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Myalgic encephalomyelitis/chronic fatigue syndrome

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Myalgic encephalomyelitis/chronic fatigue syndrome
SpecialtyNeurology, rheumatology Edit this on Wikidata

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[1]) 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),[2] 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, for unknown reasons. CFS is most easily diagnosed when formerly active adults become ill, and is most commonly diagnosed in young to middle aged adults, although it is also reported, albeit less commonly, in adolescents and the elderly [3].

Patients with this diagnosis may report many other symptoms which are far more wide-ranging than these research diagnostic criteria, including: muscle weakness, loss of brain function, hypersensitivity, orthostatic intolerance, digestive disturbances, depression, immune system weakness, and cardiac and respiratory problems. However, these symptoms may represent comorbid or overlapping conditions rather than ME/CFS itself [4]. These symptoms, like the syndrome's hallmark 'fatigue', range from mild to 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. Recently, genetics and stress have been found to be factors in the development of CFS.

History

Originally studied in 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. The Centers for Disease Control & Prevention (CDC) have now recognized CFS as a serious illness and launched a campaign in June 2006 to raise public and medical awareness about it [2].

Nomenclature

There are a number of different terms which have been identified at various times with this disorder.

  • Myalgic encephalomyelitis (pronounced [my-al'jik en-sef'a-lo-my'e-ly'tis]) or M.E, "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;[5] 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). Also, many CFS patients to not experience the muscle pain (or indeed any type of pain) required for ME. United Kingdom and Canadian researchers and patients generally use this term in preference to CFS.
  • Myalgic encephalopathy, similar to the above, with 'pathy' referring to a general sickness or illness.
  • 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.[6]
  • 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[7] and Dr. Jim Jones[8] 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.

Symptoms

According to the 1994 Fukuda definition[2] 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.[9][10] The verbal working memory of people with CFS has been shown under fMRI to be affected, resulting in altered brain function when performing certain tasks, especially as they got more demanding.[11]
  • 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 always relieve the physical symptoms of CFS.
  • Disturbances in the autonomic nervous system and hormones:

Course

Onset

The majority of CFS cases begin after a period of stress in the year preceeding the illness.[12] [13] 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,[14] 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 patients may have had high levels of physical health and activity before onset.

Another sufferer was Stuart Murdoch of the Scottish indie-rock band, Belle & Sebastian. Murdoch was afflicted before graduating from university and was unable to work. He has commented that the degree of isolation he suffered directly contributed to his strong Christian faith and his choice to become a song-writer and singer.

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.

The CDC, using DNA microarray analysis, has recently determined that patients with CFS have specific deficiencies in expression of multiple genes which are involved in energy metabolism and oxygen consumption. The gene expression deficit becomes accentuated when CFS patients perform on treadmills. The conclusion of this research is: "These results highlight the potential use of an exercise challenge combined with microarray gene expression analysis in identifying gene ontologies associated with CFS" (Whistler T, et.al. BMC Physiology 5, 5 (2005)[3].

Outcome

A systematic review of 14 studies of the outcome of untreated people with CFS found that "the median full recovery rate was 5% (range 0–31%) and the median proportion of patients who improved during follow-up was 39.5% (range 8–63%). Return to work at follow-up ranged from 8 to 30% in the three studies that considered this outcome." .... "In five studies, a worsening of symptoms during the period of follow-up was reported in between 5 and 20% of patients." [15] It is not known whether any patients truly 'recover' entirely from the illness, or achieve remission from a relapsing, remitting illness. Few untreated patients report a total 'cure'.

People diagnosed with CFS may die, as in the case in the UK of Sophia Mirza, where the coroner recorded a verdict of "Acute anuric renal failure due to dehydration arising as a result of CFS". 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). A systematic review of 14 studies of the outcome of CFS reported 8 deaths, but none were considered directly attributable to CFS.[16] CFS has been linked[4] 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 have been two studies on CFS life expectancy.[17][18] The largest study of some 641 patients with CFS, who were followed up for a mean of 9 years, found no excess mortality.[19]

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.

