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Douche-Aourik, F., Berlier, W., Feasson, L., Bourlet, T., Harrath, R., Omar, S., Grattard, F., Denis, C and Pozzetto, B. Detection of enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy subjects. Journal of Medical Virology, 2003, 71, 540-547.
Enterovirus RNA has been found previously in specimens of muscle biopsy from patients with idiopathic dilated cardiomyopathy, chronic inflammatory muscle diseases, and fibromyalgia or CFS. These results suggest that skeletal muscle may host enteroviral persistent infection. To test this hypothesis, we investigated by reverse transcription-polymerase chain reaction (RT-PCR) assay the presence of enterovirus in skeletal muscle of patients with chronic inflammatory muscle diseases or fibromyalgia/chronic fatigue syndrome (Buchwald 1996*), and also of healthy subjects.
Three of 15 (20%) patients with chronic inflammatory muscle diseases, 4 of 30 (13%) patients with fibromyalgia/CFS, and none of 29 healthy subjects was found positive. The presence of VP-1 enteroviral capsid protein was assessed by an immunostaining technique using the 5-D8/1 monoclonal antibody; no biopsy muscle from any patient or healthy subject was found positive. The presence of viral RNA in some muscle biopsies from patients exhibiting muscle disease, together with the absence of VP-1 protein, is in favor of a persistent infection involving defective viral replication.
[Ed. note: Differentiation between CFS and FM and the use of more specific criteria for the former might have increased identification of positive cases, cf Archard et al 1988, Cunningham et al 1990, 1991). The replication of the earlier British findings in a more heterogeneous group is significant. The cited paper by Buchwald lists only established criteria.]
Zachrisson, O., Colque-Navarro, P., Gottfries, CG., Regland, B and and Mollby, R. Immune modulation with a Staphylococcal preparation in fibromyalgia/chronic fatigue syndrome: relation between antibody levels and clinical improvement. European Journal of Clinical Microbiology & Infectious Diseases, 2004, Jan 20 [Epub ahead of print].
The aims of this study were to evaluate the serological response to treatment with staphylococcal vaccine in patients with fibromyalgia (FM) and CFS (CDC criteria '94) and to explore the relationship between serological response and clinical effect.
Twenty-eight patients, half of whom served as controls, were recruited from a 6-month randomised trial in which repeated administration of the staphylococcal toxoid vaccine Staphypan Berna (Berna Biotech, Switzerland) was tested against placebo. Antibody status against extracellular toxins/enzymes, cell-wall components, and enterotoxins was evaluated at baseline and at endpoint. The clinical response to treatment was recorded in rating scales.
In the group receiving active treatment, significant serological changes were recorded, whereas no significant changes were found in controls. Treatment led to a significantly increased capacity of serum to neutralise alpha-toxin and a significant increase in serum IgG to alpha-toxin and lipase. Furthermore, the increase in these parameters combined paralleled the improvement in clinical outcome. Thus, the greater the serological response, the greater was the clinical effect.
In conclusion, this explorative study has shown that repeated administration of the Staphypan Berna vaccine in patients with FM/CFS causes a serological response to several staphylococcal antigens, particularly to certain extracellular toxins and enzymes... This response is related to the clinical outcome of treatment.
[Ed. note: The authors suggest that alpha-toxin antibodies may be markers of the general response capacity of the immune system. A poor response against alpha-toxin thus reflects poor functioning of the immune system. Staphylococcal antigens in the vaccine may work as unspecified inducers of cell-mediated immunity. The vaccine may therefore have exerted an effect, "boosting the immune system".]
Skowera, A., Cleare, A., Blair, D., Bevis, L., Wessely, SC and Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clinical and Experimental Immunology, 2004, 135, 2, 294-302.
...It has been suggested that CFS may be associated with underlying immune activation resulting in a Th2-type response. We measured intracellular production of interferon (IFN)-γ and interleukin (IL)-2; type 1 cytokines), IL-4 (type 2) and IL-10 (regulatory) by both polyclonally stimulated and non-stimulated CD4 and CD8 lymphocytes from 35 patients with CFS (CDC criteria '94) and control subjects by flow cytometry.
After polyclonal activation we found evidence of a significant bias towards Th2- and Tc2-type immune responses in CFS compared to controls. In contrast, levels of IFN-g, IL-2 and IL-10-producing cells were similar in both study groups. Non-stimulated cultures revealed significantly higher levels of CD4 and CD8 T cells producing IFN-γ or IL-4 in CFS patients.
