Chronic fatigue syndrome

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Chronic fatigue syndrome (CFS) is one of several names given to a poorly understood, variably debilitating disorder of uncertain cause/causes. Based on a 1999 study of adults in the United States, CFS is thought to affect approximately 4 per 1,000 adults. For unknown reasons, CFS occurs more often in women, and adults in their 40s and 50s. The illness is estimated to be less prevalent in children and adolescents, but study results vary as to the degree.

CFS often manifests with widespread myalgia and arthralgia, cognitive difficulties, chronic mental and physical exhaustion, often severe, and other characteristic symptoms in a previously healthy and active person. Despite promising avenues of research, there remains no assay or pathological finding which is widely accepted to be diagnostic of CFS. It remains a diagnosis of exclusion based largely on patient history and symptomatic criteria, although a number of tests can aid diagnosis. Whereas 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 treatments, resulting in controversy about nearly all aspects of the disorder. Even the term chronic fatigue syndrome is controversial because a large part of the patient community believes the name trivializes the illness. Chronic fatigue syndrome is not the same as "chronic fatigue”. Fatigue is a common symptom in many illnesses, but CFS is a multi-systemic disease and is relatively rare by comparison. Definitions (other than the 1991 UK Oxford criteria) require a number of features, the most common being severe mental and physical exhaustion which is "unrelieved by rest" (1994 Fukuda definition), and may be worsened by even trivial exertion (a mandatory diagnostic criterion according to some systems). Most diagnostic criteria require that symptoms must be present for at least six months, and all state the symptoms must not be caused by other medical conditions. CFS patients may report many 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 an underlying etiology of CFS. Some cases improve over time, and treatments (though none are universally accepted) bring a degree of improvement to many others, though full resolution may be only 5-10% according to the United States Centers for Disease Control and Prevention (CDC).

Nomenclature

The naming 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 central nervous system, metabolic, (post-)infectious, immune system or neuropsychiatric 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 first appeared as "benign myalgic encephalomyelitis" in a Lancet editorial by Sir Donald Acheson in 1956. In a 1959 review he referred to several older reports that appeared to describe a similar syndrome. The neurologist Lord Brain included ME in the 1962 sixth edition of his textbook of neurology, A 1978 British Medical Journal article stated the Royal Society of Medicine conference to discuss the illness during that year clearly agreed Myalgic Encephalomyelitis was a distinct name for the disease. The article also stated the previous word (benign) used with ME was rejected as unsatisfactory and misleading because the condition may be devastating to the patient. 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 state that there is no objective evidence of inflammation. In some patients diagnosed with CFS (e.g. the case of Sophia Mirza), central nervous system inflammation has been documented. Many patients, and some research and medical professionals in the United Kingdom and Canada, use this term in preference to or in conjunction with CFS (ME/CFS or CFS/ME). The international association of researchers and clinicians is named IACFS/ME.
• 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 Epstein-Barr virus (CEBV) or Chronic Mononucleosis; the term CEBV was introduced in 1985 by virologists Dr. Stephen Straus and Dr. Jim Jones 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.
• Chronic fatigue syndrome (CFS) was proposed in 1988 by researchers from the U.S. Centers for Disease Control and Prevention (CDC) to replace the name chronic Epstein-Barr virus syndrome when they published an initial case definition for research of the illness after investigating the 1984 Lake Tahoe ME epidemic. CFS is used increasingly over other designations, particularly in the United States. Many patients and clinicians perceive the term as trivializing, and as the 1994 Fukuda paper itself cedes, stigmatizing, which led to a movement in the United States to change the name and definition. Eighty-five percent of respondents to a 1997 survey conducted by the Chronic Fatigue Immune Dysfunction Syndrome Association of America wanted the name changed. The CFS Coordinating Committee (CFSCC) of the U.S. Department of Health and Human Services formed a name change workgroup in 2000. Terms were recommended which implied specific underlying etiologies or pathologic processes, but work was shelved in December 2003 when the successor CFS Advisory Committee (CFSAC) decided a name change would be too disruptive at that time.
• Chronic fatigue immune dysfunction syndrome (CFIDS); many patients and advocacy groups in the USA use the term CFIDS, in an attempt to reduce the psychiatric stigma attached to "chronic fatigue," as well as the public perception of CFS as a psychiatric syndrome. The term also calls attention to the immune dysfunction in patients which research suggests is an integral part of the illness.
• Post-viral fatigue syndrome (PVFS); this is a related disorder. According to 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.
• Low Natural Killer Syndrome (LNKS); this term reflected research on patients showing diminished in-vitro natural killer cell activity in a small 1987 study in Japan. A case definition for CFS in Japan was adopted in 1991 based on the CDC 1988 criteria, an updated diagnostic guideline is planned.
• Yuppie Flu; this was a factually inaccurate term first published in a November 1990 Newsweek cover story 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, and is not a form of flu. The phrase is considered offensive by patients and clinicians.
• Uncommonly used terms include Akureyri Disease, Iceland disease (in Iceland), Royal Free disease (after the location of an outbreak), atypical poliomyelitis, epidemic neuromyasthenia, 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

Sudden onset cases

The majority of CFS cases start suddenly, usually accompanied by a "flu-like illness" which is more likely to occur in winter, while a significant proportion of cases begin within several months of severe adverse stress. Many people report getting a case of a flu-like or other respiratory infection such as bronchitis, from which they seem never to fully recover and which evolves into CFS. The diagnosis of Post Viral Fatigue Syndrome is sometimes given in the early stage of the illness. One study reported CFS occurred in some patients following a vaccination or a blood transfusion. The accurate prevalence and exact roles of infection and stress in the development of CFS however are currently unknown.

Gradual onset cases

Other cases have a gradual onset, sometimes spread over years. Patients with Lyme disease may, despite a standard course of treatment, "evolve" clinically from the symptoms of acute Lyme to those similar to CFS. This has become an area of great controversy.