CFS is a diagnosis of exclusion[20] and subsequently tests should be run to exclude other abnormalities in the immune and central nervous system that cause the same or similar symptoms as seen in CFS patients.

Testing

Although it was originally thought that CFS was related to a viral etiology, more recent studies have failed to find any predictable association between CFS and any particular virus.

A National Institute of Health (NIH) consensus conference recommended a list of exclusionary laboratory tests that were considered appropriate for the work-up of a patient with suspected CFS. Since that time, there have been investigations into the immune function of patients with CFS, such as quantitative studies of natural killer cells, B and T cell subsets, and the production of cytokines, such as interferons and interleukin-2.

  • Complete blood count (CBC) with differential cell count
  • Urinalysis
  • Blood and serum chemistries (serum electrolytes, blood urea nitrogen, glucose, creatinine, calcium)
  • Liver function tests (chemistries)
  • Thyroid function tests (thyroid hormone [T3 or T4] uptake or thyroid hormone binding ratio [THBR], TSH)
  • Erythrocyte sedimentation rate (ESR)
  • Anti-nuclear antibodies (ANA)
  • Serum cortisol
  • Immunoglobulin levels (IgG, IgA, IgM and subfactors)
  • Rheumatoid factor (RF)
  • TB skin test
  • HIV serology
  • Lyme serology (when endemic)
  • MRI of head (to rule out multiple sclerosis)
  • Polysomnography (to rule out sleep disorder).

Optional tests to be used when clinically indicated include:

  • Quantification of natural killer (NK) cells
  • Quantification of B and T cell subsets
  • Functional elevation of NK cells
  • T cell response to mitogenic stimulation
  • Measurements of delayed hypersensitivity
  • Production and response to cytokines
  • ELISA/ACT testing
  • Serological tests for Candida albicans
  • RNAse L enzymatic activity assay or RNase L protein quantification
  • Spinal tap for oligoclonal bands
  • Tilt table
  • Catecholamine testing
  • Nerve conduction studies including EMG
  • AChR antibodies.
  • B12 deficiency
  • Circulating immune complexes including Cd3 and Cd4.
  • Rigid sigmoidoscopy
  • Flexible nasendoscopy
  • 24 hour faecal fat analysis (an excess of faecal fats can predispose to lipophilic yeast overgrowth).
  • Serum cadmium, lead and mercury assays.
  • Neuropenic studies.
  • Viral serologies including but not limited to:

Herpes virus serologies (e.g., Epstein Barr virus, cytomegalovirus, human herpes virus-6), Coxsackie virus serology, Enterovirus serology and Retrovirus serologies (except HIV).

PET and SPECT scans may helpful as indicators for empirical evidence additionally as they measure chemical balances, and cerebral blood flow respectively.

CDC 1994 criteria (aka "Fukuda")

According to the 1994 CDC,[2] a diagnosis of CFS requires that the following conditions be met (otherwise, the diagnosis is idiopathic chronic fatigue).

Primary symptom: incapacitating fatigue

Incapacitating fatigue that is:

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

Additional symptoms

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

  1. Impairment of short-term memory and concentration
  2. Sore throat
  3. Tender lymph nodes
  4. Muscle pain
  5. Multi-joint pain
  6. Headaches of a new type, pattern, or severity
  7. Unrefreshing sleep or insomnia
  8. Post-exertional malaise (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.[21] Also sometimes called "CDC 1988", to distinguish from the newer CDC system.
  • Oxford criteria (1991)[1]
  • Carruthers et al (2003) Canadian Case definition for ME/CFS[22]
  • Australian Guidelines (2004)[23]

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. Many people are inclined to believe that a condition with few or no specific biomedical markers may be psychological in origin. This had led to a frustration in many patients, who feel that their disability is not psychological, but biological. Some patients' groups and experts 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".[citation needed] 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 principal 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 — between 60 and 85% of cases are women; however, there is some indication that the prevalence among men is under reported. Members of ethnic minorities and low income classes are slightly more likely to develop CFS. Though people of all ages can get CFS, and precise statistics are not available, the prevalence among children and adolescents appears to be lower than for adults. Among minors with CFS, about half are boys and half girls.

