(Redirected from CFIDS)
'Chronic fatigue syndrome' ('CFS') is one of several names given to a poorly understood, highly debilitating disorder of uncertain
cause/causes, which is thought to affect approximately 4 per 1,000 adults
[1] in the
United States and other countries, and a smaller fraction of children.
[2]
The disorder is marked by severe, chronic mental and physical exhaustion and by other specific symptoms, arising in previously healthy and active persons. Despite promising avenues of
research, there remains no objective
assay or
pathological finding which is widely accepted to be diagnostic of CFS. It remains largely a
diagnosis of exclusion, made on the basis of patient history and
symptomatic criteria, although a number of tests exist which can help aid diagnosis.
[3] Although there is agreement on the genuine threat to health, happiness, and productivity posed by CFS, various
physicians' groups, researchers, and patient activists champion very different nomenclature, diagnostic criteria, etiologic hypotheses, and favored treatments, resulting in ongoing controversy about nearly all aspects of the disorder. The name ''chronic fatigue syndrome'' is itself controversial, with some patient advocates and other authorities preferring terms such as 'myalgic encephalomyelitis' ("ME" or "ME/CFS") and
post-viral fatigue syndrome ("PVFS"), which imply specific underlying etiologies or pathologic processes.
[4]
CFS is not the same as "chronic fatigue†- while fatigue as a symptom is very common, CFS itself is relatively rare by comparison.
[5] Definitions (other than the 1991
UK Oxford criteria
[6]) require a number of features, the most common being severe mental and physical exhaustion which is "unrelieved by rest" (according to the 1994 Fukuda definition),
[7] and may be worsened by even trivial exertion (a mandatory diagnostic criterion according to some systems). Most diagnostic criteria insist that the symptoms must be present for at least six months, and all insist on there being no other cause for them: i.e. the symptoms must be
idiopathic, not caused by other medical conditions such as
diabetes,
hypothyroidism or
anemia. CFS patients may report many other symptoms which are not included in all diagnostic criteria, including
muscle weakness,
cognitive dysfunction,
hypersensitivity,
orthostatic intolerance, digestive disturbances,
depression, poor
immune response, and
cardiac and
respiratory problems. It is unclear if these symptoms represent co-morbid conditions or are produced by the same underlying etiology as CFS itself.
[8] Some cases improve over time, and treatments (though none are universally accepted) bring a degree of improvement to many others, though resolution is rare.
CFS occurs more often, but not exclusively, in women, for unknown reasons. CFS is most easily diagnosed when formerly active adults become ill, and is most commonly diagnosed in young to middle aged adults, although it is also reported in adolescents and the elderly.
[9]
Classification
The classification of chronic fatigue syndrome has been challenging, since consensus is lacking within the medical, research, and patient communities regarding the defining features of the syndrome. It may be considered by different authorities to be a neuropsychiatric, metabolic, infectious, or immune system disorder.
There are a number of different terms which have been identified at various times with this disorder.
★ ''Myalgic encephalomyelitis'' or ME translates to "inflammation of the brain and spinal cord with muscle pain" and 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.
[10] 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 objective evidence of inflammation, although central nervous system inflammation has been documented in some patients diagnosed with CFS (e.g. the case of
Sophia Mirza). There is no evidence that this inflammation is causally related to CFS (the pathologist in the Mirza case concluded that the inflammation was due to a
herpes virus infection). Also, some CFS patients do not experience the muscle pain (or indeed any type of pain) typical of ME
, which is unsurprising given that pain symptoms are not essential diagnostic criteria of CFS. Many patients, and some research and medical professionals in the United Kingdom and Canada, use this term in preference to CFS.
★ ''Myalgic encephalopathy'', similar to the above, with "pathy" referring to unspecified pathology rather than inflammation; this term has some support in the UK and US.
★ ''Chronic fatigue syndrome'' (CFS); this name was introduced non-unanimously in 1988 by a group of United States researchers based at the
Centers for Disease Control and Prevention in response to the 1984 Lake Tahoe ME epidemic, and is used increasingly over other designations, particularly in the United States. Many patients and clinicians perceive the term as trivializing
[11] and as the 1994 Fukuda paper itself cedes, stigmatizing; or even suggestive of a "confused and distorted view of reality"
[12] which has led to a campaigning movement to change the name and definition.
★ ''Chronic fatigue immune dysfunction syndrome'' (CFIDS); many patients and advocacy groups in the USA use the term CFIDS, introduced by patients current with the biomedical research in an attempt to reduce the psychiatric stigma attached to "chronic fatigue," as well as the public perception of CFS as a psychiatric syndrome.
[13] 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.
[14]
★ ''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). Other researchers and advocates argue that other post-viral syndromes (such as
post-polio syndrome) do show similar variability. Some point to the striking similarity between post-viral fatigue syndrome and CFS symptoms, noting that many CFS cases are triggered by a viral illness, however Ramsay was not a supporter of the CFS conceptualisation, and in the particular case of post-viral syndromes his example was post-inflenzal incapacity which he said compared to ME was "in all these three particulars ... a complete contrast".
[15]
★ ''Chronic Epstein-Barr virus'' (CEBV) or ''Chronic Mononucleosis''; the term CEBV was introduced by virologists Dr. Stephen Straus
[16] and Dr. Jim Jones
[17] in the United States. The
Epstein-Barr virus, a neurotropic virus that more commonly causes
infectious mononucleosis, was thought by Straus and Jones to be the cause of CFS. Subsequent discovery of the closely related ''
human herpesvirus 6'' shifted the direction of biomedical studies, although a vastly expanded and substantial body of published research continues to show active viral infection or reinfection of CFS patients by these two viruses. These viruses are also found in healthy controls, lying dormant.
★ ''Low Natural Killer cell disease''; this name is used widely in Japan. It reflects research showing a reduction in the number of
natural killer cells in many CFS patients. More significantly, in-vitro activity of the remaining natural killer cells is reduced, often by as much as two thirds.
