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.

Copyright 2001 Harcourt Publishers Ltd.

 

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.

Copyright 2001 Harcourt Publishers Ltd.

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

 

Metal-specific lymphocytes: biomarkers of sensitivity in man

Abstract:

Many patients attribute their health problems to amalgam and other dental metals. In genetically susceptible indviduals, mercury and gold may function as haptens and elicit allergic and autoimmune reactions.

The frequency of metal-induced lymphocyte responses was examined in 3,162 patients in three European laboratories using MELISA(R), an optimized lymphocyte proliferation test. The patients suffered from local and systemic symptoms attributed to dental restorations. The effect of dental metal removal was studied in 111 patients with metal hypersensitivity and symptoms resembling Chronic Fatigue Syndrome (CFS).

After consultation with a dentist the patients decided to replace their metal restorations with non-metallic materials. The changes in health and in vitro lymphocyte reactivity were studied by inquiries and follow-up MELISA(R). Lymphocyte reactivity was also analyzed in 116 healthy subjects with no complaints of metal allergy.

A significant number of patients had metal-specific lymphocytes in the blood. Nickel was the most common sensitizer, followed by inorganic mercury, gold, phenylmercury, cadmium and palladium. As compared to lymphocyte responses in healthy subjects, the CFS group had significantly increased responses to several metals, especially to inorganic mercury, phenylmercury and gold.

Following dental metal removal, 83 patients (76%) reported long-term health improvement. Twenty-four patients (22%) reported unchanged health and two (2%) reported worsening of symptoms. Following dental metal replacement, the lymphocyte reactivity to metals decreased as well.

We propose that an inflammatory process induced by metals may modulate the hypothalamic-pituitary-adrenal axis (HPA axis) and trigger multiple non-specific symptoms characterizing CFS and other chronic conditions like myalgic encephalitis (ME) and multiple chemical sensitivity (MCS).

 

Source: Stejskal VD, Danersund A, Lindvall A, Hudecek R, Nordman V, Yaqob A, Mayer W, Bieger W, Lindh U. Metal-specific lymphocytes: biomarkers of sensitivity in man. Neuro Endocrinol Lett. 1999;20(5):289-298. http://www.ncbi.nlm.nih.gov/pubmed/11460087

 

Chronic fatigue in general practice

Comment on: Chronic fatigue in general practice: is counselling as good as cognitive behaviour therapy? A UK randomised trial. [Br J Gen Pract. 2001]

 

Ridsdale and colleagues are to be congratulated on performing a randomised controlled trial of different treatments for chronic fatigue. However, their data do not substantiate their conclusions.

The trial was set up to demonstrate that cognitive behavioural therapy was better than counselling for patients seen in general practice with fatigue symptoms. No difference in the main outcome measures was found between the intervention and control groups. This has been interpreted as showing that the two treatments are equivalent. The sample size required for, and analysis of, equivalence studies are different than those required for trials designed to show differences,2 not least the requirement that equivalence be defined before the trial starts. This trial was not designed to show equivalence. Thus, although the results for the main outcome measures are similar they should not be reported as being equivalent. Without a definition of equivalence, calculating the study’s power to show equivalence is not possible. Also, part of the conclusions depend on a sub-group analysis which, while acknowledged as being underpowered, is given more weight than is justified. If equivalence is defined as six points on the fatigue score then, in this subgroup, the trial only has a power of 36% to show equivalence based on a 95% confidence interval. With a more conservative definition of equivalence even the main study lacks power.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1313987/pdf/11458490.pdf

 

Source: Underwood M, Eldridge S. Chronic fatigue in general practice. Br J Gen Pract. 2001 Apr;51(465):317-8. http://www.ncbi.nlm.nih.gov/pubmed/11458490

 

Cognitive behaviour therapy and chronic fatigue syndrome

Comment on: Chronic fatigue in general practice: is counselling as good as cognitive behaviour therapy? A UK randomised trial. [Br J Gen Pract. 2001]

 

Ridsdale and colleagues state that there is evidence that cognitive behaviour therapy (CBT) is effective for patients with chronic fatigue syndrome (CFS), but fail to point out that such evidence derives only from studies performed in the United Kingdom, where CFS is diagnosed on the basis of the Oxford criteria. There is no evidence that CBT is beneficial to patients fulfilling the Australian criteria for CFS or the American ones, namely, the original criteria of the Centers for Disease Control.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1313986/pdf/11458489.pdf

 

Source: Baschetti R. Cognitive behaviour therapy and chronic fatigue syndrome. Br J Gen Pract. 2001 Apr;51(465):316-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1313986/ (Full comment)

 

Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion

Abstract:

OBJECTIVE: Previous studies have suggested that chronic fatigue syndrome (CFS) is associated with changes in appetite and weight, and also with mild hypocortisolism. Because both of these features may be related to leptin metabolism, we undertook a study of leptin in CFS.

