Myalgic encephalomyelitis/chronic fatigue syndrome

Myalgic encephalomyelitis/chronic fatigue syndrome
Specialty	Neurology, rheumatology

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 CFS. 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 CFS, various physicians' groups, researchers, and patient activists champion very different nomenclature, diagnostic criteria, etiologic hypotheses, and favored treatments, resulting in ongoing controversy about nearly all aspects of the disorder. The name chronic fatigue syndrome is itself controversial, with some patient advocates and other authorities preferring terms such as myalgic encephalomyelitis ("ME" or "ME/CFS") and post-viral fatigue syndrome ("PVFS"), which imply specific underlying etiologies or pathologic processes.

Chronic fatigue syndrome is not the same as "chronic fatigue”. While fatigue is a common symptom in many illnesses, CFS is a multi-symptom 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" (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 insist that the symptoms must be present for at least six months, and all insist on there being no other cause for them: i.e. the symptoms must be idiopathic, not caused by other medical conditions such as diabetes, hypothyroidism or anemia. CFS patients may report many other symptoms which are not included in all diagnostic criteria, including muscle weakness, cognitive dysfunction, hypersensitivity, orthostatic intolerance, digestive disturbances, depression, poor immune response, and cardiac and respiratory problems. It is unclear if these symptoms represent co-morbid conditions or are produced by the same underlying etiology as CFS itself. Some cases improve over time, and treatments (though none are universally accepted) bring a degree of improvement to many others, though resolution is rare.

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

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 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, and in 1978 the Royal Society of Medicine accepted ME as a distinct clinical entity. In 1988 both the UK Department of Health and Social Services and the British Medical Association officially recognized it as a legitimate and potentially distressing disorder. Opponents of the term ME maintain there is no objective evidence of inflammation, although central nervous system inflammation has been documented in some patients diagnosed with CFS (e.g. the case of Sophia Mirza). Many patients, and some research and medical professionals in the United Kingdom and Canada, use this term in preference to or in conjuction 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 fatigue syndrome (CFS); this name was introduced non-unanimously in 1988 by a group of United States researchers based at the Centers for Disease Control and Prevention in response to the 1984 Lake Tahoe ME epidemic, and is used increasingly over other designations, particularly in the United States. Many patients and clinicians perceive the term as trivializing and as the 1994 Fukuda paper itself cedes, stigmatizing which has led to a campaigning movement to change the name and definition.
• Chronic fatigue immune dysfunction syndrome (CFIDS); many patients and advocacy groups in the USA use the term CFIDS, introduced by patients current with the biomedical research in an attempt to reduce the psychiatric stigma attached to "chronic fatigue," as well as the public perception of CFS as a psychiatric syndrome. 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 original ME researcher Dr. Melvin Ramsay, "The crucial differentiation between ME and other forms of post-viral fatigue syndrome lies in the striking variability of the symptoms not only in the course of a day but often within the hour.
• Chronic Epstein-Barr virus (CEBV) or Chronic Mononucleosis; the term CEBV was introduced 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.
• Low Natural Killer cell disease; this name is used widely in Japan. It reflects research showing a reduction in the number of natural killer cells in many CFS patients. More significantly, in-vitro activity of the remaining natural killer cells is reduced, often by as much as two thirds.
• Yuppie Flu; this was a factually inaccurate term first published in a November 1990 Newsweek 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

The majority of CFS cases begin after a period of stress in the year preceding the illness or after a flu-like illness and is therefore more likely to occur during winter. 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.

Sudden onset cases

Many people with CFS report a sudden, drastic start to their illness. Some people can remember a specific day or even hour when they first became ill. Often CFS starts with, or is triggered by, another illness. Many people report getting a case of a flu-like or other respiratory infection such as bronchitis, from which they seem never to fully recover and which evolves into CFS. Some patients report that it began after a vaccination or a blood transfusion.

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, symptom exacerbation after exertion, plus a pathologically slow recovery period usually 24 hours or longer.

• Sleep dysfunction: "Unrefreshing" sleep/rest, poor sleep quantity, insomnia or rhythm disturbances. A study found that most CFS patients have clinically significant sleep abnormalities that are potentially treatable. 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 patterns may be further interrupted by vivid "feverish" dreams, and unlike in healthy persons, exercise can worsen the 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).