Course

It can be inferred from the 2003 Canadian clinical working definition of ME/CFS 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, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms to worsen with a pathologically slow recovery period of usually 24 hours or longer. According to the authors of the Canadian clinical working definition of ME/CFS, the malaise that follows exertion is often reported to be similar to the generalized pain, discomfort and fatigue associated with the acute phase of influenza. Although common in CFS, this may not be the most severe symptom in the individual case, where other symptoms (such as headaches, neurocognitive difficulties, pain and sleep disturbances) can dominate.
• 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. 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. Sleep may present with vivid disturbing dreams, and exhaustion can worsen sleep dysfunction.
• Pain: Pain is often widespread and migratory in nature, including a significant degree of muscle pain and/or joint pain (without joint swelling or redness, and may be transitory). Other symptoms include headaches (particularly of a new type, severity, or duration), lymph node pain, sore throats, and abdominal pain (often as a symptom of irritable bowel syndrome). Patients also report bone, eye and testicular pain, nerve pain and painful skin sensitivity. Chest pain has been attributed variously to microvascular disease or cardiomyopathy by researchers, and many patients also report painful tachycardia. A systematic review assessing the studies of chronic pain in CFS found that although the exact prevalence is unknown, it is strongly disabling in patients, but unrelated to depression.
• 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). A review of research relating to the neuropsychological functioning in CFS was published in 2001 and found that slowed processing speed, impaired working memory and poor learning of information are the most prominent features of cognitive dysfunctioning in patients with CFS, which couldn't be accounted solely by the severity of the depression and anxiety.
• Autonomic manifestations: Common occurrences include orthostatic intolerance, neurally mediated hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural hypotension, lightheadedness, extreme pallor, nausea and irritable bowel syndrome, urinary frequency and bladder dysfunction, palpitations with or without cardiac arrhythmias, and exertional dyspnea (perceived difficulty breathing or pain on breathing).
• 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, digestive disturbances and/or 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 (although the cause of this is unknown and may not be strictly "immunological" as implied by the symptom list).

Activity levels

Patients report critical reductions in levels of physical activity and are as impaired as persons whose fatigue can be explained by another medical or a psychiatric condition. According to the CDC, 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. The severity of symptoms and disability is the same in both genders, and chronic pain is strongly disabling in CFS patients, but despite a common diagnosis the functional capacity of CFS patients varies greatly. While some patients are able to lead a relatively normal life, others are totally bed-bound and unable to care for themselves. A systematic review found that in a synthesis of studies, 42% of patients were employed, 54% were unemployed, 64% reported CFS-related work limitations, 55% were on disability benefits or temporary sick leave, and 19% worked full-time.

Proposed causes and pathophysiology

The cause of CFS is unknown, although a large number of causes have been proposed. 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. 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. MRI and SPECT scans show abnormalities within the brain. Studies have shown that CFS patients have abnormalities in blood flow to the brain possibly indicative of viral cause and similar but not identical compared to patients with clinical depression. A number of studies have shown that CFS patients have abnormal levels of neurotransmitters including increased serotonin (the opposite of what is found in primary depression). Reduced brain serotonin receptor sensitivity or number, and high auto antibodies to serotonin have also been found. Recent studies found altered gene expression in the brain’s serotonin and sympathetic nervous system pathways, with altered responses of the HPA axis to serotonin. Other reported neurotransmitter irregularities include glutamate, acetylcholine sensitivity associated increased cutaneous microcirculation, and autoantibodies to cholinergic receptors associated with central pain. Beta-endorphin, a natural pain killer, has been found to be low in CFS patients, the opposite of what is found in primary depression.Dysautonomia Dysautonomia is the disruption of the function of the autonomic nervous system (ANS). The ANS controls many aspects of homeostasis. 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) and hypocapnia. 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. Inner-ear disorders

Problems such as Meniere's, also tumor in the inner ear, or Benign Paroxysmal Positional Vertigo (BPPV) can cause dizziness, vertigo, and fatigue. Tinnitus is also quite common. Antibodies associated with hearing loss have been found in CFS and FMS patients with inner ear disordersOrthostatic 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. These conditions, which reduce blood flow to the brain after periods of standing, can be diagnosed with a tilt table test. A clinical trial of fludrocortisone, a drug sometimes used to treat low blood pressure, showed little or no benefit for people with CFS.

Psychiatric abnormalities

Depression There is some overlap in symptoms between depression and CFS, and sometimes cases of CFS are mistakenly attributed to clinical depression. There are, however, many clinical differences between the two.

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.) Comorbid depression occurs in 10-15% of CFS patients and should be treated as usual, except that the patient’s energy level, cognitive dysfunction and drug sensitivity must be taken into account. Comorbid depression may be a pre-existing condition, or the result of living with CFS.

Stress and trauma

The majority of people who experience stress/trauma do not develop CFS, but these factors (including infection) increase the likelihood of acquiring CFS within one year and a genetic disposition to CFS has been demonstrated. Two studies suggest that self-reported childhood stress/trauma significantly increases the likelihood of acquiring CFS as an adult: A preliminary study found a 3 to 8 fold increase (depending on the trauma type). A study involving participants from the Swedish Twin Registry found that in matched case-control analyses, higher emotional instability and self-reported stress were significant risk factors (odds ratios, 1.72 and 1.64, respectively), while in co-twin control analyses the risk of emotional instability decreased to 1.02 whereas that of stress increased to 5.81 (suggesting genetic influences); there was also no association between extraversion and fatigue. Anxiety disorders have been associated with CFS in 5-15 year olds.

The CDC stated in 2006, their studies found gene mutation and abnormal gene activity levels in CFS patients that relate to the function of the hypothalamus-pituitary-adrenal (HPA) axis, which helps regulate the body's stress response. Earlier CFS research also found evidence that suggested abnormal stress response was associated with subtle dysfunction of the HPA axis. Questions remain about the pathophysiology of these findings. The controversy surrounding CFS has caused some social issues for patients and may contribute to their stress (see the Social issues section).

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 and a review have implicated oxidative stress in CFS symptoms; especially relating to fatigue, pain and postexertional malaise/exercise intolerance. According to research, the findings on oxidative stress and nitrosative stress (nitric oxide-related toxicity); are associated with an inflammatory response, seem consistent with abnormal 2-5A synthetase/RNase L enzyme (antiviral) activity and involves an immune response, against disrupted lipid membrane components, (by-products of lipid peroxidation ) and to nitric-oxide modified amino acids that have have become immunogenic; related to symptoms and severity in CFS. Gene expression studies suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired nerve balance strongly reflected in abnormal heart rate variability.