DESIGN: (i) A comparison of morning leptin concentration in patients with CFS and controls and (ii) a randomized, placebo-controlled crossover study of the effects of hydrocortisone on leptin levels in CFS.

PATIENTS: Thirty-two medication free patients with CFS but not comorbid depression or anxiety. Thirty-two age, gender, weight, body mass index and menstrual cycle matched volunteer subjects acted as controls.

MEASUREMENTS: We measured basal 0900 h plasma leptin levels in patients and controls. All 32 patients were taking part in a randomized, placebo-controlled crossover trial of low dose (5 or 10 mg) hydrocortisone as a potential therapy for CFS. We measured plasma leptin after 28 days treatment with hydrocortisone and after 28 days treatment with placebo.

RESULTS: At baseline, there was no significant difference in plasma leptin between patients [mean 13.8, median 7.4, interquartile range (IQR) 18.0 ng/ml] and controls (mean 10.2, median 5.5, IQR 11.3 ng/ml). Hydrocortisone treatment, for both doses combined, caused a significant increase in leptin levels compared to placebo. When the two doses were analysed separately, only 10 mg was associated with a significant effect on leptin levels. We also compared the hydrocortisone induced increase in leptin between those who were deemed treatment-responders and those deemed nonresponders. Responders showed a significantly greater hydrocortisone-induced rise in leptin than nonresponders. This association between a clinical response to hydrocortisone and a greater rise in leptin levels may indicate a greater biological effect of hydrocortisone in these subjects, perhaps due to increased glucocorticoid receptor sensitivity, which may be present in some patients with CFS.

CONCLUSIONS: We conclude that, while we found no evidence of alterations in leptin levels in CFS, low dose hydrocortisone therapy caused increases in plasma leptin levels, with this biological response being more marked in those CFS subjects who showed a positive therapeutic response to hydrocortisone therapy. Increases in plasma leptin levels following low dose hydrocortisone therapy may be a marker of pretreatment physiological hypocortisolism and of response to therapy.

 

Source: Cleare AJ, O’Keane V, Miell J. Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low-dose hydrocortisone on leptin secretion. Clin Endocrinol (Oxf). 2001 Jul;55(1):113-9. http://www.ncbi.nlm.nih.gov/pubmed/11453960

 

Chronic Fatigue Syndrome (CFS) in 15 dogs and cats with specific biochemical and microbiological anomalies

Abstract:

A great deal of controversy and speculation surrounds the etiology of Chronic Fatigue Syndrome (CFS) in human patients and the existence of a similar illness in animals. To evaluate the association with a presumptive staphylococcal infection and bacteremia, seven dogs and eight cats diagnosed with CFS (two meeting the CDC working case definition) were submitted to rapid blood cultures and fresh blood smears investigations.

Nine out of 15 blood cultures proved Staph-positive and four isolates were specified as S. xilosus (3) and S. intermedius (1). The presence of micrococci-like organisms in the blood was of common observation among these subjects, in association with fatigue/pain-related symptoms and biochemical abnormalities suggestive of a myopathy. Following treatment with a low dosage arsenical drug (thiacetarsamide sodium, Caparsolate, i.v., 0.1 ml/kg/day) all patients experienced complete remission. Micrococci disappeared from the blood at post-treatment controls made 10-30 days later. The outcomes were compared with those of five healthy controls and five ‘sick with other illness’ patients showing significant difference.

 

Source: Tarello W. Chronic Fatigue Syndrome (CFS) in 15 dogs and cats with specific biochemical and microbiological anomalies. Comp Immunol Microbiol Infect Dis. 2001 Jul;24(3):165-85. http://www.ncbi.nlm.nih.gov/pubmed/11440190

 

Patient education to encourage graded exercise in chronic fatigue syndrome. Trial has too many shortcomings

Comment on: Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome. [BMJ. 2001]

 

Editor—Powell et al’s controlled trial of graded physical exercise in chronic fatigue syndrome has several shortcomings.1

Firstly, the only tool that was used to assess the level of physical activity was entirely subjective. This was a single item (the third item) of the 11 item standardised SF-36 health survey questionnaire. Use of this single item alone as a valid measure of physical fitness is hardly acceptable in the absence of objective data.