Levels of CD4 cells producing IFN-g or IL-4 were correlated positively with each other in the CFS patients (r=.58, p=.0004) suggesting that they may be produced by the same subset of cells, or that the stimuli driving their induction are similar or related.
Ten patients had a concurrent psychiatric disorder but there was no differences in the immune parameters between those with and without. There was no significant relationship between the findings and fatigue (Chalder Fatigue Scale) or GHQ scores. (No other symptoms were measured, Ed.). There was no difference in IgE levels between patients and controls. (Allergic reactions are often reported and have been associated with a Th2 type of response.)
Concluding, we show evidence for an effector memory cell bias towards type 2 responsiveness in patients with CFS, as well as ongoing type 0 immune activation in unstimulated cultures of peripheral blood cells.
[Ed. note: The researchers did not assess viral infection, which could explain the findings. Moreover, they apparently did not compare those with a post-viral onset and those without. The tendency to limit the measurement of symptoms to tiredness and emotional distress means that significant associations may be overlooked.]
Liu, Z., Wang, D., Xue, Q., Chen, J., Li, Y., Bai, X and Chang, L. Determination of fatty acid levels in erythrocyte membranes of patients with chronic fatigue syndrome. Nutritional Neuroscience, 2003, 6, 6, 389-392.
Research from China. In this study, 42 patients with CFS (CDC criteria '88?) were compared to 37 age- and sex-matched controls, selected from healthy medical staffs and volunteers.
After lipid analysis, it was found that the levels of the arachidonic acid (ARA) and docosahexanoic acid (DHA) were decreased in patients suffered from CFS. However, the levels of the palmitic acid and oleic acid were increased.
The authors speculate that there are two possible mechanisms- one of which is that oxidative stress has led to an excessive oxidation and resulting in the above fatty acids. An insufficiency of ingestion of fatty acids was considered but not thought be the major cause. The results appear consistent with those of Behan et al (1990).
Roberts, ADL., Wessely, S., Chalder, T., Papadopoulos, A and Cleare, AJ. Salivary cortisol response to awakening in chronic fatigue syndrome. British Journal of Psychiatry, 2004, 184, 136-141.
There is accumulating evidence of hypothalamic-pituitary-adrenal (HPA) axis disturbances in CFS. The salivary cortisol response to awakening has been described recently as a non-invasive test of the capacity of the HPA axis to respond to stress. The results of this test correlate closely with those of more invasive dynamic tests reported in the literature; furthermore, it can be undertaken in a naturalistic setting.
Aims: To assess the HPA axis using the salivary cortisol response to awakening in CFS.
Method: We measured salivary cortisol upon awakening and 10, 20, 30 and 60 min afterwards in 56 patients with CFS (Oxford and CDC criteria '94) and 35 healthy volunteers. Among the measures were the Beck Depression Inventory and a report of hassles during the hour previous to testing.
Results: Patients had a lower cortisol response to awakening, measured by the area under the curve. There was no group difference on awakening itself. There was no effect of depression or smoking. However, the average scores for the BDI were high, as were those on the GHQ-12.
Conclusions: This naturalistic test of the HPA axis response to stress showed impaired HPA axis function in CFS.
[Ed. note: Chronic stress is associated with lower cortisol so the first test scores are of interest. There is no explanation for the high GHQ scores. There is no data relating to onset (e.g. acute postviral vs gradual, or of symptoms other than fatigue and emotional distress. A study on healthy individuals found that those given bright light therapy early in the morning (dawn simulation) showed higher cortisol levels than those in the control condition. Thorn, L et al. Proceedings of the BPS, 2004, 12, 1, 73. Exposure to light may therefore play a role in CFS too.]
Whistler, T., Unger, ER., Nisenbaum, R and Vernon, SD. Integration of gene expression, clinical, and epidemiologic data to characterize chronic fatigue syndrome. Journal of Translational Medicine, 2003, 1:10. Epub Dec 01, 2003.
The CFS research case definition recommends stratifying subjects by co-morbid conditions, fatigue level and duration, or functional impairment. But to date, this analysis approach has not yielded any further insight into CFS pathogenesis. This study used the integration of peripheral blood gene expression results with epidemiologic and clinical data to determine whether CFS is a single or heterogeneous illness.
Results: 23 patients with CFS (CDC criteria '94, 12 with gradual onset, 10 classed as 'obese') were studied. The majority of subjects clustered according to onset type and the genes fell into two distinct clusters. Expression of 19 of the 117 genes was increased in the gradual compared to sudden onset group, while the expression of the remaining 98 genes was decreased.
