CHRONIC FATIGUE SYNDROME

Chronic fatigue syndrome (CFS) is one of several names given to a poorly understood, highly debilitating disorder of uncertain cause/causes, which is thought to affect approximately 4 per 1,000 adults in the United States and other countries, and a smaller fraction of children. The disorder is marked by chronic mental and physical exhaustion, often severe, and by other specific symptoms, arising in previously healthy and active persons. Despite promising avenues of research, there remains no objective assay or pathological finding which is widely accepted to be diagnostic of Chronic Fatigue Syndrome. It remains largely a diagnosis of exclusion, made on the basis of patient history and symptomatic criteria, although a number of tests exist which can help aid diagnosis. Although there is agreement on the genuine threat to health, happiness, and productivity posed by Chronic Fatigue Syndrome, 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 the disorder. The name chronic fatigue syndrome is itself controversial because a large part of the patient community feels the term trivializes the illness. Chronic fatigue syndrome is not the same as "chronic fatigue. While fatigue is a common symptom in many illnesses, Chronic Fatigue Syndrome is a multi-symptom disease and is relatively rare by comparison. Definitions 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), and may be worsened by even trivial exertion (a mandatory diagnostic criterion according to some systems). Most diagnostic criteria require the symptoms must be present for at least six months, and all state the symptoms must be idiopathic, not caused by other medical conditions such as diabetes, hypothyroidism or anemia. Chronic Fatigue Syndrome 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. Some cases improve over time, and treatments (though none are universally accepted) bring a degree of improvement to many others, though resolution is rare. Chronic Fatigue Syndrome occurs more often, but not exclusively, in women, for unknown reasons. Chronic Fatigue Syndrome 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 children, adolescents and the elderly

Nomenclature in Chronic Fatigue Syndrome:
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 back to several older reports that appeared to describe a similar syndrome. In 1962 the distinguished neurologist Lord Brain included ME in the 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. Also, the previous word (benign) used with ME was considered misleading and unsatisfactory because the condition may be permanently incapacitating. 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, although central nervous system inflammation has been documented in some patients diagnosed with Chronic Fatigue Syndrome. 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 has led to a campaigning movement 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 indicated they wanted the name changed. The association prefers terms such as myalgic encephalomyelitis ("ME" or "ME/CFS") and post-viral fatigue syndrome ("PVFS"), which imply specific underlying etiologies or pathologic processes. 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 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. 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 cell disease; this name is used widely in Japan. It reflects research showing a reduction in the number of natural killer cells in many Chronic Fatigue Syndrome 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 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. Chronic Fatigue Syndrome, 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.



Signs and Symptoms in Chronic Fatigue Syndrome:
The onset of most cases of Chronic Fatigue Syndrome seems to be 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. However, the accurate prevalence and exact roles of infection and stress in the development of Chronic Fatigue Syndrome are still currently unknown. Some cases of CFS start gradually, but the majority start suddenly, usually triggered by a flu-like viral infection. The diagnosis of Post Viral Fatigue Syndrome is sometimes given in the early stage of the illness. 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 a flu-like or other respiratory infection such as bronchitis, from which they seem never to fully recover and which evolves into Chronic Fatigue Syndrome. Some patients report that it began after a vaccination or a blood transfusion. 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 Chronic Fatigue Syndrome. This has become an area of great controversy. 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 Chronic Fatigue Syndrome, 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 Chronic Fatigue Syndrome. 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 Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome 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 in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome patients, but despite a common diagnosis the functional capacity of Chronic Fatigue Syndrome 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.

Post-exertion symptom exacerbation in Chronic Fatigue Syndrome:
One of the most common and recognizable aspects of Chronic Fatigue Syndrome is what is called "post-exertional malaise". Patients also frequently experience rapid weakening and loss of muscle strength. When people with Chronic Fatigue Syndrome exert themselves, physically or cognitively beyond their limits in either intensity or frequency, their symptoms worsen. This is to say that exertion is unsustainable. Although symptoms may increase immediately and proportionally, the decompensation effects usually takes 24 hours or more to reach full extent, and can sometimes take several days or longer to gradually accumulate Muscles which are frequently used tend to be weakest. Proposed causes and pathophysiology in Chronic Fatigue Syndrome:
The cause of Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome may be different for different patients, but if so, the various causes may result in a common clinical outcome. Neurological abnormalities in Chronic Fatigue Syndrome:
Researchers have found evidence that Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome 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 neurotramsmitters have been found affected including glutamate, sensitivity to acetylcholine associated with vasoconstriction, and autoantibodies to cholinergic receptors, associated with central pain. Beta-endorphin, a natural pain killer, has been found to be low in Chronic Fatigue Syndrome patients, the opposite of what is found in primary depression. Dysautonomia in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome indicates it is very similar to that found in postural orthostatic tachycardia syndrome (POTS). POTS and Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome patients report symptoms of orthostatic intolerance and low or lowered blood pressure. Inner-ear disorders in Chronic Fatigue Syndrome:
Problems such as Meniere's, tumor in the inner ear, or Benign Paroxysmal Positional Vertigo (BPPV) can cause dizziness, vertigo, and fatigue. Recurrent ear infections are common in some Chronic Fatigue Syndrome sufferers. Tinnitus is also quite common Antibodies associated with hearing loss have been found in Chronic Fatigue Syndrome and FMS patients with inner ear disorders. Orthostatic hypotension in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome.

