Myalgic encephalomyelitis/chronic fatigue syndrome

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Myalgic encephalomyelitis/chronic fatigue syndrome
SpecialtyNeurology, rheumatology Edit this on Wikidata

Chronic fatigue syndrome (CFS) is one of several names given to a poorly understood, highly debilitating disorder of uncertain etiology, which is thought to affect approximately 4 per 1,000 adults[1] in the United States and other industrialized countries, and a smaller fraction of adolescents.

The disorder is marked by severe, chronic mental and physical exhaustion, arising in a previously healthy and active person, as well as other specific symptoms. Despite promising avenues of research, there remains no objective assay or pathological finding which is widely accepted to be diagnostic of CFS, and it remains a diagnosis of exclusion, made on the basis of patient history and symptomatic criteria. Although there is agreement on the genuine threat to health, happiness, and productivity posed by CFS, various physicians' groups, researchers, and patient activists champion very different nomenclature, diagnostic criteria, etiologic hypotheses, and favored treatments, resulting in ongoing controversy about nearly all aspects of this enigmatic disorder. Even the name chronic fatigue syndrome is controversial, with some patient advocates and other authorities preferring terms such as myalgic encephalomyelitis ("ME" or "ME/CFS") and post-viral fatigue syndrome ("PVFS"), which imply specific underlying etiologies or pathologic processes.[2]

CFS is not the same as "chronic fatigue” - while fatigue as a symptom is very common, CFS itself is relatively rare by comparison.[3] Most definitions (other than the 1991 UK Oxford criteria[4]) require a number of features, the most common being severe mental and physical exhaustion which is "unrelieved by rest" (according to the 1994 Fukuda definition),[5] and may be worsened by even trivial exertion (a mandatory diagnostic criterion according to some systems). Most diagnostic criteria insist that the symptoms must be present for at least six months, and all insist on there being no other cause for the fatigue: i.e. the fatigue must be idiopathic, not caused by other medical conditions such as diabetes, hypothyroidism or anemia. CFS patients may report many other symptoms which are not included in all diagnostic criteria, 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 the same underlying etiology as CFS itself.[6] Some cases resolve or improve over time, and treatments (though none are universally accepted) bring a degree of improvement to many others.

CFS occurs more often, but not exclusively, in women, for unknown reasons. CFS is most easily diagnosed when formerly active adults become ill, and is most commonly diagnosed in young to middle aged adults, although it is also reported in adolescents and the elderly.[7]

Classification

The classification of chronic fatigue syndrome has been challenging, since consensus is lacking within the medical, research, and patient communities regarding the defining features of the syndrome. It may be considered by different authorities to be a neuropsychiatric, metabolic, infectious, or immune system disorder.

There are a number of different terms which have been identified at various times with this disorder.

  • Myalgic encephalomyelitis or ME translates to "inflammation of the brain and spinal cord with muscle pain" and as a disease entity has been recognized and described in the medical literature since 1938, with the seminal paper being that by Wallis in 1957; Sir Donald Acheson's (a former Chief Medical Officer) major review of ME was published in 1959.[8] In 1962 the distinguished neurologist Lord Brain included ME in his textbook of neurology, and in 1978 the Royal Society of Medicine accepted ME as a distinct clinical entity. In 1988 both the UK Department of Health and Social Services and the British Medical Association officially recognized it as a legitimate and potentially distressing disorder. Opponents of the term ME maintain there is no objective evidence of inflammation, although central nervous system inflammation has been documented in some patients diagnosed with CFS (e.g. the case of Sophia Mirza) who meet the definition of ME. There is no evidence of an association that this inflammation is causally related to all CFS cases although cerebral atrophy does appear to correspond with severity. Also, some CFS patients do not experience the muscle pain (or indeed any type of pain) typical of ME. Many patients, and some research and medical professionals in the United Kingdom and Canada, use this term in preference to CFS.
  • Myalgic encephalopathy, similar to the above, with "pathy" referring to unspecified pathology rather than inflammation; this term has some support in the UK and US.
  • Chronic fatigue syndrome (CFS); this name was introduced non-unanimously in 1988 by a group of United States researchers based at the Centers for Disease Control and Prevention in response to the 1984 Lake Tahoe ME epidemic, and is used increasingly over other designations, particularly in the United States. Many patients and clinicians perceive the term as trivializing[9] and as the 1994 Fukuda paper itself cedes, stigmatizing; or even suggestive of a "confused and distorted view of reality"[10] which has lead to a campaigning movement to change the name and definition.
  • Chronic fatigue immune dysfunction syndrome (CFIDS); many patients and advocacy groups in the USA use the term CFIDS, introduced by patients current with the biomedical research in an attempt to reduce the psychiatric stigma attached to "chronic fatigue," as well as the public perception of CFS as a psychiatric syndrome.[11] The term also calls attention to the immune dysfunction in patients for which evidence has been steadily growing since the illness was first identified, and which now appears to be an integral part of this illness.[12]
  • Post-viral [fatigue] syndrome (PVS or PVFS); this is a related disorder. According to original ME researcher Dr. Melvin Ramsay, "The crucial differentiation between ME and other forms of post-viral fatigue syndrome lies in the striking variability of the symptoms not only in the course of a day but often within the hour. This variability of the intensity of the symptoms is not found in post-viral fatigue states" (Ramsay 1989[specify]). However, other researchers and advocates argue that other post-viral syndromes (such as post-polio syndrome) do show similar variability, and point to the striking similarity between post-viral fatigue syndrome and CFS symptoms, noting that many CFS cases are triggered by a viral illness.
  • Chronic Epstein-Barr virus (CEBV) or Chronic Mononucleosis; the term CEBV was introduced by virologists Dr. Stephen Straus[13] and Dr. Jim Jones[14] in the United States. The Epstein-Barr virus, a neurotropic virus that more commonly causes infectious mononucleosis, was thought by Straus and Jones to be the cause of CFS. Subsequent discovery of the closely related human herpesvirus 6 shifted the direction of biomedical studies, although a vastly expanded and substantial body of published research continues to show active viral infection or reinfection of CFS patients by these two viruses. These viruses are also found in healthy controls, lying dormant.
  • Low Natural Killer cell disease; this name is used widely in Japan. It reflects research showing a reduction in the number of natural killer cells in many CFS patients. More significantly, in-vitro activity of the remaining natural killer cells is reduced, often by as much as two thirds.
  • Yuppie Flu; this was a factually inaccurate term first published in a November 1990 Newsweek article[specify] and never official medical terminology. It reflects a stereotypical assumption that CFS mainly affects the affluent ("yuppies"), and implies that it is a form of burnout. CFS, however, affects people of all races, genders, and social standings[15]; and is not a form of 'flu. The phrase is considered offensive by patients and clinicians.[16][17][18]
  • Uncommonly used terms include Akureyri Disease, Iceland disease (in Iceland),[19] Royal Free disease (after the location of an outbreak),[20] atypical poliomyelitis, epidemic vasculitis, raphe nucleus encephalopathy, and Tapanui flu (after the New Zealand town Tapanui where the first doctor in the country to investigate the disease, Dr Peter Snow, lived).

Signs and Symptoms

Onset

The majority of CFS cases begin after a period of stress in the year preceding the illness.[21][22] Some cases of CFS start gradually, but the majority start suddenly, often triggered by a flu-like viral or similar illness.

Sudden onset cases

Many people with CFS report a sudden, drastic start to their illness. Some people can remember a specific day or even hour when they first became ill. Often CFS starts with, or is triggered by, another illness. Many people report getting a case of the flu, exposure to an allergen (a cough or sniffle caused by paint, a new pet, or construction dust), or an infection such as bronchitis, from which they seem never to fully recover and which evolves into CFS. Some patients claim that vaccination, especially with recombinant vaccine against hepatitis B, is another cause of acute onset CFS.[citation needed] Other patients begin with Lyme disease, which despite a standard course of treatment, may "evolve" clinically from the symptoms of acute Lyme to those of CFS. Because CFS symptoms bear a striking similarity to those of late-stage Lyme disease,[23] this has become an area of great controversy. Other, noninfectious triggers may include car accidents, moving house, and stressful life situations. Some patients say they felt unusual or uneasy for a short period (days or weeks) before the onset.

Gradual onset cases

Other cases have a very slow, gradual onset, sometimes spread over years.[citation needed] People with gradual onsets may not realize there is anything wrong for quite some time. Patients may believe they have a minor illness, or ascribe their weakened condition to stress, and assume they will improve with time. It is only when the patient realized that their condition is truly debilitating, or the stress is removed and the symptoms remain, that the patient will begin to seek treatment.

