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Copy of created Article 14/04/08 for security and record purpose

ME/CFS HYPOTHESES DRAFT
The etiology or cause(s) of ME/CFS are unknown, although a large number of causes have been proposed. The cause may be different for different patients, but if so, the various causes may result in a common clinical outcome." Major hypotheses are (1) CFS is often associated with viral infection, although the presence of viruses has as yet not been consistently detected. (2) It is not clear whether anomalies of the HPA axis often observed in CFS, are cause or the consequences of the disorder. (3) Immune dysfunction as the cause of CFS is another hypothesis. (4) The psychiatric and psychosocial hypothesis denies the existence of CFS as a disease entity. Accordingly, the fatigue symptoms are assumed to be the consequence of other (somatic) diseases. Other possible causes of CFS are (5) oxidative stress and (6) genetic predisposition.  Or it may be due to a combination of several of these factors. Whilst many hypotheses about CFS are made on the basis of specific findings others are proposed as a result of wider literature reveiw into the condition and the basic science.

Infection
Partly due to association with past epidemics there has long been hypotheses linking ME/CFS with infection. From the very first well documented epidemic in 1934 the question has arisen concerning the relationship between an infection and immnunization. Many patients prior to 1956 suffered a paralytic association along with typical ME/CFS symptoms, however post 1956 patients have been spared paralysis, and it was hypothesised that polio immunization altered the symptoms common in earlier epidemics. Evidence of exogenous insults, for example, various viral infections Epstein-Barr virus, Enteroviruses, Parvovirus B19, and bacterial infections Coxiella burnetii and Chlamydia pneumoniae are found associated with CFS Others argue that although the ailment clearly can occur after severe infection, no convincing data exist to support an infectious (or immunologic) process in disease maintenance.

In CFS, acute viral infection studies during 2007 found that initial infection severity was the single best predictor of persistent fatigue. Genomic studies showed that persistent cases express Epstein Barr virus-specific genes. Other research has focused on a subgroup of patients with reactivated viral infection.

The higher winter onset of CFS supports the hypothesis that there is a subgroup of patients in which symptom onset is precipitated by a viral infection.

Immune activation
Epidemiological studies reveal that a flu-like sickness precedes the onset in the majority of cases. A major hypothesis of the pathogenesis of CFS is that infectious agents such as viruses, may trigger and lead to chronic activation of the immune system with abnormal regulation of cytokine production. The possibility exists that stress and/or the reactivation/replication of a latent virus (such as Epstein Barr virus) could modulate the immune system to induce CFS.

Beta endorphin changes are consistent with the hypothesis that the immune system is activated in both chronic fatigue syndrome and fibromyalgia syndrome.

An hypothesis that altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and neurological symptoms found in CFS. The monocyte /macrophage, which crosses the blood brain barrier is an essential candidate cell in the study of psychoneuroimmunology. In a reveiw of recent literature, support for the hypothesis that macrophages play an important role in neurodevelopment and in the pathophysiology of various conditions was found.

A sensitivity analysis found differences between groups and evidence of cytokine changes that are consistent with the hypothesis that CFS symptoms are a consequence of immune system dysregulation. New findings on NK cell-brain interactions put forth a specific hypothesis for the role of NK cells in the pathogenesis of CFS.

The hypothesis that abnormal cytokine release plays a role in the pathogenesis of CFS was reviewed. Neuropsychiatric symptoms in patients with CFS may be more closely related to disordered cytokine production by glial cells within the central nervous system (CNS) than to circulating cytokines.

HPA axis
A review of results of studies of the HPA and other neuroendocrine axiis in CFS, concluded, disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to: (1) low circulating cortisol; (2) disturbance of central neurotransmitters; or (3) disturbance of the relationship between cortisol and central neurotransmitter function. Accumulating evidence of the complex relationship between cortisol and serotonin function, make some form of hypothesis most likely. The opioid system, and arginine vasopressin (AVP) may also be abnormal, though the growth hormone (GH) axis appears to be intact, in CFS.

Novel hypothesis that CFS in a subset is a neurophysiological disorder focussing on the amygdala. The unconscious amygdala may become conditioned to be chronically sensitised to negative symptoms arising from the body. Negative signals from the viscera or physiological, chemical and dietary stressors, become conditioned stimuli and the conditioned response is a chronic sympathetic outpouring from the amygdala via various brain pathways including the hypothalamus (thus HPA axis). This cell assembly then produces the CFS vicious circle, where an unconscious negative reaction to symptoms causes immune reactivation/dysfunction, chronic sympathetic stimulation, leading to sympathetic dysfunction, mental and physical exhaustion, and a host of other distressing symptoms and secondary complications. A state of low cortisol might sensitise the HPA axis to development of persistent central fatigue after stress.