Immune dysfunction

When compared with CFS patients with normal natural killer cell activity, a 2006 study found those with lower levels reported less vigor, more daytime dysfunction, and more cognitive impairment; with the researchers suggesting this to be useful at subtyping. A 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. In 2006 an updated review on the phenomenology and pathophysiology of CFS found that, "immune system involvement in the pathogenesis of CFS seems certain but the findings on the specific mechanisms are still inconsistent." 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 detected an abnormal form and activity level of 2-5A synthetase/RNase L enzyme (antiviral immune response) in some CFS patients that appears to correlate with a reduction in exercise capacity. 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. A study found that elevated RNase L did not correlate with alpha-delta sleep.

Hyperactive immunity

Autoimmune disorders, representing a hyperactive immune system, most likely through a cell-mediated process, have been suggested. 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.

Allergies

Patients with CFS commonly develop additional problems with allergies or food intolerance.

Immunodeficiency

Immunodeficiency disorders (underactive immune system) have been reported. In 1989, an Australian study documented a loss of immunological integrity in one hundred CFS sufferers. The authors found disordered ratios of T-cell subsets and reduced levels of immunoglobulins specifically IgG 1 and IgG 3; there have since been other similar findings, and a review 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 hypoallergic, meaning they had a reduced immune response to the tested antigens, while an additional 55% were completely anergic (no immune response to the antigens).

Other immunological findings

• 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.
• Cytokine pattern; several studies and a number of reviews indicate there is a cytokine pattern of type 2 response including Th2 T helper cell, bias in CFS. This promotes the humoral immune system which stimulates B cells and increases antibody production. It is suggested that this explains some immune dysfunctions in CFS. A reduction in Th1 response has also been found in some CFS studies. with implications for altered Th1/Th2 balance Therapeutic interventions aimed at induction of a more favorable cytokine expression pattern and immune status are being investigated.
• 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.

Psychoneuroimmunological interactions

A 2006 review published in Current neurovascular research states that there is growing evidence of autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets in psychiatric disorders and hypothesizes how autoantibodies can play a role in the psychiatric disorders present in CFS. 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. 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". Elevated levels of nitric oxide (not to be confused with nitrous oxide) has been found in some CFS patients. One hypothesis is that elevated levels of nitric oxide may contribute to a "sensitization" of the nervous system that results in behavioral changes.

Infectious etiology

Enteroviruses Often, there is evidence of enteroviruses, e.g. the Coxsackie virus. The type of enterovirus varies, which can affect symptoms. In the times of polio outbreaks, paresis was often found in ME patients; this is no longer the case. Stomach biopsies of 80% of CFS patients showed the presence of enteroviruses in one study, as opposed to only 20% among controls, and nearly all biopsy specimens had microscopic evidence of mild chronic inflammation. Hyde and others suggest that these enteroviruses had been latent to be awakened by another, triggering infection, after which the immune system stays chronically active to combat the enterovirus.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. Subsequent studies using various types of controls have had mixed conclusions.Other viruses Other implicated viruses include Ross river virus, Borna disease, Parvovirus B19 also herpes viruses Cytomegalovirus (HHV-5), Human Herpesvirus Six (HHV-6) and HHV-7, A review by Soto and Straus in 2000 states the evidence argues against an ongoing active herpes virus infection, more recent reviews suggest these viruses may play a role in triggering or perpetuating CFS in subtypes.

Endocrine dysfunction

Thyroid and adrenal disorders can cause CFS-like symptoms, as can several other known endocrine disorders.HPA Axis

The HPA axis controls levels of hormones such as cortisol in the body. It is activated in a circadian (daily) cycle and modulated by stress, digestion, illness and other factors, and is important in regulating energy metabolism, the immune system, stress responses and inflammation in the body.

The HPA axis has been much studied in CFS which has shown underactivation with low cortisol not caused by adrenal insufficiency. These results have not been replicated in all CFS patients, so it is not clear whether this is just a subset of patients. It is also not clear if the HPA axis abnormalities are a cause or a result of the illness. However, a review has concluded, that even if the HPA axis dysfunctions are secondary to other factors; they are a likely factor in symptom propagation in CFS.

Gene expression

Gene expression is the process by which the inheritable information in a gene, such as the DNA sequence, is made into a functional gene product, such as protein or RNA. Research into CFS has found abnormalities in gene expression, and the CDC has conducted over twenty related studies itself. 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. 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. Several other studies have also suggested a genetic component to CFS involving immune dysfunction; T cell activation, perturbation of neuronal and mitochondrial function, possible links to organophosphate exposure and virus infection; immune response, apoptosis, ion channel activity, signal transduction, cell-cell signaling, regulation of cell growth and neuronal activity; some of which may be treatable with drugs that are already available. Gene expression abnormalities have been found relating to the central nervous system, metabolism and immune system; and has been associated by the CDC with impaired response to physical and psychological stresses in people with CFS. Linking genes to specific symptoms has been difficult, although is likely to be an important means to elucidate the pathogenesis of CFS.Seven subtypes of CFS/ME patients with distinct clinical differences have been identied in one gene expression study.

Genetic polymorphisms

Polymorphism in biology occurs when two or more clearly different types exist in the same population of the same species. Preliminary studies have suggested that the risk of developing CFS may be influenced by polymorphisms in genes affecting the central nervous, endocrine, immune, and/or cardiovascular systems. A review published in 2007 stated that certain genetic polymorphisms might be regarded as predisposing factors.

Metabolic disorders

Metabolic disorders and mitochondrial disorders can cause symptoms that strongly resemble CFS. Mitochondrial disturbances have been discovered in patients diagnosed with postviral fatigue syndrome. and mitochondrial dysfunction is considered a factor in PVFS and CDC defined CFS patients.

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

Toxic agents

Insecticides have a possible effect on the cause and/or course of CFS.