• 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).

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

Activity levels

Patients report critical reductions in levels of physical activity with the severity of symptoms and disability the same in both genders; but despite a common diagnosis, the functional capacity of CFS patients varies greatly., and chronic pain is strongly disabling in CFS patients. 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. While some patients are able to lead a relatively normal life, others are totally bed-bound and unable to care for themselves. Almost all patients find they must drastically reduce their activity from pre-illness levels, regardless of their previous level of athleticism, and must severely modify or give up physical hobbies and exercise. Many patients find themselves unable to work full-time, or at all. A considerable number of CFS cases in many countries are on disability benefits or private insurance, or have made claims and been denied.

Post-exertion symptom exacerbation

One of the most common and recognizable aspects of CFS is what is called "post-exertional malaise". Patients also frequently experience rapid weakening and loss of muscle strength. When people with CFS exert themselves, physically or cognitively beyond their limits in either intensity or frequency, their symptoms worsen. This is to say that exertion is unsustainable. The harder the exertion and the longer it lasts, the worse the decompensation will be afterward, and with greater recovery time. 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. This can make judging appropriate activity difficult. Time to recover strength has been described as inordinate and "pathological" and limits often change daily and from hour-to-hour, as well as through longer relapses and remissions. Severely affected patients may have "hard" limits such as severe loss of muscle power or drastic postural hypotension causing collapse or blackouts, rendering complete if usually temporary debilitation, and imposing strict, if variable, limitations. It is such limitations that usually enforce disability upon patients sooner or later, after an initial cyclical "push-crash" period, which can be prolonged through poor advice or diagnostic delay. Typically symptoms lessen or disappear with recumbency, due to othostasis as a form of exertion and neuro-vascular adaptability. Therefore patients need to intersperse any activity with rest periods, which is referred to as pacing. Muscles which are frequently used tend to be weakest.

In patients without a diagnosis of CFS, or a proper understanding of how CFS affects exertion, a "downward spiral," can occur where a sufferer will try to work harder to make up for the previous day or week's lack instead of resting. This causes further deterioration and often can trigger a relapse or worsening of their condition. It must be noted that patients may be compelled to exert themselves in a society that does not yet afford CFS total medical and social acceptance or trivialises the illness (see below). Sometimes acute onset cases start with severe illness imposing drastic limitations, and patients may be admitted to hospital. Complications, co-morbid illness, and unknown factors can cause exacerbation, which may not be within patients' control. Since CFS is not defined as the result of ongoing exertion, at least some patients with a relapse or progressive course cannot be explained through activity levels.

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

Proposed causes and pathophysiology

The cause of CFS is unknown, although a large number of causes have been proposed, and several proposed causes have very vocal and partisan advocates. In a basic overview of CFS for health professionals, the CDC states that "After more than 3,000 research studies, there is now abundant scientific evidence that CFS is a real physiological illness." 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 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 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 is tightly tied to the body's endocrine system and also directly controls some aspects of blood pressure control and metabolism. The dysautonomia that evidences itself in CFS shows up mostly in problems of orthostatic intolerance - the inability to stand up without feeling dizzy, faint, nauseated, etc. Research into the orthostatic intolerance found in CFS indicates it is very similar to that found in postural orthostatic tachycardia syndrome (POTS). POTS and CFS patients exhibit reduced blood flows to the heart upon standing that result in reduced blood flow to the brain. The reduced blood flows to the heart are believed to originate in blood pooling in the lower body upon standing. Many CFS patients report symptoms of orthostatic intolerance and low or lowered blood pressure.

Inner-ear disorders

Main article: balance disorder

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 CFS sufferers. Tinnitus is also quite common Antibodies associated with hearing loss have been found in CFS and FMS patients with inner ear disorders

Orthostatic hypotension

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

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 the result of living with CFS or a pre-existing condition.

Low dosages of antidepressants are sometimes prescribed to help a CFS patient sleep better.

Stress and trauma

Stress contributes to many different illnesses, and can cause a series of responses that in genetically predisposed individuals may lead to stress-related brain disease after adverse experiences. Although the majority of people who experience stress/trauma do not develop CFS, these (including infection) increase the likelihood of acquiring CFS within one year and a genetic disposition to CFS 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.

