post-infectious, cardiovascular, immune system or psychiatric disorder, and also consider the possibility that it is not a single homogenous disorder with a range of possible clinical presentations, but a group of several distinct disorders with many clinical characteristics in common.citation needed

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 (now considered pejorative).104105 Many patients particularly prefer what they feel is a more "medical-sounding" term, such as "chronic fatigue immune dysfunction syndrome" (CFIDS)106 or "myalgic encephalomyelitis" (ME), believing the name "chronic fatigue syndrome" trivializes the condition and prevents it from being seen as a serious health problem.107108

Researchers question the accuracy of the term "myalgic encephalomyelitis" since there is "no recognized pathology in muscles and in the central nervous system."1109 For this reason, in 1999 the Royal Colleges of Physicians, Psychiatrists, and General Practitioners in the United Kingdom called for doctors to stop using the diagnosis.1 The Royal Colleges later bowed to protests by patient groups and endorsed using ME along with CFS.110 A recent review states an article from 1959 suggests ME could be a distinct condition, but CFS and ME are usually used as synonyms.50

References

  1. ^ a b c Evangard B, Schacterie R.S., Komaroff A. L. (1999). "Chronic fatigue syndrome: new insights and old ignorance". Journal of Internal Medicine Nov;246 (5): 455-469. PMID 10583715. http://www.blackwell-synergy.com/doi/pdf/10.1046/j.1365-2796.1999.00513.x. Retrieved on 3 November 2008. 
  2. ^ Ranjith G (2005). "Epidemiology of chronic fatigue syndrome.". Occup Med (Lond) 55 (1): 13-29. doi:10.1093/occmed/kqi012. PMID 15699086. 
  3. ^ a b c Wyller VB (2007). "The chronic fatigue syndrome--an update". Acta neurologica Scandinavica. Supplementum 187: 7-14. doi:10.1111/j.1600-0404.2007.00840.x. PMID 17419822. 
  4. ^ a b Afari N, Buchwald D (2003). "Chronic fatigue syndrome: a review". Am J Psychiatr 160 (2): 221-36. doi:10.1176/appi.ajp.160.2.221. PMID 12562565. http://ajp.psychiatryonline.org/cgi/content/full/160/2/221. 
  5. ^ a b c d e f "Chronic Fatigue Syndrome Basic Facts" (htm). Centers for Disease Control and Prevention (May 9, 2006). Retrieved on 2008-02-07.
  6. ^ Jason LA et al. (1999). "A community-based study of chronic fatigue syndrome". Arch. Intern. Med. 159 (18): 2129-37. doi:10.1001/archinte.159.18.2129. PMID 10527290. http://archinte.ama-assn.org/cgi/content/full/159/18/2129. 
  7. ^ Gallagher AM, Thomas JM, Hamilton WT, White PD (2004). "Incidence of fatigue symptoms and diagnoses presenting in UK primary care from 1990 to 2001". J R Soc Med 97 (12): 571-5. doi:10.1258/jrsm.97.12.571. PMID 15574853. 
  8. ^ a b c "Chronic Fatigue Syndrome Who's at risk?". Centers for Disease Control and Prevention (March 10, 2006). Retrieved on 2008-02-07.
  9. ^ a b Ross SD, Estok RP, Frame D, Stone LR, Ludensky V, Levine CB (2004). "Disability and chronic fatigue syndrome: a focus on function.". Arch Intern Med 164 (10): 1098–107. doi:10.1001/archinte.164.10.1098. PMID 15159267. http://archinte.ama-assn.org/cgi/content/full/164/10/1098. 
  10. ^ a b Salit IE (1997). "Precipitating factors for the chronic fatigue syndrome.". J Psychiatr Res 31 (1): 59-65. doi:10.1016/S0022-3956(96)00050-7. PMID 9201648. 
  11. ^ Jason LA, Taylor RR, Carrico AW (2001). "A community-based study of seasonal variation in the onset of chronic fatigue syndrome and idiopathic chronic fatigue.". Chronobiol Int 18 (2): 315-9. doi:10.1081/CBI-100103194. PMID 11379670. 
  12. ^ Zhang QW, Natelson BH, Ottenweller JE, Servatius RJ, Nelson JJ, De Luca J, Tiersky L, Lange G (2000). "Chronic fatigue syndrome beginning suddenly occurs seasonally over the year.". Chronobiol Int 17 (1): 95-9. doi:10.1081/CBI-100101035. PMID 10672437. 
  13. ^ Hatcher S, House A (2003). "Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study." (PDF). Psychol Med 33 (7): 1185-92. doi:10.1017/S0033291703008274. PMID 14580073. http://eprints.whiterose.ac.uk/1226/1/house3.pdf. 
  14. ^ Theorell T, Blomkvist V, Lindh G, Evengard B. "Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis.". Psychosom Med. 61 (3): 304-10. PMID 10367610. 
  15. ^ Hickie I, Davenport T, Wakefield D, et al (2006). "Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study". BMJ 333 (7568): 575. doi:10.1136/bmj.38933.585764.AE. PMID 16950834. 