★ ''Yuppie Flu''; this was a factually inaccurate term first published in a November 1990
Newsweek article and never official medical terminology. It reflects a stereotypical assumption that CFS mainly affects the affluent ("
yuppies"), and implies that it is a form of
burnout. CFS, however, affects people of all races, genders, and social standings
[18]; and is not a form of
'flu. The phrase is considered
offensive by patients and clinicians.
[19][20][21]
★ Uncommonly used terms include ''Akureyri Disease'', ''Iceland disease'' (in
Iceland),
[22] ''
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).
Signs and Symptoms
Onset
The majority of CFS cases begin after a period of stress in the year preceding the illness.
[23][24] Some cases of CFS start gradually, but the majority start suddenly, often triggered by a
flu-like viral or similar illness.
;Sudden onset cases
Many people with CFS report a sudden, drastic start to their illness. Some people can remember a specific day or even hour when they first became ill. Often CFS starts with, or is triggered by, another illness. Many people report getting a case of the
flu, exposure to an allergen (a cough or sniffle caused by paint, a new pet, or construction dust), or an infection such as
bronchitis, from which they seem never to fully recover and which 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,
[25] this has become
an area of great 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 cases
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.
Course
It can be inferred from the 2003 "Canadian" clinical working definition of ME/CFS
that there are 8 categories of symptoms:
★
Fatigue: Unexplained, persistent, or recurrent physical and mental fatigue/
exhaustion that substantially reduces activity levels and is not relieved (or not completely relieved) by rest.
★ Post-exertional
malaise: An inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, symptom exacerbation after exertion, plus a pathologically slow recovery period usually 24 hours or longer.
★
Sleep dysfunction: "Unrefreshing" sleep/rest, poor sleep quantity,
insomnia or rhythm disturbances. A study found that most CFS patients have clinically significant sleep abnormalities that are potentially treatable.
[26] Several studies suggest that while CFS patients may experience altered sleep architecture (such as reduced sleep efficiency, a reduction of deep sleep, prolonged sleep initiation, and alpha-wave intrusion during deep sleep) and mildly disordered breathing, overall sleep dysfunction does not seem to be a critical or causative factor in CFS.
[27][28][29][30] Sleep patterns may be further interrupted by vivid "feverish" dreams, and unlike in healthy persons, exercise can worsen the sleep dysfunction.
★
Pain: Pain is often widespread and migratory in nature, including a significant degree of
muscle pain and/or
joint pain (without joint swelling or redness, and may be transitory). Other symptoms include
headaches (particularly of a new type, severity, or duration),
lymph node pain,
sore throats, and
abdominal pain (often as a symptom of
irritable bowel syndrome). Patients also report; bone, eye and
testicular pain,
nerve pain and painful skin sensitivity.
Chest pain has been attributed variously to
microvascular disease or
cardiomyopathy by researchers, and many patients also report painful
tachycardia. A systematic review assessing the studies of chronic pain in CFS found that although the exact prevalence is unknown, it is strongly disabling in patients, but unrelated to depression.
[31]
★
Neurological/
cognitive manifestations: Common occurrences include
confusion,
forgetfulness, mental fatigue/
brain fog, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perceptual and sensory disturbances (e.g. spatial instability and disorientation and inability to focus vision),
ataxia (unsteady and clumsy motion of the limbs or torso), muscle weakness and "twitches". There may also be cognitive or sensory overload (e.g. photophobia and hypersensitivity to noise and/or emotional overload, which may lead to "crash" periods and/or anxiety).
★
Autonomic manifestations: Common occurrences include
orthostatic intolerance, neurally mediated
hypotension (NMH),
postural orthostatic tachycardia syndrome (POTS), delayed postural
hypotension,
lightheadedness, extreme
pallor,
nausea and
irritable bowel syndrome, urinary frequency and bladder dysfunction,
palpitations with or without
cardiac arrhythmias, and exertional
dyspnea (perceived difficulty breathing or pain on breathing).
★
Neuroendocrine manifestations: Common occurrences include poor
temperature control or loss of thermostatic stability, subnormal body temperature and marked daily fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities, intolerance of extremes of heat and cold, marked weight change anorexia or abnormal appetite, loss of adaptability and worsening of symptoms with stress.
★
Immune manifestations: Common occurrences include tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms, general malaise, new sensitivities to food and/or medications and/or chemicals (which may complicate treatment). At least one study has confirmed that most CFS patients reduce or cease alcohol intake, mostly due to personal experience of worsening symptoms
[32] (although the cause of this is unknown and may not be strictly "immunological" as implied by the symptom list).
There may also be other
psychological/
psychiatric symptoms/comorbidities in some patients. See the
Proposed causes and pathophysiology section for more information about the possible causes of, and treatments for, the above listed symptoms.
Activity levels
Patients report critical reductions in levels of physical activity
[33] with the severity of symptoms and disability the same in both genders
[34]; but despite a common diagnosis, the functional capacity of CFS patients varies greatly.
[35], and chronic pain is strongly disabling in CFS patients.
[36] According to the
CDC [37][38], studies show that the disability in CFS patients is comparable to some well-known, very severe medical conditions, such as;
multiple sclerosis,
AIDS,
lupus,
rheumatoid arthritis,
heart disease, end-stage
renal disease,
chronic obstructive pulmonary disease (COPD) and similar chronic conditions. While some patients are able to lead a relatively normal life, others are totally bed-bound and unable to care for themselves. Almost all patients find they must drastically reduce their activity from pre-illness levels, regardless of their previous level of athleticism, and must severely modify or give up physical hobbies and exercise. Many patients find themselves unable to work full-time, or at all. A considerable number of CFS cases in many countries are on disability benefits or private insurance, or have made claims and been denied.
