Chronic fatigue syndrome

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS) and various other names, is a syndrome of unknown and possibly multiple etiology, affecting the central nervous system (CNS), immune, and many other systems and organs. Most definitions other than the 1991 UK "Oxford", require a number of features, the most common being severe mental and physical depletion, which according to the 1994 Fukuda definition is "unrelieved by rest", and is usually made worse by even trivial exertion (controversially the Oxford and Fukuda require this to be optional only). However, patients usually contend that they have many, often severe symptoms which are far more onerous than the research diagnostic criteria, such as pain, muscle weakness, loss of brain function, hypersensitivity, orthostatic intolerance, digestive disturbances, depression, immune and in some cases life-threatening cardiac and respiratory problems, and it is these symptoms exacerbated by extremely low stamina that cause greatest suffering, not "fatigue", which more properly describes a normal state of recovery unrelated to pathology. Some cases resolve or improve over time, and where available, treatments bring a degree of improvement to many others.

History
Originally studied since the late 1930s as an immunological neurological disorder under the medical term "myalgic encephalomyelitis" (ME), CFS has been classified by the World Health Organization (WHO) as a disease of the central nervous system since 1969. In 1992 and early 1993 the terms "post-viral fatigue syndrome" (PVFS) and "chronic fatigue syndrome" (CFS) were added to ME under the exclusive ICD-10 designation of G93.3. This is an artifact of the WHO not allowing multiple categorizations of a single condition, rather than being an indication of two disjoint disorders.

Nomenclature
There are a number of different terms which have been at various times identified with this organic neuroimmune disorder.
 * Myalgic encephalomyelitis (ME, "inflammation of the brain and spinal cord with muscle pain") as a disease entity has been recognized and described in the medical literature since 1938, with the seminal paper being that by Wallis in 1957; Sir Donald Acheson's (a former Chief Medical Officer) major review of ME was published in 1959; in 1962 the distinguished neurologist Lord Brain included ME in his textbook of neurology, and in 1978 the Royal Society of Medicine accepted ME as a distinct clinical entity. In 1988 both the UK Department of Health and Social Services and the British Medical Association officially recognized it as a legitimate and potentially distressing disorder. Opponents to the term ME maintain there is no inflammation and that not all patients report muscle pain. United Kingdom and Canadian researchers and patients generally use this term in preference to CFS.
 * Chronic fatigue syndrome (CFS); this name was introduced in 1988 by a group of United States researchers based at the Centers for Disease Control and Prevention, and is used increasingly over other designations, particularly in the United States.
 * Chronic fatigue immune dysfunction syndrome (CFIDS); many people, especially patients in the United States, use the term CFIDS (pronounced [See-Fids]), which was originally an acronym for the above or "Chronic Fatigue & Immune Dysregulation Syndrome". This term was 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.
 * Post-viral [fatigue] syndrome (PVS or PVFS); this is a related disorder. According to original ME researcher Dr. Melvin Ramsay, "The crucial differentiation between ME and other forms of post-viral fatigue syndrome lies in the striking variability of the symptoms not only in the course of a day but often within the hour. This variability of the intensity of the symptoms is not found in post-viral fatigue states" (Ramsay 1989).
 * 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 ME/CFS patients by these two viruses. As these viruses are also found in healthy controls, however, it is uncertain what role they play in CFS.
 * 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.
 * Yuppie Flu; this was a factually inaccurate nickname for CFS, first published in a November 1990 Newsweek article. It reflects the belief that CFS mainly affects the affluent ("yuppies"), and implies that it is a form of malingering or burnout. CFS, however, affects people of all races, genders, and social standings, and this nickname is inaccurate and considered offensive by patients. It is likely that this article contributed to the damaging public (and even medical) perception of CFS as a psychiatric or even psychosomatic condition.
 * Uncommonly used terms include Akureyri Disease, Iceland disease (in Iceland), Royal Free disease (after the location of an outbreak), 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).