CFS occurs both in isolated cases and large-scale outbreaks. In a number of documented cases several people in a building or large numbers of people in a community came down with the disease essentially simultaneously, suggesting that it is (in at least some cases) partly due to an infectious agent. Blood relatives of people who have CFS appear to be more predisposed. However, CFS does not appear directly contagious; caretakers, partners and others in close contact with persons with CFS for years do not develop CFS any more frequently (excluding relatives, as earlier).

Disease associations

Some diseases show a considerable overlap with CFS, and it may be hard to distinguish between them. People with fibromyalgia (FM, or Fibromyalgia Syndrome, FMS) have muscle pain and sleep disturbances. Those with multiple chemical sensitivities (MCS) are sensitive to chemicals and have sleep disturbances. Many veterans with Gulf War syndrome (GWS) have symptoms almost identical to CFS.[24] Post-polio syndrome also bears a strong and remarkable resemblance to CFS. Some researchers maintain these disorders are all expressions of a general, yet undefined, syndrome with protean symptoms. The suffering that can be experienced by a patient with ME/CFIDS has been likened to an AIDS patient in the last two months of life and/or a terminal cancer patient. Often, Multiple Sclerosis needs to also be excluded as a diagnosis.

Other disorders with known causes and treatments that may produce CFS-like symptoms are Lyme disease,[25] 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, such as somatoform disorders (particularly undifferentiated somatoform disorder) and depression, can present similar symptoms and should be carefully considered in the differential diagnosis. Depression, however, can be comorbid with, causative of, or caused by CFS or another condition. Depression is also frequently a realistic reaction to any chronic illness and may be experienced by a person with ME/CFIDS as such a response and/or a response to the often many grievous losses to a sufferer's life.

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, temporomandibular joint pain, headache including migraines, and other forms of myalgia. Clinical depression and anxiety are also commonly co-morbid. CFS is also a frequent symptom of male chronic pelvic pain syndrome (CP/CPPS).

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. Because the placebo effect is commonly stronger in highly 'subjective' symptoms, some medical professionals believed this also applied to CFS, however patients with CFS actually have a significantly lower response rate to placebos compared with patients of many other illnesses (about 20% vs 30% respectively).[26] In a basic overview of CFS for health professionals, the CDC states that "After more than 3,000 research studies, there is now abundant scientific evidence that CFS is a real physiological illness."[27]

Researchers have found evidence that CFS may involve distinct neurological abnormalities. When testing the spinal cord fluid of people with CFS or related illnesses (including fibromyalgia and Gulf War syndrome), they found 16 proteins that were absent from the control group. 5 of these proteins were found in all illness groups; suggestive of a biosignature that could be used to diagnose CFS, and providing more physiological evidence of a legitimate medical condition.[28]

Genetics and stress have been found to be factors in the development of CFS. Genetics: The CDC found that CFS patients have expressional abnormalities in some genes which are involved in energy metabolism and oxygen consumption (see Chronic fatigue syndrome#Post-exertion symptom exacerbation above). Several other studies have highlighted a genetic component to CFS, relating to the brain and immune system, and point towards the impaired response to physical and psychological stresses in people with CFS.[29][30][31] Stress: CFS has been linked with an impaired stress response, with one study suggesting subtle dysregulations of the hypothalamus-pituitary-adrenal axis; the HPA axis helps the body remain stable under physiological and psychological stress. [32] Interestingly, two other studies suggest that having a 'stressful childhood' significantly increases the probability of acquiring CFS as an adult (with one of the studies finding a greatly increased probability of as much as 5 times).[33] Combination: In regards to the 'nature vs nurture' debate, the interaction between genetics and stress suggest that some people may be genetically predisposed to developing CFS after physiological and/or psychological triggers.