Course

It can be inferred from the 2003 "Canadian" clinical working condition of CFS[24] that there are 8 categories of symptoms:

  • Fatigue: Unexplained, persistent, or recurrent physical and mental fatigue/exhaustion that substantially reduces activity levels and is not relieved (or not completely relieved) by rest.
  • Post-exertional malaise: An inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, symptom exacerbation after exertion, plus a pathologically slow recovery period usually 24 hours or longer.
  • Sleep dysfunction: "Unrefreshing" sleep/rest, poor sleep quantity, insomnia or rhythm disturbances. A study found that most CFS patients have clinically significant sleep abnormalities that are potentially treatable.[25] Several studies suggest that while CFS patients may experience altered sleep architecture (such as reduced sleep efficiency, a reduction of deep sleep, prolonged sleep initiation, and alpha-wave intrusion during deep sleep) and mildly disordered breathing, overall sleep dysfunction does not seem to be a critical or causative factor in CFS.[26][27][28][29] Sleep patterns may be further interrupted by vivid "feverish" dreams[citation needed], and unlike in healthy persons, exercise can worsen the sleep dysfunction.[citation needed]
  • Neurological/cognitive manifestations: Common occurrences include confusion, forgetfulness, mental fatigue/brain fog, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perceptual and sensory disturbances (e.g. spatial instability and disorientation and inability to focus vision), ataxia (unsteady and clumsy motion of the limbs or torso), muscle weakness and "twitches". There may also be cognitive or sensory overload (e.g. photophobia and hypersensitivity to noise and/or emotional overload, which may lead to "crash" periods and/or anxiety).
  • Neuroendocrine manifestations: Common occurrences include poor temperature control or loss of thermostatic stability, subnormal body temperature and marked daily fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities, intolerance of extremes of heat and cold, marked weight change anorexia or abnormal appetite, loss of adaptability and worsening of symptoms with stress.
  • Immune manifestations: Common occurrences include tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms, general malaise, new sensitivities to food and/or medications and/or chemicals (which may complicate treatment). At least one study has confirmed that most CFS patients reduce or cease alcohol intake, mostly due to personal experience of worsening symptoms[31] (although the cause of this is unknown and may not be strictly "immunological" as implied by the symptom list).

There may also be other psychological/psychiatric symptoms/comorbidities in some patients.[citation needed] See the Proposed causes and pathophysiology section for more information about the possible causes of, and treatments for, the above listed symptoms.

Activity levels

Patients report critical reductions in levels of physical activity[32] with the severity of symptoms and disability the same in both genders[33]; but despite a common diagnosis, the functional capacity of CFS patients varies greatly.[34] Musculoskeletal pain is the most frequent and most expensive condition for sickness compensation or disability[35], and chronic pain is strongly disabling in CFS patients.[30] According to the CDC[36][37], studies show that the disability in CFS patients is comparable to some well-known, very severe medical conditions, such as; multiple sclerosis, AIDS, lupus, rheumatoid arthritis, heart disease, end-stage renal disease, chronic obstructive pulmonary disease (COPD) and similar chronic conditions. While some patients are able to lead a relatively normal life, others are totally bed-bound and unable to care for themselves. Almost all patients find they must drastically reduce their activity from pre-illness levels, regardless of their previous level of athleticism, and must severely modify or give up physical hobbies and exercise. Many patients find themselves unable to work full-time, or at all. A considerable number of CFS cases in many countries are on disability benefits or private insurance, or have made claims and been denied.

Post-exertion symptom exacerbation

One of the most common and recognizable aspects of CFS is what is called "post-exertional malaise". When people with CFS exert themselves beyond their limits (and their limits may change daily), their symptoms worsen. Exertion includes cognitive effort. The harder the exertion and the longer it lasts, the worse the symptoms will be afterward, and with greater recovery time. Although symptoms may increase immediately and proportionally, usually their full extent is delayed by 24 or more hours, which can make judging appropriate activity difficult. A cyclical pattern can occur when patients work harder because they "feel better" or are having a "good day," leading them to think they can exert themselves more than usual. However, the excess exertion leads to worse symptoms on the following day. Thus it is difficult for patients to maintain an even level of activity, or to tell if they are improving.[citation needed]

In sufferers without a diagnosis of CFS, or a proper understanding of how CFS affects exertion, this can lead to a "downward spiral," where a sufferer will try to work harder to make up for the previous day's lack instead of resting. This exhausts them further, and often can trigger a relapse or worsening of their condition. If the original exertion, which can be physical or mental in nature, was particularly severe, the sufferer may deteriorate to a point where they are unable to care for themselves. Many cases then result in hospitalisation because the condition has deteriorated a great deal.However, it must be noted that patients may deteriorate due to external stressors, complications, co-morbid illness, or for unknown reasons, and in those cases, patient exertion cannot be blamed for a patient's deterioration. Also, some patients have a progressive course which cannot be explained through activity levels.[citation needed]

When the illness is coupled with unaccommodating family, friends, colleagues, often due to stigma, and social repercussions such as financial needs, housing problems, the struggle to obtain disability benefits or insurance, discrimination and misconception within the care sector, it can put demands on the sufferer exceeding their safe capabilities. Many sufferers describe needing to do things for themselves in the times they feel better simply because there is no-one to delegate to.[citation needed]

Proposed causes and pathophysiology

The cause of CFS is unknown, although a large number of causes have been proposed, and several proposed causes have very vocal and partisan advocates. In a basic overview of CFS for health professionals, the CDC states that "After more than 3,000 research studies, there is now abundant scientific evidence that CFS is a real physiological illness."[38] The cause of CFS may be different for different patients, but if so, the various causes may result in a common clinical outcome.

Neurological abnormalities

Researchers have found evidence that CFS may involve distinct neurological abnormalities, supporting the WHO's classification of ME/CFS as a neurological illness. When testing the spinal cord fluid of people with CFS or related illnesses (including fibromyalgia and Gulf War syndrome), they found 16 proteins that were absent from the control group. 5 of these proteins were found in all illness groups; suggestive of a biosignature that could be used to diagnose CFS, and providing more physiological evidence of a common underlying medical condition.[39] In another study on cerebrospinal fluid, researchers found that corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with fibromyalgia, an illness with considerable overlap with ME/CFS.[40]

Dysautonomia

Dysautonomia is the disruption of the function of the autonomic nervous system (ANS). The ANS is tightly tied to the body's endocrine system and also directly controls some aspects of blood pressure control and metabolism. The dysautonomia that evidences itself in CFS shows up mostly in problems of orthostatic intolerance - the inability to stand up without feeling dizzy, faint, nauseated, etc. Research into the orthostatic intolerance found in CFS indicates it is very similar to that found in postural orthostatic tachycardia syndrome (POTS). POTS and CFS patients exhibit reduced blood flows to the heart upon standing that result in reduced blood flow to the brain. The reduced blood flows to the heart are believed to originate in blood pooling in the lower body upon standing. Many CFS patients report symptoms of orthostatic intolerance and low or lowered blood pressure.[citation needed]

Damage to ascending reticular activating system

The reticular activating system (RAS) is an area in the brain that extends upward from the reticular formation. It has been known since the early part of the 20th century to be associated with sleep function, and research since roughly 1950 has greatly extended this knowledge. Postmortem examination of the brains of polio patients and imaging studies of the brains of people with post-polio syndrome have shown lesions in the area of the ARAS and reticular formation. Other imaging studies of the brains of CFS patients have shown metabolic abnormalities in this area, though the results have often been equivocal. It seems likely, however, that damage to the RAS may be responsible for at least some cases of CFS.[citation needed] Such damage could arise from direct bacterial or viral damage to the area, or from an autoimmune attack on the region. Lesions in the RAS have been found in Multiple Sclerosis. Studies with animal models (primarily cats) have shown that a malfunction of the ARAS[clarification needed] is capable of causing behaviors similar to those of CFS patients.

Arnold-Chiari malformation and other spinal problems

Arnold-Chiari malformation is constriction where the cerebellum meets the spinal cord. This area can become constricted due to a portion of the cerebellum sagging too low or problems with the bone structure of the lower skull or upper spinal column. The constriction can impede the flow of cerebrospinal fluid between brain and spinal column, and can also compress some nerves in the area. This may cause paralysis or hydrocephalus in extreme cases, but this or other spinal problems may cause autonomic nervous system problems in less severe cases. This can be determined via an MRI, which may also be valuable in ruling out inner-ear conditions, or chronic sinusitis (see below).[citation needed]

Inner-ear disorders
Main article: balance disorder

Problems such as Meniere's, tumor in the inner ear, [citation needed] or Benign Paroxysmal Positional Vertigo (BPPV) can cause dizziness, vertigo, and fatigue. Recurrent ear infections are common in some CFS sufferers. Tinnitus is also quite common [citation needed].

Orthostatic hypotension

Syndromes of orthostatic intolerance, in particular neurally mediated hypotension (NMH) and Postural orthostatic tachycardia syndrome (POTS), have been shown to be associated with chronic fatigue syndrome.[41][42] These conditions, which reduce blood flow to the brain after periods of standing, can be diagnosed with a tilt table test. Unfortunately, fludrocortisone, a drug sometimes used to treat low blood pressure, seems to have little or no benefit for people with CFS.[43]

Psychiatric abnormalities

Depression

Many cases of CFS are mistakenly attributed to depression. However, clinical depression often responds well to physical exercise, whereas CFS is characterised by exercise intolerance but with a willingness to be active. (See section on post-exertion symptom exacerbation.) Furthermore, brain changes observed in clinical scans of CFS patients tend to be of a very different type than changes observed in patients with depression.[citation needed]

While depression is not uncommon among CFS patients, there are many CFS patients without depressive signs, suggesting that depression is not a direct cause of the symptoms. There are also patients with pre-existing depression which responded to treatment, but whose CFS symptoms did not improve; and treatment for depression is not particularly effective on CFS patients without depression. While depression may occur in CFS patients, it may be a result of living with CFS, or a secondary product of exercise intolerance, rather than the cause.[citation needed]

Psychosomatic causes

Many doctors and some researchers believe that CFS is a complex psychosomatic disorder caused by chronic stress.[citation needed] Cognitive Behavioral Therapy, Antidepressants and Graded Exercise Therapy have been claimed to be effective treatments for some people with CFS. See CBT and GET, below.