Other findings

Other findings regarding CFS in general include:

• 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.
• 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.
• 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.
• 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. 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.
• Abnormal lactic acid responses to exercise in some CFS patients, has been suggested to be a factor in CFS because it is 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.
• Essential fatty acid levels: Several studies published between 1990 a 2005 reported finding reduced levels of Omega-6 or Omega-3 essential fatty acids in cell membranes or serum in patients diagnosed with postviral fatigue syndrome or CDC defined CFS.One study conducted in 1999 on Oxford criteria defined CFS patients (Warren et al.) found no significant differences in fatty acid levels between treatment and placebo groups. There have also been two controlled systematic proton neurospectroscopy studies of CFS patients that found raised levels of choline in brain areas consistent with an abnormality of essential fatty acid and phospholipid metabolism in the brain in CFS patients. These changes have been considered due to essential fatty acid deficiencies resulting from delta 6 desaturase (D6D) enzyme inhibition in CFS. Some researchers have suggested D6D inhibition is linked to a possible viral cause. However, researchers at an Australian University of Newcastle who reported finding, in CDC criteria defined CFS patients; a dysregulation in D6D enzyme activity and fatty acid changes consistent with an inflammatory mediated event. Found that both gradual and sudden onset had the same fatty acid anomaly differentiaiting them from controls, the primary lipid changes were potentially non-viral induced. Whilst sudden onset CFS patients could be differentiated by a key post-viral modification to fatty acids. Other studies have shown that altered ratios of fatty acids and decreased availability of omega-3 EFAs plays a role in CFS symptoms and severity and is related to findings of lowered zinc and immune dysfunction, including the lowered mitogen-stimulated activation of some T cells. The decreased cell markers are also indicators of increased inflammation and low natural killer cell activation. The reduced EFA findings are considered indicative of; oxidative stress with reduced anti-oxidant status,
• Carnitine deficiency; is said to produce symptoms of fatigue and myalgia similar to PVFS, ME and CFS. Several studies have reported finding carnitine abnormalities in CFS patients. including lower serum total carnitine, free carnitine and acylcarnitine levels.The findings of reduced brain uptake of acetylcarnitine suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of CFS patients. There has been a contradictory study that included Oxford criteria defined patients. Others report of finding reduced levels of carnitine together with reduced essential fatty acids in patients with CDC defined CFS. Carnitine and its esters are considered to regulate the immune networks and inflammation, through carnitine-dependent; transfer of fatty acids into cells, and mitochondrial energy production from beta-oxidation of long-chain fatty acids. A gene expression study indicates altered; carnitine function, mitochondrial function, and fatty acid metabolism in PVFS. Also that profiles of plasma lipids in subgroups of CDC defined CFS patients suggest anomalies including beta-oxidation of fatty acids. As carnitine is considered an anti-oxidant, the lower plasma acetylcarnitine level may indicate, consumption by the increased oxidative stress in CFS.
• Researchers have found that children and teenagers with CFS are several times more likely to have some hyperflexible joints in an association with Ehlers-Danlos syndrome.

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, as "chronic fatigue" and related symptoms can be caused by a wide variety of conditions which should be investigated and managed.

CDC 1994 criteria

The criteria most used in scientific research are those of the Centers for Disease Control and Prevention of 1994 by Fukuda e.a. The following conditions must be met.Primary symptom Clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is:

• of new or definite onset (has not been lifelong);
• is not the result of ongoing exertion;
• is not substantially alleviated by rest;
• and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.Additional requirement

The concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue:

1. self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities;
2. sore throat;
3. tender cervical or axillary lymph nodes;
4. muscle pain;
5. multi-joint pain without joint swelling or redness;
6. headaches of a new type, pattern, or severity;
7. unrefreshing sleep;
8. post-exertional malaise lasting more than 24 hours.Final requirement

All other known causes of chronic fatigue must have been ruled out, specifically clinical depression, side effects of medication, eating disorders and substance abuse.

The clinical evaluation should include:

1. A thorough history that covers medical and psychosocial circumstances at the onset of fatigue; depression or other psychiatric disorders; episodes of medically unexplained symptoms; alcohol or other substance abuse; and current use of prescription and over-the-counter medications and food supplements.
2. A mental status examination to identify abnormalities in mood, intellectual function, memory, and personality. Particular attention should be directed toward current symptoms of depression or anxiety, self-destructive thoughts, and observable signs such as psychomotor retardation. Evidence of a psychiatric or neurologic disorder requires that an appropriate psychiatric, psychological, or neurologic evaluation be done.
3. A thorough physical examination.
4. A minimum battery of laboratory screening tests including complete blood count with leukocyte differential; erythrocyte sedimentation rate; serum levels of alanine aminotransferase, total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose, blood urea nitrogen, electrolytes, and creatinine; determination of thyroid-stimulating hormone; and urinalysis.

According to Fukuda e.a., other tests have no known value, unless indicated on an individual basis to confirm or exclude a differential diagnosis, such as multiple sclerosis.

NICE (UK) 2007 criteria

The UK National Institute for Health and Clinical Excellence (NICE), published a multidisciplinary clinical practice guideline in 2007 in which the following criteria are employed:

• fatigue that is new, persistent and/or recurrent, not explained by other conditions and has resulted in a substantial reduction in activity level characterised by post-exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days) and
• one or more of the following list of symptoms: difficulty with sleeping, muscle and/or joint pain at multiple sites without evidence of inflammation, headaches, painful lymph nodes that are not pathologically enlarged, sore throat, cognitive dysfunction, worsening of symptoms by physical or mental exertion, general malaise, dizziness and/or nausea and palpitations with no identifiable heart problem.

The diagnosis should be reconsidered if none of the following symptoms remain: post-exertional fatigue or malaise, cognitive difficulties, sleep disturbance, chronic pain.

The guideline requires fatigue to have been present for 4 months in an adult or 3 months in a child. It expects a diagnosis in a child to be made by a pediatrician. There are no recommendations on who is to make the diagnosis in an adult. The guideline states that a referral to a ME/CFS specialist should be offered immediately to the severely ill.

The NICE criteria have been criticized by patients' associations for being far too relaxed, recommending controversial CBT/GET and ignoring the WHO classification of CFS/ME as a neurological condition.