The above findings improve the possibility of a diagnostic test and perhaps even a cure, but further research is needed.

Other findings regarding CFS in general include:

  • A large study found that playing sport in childhood reduces the chances of developing CFS later on. It also found that the development of CFS was not associated with other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity.[34]
  • Researchers compared 48 CFS patients with 29 controls and found that 10 of the CFS patients tested positive for enterovirus RNA (most closely to that of the coxsackie B virus) in their muscles while all of the 29 controls tested negative. 28 of the 48 CFS patients had an abnormal lactate response to exercise, including 9 of the 10 who tested positive for enterovirus RNA.[35]
  • In a study on people who had glandular fever (which is caused by the Epstein-Barr virus), no difference was found between the levels of virus in the blood from patients who recovered quickly when compared with those whose fatigue lasted more than six months. The scientists involved believed this suggests CFS can be caused by neurological damage done (during the acute infection phase) to parts of the brain which control perception of fatigue and pain.[36]
  • Lactic acid has been suggested to be a factor in CFS because for many decades it has been commonly believed to be responsible for muscle fatigue. However, some scientists have found that lactic acid actually helps prevent muscle fatigue rather than cause it, by keeping muscles properly responding to nerve signals.[37]
  • Oddly, researchers have found that children and teenagers with CFS are several times more likely to have some hyperflexible joints.[38]

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.[39] Alternative treatments may also be more affordable or accessible to patients with limited funds or health care coverage.

Cognitive Behavioral Therapy and Graded Exercise Therapy

Behavioural interventions including cognitive behavioral therapy (CBT) and graded exercise therapy (GET) have been shown to be at least partially effective in some people with CFS. An updated systematic review which was published in the Journal of the Royal Society of Medicine (October 2006)[40] found these are the only two known treatments that seem helpful. The statement of principal findings regarding CBT/GET was: "A number of RCTs (randomised controlled trials) suggest that behavioural interventions, including elements of CBT, GET and rehabilitation, may reduce symptoms and improve physical functioning of people with CFS/ME".

However some uncertainty still exists over the efficacy of these treatments, especially GET for severely affected patients as none were included in studies that passed the inclusion criteria of the review. The review also emphasised the need for more and better conducted studies of both therapies, as well as more research into the adverse affects of treatments in general as they may be under reported or poorly quantified (although the review did find that immunological treatments often had adverse side effects).

As mentioned in the review under the 'unanswered questions/further research' section, very few studies assessed the effectiveness of "interventions for children and young people and for severely affected patients". More research is needed on severely affected patients in general; because many treatments and studies require patients to attend a clinic, and those with the worst symptoms often receive the least support from health and social services. This may bias the results towards those with less severe symptoms.

The review also found that no intervention had been proved to be effective in restoring the ability to work. In addition to this review, the "Gibson Report" (Report of the Group on Scientific Research into Myalgic Encephalomyelitis 2006)[41] provides similar information about treating CFS with CBT and/or GET. However, the report itself has been criticised by several groups, for: being poorly conducted, misrepresentations, omissions, lack of references, factual inaccuracies or bias, and even potentially damaging implications.[42][43][44] According to the Countess of Mar (GSRME panel member), the report was a political inquiry into the science, not a scientific inquiry, of CFS.[45] In the "25% ME Group Submission to Gibson"[46] they state that both CBT and GET are not only just unhelpful to many severely affected CFS patients but also dangerous/harmful.