Post-exertion symptom exacerbation
One of the most common and recognizable aspects of CFS is what is called "post-exertional malaise". Patients also frequently experience rapid weakening and loss of muscle strength. When people with CFS exert themselves, physically or cognitively beyond their limits in either intensity or frequency, their symptoms worsen. This is to say that 'exertion is unsustainable'. The harder the exertion and the longer it lasts, the worse the decompensation will be afterward, and with greater recovery time. Although symptoms may increase immediately and proportionally, the
decompensation effects usually takes 24 hours or more to reach full extent, and can sometimes take several days or longer to gradually accumulate. This can make judging appropriate activity difficult. Time to recover strength has been described as inordinate and "pathological" and limits often change daily and from hour-to-hour, as well as through longer relapses and remissions. Severely affected patients may have "hard" limits such as severe loss of muscle power or drastic postural hypotension causing collapse or blackouts, rendering complete if usually temporary debilitation, and imposing strict, if variable, limitations. It is such limitations that usually enforce disability upon patients sooner or later, after an initial cyclical "push-crash" period, which can be prolonged through poor advice or diagnostic delay. Typically symptoms lessen or disappear with recumbency, due to othostasis as a form of exertion and neuro-vascular adaptability. Therefore patients need to intersperse any activity with rest periods, which is referred to as ''pacing''. Muscles which are frequently used tend to be weakest.
In patients without a diagnosis of CFS, or a proper understanding of how CFS affects exertion, a "downward spiral," can occur where a sufferer will try to work harder to make up for the previous day or week's lack instead of resting. This causes further deterioration and often can trigger a relapse or worsening of their condition. It must be noted that patients may be compelled to exert themselves in a society that does not yet afford CFS total medical and social acceptance or trivialises the illness (see below).
[39][40] Sometimes acute onset cases start with severe illness imposing drastic limitations, and patients may be admitted to hospital. Complications, co-morbid illness, and unknown factors can cause exacerbation, which may not be within patients' control. Since CFS is not defined as the result of ongoing exertion, at least some patients with a relapse or progressive course cannot be explained through activity levels.
When the illness is coupled with unaccommodating family, friends, colleagues, often due to
stigma, and social repercussions such as financial needs, housing problems, the struggle to obtain disability benefits or insurance, discrimination and misconception within the care sector, it can put demands on the sufferer exceeding their safe capabilities. Many sufferers describe needing to do things for themselves in the times they feel better simply because there is no-one to delegate to.
Proposed causes and pathophysiology
The cause of CFS is unknown, although a large number of causes have been proposed, and several proposed causes have very vocal and partisan advocates. In a basic overview of CFS for health professionals, the CDC states that "''After more than 3,000 research studies, there is now abundant scientific evidence that CFS is a real physiological illness.''"
[41] The cause of CFS may be different for different patients, but if so, the various causes may result in a common clinical outcome.
Neurological abnormalities
Researchers have found evidence that CFS may involve distinct neurological abnormalities, supporting the WHO's classification of ME/CFS as a neurological illness. 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 common underlying medical condition.
[42] In another study on
cerebrospinal fluid, researchers found that
corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with
fibromyalgia, an illness with considerable overlap with ME/CFS.
[43]
;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.
;Damage to ascending reticular activating system
The
reticular activating system (RAS) 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 RAS may be responsible for at least some cases of CFS. Such damage could arise from direct bacterial or viral damage to the area, or from an
autoimmune attack on the region. Lesions in the RAS have been found in
Multiple Sclerosis. 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.
;Inner-ear disorders
Main articles: balance disorder
Problems such as
Meniere's,
tumor in the inner ear, or
Benign Paroxysmal Positional Vertigo (BPPV) can cause dizziness,
vertigo, and fatigue. Recurrent
ear infections are common in some CFS sufferers.
Tinnitus is also quite common .
;Orthostatic hypotension
Syndromes of
orthostatic intolerance, in particular
neurally mediated hypotension (NMH) and
Postural orthostatic tachycardia syndrome (POTS), have been shown to be associated with chronic fatigue syndrome.
[44][45] These conditions, which reduce blood flow to the brain after periods of standing, can be diagnosed with a
tilt table test. Unfortunately,
fludrocortisone, a drug sometimes used to treat low blood pressure, seems to have little or no benefit for people with CFS.
[46]
Psychiatric abnormalities
;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.
;Psychosomatic causes
Many doctors and some researchers believe that CFS is a complex
psychosomatic disorder caused by chronic
stress.
Stress and trauma
Stress contributes to many different illnesses, and can cause a series of responses that in genetically predisposed individuals may lead to stress-related brain disease after adverse experiences.
[47] Although the majority of people who experience stress/trauma do not develop CFS, these (including infection) increase the likelihood of acquiring CFS within one year
[23][24] and a genetic disposition to CFS has been proposed. Other studies also suggest that childhood stress/trauma significantly increases the likelihood of acquiring CFS as an adult, with one study finding a 3 to 8 fold increase (depending on the trauma type).
[50] Another study found both stress and emotional instability to be significant risk factors, an effect which may be buffered by genetic influences, with the researchers also concluding that "emotional instability assessed 25 years earlier is associated with chronic fatigue through genetic mechanisms contributing to both personality style and expression of the disorder ... these findings suggest plausible mechanisms for chronic fatiguing illness." They also found no association between
extraversion and fatigue.
[51] Anxiety disorders have also been found to be a risk factor in 5-15 year olds.
[ Epidemiology of chronic fatigue syndrome and self reported myalgic encephalomyelitis in 5-15 year olds: cross sectional study., T Chalder, R Goodman, S Wessely, M Hotopf, H Meltzer, , , BMJ, 2003 ]
CFS has been linked to an impaired stress response (see the
Post-exertion symptom exacerbation section). It has also been proposed that this was associated with dysfunction of the hypothalamus-pituitary-adrenal axis (the HPA axis helps the body remain stable under physiological and psychological stress) and some evidence for this has been found
[52]; although this may only be subtle
[53], and acquired as a result of CFS.
[54] The controversy surrounding CFS has caused some social issues for patients and may contribute to their stress (see the
Social issues section).