Stress and trauma

Stress contributes to many different illnesses, and can cause a series of responses that in genetically predisposed individuals may lead to stress-related brain disease after adverse experiences.[44] Although the majority of people who experience stress/trauma do not develop CFS, these (including infection) increase the likelihood of acquiring CFS within one year[21][22] and a genetic disposition to CFS has been proposed.[citation needed] Other studies also suggest that childhood stress/trauma significantly increases the likelihood of acquiring CFS as an adult, with one study finding a 3 to 8 fold increase (depending on the trauma type).[45] Another study found both stress and emotional instability to be significant risk factors, an effect which may be buffered by genetic influences, with the researchers also concluding that "emotional instability assessed 25 years earlier is associated with chronic fatigue through genetic mechanisms contributing to both personality style and expression of the disorder ... these findings suggest plausible mechanisms for chronic fatiguing illness." They also found no association between extraversion and fatigue.[46] Anxiety disorders have also been found to be a risk factor in 5-15 year olds.[47]

CFS has been linked to an impaired stress response (see the Post-exertion symptom exacerbation section). It has also been proposed that this was associated with dysfunction of the hypothalamus-pituitary-adrenal axis (the HPA axis helps the body remain stable under physiological and psychological stress) and some evidence for this has been found[48]; although this may only be subtle[49], and acquired as a result of CFS.[50] The controversy surrounding CFS has caused some social issues for patients and may contribute to their stress (see the Social issues section).

Oxidative stress

Further information: Oxidative stress

Oxidative stress is an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. Several studies[51][52][53][54][55][56] and a review[57] have implicated oxidative stress in CFS symptoms; especially relating to fatigue, pain and postexertional malaise / exercise intolerance. According to researchers of one study, the findings on oxidative stress (and nitric oxide-related toxicity) seem consistent with their findings of the abnormal 2-5A synthetase/RNase L enzyme (antiviral) activity which has previously been implicated in the pathology of exercise intolerance in CFS.[58]

Immune dysfunction

When compared with CFS patients with normal natural killer cell activity, those with lower levels reported less vigor, more daytime dysfunction, and more cognitive impairment; with the researchers suggesting this to be useful at subtyping.[59] However an earlier systematic review on the immunology of CFS published in 2003 found an inverse association between study quality and findings of low levels of natural killer cells (suggesting that the association may be related to study methodology), although no such association was found with studies finding abnormalities in T cells and cytokine levels.[60] The researchers also concluded that no consistent pattern of immunological abnormalities had been identified, however, a later updated review on the phenomenology and pathophysiology of CFS published in 2006 found that immune system involvement in the pathogenesis of CFS seems certain but the findings on the specific mechanisms are still inconsistent.[61] There is also evidence that people with CFS have improper gene expression including both over expression and under expression of genes involved in the immune system (see the gene expression section).

RNase L deregulation

Several studies have highlighted the existence of abnormal 2-5A synthetase/RNase L enzyme (antiviral) activity in some CFS patients[62][63][64][65][66][67], with several more studies finding this to correlate with the worsening of symptoms after exercise.[68][69][70][58] A review published in 2005 suggested that this impaired pathway is of clinical importance and that further studies addressing treatment of this deregulation are warranted.[71] A study found that elevated RNase L did not correlate with alpha-delta sleep.[72]

Hyperactive immunity

Autoimmune disorders, representing a hyperactive immune system, most likely through a cell-mediated process, have been suggested.[73][74] In July 2005, researchers in the UK reported significant gene changes in the white blood cells in CFS patients consistent with the theory of immune system activation, possibly by an antigen triggering a constant immune fatigue state. The study, led by Dr Jonathan Kerr, discovered that 35 white blood cell genes, out of a total of 9,522 genes scanned were demonstrating differential function. There was also suggestion of neuronal and mitochondrial dysfunction as a result.[75]

Allergies

Similarly to the theory of immune dysfunction, some doctors believe that CFS patients suffer from immune dysfunction caused by exposure to allergens, ranging from food allergies or food intolerances (see below) to pollen and dander allergies. However, this theory fails to explain the many reported and documented cluster outbreaks of CFS, and is therefore not taken seriously by leading researchers in the field. Instead, severe allergies may occasionally cause CFS-like symptoms, or patients with CFS may develop additional problems with allergies or food intolerances, which is common. However, there is no evidence that allergies are at the root of CFS.

Immunodeficiency

Immunodeficiency disorders (representing an underactive immune system) have been reported. As early as 1989, a study was published in Australia that documented a loss of immunological integrity in one hundred CFS sufferers.[76] The authors reported finding disordered ratios of T-cell subsets and reduced levels of immunoglobulins specifically IgG 1 and IgG 3; these findings corresponded with similar findings in the U.S. among leading researchers. Most strikingly, using the French Multitest to measure the body's response to a variety of antigens, the Australian group found that 33% of the subjects were hypoergic, meaning they had a reduced immune response, while an additional 55% were completely anergic, meaning they had no immune response at all. Some theories propose that an infection with one of the below-listed disease agents somehow leads to immune dysfunction and chronic fatigue in cases of CFS. This is partly supported by test results indicating lowered or changed immune responses in some patients, as well as elevated levels of infectious agents in some patients' blood.

Other immunological findings
  • Several studies have implicated a higher level of bioactive transforming growth factor-beta (TGF-beta) in CFS patients.[77]
  • A study published in 1995 found that 3 immunological tests (protein A binding, Raji cell, or C3/C4) best discriminated CFS patients from fatigued controls.[78]
  • A recent study suggested that CFS may be characterized by an IgM-related immune response directed against disrupted lipid membrane components, by-products of lipid peroxidation, S-farnesyl-L-cysteine, and NO-modified amino-acids, which are normally not detected by the immune system but due to oxidative and nitrosative damage have become immunogenic.[79]
  • A study found that while exercise worsened symptoms in CFS patients, it also increased allergen challenge response only in the CFS group, regardless of allergy status.[80]

Psychoneuroimmunological interactions

Further information: psychoneuroimmunology

A recent review states that there is growing evidence of autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets in psychiatric disorders and that autoantibodies may play a role in psychiatric disorders present in CFS.[81] Researchers involved in a review examining an immunological basis for CFS concluded that neuropsychiatric symptoms in CFS patients may be more closely related to disordered cytokine production by glial cells within the central nervous system rather than to circulating cytokines.[82] In one study, autoantibodies for muscarinic cholinergic receptor had been found in over half of the CFS patients and seemed to correlate with the severity of the "feeling of muscle weakness".[83] Elevated levels of nitric oxide (not to be confused with nitrous oxide) has been found in some CFS patients[68] and may help explain a "sensitization" of the nervous system that results in behavioral changes.[84]

Infectious etiology

Bacterial infections
  • Lyme disease and related tick-borne infections. Lyme disease does not always present acutely with a rash, and less than half of sufferers recall a tickbite (the nymphal deer tick is the size of a poppy seed, and secretes an anesthetic to prevent the host from feeling its bite). Furthermore, the characteristic joint pain is not always present. For these reasons Lyme can be difficult to diagnose, particularly in its later stages, at which point symptoms are virtually identical to those of CFS.[85] The accuracy of blood tests for Lyme remains highly controversial, especially since they depend on an effective immune system response, which many researchers believe is compromised by the disease. As a result, some clinicians believe Lyme is under-diagnosed.[86]
  • Bacterial respiratory infections such as mycoplasmic bronchitis/pneumonia, Legionnaire's disease, and possibly other bacteria associated with bacterial pneumonia.
  • Sinusitis. Sinusitis is a chronic infection of the sinuses which can be difficult to diagnose, and can cause symptoms similar to those of CFS. Sinusitis can occur after dental surgeries or infections, and thus may be related to reaction to mercury in dental amalgams as above, or dental infections, as below.
  • Toxoplasma gondii. Toxoplasma gondii is a parasitic infection. If let untreated it can cause severe immune suppression and neurologic symptoms.
  • Dental infections. Some have implicated focal infections from root canals and cavitations in tooth sockets where the periodontal ligament was not removed when a tooth was extracted. The theory is that anaerobic bacteria can exist inside a tooth with a root canal or a cavitation because of the lack of blood supply. The bacteria produce toxins that cause system wide problems. Some individuals with CFS like symptoms have seen great improvement after the removal of all root canals and/or cavitation surgery to clean out the sockets from tooth extraction sites.
Fungal infection

Yeast and other fungi. Some nutritionists believe that CFS is caused by an overgrowth of yeast, known as "candidiasis", but treatment of candidiasis has not helped all CFS patients. This etiology of CFS is highly hypothetical.[citation needed]

Epstein-Barr virus

For many years the ubiquitous Epstein-Barr virus, present in 90% of the population, was the principal suspect based on abnormal immunologic responses observed in uncontrolled studies.[14][13] Subsequent studies using various types of controls have had mixed conclusions. [87][88][89]

Other viruses

Other implicated viruses include cytomegalovirus, and human herpesvirus type-6 (HHV-6).[90][91][92][93][94][95][96][97] More recently, however, similarities to post-polio syndrome have led to a reexamination of the viral link.[98]

A number of viruses of the enterovirus family, notably the Coxsackie virus, can produce an infection of the nervous system similar to that caused by the poliovirus, and an even wider range of viruses have been shown capable of triggering an autoimmune reaction that attacks the nervous system.

