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

 

Attributions in chronic fatigue syndrome and fibromyalgia syndrome in tertiary care

Abstract:

OBJECTIVE: To evaluate the attributions of patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM) consulting at a university fatigue and pain clinic.

METHODS: Consecutive attenders (n = 192) who met the CFS criteria (n = 95) or FM criteria (n = 56) or who had medically unexplained chronic pain and/or fatigue without meeting both criteria (CPF) (n = 41) were evaluated. All subjects completed an extended form of the Cause of Illness Inventory. Descriptive statistics, frequency analyses, chi-square tests, one-way analysis of variance, and sequential Fisher least significant difference tests were performed.

RESULTS: In total, 48 patients reported physical causes only and 10 patients psychosocial causes only; the majority (70%) mentioned both types of causes. With regard to the contents, “a chemical imbalance in my body” (61%), “a virus” (51%), “stress” (61%), and “emotional confusion” (40%) were reported most frequently. The diagnostic label did not have a significant influence on number and type of attributions. Small to moderate effect sizes were registered concerning the association of specific attributions and diagnosis, sex, duration of the symptoms, contact with a self-help group, and premorbid depression.

CONCLUSION: The majority of patients with CFS, FM, and CPF reported a great diversity of attributions open to a preferably personalized cognitive behavioral approach. Special attention should be paid to patients with symptoms existing for more than one year and those who had previous contacts with a self-help group. They particularly show external, stable, and global attributions that may compromise feelings of self-efficacy in dealing with the illness.

 

Source: Neerinckx E, Van Houdenhove B, Lysens R, Vertommen H, Onghena P. Attributions in chronic fatigue syndrome and fibromyalgia syndrome in tertiary care. J Rheumatol. 2000 Apr;27(4):1051-5. http://www.ncbi.nlm.nih.gov/pubmed/10782836

 

Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome

Abstract:

GH deficiency states and chronic fatigue syndrome (CFS) share several characteristics, and preliminary studies have revealed aspects of GH dysfunction in CFS.

This study assessed indexes of GH function in 37 medication-free CFS patients without comorbid psychiatric illness and 37 matched healthy controls. We also assessed GH function before and after treatment with low dose hydrocortisone, which has been shown recently to reduce fatigue in CFS. We measured basal levels of serum insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-3 together with 24-h urinary GH excretion. We also performed 2 dynamic tests of GH function: a 100-microg GHRH test and an insulin stress test using 0.15 U/kg BW insulin.

There were no differences between patients and controls in basal levels of IGF/IGFBP or in urinary GH excretion. GH responses to both the GHRH test and the insulin stress test were no different in patients and controls.

CFS patients did have a marginally reduced suppression of IGFBP-1 during the insulin stress test. Hydrocortisone treatment had no significant effect on any of these parameters. There is no evidence of GH deficiency in CFS. At the doses used, hydrocortisone treatment appears to have little impact on GH function.

 

Source: Cleare AJ, Sookdeo SS, Jones J, O’Keane V, Miell JP. Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 2000 Apr;85(4):1433-9. http://www.ncbi.nlm.nih.gov/pubmed/10770178

 

Nutritional strategies for treating chronic fatigue syndrome

Abstract:

Despite considerable worldwide efforts, no single etiology has been identified to explain the development of chronic fatigue syndrome (CFS). It is likely that multiple factors promote its development, sometimes with the same factors both causing and being caused by the syndrome.

A detailed review of the literature suggests a number of marginal nutritional deficiencies may have etiologic relevance. These include deficiencies of various B vitamins, vitamin C, magnesium, sodium, zinc, L-tryptophan, L-carnitine, coenzyme Q10, and essential fatty acids. Any of these nutrients could be marginally deficient in CFS patients, a finding that appears to be primarily due to the illness process rather than to inadequate diets. It is likely that marginal deficiencies not only contribute to the clinical manifestations of the syndrome, but also are detrimental to the healing processes.