Oxidative stress
Oxidative stress is an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage. Several studies
[55][56][57][58][59][60] and a review
[61] have implicated oxidative stress in CFS symptoms; especially relating to fatigue, pain and postexertional malaise / exercise intolerance. According to researchers of one study, the findings on oxidative stress (and nitric oxide-related toxicity) seem consistent with their findings of the abnormal 2-5A synthetase/
RNase L enzyme (antiviral) activity which has previously been implicated in the pathology of exercise intolerance in CFS.
[62]
Immune dysfunction
When compared with CFS patients with normal natural killer cell activity, those with lower levels reported less vigor, more daytime dysfunction, and more cognitive impairment; with the researchers suggesting this to be useful at subtyping.
[63] However an earlier systematic review on the immunology of CFS published in 2003 found an inverse association between study quality and findings of low levels of natural killer cells (suggesting that the association may be related to study methodology), although no such association was found with studies finding abnormalities in T cells and cytokine levels.
[64] The researchers also concluded that no consistent pattern of immunological abnormalities had been identified, however, a later updated review on the phenomenology and pathophysiology of CFS published in 2006 found that immune system involvement in the pathogenesis of CFS seems certain but the findings on the specific mechanisms are still inconsistent.
[ Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology., Cho HJ, Skowera A, Cleare A, Wessely S, , , Curr Opin Psychiatry, 2006 ] There is also evidence that people with CFS have improper gene expression including both over expression and under expression of genes involved in the immune system (see the
gene expression section).
;RNase L deregulation
Several studies have highlighted the existence of abnormal 2-5A synthetase/
RNase L enzyme (antiviral) activity in some CFS patients
[65][66][67][68][69][70], with several more studies finding this to correlate with the worsening of symptoms after exercise.
[71][72][73][62] A review published in 2005 suggested that this impaired pathway is of clinical importance and that further studies addressing treatment of this deregulation are warranted.
[75] A study found that elevated RNase L did not correlate with alpha-delta sleep.
[29]
;Hyperactive immunity
Autoimmune disorders,
representing a hyperactive immune system, most likely through a
cell-mediated process, have been suggested.
[77][78] In July 2005, researchers in the UK reported significant gene changes in the
white blood cells in CFS patients consistent with the theory of immune system activation, possibly by an
antigen triggering a constant immune fatigue state. The study, led by Dr Jonathan Kerr, discovered that 35 white blood cell genes, out of a total of 9,522 genes scanned were demonstrating differential function. There was also suggestion of neuronal and mitochondrial dysfunction as a result.
[79]
;Allergies
Similarly to the theory of immune dysfunction, some doctors believe that CFS patients suffer from immune dysfunction caused by exposure to allergens, ranging from
food allergies or food intolerances (see below) to pollen and dander allergies. However, this theory fails to explain the many reported and documented cluster outbreaks of CFS, and is therefore not taken seriously by leading researchers in the field. Instead, severe allergies may occasionally cause CFS-like symptoms, or patients with CFS may develop additional problems with allergies or
food intolerances, which is common.
[80]
[81]
[82]
However, there is no evidence that allergies are at the root of CFS.
;Immunodeficiency
Immunodeficiency disorders (representing an underactive immune system) have been reported. As early as 1989, a study was published in Australia that documented a loss of immunological integrity in one hundred CFS sufferers.
[83] The authors reported finding disordered ratios of T-cell subsets and reduced levels of
immunoglobulins specifically IgG 1 and IgG 3; these findings corresponded with similar findings in the U.S. among leading researchers. Most strikingly, using the French Multitest to measure the body's response to a variety of antigens, the Australian group found that 33% of the subjects were
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.
;Other immunological findings
★ Several studies have implicated a higher level of bioactive transforming growth factor-beta (TGF-beta) in CFS patients.
[84]
★ A study published in 1995 found that 3 immunological tests (protein A binding, Raji cell, or C3/C4) best discriminated CFS patients from fatigued controls.
[85]
★ A recent study suggested that CFS may be characterized by an IgM-related immune response directed against disrupted lipid membrane components, by-products of lipid peroxidation, S-farnesyl-L-cysteine, and NO-modified amino-acids, which are normally not detected by the immune system but due to oxidative and nitrosative damage have become immunogenic.
[86]
★ A study found that while exercise worsened symptoms in CFS patients, it also increased allergen challenge response only in the CFS group, regardless of allergy status.
[87]
Psychoneuroimmunological interactions
A recent review states that there is growing evidence of autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets in psychiatric disorders and that autoantibodies may play a role in psychiatric disorders present in CFS.
[88] Researchers involved in a review examining an immunological basis for CFS concluded that neuropsychiatric symptoms in CFS patients may be more closely related to disordered cytokine production by
glial cells within the central nervous system rather than to circulating cytokines.
[89] In one study,
autoantibodies for muscarinic cholinergic receptor had been found in over half of the CFS patients and seemed to correlate with the severity of the "feeling of muscle weakness".
[90] Elevated levels of nitric oxide (not to be confused with nitrous oxide) has been found in some CFS patients
[71] and may help explain a "sensitization" of the nervous system that results in behavioral changes.
[92]
Infectious etiology
;Bacterial infections
★
Lyme disease and related tick-borne
infections. Lyme disease does not always present acutely with a rash, and less than half of sufferers recall a tickbite (the nymphal
deer tick is the size of a poppy seed, and secretes an anesthetic to prevent the host from feeling its bite). Furthermore, the characteristic joint pain is not always present. For these reasons Lyme can be difficult to diagnose, particularly in its later stages, at which point symptoms are virtually identical to those of CFS.
[93] 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.
[94]
★
Bacterial respiratory infections'' such as
mycoplasmic bronchitis/pneumonia,
Legionnaire's disease, and possibly other bacteria associated with
bacterial pneumonia.
★
Sinusitis. Sinusitis is a chronic infection of the sinuses which can be difficult to diagnose, and can cause symptoms similar to those of CFS. Sinusitis can occur after dental surgeries or infections, and thus may be related to reaction to mercury in dental amalgams as above, or dental infections, as below.