Cognitive Behavioral Therapy (CBT)

Cognitive therapy, together with graded exercise (which is often an integral component), is a controversial therapy as the Canadian Expert Consensus Panel Guidelines and the Gibson Report state. It is said CBT should not imply that CFS is a psychiatric condition, but rather the protracted course of the illness may cause depression, anxiety and mental distress. In addition, it is maintained CBT may teach patients various "coping strategies" to help them deal with cognitive impairments such as a deterioration of short-term memory or abbreviated attention span, although it is uncertain how changing one's schemas, as CBT theory contends, would effect improvement in these serious pathological symptoms. Dr. David Smith, a former medical advisor to the ME Association in the UK who has successfully treated many children using anti-depressants and therapy, offers a possible explanation on his website [47]. Some patients and patient groups dispute such claims, pointing out that CBT is invariably described as an "exposure therapy" e.g. UK mental health charity MIND[48], that virtually all the conditions commonly listed as being suitable for CBT are behavioural and that the 2002 UK CMO's Report describes CBT as "a tool for constructively modifying attitude and behaviour." Some patients and advocates suggest that there are “good” and “bad” forms of CBT, and it is important for patients to decide whether CBT is advisable in their case; others point out that, as supported by Carruthers and Van de Sande in their Overview of the Canadian Consensus Guidelines, that to avoid such confusion supportive counselling should not be mis-termed CBT.

Additional to the positive findings of the above mentioned updated systematic review on CBT, the above mentioned Gibson Report also states that CBT in general is helpful to many people with other illnesses; and while it is controversial in regards to CFS, it seems to be most effective in those with less severe forms but much less effective in the severely affected. Commenting on the relevance of CBT for CFS, the report states that it has a role to play in treatment but at best is only a partial answer and more research is needed.

Some approaches aim at active rehabilitation rather than just adapting to the illness. CBT does not seem to be as efficacious when provided by general practitioners or when given in a group. The effect of CBT has been demonstrated up to five years after therapy. The place of CBT for children, young people and the severely affected needs to be better established, although some open studies suggest that it is helpful, so long as it is adapted for the individual patient. It has not been shown that CBT causes a significant worsening of symptoms; but because some severely affected patients are worsened by even minor efforts or stresses (which includes verbal communication), it is understandable if they remain cautious about attempting CBT.

Similar/Related Treatments
  • Counselling: 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.

Graded Exercise Therapy (GE, GA or GET)

Several rehabilitation programs have been proposed which involve supervised or self-monitored graded exercise or activity. Such programs are designed to overcome decontitioning, increase strength and cardiovascular health. The program should incorporate considerable education wherein the sufferer learns to start at an appropriate level of activity (based upon intensity and duration) which is incrementally increased, at a rate which does not substantially increase symptoms. Those who fit a 2003 ME/ICD-CFS definition with post exertional malaise may wish to consider whether graded exercise is recommended in their case because it can cause serious deterioration in the exertional intolerant, and the 25% ME Group[49] point out that many severe cases were in fact mild cases before undergoing such therapy.

More encouringly and in addition to the positive findings of the previously mentioned updated systematic review on GET, the Gibson Report also states that GET is one of the most common treatments for CFS and found 50-70% of patients improved somewhat with GET. However this level of efficacy was only found in several small trials and were not even compared with specialist medical care or pacing.

Similarly, like with CBT, GET seems more effective in less severely affected patients than those who are more severely affected. Its role in helping severely disabled patients has not yet been properly established, but uncontrolled studies suggest it can help so long as it is tailored to the individual patient. However the Gibson Report also mentions the 25% ME Group findings that only 5% of their members found GET helpful and 95% found it unhelpful; and while the report used the word "unhelpful", the 25% ME Group insists that GET can also be dangerous/harmful. Many other patients who submitted personal evidence to the report's inquiry had similarly negative experiences of GET. Due to the potential risks of GET for CFS patients, the report stressed concern about GET treatment guidelines for CFS that lacked cautions about these risks, and even raised suggestions of checking for heart trouble before attempting GET. Again, both the report and the review acknowledges the need for more research.

One small study done with 9 to 17 year olds showed that a rehabilitation program (involving graded activities/exercise) was successful, with 43% reporting a "complete resolution" of symptoms by the CDC/Fukuda definition.[50]

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

Delayed onset of symptoms, 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.