It is believed by some that one of these mechanisms causes damage to areas of the brain responsible for alertness and metabolism, resulting in many of the symptoms of CFS.

Endocrine dysfunction

Thyroid and adrenal disorders can cause CFS-like symptoms, as can several other known endocrine disorders. It's possible that disruption of the hormonal "master control" in the hypothalamus somehow causes CFS by upsetting the body's hormone balance. This theory is supported by changes in cortisol response in some CFS patients.

Metabolic disorders

Metabolic disorders such as McArdle disease, CPT II deficiency, myoadenylate deaminase deficiency, and mitochondrial disorders can cause symptoms that strongly resemble CFS. Mitochondrial disturbances have been discovered in some CFS patients.

Folate deficiency (suspicion by elevated homocysteine and low serum folate) may mimick CFS symptoms.[99][100]

Nutritional disorders

Certain dietary practices, particularly the consumption of large amounts of carbohydrates, or poorly nutritive vegan diets (see below, "malnutrition"), are sometimes blamed for CFS. Celiac disease or gluten intolerance is known to cause CFS-like symptoms in some individuals, as is vitamin B12 or vitamin D deficiency. Other forms of food allergies are also often blamed, especially in cases of leaky gut syndrome. While many nutritional supplements are touted as cures or palliatives for CFS, research on these is scattered and inconclusive.

Malnutrition

In some cases, simple malnutrition may be responsible for CFS-like symptoms and would thus be a diagnostic exclusion. Particularly highly restrictive vegetarian or vegan diets could cause problems, even though they appear sufficient from the standpoint of food energy and essential vitamins and amino acids. Most people cannot manufacture the entire amounts of ribose, carnitine, CoQ10, fatty acids, and several other "semi-essential" nutrients that are critical for cellular metabolism and for nervous system health. A diet deficient in these can lead to a form of malnutrition that results in the classical CFS-like symptoms.

Toxic agents

Mercury, particularly from dental amalgams and vaccines, various organic solvents, herbicides, and several other chemical compounds are often named. The artificial sweetener aspartame is also often blamed. In the cases of mercury and aspartame, this suspicion is not borne out by available evidence.

Other findings

Other findings regarding CFS in general include:

  • Recent genetic research into CFS has found abnormalities in gene expression, and the CDC has conducted over a dozen related studies itself.[101] It has been found that patients with CFS have specific abnormalities in expression of multiple genes which are involved in the biological process of transport (both vesicle-mediated and protein transport) and this became accentuated when CFS patients exercise.[102] Another study found that "the differentially expressed genes imply fundamental metabolic perturbations", such as those involved in purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism.[103] Several other studies have also highlighted a genetic component to CFS involving immune dysfunction[104]; T cell activation, perturbation of neuronal and mitochondrial function, possible links to organophosphate exposure and virus infection[105]; immune response, apoptosis, ion channel activity, signal transduction, cell-cell signaling, regulation of cell growth and neuronal activity[106]; some of which may be treatable with drugs that are already available.[107] Gene expression abnormalities have been found relating to the central nervous system, metabolism and immune system; and may point towards the impaired response to physical and psychological stresses in people with CFS. However, linking genes to specific symptoms has so far been elusive, although is likely to be an important means to elucidate the pathogenesis of CFS.[108]
  • A large study found that higher levels of exercise in childhood is associated with a lower risk of developing CFS later on. It also found that the development of CFS was not associated with other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity.[109]
  • Researchers compared 48 CFS patients with 29 controls and found that 10 of the CFS patients tested positive for enterovirus RNA (most closely to that of the coxsackie B virus) in their muscles while all of the 29 controls tested negative. 28 of the 48 CFS patients had an abnormal lactate response to exercise, including 9 of the 10 who tested positive for enterovirus RNA.[110]
  • A study found that fatigue persists in a significant minority of patients for six months or more after infections, suggesting post-infective fatigue syndrome is a valid illness model for investigating CFS.[111]
  • In a study on people who had glandular fever (which is caused by the Epstein-Barr virus), no difference was found between the levels of virus in the blood from patients who recovered quickly when compared with those whose fatigue lasted more than six months, although the latter had an altered immune response.[112] The scientists involved believed this suggests CFS can be caused by neurological damage done (during the acute infection phase) to parts of the brain which control perception of fatigue and pain.[113]
  • Lactic acid has been suggested to be a factor in CFS because for many decades it has been commonly believed to be responsible for muscle fatigue. However, some scientists have found that lactic acid may actually help prevent muscle fatigue rather than cause it, by keeping muscles properly responding to nerve signals.[114]
  • Oddly, researchers have found that children and teenagers with CFS are several times more likely to have some hyperflexible joints.[115]

Diagnosis

At this time, there is no accepted conclusive test or series of tests of chronic fatigue syndrome. CFS is therefore largely an exclusionary diagnosis. If a doctor suspects a patient may have CFS they should begin the diagnostic process by eliminating other potential causes of the patient's symptoms.[116] "Chronic fatigue" and similar symptoms can be caused by a wide variety of conditions which should be investigated, although treatment of the patient's symptoms can begin before a complete diagnosis is made. Subsequently tests should be run to exclude other abnormalities in the immune and central nervous system that cause the same or similar symptoms as seen in CFS patients.

CDC 1994 criteria (aka "Fukuda")

According to the 1994 CDC,[5] a diagnosis of CFS requires that the following conditions be met (otherwise, the diagnosis is idiopathic chronic fatigue).

Primary symptom
incapacitating fatigue

Incapacitating fatigue that is:

  • of new or definite onset (not since birth)
  • unexplained by other medical cause,
  • lasts for at least six months (from onset, not necessarily from when the patient becomes aware that the fatigue is an ongoing symptom)
  • and is not improved by rest.
Additional symptoms

The fatigue must be accompanied by a minimum of 4 of the following eight symptoms:

  1. Impairment of short-term memory and concentration
  2. Sore throat
  3. Tender lymph nodes
  4. Muscle pain
  5. Multi-joint pain
  6. Headaches of a new type, pattern, or severity
  7. Unrefreshing sleep or insomnia
  8. Post-exertional malaise (fatigue lasting more than 24 hours after exertion)

Other systems

Other scoring systems have also been proposed to quantify CFS symptoms for research purposes. These include:

  • Holmes et al (1988) scoring system.[117] Also sometimes called "CDC 1988," to distinguish from the newer CDC system.
  • Oxford criteria (1991)[4]
  • Carruthers et al (2003) Canadian Case definition for ME/CFS[118]
  • Australian Guidelines (2004)[119]

Other ability/disability scales designed for similar symptoms to those of CFS have also been used.

Issues with the definitions/criteria

Selection bias and inconsistencies

Several studies have found that using different case definitions ( eg broad vs conservative[120] ) has major influence on the types of patients selected and have also highlighted the need for specific subgroups of CFS to be identified and/or for the case definition to be further clarified with emphasis on using empirical studies: An international CFS study group for the CDC found ambiguities in the CDC 1994 CFS research case definition which contribute to inconsistent case identification.[121] Researchers have found that a difference in the self-reported cause of a patient's CFS is associated with significant differences in clinical measures and outcomes, and concluded it is likely that their response to treatment may vary and the CFS definition should be improved to define more homogeneous groups of patients for the purposes of research and treatment.[122] It also may be inappropriate to synthesize results from CFS studies that use different definitions to select study populations.[123] It has been found that identification of new diagnostic symptoms, the use of severity ratings for symptomatology, and the identification of standardized measures that differentiate cases of CFS from other conditions; all hold promise for improving the sensitivity, specificity, and reliability of the diagnostic criteria for CFS.[124]

Improving accuracy

A study found that the best predictors for people accurately fitting the CDC 1994 definition of CFS were the presence of postexertional malaise, unrefreshing sleep, and impaired memory-concentration, and this accuracy increased when severity of these symptoms were taken into account.[125] Another examination of the CDC's working case definition(s) of CFS found that the differential accuracy is strengthened when eliminating three symptoms (muscle weakness, joint pain, sleep disturbance) and adding two others (anorexia, nausea).[126] It has also been found that the Canadian 2003 definition (a less used but stricter criteria) selects cases with less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms.[127]

Possible subtypes

Studies suggest the existence of CFS subtypes.[128][129] After examining the 'minor' diagnostic symptoms of CFS in women meeting the CDC 1994 criteria, researchers found that 3 subtypes could be identified; musculoskeletal, infectious and neurological; with associated impairment characteristic of each subtype. "Extreme scores" characterized about 2/3 of the sample, with higher disability in those with the highest scores. Depression and anxiety were not more prevalent in any particular subtype, and did not increase with the severity of specific symptom reports.[130]

Diagnosis inaccuracies

A review published in 2006 found that the accurate diagnosis of CFS is low[131] and another study found that physicians have a tendency to underrecognize psychiatric illness in people diagnosed with CFS, especially when assessing patients whose chronic fatigue is fully explainable by a psychiatric disorder.[132]

Terminology implications

Because of the similarity in terminology, CFS is often confused with "chronic fatigue". A study found that while most medical trainees consider the symptom complex of CFS to be a serious illness resulting in poor quality of life, the "chronic fatigue syndrome" name may be regarded less seriously than the "myalgic encephalopathy" name.[133] Another study found that nurses and physician assistants viewed a patient's CFS symptoms as more severe and disabling if they were told the patient had a more medical sounding diagnosis of "chronic neuroendocrineimmune dysfunction syndrome".[134]

Testing

Although it was originally thought that CFS was related to a viral etiology, more recent studies have failed to find any predictable association between CFS and any particular virus. While there is no test for CFS, a number of exclusionary laboratory tests can be done to rule out other conditions. The CDC recommends the following tests:[135]

  • Complete blood count (CBC) - Helps rule out anemia, leukemia and other blood disorders as well as collagen vascular disorders such as lupus.
  • Blood chemistry - Confirms normal blood sugar, electrolytes, renal and liver function, calcium and bone metabolism and serum proteins.
  • Thyroid function studies - Confirms normal thyroid function, a common cause of muscle aches and fatigue.
  • Sedimentation rate - General indicator of inflammation, infection and collagen vascular disorders.
  • Urinalysis - Excludes infection, renal disease and possibly collagen vascular disorders.

