hypothesis – Page 8 – American ME and CFS Society

Treatment of chronic fatigue syndrome by dietary supplementation with omega-3 fatty acids–a good idea?

Abstract:

Minor alterations of immune, neuroendocrine, and autonomic function may be associated with the chronic fatigue syndrome. omega-3 fatty acids decrease the production of putative mediators of inflammation, including interleukin-1, and tumor necrosis factor. Since interleukin-1 and tumor necrosis factor are the principal polypeptide mediators of immunoregulation, reduced production of these cytokines by dietary supplementation with omega-3, may be a possible mechanism for the treatment of chronic fatigue syndrome.

Source: Tamizi far B, Tamizi B. Treatment of chronic fatigue syndrome by dietary supplementation with omega-3 fatty acids–a good idea? Med Hypotheses. 2002 Mar;58(3):249-50. http://www.ncbi.nlm.nih.gov/pubmed/12018979

Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity,chronic fatigue syndrome, and posttraumatic stress disorder

Abstract:

Various types of evidence implicate nitric oxide and an oxidant, possibly peroxynitrite, in MCS and chemical intolerance (CI). The positive feedback loops proposed earlier for CFS may explain the chronic nature of MCS (CI) as well as several of its other reported properties. These observations raise the possibility that this proposed elevated nitric oxide/peroxynitrite mechanism may be the mechanism of a new disease paradigm, answering the question raised by Miller earlier: “Are we on the threshold of a new theory of disease?”

Source: Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity,chronic fatigue syndrome, and posttraumatic stress disorder. Ann N Y Acad Sci. 2001 Mar;933:323-9. http://www.ncbi.nlm.nih.gov/pubmed/12000033

Chronic fatigue syndrome: neurological findings may be related to blood–brain barrier permeability

Abstract:

Despite volumes of international research, the etiology of chronic fatigue syndrome (CFS) remains elusive. There is, however, considerable evidence that CFS is a disorder involving the central nervous system (CNS).

It is our hypothesis that altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and symptoms found in CFS. To support this hypothesis we have examined agents that can increase the blood-brain barrier permeability (BBBP) and those that may be involved in CFS.

The factors which can compromise the normal BBBP in CFS include viruses, cytokines, 5-hydroxytryptamine, peroxynitrite, nitric oxide, stress, glutathione depletion, essential fatty acid deficiency, and N-methyl-D-aspartate overactivity. It is possible that breakdown of normal BBBP leads to CNS cellular dysfunction and disruptions of neuronal transmission in CFS. Abnormal changes in BBBP have been linked to a number of disorders involving the CNS; based on review of the literature we conclude that the BBB integrity in CFS warrants investigation.

Source: Bested AC, Saunders PR, Logan AC. Chronic fatigue syndrome: neurological findings may be related to blood–brain barrier permeability. Med Hypotheses. 2001 Aug;57(2):231-7. http://www.ncbi.nlm.nih.gov/pubmed/11461179

Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite

Abstract:

Three types of overlap occur among the disease states chronic fatigue syndrome (CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS) and posttraumatic stress disorder (PTSD). They share common symptoms. Many patients meet the criteria for diagnosis for two or more of these disorders and each disorder appears to be often induced by a relatively short-term stress which is followed by a chronic pathology, suggesting that the stress may act by inducing a self-perpetuating vicious cycle. Such a vicious cycle mechanism has been proposed to explain the etiology of CFS and MCS, based on elevated levels of nitric oxide and its potent oxidant product, peroxynitrite.

Six positive feedback loops were proposed to act such that when peroxynitrite levels are elevated, they may remain elevated. The biochemistry involved is not highly tissue-specific, so that variation in symptoms may be explained by a variation in nitric oxide/peroxynitrite tissue distribution. The evidence for the same biochemical mechanism in the etiology of PTSD and FM is discussed here, and while less extensive than in the case of CFS and MCS, it is nevertheless suggestive. Evidence supporting the role of elevated nitric oxide/peroxynitrite in these four disease states is summarized, including induction of nitric oxide by common apparent inducers of these disease states, markers of elevated nitric oxide/peroxynitrite in patients and evidence for an inductive role of elevated nitric oxide in animal models.