Other systems

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

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

Issues with the definitions/criteria

Selection bias and inconsistencies Several studies have found that using different case definitions (eg broad vs conservative ) has major influence on the types of patients selected and have also supported the distinction between 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. 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. It also may be inappropriate to synthesize results from CFS studies that use different definitions to select study populations. 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.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. 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). 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.Possible subtypes Studies suggest the existence of CFS subtypes. 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.Diagnosis inaccuracies A review published in 2006 found that the accurate diagnosis of CFS is low and another study found that physicians have a tendency to underrecognize psychiatric illness, especially when assessing patients whose chronic fatigue is fully explainable by a psychiatric disorder and who may be misdiagnosed with CFS.Terminology implications Because of the similarity in terminology, CFS is often confused with "chronic fatigue". Fatigue in the perceived absence of disease has traditionally been seen within the purview of psychiatry. 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. 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".

Testing

There is no generally accepted diagnostic test to reliably diagnose or exclude chronic fatigue syndrome. Research has not identified an association between CFS and one particular virus.

According to the CDC, the main purpose of performing diagnostic tests of any sort is to rule out other causes for fatigue and other symptoms of CFS. Routine tests recommended by the CDC:

• Complete blood count
• Blood chemistry (electrolytes, glucose, renal function, liver enzymes, protein levels and calcium)
• Thyroid function tests
• Erythrocyte sedimentation rate (ESR)
• Urinalysis for blood cells, protein and glucose

The 2007 UK NICE guideline includes, in addition to the CDC panel: C-reactive protein (a marker of inflammation), creatine kinase (a muscle-related enzyme), plasma viscosity (optional if ESR done) and serology for celiac disease. Ferritin determination may be performed in children and young people, and in adults only if other tests suggest iron deficiency. The guideline recommends clinical judgement in decisions to perform other tests in addition to the standard set. Testing for infections (e.g. Lyme disease, viral hepatitis, HIV, mononucleosis, toxoplasmosis or cytomegalovirus) is only recommended if the patient gives a specific history for this. Routine performance of the head-up tilt test, auditory brainstem responses and electrodermal conductivity is discouraged.

In contrast, the Nightingale Research Foundation recommends extensive testing including brain imaging and tests for neuropsychological, sleep, muscle, vascular and cardiac dysfunction to diagnose ME/CFS.

Suhadolnik, DeMeirleir e.a. developed a test to measure the fragmentation of the enzyme RNAse L. This fragmentation was found to be significant in CFS and has some use as a marker, but the test has limited availability.

Diagnostic controversies

Historically, many doctors have been unfamiliar with CFS, and some have refused to diagnose it. Others minimised the seriousness of CFS. This situation is changing somewhat, with more doctors willing to diagnose it. In the UK, the 2002 Chief Medical Officer's report stated that all doctors should consider CFS as a serious chronic 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 and its largely exclusionary definition. 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, and point to the epidemic history and biomedical research trends. Alternatively, some doctors and patients believe that the illnesses are real, but conceptualising them under a CFS banner amounts to misdiagnosis, largely due to the near-absolute exclusion of physical and laboratory signs required by the popular CFS criteria and the excuse to give up looking for treatable abnormalities.

Some patients' groups and experts state that research into CFS (ME) in the UK has been mostly hijacked by a "lobby of psychologists and psychiatrists",, who they claim hold significant power within the medical fraternity, with a resultant "gross abuse/neglect of patients." 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" or "rehabilitated" by psychotherapy and exercise.

Further controversy persists regarding the redefinition of ME as CFS in 1988 and whether they are in fact essentially different, if perhaps overlapping, entities. This dispute is reflected in debate over nomenclature or definition writ small, with stakes being high for all parties as this informs choice of treatment, research, management and funding policy. Psychiatrists refute the suggestion of the Gibson Report that excessive funding has been given to psychiatric research, despite that extremely few Medical Research Council studies have been into the pathoetiology of the illness. In his submission to the NICE guidelines panel, UK CFS specialist psychologist Peter Denton White disputed needs for disability aids for the severely affected and rejected the possibility of neuropathic pain and other features found in ME. Following a recent BBC radio show Dr White is reported to have contradicted his own broadcast stance by allegedly clarifying to co-guest, Dr William Weir, that ME "is an abnormal illness belief”. Dr White claims to have misinterpreted the question as one of abnormal illness beliefs in general.

Proponents of "lumping" insist there is insufficient evidence as to the existence of a discrete ME, and that they are equivalent. Detractors respond that if they were equivalent, there would be no resistance to referencing the term ME, that the popular CFS definition bears little or no resemblance to ME, and that ever-increasingly vague, misleading criteria and heterogeneity benefit no-one. ME activists insist that medical education of the historical database of published ME findings is suppressed in favour of biased appeals to the psychiatric paradigm such as the criticised 1996 Royal Colleges Report, reviews which cherry-pick study inclusions and a publishing "preference" of some journals such as the BMJ for psychosocial papers revolving around unsupportable psychosomatic explanations such as "interoception". The assertion of equivalency relies on disputing any definitive ME signs and findings, despite advances such as the 2003 Consensus definition which even use compound terminology.

All three ME specialists present at the CDC's naming board refused to endorse the descriptor of CFS and Dr Holmes was unknown for any work in this field previously; since then co-author Professor Komaroff has admitted the CFS definition was "a mistake". Dr Reeves of the CDC has stated that the epidemics described historically as ME were "not CFS". Recently the IACFS has voted to change its name to the IACFSME with a view to phasing out CFS, although they have made no associated changes to definition. Reasons cited for keeping CFS are American insurance claims and easy recognition of recent research carried out under the CFS umbrella.

The UK Department of Health has in parliament recognised the WHO classifaction and ME is recognised in a 1988 Bill of Rights, despite the establishment largely insisting on ME-CFS equivalency. It is debatable whether the NHS recognises ME at all and frequently documentation on CFS refers to "chronic fatigue", insisting that there are no signs or testable abnormalities.

Recently the CDC has made its position clear, stating on 26th December 2007 that:

"Various terms are incorrectly used interchangeably with CFS. CFS has an internationally accepted case definition that is used in research and clinical settings. ... The name myalgic encephalomyelitis (ME) was coined in the 1950s to clarify well-documented outbreaks of disease; however, ME is accompanied by neurologic and muscular signs and has a case definition distinct from that of CFS"

Treatment

Many patients do not fully recover from CFS, even with treatment. Some management strategies are suggested to reduce the consequences of having CFS. A sytematic review has shown that CFS patients are less susceptible to placebo effects than predicted, and have a low placebo response compared to patients with other diseases.