Diagnostic controversies

Historically, many doctors have been unfamiliar with CFS, and some have refused to diagnose it. This situation is changing somewhat, with more doctors willing to diagnose it. In the UK, the Chief Medical Officer's report stated that all doctors should consider CFS as a serious chronic illness — though it is not stated whether this is a serious physical illness — and treat patients accordingly. Similar progress has been made in the United States. There remains considerable skepticism amongst some medical professionals about the existence of CFS as a 'real' — i.e. medical as opposed to behavioral — condition, possibly due to the extreme uncertainty of its etiology, and the lack of testing for biomedical signs. Many people are inclined to believe that a condition with few or no specific biomedical markers may be psychological in origin. This had led to a frustration in many patients, who feel that their disability is not psychological, but biological. Some patients' groups and experts maintain that research into CFS (ME) in the UK has been mostly hijacked by the psychologists/psychiatric lobby, who they claim hold significant power within the medical fraternity, with a resultant "abuse of patients' rights."[citation needed] The UK and the Netherlands have particularly seen disagreements between biomedical researchers and their adherents, and psychiatrists (particularly proponents of cognitive behavioral therapy, or CBT) and supporters of the theory that CFS is psychological in origin, and can be "cured" entirely by psychotherapy and exercise. A UK Government website [19] allows petitions to be delivered directly to the British Prime Minister. This E-Petition asserts: "We the undersigned petition the Prime Minister to get the Health Service and medical profession to accept the WHO classification of ME/CFS as an organic neurological disorder and not as a psychosocial syndrome." Only British citizens or residents are eligible to sign this E-Petition, which has a deadline of 22nd January 2008.

Patients whose illnesses are consistent with the older and Canadian definitions tend most to resent the elevation of what they see as a trivialising, nonspecific sensation of "fatigue" to a principal descriptor. It is thus often important to be able to differentiate between the illness experience of needful patients and an epistemic construct that may or may not select the same target, until a better definition and diagnostic testing is widely accepted.

Treatment

As there is no one identifiable cause or falsifiable diagnosis for CFS, there is also no one treatment protocol or "magic bullet." Due to the multi-systemic nature of the illness, and others like it, an emerging branch of medical science called psychoneuroimmunology is exploring how all the various theories fit together.[136][137][138]

The treatments that are proposed and often attempted for CFS are as varied as the suggested causes, and can generally be classified either according to the cause that they presume, or the symptom they propose to treat. Unfortunately, since CFS symptoms tend to vary over time, it is very easy for someone to become convinced that a particular treatment has helped them (or not), regardless of its true effectiveness (see regression fallacy). Because the placebo effect is commonly stronger in highly 'subjective' symptoms, some medical professionals believed this also applied to CFS, however patients with CFS actually have a significantly lower response rate to placebos compared with patients of many other illnesses (about 20% vs 30% respectively).[139] Alternative medicine is often proposed for CFS, especially when conventional treatments are poorly tolerated or fail to relieve symptoms. Alternative treatments may also be more affordable or accessible to patients with limited funds or health care coverage.

Behavioral interventions

Behavioral interventions including cognitive behavioral therapy (CBT) and graded exercise therapy (GET) have been shown to be at least partially effective in some people with CFS. An updated systematic review which was published in the Journal of the Royal Society of Medicine (October 2006)[140] found these are the only two known treatments that seem helpful. The statement of principal findings regarding CBT/GET was: "A number of RCTs (randomised controlled trials) suggest that behavioural interventions, including elements of CBT, GET and rehabilitation, may reduce symptoms and improve physical functioning of people with CFS/ME." However some uncertainty still exists over the efficacy of these treatments, especially GET for severely affected patients, as none were included in studies that passed the inclusion criteria of the review. The review also emphasized the need for more and better conducted studies of both therapies, as well as more research into the adverse affects of treatments in general as they may be under reported or poorly quantified. As mentioned in the review under the 'unanswered questions/further research' section, very few studies assessed the effectiveness of "interventions for children and young people and for severely affected patients." More research is needed on severely affected patients in general; because many treatments and studies require patients to attend a clinic, and those with the worst symptoms often receive the least support from health and social services. This may bias the results towards those with less severe symptoms. The authors also expressed concern about possible bias in the CFS literature, a lack of uniformity in case definitions and study inclusion/exclusion criteria (studies using any CFS criteria were included), and the basic information provided about the participants; which they state makes it difficult to assess the generalizability of the findings of many of these studies. This review found that no intervention had been proved effective in restoring the ability to work. An earlier systematic review published in 2002 also found this, although CBT was "lending a possible association between improvement in the ability to work and an increase in the number of patients employed". This earlier review also found that no specific patient characteristics seemed to serve as best predictors of positive employment outcomes in CFS patients, although did find that depression of greater severity was associated with unemployment.[141] However, another systematic review published in 2004 concluded "Only cognitive behavior therapy, rehabilitation, and exercise therapy interventions were associated with restoring the ability to work."[142] The "Gibson Report" (Report of the Group on Scientific Research into Myalgic Encephalomyelitis 2006)[143] provides information about treating CFS with CBT and/or GET. However, the report itself has been criticised by several groups, for: being poorly conducted, misrepresentations, omissions, lack of references, factual inaccuracies or bias, and even potentially damaging implications.[144][145][146] According to the Countess of Mar (panel member of the Group on Scientific Research into ME), the report was a political inquiry into the science, not a scientific inquiry, of CFS.[147] In the "25% ME Group Submission to Gibson"[148] they state that both CBT and GET are not only just unhelpful to many severely affected CFS patients but also dangerous/harmful. The discrepancy between trial results and patient group surveys has been noted by the P.A.C.E. trial group, who are conducting a larger more detailed study into CBT and GET which is currently underway and is due for completion in 2009.[149]

Cognitive Behavioral Therapy (CBT)

Cognitive behavioral therapy (CBT) is claimed to be an effective evidence-based therapy for CFS[150]. The use of psychological therapies such as CBT does not imply that CFS is a psychiatric condition or that physical symptoms are not real. Some CFS patients have comorbid depression and/or anxiety.[151] In addition, it is maintained CBT may teach patients various "coping strategies" to help them deal with cognitive impairments such as a deterioration of short-term memory or abbreviated attention span[citation needed], although it is uncertain how changing one's schemas, as CBT theory contends, would cause improvement in these serious pathological symptoms. Dr. David Smith, a former medical advisor to the ME Association in the UK who reports to have successfully treated many children using antidepressants and therapy[152], offers a possible explanation on his website.[153] Some patients and patient groups dispute such claims, pointing out that CBT is invariably described as an "exposure therapy" e.g. UK mental health charity MIND,[154] that virtually all the conditions commonly listed as being suitable for CBT are behavioural and that the 2002 UK CMO's Report describes CBT as "a tool for constructively modifying attitude and behaviour." Some patients and advocates suggest that there are “good” and “bad” forms of CBT, and it is important for patients to decide whether CBT is advisable in their case[citation needed]; others point out that, as supported by Carruthers and Van de Sande in their Overview of the Canadian Consensus Guidelines[155], that to avoid such confusion supportive counselling should not be mis-termed CBT. The Gibson Report [143] states that CBT in general is helpful to many people with other illnesses; and while it is controversial in regards to CFS, it seems to be most effective in those with less severe forms but much less effective in the severely affected. Commenting on the relevance of CBT for CFS, the report states that it has a role to play in treatment but at best is only a partial answer and more research is needed. A systematic review on CBT[140] finds that, while some kind of positive result is often reported, the quality of the research into the effects of CBT is usually rather low and the patient selection is not random. The reviewers note that reasons for withdrawals typically remain unreported, and furthermore state that a degree of publication bias seems to be present. Some approaches aim at active rehabilitation rather than just adapting to the illness. CBT does not seem to be as efficacious when provided by general practitioners or when given in a group[citation needed]. In one study, the effect of CBT has been demonstrated up to five years after therapy[156]. A large evaluation study in Belgium, however, lead to the conclusion that while on average CBT may cause patients to feel somewhat better, objective measurement shows no reduction in their disability[157]. Another recent study found that CBT improved self-reported cognitive impairment but not actual neuropsychological test performance.[158] According to researchers of one study, CBT usually aims at reducing fatigue but can also reduce pain, although higher pain at baseline was associated with a negative treatment outcome.[159] The place of CBT for children, young people and the severely affected needs to be better established, although some open studies suggest that it is helpful, so long as it is adapted for the individual patient[citation needed].