Descriptive list of other etiologies/treatments

Below is a descriptive list of other (proposed) etiologies and corresponding treatments (if applicable) in alphabetical order:

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.[51]

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

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

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,[52] 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: Hyperactive

Autoimmune disorders (representing a hyperactive immune system) have been suggested. In July 2005, researchers in the UK reported significant gene changes in the white blood cells in CFS patients consistent with the theory of immune system activation, possibly by a virus triggering a constant immune fatigue state. The study, led by Dr Jonathan Kerr, discovered that 35 white blood cell genes, out of a total of 9,522 genes scanned were demonstrating differential function. There was also suggestion of neuronal and mitochondrial dysfunction as a result.[53]

Immune dysfunction: 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.[54] 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 additional 55% were completely anergic, meaning they had no immune response at all. Some theories propose that an infection with one of the below-listed disease agents somehow leads to immune dysfunction and chronic fatigue in cases of CFS. This is partly supported by test results indicating lowered or changed immune responses in some patients, as well as elevated levels of infectious agents in some patients' blood.

< 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;[55] 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; however, was stalled in the FDA approval process for a number of years.[56]

Infectious agents: Bacterial 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.

Infectious agents: 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.[57]
  • 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 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.

Infectious agents: 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.

Infectious agents: Viral

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.[58][59]

Other viruses implicated include cytomegalovirus, and human herpesvirus type-6 (HHV-6).[60][61][62][63][64][65][66][67] More recently, however, similarities to post-polio syndrome have led to a reexamination of the viral link.[68]

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.

< Treatment >

Antivirals.

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 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

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.

Orthostatic Hypotension

Syndromes of orthostatic intolerance, in particular neurally mediated hypotension (NMH) and Postural tachycardia syndrome (POTS), have been shown to be associated with chronic fatigue syndrome.[69][70] These conditions, which reduce blood flow to the brain after periods of standing, can be diagnosed with a tilt table test.

Psychosomatic causes

Many doctors and researchers still believe that CFS is a complex psychosomatic disorder caused by chronic stress. Cognitive Behavioral Therapy and Graded Exercise Therapy has been shown to be effective treatments for some people with CFS. See Chronic fatigue syndrome#Cognitive Behavioral Therapy and Graded Exercise Therapy, above.

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

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.