Twenty-four genes were associated with metabolism (p<0.01). Twenty of these genes were down-regulated in the gradual onset cluster, and they were mainly involved in regulation of glycolysis, glucose and disaccharide metabolism, oxidative phosphorylation, amino acid biosynthesis, and purine or pyrimidine metabolism. Of the 19 up-regulated genes, some were involved in metabolism, but they were not statistically significant. Interestingly, this is not the first time that type of fatigue onset has distinguished people with CFS.... Different gene expression profiles among those who describe a difference in illness onset imply distinct etiological or triggering events, and shows that these differences are maintained well into the disease process.
Conclusion: These results provide a physiologic basis that suggests CFS is a heterogeneous illness.
Kennedy, G., Abbot, NC., Spence, V., Underwood, C and Belch, JJF. The specificity of the CDC-1994 criteria for chronic fatigue syndrome: comparison of health status in three groups of patients who fulfill the criteria. Annals of Epidemiology, 2004, 14, 2, 95-100.
Purpose: The Centers for Disease Control (CDC)-1994 definition of CFS is very broad, and there have been suggestions that it lacks specificity. To test this, we have compared three groups of patients, all of whom fulfill the criteria but self-report different etiologies.
Methods: From a group of 104 individuals, patients with self-reported symptoms which developed sporadically (sCFS, n=48); after Gulf War service (GW, n=24); and following exposure to organophosphate insecticides (OP, n=25) underwent a clinical examination, completed the MOS SF-36 quality of life and Hospital Anxiety and Depression scales, and were assessed by a doctor for major and minor criteria for CDC-1994 CFS (scored 1-3).
Results: Significant differences in simple clinical measures and outcome measures were observed between groups. The GW group had significantly more severe physical symptoms-fatigue, muscle and multi-joint pain-than OP or sCFS, and the sCFS group was significantly less impaired than the other two groups in terms of role emotional and mental health. In all three groups, a majority of patients exhibited muscle weakness in the lower limbs (CFS: only 31% had normal scores), and significant numbers of patients had absent or abnormal reflexes (CFS: 44%). Physical functioning (MOS) scores were consistent with those for other medically ill populations. (None were above 60 and the CFS group was below 40).
Conclusions: Differences in simple, easily performed clinical outcome measurements can be observed between groups of patients, all of whom fulfill the CDC-1994 criteria for CFS. It is likely that their response to treatment may also vary. The specificity of the CFS case definition should be improved to define more homogeneous groups of patients for the purposes of treatment and research.
Reeves, WC., Lloyd, A., Vernon, SD., Klimas, N., Jason, L., Bleijenberg, G., Evengard, B., White, PD., Nisenbaum, R and Unger, ER. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Services Research, 2003 Dec 31 [Epub ahead of print].
Experienced investigators from around the world who are involved in CFS research met for a series of three day workshops in 2000, 2001 and 2002 intended to identify the problems in application of the current CFS case definition. The investigators were divided into focus groups and each group was charged with a topic. The investigators in each focus group relied on their own clinical and scientific knowledge, brainstorming within each group and with all investigators when focus group summaries were presented. Relevant literature was selected and reviewed independent of the workshops. The relevant literature was circulated via list-serves and resolved as being relevant by group consensus. Focus group reports were analyzed and compiled into the recommendations presented here.
Ambiguities in the current CFS research definition that contribute to inconsistent case identification were identified. Recommendations for use of the definition, standardization of classification instruments and study design issues are presented that are intended to improve the precision of case ascertainment. The International CFS Study Group also identified ambiguities associated with exclusionary and comorbid conditions and reviewed the standardized, internationally-applicable instruments used to measure symptoms, fatigue intensity and associated disability.
This paper provides an approach to guide systematic, and hopefully reproducible, application of the current case definition, so that case ascertainment would be more uniform across sites. Ultimately, an operational CFS case definition will need to be based on empirical studies designed to delineate the possibly distinct biological pathways that result in chronic fatigue.
From the text:
... CFS patients have an exaggerated fatigue response to previously well-tolerated activities and many report their fatigue is unusually sensitive to physical or mental exertion. Indeed, postexertional malaise lasting more than 24 hours is one of the accompanying symptoms that define CFS. Therefore, this requirement should be interpreted as referring to exhaustion unrelated to an excessively demanding schedule that would induce fatigue in an otherwise healthy adult.