Similar/Related Treatments

Counselling: Many CFS patients face the stress of economic and legal problems. CFS sufferers may lose jobs, marriages, and the ability to work at all, causing severe financial loss and distress. A lawyer, social worker or counsellor can be beneficial in helping the patient determine their best course, and may assist the patient with applying for work-related disability, social programs, and other aid.

Graded Exercise Therapy (GE, GA or GET)

Several rehabilitation programs have been proposed which involve supervised or self-monitored graded exercise or activity. Such programs are designed to overcome deconditioning, increase strength and cardiovascular health. The program should incorporate considerable education wherein the sufferer learns to start at an appropriate level of activity (based upon intensity and duration) which is incrementally increased, at a rate which does not substantially increase symptoms. Those who fit a 2003 ME/ICD-CFS definition with post exertional malaise may wish to consider whether graded exercise is recommended in their case because it can cause serious deterioration in the exertional intolerant, and the 25% ME Group[160] point out that many severe cases were in fact mild cases before undergoing such therapy. More encouragingly and in addition to the positive findings of the previously mentioned updated systematic review on GET[140], the Gibson Report also states that GET is one of the most common treatments for CFS and found 50-70% of patients improved somewhat with GET. However this level of efficacy was only found in several small trials and were not even compared with specialist medical care or pacing. Similarly, like with CBT, GET seems more effective in less severely affected patients than those who are more severely affected. Its role in helping severely disabled patients has not yet been properly established, but uncontrolled studies suggest it can help so long as it is tailored to the individual patient. However the Gibson Report also mentions the 25% ME Group findings that only 5% of their members found GET helpful and 95% found it unhelpful; and while the report used the word "unhelpful," the 25% ME Group insists that GET can also be dangerous/harmful. Many other patients who submitted personal evidence to the report's inquiry had similarly negative experiences of GET. Due to the potential risks of GET for CFS patients, the report stressed concern about GET treatment guidelines for CFS that lacked cautions about these risks, and even raised suggestions of checking for heart trouble before attempting GET. The authors also stated the observation that GET may make severe sufferers feel worse "has lent fuel to their often serious antipathy to the doctors offering it. Some of our evidence suggests that GET carries some risk and patients should be advised of this." Again, both the report and the review acknowledges the need for more research. One study done with 9 to 17 year olds showed that a rehabilitation program (involving graded activities/exercise) was successful, with 43% reporting a "complete resolution" of symptoms by the CDC/Fukuda definition.[161] Another study found that GET may help partially by a reduction of "focusing on symptoms" rather than improving fitness.[162]

Similar/Related Treatments
  • Self-controlled rest and exercise, "pacing": "Pacing" is being advocated by many patients as one of the few really effective means of minimising homeostatic disequilibrium. The principles involve acceptance of the patient's limitations (by both the patient and any coaches), awareness of the early signals of deterioration e.g. increased cognitive difficulties, pain, clumsiness, muscle weakness, respiratory problems; and stopping exercise/activity before exceeding limitation or "crashing." A good rule of thumb is to never exert more than 70% of capacity. An understanding nurse, doctor or physical therapist may be of help.
  • Other exercise: A few patients find health benefits and pain relief from gentle stretching, non-aerobic exercise, and gentle activity. More able persons may find gentle yoga, walking, or t'ai chi to be beneficial. Water-borne exercise and swimming is particularly beneficial for some CFS sufferers. Exercise for the severely affected or those who cannot manage the exercises can be detrimental to their health and should be avoided.
Cautions

Delayed onset of symptoms, unforeseen demands ("spilled milk,") poorly controlled or treated symptoms and inadequate social/personal caregiving for the severely affected, ensure great care is required to avoid exertional relapses, even without official programs. Cognitive, emotional and stress demands also detract from physical activity capability. The criteria for exercise intolerance is generally considered usually at a low level. The distinction between "exercise" and "activity" sometimes made is false and arbitrary, especially for the severely affected: even modestly sustainable activity can become temporarily or permanently unsustainable if over repeated and for those at their activity ceiling, only very trivial additional or cumulative activity may be sufficient to cause relapse.

Medication

Antidepressants

Antidepressants are often prescribed to CFS patients. It must be pointed out that some antidepressants can exacerbate symptoms, especially in the first few weeks of starting a new drug, and can induce muscle weakness, sleep-waking dysfunction and cardiac arrythmias, amongst other negative side effects. Some sufferers cannot tolerate any antidepressants at all, but that is true of normal controls taking antidepressants as well.

  • Antidepressants have also been shown to suppress TH1 (T helper cell) upregulation.[182][183][184][185][186]Some advances have also been achieved in the field of Hypothalamic-pituitary-adrenal axis (HPA-axis) modulation by antidepressants.[187][188][189] The role of HPA-axis in CFS has still to be determined as data has been mixed. Studies have shown patients with CFS have demonstrated subtle alterations in HPA axis activity characterized by reduced Adrenocorticotropic hormone (ACTH) over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion.[190]Other studies argue there is no HPA-axis change in CFS patients.[191]
  • These studies warrant further investigation for antidepressants for use in a psycho-neuroimmunological approach which may be required for optimal pharmacotherapy in CFS.[192] Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.[193][194]The culmination of these studies purport antidepressants can be useful in non-depressed patients.[195]
  • Overall, studies for use of antidepressants in CFS thus been performed has been mixed. Some studies have shown a reduction in symptoms with MAOI's, Tricyclics, SSRI and SNRI use.[196][197][198][199] Some studies have shown no improvement.
Autonomic nervous system stimulants

Drugs such as atomoxetine (Strattera®), which stimulate the autonomic nervous system, appear to have positive effects in some people with CFS symptoms. Amphetamines and amphetamine analogs may help some patients. For example, methylphenidate (Ritalin®) has been found to be significantly better than placebo in relieving fatigue and concentration disturbances in a minority of CFS patients but more research is needed into the long term effects.[200] Interestingly, at least some of those who experience improvement on stimulant drugs do not experience significant "payback effect," suggesting that the drug is to some degree acting to correct the underlying neurological problem rather than simply masking symptoms. Modafinil (Provigil®), a medication designed to aid in maintaining wakefulness, has had some positive effect on individuals with CFS, but has not been properly studied. A small study suggested that long-term treatment with modafinil may not be beneficial for CFS patients.[201]

Hormones

Various hormones have been tried from time to time, including specifically steroids (such as cortisol) and thyroid hormones. Though conventional steroidal treatment may produce short-term pain relief, it has not been shown to be of any general benefit. Studies performed by Dr. Jacob Teitelbaum incorporating low-dose cortisol therapy in a have demonstrated positive results,[202] but other studies have shown little benefit from cortisol itself. Thyroid hormones occasionally are effective for certain people who may either have a thyroid hormone deficiency or lack an enzyme that allows them to effectively use thyroid hormones. As Hypothalamic-pituitary-adrenal axis (HPA axis) dysfunction seems to be implicated in CFS, standard thyroid tests (including TSH) may not produce accurate results[citation needed]. Therefore, a short trial of either T3, T4, or a combination supplementation may be warranted if clinical signs seem to indicate possible hypothyroidism.

Patients with immunoglobulin deficiencies can be helped with infusions of intravenous gammaglobulin (IVIG).

Sleep aids

Sleep aids may be prescribed when a patient complains of poor or irregular sleep, or excessive fatigue. Some patients find sleep aids, whether over-the-counter or prescription, to help greatly in maintaining a sleep cycle or getting "better", more restful sleep. As with all CNS acting drugs on ME/CFS, cautious dosage ramping is required and it may be necessary to try several drugs in order to find one which is tolerable.

Pain relief

Many CFS patients experience significant amounts of physical, neuralgic pain. This "nerve pain", like that of phantom limb, diabetic neuralgia and fibromyalgia, does not generally respond well to NSAIDS, although some patients report that naprosyn or naproxen provides some relief due to its muscle relaxant properties. Tricyclic antidepressants, as above, offer better relief for some cases of nerve pain. Other pain relievers may have uses as well. Patients experiencing "other" pain (such as headache or migraine) should receive appropriate pain management for those symptoms. Hot water bathing has also been noted as relieving fibromyalgia or neuralgic pain, but patients with severe ME/CFS, low blood pressure or dizziness are advised to be cautious about the use of hot tubs or baths. Acupuncture has also been shown to relieve pain in fibromyalgia cases, and may be beneficial to CFS sufferers as well.

Antibiotics

Antibiotics are commonly used to treat Lyme disease, sinusitis and other bacterial infections. These infections can be hard to eradicate, so often when an antibiotic cure fails it is claimed that the duration of treatment was insufficient or the wrong antibiotic was used. Another view is that some antibiotics have specific immuno-modulating side effects, quite separately from their antibiotic action. In the MedLine database, ciprofloxacine, doxycycline and the penicillins are reported to be of significant (albeit temporary) effect in some patients. An even larger group of patients may have adverse effects, and a third group no effect at all.