Other treatments

Medication

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

Nutritional supplementation and dietary modification

  • Magnesium: In a small study, supplementation with oral magnesium tablets improved symptoms in those people with CFS who previously had been diagnosed with low magnesium levels, although in this study additional magnesium injections were necessary in some patients. Conversely, other researchers reported no evidence of magnesium deficiency in people with CFS. The reason for this discrepancy remains unclear. If people with CFS do consider magnesium supplementation, they should have their magnesium status checked by a physician before beginning a regimen of supplementation. It is possible that only people with a magnesium deficiency may benefit from this therapy. Some sufferers find Magnesium malate 200 to 300 mg per day relieves some of the pain and can help with sleep problems as well. Magnesium is used in the enzymatic conversion of food to energy in the Krebs cycle, and can help reduce muscle fatigue in some cases.[71][72][73][74]
  • Alpha Lipoic Acid: 200 mg per day of Alpha Lipoic Acid may additionally be beneficial because it is both a fat and water soluble antioxidant, and also helps with insulin related hypoglycemic issues.[75]
  • Glutathione: When the body is unable to properly detoxify itself, inflammatory substances like lactic acid, and phosphates can build up in the fascia and at the neuromuscular junctions causing the muscle pain and trigger point tenderness that are diagnostic of fibromyalgia/cfids. In addition, there is usually a depletion of brain chemicals called neurotransmitters that can give rise to brainfog, depression/anxiety, and which can lower the pain threshold so that pain signals are amplified. By restoring intracellular glutathione in the liver and within the immune system, the body is able to mobilize and break down toxins for elimination by the liver and kidneys, and bring the immune disregulation back into a more normal function. Glutathione is also a very powerful antioxidant with the ability to restore other antioxidants that have been reduced in the battle against the severe oxidative stress that usually accompanies these illnesses. Glutathione functions as a three pronged attack against the underlying disease process, serving to gradually normalize immune and neurological function. Increasing glutathione can be accomplished with intravenous infusions of glutathione, through oral supplementation with N-acetyl cystine (NAC),[76] oral supplementation with the herb Milk Thistle,[77][78][79][80][81][82] and through supplementation with bioactive (un-denatured) whey protein such as Immunocal,[83] or Imuplus.[84][85][86][87][88][89][90][91][92][93][94][95][96][97][98]
  • L-Theanine: In addition to the central need to treat the underlying glutathione deficiency, several other supplements may be helpful in dealing with the pain and discomfort. Most folks with CFIDS/FIBRO complain of a very troubling cognitive dysfunction commonly called "Brainfog".[99] This may be one of the more frightening symptoms of CFIDS, actually mimicking Alzheimer's disease with acute short term memory problems and extreme difficulty in concentrating. The amino acid L-Theanine is helpful with brainfog/ irritability. L-Theanine is a natural amino acid found in green tea leaves during the spring growing season and seems to act as a precursor for the neurotransmitters dopamine, and norepinephrine, which are brain chemicals directly related to cognitive function. Some research suggests that 200 to 300 mg of L-Theanine several times a day may be beneficial in restoring full cognitive function. L- Theanine has an extremely low toxicity, and doesn't pose the addictive, or tolerance potential of some of the pharmaceuticals frequently prescribed to treat this problem..[100]

Other

  • Lifestyle Adjustments: Many CFS authorities recommend making use of medical treatments where appropriate, but focusing on minimizing symptoms through lifestyle adjustments such as pacing, control of stress, and good support. Importantly, acceptance rather than "fighting" to be as healthy as the patient was before CFS onset will lead to less frustration and fewer relapses. Adjustments to daily living -- working less, making dietary changes, and more efficient use of time and energy -- can improve a patient's outlook; but, more importantly, relieve some symptoms as well. Due to the nature of ME/CFS in finding its own "exertional level", such adjustments if resisted, tend to become enforced. This may also include the use of assistive devices; many CFS patients find that a cane, walker, wheelchair, mobility scooter or power chair will greatly improve their ability to perform tasks. Simpler assistive devices -- a kitchen stool rather than standing at the stove, a phone programmed to remember phone numbers -- can also greatly improve the quality of life for CFS patients.
  • Location: Some CFS patients find relief in moving to warmer climes. This is a difficult and expensive treatment option, not always feasible or available.
  • Neck Support: Many CFS sufferers seem to benefit from wearing a soft collar around their neck. The therapeutic benefits have no evidence base but anecdotally the majority of sufferers will claim that the treatment reduces pain and stiffness
  • Tinted Lenses; As with soft collars, there is no firm evidence for therapeutic benefits but CFS sufferers often find that visual aids fitted with tinted lenses (pink ideally) will improve quality of life.

Deaths

CFS is unlikely to increase the risk of an early death. In a preliminary 2006 study of CFS self-help group members, it was reported that CFS patients were likely to die at a younger than average age for cancer, heart failure, and suicide.[108] However, a much larger study of 641 CDC criteria diagnosed patients with CFS, who were followed up for a mean of 9 years, showed no excess risk of dying from any cause.[109]

Interestingly, in June 13 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." ([110]) Previous cases have listed CFS as the cause of death in the US and Australia.[111]

Social issues

For some people, chronic fatigue syndrome still 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, some 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 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 are at a high risk of suicide.[112]

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:

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

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

Ricky Gervais muses about ME sufferers in his stand-up show "Fame". He mentions that ME is the name of a disease coined from a society of 'Nanny Culture'.

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