★
Toxoplasma gondii. Toxoplasma gondii is a parasitic infection. If let untreated it can cause severe immune suppression and neurologic symptoms.
★ 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.
;Epstein-Barr virus
For many years the ubiquitous
Epstein-Barr virus, present in 90% of the population, was the principal suspect based on abnormal immunologic responses observed in uncontrolled studies.
[95][96] Subsequent studies using various types of controls have had mixed conclusions.
[97][98][99]
;Other viruses
Other implicated viruses include
cytomegalovirus, and
human herpesvirus type-6 (HHV-6).
[100][101][102][103][104][105][14][107] More recently, however, similarities to post-polio syndrome have led to a reexamination of the viral link.
[108]
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.
Endocrine 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.
Metabolic disorders
Metabolic disorders such as
McArdle disease,
CPT II deficiency,
myoadenylate deaminase deficiency, and
mitochondrial disorders can cause symptoms that strongly resemble CFS. Mitochondrial disturbances have been discovered in some CFS patients.
Folate deficiency (suspicion by elevated homocysteine and low serum folate) may mimick CFS symptoms.
[109][110]
Nutritional disorders
Certain dietary practices, particularly the consumption of large amounts of carbohydrates, or poorly nutritive vegan diets (see below, "malnutrition"), are sometimes blamed for CFS.
Celiac disease or
gluten intolerance is known to cause CFS-like symptoms in some individuals, as is
vitamin B12 or
vitamin D deficiency. Other forms of food
allergies are also often blamed, especially in cases of
leaky gut syndrome. While many nutritional supplements are touted as cures or palliatives for CFS, research on these is scattered and inconclusive.
;Malnutrition
In some cases, simple malnutrition may be responsible for CFS-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 may resemble CFS-like symptoms.
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.
Other findings
Other findings regarding CFS in general include:
★ Recent genetic research into CFS has found abnormalities in gene expression, and the CDC has conducted over a dozen related studies itself.
[111] It has been found that patients with CFS have specific abnormalities in expression of multiple genes which are involved in the biological process of transport (both vesicle-mediated and protein transport) and this became accentuated when CFS patients exercise.
[112] Another study found that "the differentially expressed genes imply fundamental metabolic perturbations", such as those involved in purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism.
[113] Several other studies have also highlighted a genetic component to CFS involving immune dysfunction
[114]; T cell activation, perturbation of neuronal and mitochondrial function, possible links to organophosphate exposure and virus infection
[115]; immune response, apoptosis, ion channel activity, signal transduction, cell-cell signaling, regulation of cell growth and neuronal activity
[116]; some of which may be treatable with drugs that are already available.
[117] Gene expression abnormalities have been found relating to the central nervous system, metabolism and immune system; and may point towards the impaired response to physical and psychological stresses in people with CFS. However, linking genes to specific symptoms has so far been elusive, although is likely to be an important means to elucidate the pathogenesis of CFS.
[118]
★ A large study found that higher levels of exercise in childhood is associated with a lower risk of developing CFS later on. It also found that the development of CFS was not associated with other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity.
[119]
★ 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.
[120]
★ A study found that fatigue persists in a significant minority of patients for six months or more after infections, suggesting post-infective fatigue syndrome is a valid illness model for investigating CFS.
[121]
★ In a study on people who had glandular fever (which is caused by the Epstein-Barr virus), no difference was found between the levels of virus in the blood from patients who recovered quickly when compared with those whose fatigue lasted more than six months, although the latter had an altered immune response.
[122] 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.
[123]
★ Lactic acid has been suggested to be a factor in CFS because for many decades it has been commonly believed to be responsible for muscle fatigue. However, some scientists have found that lactic acid may actually help prevent muscle fatigue rather than cause it, by keeping muscles properly responding to nerve signals.
[124]
★ Researchers have found that children and teenagers with CFS are several times more likely to have some hyperflexible joints
[125] in an association with
Ehlers-Danlos syndrome.
Diagnosis
At this time, there is no accepted conclusive test or series of tests of chronic fatigue syndrome. CFS is therefore largely an ''
exclusionary diagnosis''. If a doctor suspects a patient may have CFS they should begin the diagnostic process by eliminating other potential causes of the patient's symptoms.
[126] "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.
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.
CDC 1994 criteria (aka "Fukuda")
According to the 1994 CDC,
a diagnosis of CFS requires that the following conditions be met (otherwise, the diagnosis is
idiopathic chronic fatigue).
;Primary symptom: incapacitating fatigue
Incapacitating fatigue that is:
★ of new or definite onset (not since birth)
★ unexplained by other medical cause,
★ lasts for at least six months (from onset, not necessarily from when the patient becomes aware that the fatigue is an ongoing symptom)
★ and is not improved by rest.
;Additional symptoms
The fatigue must be accompanied by a minimum of 4 of the following eight symptoms:
#Impairment of
short-term memory and
concentration
#
Sore throat
#Tender
lymph nodes
#
Muscle pain
#Multi-
joint pain
#
Headaches of a new type, pattern, or severity
#Unrefreshing
sleep or
insomnia
#Post-exertional
malaise or
fatigue lasting more than 24 hours after exertion.
NICE (UK) 2007 criteria
The UK
National Institute for Health and Clinical Excellence (NICE), published a multidisciplinary
clinical practice guideline in 2007 in which the following criteria are employed:
[National Institute for Health and Clinical Excellence. ''Guideline 53: Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy)''. London, 2007. ISBN 1846294533. NICE CG53 page.]
★ fatigue that is new, persistent and/or recurrent, not explained by other conditions and has has resulted in a substantial reduction in activity level characterised by post-exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days) ''and''
★ one or more of the following list of symptoms: difficulty with sleeping, muscle and/or joint pain at multiple sites without evidence of inflammation, headaches, painful lymph nodes that are not pathologically enlarged, sore throat, cognitive dysfunction, worsening of symptoms by physical or mental exertion, general malaise, dizziness and/or nausea and palpitations with no identifiable heart problem.