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. A systematic review published in the Journal of the Royal Society of Medicine (October 2006) 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. 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. 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.

The "Gibson Report" (Report of the Group on Scientific Research into Myalgic Encephalomyelitis 2006), a political inquiry into the science of CFS provides information about treating CFS with CBT and/or GET. However, the report has been criticised by the ME Association, for: being poorly conducted, misrepresentations, omissions, lack of references, factual inaccuracies or bias, and even potentially damaging implications. The "25% ME Group", a UK advocacy support group for severely affected M.E. sufferers, state, in their submission to the Gibson report, that both CBT and GET are unhelpful and may be dangerous/harmful to severely affected CFS patients. 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. However, it has without explanation dropped all use of objective measures such as actometers since the original research plan was published.

Cognitive Behavioral Therapy (CBT)

Results from clinical studies have suggested that cognitive behavioral therapy (CBT) is an effective, evidence-based therapy for CFS. The use of psychological therapies such as CBT does not imply that CFS is a psychiatric condition or that physical symptoms are not real, although the suggestion that they may be curative does suggest "proof of concept". Some CFS patients have comorbid depression and/or anxiety. In addition, it is argued that 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, 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, offers a possible explanation on his website. Some patients and patient groups state that this is innaccurate, arguing that CBT is described as an "exposure therapy" e.g. UK mental health charity MIND, that most of 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."

Although the Gibson Report states that CBT in general is helpful to many people with other illnesses, it is notable that RCTs of CBT in cancer have found no improvements in the course of the disease at all, and most of the helpfulness that CBT may afford illness in general is concerning matters such as e.g. high risk behaviour in a minority of AIDS patients. Dr Eleanor Stein states that the most commonly used worldwide model of illness management, the Stanford Model of Chronic Disease Self Management, shows benefits for diabetes and hypertension (conditions in which lifestyle play a strong role), but less benefit for arthritis.

Carruthers and Van de Sande in their Overview of the Canadian Consensus Guidelines, note that supportive counselling should not be mis-termed CBT to avoid misleading confusion between the two treatments amongst patients and doctors.

While it is controversial in regards to CFS, CBT seems to be more 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 finds that "CBT was associated with a significant positive effect on fatigue, symptoms, physical functioning and school attendance." The reviewers state that the quality of many recent trails on CBT are lower quality randomized controlled trials or trials that did not involve random allocation. The reviewers also state that one recent, good quality trial of CBT in children and adolescence supports the effectiveness of CBT. The reviewers state that reasons for withdrawals typically remain unreported, and that a degree of publication bias seems to be present in CFS/ME literature as a whole. In one study, the effect of CBT has been demonstrated up to five years after therapy. 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. Another recent study found that CBT improved self-reported cognitive impairment but not actual neuropsychological test performance which suggests the patients were somehow being mislead. 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. 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.

Similar and related treatments

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. A study which included 45 CFS patients found that psychodynamic counselling has comparable effectiveness to cognitive behavioral therapy (CBT) in the treatment of chronic fatigue.

Graded Exercise Therapy (GE, GA, GET or Adaptive Pacing)

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 , despite that there is no evidence that deconditioning is a significant factor in activity limitation, or that patients do not make the most of their restricted ability. Programs are said to 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 is supposed does not substantially increase symptoms.

The Gibson Report states GET is one of the most common treatments for CFS in the UK. Dr. Peter White found that in four studies 50-70% of patients improved with GET, and he stated that GET (combined with CBT) has only been shown to be efficacious in small trials. The Gibson Report mentions the 25% ME Group statement that, "only 5% of their members found GET helpful and 95% found it unhelpful". Many patients who submitted personal evidence to the Gibson inquiry said that they had similarly negative experiences which they attributed to their participation in GET. The authors of the report expressed concern about GET treatment guidelines, arguing that there are potential risks of GET for CFS patients, "Some of our evidence suggests that GET carries some risk and patients should be advised of this." The authors stated that the CFS guidlines lacked cautions about these possible risks and they said that patients should be checked for heart trouble before attempting GET. The authors said that the perception that GET may lead to deterioration in health "has lent fuel to their often serious antipathy to the doctors offering it." A New Zealand study suggests that GET may result in self-reported improvement by reducing the degree to which patients focus on their symptoms although there is no evidence that CFS patients disproportionately focus on symptoms, rather that common CFS definitions fail to describe patients' symptomology adequately.

Medication

Antidepressants

Antidepressants are often prescribed to CFS patients. Their purpose can be to treat secondary depression or mood swings, but low dosage tricyclic antidepressants are sometimes prescribed to improve sleep quality and reduce pain.. However, antidepressants often have side effects, some of which can increase CFS symptoms, and baseline metabolism differs between patients. Finding antidepressants, if any, that help the individual patient, is therefore a matter of trial and error.

Overall, studies into the use of antidepressants in CFS have had mixed results. Some studies have shown a reduction in symptoms with antidepressant use, while others have shown no benefit.

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. 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.

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 have demonstrated positive results, but other studies have shown little benefit from low dose cortisol.

Other medical treatments

Allergy identification and treatment

In cases where CFS-like symptoms may be caused by allergies, enzyme deficiencies or food intolerance, such as chronic sinusitis , coeliac disease, or irritable bowel syndrome, allergy testing, treatments, or elimination diets may prove beneficial.

Complementary and alternative medicine

Essential fatty acid treatments

Behan and Horrobin in a 1990 study of individuals diagnosed with postviral fatigue syndrome stated patients given essential fatty acids reported much greater symptom improvement verses patients given placebo. A fatty acid supplementation study conducted in 1999 using patients diagnosed by the Oxford criteria (Warren et al.) declared there were no significant differences between treatment and placebo groups. A review of CFS treatments by Reid et al. in 2000, concluded the Behan and Warren studies showed mixed results, and classified dietary supplements as "unknown effectiveness".

