Chronic fatigue

Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), and various other names, is a syndrome (or group of syndromes) of unknown and possibly multiple etiologies, affecting the central nervous system (CNS), immune, and many other systems and organs. There is no simple diagnostic test; CFS is a diagnosis of exclusion, although recent research indicates biological hallmarks of the syndrome, and a diagnostic test is predicted soon. Most definitions (other than the 1991 UK Oxford criteria) require a number of features, the most common being severe mental and physical exhaustion or depletion which is "unrelieved by rest" (according to the 1994 Fukuda definition), and is often worsened by even trivial exertion (controversially, the Oxford and Fukuda criteria require this to be optional only). CFS occurs more often, but not exclusively, in women, possibly due to immunological factors (women are overall more susceptible to similar disorders). CFS is most easily diagnosed when formerly active adults become ill, but it has been reported in persons of all ages, including young children and particularly teenagers.

Patients with this diagnosis commonly report many other symptoms which are far more wide-ranging than these research diagnostic criteria, including: pain, muscle weakness, loss of brain function, hypersensitivity, orthostatic intolerance, digestive disturbances, depression, immune system weakness, and cardiac and respiratory problems. These symptoms, like the syndrome's hallmark 'fatigue', range from mild to life-threateningly severe. Some cases resolve or improve over time, and where available, treatments bring a degree of improvement to many others. Most diagnostic criteria insist that the symptoms must be present for at least six months, and all insist on there being no other cause for the fatigue: i.e. the fatigue must be idiopathic, not caused by conditions such as radiation treatment for cancer, or diabetes. CFS remains a controversial diagnosis, and even its terminology and classification are controversial.

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.

Lacking a diagnostic test of any kind, CFS has historically 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 as hypochondriac or lazy.

However, on Tuesday, June 13th 2006 a coroner "of Brighton and Hove Coroners Court, UK, recorded the cause of death of a 32-year-old woman as acute anuric renal failure (failure to produce urine) due to dehydration as a result of CFS. The deceased woman [...] had suffered from CFS for six years." First official UK death from chronic fatigue syndrome - New Scientist Previous cases have listed CFS as the cause of death in the US and Australia Inquest Implications: Marshall E, Williams, M, June 2006

Nomenclature
There are a number of different terms which have been identified at various times with this 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 of the term ME maintain there is no inflammation, although there are cases of CFS that present inflammation (see Sophia Mirza). 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, many patients and advocacy groups in the USA use the term CFIDS (pronounced [See-Fids]), originally an acronym for the above or "Chronic Fatigue & Immune Dysfunction 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. 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. See, for example, the article by Dedra Buchwald, Anthony Komaroff, et al, which documents an extensive medical study of the Incline Village CFS outbreak of 1984-1985 (Annals of Internal Medicine 116 (January 15, 1992): 103-13).
 * 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). However, other researchers and advocates argue that other post-viral syndromes (such as post-polio syndrome) do show similar variability, and point to the striking similarity between post-viral fatigue syndrome and CFS symptoms, noting that many CFS cases are triggered by a viral illness.
 * Chronic Epstein-Barr virus (CEBV) or Chronic Mononucleosis; the term CEBV was introduced by virologists Dr. Stephen Straus 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, the activity of the remaining natural killer cells is reduced, often by as much as two thirds.
 * Yuppie Flu; this was a factually inaccurate nickname for CFS, first published in a November 1990 Newsweek article. It reflects an assumption 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), atypical poliomyelitis, epidemic vasculitis, raphe nucleus encephalopathy, and Tapanui flu (after the New Zealand town Tapanui where the first doctor in the country to investigate the disease, Dr Peter Snow, lived).

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 (often 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, and many patients also report painful tachycardia.
 * 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, and loss of cognitive body map.
 * Hypersensitivity: people with CFS are often sensitive to light, sound, and multiple chemicals and foods. Many CFS patients report an increase in allergic-type sensitivity to foods, scents, and chemicals, 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. Sensory overload is commonly reported by patients, leading to increased fatigue and even migraine or seizures.
 * Poor temperature control: people with CFS often report either feeling 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 insomnia is also common. 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. Patients report that exercise, unlike in healthy persons, worsens the insomnia and unrefreshing sleep symptoms alike.
 * Psychological/Psychiatric symptoms: emotional lability, anxiety, depression, irritability, and sometimes a curious emotional "flattening" (most likely due to exhaustion), may manifest in CFS patients. Many of these symptoms can be directly caused by the CFS mechanism or, in some cases, may be secondary symptoms created by the syndrome, as many chronic pain or illness patients also show similar psychiatric issues. CFS patients with pre-existing psychiatric symptoms may report that these worsen with the onset of CFS. Treatment for psychiatric symptoms alone does not relieve the physical symptoms of CFS, indicating that the disease is not psychological in nature.
 * 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.