Symptoms
According to the 1994 Fukuda definition there are eight main categories of symptoms in CFS:


 * Fatigue: People with CFS experience profound, overwhelming exhaustion, both mental and physical, which is worsened by exertion, and is not relieved (or not completely relieved) by rest. To receive a diagnosis of CFS, this fatigue state must last for six months.
 * Pain: Pain in CFS may include muscle pain, joint pain (without joint swelling or redness, and may be transitory), headaches (particularly of a new type, severity, or duration), lymph node pain, sore throats, and abdominal pain (as a symptom of irritable bowel syndrome). Patients also report; bone, eye and testicular pain, neuralgia and painful skin sensitivity. Chest pain has been attributed variously to microvascular disease or cardiomyopathy by researchers.
 * Cognitive problems: people with CFS may experience forgetfulness, confusion, difficulty thinking, concentration difficulties, and "mental fatigue" or "brain fog". Additional signs may be experienced; in the 2003 Canadian Definition these include aphasia, agnosia, loss of cognitive body map.
 * Hypersensitivity: people with CFS are often sensitive to light, sound, and some chemicals and foods. Many CFS patients report an increase in allergic-type sensitivity to foods, scents, and products, and many also report a sensitivity to medications, which can complicate treatment. Patients with pre-existing allergies, asthma, and similar conditions often report a worsening of symptoms. A remarkable feature of "classically defined" ME are "sensory storms", typified by sudden catastrophic incapacitation to noise, light, smell, which feels overwhelming; more pronounced as discrete earlier on in the illness.
 * Poor temperature control: people with CFS often report either running too hot or too cold, possibly due to involvement of the hypothalamus, which regulates body temperature. Many CFS patients frequently run a low fever, or report fever-like symptoms (sweating, feeling too hot or cold, etc.) without measurable fever temperature.
 * Sleep problems: "Unrefreshing sleep" and rest is a hallmark of CFS, and in one of the syndrome's greatest ironies, insomnia is also common, especially in the chronic phase. Maintaining a sleep schedule is extremely difficult for many patients. Vivid, "feverish" dreams are a symptom in many people with CFS, exacerbating disturbed sleep patterns. A hallmark sign of neurological disease is that exercise worsens the insomnia, i.e. the opposite to that found in well people.
 * Psychological/Psychiatric symptoms: emotional lability, anxiety, depression, irritability, sometimes a curious emotional "flattening", may manifest in CFS patients. It is undetermined whether any of these are directly caused by the CFS mechanism, or may be secondary symptoms created by the syndrome, as many chronic pain or illness patients also show similar psychiatric issues. However the exaggerated and sometimes random nature of emotional expression is consistent with some brain disease.
 * Disturbances in the autonomic nervous system and hormones:
 * People with CFS often have abnormalities in the autonomic nervous system such as low blood volume, orthostatic intolerance, dizziness and light-headedness, especially when standing up quickly.
 * Hormonal abnormalities may include abnormal vasopressin metabolism and a blunted ACTH response leading to hypothyroidism and/or low cortisol and reduced ability to respond to physiological and emotional stress. Patients sometimes show abnormally low levels of testosterone, growth hormone and other important hormones.

It should be noted that lists of diagnostic criteria (such as the Oxford and Fukuda lists) were designed for selection and exclusion of participants for research studies and, as such, are quite narrow in scope. Some patients have CFS despite the fact that their symptoms do not match the strict research diagnostic criteria.

Onset
Some cases of CFS start gradually, but the majority start suddenly, often triggered by a 'flu-like viral or similar illness. People with CFS may improve or recover completely after a few or many years, or not at all. It is not known whether any CFS sufferer has truly recovered to pre-illness levels, or whether their symptoms have merely subsided enough for them to live a more normal life. Some sufferers have a remission for months or years only to later relapse, often more severely.