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

Oxidative stress

Further information: Oxidative stress

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

Immune dysfunction

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

RNase L deregulation

Several studies have highlighted the existence of abnormal 2-5A synthetase/RNase L enzyme (antiviral) activity in some CFS patients, with several more studies finding this to correlate with the worsening of symptoms after exercise. 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

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

Immunodeficiency

Immunodeficiency disorders (representing an underactive immune system) have been reported. As early as 1989, a study was published in Australia that documented a loss of immunological integrity in one hundred CFS sufferers. 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. Some theories propose that an infection with one of the below-listed disease agents somehow leads to immune dysfunction and chronic fatigue in cases of CFS. This is partly supported by test results indicating lowered or changed immune responses in some patients, as well as elevated levels of infectious agents in some patients' blood.

Other immunological findings

• Several studies have implicated a higher level of bioactive transforming growth factor-beta (TGF-beta) in CFS patients.
• 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 CFS patients, it also increased allergen challenge response only in the CFS group, regardless of allergy status.

Psychoneuroimmunological interactions

Further information: psychoneuroimmunology

A recent review states that there is growing evidence of autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets in psychiatric disorders and that autoantibodies may play a role in psychiatric disorders present in CFS. 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 and may help explain a "sensitization" of the nervous system that results in behavioral changes.

Stress can have a significant effect on the immune system, due to the fact that the stress hormones cortisol, ACTH and adrenaline and the sympathetic nervous system are also important modulators of the immune system. Chronic stress has been shown to reduce levels of Natural killer cells (NK) and T cells, as well as to reduce the function of those cells. Stress has also been shown to increase levels of nitric oxide in the body.

Infectious etiology

Bacterial infections

• Lyme disease and related tick-borne infections. Lyme disease does not always present acutely with a rash, and less than half of sufferers recall a tickbite (the nymphal deer tick is the size of a poppy seed, and secretes an anesthetic to prevent the host from feeling its bite). Furthermore, the characteristic joint pain is not always present. For these reasons Lyme can be difficult to diagnose, particularly in its later stages, at which point symptoms are virtually identical to those of CFS. The accuracy of blood tests for Lyme remains highly controversial, especially since they depend on an effective immune system response, which many researchers believe is compromised by the disease. As a result, some clinicians believe Lyme is under-diagnosed.
• Bacterial respiratory infections such as mycoplasmic bronchitis/pneumonia, Legionnaire's disease, and possibly other bacteria associated with bacterial pneumonia.
• Sinusitis. Sinusitis is a chronic infection of the sinuses which can be difficult to diagnose, and can cause symptoms similar to those of CFS. Sinusitis can occur after dental surgeries or infections, and thus may be related to reaction to mercury in dental amalgams as above, or dental infections, as below.
• Toxoplasma gondii. Toxoplasma gondii is a parasitic infection. If let untreated it can cause severe immune suppression and neurologic symptoms.

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 cytomegalovirus, and human herpesvirus type-6 (HHV-6). More recently, however, similarities to post-polio syndrome have led to a reexamination of the viral link.

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

Endocrine dysfunction

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

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.

Metabolic disorders

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

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

Toxic agents

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

Other findings

Other findings regarding CFS in general include:

• Recent genetic research into CFS has found abnormalities in gene expression, and the CDC has conducted over a dozen related studies itself. 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 highlighted 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 may point towards the impaired response to physical and psychological stresses in people with CFS. However, linking genes to specific symptoms has so far been elusive, although is likely to be an important means to elucidate the pathogenesis of CFS.

• 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.

• 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

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 (aka "Fukuda")

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

Primary symptom

incapacitating fatigue

Incapacitating fatigue that is:

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

Additional symptoms

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

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

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 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 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 highlighted the need for specific subgroups of CFS to be identified and/or for the case definition to be further clarified with emphasis on using empirical studies: An international CFS study group for the CDC found ambiguities in the CDC 1994 CFS research case definition which contribute to inconsistent case identification. 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. 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. Some patients' groups and experts maintain 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.