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 after several months, 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. Some patients claim that vaccination, especially with recombinant vaccine against hepatitis B, is another cause of acute onset CFS. Other patients begin with Lyme disease, which despite a standard course of treatment, may 'evolve' clinically from the symptoms of acute Lyme to those of CFS. Because CFS symptoms bear a striking similarity to those of late-stage Lyme disease (Donta, 2002), this has become an area of great controversy. Some clinicians assume the Lyme infection has been eradicated after a course of treatment and diagnose CFS by the Fukuda definition, while others treat such cases as seronegative, chronic Lyme infection (see The Lyme controversy). Other, noninfectious triggers may include car accidents, moving house, and stressful life situations. Some patients say they felt unusual or uneasy for a short period (days or weeks) before the onset.

Gradual onset
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. 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 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, and that a few patients may have had high levels of physical health and activity before onset.

Post-exertion symptom exacerbation
One of the most common and recognizable aspects of CFS is what is called "post-exertional malaise". When people with CFS exert themselves beyond their limits (and their limits may change daily), their symptoms worsen. Exertion includes cognitive effort. The harder the exertion and the longer it lasts, the worse the symptoms will be afterward, and with greater recovery time. Although symptoms may increase immediately and proportionally, usually their full extent is delayed by 24 or more hours, which can make judging appropriate activity difficult.

A cyclical pattern can occur when patients work harder because they "feel better" or are having a "good day", leading them to think they can exert themselves more than usual. However, the excess exertion leads to worse symptoms on the following day. Thus it is difficult for patients to maintain an even level of activity, or to tell if they are improving. In sufferers without a diagnosis of CFS, or a proper understanding of how CFS affects exertion, this can lead to a "downward spiral", where a sufferer will try to work harder to make up for the previous day's lack instead of resting. This exhausts them further, and often can trigger a relapse or worsening of their condition. If the original exertion, which can be physical or mental in nature, was particularly severe, the sufferer may deteriorate to a point where they are unable to care for themselves. Many cases then result in hospitalisation because the condition has deteriorated a great deal.

However, it must be noted that patients may deteriorate due to external stressors, complications, co-morbid illness, or for unknown reasons, and in those cases, patient exertion cannot be blamed for a patient's deterioration. Also, some patients have a progressive course which cannot be explained through activity levels.

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.

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. Often, the symptoms change over time, or cycle irregularly. Relapses are common, especially after stressful life events or additional illness. Exertion can cause not merely a relapse, but a worsening of overall health. Undiagnosed 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.

Of those CFS patients moderately to severely affected, many may expect to remain so for an indeterminate period, even for the duration of their life. It is not known whether any patients truly 'recover' entirely from the illness, or merely recuperate enough to regain previous levels of activity. Few patients report a total 'cure'. CFS can prove to be fatal, 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". The pathologist said, "ME describes inflammation of the spinal cord and muscles. My work supports the inflammation theory. There was inflammation in the basal root ganglia." (It should be noted that inflammation of the 'muscles' is erroneous, as opposed to the CNS inflammation, as this has never been a criteria for a ME diagnosis). CFS has been linked to heart damage and cardiac arrest among other causes of death; research has not yet progressed to determine whether this is in fact the case, and some patients die from co-morbid diseases. To date there is one study on CFS life expectancy.

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 including 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:
 * 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
 * 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 changing somewhat, with more doctors willing to diagnose it. In the UK, the Chief Medical Officer's report stated that all doctors should consider CFS as a serious chronic illness — though it is not stated whether this is a serious physical illness — and treat patients accordingly. Similar progress has been made in the United States.

There remains considerable skepticism amongst some medical professionals about the existence of CFS as a 'real' — i.e. medical as opposed to behavioral — condition, possibly due to the extreme uncertainty of its etiology, and the lack of testing for biomedical signs. As is common historically with new or unexplained conditions, many people are inclined to believe that a condition with few or no specific and/or exclusive 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 psychotherapy 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 previously found between 75 and 420 cases of CFS for every 100,000 adults. However, the most recent estimates by the CDC (June, 2006) state that approximately 4 million Americans have CFS, which represents a prevalence of 1.3%, or 1300 cases for every 100,000 adults. The CDC further stated that approximately 80% of all CFS cases are undiagnosed.

Far more women than men get CFS &mdash; between 60 and 85% of cases are women; however, there is some indication that the prevalance 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.

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. 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, which is common. However, there is no evidence that allergies are at the root of CFS.
 * 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 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.
 * TREATMENT: ANS 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 such as methylphenidate (Ritalin®) 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®), a medication designed to aid in maintaining wakefulness, has had some positive effect on individuals with CFS, but has not been properly studied.
 * Chiropractic: Whilst this is not a therapy primarily for the treatment of Chronic Fatigue Syndrome, it may help reduce the Dysautonomia where it has been triggered by altered extrapyramidal reflexes in the grey matter of the spinal cord, known as facilitation. Facilitation is a common result of a spinal subluxation, where the joints of the neck become 'locked', and as such, the muscles of the spinal column cannot move the joints. The resultant immobility induces muscle and nerve 'atrophy', decreasing their function. If the facilitation is present in the upper spinal cord, this may predispose patients to dysautonomia, as major components of the autonomic nervous system are located nearby.