This theory appears to be the first to provide a mechanistic explanation for the multiple overlaps of these disease states and it also explains the origin of many of their common symptoms and similarity to both Gulf War syndrome and chronic sequelae of carbon monoxide toxicity. This theory suggests multiple studies that should be performed to further test this proposed mechanism. If this mechanism proves central to the etiology of these four conditions, it may also be involved in other conditions of currently obscure etiology and criteria are suggested for identifying such conditions.

Comment in: Nitric oxide and the etiology of chronic fatigue syndrome: giving credit where credit is due. [Med Hypotheses. 2005]

Source: Pall ML. Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Med Hypotheses. 2001 Aug;57(2):139-45. http://www.ncbi.nlm.nih.gov/pubmed/11461161

Chronic fatigue syndrome: a matter of enzyme deficiencies?

Abstract:

The etiology of chronic fatigue syndrome (CFS) remains an enigma. But literature concerning chronic fatigue which does not focus on CFS points to all sorts of enzyme deficiencies as possible causes. The deficiencies are probably dismissed as causes of CFS because other characteristic symptoms are lacking in CFS patients. But these symptoms are often also lacking in patients with a deficiency. Symptom patterns in enzyme deficiencies are extremely variable. Therefore, patients with CFS should be screened systematically for enzyme deficiencies.

Source: van der Steen WJ. Chronic fatigue syndrome: a matter of enzyme deficiencies? Med Hypotheses. 2000 May;54(5):853-4. http://www.ncbi.nlm.nih.gov/pubmed/10859701

Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome

Abstract:

The etiology of chronic fatigue syndrome (CFS) has been both obscure and highly contentious, leading to substantial barriers to both clear diagnosis and effective treatment.

I propose here a novel hypothesis of CFS in which either viral or bacterial infection induces one or more cytokines, IL-1beta IL-6, TNF-alpha and IFN-gamma. 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.

This proposed mechanism may lower the HPA axis activity and be maintained by consequent lowered glucocorticoid levels. Similarities are discussed among CFS and autoimmune and other diseases previously shown to be associated with elevated peroxynitrite. Multiple pharmacological approaches to the treatment of CFS are suggested by this hypothesis.

Comment in: Nitric oxide and the etiology of chronic fatigue syndrome: giving credit where credit is due. [Med Hypotheses. 2005]

Source: Pall ML. Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome. Med Hypotheses. 2000 Jan;54(1):115-25. http://www.ncbi.nlm.nih.gov/pubmed/10790736

The symptoms of chronic fatigue syndrome are related to abnormal ion channel function

Abstract:

The pathogenesis of chronic fatigue syndrome (CFS) is unknown but one of the most characteristic features of the illness is fluctuation in symptoms which can be induced by physical and/or mental stress. Other conditions in which fluctuating fatigue occurs are caused by abnormal ion channels in the cell membrane.

These include genetically determined channelopathies, e.g. hypokalemic periodic paralysis, episodic ataxia type 2 and acquired conditions such as neuromyotonia, myasthenic syndromes, multiple sclerosis and inflammatory demyelinating polyneuropathies.

Our hypothesis is that abnormal ion channel function underlies the symptoms of CFS and this is supported also by the finding of abnormal cardiac-thallium201 SPECT scans in CFS, similar to that found in syndrome X, another disorder of ion channels. CFS and syndrome X can have identical clinical symptoms. CFS may begin after exposure to specific toxins which are known to produce abnormal sodium ion channels.

Finally, in CFS, increased resting energy expenditure (REE) occurs, a state influenced by transmembrane ion transport. The hypothesis that ion channels are abnormal in CFS may help to explain the fluctuating fatigue and other symptoms.