Magnesium

One small randomised controlled trial compared intramuscular injections with magnesium sulphate to placebo. The study stated greater improvement was found in the treatment group compared to the control group, as measured by the Nottingham health profile. The previously noted review by Reid et al. determined subsequent studies have failed to find a deficiency of magnesium in people with chronic fatigue syndrome, and classified magnesium treatments in dietary supplements having "unknown effectiveness".

Complementary and alternative medicine usage

Two studies reported increased utilization of alternative treatments by people with CFS vs. without. In one study designed to assess use of alternative medicines and perceived benefits with 63 paired CFS and non-CFS co-twins, 91% of twins with CFS and 71% without CFS used at last one alternative treatment in their life, and a large proportion of all twins considered them helpful. Future research should ascertain the usefulness of alternative practices in the management of CFS.

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." 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. A systematic review of 14 studies of the outcome of CFS reported 8 deaths, but none were considered directly attributable to CFS. To date there have been two studies directly addressing life expectancy in CFS. 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. 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.

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." According to Sophia's mother, Sophia became intolerant to water and managed only 4 fluid ounces per day. 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." This was seen as a form of recognition by the ME community. Previous cases have listed CFS as the cause of death in the US and Australia

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. The CDC states that more than 1 million Americans have CFS and approximately 80% of the cases are undiagnosed. All ethnic and racial groups appear susceptible to the illness, and lower income groups are slightly more likely to develop CFS. More women than men get CFS — between 60 and 85% of cases are women; however, there is some indication that the prevalence among men is under reported. The illness is reported to occur more frequently in people between the ages of 40 and 59. Blood relatives of people who have CFS appear to be more predisposed. 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).

Epidemiological research on children and adolescents has received minimal focus according to a 2006 research review. Among minors, prevalence appears to be lower than for adults and various studies have found a range of 50-80% of the cases occur in girls. The authors hypothesize the differences in estimates of ME/CFS among pediatric studies may result because of the lack of a reliable pediatric case definition.

CFS generally occurs in endemic cases. In addition, over 50 instances have been documented, such as the Royal Free Hospital incident, where epidemic clusters were reported. In these instances, significant numbers of people came down with illnesses described as ME or CFS simultaneously, confined to a local area or even a single building. An infectious origin for these clusters was considered highly likely due to:

• transference by inoculation to monkeys which developed symptomology and on post-mortem demonstrated neurological, vascular and cardiac damage (Fellow and Miles, 1955).
• human post-mortems or scans demonstrating abnormalities consistent with chronic infection (Wallis 1957, Schwartz et al 1994)
• serologic evidence of Iceland Disease blocking spread of polio type I spreading northwards (Sigurdsson et al, 1958).
• the pattern of acute onset with pharyngitis, mild fever, muscular pain, neck stiff­ness, cervical lymphadenopathy, gastroenteric symptoms, diffuse CNS involvement and photosensitivity were consistent with viral infection with an observed incubation period of 5-7 days. The biphasic clinical picture echoes pathogenesis through the pharynx, spreading through the reticuloendothelial barrier, then the CNS, resulting in morphological changes in mature lymphocytes and antibody creation. (Acheson, Ramsay, RIchardson, Crowley, Dillon et al)
• A predeliction for residential communities and most outbreaks occurring in summer (Acheson)
• The isolation of the non-polio enterovirus ECHO-9 in patients (Lyle, Annals of Internal Medicine 1959; 51: 248-269)
• psychiatric disease was a widely regarded exclusion for M.E. diagnosis (e.g. Acheson) and positive criteria for hysteria were absent (Gosling, Mayne, 1970).
• At the 1978 RSM Symposium, new evidence was presented of increased anti-complementary activity and the ability of lymphocytes to proliferate and survive in vitro for up to 19 weeks. (Compston 1978).

Since most current definitions of CFS exclude such findings and signs, it is disputed whether they refer to a differential diagnosis (but see below).

According to the CDC, CFS itself is not contagious.

Disease associations

Some diseases show a considerable overlap with CFS. According to an article in American Family Physician in 2002, Multiple Sclerosis, Thyroid disorders, anemia, and diabetes are but a few of the diseases that must be ruled out if the patient presents with appropriate symptoms.

People with fibromyalgia (FM, or Fibromyalgia Syndrome, FMS) have muscle pain and sleep disturbances. Fatigue and muscle pain occurs frequently in the initial phase of various hereditary muscle disorders and in several autoimmune, endocrine and metabolic syndromes; and are frequently labelled as CFS or fibromyalgia in the absence of obvious biochemical/metabolic abnormalities and neurological symptoms. 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. One study found several parallels when relating the symptoms of Post-polio syndrome with CFS, and postulates a possible common pathophysiology for the illnesses.

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.

One review (2006) found that there was a lack of literature to establish the discriminant validity of undifferentiated somatoform disorder from CFS. The author stated that there is a need for proponents of chronic fatigue syndrome to distinguish it from undifferentiated somatoform disorder. The author also mentioned that the experience of fatigue as exclusively physical and not mental is captured by the definition of somatoform disorder but not CFS. Hysterical diagnoses are not merely diagnoses of exclusion but require criteria to be met on the positive grounds of both primary and secondary gain. Primary Depression can be excluded in the differential diagnosis due to the absence of anhedonia and la belle indifference, the variability (lability) of mood, and the presence of sensory phenomena and somatic signs such as ataxia, myclonus and most importantly, exercise intolerance with paresis, malaise and general deterioration,. Feeling depressed is also a commonplace reaction to the losses caused by chronic illness which can in some cases become a comorbid situational depression.

Co-morbidity

Many CFS patients will also have, or appear to have, other medical problems or related diagnoses. Co-morbid fibromyalgia is common, although there are differences in pain complaints. 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. 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. CFS is significantly more common in women with endometriosis compared with women in the general USA population.

Social issues

Many patients find that a chronic fatigue syndrome diagnosis carries a considerable stigma, and has frequently been viewed as malingering, hypochondriac, phobic, "wanting attention" or "yuppie flu". As there is no objective test for the condition at this time, it has been argued that it is easy to invent or feign 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. A study found that CFS patients endure a heavy psychosocial burden. 2,338 respondents of a survey by a UK patient organization highlights that those with the worst symptoms often receive the least support from health and social services. 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. A survey by the Thymes Trust found that children with CFS often state that they struggle for recognition of their needs and/or they feel bullied by medical and educational professionals. The ambiguity of the status of CFS as a medical condition may cause higher perceived stigma. A study suggests that while there are no gender differences in CFS symptoms, men and women have different perceptions of their illness and are treated differently by the medical profession. 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.