The guideline requires fatigue to have been present for 4 months in an adult or 3 months in a child; it expects a diagnosis in a child to be made by a pediatrician, while there are no limitations on who is to make the diagnosis in an adult.
Other systems
Other scoring systems have also been proposed to quantify CFS symptoms for research purposes. These include:
★ Holmes ''et al'' (1988) scoring system.[127] Also sometimes called "CDC 1988," to distinguish from the newer CDC system.
★ Oxford criteria (1991)
★ Carruthers ''et al'' (2003) Canadian Case definition for ME/CFS
★ Australian Guidelines (2004)[128]
Issues with the definitions/criteria
;Selection bias and inconsistencies
Several studies have found that using different case definitions ( eg broad vs conservative[129] ) has major influence on the types of patients selected and have also highlighted the need for specific subgroups of CFS to be identified and/or for the case definition to be further clarified with emphasis on using empirical studies: An international CFS study group for the CDC found ambiguities in the CDC 1994 CFS research case definition which contribute to inconsistent case identification.[130] Researchers have found that a difference in the self-reported cause of a patient's CFS is associated with significant differences in clinical measures and outcomes, and concluded it is likely that their response to treatment may vary and the CFS definition should be improved to define more homogeneous groups of patients for the purposes of research and treatment.[131] It also may be inappropriate to synthesize results from CFS studies that use different definitions to select study populations.[132] It has been found that identification of new diagnostic symptoms, the use of severity ratings for symptomatology, and the identification of standardized measures that differentiate cases of CFS from other conditions; all hold promise for improving the sensitivity, specificity, and reliability of the diagnostic criteria for CFS.[133]
;Improving accuracy
A study found that the best predictors for people accurately fitting the CDC 1994 definition of CFS were the presence of postexertional malaise, unrefreshing sleep, and impaired memory-concentration, and this accuracy increased when severity of these symptoms were taken into account.[134] Another examination of the CDC's working case definition(s) of CFS found that the differential accuracy is strengthened when eliminating three symptoms (muscle weakness, joint pain, sleep disturbance) and adding two others (anorexia, nausea).[135] It has also been found that the Canadian 2003 definition (a less used but stricter criteria) selects cases with less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms.[ Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome., Jason LA, Torres-Harding SR, Jurgens A, Helgerson J, , , Journal of Chronic Fatigue Syndrome, 2004 ]
;Possible subtypes
Studies suggest the existence of CFS subtypes.[136][137] After examining the 'minor' diagnostic symptoms of CFS in women meeting the CDC 1994 criteria, researchers found that 3 subtypes could be identified; musculoskeletal, infectious and neurological; with associated impairment characteristic of each subtype. "Extreme scores" characterized about 2/3 of the sample, with higher disability in those with the highest scores. Depression and anxiety were not more prevalent in any particular subtype, and did not increase with the severity of specific symptom reports.[138]
;Diagnosis inaccuracies
A review published in 2006 found that the accurate diagnosis of CFS is low[139] and another study found that physicians have a tendency to underrecognize psychiatric illness, especially when assessing patients whose chronic fatigue is fully explainable by a psychiatric disorder and who may be misdiagnosed with CFS.[140]
;Terminology implications
Because of the similarity in terminology, CFS is often confused with "chronic fatigue". Fatigue in the perceived absence of disease has traditionally been seen within the purview of psychiatry.[141] A study found that while most medical trainees consider the symptom complex of CFS to be a serious illness resulting in poor quality of life, the "chronic fatigue syndrome" name may be regarded less seriously than the "myalgic encephalopathy" name.[142] Another study found that nurses and physician assistants viewed a patient's CFS symptoms as more severe and disabling if they were told the patient had a more medical sounding diagnosis of "chronic neuroendocrineimmune dysfunction syndrome".[143]
Testing
No diagnostic test reliably diagnoses or excludes chronic fatigue syndrome. Although it was originally thought that CFS was related to a viral etiology, use of recent inclusion cohorts have failed to find a predictable association between CFS and any particular virus. The main purpose of performing diagnostic tests of any sort is to rule out other causes for fatigue and other symptoms of CFS.
★ Complete blood count
★ Blood chemistry (electrolytes, glucose, renal function, liver enzymes, protein levels and calcium)
★ Thyroid function tests
★ Erythrocyte sedimentation rate (ESR)
★ Urinalysis for blood cells, protein and glucose
The 2007 UK NICE guideline includes, in addition to the CDC panel: C-reactive protein (a marker of inflammation), creatine kinase (a muscle-related enzyme), plasma viscosity (optional if ESR done) and serology for celiac disease. Ferritin determination may be performed in children and young people, and in adults only if other tests suggest iron deficiency. The guideline recommends clinical judgement in decisions to perform other tests in addition to the standard set. Testing for infections (e.g. Lyme disease, viral hepatitis, HIV, mononucleosis, toxoplasmosis or cytomegalovirus) is only recommended if the patient gives a specific history for this. Routine performance of the head-up tilt test, auditory brainstem responses and electrodermal conductivity is discouraged.
Diagnostic controversies
Historically, many doctors have been unfamiliar with CFS, and some have refused to diagnose it. This situation is changing somewhat, with more doctors willing to diagnose it. In the UK, the 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 and its largely exclusionary definition. Many people are inclined to believe that a condition with few or no specific biomedical markers may be psychological in origin. This had led to a frustration in many patients, who feel that their disability is not psychological, but biological, and point to the epidemic history and biomedical research trends. Some patients' groups and experts maintain that research into CFS (ME) in the UK has been mostly hijacked by the psychologists/psychiatric lobby[144], who they claim hold significant power within the medical fraternity, with a resultant "gross abuse/neglect of patients."
Treatment
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.[145][146][147]
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 (see regression fallacy). 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).[148] Alternative medicine is often proposed for CFS, especially when conventional treatments are poorly tolerated or fail to relieve symptoms. Alternative treatments may also be more affordable or accessible to patients with limited funds or health care coverage.