Comment in:

Chronic fatigue syndrome and channelopathies. [Med Hypotheses. 2000]

Re: Letter from professors Waxman and Ptacek (Med Hypotheses 2000; 55: 457). [Med Hypotheses. 2000]

Source: Chaudhuri A, Watson WS, Pearn J, Behan PO. The symptoms of chronic fatigue syndrome are related to abnormal ion channel function. Med Hypotheses. 2000 Jan;54(1):59-63. http://www.ncbi.nlm.nih.gov/pubmed/10790725

Chronic fatigue syndrome: a hypothesis focusing on the autonomic nervous system

Abstract:

Chronic fatigue syndrome is a debilitating illness of unknown aetiology, with estimated levels of prevalence of up to about 8. 7/100 000 in the U.S.A. Like pain fatigue it is a personal, emotionally rich experience, which may originate from peripheral or central sites (or both). The nature of the symptoms is complex and reflects the interaction of the patient with the environment and cultural milieu. Accordingly the common use of the same terminology for different types of fatigue may be misleading.

Autonomic activation is a key component of both real and simulated physical exercise. Alterations in autonomic nervous system activity are a key component of several physiopathological conditions. In chronic fatigue syndrome disturbances in autonomic activity, and in other homoeostatic mechanisms, such as the hormonal and immune systems, have been reported recently.

In this review we followed the hypothesis that in chronic fatigue syndrome the paradoxical condition of disturbing somatic symptoms in the absence of organic evidence of disease might be addressed by focusing on attending functional correlates. In particular we addressed possible alterations in cardiovascular autonomic control, as can be assessed by spectral analysis of R-R interval and systolic arterial pressure variability.

With this approach, in subjects complaining of unexplained fatigue, we obtained data suggesting a condition of prevailing sympathetic modulation of the sino-atrial node at rest, and reduced responsiveness to excitatory stimuli. Far from considering the issue resolved, we propose that in the context of the multiple physiological and psychological interactions involved in the perception and self-reporting of symptoms, attendant changes in physiological equivalents might furnish a convenient assessment independent from subjective components.

Indices of sympathetic modulation could, accordingly, provide quantifiable signs of the interaction between subject’s efforts and environmental demands, independently of self descriptions, which could provide convenient measurable outcomes, both for diagnosis and treatment titration in chronic fatigue syndrome.

Comment in: Long- and short-term blood pressure and RR-interval variability and psychosomatic distress in chronic fatigue syndrome. [Clin Sci (Lond). 1999]

Source: Pagani M, Lucini D. Chronic fatigue syndrome: a hypothesis focusing on the autonomic nervous system. Clin Sci (Lond). 1999 Jan;96(1):117-25. http://www.ncbi.nlm.nih.gov/pubmed/9857114

Natural killer cells and natural killer cell activity in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is associated with insidious and persistent immunologic abnormalities that have proved difficult to reproduce. The heterogeneity of CFS, the variable quality of immunologic assays and their performance, along with an almost complete absence of longitudinal studies of cellular immune abnormalities in CFS may explain this difficulty. However, in a significant proportion of cases, low levels of natural killer (NK) cell activity have been reported.

This article will explore the mechanisms responsible for low NK cell activity, discuss the relation between levels of NK cell activity and health/disease, describe new findings on NK cell-brain interactions, and put forth a specific hypothesis for the role of NK cells in the pathogenesis of CFS.

Source: Whiteside TL, Friberg D. Natural killer cells and natural killer cell activity in chronic fatigue syndrome. Am J Med. 1998 Sep 28;105(3A):27S-34S. http://www.ncbi.nlm.nih.gov/pubmed/9790479

Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms

Abstract:

Patients with unexplained chronic pain and/or fatigue have been described for centuries in the medical literature, although the terms used to describe these symptom complexes have changed frequently. The currently preferred terms for these syndromes are fibromyalgia and chronic fatigue syndrome, names which describe the prominent clinical features of the illness without any attempt to identify the cause.

This review delineates the definitions of these syndromes, and the overlapping clinical features. A hypothesis is presented to demonstrate how genetic and environmental factors may interact to cause the development of these syndromes, which we postulate are caused by central nervous system dysfunction. Various components of the central nervous system appear to be involved, including the hypothalamic pituitary axes, pain-processing pathways, and autonomic nervous system. These central nervous system changes lead to corresponding changes in immune function, which we postulate are epiphenomena rather than the cause of the illnesses.

Source: Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation. 1997 May-Jun;4(3):134-53. http://www.ncbi.nlm.nih.gov/pubmed/9500148