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Page: Proposed Causes and Pathophysiology
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The cause of CFS is unknown, although a large number of causes have been proposed, and several proposed causes have very vocal and partisan advocates. In a basic overview of CFS for health professionals, the CDC states that "After more than 3,000 research studies, there is now abundant scientific evidence that CFS is a real physiological illness." The cause of CFS may be different for different patients, but the pathophysiology of the initial insult to the immune system, disrupting homeostasis, has the same or similar 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 legitimate medical condition.[19] 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.
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.
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).
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.
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. These conditions, which reduce blood flow to the brain after periods of standing, can be diagnosed with a tilt table test. Unfortunately, fludrocortisone, a drug sometimes used to treat low blood pressure, seems to have little or no benefit for people with CFS.
Psychiatric abnormalities
Depression
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 researchers still believe that CFS is a complex psychosomatic disorder caused by chronic stress. Cognitive Behavioral Therapy, Antidepressants and Graded Exercise Therapy have been claimed to be effective treatments for some people with CFS. See Chronic fatigue syndrome#Cognitive Behavioral Therapy and Graded Exercise Therapy, above.
Genetics and Stress/Trauma
Further information: psychoneuroimmunology
Genetics and stress have been found to be factors in the development of CFS. The interaction between genetics and stress suggest that some people may be genetically predisposed to developing CFS after physiological and/or psychological triggers. The below findings improve the possibility of a diagnostic test and perhaps even a cure, but further research is needed:
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.
Stress/Trauma: CFS has been linked with an impaired stress response, with another study suggesting subtle dysregulations of the hypothalamus-pituitary-adrenal axis (the HPA axis helps the body remain stable under physiological and psychological stress). Other studies suggest that childhood stress/trauma significantly increases the likelihood of acquiring CFS as an adult, with one study finding a 3 to 8 fold increase (depending on the trauma type). Another study found both stress and emotional instability to be significant risk factors, an effect which may be buffered by genetic influences. The researchers also concluded 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.
Immune disorder
Hyperactive immunity
Autoimmune disorders, representing a hyperactive immune system, most likely through a cell-mediated process, have been suggested. In July 2005, researchers in the UK reported significant gene changes in the white blood cells in CFS patients consistent with the theory of immune system activation, possibly by an antigen triggering a constant immune fatigue state. The study, led by Dr Jonathan Kerr, discovered that 35 white blood cell genes, out of a total of 9,522 genes scanned were demonstrating differential function. There was also suggestion of neuronal and mitochondrial dysfunction as a result.
Allergies
Similarly to the theory of immune dysfunction, some doctors believe that CFS patients suffer from immune dysfunction caused by exposure to allergens, ranging from food allergies or 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.
Immunodeficiency
Immunodeficiency disorders (representing an underactive immune system) have been reported. As early as 1989, a study was published in Australia that documented a loss of immunological integrity in one hundred CFS sufferers. The authors reported finding disordered ratios of T-cell subsets and reduced levels of immunoglobulins specifically IgG 1 and IgG 3; these findings corresponded with similar findings in the U.S. among leading researchers. Most strikingly, using the French Multitest to measure the body's response to a variety of antigens, the Australian group found that 33% of the subjects were 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.
Infectious etiology
Bacterial infections
* Lyme disease and related tick-borne infections. Lyme disease does not always present acutely with a rash, and less than half of sufferers recall a tickbite (the nymphal deer tick is the size of a poppy seed, and secretes an anesthetic to prevent the host from feeling its bite). Furthermore, the characteristic joint pain is not always present. For these reasons Lyme can be difficult to diagnose, particularly in its later stages, at which point symptoms are virtually identical to those of CFS. The accuracy of blood tests for Lyme remains highly controversial, especially since they depend on an effective immune system response, which many researchers believe is compromised by the disease. As a result, some clinicians believe Lyme is under-diagnosed.
* Bacterial respiratory infections such as mycoplasmic bronchitis/pneumonia, Legionnaire's disease, and possibly other bacteria associated with bacterial pneumonia.
* Sinusitis. Sinusitis is a chronic infection of the sinuses which can be difficult to diagnose, and can cause symptoms similar to those of CFS. Sinusitis can occur after dental surgeries or infections, and thus may be related to reaction to mercury in dental amalgams as above, or dental infections, as below.
* Toxoplasma gondii. Toxoplasma gondii is a parasitic infection. If let untreated it can cause severe immune supression 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.
Fungal infection
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. This etiology of CFS is highly hypothetical.
Viral infection
Dissection studies of the brains of persons with post-polio syndrome have shown microscopic damage to areas of the brain responsible for alertness and metabolism, and possibly other motor functions, consistent with the symptoms of both CFS and post-polio syndrome. It is theorized that an infectious agent could cause similar damage in CFS cases, but no post-mortem studies on CFS patients have been done at this time (see "viral hypothesis", below), although post-mortems have been done on patients where CFS was a cause of death (see Sophia Mirza). Many members of the Herpesvirus family have been implicated as causative agents in CFS. For many years the ubiquitous Epstein-Barr virus, present in 90% of the population, was the principal suspect. Other viruses implicated include cytomegalovirus, and human herpesvirus type-6 (HHV-6). More recently, however, similarities to post-polio syndrome have led to a reexamination of the viral link. A number of viruses of the enterovirus family, notably the Coxsackie virus, can produce an infection of the nervous system similar to that caused by the poliovirus, and an even wider range of viruses have been shown capable of triggering an autoimmune reaction that attacks the nervous system. It is believed by some that one of these mechanisms causes damage to areas of the brain responsible for alertness and metabolism, resulting in many of the symptoms of CFS.
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.
Nutritional deficiency or imbalance
Certain dietary practices, particularly the consumption of large amounts of carbohydrates, or poorly nutritive vegan diets (see below, 'malnutrition'), are sometimes blamed for CFS. Celiac disease or gluten intolerance is known to cause CFS-like symptoms in some individuals, as is vitamin B12 or vitamin D deficiency. Other forms of food allergies are also often blamed, especially in cases of leaky gut syndrome. While many nutritional supplements are touted as cures or palliatives for CFS, research on these is scattered and inconclusive.
Malnutrition
In some cases, simple malnutrition may be responsible for CFS-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.
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:
* A large study found that higher levels of exercise in childhood is associated with a lower risk of developing CFS later on. It also found that the development of CFS was not associated with other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity.
* Researchers compared 48 CFS patients with 29 controls and found that 10 of the CFS patients tested positive for enterovirus RNA (most closely to that of the coxsackie B virus) in their muscles while all of the 29 controls tested negative. 28 of the 48 CFS patients had an abnormal lactate response to exercise, including 9 of the 10 who tested positive for enterovirus RNA.
* A study found that fatigue persists in a significant minority of patients for six months or more after infections, suggesting post-infective fatigue syndrome is a valid illness model for investigating CFS.
* In a study on people who had glandular fever (which is caused by the Epstein-Barr virus), no difference was found between the levels of virus in the blood from patients who recovered quickly when compared with those whose fatigue lasted more than six months, although the latter had an altered immune response. The scientists involved believed this suggests CFS can be caused by neurological damage done (during the acute infection phase) to parts of the brain which control perception of fatigue and pain.
* Lactic acid has been suggested to be a factor in CFS because for many decades it has been commonly believed to be responsible for muscle fatigue. However, some scientists have found that lactic acid may actually help prevent muscle fatigue rather than cause it, by keeping muscles properly responding to nerve signals.
* Oddly, researchers have found that children and teenagers with CFS are several times more likely to have some hyperflexible joints.
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