Secondly, in a randomised study one can only compare like with like. In this case, all patients in the intervention arms had a minimum of three telephone contacts during the first three months. Patients in the control group were abandoned to primary care after the randomisation. Why did the investigators not maintain the same number of telephone contacts with the control group? They could have discussed anything but chronic fatigue.

Thirdly, frequent early contacts with patients in the three intervention groups (and not the control group) might have confounded the outcome measures by positively influencing the results. This view is supported by the maximum difference emerging as early as three months among patients who had had the illness for an average of over four years, with little change thereafter. By speaking to the patients Powell et al might have provided them with a coping strategy that the control group could not access. Furthermore, did the authors ask the patients to keep an activity diary to record the intensity (mild/moderate) and duration (minutes/hours a day) of physical exercise so that they could note any difference across the intervention groups?

Because no objective measures of physical activity (for example, exercise endurance) were included before and after the interventions for assessing outcome in this study, the reported beneficial effects of graded physical exercise are based on weak evidence. Moreover, the authors did not use the current diagnostic criteria to select patients with chronic fatigue syndrome. Why are we reading this in the BMJ?

You can read the full comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1120585/

 

Source: Chaudhuri A. Patient education to encourage graded exercise in chronic fatigue syndrome. Trial has too many shortcomings. BMJ. 2001 Jun 23;322(7301):1545-6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1120585/ (Full comment)

 

Delayed-type hypersensitivity and chronic fatigue syndrome: the usefulness of assessing T-cell activation by flow cytometry–preliminary study

Abstract:

Chronic fatigue syndrome or benign myalgic encephalomyelitis has been extensively described and investigated. Although numerous immunological abnormalities have been linked with the syndrome, none have been found to be specific.

This article describes the detection of delayed-type hypersensitive responses to certain common environmental antigens in almost fifty per cent of patients with this syndrome. Such hypersensitivity can be detected by the intradermal administration of antigens derived from commensal organisms like the yeast Candida albicans albicans, and then monitoring for a systemic reaction over the following six to forty-eight hours.

This approach can be consolidated by performing lymphocyte activation tests in parallel and measuring in vitro T-cell activation by Candida albicans albicans antigens by three-colour flow cytometry based on CD3, CD4 and either CD69 or CD25. Another useful parameter is the kinetics of neopterin excretion in the urine over the course of the skin test. The results showed that the intensity of the DTH response correlated with the number of T-cells activated in vitro.

Various factors have been implicated in the fatigue of many patients, notably lack of sleep. However, it remains difficult to establish causality in either one direction or the other. This work is in the spirit of a multifactorial approach to the group of conditions referred to as “chronic fatigue syndrome”.

 

Source: Brunet JL, Liaudet AP, Later R, Peyramond D, Cozon GJ. Delayed-type hypersensitivity and chronic fatigue syndrome: the usefulness of assessing T-cell activation by flow cytometry–preliminary study. Allerg Immunol (Paris). 2001 Apr;33(4):166-72. http://www.ncbi.nlm.nih.gov/pubmed/11434196

 

Lack of association between HLA genotype and chronic fatigue syndrome

Abstract:

Although the aetiology of chronic fatigue syndrome is controversial, evidence that infective agents including viruses may have a role in the development of the condition has led to studies seeking an association with the immunomodulatory HLA genes.

In the present study, we sought to extend previous work using a well-characterized patient group and modern HLA genotyping techniques. Fifty-eight patients were phenotyped for HLA A and B by microcytotoxicity and genotyped for HLA DRB, DQB and DPB by PCR oligoprobing, and the frequencies of antigens so assigned were compared with those from a control group of 134. No significant differences in HLA frequencies were found between patient and control groups.

Thus, this study does not confirm previous findings of an HLA association with chronic fatigue syndrome, suggesting that neither presentation of viral antigen by HLA class I nor antigen processing genes in the HLA region is a major contributory factor in the development of the disease.

 

Source: Underhill JA, Mahalingam M, Peakman M, Wessely S. Lack of association between HLA genotype and chronic fatigue syndrome. Eur J Immunogenet. 2001 Jun;28(3):425-8. http://www.ncbi.nlm.nih.gov/pubmed/11422420