A lack of information and awareness has led to many patients to feel stigmatized. CFS patients may not receive total medical and social acceptance and they state that some people trivialise the illness. 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 say that they need to do things for themselves during the time in which they feel better as there is no-one to delegate these tasks to.

History

The concept

In 1681, the diagnosis of muscular rheumatism was introduced by Thomas Sydenham, which according to Hyde is likely to have included cases of ME.

Sir Richard Manningham in 1750 published his description of febricula or little fever., an antiquated diagnosis which has also been attributed to some cases of ME by Shepherd.

In the 19th century, neurologist George Miller Beard popularised the concept of neurasthenia, in which symptoms included; fatigue, anxiety, headache, impotence, neuralgia and depression. This concept remained popular until well into the 20th century, although by then this diagnosis was viewed as primarily behavioural rather than physical, and to exclude postviral syndromes. It has largely been abandoned as a medical diagnosis.

In 1938 Gilliam made a detailed description of an illness that resembled poliomyelitis, interviewing patients and reviewing records of one of several clusters which had occurred in Los Angeles, United States in 1934. His common "atypical poliomyelitis" features of rapid muscle weakness, vasomotor instability, clonic twitches and cramps, ataxia, severe pain usually aggravated by exercise, neck and back stiffness, menstrual disturbance and dominant sensory involvement et cetera, constituted a twenty-point definition which was later viewed as the first recognisable description of ME. In the 1950s, the British public eye was caught by several outbreaks of a polio'-resembling illness and by now several tens of epidemics had occurred worldwide, including those in Iceland, Norway and New Zealand. 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 and on the rare human casualties, led to the conclusion that the disorder was caused by inflammation of the brain and the spinal cord, particularly the afferent nerve roots, and in 1956 it was named accordingly as myalgic encephalomyelitis, reflecting a presumed neuroimmune etiology.

Although non-epidemic cases were recognised, the disorder was in 1970 dismissed as mass hysteria by two psychiatrists. They were strongly criticized (Gosling; Hopkins; Galpine; Scott; Mayne: 1970 BMJ),(Compston, 1978 BMJ) for not adequately investigating the patients they described. In a 1978 symposium held at the Royal Society of Medicine (RSM) where there was clear agreement that ME is a distinct disease entity, and new pathology findings were discussed.

The illness gained national attention in the United States when the popular magazine Hippocrates ran a cover story of an epidemic in the mid-1980s at Lake Tahoe, Nevada. The designation Chronic Epstein-Barr Virus was in use in the U.S., but the magazine used the term "Raggedy Ann Syndrome" to note the fatigue and loss of muscle power patients felt.

After investigating the Lake Tahoe cluster, Centers for Disease Control & Prevention researchers attached a different kind of name to the phenomenon: chronic fatigue syndrome, involving some of the symptoms rather than disease taxonomy. They published the first working case definition for CFS in 1988. Research increased considerably, and more so after the criteria were relaxed in 1994.

In the United Kingdom, the Chief Medical Officer Kenneth Calman requested a report from the medical Royal Colleges in 1996. This led to the publication of a joint report in which the term "chronic fatigue syndrome" was found to be most representative. This was followed in 2002 by a further report by the new CMO, Liam Donaldson.

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.

WHO classification

Since its introduction into the eighth edition of the International Classification of Diseases in 1969, CFS/ME has been classified as a disease of the central nervous system. 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.

Controversy

Two contrasting viewpoints among ME/CFS experts have become apparent. In a letter to the Lancet, psychiatrists David and Wessely contested the WHO classification, arguing that CFS was a form of neurasthenia to be classified as a psychiatric condition. Dutch researchers tested a model where behavioral, cognitive, and affective factors played a role in perpetuating fatigue, and concluded that this was the correct model for CFS. This result could, however, not be replicated in a population-based study, where fatigue in psychiatric disorders, but not in CFS, proved to be a match.

In 2001 the WHO's Collaborating Center, King's College, London, published a "Guide to Mental Health in Primary Care", in which both ME and CFS were reclassified as mental illnesses in ICD-10, under the code F48.0. The guide was also on the website of The Collaborating Center; King's College. In response to activist protests to the Collaborating Center and the WHO's Headquarters, the web page was corrected and a correction to the Guide promised. The latter was tardy and when a correction slip was printed around 30,000 copies had already been distributed. On 28th June 2001 Andre L'Hours, Technical Officer at the WHO headquarters in Geneva, confirmed that it was "unacceptable" to classify one disorder in two places in the ICD-10 under the WHO's rubric.

The Countess of Mar brought the matter to the attention of the House of Lords on January 22nd, 2004, citing WHO Headquarters position of how ME and CFS are classified (G93.3), and that WHO intend no changing of this. Subsequently Lord Warner wrotestating The London WHO Collaborating Center had ceded to WHO authority and would ensure future editions of the Guide were corrected. In response to an activist, Professor Anthony Sheehan, Professor of Care Services at the Department on Health, on behalf of Sir Liam Donaldson, then Medical Chief Officer, replied "The WHO; the WHO Collaborating Centre; and the Department of Health have now agreed a position on the classification of CFS/ME. It has been agreed that the second edition of the WHO Guide to Mental Health and neurology in primary care will have only one ICD-10 code for CFS. This is G93.3. [...] I can only say that the Department of Health has no plans to seek a reclassification of CFS within ICD-10."

A common misconception is that ME was initially classified at G93.3 due to political activist pressure; however this is not true. The WHO recognised ME in 1965 at a time it was well established with many supporting papers and inclusion medical textbooks. The WHO classified ME in 1969, some years before the first patient support/activist groups were formed. Again in 1992 the WHO maintained their rubric with no need of patient pressure; the only interference has of late come from psychiatric disgruntlement and the only propaganda a distortion of these facts.

See also

• Notable sufferers from Chronic fatigue syndrome
• Cultural references of Chronic fatigue syndrome

References

External links

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