Psychiatric and psychosocial
A prospective study suggests that previous psychiatric disorders, or shared risk factors for psychiatric disorders, are likely to have an etiological role in some cases of CFS/ME. An alternative hypothesis is that the presence of multiple comorbid disorders is a marker for psychological influences on etiology.
 * Psychological

There is an hypothesis of neuropsychological impairments in CFS. However neuropsychological, neuroendocrine studies and brain imaging have now confirmed the occurrence of neurobiological abnormalities in most patients with CFS.

The pathophysiology of CFS leads to the hypothesis that central sensitization is responsible for the sustaining pain complaints in CFS. This hypothesis is based on the hyperalgesia and allodynia reported in CFS, on the elevated concentrations of nitric oxide presented in the blood of CFS patients, on the typical personality styles seen in CFS and on the brain abnormalities shown on brain images , The results of several studies provide further support for the hypothesis that a high level of "action-proneness" may play a predisposing, initiating and/or perpetuating role in CFS and FM.
 * Psychosocial
 * Behavioural

It is hypothesized that in CFS the health threat is no longer the illness, but rather anything that threatens to disrupt a precarious accommodation to it. It is argued that due to established vicious circles, attempts at threat regulation may become inadvertently self-defeating, promoting the threats they attempt to diminish.

CFS patients consulted their GP more frequently in the 15 years before development of their condition, for a wide variety of complaints. Several possibilities may explain these findings. The results support the hypothesis that behavioural factors have a role in the etiology of CFS.

CFS may be an adaptive response to nasal impairment. The proposed nasal fatigue reflex should be examined as a possible ancient adaptive response to nasal malfunction.

Oxidative stress
Hypothesis of CFS in which either viral or bacterial infection induces one or more cytokines. These induce nitric oxide synthase (iNOS), leading to increased nitric oxide levels. Nitric oxide, in turn, reacts with superoxide radical to generate the potent oxidant peroxynitrite. Multiple amplification and positive feedback mechanisms are proposed by which once peroxynitrite levels are elevated, they tend to be sustained at a high level. Such a vicious cycle mechanism has been proposed to explain the etiology of CFS, FMS and MCS. Stressors, acting primarily through the nitric oxide product, peroxynitrite, are thought to initiate a complex vicious cycle mechanism, known as the NO/ONOO- cycle that is responsible for symptoms in chronic illness. The role of peroxynitrite in the NO/ONOO- cycle also implies that such uncoupling is part of the chronic phase cycle mechanism such that agents that lower uncoupling will be useful in treatment.

The role of oxidative stress in CFS is an emerging focus of research due to evidence of its association with some pathological features of this syndrome. New data collectively supports the presence of specific critical points in the muscle membranes that are affected by free radicals and in view of these considerations, the possible role of skeletal muscle oxidative imbalance in CFS is considered. The oxidative stress induced muscle membrane modifications may be related to alteration of membrane fluidity with deregulation of pump activities, sodium / potassium (Na(+)/K(+) and calcium (Ca(2+)-ATPase).

Selective n-6 fatty acid depletion suggest that oxidative stress and more specifically lipid peroxidation might play a role in CFS pathogenesis. The results of a study indicate that patients with CFS have increased susceptibility to peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS.

Evidence is put forward to suggest that myalgic encephalomyelitis, also known as chronic fatigue syndrome, may be associated with persistent viral infection. In turn, such infections are likely to impair the ability of the body to biosynthesise n-3 and n-6 long-chain polyunsaturated fatty acids by inhibiting the delta-6 desaturation of the precursor essential fatty acids--namely, alpha-linolenic acid and linoleic acid. This would, in turn, impair the proper functioning of cell membranes. Alternatively oxidative stress might reduce essential fatty acids in membranes of chronic fatigue syndrome patients.

Several papers explain that depletion of essential fatty acids can result from an immune hyper-response, mediated either by immuno-globulins, by sustained cytokines, and/or by reduced lipo-cortin control (due to HPA hypo function) or by excessive metabolic mobilization of essential fatty acids. Oxygenases are suppressed in normal tissues but are activated by lipid hydroperoxides. Hydroperoxides are needed as activators to sustain production but one immediate product of fatty acid oxygenase action is lipid hydroperoxide. Positive feeback amplifies the peroxide in vicinity to the oxygenase, leading to free radical generation, oxidative stress and substrate depletion; the result of sustained extracellular signalling and intracellular amplification.

Hypothesis that changes in ratio of essential fatty acid metabolites are the normal physiological responses to stressors, but when stressors are excessive or prolonged, systems may become unpredictably hypo-responsive after sustained hyper responses owing to factors such as receptor down regulation and substrate depletion. In time, many homeostatic systems become deranged and vicious circles held in that state by minor stressors.

The inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) have been found raised in CFS patients associated with symptoms and provides evidence to support hypotheses that CFS is accompanied by increased oxidative stress and inflammation.

