2002 – American ME and CFS Society

Chronic Fatigue Syndrome Linked To Impaired Stress Response

Subtle alterations of a hormonal stress response system called the HPA axis may play a role in chronic fatigue syndrome, according to a study in the November/December issue of Psychosomatic Medicine.

A smoothly functioning hypothalamus-pituitary-adrenal, or HPA, axis helps the body remain stable under physiological and psychological stress through the actions of three hormones. First, the brain portion called the hypothalamus secretes a hormone that stimulates the pituitary gland to secrete a second hormone. This second hormone causes the adrenal glands to create cortisol.

Problems can occur at any point in this process and result in a variety of diseases. A research team led by Jens Gaab, Ph.D., of the Center for Psychobiological and Psychosomatic Research at the University of Trier in Trier, Germany; and the Institute of Psychology at the University of Zürich in Switzerland are proposing that chronic fatigue syndrome may be one of them.

Chronic fatigue syndrome is characterized by debilitating fatigue that can include including muscle aches, low-grade fever and sleep disturbances. Its cause is not understood.

Gaab and colleagues recruited approximately 40 study participants between the ages of 30 and 50. Half of the participants were chronic fatigue sufferers and the other half were healthy volunteers. All participants completed questionnaires measuring fatigue, depression and coping skills.

To examine the HPA axis in action, participants were given blood, cardiovascular and saliva tests before and after taking two stress tests. The first, a psychosocial stress test, involved preparing for a fake job interview and completing an arithmetic problem before an audience while under the impression they were being videotaped. The second test measured physical stress on a stationary bicycle.

Participants were also given a series of insulin injections known as the insulin tolerance test. “The ITT is considered the gold standard for testing the integrity of the entire HPA axis,” Gaab says.

The researchers found significantly lower response levels of one of the HPA hormones, called ACTH, among the chronic fatigue patients compared with the healthy volunteers, during both stress tests as well as the ITT test. In fact, the chronic fatigue patients had significantly lower levels of the hormone before the testing even began.

“These results suggest that on a central level, subtle dysregulations of the HPA axis exist” in chronic fatigue syndrome patients, Gaab says, adding that future studies should include repeated evaluation of the HPA axis over the course of the syndrome.

Gaab and colleagues note that the possible role of cortisol in chronic fatigue syndrome still merits investigation, as low doses of hydrocortisone have shown some positive results in chronic fatigue patients.

Source: Center For The Advancement Of Health. “Chronic Fatigue Syndrome Linked To Impaired Stress Response.” ScienceDaily. ScienceDaily, 27 November 2002. https://www.sciencedaily.com/releases/2002/11/021126202215.htm

Influenza vaccination: is it appropriate in chronic fatigue syndrome?

Abstract:

Chronic fatigue syndrome (CFS) is a recognized clinical illness of unknown cause and pathophysiologic mechanisms. Immunizing patients against influenza would seem to be a prudent strategy since infection has been associated with symptom exacerbation. However, patients with CFS have demonstrated variable abnormalities in the immune system, the clinical significance of which is unclear. Anecdotal information has suggested that, due to the etiologic uncertainty surrounding CFS, many patients reject immunization, fearful of untoward effects. This article attempts to clarify the situation by reviewing immunologic findings in CFS and influenza vaccines in current use. Results from a recent survey of perceptions of patients with CFS regarding immunization revealed that 31% felt immunization was neither safe nor beneficial. This opinion was universal in those patients who had never received influenza vaccine. Among patients who had received vaccine and experienced an adverse effect, 26% felt the vaccine was safe and 28% felt it was beneficial. Among those who had received vaccine without an adverse effect, 45% believed the vaccine was safe, and 55% felt it was effective. CFS patients as a group expressed concern that influenza vaccine would alter an already dysfunctional immune system, or worsen CFS symptoms.

Significantly more patients with CFS who had never received influenza vaccine voiced this opinion than did patients who had received immunization for influenza in the past. Contrary to the opinions expressed by the sample, clinical trials in CFS have yet to find that any type of immunization has produced a deleterious effect on symptoms or functioning. Moreover, patients with CFS in a randomized, placebo-controlled, double-blind trial of influenza immunization produced an antibody titer in the protective range to inactivated trivalent influenza vaccine, although the geometric mean titer was slightly blunted compared with healthy vaccinees.