While many patients still show evidence of an infectious agent in their system after antibiotic treatment, blood antibody levels are often low, producing a negative blood test result. For example, a patient with Lyme disease who has received antibiotic treatment may be pronounced 'cured' of Lyme when their antibody levels are at or below those found in healthy persons, although the patient may still have symptoms characteristic of both CFS and Lyme. Controversy has arisen over whether to diagnose such patients with CFS or chronic Lyme, because there is no way to prove that the Lyme organism has been eradicated, and numerous studies document both persistent infection and false negative tests in Lyme disease. Extended courses of antibiotics (sometimes given intravenously) are recommended by some physicians for these cases, and have had a beneficial effect for some patients diagnosed with chronic Lyme disease; however this treatment remains controversial.

Antifungals

Antifungal drugs, specifically of the azole class, are used to treat yeast and fungus infections. Proponents of the yeast hypothesis for CFS claim, however, that the drugs are largely useless unless combined with a low-carbohydrate diet that effectively "starves" the fungus at the same time. Research studies have shown the contrary.[203]

Antivirals

A recent study found Valganciclovir effective in treating and possibly curing CFS.[20]

Other medical treatments

Allergy identification and treatment

In cases where CFS-like symptoms may be being caused by gluten intolerance, celiac disease, or chronic sinusitis, allergy testing, treatments, or elimination diets may prove beneficial. Since some CFS patients show decreased immune response or symptoms of MLS, pre-existing mild allergies may increase to harmful levels after CFS onset. Some studies suggest that a form of CFS may be triggered by a rare reaction to dental metals. Tests in Sweden showed that 76% of CFS patients who tested positive to metal allergy and swapped metal fillings for ceramic substitute achieved partial or full health improvement. Metal allergy can be detected by a blood test named MELISA.[204]

Dental cleanup

Some individuals suffering from CFS have reported a major reduction of symptoms and improvement in health after the removal of teeth with root canals. Cavitation surgery to clean up the sockets of sites where the periodontal ligament was not removed after a tooth extraction has also been helpful to some.[citation needed]

Surgery

For Chiari malformation and some other disorders (e.g., thoracic outlet syndrome) that are occasionally blamed for CFS symptoms, surgery to release trapped nerves or otherwise correct neurological problems may be helpful, if manual therapies such as Chiropractic have not enjoyed any success.[citation needed]

Dietary/nutritional modification

Essential Fatty Acid Treatments

In 1990 the Behans found in CFS patients, reduced cell membrane essential fatty acids that are suggestive of chronically elevated utilization and production of essential fatty acid metabolites, given that diets were not deficient. [205] And confirmed more recently [206] These metabolites are the basis for many immune product responses in the body, exhaustion of the cell membrane feedstocks, means a compromised immune response. Essential fatty acids are essential because they must be obtained in the diet, as our bodies cannot manufacture them. It is not simply a matter of eating more foods that contain them because there is enzyme competition for the processing and incorporation of the acids and their products. [207]

Given this discovery a trial was carried out by Horriban and Behan in 1990 using high doses of supplemental essential fatty acids of mixed types. A large number of CFS patients were given the supplements and on testing after 3 months their cellular membrane phospholipids (feedstock’s) had returned to normal or towards normal and symptoms had improved [208] It was thought that CFS involved a deficiency in the D6D enzyme for fatty acid metabolite production. Unfortunately later attempts to duplicate the work met with mixed results. [209]

This can be explained because these trials did not attempt to control for other intake or lifestyle factors that effect essential fatty acid utilization. For instance the amounts of different fats in the diet, amount of protein, alcohol, zinc and magnesium status, exercise amounts, level of conditioning, stress and other infections etc. all affect the results. Other nutrients may be deficient in CFS that can also effect utilization. [210]

Essential fatty acid profiles of cell membranes can be manipulated and the produced metabolites (immune products) altered by carefully planned diets, which is important in CFS, as it means that immune responses producing symptoms can be tweaked.

In the early 1990’s Martinovic carried out a clinical trial on CFS patients in which such factors were controlled for and obtained remarkable results, many of whom became fit for work, after about 4 months, and were still well 16 months later. The trial used essential fatty acid modulation rather than supplementation, in which the dietary intake was adjusted for each patient, and varied according to their symptom fluctuations. Exercise and activity, physical and mental was set according to patient abilities, such that exacerbation of symptoms did not occur and levels increased over time to set formula. Cognitive behaviour (CB) was used to show patients (make cognitive) how symptoms varied with activity and dietary changes. Also behaviour therapy, (BT) was applied so that patients learnt to adjust the factors for themselves. [211]

The protocol for this therapy has yet to be published. Unfortunately it is not a ‘one pill fits all’ type of treatment, as each patient requires individual adjustments, and therefore more time consuming than practical under General Practitioner attendances under Medicare. It does however demonstrate the potential and point to an area for future research.

Subsequent work by researchers at an Australian University of Newcastle has confirmed an alteration in the D6D enzyme activity,[212] and therefore an inability in CFS to produce sufficient immune metabolites, unless enzyme competition is reduced such as in the Martinovic trial using modulation.[211] This explains the difference in results between modulation and supplementation and the reason why simple fatty acid supplementation by itself may be ineffective.

Magnesium

In a small study, supplementation with oral magnesium tablets improved symptoms in those people with CFS who previously had been diagnosed with low magnesium levels, although in this study additional magnesium injections were necessary in some patients. Conversely, other researchers reported no evidence of magnesium deficiency in people with CFS. The reason for this discrepancy remains unclear. If people with CFS do consider magnesium supplementation, they should have their magnesium status checked by a physician before beginning a regimen of supplementation. It is possible that only people with a magnesium deficiency may benefit from this therapy. Some sufferers find Magnesium malate 200 to 300 mg per day relieves some of the pain and can help with sleep problems as well. Magnesium is used in the enzymatic conversion of food to energy in the Krebs cycle, and can help reduce muscle fatigue in some cases.[213][214][215][216]

Alpha lipoic acid

Alpha Lipoic Acid may be beneficial because it is both a fat and water soluble antioxidant.[217]

Other

Chiropractic

Whilst this is not a therapy primarily for the treatment of Chronic Fatigue Syndrome, it may help reduce the Dysautonomia where it has been triggered by altered extrapyramidal reflexes in the grey matter of the spinal cord, known as facilitation. Facilitation is a common result of a spinal subluxation, where the joints of the neck become 'locked,' and as such, the muscles of the spinal column cannot move the joints. The resultant immobility induces muscle and nerve 'atrophy,' decreasing their function. If the facilitation is present in the upper spinal cord, this may predispose patients to dysautonomia, as major components of the autonomic nervous system are located nearby.[citation needed]

Lifestyle adjustments

Many CFS authorities recommend making use of medical treatments where appropriate, but focusing on minimizing symptoms through lifestyle adjustments such as pacing, control of stress, and good support. Importantly, acceptance rather than "fighting" to be as healthy as the patient was before CFS onset will lead to less frustration and fewer relapses. Adjustments to daily living -- working less, making dietary changes, and more efficient use of time and energy -- can improve a patient's outlook; but, more importantly, relieve some symptoms as well. Due to the nature of ME/CFS in finding its own "exertional level", such adjustments if resisted, tend to become enforced. This may also include the use of assistive devices; many CFS patients find that a cane, walker, wheelchair, mobility scooter or power chair will greatly improve their ability to perform tasks. Simpler assistive devices -- a kitchen stool rather than standing at the stove, a phone programmed to remember phone numbers -- can also greatly improve the quality of life for CFS patients.[citation needed]

Location

Some CFS patients find relief in moving to warmer climes. This is a difficult and expensive treatment option, not always feasible or available.[citation needed]

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."[218] It is not known whether any patients truly "recover" entirely from the illness, or achieve remission from a relapsing, remitting illness. Few untreated patients report a total "cure".

Deaths

CFS is unlikely to increase the risk of an early death. In a preliminary 2006 study of CFS self-help group members, it was reported that CFS patients were likely to die at a younger than average age for cancer, heart failure, and suicide.[219] However, a much larger study of 641 CDC criteria diagnosed patients with CFS, who were followed up for a mean of 9 years, showed no excess risk of dying from any cause.[220]

People diagnosed with CFS may die, as in the case in the UK of Sophia Mirza, where the coroner recorded a verdict of "Acute anuric renal failure due to dehydration arising as a result of CFS." (It should be noted, however, that according to Sophia's mother, Sophia reduced her water intake to 4 fluid ounces per day because she believed that she was allergic to it, and this is the likely reason for the dehydration[221]). The pathologist said, "ME describes inflammation of the spinal cord and muscles. My work supports the inflammation theory...The changes of dorsal root ganglionitis seen in 75% of Sophia‘s spinal cord were very similar to that seen during active infection by herpes viruses."

A systematic review of 14 studies of the outcome of CFS reported 8 deaths, but none were considered directly attributable to CFS.[222] CFS has been linked[21] to heart damage and cardiac arrest among other causes of death; research has not yet progressed to determine whether this is in fact the case, and some patients die from co-morbid diseases.