Therefore, when feasible, objective testing should identify them and their resolution should be assured by repeat testing following initiation of treatment. Moreover, because of the rarity of serious adverse reactions, the difficulty in ruling out marginal deficiencies, and because some of the therapeutic benefits of nutritional supplements appear to be due to pharmacologic effects, it seems rational to consider supplementing CFS patients with the nutrients discussed above, along with a general high-potency vitamin/mineral supplement, at least for a trial period.

Comment in: Nutritional strategies for treating chronic fatigue syndrome. [Altern Med Rev. 2001]

 

Source: Werbach MR. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev. 2000 Apr;5(2):93-108. http://www.altmedrev.com/publications/5/2/93.pdf (Full article)

 

Chronic fatigue syndrome in childhood

Abstract:

Chronic fatigue occurring in previously healthy children and adolescents is one of the most vexing problems encountered by pediatric practitioners.

We report three cases, 11, 12 and 13-year-old children, with chronic fatigue syndrome (CFS). They initially developed a low grade fever and generalized fatigue, followed by sleep disturbance and psychosomatic symptoms, and their performance ability deteriorated. They were diagnosed as having CFS on the basis of criteria.

To investigate the brain function in CFS patients, we examined the regional cerebral blood flow by single-photon emission-computed tomography (SPECT) with 111 MBq [123I]-iodoamphetamine (123I-IMP) or xenon-computed tomography (Xe-CT), and brain metabolic levels by MR spectroscopy (MRS).

Blood flow, expressed as the corticocerebellar ratio (CCR), in the left temporal and occipital lobes was markedly lower in cases 2 and 3 than that in healthy subjects reported by another investigator. In case 1, however, blood flow in the left basal ganglia and thalamus was markedly higher than in healthy subjects. The MR spectroscopy (MRS) study revealed remarkable elevation of the choline/creatine ratio in the patients with CFS. None of our patients exhibited evidence of focal structural abnormalities on MRI.

These findings suggest that the various clinical symptoms in CFS patients may be closely related to an abnormal brain function.

 

Source: Tomoda A, Miike T, Yamada E, Honda H, Moroi T, Ogawa M, Ohtani Y, Morishita S. Chronic fatigue syndrome in childhood. Brain Dev. 2000 Jan;22(1):60-4. http://www.ncbi.nlm.nih.gov/pubmed/10761837

 

Cognitive behavior therapy for chronic fatigue syndrome: a case study

Abstract:

The case of a 26-year old woman with Chronic Fatigue Syndrome (CFS) is presented. Multidimensional assessment showing severe debilitating fatigue and considerable psychological, social and occupational impairment confirmed the diagnosis. Cognitive behavior therapy (CBT) was based on a tested causal model of CFS and individual behavioral analyses. Key elements in CBT were process variables from the CFS model, like sense of control, causal attributions, physical activity and focusing on bodily functions. Goals were recovery from fatigue, returning to work and relapse prevention. The course of therapy is described in detail to illustrate difficulties in treating CFS. Assessments were made five times, at baseline and at 8, 14, 21 and 33 months. Comparison of the pretest, post-test and follow-up scores of the outcome variables, fatigue and functional impairment and of the process variables showed clinically significant improvement from the range of CFS patients to the range of healthy controls.

 

Source: Prins JB, Bleijenberg G. Cognitive behavior therapy for chronic fatigue syndrome: a case study. J Behav Ther Exp Psychiatry. 1999 Dec;30(4):325-39. http://www.ncbi.nlm.nih.gov/pubmed/10759328

 

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Abstract:

Fibromyalgia and widespread pain were common in Gulf War veterans with unexplained illness referred to a rheumatology clinic. Increased tenderness was demonstrated in the postmenstrual phase of the cycle compared with the intermenstrual phase in normally cycling women but not in users of oral contraceptives. Patients with fibromyalgia had high levels of symptoms that have been used to define silicone implant-associated syndrome. Tender points were found to be a common transient finding associated with acute infectious mononucleosis, but fibromyalgia was an unusual long-term outcome. The common association of fibromyalgia with other rheumatic and systemic illnesses was further explored. A preliminary study revealed a possible linkage of fibromyalgia to the HLA region. Patients with fibromyalgia were found to have an impaired ability to activate the hypothalamic pituitary portion of the hypothalamic pituitary adrenal axis as well as the sympathoadrenal system, leading to reduced corticotropin and epinephrine response to hypoglycemia. Much interest has been expressed in the literature on the possible role of autonomic dysfunction in the development or exacerbation of fatigue and other symptoms in chronic fatigue syndrome. Mycoplasma genus and mycoplasma fermentans were detected by polymerase chain reaction in patients with chronic fatigue syndrome. It was reported that myofascial temporomandibular disorder does not run in families. No major therapeutic trials in fibromyalgia, chronic fatigue syndrome, or myofascial pain syndrome were reported over the past year. The effectiveness of cognitive behavioral therapy and behavior therapy for chronic pain in adults was emphasized. A favorable outcome of fibromyalgia and chronic fatigue syndrome in children and adolescents was reported.

 

Source: Buskila D. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 2000 Mar;12(2):113-23. http://www.ncbi.nlm.nih.gov/pubmed/10751014

 

Symptom patterns in long-duration chronic fatigue syndrome

Abstract:

OBJECTIVE: Our objective was to evaluate symptom patterns in patients with chronic fatigue syndrome (CFS) who were ill for 10 or more years.

METHODS: This cross-sectional self-report study compared patient groups with long-duration (median = 18 years; n = 258) and short-duration (median = 3 years; n = 28) CFS to a group of healthy significant others (n = 79) on symptomatic, neurocognitive, and psychological variables. Data were gathered from a 574-item postal questionnaire.

RESULTS: A principal-components analysis of CFS symptom data yielded a three-factor solution: cognitive problems; flu-like symptoms; and neurologic symptoms. Compared with the short-duration CFS group, the long-duration group had significantly higher CFS symptom severity scores (p < 0.04), largely attributable to increased cognitive difficulties. A subgroup comparison of subjects ill for < 3 years versus those ill 4-7 years suggested that denial coping strategies were more likely in those participants with the shorter illness duration. Significant differences between both CFS groups and healthy controls were found in a number of comorbid disorders. Participants with CFS most often endorsed immune/viral abnormalities and persistent stress as important perceived causes of their illness.

CONCLUSION: Participants with long-duration CFS reported a large number of specific cognitive difficulties that were greater in severity than those reported by participants with short-duration CFS. The pattern of comorbid disorders in the CFS groups was consistent with hypersensitivity and viral reactivation hypotheses.

 

Source: Friedberg F, Dechene L, McKenzie MJ 2nd, Fontanetta R. Symptom patterns in long-duration chronic fatigue syndrome. J Psychosom Res. 2000 Jan;48(1):59-68. http://www.ncbi.nlm.nih.gov/pubmed/10750631

 

Does severe nutcracker phenomenon cause pediatric chronic fatigue?

Abstract:

BACKGROUND: In the past five years we experienced 9 fatigued disabled children who were intermittently or persistently absent from school.

PATIENTS: They had been suspected to be burdened with psychosomatic disorders, having orthostatic hypotension, postural tachycardia, or other autonomic dysfunction symptoms.

RESULTS: Investigating the cause of moderate orthostatic proteinuria in some of them, we found by chance severe typical nutcracker phenomenon (NC), which was present in all 9 children complaining of chronic fatigue.

CONCLUSION: Their symptoms filled the criteria of chronic fatigue syndrome or idiopathic chronic fatigue (CFS/CF). An association between severe NC and autonomic dysfunction symptoms in children with CFS/CF has been presented.

Source: Takahashi Y, Ohta S, Sano A, Kuroda Y, Kaji Y, Matsuki M, Matsuo M. Does severe nutcracker phenomenon cause pediatric chronic fatigue? Clin Nephrol. 2000 Mar;53(3):174-81. http://www.ncbi.nlm.nih.gov/pubmed/10749295