Although patients with CFS in placebo and active groups reported four times the number of post-injection adverse effects of healthy vaccinees, data re-analysis revealed that this finding was related to the overlap of common, post-influenza immunization symptoms and CFS constitutional symptoms. CFS is a poorly understood illness and some patients may believe in causal theories that lead to the rejection of disease prevention strategies such as immunization. However, influenza immunization appears to provide protective antibody levels without worsening CFS symptoms or causing excessive adverse effects. Efforts to motivate patients with CFS to obtain annual influenza immunization should take into account illness perceptions and concentrate on education based on placebo-controlled trials.

Source: Sleigh KM, Marra FH, Stiver HG. Influenza vaccination: is it appropriate in chronic fatigue syndrome? Am J Respir Med. 2002;1(1):3-9. http://www.ncbi.nlm.nih.gov/pubmed/14720070

Role of antioxidants in chronic fatigue syndrome in mice

Abstract:

The present study was carried out using mice model of chronic fatigue syndrome (CFS) in which mice were forced to swim everyday for 7 days for a 6 min session. There was a significant increase in despair behavior (immobility period) in saline treated mice on successive days.

Treatment with potent antioxidants carvedilol (5 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) produced a significant reduction in immobility period. Similar results were observed with herbal products St. John’s Wort (Hypericum perforatum L) (10 mg/kg, p.o.) and GS-02 (20 mg/kg, p.o.). Fluoxetine, a selective serotonin reuptake inhibitor produced a significant effect only on first and second day of its treatment.

Biochemical analysis revealed that chronic swim test significantly increased lipid peroxidation and catalase levels in whole brains of mice. There was a decrease in the levels of super oxide dismutase (SOD) and glutathione reductase (GSH) in the brain.

Administration of carvedilol, melatonin, GS-02 and St. John’s Wort restored the levels of lipid peroxidation and glutathione. The enzymes SOD and catalase were also restored. Fluoxetine affected the biochemical variables not to the same extent as other treatments. The findings of the present study suggest that oxidative stress might play a significant role in the pathophysiology of CFS. Thus antioxidants and herbal products like St. Johns wort and GS-02 could be useful in the treatment of CFS.

Source: Singh A, Garg V, Gupta S, Kulkarni SK. Role of antioxidants in chronic fatigue syndrome in mice. Indian J Exp Biol. 2002 Nov;40(11):1240-4. http://www.ncbi.nlm.nih.gov/pubmed/13677625

Primary haemochromatosis: a missed cause of chronic fatigue syndrome?

Abstract:

OBJECTIVE: To determine whether patients previously diagnosed as chronic fatigue syndrome (CFS) actually have primary haemochomatosis (PH).

METHODS: The setting was a Dutch referral centre. Transferrin saturation (TS) was retrospectively evaluated in banked blood samples of 88 patients diagnosed as CFS. Patients with elevated TS values were asked to provide a new overnight fasting blood sample for a second determination of TS and measurement of serum ferritin. The DNA was investigated for mutations in the HFE gene when one of these iron parameters was elevated.

RESULTS: For 19 out of 88 patients with CFS an elevated TS was found. A new blood sample was obtained from 11 of these 19: six had increased TS and two had elevated serum ferritin values. These eight patients were neither C282Y homozygotes nor compound C282Y-H63D heterozygotes. In the eight cases where no new blood samples could be obtained, the TS was > 50% for two of the five men and < 45% for the three female patients.

CONCLUSION: In a group of 88 CFS patients we could exclude PH in all but two of them (prevalence 2.3%; 95% confidence interval 0-5.5%). In our population of CFS patients PH is not more common than in a control population of northern European descent (prevalence 0.25-0.50%).

Comment in: Prevention of organ failure in hereditary haemochromatosis. [Neth J Med. 2002]

Source: Swinkels DW, Aalbers N, Elving LD, Bleijenberg G, Swanink CM, van der Meer JW. Primary haemochromatosis: a missed cause of chronic fatigue syndrome? Neth J Med. 2002 Dec;60(11):429-33. http://www.ncbi.nlm.nih.gov/pubmed/12685490

Prevention of organ failure in hereditary haemochromatosis

Abstract:

In this editorial the dominant sites of organ manifestations in hereditary haemochromatosis are discussed as well as conditions that can occur as a result of iron-mediated manifestations: liver disease, diabetes mellitus, arthritis, and cardiomyopathy. The incidences of these organ manifestations and their well-known typical symptomatology are mentioned, in order to investigate hereditary haemochromatosis as a possible (missed?) cause of the chronic fatigue syndrome. In particular the limitations of most studies about the prevalence of hereditary haemochromatosis in patients with the chronic fatigue syndrome are clearly summarised.