Genetic predisposition
Present knowledge suggests that certain genetic polymorphisms might be regarded as predisposing factors for CFS. Polymorphism in biology occurs when two or more clearly different types exist in the same population of the same species. Preliminary studies have suggested that the risk of developing CFS may be influenced by polymorphisms in genes affecting the central nervous system (see ME/CFS pathophysiology for findings)

A hypothesis is presented to demonstrate how genetic and environmental factors may interact to cause the development of the syndromes CFS and FMS, which is postulated are caused by central nervous system dysfunction.

Another hypothesis is that CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature probably secondary to one or more environmental insults of unknown nature.

Twin studies, where only one has illness, indicate current fatiguing illness appears to be a complex trait resulting from both environmental and genetic sources of variation without pronounced differences by gender, Another twin study found somatic symptoms are relatively etiologically distinct both genetically and environmentally from symptoms of anxiety and depression.

Hypothesised that while WBC fat oxidation is not significantly affected by sex or acute exercise, and only by 15-20% with training, genetic factors play a role in determining both high and low fat oxidation in certain groups of individuals. White blood cell (WBC) fat oxidation rate is high in CFS patients on a proposed scale based on genetic factors evaluated in this study, supporting a likely genetic factor in CFS.

The observation in a study, that family members of CFS and FMS patients also had antibodies to serotonin, gangliosides and phospholipids represents an argument in favour of a genetic predisposition.

Other

 * This hypothesis is based on the recent recognition of chaos fractals and complex systems mathematical analysis in human physiology. Studies using novel nonlinear methodologies have shown that fibromyalgia and similar maladies may be caused by the degraded performance of our main complex adaptive system.


 * Postulated vasoactive neuropeptide (VN) autoimmunity in fatigue-related conditions: a brief review and hypothesis. These papers describe a biologically plausible mechanism for the development of certain fatigue-related syndromes based on loss of immunological tolerance to these VNs or their receptors following infection, other events or de novo resulting in significant pathophysiology. They exert significant control over carbohydrate and lipid metabolism. The hypothesis is that because these substances have vital and indispensable roles in cellular processes, loss or compromise of these roles would lead to predictable and severe cellular and systemic effects. There have been recent (Dec. 2007) findings of increased auto-immune-antibodies directed against phosholipids (phosphatidyl inositol) (Pi) in chronic fatigue syndrome (CFS).


 * Thyroid hormone function; Overlapping symptom complexes suggest that chronic fatigue syndrome, is similar enough to fibromyalgia to merit investigation for possible thyroid hormone resistance. Molecular mechanisms could explain the development of a clinical hypothyroid state in the presence of a normal thyroid function, such as in CFS. Substances may induce tissue specific resistance to thyroid hormone (RTH), e.g. by affecting numbers of different TR isoforms. Recent literature also indicates mechanisms by which different conditions, for example, chronic fatigue syndrome (CFS), can be accompanied by acquired RTH. We hypothesise that observed clinical symptoms of hypothyroidism in chemically euthyroid patients are typically caused by changes in hormonal systems, autoimmune antibodies, metabolites or other substances in the body, leading to reduced sensitivity to thyroid hormone (TH) in peripheral tissues. These changes may be a by-product of other processes and a reversible biological response in the body, and may also result in chronic acquired RTH.


 * Hypothesis is that abnormal ion channel function underlies the symptoms of CFS, and this is supported also by the finding of abnormal cardiac-thallium 201 SPECT scans in CFS. Also, in CFS, increased resting energy expenditure (REE) occurs, indicative of influenced transmembrane ion transport. In some cases it may begin after exposure to specific toxins which are known to produce abnormal sodium ion channels. Supported more recently by results of gene expression studies.


 * A hypothesis focusing on the autonomic nervous system changes in CFS, as a convenient assessment independent from subjective components, in the context of the multiple physiological and psychological interactions in self-reporting of symptoms. In particular a study addressed possible alterations in cardiovascular autonomic control, and obtained data suggesting a condition of prevailing sympathetic predominance of heart rate at rest, and reduced responsiveness to excitatory stimuli.


 * The results of several studies suggest that repeated thermal therapy (sauna) may be a promising method for the treatment of CFS. Also an hypothesis that repeated cold stress may reduce fatigue in CFS because brief exposure to cold may transiently reverse some physiological changes associated with this illness. Cold stress has been shown to reduce the level of serotonin in most regions of the brain (except brainstem), which would be consistent with reduced fatigue according to models of exercise-related fatigue. Finally, exposure to cold increases metabolic rate and transiently activates the HPA axis as evidenced by a temporary increase in the plasma levels of ACTH, beta-endorphin and a modest increase in cortisol.


 * The hypothesis that colonization of the intestinal tract by yeasts (e.g. Candida albicans) can lead to disease in immunocompromised individuals that toxins produced by the fungi can trigger such complaints as irritable bowel syndrome of the chronic fatigue syndrome, More recently it has been found that the pathogenic yeast Candida albicans has the ability to synthesize unique substances that act as adhesins, induce cytokine production, and generate antibodies.