Psychiatric abnormalities in Chronic Fatigue Syndrome:
Depression in Chronic Fatigue Syndrome:
There is some overlap in symptoms between depression and Chronic Fatigue Syndrome, and sometimes cases of Chronic Fatigue Syndrome are mistakenly attributed to clinical depression. There are, however, many clinical differences between the two. Clinical depression often responds well to physical exercise, whereas Chronic Fatigue Syndrome is characterised by exercise intolerance but with a willingness to be active. 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. Low dosages of antidepressants are sometimes prescribed to help a Chronic Fatigue Syndrome patient sleep better. Stress and trauma in Chronic Fatigue Syndrome:
The majority of people who experience stress/trauma do not develop Chronic Fatigue Syndrome, but these factors (including infection) increase the likelihood of acquiring CFS within one year and a genetic disposition to Chronic Fatigue Syndrome has been demonstrated. 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). 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. Anxiety disorders have also been found to be a risk factor in 5-15 year olds. Chronic Fatigue Syndrome 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; although this may only be subtle, and acquired as a result of Chronic Fatigue Syndrome. The controversy surrounding CFS has caused some social issues for patients and may contribute to their stress. Oxidative stress in Chronic Fatigue Syndrome:
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[92] have implicated oxidative stress in Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome. Immune dysfunction in Chronic Fatigue Syndrome:
When compared with Chronic Fatigue Syndrome 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.



Hyperactive immunity in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome patients consistent with the theory of immune system activation, possibly by an antigen triggering a constant immune fatigue state. The study, 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 in Chronic Fatigue Syndrome:
Patients with Chronic Fatigue Syndrome commonly develop additional problems with allergies or food intolerances. Immunodeficiency in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome sufferers. 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 hypoallergic, meaning they had a reduced immune response, while an additional 55% were completely anergic, meaning they had no immune response at all. Other immunological findings in Chronic Fatigue Syndrome:
Several studies have implicated a higher level of bioactive transforming growth factor-beta (TGF-beta) in Chronic Fatigue Syndrome patients. 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. 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. A study found that while exercise worsened symptoms in Chronic Fatigue Syndrome patients, it also increased allergen challenge response only in the Chronic Fatigue Syndrome group, regardless of allergy status

Infectious etiology in Chronic Fatigue Syndrome:
Enteroviruses in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome 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 in Chronic Fatigue Syndrome:
For many years the ubiquitous Epstein-Barr virus, present in 90% of the population. Other viruses in Chronic Fatigue Syndrome:
Other implicated viruses include cytomegalovirus, and human herpesvirus type-6 (HHV-6).

Endocrine dysfunction in Chronic Fatigue Syndrome:
Thyroid and adrenal disorders can cause Chronic Fatigue Syndrome like symptoms, as can several other known endocrine disorders. HPA Axis in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome 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. Gene expression in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome has found abnormalities in gene expression, and the CDC has conducted over a dozen related studies itself. It has been found that patients with Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome 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 highlighted a genetic component to Chronic Fatigue Syndrome 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 may point towards the impaired response to physical and psychological stresses in people with Chronic Fatigue Syndrome. However, linking genes to specific symptoms has so far been elusive, although is likely to be an important means to elucidate the pathogenesis of Chronic Fatigue Syndrome.

Metabolic disorders in Chronic Fatigue Syndrome:
Metabolic disorders such as McArdle disease, CPT II deficiency, myoadenylate deaminase deficiency, and mitochondrial disorders can cause symptoms that strongly resemble Chronic Fatigue Syndrome. Mitochondrial disturbances have been discovered in patients diagnosed with Postviral fatigue syndrome. Folate deficiency (suspicion by elevated homocysteine and low serum folate) may mimick Chronic Fatigue Syndrome symptoms

Toxic agents in Chronic Fatigue Syndrome:
Insecticides have a possible effect on the cause and/or course of Chronic Fatigue Syndrome.

Other findings in Chronic Fatigue Syndrome:
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 Chronic Fatigue Syndrome patients with 29 controls and found that 10 of the Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome. 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. 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. 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 in Chronic Fatigue Syndrome:
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.

Testing in Chronic Fatigue Syndrome:
There is no generally accepted diagnostic test to reliably diagnose or exclude chronic fatigue syndrome. Research has not identified an association between Chronic Fatigue Syndrome 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 Chronic Fatigue Syndrome.
Routine tests recommended by the CDC:
Complete blood count
Blood chemistry (electrolytes, glucose, renal function, liver enzymes, protein levels and calcium)
Thyroid function tests in Chronic Fatigue Syndrome:
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



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