Treatment

At this time, no cure for CFS is known. Treatment protocols that attempt to cure CFS are many, usually linked to a presumed cause, but none stand out as promising. Other treatments, that address specific symptoms such as pain, sleep deprivation and food intolerances, and some that affect the metabolism, can have a beneficial effect but do not cure CFS. Some management strategies can be effective to reduce the consequences of having CFS.

Since CFS symptoms tend to vary over time, in practice it is not always clear if a change in severity is due to a received treatment. The same difficulty arises in research, even while it seems that CFS patients are significantly less susceptible to placebo effects than patients of many other diseases (about 20% v 30%).

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. This may bias the results towards those with less severe symptoms. The authors also expressed concern about possible bias in the CFS literature, a lack of uniformity in case definitions and study inclusion/exclusion criteria (studies using any CFS criteria were included), and the basic information provided about the participants; which they state makes it difficult to assess the generalizability of the findings of many of these studies. This review found that no intervention had been proved effective in restoring the ability to work. An earlier systematic review published in 2002 also found this, although CBT was "lending a possible association between improvement in the ability to work and an increase in the number of patients employed". This earlier review also found that no specific patient characteristics seemed to serve as best predictors of positive employment outcomes in CFS patients, although did find that depression of greater severity was associated with unemployment. 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) provides information about treating CFS with CBT and/or GET. However, the report itself has been criticised by several groups, for: being poorly conducted, misrepresentations, omissions, lack of references, factual inaccuracies or bias, and even potentially damaging implications. According to the Countess of Mar (panel member of the Group on Scientific Research into ME), the report was a political inquiry into the science, not a scientific inquiry, of CFS. In the "25% ME Group Submission to Gibson" they state that both CBT and GET are not only just unhelpful to many severely affected CFS patients but also dangerous/harmful. The discrepancy between trial results and patient group surveys has been noted by the P.A.C.E. trial group, who are conducting a larger more detailed study into CBT and GET which is currently underway and is due for completion in 2009.

Cognitive Behavioral Therapy (CBT)

Cognitive behavioral therapy (CBT) is claimed to be 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. Some CFS patients have comorbid depression and/or anxiety. In addition, it is maintained CBT may teach patients various "coping strategies" to help them deal with cognitive impairments such as a deterioration of short-term memory or abbreviated attention span, 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 dispute such claims, pointing out that CBT is invariably described as an "exposure therapy" e.g. UK mental health charity MIND, that virtually all the conditions commonly listed as being suitable for CBT are behavioural and that the 2002 UK CMO's Report describes CBT as "a tool for constructively modifying attitude and behaviour." Some patients and advocates suggest that there are “good” and “bad” forms of CBT, and it is important for patients to decide whether CBT is advisable in their case; others point out that, as supported by Carruthers and Van de Sande in their Overview of the Canadian Consensus Guidelines, that to avoid such confusion supportive counselling should not be mis-termed CBT. The Gibson Report states that CBT in general is helpful to many people with other illnesses; and while it is controversial in regards to CFS, it seems to be most effective in those with less severe forms but much less effective in the severely affected. Commenting on the relevance of CBT for CFS, the report states that it has a role to play in treatment but at best is only a partial answer and more research is needed. A systematic review on CBT finds that, while some kind of positive result is often reported, the quality of the research into the effects of CBT is usually rather low and the patient selection is not random. The reviewers note that reasons for withdrawals typically remain unreported, and furthermore state that a degree of publication bias seems to be present. Some approaches aim at active rehabilitation rather than just adapting to the illness. CBT does not seem to be as efficacious when provided by general practitioners or when given in a group. 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. 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/Related Treatments

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

Graded Exercise Therapy (GE, GA or GET)

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

Similar/Related Treatments

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

Cautions

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

Medication

Antidepressants

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

• Although CFS patients may not be suffering from any distinct Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses indicating a depressive disorder, similarities have been seen in brain chemistry between those with depression or those with CFS, specifically in the anterior cingulate cortex and frontal cortex as well as reduced blood flow (cerebral hypoperfusion) in gray matter as seen on SPECT imaging. The pattern found in CFS via SPECT is different from what one would see with normal controls or patients with depression, but CFS patients have been found to have increased perfusion in the left thalamus compared to patients with depression. Changes have also been seen in reticular activating system (RAS) in CFS patients by SPECT. The RAS controls circadian rhythm, the sleep-wake cycle, which Tricyclics are often used to help regulate.