Sudden onset cases
Many people with CFS report a sudden, drastic start to their illness. Some people can remember a specific day or even hour when they first became ill.

Often CFS starts with, or is triggered by, another illness. Many people report getting a case of the 'flu', exposure to an allergen (a cough or sniffle caused by paint, a new pet, or construction dust), or a severe infection such as bronchitis, from which they seem never to fully recover and which slowly evolves into CFS. Other patients begin with Lyme disease, which despite adequate Lyme treatment, may 'evolve' from the clinical symptoms and definition of Lyme to those of CFS (this is permitted by the Fukuda definition). Other triggers can include car accidents, moving house, and stressful life situations. Some patients say they felt unusual or uneasy for a short period (days or weeks) before the onset.

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

There is no standard course for CFS. For a patient to be officially diagnosed with chronic fatigue syndrome, the symptoms must have persisted for at least six months. It is possible that not all cases of CFS are chronic: some people may have CFS for four months, recover, and never get diagnosed, some claim. However, the Fukuda paper also contains a definition of "chronic fatigue" which is reserved for those who do not meet the full criteria for CFS. Since the 50% rule of Holmes et al was dropped, it is possible that there are people with CFS whose level of disability is so low that they never seek treatment, or receive an accurate diagnosis, though this is not permitted by the Canadian definition.

Activity levels
Activity levels vary widely among CFS patients. While some are able to lead a relatively normal and active 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.

One notable CFS sufferer is soccer legend Michelle Akers, who reported struggling with the illness for many of the later years of her career. However, more severe sufferers felt that an active professional athlete "poster child" like Akers helped to trivialize the syndrome in the eyes of the public, and made it much more difficult for highly incapacitated patients to be taken seriously. It is worth noting that the condition can strike persons of all activity levels, however.

Post-exertion symptom exacerbation
One of the most common and recognizable aspects of CFS is what is called "post-exertional malaise". When people with CFS exert themselves beyond their limits (and their limits may change daily), their symptoms worsen. The harder the exertion and the longer it lasts, the worse the symptoms will be afterward with greater recovery time. Some contend from this that prognoses such as deterioration or relapse-remission must be due to sufferers' activity patterns, however this is far from proven, since in many sufferers at least, fluctuations are not solely related to exertion but can include responses to infection, changes in temperature (e.g. hot or cold weather), physical or emotional stressors, and unknown disease process, but they maintain:

The cyclical pattern occurs when patients work harder because they "feel better" or are having a "good day", leading them to think they can exert themselves more than usual. However, the excess exertion leads to worse symptoms on the following day. Thus it is difficult for patients to maintain an even level of activity, or to tell if they are improving.

In sufferers without a diagnosis of CFS, or a proper understanding of how CFS affects exertion, this can lead to a "downward spiral", where a sufferer will try to work harder to make up for the previous day's lack instead of resting. This exhausts them further, and often can trigger a relapse or worsening of their condition.

However, many sufferers who are severely affected particularly find this "behaviourist" hypothesis simplistic and offensive as it leads to the blaming of patients and denial of social support and medical care since the condition can be seen as supposedly self-controllable and self-limiting and already scarce services may be withdrawn if the sufferer is unfortunate enough to deteriorate.

Duration
People with CFS may improve after a few months, or after many years, or never at all. They may reach a plateau at some constant level of health, or may progressively decline, although CFS does not appear to be directly fatal or damagingly progressive. Often, the symptoms change over time, or cycle through time. Relapses are common, especially after stressful life events or additional illness. Exertion can cause not merely a relapse, but a worsening of overall health. Un-diagnosed cases of CFS often worsen as the sufferer attempts to return to a 'normal' level of activity, only to make their condition worse through exertion.

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. "Chronic fatigue" and similar symptoms can be caused by a wide variety of conditions which should be investigated, although treatment of the patient's symptoms can begin before a complete diagnosis is made. In a patient displaying CFS symptoms, fatigue and new migraines, for example, it is safe and reasonable to treat the migraines while attempting to rule out other possible causes of the patient's fatigue.