To date there have been two studies on CFS life expectancy.[223][224] The largest study of some 641 patients with CFS, who were followed up for a mean of 9 years, found no excess mortality.[225]

Previous cases have listed CFS as the cause of death in the US and Australia.[226]

Epidemiology

Due to problems with the 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. However, the most recent estimates by the CDC are that more than 1 million Americans have CFS.[22] The CDC further states that approximately 80% of all CFS cases are undiagnosed. Far 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 under reported. Members of ethnic minorities and low income classes are slightly more likely to develop CFS. Though people of all ages can get CFS, and precise statistics are not available, the prevalence among children and adolescents appears to be lower than for adults. Among minors with CFS, about half are boys and half girls. CFS occurs both in isolated cases and large-scale outbreaks. In a number of documented cases several people in a building or large numbers of people in a community came down with the disease essentially simultaneously, suggesting that it is (in at least some cases) partly due to an infectious agent. Blood relatives of people who have CFS appear to be more predisposed.[227] However, CFS does not appear directly contagious; caretakers, partners and others in close contact with persons with CFS for years do not develop CFS any more frequently (excluding relatives, as earlier).

Disease associations

Some diseases show a considerable overlap with CFS, and it may be hard to distinguish between them. People with fibromyalgia (FM, or Fibromyalgia Syndrome, FMS) have muscle pain and sleep disturbances. Those with multiple chemical sensitivities (MCS) are sensitive to chemicals and have sleep disturbances. Many veterans with Gulf War syndrome (GWS) have symptoms almost identical to CFS.[228] Post-polio syndrome also bears a strong and remarkable resemblance to CFS. Some researchers maintain these disorders are all expressions of a general, yet undefined, syndrome with protean symptoms. The suffering that can be experienced by a patient with ME/CFIDS has been likened to an AIDS patient in the last two months of life and/or a terminal cancer patient. Often, Multiple Sclerosis needs to also be excluded as a diagnosis. Thyroid disorders, anemia, and diabetes can present similar symptoms, and must be ruled out. Other disorders with known causes and treatments that may produce CFS-like symptoms are Lyme disease[229], temporomandibular disorder (TMD), gluten intolerance (celiac disease and related disorders), and vitamin B12 deficiency. There may also be correlation with polycystic ovary syndrome (PCOS)[citation needed]. 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.[230] 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.[231]

A proposed similarity between psychiatric disorders, such as somatoform disorders (particularly undifferentiated somatoform disorder) is that according to some definitions, physical symptoms or their severity are unsupported by medical evidence. One review (2006) found a lack in literature on comparing undifferentiated somatoform disorder with CFS, however mentioned that a critical feature is implied in the definition of undifferentiated somatoform disorder that is absent from CFS: that some patients experience their symptoms as being exclusively physical and not as mental.[232] Hysterical diagnoses are not merely diagnoses of exclusion but require criteria to be met on the positive grounds of both primary and secondary gain. [233] 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 deteriorationCite error: A <ref> tag is missing the closing </ref> (see the help page). Fibromyalgia will occur in a large percentage of CFS patients between onset and the second year, and some researchers suggest that fibromyalgia and CFS are related. 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.[234] As previously mentioned, many CFS sufferers also experience symptoms of irritable bowel syndrome, temporomandibular joint pain, headache including migraines, and other forms of myalgia. Clinical depression and anxiety are also commonly co-morbid. 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.[235] CFS is significantly more common in women with endometriosis compared with women in the general USA population.[236]

Social issues

For some people, chronic fatigue syndrome still carries a considerable stigma, and has frequently been viewed as malingering, hypochondriacal behavior, "wanting attention" or "yuppie flu". As there is no objective test for the condition at this time, some argue that it is easy to "invent" CFS-like symptoms for financial, social or emotional benefits. 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. Furthermore, studies have found that CFS patients are not malingering[237] and endure a heavy psychosocial burden.[238] Surveys by patient organizations highlight that those with the worst symptoms often receive the least support from health and social services.[239] 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.[240] CFS has been found to be the biggest cause of long-term sickness leading to absence from school, in both staff and pupils; yet children with CFS often struggle for recognition of their needs and/or are bullied by medical and educational professionals.[241] The ambiguity of the status of CFS as a medical condition may cause higher perceived stigma.[242] Patients may find themselves surrounded with misunderstanding of their condition. Since CFS is often invisible to some -- although many sufferers present a somewhat poorly picture -- many will not understand why a newly diagnosed co-worker suddenly needs to work from home, use a better chair, or take time off. A CFS sufferer may face disbelief and misunderstanding, and even anger, from persons previously part of the social support structure. Many CFS patients have faced unsupportive families and dubious physicians, and have lost jobs, careers, scholarships and relationships to the syndrome. Anxiety and depression often result from the emotional, social and financial crises caused by CFS. While few studies have been made, it is believed that CFS patients are at a high risk of suicide.[243] One of the worst side-effects of the illness is social isolation. Many CFS sufferers are confined to their house and/or bed. They are unable to take part in normal social activity. They are also excluded from workplace and school socialising. Interestingly, the growth of the internet and the improvements of online speeds have been a boon to many people with CFS, especially in the developed countries. The internet has provided access to social contacts, to knowledge and learning, to purchasing and to services, which has improved the lives of many with CFS.

History

The concept

CFS is a working case definition for the neuroimmune disorder known as Myalgic encephalomyelitis (ME) since 1956.[244] ME has been included in the classification of the World Health Organization (WHO) as a disease of the central nervous system since 1969. In the ICD-10, ME is the only disorder listed in the tabular classification under G93.3, Post-viral fatigue syndrome (PVFS). In 1993 the term Chronic fatigue syndrome (CFS) was added to the alphabetic list of the classification with the same designation. In the 1950s, the public eye was caught by several outbreaks of a mysterious illness that resembled, but proved not to be, poliomyelitis.[20] Afterwards, it was established that the disorder was primarily found among the general population and the epidemic form was the exception. Autopsy findings, both on monkeys[245] and on the rare human casualties[246], led to the conclusion that the disorder was caused by inflammation of the brain and the spinal cord, and in 1956 it was named accordingly as Myalgic encephalomyelitis. Despite the existence of non-epidemic cases, the disorder was soon dismissed by some as mass hysteria and interest dropped, to be rekindled only after a similar outbreak at Incline Village, Lake Tahoe, Nevada in the mid-1980s. Unaware of the earlier findings, researchers now attached a different kind of name to the phenomenon: Chronic Fatigue Syndrome (CFS), after the symptoms rather than the (there unestablished) nature of the disorder. The Centers for Disease Control & Prevention published a first working case definition for CFS in 1988,[247] even though by then the CDC were aware of the ME connection. The use of a syndrome definition had the advantage that the diagnostics were simplified. Research picked up considerably, and more so after the criteria were relaxed in 1994.[248] The obvious drawback was the possibility of misdiagnosis. Lacking a diagnostic laboratory test of any kind, CFS has frequently been mis-diagnosed, for example in patients presenting CFS symptoms with similar biological conditions or infections (such as Lyme or Epstein-Barr) (the latter of which is often the cause of glandular fever, or infectious mononucleosis), or psychological conditions (ranging from depression to hypochondria). A lack of information and awareness has led to many patients being stigmatized, sometimes as hypochondriac or lazy, yet at other times as over-active and perfectionistic.[citation needed] Because immune related symptoms are common in CFS patients, their immune system was earlier suspected to be dysfunctional, or responding inappropriately to specific viruses; this lead to the proposal of the alternative name "chronic fatigue immune dysfunction syndrome" (CFIDS). Although some immunological abnormalities have since been found in some patients, a review published in 1991 did not find evidence of a definable viral etiology for CFS/ME.[249] Researchers in a study of patient perspectives have argued that the earlier failure of Western medicine to demonstrate a viral etiology for CFS led to a paradigmatic shift to psychiatric and socialcultural research, which effectively delegitimized CFS as a biomedical phenomenon within medical, academic, governmental, and public arenas; they also suggest that the history of medical attitudes toward CFS may eventually parallel the transformations that occurred in relation to multiple sclerosis, as the discovery of biological markers for CFS may lay to rest the categorization of CFS as largely within the psychiatric realm.[250] Other researchers have stated that physicians have since minimized the seriousness of CFS and also interpreted the syndrome as being psychiatric, which had negative consequences for the treatment of CFS; and the revised CFS case definition might have produced heterogeneous patient groups which possibly include some patients with pure psychiatric disorders.[251] More recently, neurocognitive dysfunction has been objectively observed; and physiological abnormalities relating to immune activity, gene expression, oxidative stress and the nervous system have also been found, plus many psychological and psychiatric studies have also been done (see the Proposed causes and pathophysiology section). The U.S. Centers for Disease Control & Prevention (CDC) have now recognized CFS as a serious illness and launched a campaign in June 2006 to raise public and medical awareness about it.[252]

Notable cases

Some notable persons who are believed to have suffered from CFS are:

Cultural references

A 1989 episode of The Golden Girls ("Sick and Tired") dealt with Dorothy developing the illness and trying to cope with doctors who told her it was mental. Bea Arthur (who played Dorothy) wanted to raise social awareness of the issue.

In the first series of Alan Partridge, during a meal with the head of the BBC Alan suggests a program he has thought of involving the illness Knowing ME Knowing You. "You've got to keep the energy up."

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