• Recent studies show pro-inflammatory cytokine processes take place during somatic and psychosomatic disease including both depression and CFS, and is possible that symptoms manifest in CFS can attenuated by pharmacological affect of antidepressants on the immune system.

• Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes may reduce the affect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones. Recent studies indicate a reduction of 5-HT transporter (serotonin transporter) and raised levels of tryptophan (a serotonin precursor) in many CFS patients which may contribute to fatigue and cognitive disturbances.

• Antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). IL-6 has been demonstrated in CFS, and is a singaling pathway inducer of fatigue. IL-6 has been shown to cause cognitive problems in a variety of diseases.

• Antidepressants have also been shown to suppress TH1 (T helper cell) upregulation.Some advances have also been achieved in the field of Hypothalamic-pituitary-adrenal axis (HPA-axis) modulation by antidepressants. The role of HPA-axis in CFS has still to be determined as data has been mixed. Studies have shown patients with CFS have demonstrated subtle alterations in HPA axis activity characterized by reduced Adrenocorticotropic hormone (ACTH) over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion.Other studies argue there is no HPA-axis change in CFS patients.

• These studies warrant further investigation for antidepressants for use in a psycho-neuroimmunological approach which may be required for optimal pharmacotherapy in CFS. Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.The culmination of these studies purport antidepressants can be useful in non-depressed patients.

• Overall, studies for use of antidepressants in CFS thus been performed has been mixed. Some studies have shown a reduction in symptoms with MAOI's, Tricyclics, SSRI and SNRI use. Some studies have shown no improvement.

Autonomic nervous system stimulants

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

Hormones

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

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

Sleep aids

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

Pain relief

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

Antibiotics

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

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

Antifungals

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

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. Since some CFS patients show decreased immune response or symptoms of MLS, pre-existing mild allergies may increase to harmful levels after CFS onset. Some studies suggest that a form of CFS may be triggered by a rare reaction to dental metals. Tests in Sweden showed that 76% of CFS patients who tested positive to metal allergy and swapped metal fillings for ceramic substitute achieved partial or full health improvement . Metal allergy can be detected by a blood test named MELISA.

Dietary/nutritional modification

Essential Fatty Acid Treatments

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

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

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

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

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

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

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

Magnesium

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

Other

Lifestyle adjustments

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

Alternative medicine

Alternative medicine is sometimes proposed for CFS, especially when conventional treatments are poorly tolerated or fail to relieve symptoms, but research has failed to show that any alternative treatments are actually effective.

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 patients' 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. However, the most recent estimates by the CDC are that more than 1 million Americans have CFS.[18] The CDC further states that approximately 80% of all CFS cases are undiagnosed. Far more women than men get CFS — between 60 and 85% of cases are women; however, there is some indication that the prevalence among men is under reported. Members of ethnic minorities and low income classes are slightly more likely to develop CFS. Though people of all ages can get CFS, and precise statistics are not available, the prevalence among children and adolescents appears to be lower than for adults. Among minors with CFS, about half are boys and half girls. CFS occurs both in isolated cases and large-scale outbreaks. In a number of documented cases several people in a building or large numbers of people in a community came down with the disease essentially simultaneously, suggesting that it is (in at least some cases) partly due to an infectious agent. Blood relatives of people who have CFS appear to be more predisposed. However, CFS does not appear directly contagious; caretakers, partners and others in close contact with persons with CFS for years do not develop CFS any more frequently (excluding relatives, as earlier).