CDC 1994 criteria (aka "Fukuda")
According to the 1994 CDC case definition, 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:
 * unexplained by medical cause,
 * lasts for at least six months (from the very beginning of becoming less than totally well - this is not six months from the date that it's realised enough for the patient to see their GP),
 * 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
 * 8) Post-exertional malaise (fatigue lasting more than 24 hours after exertion)

Other systems
Some scoring systems, while being considered imperfect, have 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) (also see here and here)
 * Carruthers et al (2003) Canadian Case definition for ME/CFS

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

Controversies
Historically, many doctors have been unfamiliar with CFS, and some have refused to diagnose it. This situation is rapidly changing, with more doctors willing to diagnose it and more diagnoses occurring each year. In the UK, the Chief Medical Officer's report stated that all doctors should consider CFS as a serious chronic illness -- though it is not stated whether this is a serious physical illness -- and treat patients accordingly. Similar progress has been made in the United States.

There remains considerable skepticism amongst some medical professionals about the existence of CFS as a 'real' -- i.e. medical as opposed to behavioural -- condition, possibly due to the extreme uncertainty of its etiology, and the lack of accepted biomedical signs. As is common historically with new or unexplained conditions, many people are inclined to believe that a condition with few to no biomedical markers may be, or even must be, psychological in origin. This has led to frustration in many patients, who feel strongly that their disability is not psychological, but biological, in cause and effect. Some more vocal patients' groups maintain that research into CFS (ME) in the UK has been mostly hijacked by the psychologists/psychiatric lobby, who they claim hold significant power within the medical fraternity, with a resultant "abuse of patients' rights". The UK and the Netherlands have particularly seen disagreements between biomedical researchers and their adherents, and psychiatrists (particularly proponents of cognitive behavioral therapy, or CBT) and supporters of the theory that CFS is psychological in origin, and can be "cured" entirely by therapy and exercise.

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

Epidemiology
Due to problems with the definition of CFS, estimates of its prevalence vary widely. Studies in the United States have found between 75 and 420 cases of CFS for every 100,000 adults.

Far more women than men get CFS &mdash; between 60 and 85% of cases are women. 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.

Disease associations
Some diseases show a considerable overlap with CFS, and it may be hard to distinguish between them. People with fibromyalgia 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.

Other disorders with known causes and treatments that may produce CFS-like symptoms are Lyme disease, gluten intolerance (celiac disease and related disorders), and vitamin B12 deficiency. There may also be correlation with polycystic ovary syndrome (PCOS). Thyroid disorders, anemia, and diabetes can present similar symptoms, and must be ruled out. Psychiatric disorders, especially depression, can appear to cause similar symptoms as well, and patients must be carefully screened to determine whether depression is co-morbid with, causing, or being caused by CFS or another syndrome.

Co-morbidity
Many CFS patients will also have, or appear to have, other medical problems or related diagnoses. 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. As previously mentioned, many CFS sufferers also experience symptoms of irritable bowel syndrome (IBS), temporomandibular joint pain (as in TMJ), headache including migraines, and other forms of myalgia. Clinical depression and anxiety are also commonly co-morbid.

Proposed etiologies and corresponding treatments
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.

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

The treatments that are proposed and often attempted for CFS are as varied as the suggested causes, and can generally be classified either according to the cause that they presume, or the symptom they propose to treat. Unfortunately, since CFS symptoms tend to vary over time, it is very easy for someone to become convinced that a particular treatment has helped them (or not), regardless of its true effectiveness. Alternative medicine is often proposed for CFS, especially when conventional treatments are too toxic or otherwise poorly tolerated, or simply fail to relieve symptoms. Alternative treatments may also be more affordable or accessible to patients with limited funds or health care coverage.