Comment on: Primary haemochromatosis: a missed cause of chronic fatigue syndrome? [Neth J Med. 2002]

Source: Marx JJ. Prevention of organ failure in hereditary haemochromatosis. Neth J Med. 2002 Dec;60(11):419-22. http://www.ncbi.nlm.nih.gov/pubmed/12685487

Use of IVIG in secondary immunodeficiencies

Abstract:

The research connects usefulness of intravenous preparates of immunoglobulins in patients with secondary immunodeficiencies. Basing on the data of literature there was discussed the using IVIG in patients with HIV infection and with the chronic fatigue syndrome. There was also discussed the matter of using IVIG after multiorgans traumas, burns and operations with high risk complications.

Source: Zeman K, Lewandowicz-Uszyńska A. Use of IVIG in secondary immunodeficiencies. Postepy Hig Med Dosw. 2002;56 Suppl:91-102. [Article in Polish] http://www.ncbi.nlm.nih.gov/pubmed/12661419

Systematic review of the current literature related to disability and chronic fatigue syndrome

Abstract:

Objective: The objective of this evidence report was to perform a systematic review of the published literature to provide the Social Security Administration (SSA) with the best available evidence and most current medical knowledge regarding disability in persons with Chronic Fatigue Syndrome (CFS).

Search Strategy: English language and adult population published literature from 1988 to November 2001 was searched using MEDLINE, Current Contents, Cochrane Library, and PsychINFO databases and supplemented by a manual review of bibliographies of all accepted papers.

Selection Criteria: Interventional or observational studies of at least two adult patients reporting CFS according to either the CDC 1988, CDC 1994, Oxford 1991, or Australia 1990 criteria were accepted. Studies were required to report disability (evidence of a medically determinable physical or mental impairment) and data regarding employment or work.

Data Collection and Analysis: Data on patients, interventions, and outcomes were extracted from accepted studies. Studies were scored for quality and level of evidence. Data were summarized for study, patient, and treatment level characteristics as well as outcomes of interest. A panel of diverse technical experts and peer reviewers provided review and commentary on the draft report.

Main Results: Of 3,840 citations identified, 53 studies describing 4,558 patients with CFS met all eligibility criteria. Twenty-two of these studies described comparator groups of healthy controls totaling 775 patients. The majority of CFS patients represented in the 37 studies reporting employment status were unemployed. The evidence suggests that some individuals with CFS have cognitive or affective impairments on neuropsychological tests, but results are not consistent. Depression of greater severity is associated with unemployment, but no other impairment appeared to be consistently associated with disability or work outcomes. No specific interventions have been proven to be effective in restoring the ability to work. No specific patient characteristics have been identified as best predictors of positive employment outcomes in CFS patients. The patient’s level of functioning at the time of diagnosis should be compared to functioning prior to the onset of illness especially as it relates to work, school, social and home activities.

The major limitations of this review are related to the weaknesses inherent in the current medical and scientific published literature regarding CFS. Study designs were not sufficiently homogeneous to allow quantitative synthesis of individual study results, and external validity was low. While some studies reported test and scale results, this was highly variable with relatively sparse and inconsistent reporting of both baseline and outcome data. No studies specifically measured the impact of baseline impairment data or treatment interventions on work function or employment outcomes.

Conclusions: While relationships between various impairment measures and work/disability status might be explored in some cases, the best available evidence from the literature did not allow for determination of causality. The limitations inherent in the current literature review are noted and the research community is urged to conduct methodologically rigorous, longitudinal, interventional studies to determine what baseline characteristics are associated with inability to work, and what interventions are effective in restoring the ability to work in the CFS population.