Disease associations

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

A proposed similarity between psychiatric disorders, such as somatoform disorders (particularly undifferentiated somatoform disorder) is that according to some definitions, physical symptoms or their severity are unsupported by medical evidence. One review (2006) found a lack in literature on comparing undifferentiated somatoform disorder with CFS, however mentioned that a critical feature is implied in the definition of undifferentiated somatoform disorder that is absent from CFS: that some patients experience their symptoms as being exclusively physical and not as mental. 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 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, some argue that it is easy to "invent" CFS-like symptoms for supposed financial, social or emotional benefits. CFS sufferers argue in turn that the perceived "benefits" are hardly as generous as some may believe, and that CFS patients would greatly prefer to be healthy and independent. Furthermore, studies have found that CFS patients are not malingering and endure a heavy psychosocial burden. Surveys by patient organizations highlight 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. CFS has been found to be the biggest cause of long-term sickness leading to absence from school, in both staff and pupils; yet children with CFS often struggle for recognition of their needs and/or are bullied by medical and educational professionals. 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. Patients may find themselves surrounded with misunderstanding of their condition. Since CFS is often invisible to some -- although many sufferers present a somewhat poorly picture -- many will not understand why a newly diagnosed co-worker suddenly needs to work from home, use a better chair, or take time off. A CFS sufferer may face disbelief and misunderstanding, and even anger, from persons previously part of the social support structure. Many CFS patients have faced unsupportive families and dubious physicians, and have lost jobs, careers, scholarships and relationships to the syndrome. Anxiety and depression often result from the emotional, social and financial crises caused by CFS. While few studies have been made, it is believed that CFS patients are at a high risk of suicide. One of the worst side-effects of the illness is social isolation. Many CFS sufferers are confined to their house and/or bed. They are unable to take part in normal social activity. They are also excluded from workplace and school socialising. Interestingly, the growth of the internet and the improvements of online speeds have been a boon to many people with CFS, especially in the developed countries. The internet has provided access to social contacts, to knowledge and learning, to purchasing and to services, which has improved the lives of many with CFS.

History

The concept

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

In the 19th century, neurologist George Miller Beard popularised the concept of neurasthenia, in which fatigue was the predominant symptom. 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 outbreaks which had occurred in Los Angeles 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 later criticized for not adequately investigating the patients they described. 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. An outbreak at Incline Village, Lake Tahoe, Nevada in the mid-1980s, regained initially local attention for the characteristic loss of muscle power or muscle fatiguability characteristic of ME, as "Raggedy Ann Syndrome". Researchers now attached a different kind of name to the phenomenon: chronic fatigue syndrome, involving some of the symptoms rather than disease taxonomy. The Centers for Disease Control & Prevention published a first working case definition for CFS in 1988, even though by then the CDC were aware of the ME connection. Research increased considerably, and more so after the criteria were relaxed in 1994. The obvious drawback was the possibility of misdiagnosis. Lacking a diagnostic laboratory test of any kind, CFS has frequently been mis-diagnosed, for example in patients presenting CFS symptoms with similar biological conditions or infections (such as Lyme or Epstein-Barr) (the latter of which is often the cause of glandular fever, or infectious mononucleosis), or psychological conditions (ranging from depression to hypochondria). A lack of information and awareness has led to many patients being stigmatized, sometimes as hypochondriac or lazy, yet at other times as over-active and perfectionistic.

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, Simon Wessely et al. 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. The vast majority of international ME/CFS specialists support the classification of CFS as a physical condition. The CFS Toolkit of the US Centers for Disease Control and Prevention reads: "After more than 3,000 research studies, there is now abundant scientific evidence that CFS is a real physiological illness".

Notable sufferers

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

• Olaf Bodden, former German soccer player
• Cher, pop singer, actress
• Susan Harris, television writer and producer, who incorporated her experiences into the fifth season of The Golden Girls
• Laura Hillenbrand, author of the book Seabiscuit: An American Legend, the basis for the film Seabiscuit
• Blair Hornstine, a New Jersey student
• Keith Jarrett, jazz pianist
• Peter Marshall, former British squash player
• Andrew Oldcorn, golfer
• Alastair Lynch, Australian rules footballer
• Ali Smith, author

Cultural references

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

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

• The 2000 film I Remember Me chronicles a sufferer of CFS.

• In the premiere episode of Buffy the Vampire Slayer ("Welcome to the Hellmouth"), popular girl Cordelia remarks, "My mom doesn't even get out of bed anymore. And the doctor says it's Epstein-Barr. I'm like, pleeease! It's chronic hepatitis, or at least chronic fatigue syndrome. I mean, nobody cool has Epstein-Barr anymore."