Behavioral interventions
Behavioral interventions including cognitive behavioral therapy (CBT) and graded exercise therapy (GET) have been shown to be at least partially effective in some people with CFS. An updated systematic review which was published in the ''Journal of the Royal Society of Medicine'' (October 2006)[149] found these are the only two known treatments that seem helpful. The statement of principal findings regarding CBT/GET was: "A number of RCTs (randomised controlled trials) suggest that behavioural interventions, including elements of CBT, GET and rehabilitation, may reduce symptoms and improve physical functioning of people with CFS/ME." However some uncertainty still exists over the efficacy of these treatments, especially GET for severely affected patients, as none were included in studies that passed the inclusion criteria of the review. The review also emphasized the need for more and better conducted studies of both therapies, as well as more research into the adverse affects of treatments in general as they may be under reported or poorly quantified. As mentioned in the review under the 'unanswered questions/further research' section, very few studies assessed the effectiveness of "interventions for children and young people and for severely affected patients." More research is needed on severely affected patients in general; because many treatments and studies require patients to attend a clinic, and those with the worst symptoms often receive the least support from health and social services. This may bias the results towards those with less severe symptoms. The authors also expressed concern about possible bias in the CFS literature, a lack of uniformity in case definitions and study inclusion/exclusion criteria (studies using any CFS criteria were included), and the basic information provided about the participants; which they state makes it difficult to assess the generalizability of the findings of many of these studies. This review found that no intervention had been proved effective in restoring the ability to work. An earlier systematic review published in 2002 also found this, although CBT was "lending a possible association between improvement in the ability to work and an increase in the number of patients employed". This earlier review also found that no specific patient characteristics seemed to serve as best predictors of positive employment outcomes in CFS patients, although did find that depression of greater severity was associated with unemployment.[150] However, another systematic review published in 2004 concluded "Only cognitive behavior therapy, rehabilitation, and exercise therapy interventions were associated with restoring the ability to work."[151] The "Gibson Report" (Report of the Group on Scientific Research into Myalgic Encephalomyelitis 2006)
Cognitive Behavioral Therapy (CBT)
Cognitive behavioral therapy (CBT) is claimed to be an effective evidence-based therapy for CFS[http://www.clinicalevidence.com/ceweb/conditions/msd/1101/1101_I1.jsp]. The use of psychological therapies such as CBT does not imply that CFS is a psychiatric condition or that physical symptoms are not real. Some CFS patients have comorbid depression and/or anxiety.[158] In addition, it is maintained CBT may teach patients various "coping strategies" to help them deal with cognitive impairments such as a deterioration of short-term memory or abbreviated attention span, although it is uncertain how changing one's schemas, as CBT theory contends, would cause improvement in these serious pathological symptoms. Dr. David Smith, a former medical advisor to the ME Association in the UK who reports to have successfully treated many children using antidepressants and therapy[159], offers a possible explanation on his website.[160] 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,[161] 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[162], that to avoid such confusion supportive counselling should not be mis-termed CBT.
The Gibson Report
;Similar/Related Treatments
''Counselling'': Many CFS patients face the stress of economic and legal problems. CFS sufferers may lose jobs, marriages, and the ability to work at all, causing severe financial loss and distress. A lawyer, social worker or counsellor can be beneficial in helping the patient determine their best course, and may assist the patient with applying for work-related disability, social programs, and other aid.
Graded Exercise Therapy (GE, GA or GET)
Several rehabilitation programs have been proposed which involve supervised or self-monitored graded exercise or activity. Such programs are designed to overcome deconditioning, increase strength and cardiovascular health. The program should incorporate considerable education wherein the sufferer learns to start at an appropriate level of activity (based upon intensity and duration) which is incrementally increased, at a rate which does not substantially increase symptoms. Those who fit a 2003 ME/ICD-CFS definition with post exertional malaise may wish to consider whether graded exercise is recommended in their case because it can cause serious deterioration in the exertional intolerant, and the 25% ME Group[167] point out that many severe cases were in fact mild cases before undergoing such therapy. More encouragingly and in addition to the positive findings of the previously mentioned updated systematic review on GET
;Similar/Related Treatments
★ ''Self-controlled rest and exercise, "pacing"'': "Pacing" is being advocated by many patients as one of the few really effective means of minimising homeostatic disequilibrium. The principles involve acceptance of the patient's limitations (by both the patient and any coaches), awareness of the early signals of deterioration e.g. increased cognitive difficulties, pain, clumsiness, muscle weakness, respiratory problems; and stopping exercise/activity before exceeding limitation or "crashing." A good rule of thumb is to never exert more than 70% of capacity. An understanding nurse, doctor or physical therapist may be of help.
★ ''Other exercise'': A few patients find health benefits and pain relief from gentle stretching, non-aerobic exercise, and gentle activity. More able persons may find gentle yoga, walking, or t'ai chi to be beneficial. Water-borne exercise and swimming is particularly beneficial for some CFS sufferers. Exercise for the severely affected or those who cannot manage the exercises can be detrimental to their health and should be avoided.
;Cautions
Delayed onset of symptoms, unforeseen demands ("spilled milk,") poorly controlled or treated symptoms and inadequate social/personal caregiving for the severely affected, ensure great care is required to avoid exertional relapses, even without official programs. Cognitive, emotional and stress demands also detract from physical activity capability. The criteria for exercise intolerance is generally considered usually at a low level. The distinction between "exercise" and "activity" sometimes made is false and arbitrary, especially for the severely affected: even modestly sustainable activity can become temporarily or permanently unsustainable if over repeated and for those at their ''activity ceiling'', only very trivial additional or cumulative activity may be sufficient to cause relapse.
Medication
;Antidepressants
Antidepressants are often prescribed to CFS patients. It must be pointed out that some antidepressants can exacerbate symptoms, especially in the first few weeks of starting a new drug, and can induce muscle weakness, sleep-waking dysfunction and cardiac arrythmias, amongst other negative side effects. Some sufferers cannot tolerate any antidepressants at all, but that is true of normal controls taking antidepressants as well.