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

While depression is not uncommon among CFS patients, there are many CFS patients without depressive signs, suggesting that depression is not a direct cause of the symptoms. There are also patients with pre-existing depression which responded to treatment, but whose CFS symptoms did not improve; and treatment for depression is not particularly effective on CFS patients without depression. While depression may occur in CFS patients, it may be a result of living with CFS, or a secondary product of exercise intolerance, rather than the cause. 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. However, it must be pointed out that some antidepressants can exacerbate symptoms, especially muscle weakness, sleep-waking dysfunction and cardiac arrythmias, and many sufferers have suggested that the drugs have in fact caused relapses. Some sufferers cannot tolerate any antidepressants at all. The problems here may center around the significant differences in brain chemistry between those with depression or those with CFS. Overall, there is no clinical evidence that antidepressants provide significant relief of the core symptoms of CFS.

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). As hypothalamus 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.

Immune dysfunction
It is probable that both overactive and underactive componenents explain the immune dysfunction in ME/CFS. It is also possible that there are different manifestations of dysfunction according to the different phases of ME/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 reported. As early as 1989, a study was published in Australia that documented a loss of immunological integrity in one hundred CFS sufferers. (Andrew R. Lloyd et al., "Immunological Abnormalities in the Chronic Fatigue Syndrome," Medical Journal of Australia 151, no. 3:122-24.) The authors reported finding disordered ratios of T-cell subsets and reduced levels of immunoglobins; these findings corresponded with similar findings in the U.S. among leading researchers. Most strikingly, using the French Multitest to measure the body's response to a variety of antigens, the Australian group found that 33% of the subjects were hypoergic, meaning they had a reduced immune response, while an addition 55% were completely anergic, which means that 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.
 * 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. High rates of success were reported in using IV ganciclovir to treat CFS patients in trials as early as 1993-1994 (see U.S. Patent 6,894,056 for details); more recently, trials with valganciclovir, an oral prodrug for ganciclovir, have produced similar positive results. The antiviral drug Ampligen also produced extremely positive results in clinical trials as early as 1991; unfortunately, it has been stalled in the FDA approval process for many years.

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 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.
 * TREATMENT: 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.

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), although post-mortems have been done on patients where CFS was a cause of death (see Sophia Mirza).

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).

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. Recurrent ear infections are common in some CFS sufferers. Tinnitus is also quite common.

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

Psychosomatic causes

 * Psychosomatic causes: many doctors and researchers still believe that CFS is a complex psychosomatic disorder caused by chronic stress. 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, if manual therapies such as Chiropractic have not enjoyed any success.

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. 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.
 * 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 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.
 * TREATMENT: 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.
 * 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 (GE, GA or GET): Several rehabilitation programs have been proposed which basically fall into either imposed or self-monitored graded exercise or activity. Such programs are designed to increase strength and cardiovascular health. However, the risks of post-exertional malaise, which can cause significant, often permanent, worsening of symptoms, make this a difficult and often dangerous regimen to implement successfully.
 * TREATMENT: 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.
 * TREATMENT: 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, unforseen 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.

Involving therapy

 * TREATMENT: Cognitive behavioral therapy: Cognitive therapy This should not imply that CFS is a psychiatric condition, but rather that the protracted course of the illness may cause depression, anxiety and mental distress. In addition, 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. 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. Many 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. Those with severe ME may wish to consider whether graded exercise or CBT is recommended in their case because the two can cause serious deterioration in those who CFS is particularly severe.
 * 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.

Deaths
CFS may increase the risk of an early death, especially from organ failure or cancer. In a preliminary 2006 study it was reported that CFS patients are likely to die at a younger than average age for cancer, heart failure, and suicide.

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 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, like other highly disabled and dependent persons, 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.

Notable sufferers
Some notable persons who are believed to have suffered from 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
 * 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
 * Kelly Holmes, athlete
 * Blair Hornstine, New Jersey student who sued her school district when it wanted her to share valedictorian honors with a classmate
 * Andy Hunt, former British soccer player
 * Keith Jarrett, jazz pianist
 * Katharine, Duchess of Kent
 * Henry Percy, 11th Duke of Northumberland
 * Alastair Lynch, Australian rules footballer
 * Stuart Murdoch, of the band Belle & Sebastian
 * Barry Sheen, motorcyclist
 * Martin Speight, artist and former cricket player, Sussex CCC and Durham CCC.
 * Ali Smith,writer
 * Frank Iero, musician, My Chemical Romance.
 * Anna Hemmings, Britain’s leading female marathon canoeist.
 * Andrew Oldcorn, golfer.
 * Joanna Griggs, Commonwealth swimmer (Australian)

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 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.