Allergies

 * 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 intolerances (see below) to pollen and dander allergies.


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

Autonomic nervous system disruption

 * 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 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 (though this reduced blood flow by itself does not account for the symptoms of CFS).  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.


 * TREATMENT: ANS stimulants: Drugs such as atomoxetine (Strattera&reg;), which stimulate the autonomic nervous system, appear to have significant positive effects in some people with CFS symptoms.  Amphetamines and amphetamine analogs such as methylphenidate (Ritalin&reg;) also seem to help some patients.  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&reg;), a medication designed to aid in maintaining wakefulness, has had some positive effect on individuals with CFS, but has not been properly studied.

Damage to ascending reticular activating system

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

Depression

 * Depression: many cases of CFS are attributed to depression, and there is no doubt that severe depression can cause most of the symptoms of CFS. However, clinical depression often responds well to physical exercise, whereas CFS is characterised by exercise intolerance. (See section on Post-exertion symptom exacerbation).

While depression is not uncommon among CFS patients, there are many CFS patients without depressive signs, suggesting that depression is not a direct cause of the symptoms. There also patients with pre-existing depression which responded to treatment, but whose CFS symptoms did not improve; and treatment for depression is not particularly effective on CFS patients without depression. While depression may occur in CFS patients, it may be a result of living with CFS, or a secondary product of exercise intolerance, rather than the cause. Depression sufferers have been shown to have lowered immune system responses in some cases, which may explain the slight correspondence between pre-existing depression and CFS.


 * TREATMENT: Antidepressants: Antidepressants are often prescribed to CFS patients, for a number of reasons: the doctor may believe depression is the cause of the symptoms, or to treat co-existing depression caused by CFS. Tricyclics may also help adjust sleep cycles. For patients with muscle or joint pain, or co-existing fibromyalgia, tricyclic antidepressants (prescribed at much lower doses than are usual for depression) have been shown to be effective for neuralgic pain in fibromyalgia sufferers, and persons with diabetic myalgia.

Hormonal dysfunction

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


 * TREATMENT: 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 holistic approach have demonstrated positive results, but other studies have shown little benefit from cortisol itself.  (Dr. Teitelbaum argues that the approach taken in those studies is flawed.)  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 (though one could question whether the disorder in such a case is correctly classified as CFS).

Hyperactive

 * Autoimmune disorders (representing a hyperactive immune system) have been suggested.


 * White Blood Cells: 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 a virus triggering a constant immune fatigue state.

Underactive

 * Immunodeficiency disorders (representing an underactive immune system) have been suggested.


 * 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.


 * TREATMENT: Immune enhancers: These are generally "food supplements" of various types that are claimed to enhance the immune system, although they can include various antiviral drugs. They are often proposed either to treat some presumed viral infection or to treat a presumed general immune deficiency.

Bacterial dental infections

 * Dental infections: Some have implicated focal infections from root canals and cavitations in tooth sockets where the periodontal ligament was not removed when a tooth was extracted. The theory is that anaerobic bacteria can exist inside a tooth with a root canal or a cavitation because of the lack of blood supply. The bacteria produce toxins that cause system wide problems.  Some individuals with CFS like symptoms have seen great improvement after the removal of all root canals and/or cavitation surgery to clean out the sockets from tooth extraction sites.


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

Bacterial infections, other

 * Lyme and related tick-borne bacteria


 * 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.


 * TREATMENT: Antibiotics: Antibiotics are commonly used to treat Lyme disease, sinusitis and 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 penicillines are reported to be of significant (albeit temporary) effect in some patients. It's worth noting that 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 the infectious agent in their system after antibiotic treatments, these levels are generally too low to qqualify for a diagnosis of an infection; that is, a patient with Lyme who has received Lyme antibiotic treatment will be pronounced 'cured' of Lyme disease when their blood levels of Lyme are at or below those found in healthy persons, although a Lyme-CFS case may still have CFS symptoms after treatment. Some patients may receive antibiotic treatment for the causative infection, and recover from the original infection, but still have CFS. High doses of antibiotics (sometimes intravenous doses) over longer than generally prescribed courses are recommended by some physicians in these cases of "late Lyme", and have had some beneficial effect for some sufferers, but this treatment remains highly controversial.