★ Although CFS patients may not be suffering from any distinct Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses indicating a depressive disorder, similarities have been seen in brain chemistry between those with depression or those with CFS, specifically in the anterior cingulate cortex and frontal cortex as well as reduced blood flow (cerebral hypoperfusion) in gray matter as seen on SPECT imaging.[170] The pattern found in CFS via SPECT is different from what one would see with normal controls or patients with depression, but CFS patients have been found to have increased perfusion in the left thalamus compared to patients with depression.[171] Changes have also been seen in reticular activating system (RAS) in CFS patients by SPECT.[172] The RAS controls circadian rhythm, the sleep-wake cycle, which Tricyclics are often used to help regulate.
★ Recent studies show pro-inflammatory cytokine processes take place during somatic and psychosomatic disease including both depression and CFS,[173][174][175] and is possible that symptoms manifest in CFS can attenuated by pharmacological affect of antidepressants on the immune system.[176][177][178][179][180][181]
★ Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes may reduce the affect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones.[179] Recent studies indicate a reduction of 5-HT transporter (serotonin transporter) and raised levels of tryptophan (a serotonin precursor) in many CFS patients which may contribute to fatigue and cognitive disturbances.[183] [184][185][186][187]
★ Antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). IL-6 has been demonstrated in CFS, and is a singaling pathway inducer of fatigue. IL-6 has been shown to cause cognitive problems in a variety of diseases.[188]
★ Antidepressants have also been shown to suppress TH1 (T helper cell) upregulation.[189][190][191][192][193]Some advances have also been achieved in the field of Hypothalamic-pituitary-adrenal axis (HPA-axis) modulation by antidepressants.[194][195][196] The role of HPA-axis in CFS has still to be determined as data has been mixed. Studies have shown patients with CFS have demonstrated subtle alterations in HPA axis activity characterized by reduced Adrenocorticotropic hormone (ACTH) over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion.[197]Other studies argue there is no HPA-axis change in CFS patients.[198]
★ These studies warrant further investigation for antidepressants for use in a psycho-neuroimmunological approach which may be required for optimal pharmacotherapy in CFS.[199] Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.[200][201]The culmination of these studies purport antidepressants can be useful in non-depressed patients.[202]
★ Overall, studies for use of antidepressants in CFS thus been performed has been mixed. Some studies have shown a reduction in symptoms with MAOI's, Tricyclics, SSRI and SNRI use.[203][204][205][206] Some studies have shown no improvement.
;Autonomic nervous system stimulants
Drugs such as atomoxetine (Strattera®), which stimulate the autonomic nervous system, appear to have positive effects in some people with CFS symptoms. Amphetamines and amphetamine analogs may help some patients. For example, methylphenidate (Ritalin®) has been found to be significantly better than placebo in relieving fatigue and concentration disturbances in a minority of CFS patients but more research is needed into the long term effects.[207] Interestingly, at least some of those who experience improvement on stimulant drugs do not experience significant "payback effect," suggesting that the drug is to some degree acting to correct the underlying neurological problem rather than simply masking symptoms. Modafinil (Provigil®), a medication designed to aid in maintaining wakefulness, has had some positive effect on individuals with CFS, but has not been properly studied. A small study suggested that long-term treatment with modafinil may not be beneficial for CFS patients.[208]
;Hormones
Various hormones have been tried from time to time, including specifically steroids (such as cortisol) and thyroid hormones. Though conventional steroidal treatment may produce short-term pain relief, it has not been shown to be of any general benefit. Studies performed by Dr. Jacob Teitelbaum incorporating low-dose cortisol therapy in a have demonstrated positive results,[209] but other studies have shown little benefit from cortisol itself. Thyroid hormones occasionally are effective for certain people who may either have a thyroid hormone deficiency or lack an enzyme that allows them to effectively use thyroid hormones. As Hypothalamic-pituitary-adrenal axis (HPA axis) dysfunction seems to be implicated in CFS, standard thyroid tests (including TSH) may not produce accurate results. Therefore, a short trial of either T3, T4, or a combination supplementation may be warranted if clinical signs seem to indicate possible hypothyroidism.
Patients with immunoglobulin deficiencies can be helped with infusions of intravenous gammaglobulin (IVIG).
;Sleep aids
Sleep aids may be prescribed when a patient complains of poor or irregular sleep, or excessive fatigue. Some patients find sleep aids, whether over-the-counter or prescription, to help greatly in maintaining a sleep cycle or getting "better", more restful sleep. As with all CNS acting drugs on ME/CFS, cautious dosage ramping is required and it may be necessary to try several drugs in order to find one which is tolerable.
;Pain relief
Many CFS patients experience significant amounts of physical, neuralgic pain. This "nerve pain", like that of phantom limb, diabetic neuralgia and fibromyalgia, does not generally respond well to NSAIDS, although some patients report that naprosyn or naproxen provides some relief due to its muscle relaxant properties. Tricyclic antidepressants, as above, offer better relief for some cases of nerve pain. Other pain relievers may have uses as well. Patients experiencing "other" pain (such as headache or migraine) should receive appropriate pain management for those symptoms. Hot water bathing has also been noted as relieving fibromyalgia or neuralgic pain, but patients with severe ME/CFS, low blood pressure or dizziness are advised to be cautious about the use of hot tubs or baths. Acupuncture has also been shown to relieve pain in fibromyalgia cases, and may be beneficial to CFS sufferers as well.
;Antibiotics
Antibiotics are commonly used to treat Lyme disease, sinusitis and other bacterial infections. These infections can be hard to eradicate, so often when an antibiotic cure fails it is claimed that the duration of treatment was insufficient or the wrong antibiotic was used. Another view is that some antibiotics have specific immuno-modulating side effects, quite separately from their antibiotic action. In the MedLine database, ciprofloxacine, doxycycline and the penicillins are reported to be of significant (albeit temporary) effect in some patients. An even larger group of patients may have adverse effects, and a third group no effect at all.
While many patients still show evidence o 
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