  16. ^ a b CDC website "Chronic Fatigue Syndrome"
  17. ^ McCully KK, Sisto SA, Natelson BH (1996). "Use of exercise for treatment of chronic fatigue syndrome.". Sports Med 21 (1): 35–48. doi:10.2165/00007256-199621010-00004. PMID 8771284. 
  18. ^ Solomon L, Nisenbaum R, Reyes M, Papanicolaou DA, Reeves WC (2003). "Functional status of persons with chronic fatigue syndrome in the Wichita, Kansas, population.". Health Qual Life Outcomes 1 (1): 48–58. doi:10.1186/1477-7525-1-48. PMID 14577835.  Full text at PMC: 239865
  19. ^ Press Conference: The Chronic Fatigue and Immune Dysfunction Syndrome Association of America and The Centers For Disease Control and Prevention Press Conference at The National Press Club to Launch a Chronic Fatigue Syndrome Awareness Campaign - November 3, 2006
  20. ^ "Chronic Fatigue Syndrome: Clinical Course". CDC.
  21. ^ Ho-Yen DO, McNamara I (1991). "General practitioners' experience of the chronic fatigue syndrome". Br J Gen Pract 41 (349): 324–6. PMID 1777276. 
  22. ^ Meeus M, Nijs J, Meirleir KD (2007). "Chronic musculoskeletal pain in patients with the chronic fatigue syndrome: A systematic review.". Eur J Pain 11 (4): 377–386. doi:10.1016/j.ejpain.2006.06.005. PMID 16843021. 
  23. ^ Vanness JM, Snell CR, Strayer DR, Dempsey L 4th, Stevens SR (2003). "Subclassifying chronic fatigue syndrome through exercise testing.". Med Sci Sports Exerc 35 (6): 908–13. doi:10.1249/01.MSS.0000069510.58763.E8. PMID 12783037. 
  24. ^ Vercoulen JH, Swanink CM, Galama JM, et al (1998). "The persistence of fatigue in chronic fatigue syndrome and multiple sclerosis: development of a model". J Psychosom Res 45 (6): 507–17. doi:10.1016/S0022-3999(98)00023-3. PMID 9859853. 
  25. ^ a b Cho HJ, Hotopf M, Wessely S (2005). "The placebo response in the treatment of chronic fatigue syndrome: a systematic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME)". Psychosom Med 67 (2): 301–13. PMID 15784798. http://www.psychosomaticmedicine.org/cgi/content/full/67/2/301. Retrieved on 12 December 2008. 
  26. ^ Sanders P, Korf J (2007). "Neuroaetiology of chronic fatigue syndrome: An overview". World J Biol Psychiatry: 1–7. doi:10.1080/15622970701310971. PMID 17853290. http://www.informaworld.com/openurl?genre=article&doi=10.1080/15622970701310971&magic=pubmed. 
  27. ^ Dietert RR, Dietert JM (May 2008). "Possible role for early-life immune insult including developmental immunotoxicity in chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME)". Toxicology 247 (1): 61–72. doi:10.1016/j.tox.2008.01.022. PMID 18336982. 
  28. ^ Appel S, Chapman J, Shoenfeld Y (2007). "Infection and vaccination in chronic fatigue syndrome: myth or reality?". Autoimmunity 40 (1): 48–53. doi:10.1080/08916930701197273. PMID 17364497. 
  29. ^ Kerr JR (2008). "Gene profiling of patients with chronic fatigue syndrome/myalgic encephalomyelitis.". Curr Rheumatol Rep 10 (6): 482–91. PMID 19007540. 
  30. ^ Nijs J, Meeus M, De Meirleir K (2006). "Chronic musculoskeletal pain in chronic fatigue syndrome: recent developments and therapeutic implications.". Man Ther 11 (3): 187–91. PMID 16781183. 
  31. ^ Thambirajah AA, Sleigh K, Stiver HG, Chow AW (2008). "Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls.". Clin Invest Med 31 (6): 319–27. PMID 19032901. 
  32. ^ Snell CR, Vanness JM, Strayer DR, Stevens SR (2005). "Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS).". In Vivo 19 (2): 387–90. PMID 15796202. 
  33. ^ Cho HJ, Skowera A, Cleare A, Wessely S (2006). "Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology". Curr Opin Psychiatry 19 (1): 67–73. doi:10.1097/01.yco.0000194370.40062.b0. PMID 16612182. 
  34. ^ Smith AK, Dimulescu I, Falkenberg VR, et al (2008). "Genetic evaluation of the serotonergic system in chronic fatigue syndrome". Psychoneuroendocrinology 33 (2): 188–97. doi:10.1016/j.psyneuen.2007.11.001. PMID 18079067. 
  35. ^ Chaudhuri A, Behan PO (2004). "Fatigue in neurological disorders". Lancet 363 (9413): 978–88. doi:10.1016/S0140-6736(04)15794-2. PMID 15043967. 
  36. ^ Covelli V, Passeri ME, Leogrande D, Jirillo E, Amati L (2005). "Drug targets in stress-related disorders". Curr. Med. Chem. 12 (15): 1801–9. doi:10.2174/0929867054367202. PMID 16029148. 
  37. ^ a b Prins JB, Bos E, Huibers MJ, Servaes P, van der Werf SP, van der Meer JW, Bleijenberg G (2004). "Social