Source: Ross SD, Levine C, Ganz N, Frame D, Estok R, Stone L, Ludensky V. Systematic review of the current literature related to disability and chronic fatigue syndrome. Evid Rep Technol Assess (Summ). 2002 Dec;(66):1-3. http://www.ncbi.nlm.nih.gov/books/NBK36735/ (Full article)

Effect of natural and synthetic antioxidants in a mouse model of chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is an illness characterized by persistent and relapsing fatigue, often accompanied by numerous symptoms involving various body systems. The etiology of CFS remains unclear; however, a number of studies have shown that oxidative stress may be involved in its pathogenesis. In the present study, a mouse model of CFS was used in which mice were forced to swim for one 6-minute session on each day for 15 days and the immobility period was recorded.

There was a significant increase in immobility period in saline-treated mice on successive days. Intraperitoneal treatment with the potent antioxidants carvedilol (5 mg/kg) and melatonin (5 mg/kg) produced a significant reduction in immobility period. Similar results were observed with herbal preparations administered orally: Withania somnifera (100 mg/kg), quercetin (50 mg/kg), and St. John’s wort (Hypericum perforatum L., 10 mg/kg). Biochemical analysis revealed that chronic swimming significantly induced lipid peroxidation and decreased glutathione (GSH) levels in the brains of mice. The rats also showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Co-administration of antioxidants carvedilol, melatonin, W. somnifera, quercetin or St. John’s wort significantly reduced lipid peroxidation and restored the GSH levels decreased by chronic swimming in mice. Further, the treatment increased levels of SOD in the forebrain and of catalase.

The findings strongly suggest that oxidative stress plays a significant role in the pathophysiology of CFS and that antioxidants could be useful in the treatment of CFS.

Source: Singh A, Naidu PS, Gupta S, Kulkarni SK. Effect of natural and synthetic antioxidants in a mouse model of chronic fatigue syndrome. J Med Food. 2002 Winter;5(4):211-20. http://www.ncbi.nlm.nih.gov/pubmed/12639396

Does graded activity increase activity? A case study of chronic fatigue syndrome

Abstract:

The reliance on self-report outcome measures in clinical trials of graded activity-oriented cognitive-behavior therapy in chronic fatigue syndrome (CFS) makes it difficult to draw definitive conclusions about actual behavioral change.

The participant in this case study was a 52-year-old married male with CFS who was working full-time. Outcome measures included a step counter to objectively measure physical activity as well as a daily diary measure of exercise activity and in vivo ratings of perceived energy, fatigue, and affect. The following psychometric instruments were also used: the CFS Symptom Inventory, the SF-36, the Beck Depression Inventory, and the Beck Anxiety Inventory. The 26-session graded activity intervention involved gradual increases in physical activity.

From baseline to treatment termination, the patient’s self-reported increase in walk time from 0 to 155 min a week contrasted with a surprising 10.6% decrease in mean weekly step counts. The final follow-up assessment revealed a “much improved” global rating, substantial increases in patient-recorded walk time and weight lifting intensity, yet a relatively modest increment in weekly step counts. It appeared that improvement was associated with mood-enhancing, stress-reducing activities that were substituted for stress-exacerbating activities.

Source: Friedberg F. Does graded activity increase activity? A case study of chronic fatigue syndrome. J Behav Ther Exp Psychiatry. 2002 Sep-Dec;33(3-4):203-15. http://www.ncbi.nlm.nih.gov/pubmed/12628637

Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating illness lacking consistent anatomic lesions and eluding conventional laboratory diagnosis. Demonstration of the utility of the blood for gene expression profiling and biomarker discovery would have implications into the pathophysiology of CFS. The objective of this study was to determine if gene expression profiles of peripheral blood mononuclear cells (PMBCs) could distinguish between subjects with CFS and healthy controls.

Total RNA from PBMCs of five CFS cases and seventeen controls was labeled and hybridized to 1764 genes on filter arrays. Gene intensity values were analyzed by various classification algorithms and nonparametric statistical methods. The classification algorithms grouped the majority of the CFS cases together, and distinguished them from the healthy controls.

Eight genes were differentially expressed in both an age-matched case-control analysis and when comparing all CFS cases to all controls. Several of the differentially expressed genes are associated with immunologic functions (e.g., CMRF35 antigen, IL-8, HD protein) and implicate immune dysfunction in the pathophysiology of CFS. These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls and for identifying genes that could serve as CFS biomarkers.

Source: Vernon SD, Unger ER, Dimulescu IM, Rajeevan M, Reeves WC. Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome. Dis Markers. 2002;18(4):193-9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851413/ (Full article)