Fungal

 * yeast and other fungi. Some nutritionists believe that CFS is caused by an overgrowth of yeast, known as "candidiasis", but treatment of candidiasis has not helped all CFS patients.


 * TREATMENT: Antifungals: Antifungal drugs 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.

Viral

 * Brainstem Damage: Dissection studies of the brains of persons with post-polio syndrome have shown microscopic damage to areas of the brain responsible for alertness and metabolism, and possibly other motor functions, consistent with the symptoms of both CFS and post-polio syndrome. It is theorized that an infectious agent could cause similar damage in CFS cases, but no post-mortem studies on CFS patients have been done at this time. (See "viral hypothesis", below.)

Many members of the Herpesvirus family have been implicated as causative agents in CFS. For many years the ubiquitous Epstein-Barr virus, present in 90% of the population, was the principal suspect. Other viruses implicated include cytomegalovirus, and human herpesvirus type-6 (HHV-6). The evidence has not been consistent with these hypotheses, however, and they are generally no longer believed to explain the etiology of CFS. (Soto & Straus, 2000)

More recently, however, similarities to post-polio syndrome have led to a reexamination of the viral link. A number of viruses of the enterovirus family, notably the Coxsackie virus, can produce an infection of the nervous system similar to that caused by the poliovirus, and an even wider range of viruses have been shown capable of triggering an autoimmune reaction that attacks the nervous system. It is believed by some that one of these mechanisms causes damage to areas of the brain responsible for alertness and metabolism, resulting in many of the symptoms of CFS.

Inner-ear disorders

 * Inner-ear disorders: Problems such as Meniere's, tumor in the inner ear, or Benign Paroxysmal Positional Vertigo (BPPV) can cause dizziness, vertigo, and fatigue.

Metabolic disorders

 * 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 recently been discovered in some CFS patients.


 * TREATMENT: Mito cocktail: Given that the symptoms of CFS generally resemble those of metabolic and mitochondrial disorders, a combination of supplements often known as a mito cocktail is sometimes used to treat the disorder.  This "cocktail" consists of relatively large amounts of l-carnitine and CoQ10, and possibly d-ribose, vitamin B12, biotin, and several other nutrients.  As with mitochondrial disorder, it is believed that large amounts (eg, 2-10g/day l-carnitine) are necessary to have a significant effect, and smaller amounts of these nutrients will not generally be helpful.

Nutritional deficiency or imbalance

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


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

Psychosomatic causes

 * Psychosomatic causes: many doctors and researchers believe that CFS is a complex psychosomatic disorder caused by chronic stress. Patients generally disagree with this theory, believing their disorder to have organic components, and to date, psychological treatment alone has not been shown to be particularly effective in treating CFS. (See Chronic_fatigue_syndrome, above)

Spinal problems

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


 * TREATMENT: Surgery: For Chiari malformation and some other disorders (e.g., thoracic outlet syndrome) that are occasionally blamed for CFS symptoms, surgery to release trapped nerves or otherwise correct neurological problems may be helpful.

Toxic agents

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


 * TREATMENT: Detoxifiers: Various detoxification agents are often advocated, from simple intestinal purgatives to "liver cleanses" to various types of chelating agents for the removal of mercury and other heavy metals.

For underlying symptoms and for lifestyle adjustments

 * TREATMENT: 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.


 * TREATMENT: Pain relievers: 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 low blood pressure and 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.


 * TREATMENT: Lifestyle Adjustments: Many CFIDS 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. This may also include the use of assistive devices; many CFS patients find that a cane, walker, wheelchair 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.


 * TREATMENT: Location: Some CFS patients find relief in moving to warmer climes. This is a difficult and expensive treatment option, not always feasible or available.


 * TREATMENT: Graded exercise: A monitored 'self-developed' gradual exercise program to increase strength and cardiovascular health has proven helpful to some patients. However, the risks of post-exertional malaise, which can cause significant, if usually temporary, worsening of symptoms, make this a difficult regimen to implement successfully. Some studies which have suggested that graded exercise can improve the condition of sufferers have been criticized for ignoring individuals who fall out of the trials because they can't cope with the exercise program required. Indeed, in the UK, rigid enforcement of GE by medical professionals on people seriously ill with CFS may have led to many becoming much more ill than before. Patients and advocates strongly suggest that, where graded exercise is used, the patient be in control of the amount of increases, and allowed to set limits when those are recognized.


 * TREATMENT: Self-controlled exercise, "pacing": although accepting the above conclusions about 'graded exercise,' some exercise, is necessary and beneficial to all persons. "Pacing" is being advocated by a large number of patients as one of the few really effective means of improvement. The principles involve: acceptance of the patient's limitations (by both the patient and any coaches), awareness of the early signals of physical fatigue, and stopping exercise before becoming noticeably tired. 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.


 * TREATMENT: Other exercise: Most 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 many CFS sufferers.

Involving therapy

 * TREATMENT: Cognitive behavioral therapy: Cognitive therapy may benefit up to 25% of CFS patients. This should not imply that CFS is a primary psychiatric condition, but rather that the protracted course of the illness may cause depression, anxiety and mental distress. In addition, CBT can teach patients various "coping strategies" to help them deal with cognitive impairments such as a deterioration of short-term memory or abbreviated attention span. CBT should always be used in conjunction with medical care and treatment, as it is not a substitute for such, and cannot fully treat the physical aspects of CFS.


 * TREATMENT: Counselling, various: Many CFS patients face the stress of economic and legal problems, which can cause a serious deterioration and paralysis of the patient. CFS sufferers may lose jobs, marriages, and the ability to work at all, causing severe financial loss and distress. A lawyer, social worker or counselor 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.

Social issues
Chronic fatigue syndrome carries a considerable stigma, and has frequently been viewed as malingering, hypochondriacal behavior, "wanting attention" or "yuppie flu". As there is no objective test for the condition at this time, many argue that it is easy to "invent" CFS-like symptoms for financial, social or emotional benefits. CFS sufferers argue in turn that the perceived "benefits" are hardly as generous as some may believe, and that most CFS patients would greatly prefer to be healthy and independent.

Patients may find themselves surrounded with misunderstanding of their condition. Since CFS is invisible, many persons 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, like other highly disabled and dependent persons, are at a high risk of suicide.

Notable sufferers
Some notable persons with CFS are:
 * Michelle Akers, soccer player
 * Brian Aldiss, author
 * Susan Blackmore, parapsychologist, author
 * Howard Bloom, evolutionary psychologist, author
 * Cher, pop singer, actress
 * Neil Codling, formerly of Suede
 * Blake Edwards, writer and director of such movies as Breakfast at Tiffany's, 10, and The Pink Panther
 * John Fahey, folk guitarist
 * Flea, musician
 * Clare Francis, international yachtswoman and author
 * Laura Hillenbrand, author of the book Seabiscuit: An American Legend
 * Kelly Holmes, athlete
 * Blair Hornstine, New Jersey student who sued her school district when it wanted her to share valedictorian honors with a classmate
 * Keith Jarrett, jazz pianist
 * Katharine, Duchess of Kent
 * Alastair Lynch, Australian footballer
 * Stuart Murdoch, of the band Belle & Sebastian
 * Barry Sheen, motorcyclist
 * Martin Speight, artist and former cricket player, Sussex CCC and Durham CCC.

Popular culture 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 make a social awareness of the issue.