The requirement that rest should not substantially alleviate the fatigue is also unclear. It was intended to exclude the type of fatigue associated with overwork that resolves when the excessive demands end. Most persons with CFS experience some alleviation of fatigue and accompanying symptoms if they rest, but this relief does not allow for recovery of pre-illness physical and mental stamina. Some CFS patients use resting as a strategy to avoid over-exertion and the attendant exacerbation of symptoms. Therapeutic use of rest or a partial response to rest should not exclude a subject's illness from classification as CFS.
[Note: See http://www.biomedcentral.com/content/pdf/1472-6963-3-25.pdf
[Ed. note: The recognition of the relationship between exertion and symptoms, the existence of post-exertional fatigue lasting more 24 hours and the value of rest is noteworthy. To date, few trials have examined the response of patients with true post-exertional fatigue to gradual increases in activity. The one study where activity was measured objectively (Prins et al) found no appreciable differences in activity levels following CBT. Though CBT may reduce tired-ness and emotional distress, there is as yet little evidence that those symptoms are either caused by a lack of activityor that increasing activity is effective in people with exertion-linked symptoms. Considering CFS as described above, i.e. where symptoms are triggered or exacerbated by trivial exertion, and given the dearth of evidence that deconditioning is significantly associated with CFS, advocating increases in activity seems to this author as rational as advising smokers with lung cancer to increase smoking. A positive response to increases in activity appears to conflict with the diagnosis of CFS although failure to upgrade post-exertional fatigue to a major criterion may perpetuate the confusion with other fatigue states. The discussion indicates a continuing difference in concepts e.g. compared with the experts advising the Canadians. There were no ME specialists involved in the drafting of the CDC document.]
Busichio, K., Tiersky, LA., Deluca, J and Natelson, BH. Neuropsychological deficits in patients with chronic fatigue syndrome. Journal of the International Neuropsychological Society, 2004, 278-285. [Epub ahead of print].
The degree of neuropsychological dysfunction across multiple domains was examined in individuals suffering from CFS. In this descriptive study, a similar series of neuropsychological tests was administered to a group of CFS patients and healthy participants. More specifically, CFS patients (n=141) who met the (modified) 1994 criteria were compared to 76 healthy control participants on tests of memory, attention (concentration), speed of information processing, motor speed, and executive functioning.
On the 18 measures administered, CFS patients scored 1 standard deviation below the healthy mean on nine measures and scored 2 standard deviations below the healthy mean on four of the measures. Moreover, results indicated that CFS patients were more likely than healthy controls to fail (1.6 SD below the healthy mean) at least one test in each of the following domains: attention, speed of information processing, and motor speed, but not on measures of memory and executive functioning. Finally, CFS patients demonstrated a greater total number of tests failed across domains.
Problems with memory were subtle and may reflect an information-processing rather than retrieval deficiency. The research in the lab shows that CFS patients do worse on tasks which require simultaneous processing, as well as complex information processing. There was no significant correlation between depression (BDI) and total cognitive failures.
Deluca, J., Christodoulou, C., Diamond, BJ., Rosenstein, ED., Kramer, N and Natelson, BH. Working memory deficits in chronic fatigue syndrome: differentiating between speed and accuracy of information processing. Journal of International Neuropsychological Society, 2004, 10, 1, 101-109.
To examine the relative influence of speed of information processing versus working memory ability, CFS participants with psychiatric comorbidity, current or since diagnosis (CFS-Psych, n=22) and CFS without a psychiatric history (CFS-noPsych, n=29) were examined on tests of visual and auditory processing speed and visual and auditory working memory.
Compared to healthy controls (HC, n=29) and a group of participants with rheumatoid arthritis (RA, n=18), the CFS-noPsych group displayed significantly reduced performance on tests of information processing speed, but not on tests of working memory. No significant differences were observed between the CFS-Psych group and any other group in the study.
The CFS group with no concurrent depression therefore displayed significant deficits in the speed of complex information processing. Relative to healthy controls, there was no evidence of cognitive impairment in patients with CFS plus a psychiatric condition. This is consistent with previous research. The researchers discuss earlier findings showing that the CFS-noPsych group had cerebral abnormalities on MRI while the CFS-Psych group did not (see also Costa et al 1995). These and other studies underline the heterogeneity of this population. The RA group, who also experience chronic pain and fatigue though no neurological impairments, showed no cognitive disorder.
[Ed. note: The study used the CDC criteria '94, but most also fulfilled the '88 guidelines.]
De Ridder, D., Leseman, P and de Rijk, A. Predicting the short-term cause of fatigue symptoms: does adjustment of habitual coping strategies matter? British Journal of Health Psychology, 2004, 9, 67-80.
Study on 221 patients with fatigue of at least two weeks duration. Measures included fatigue, Illness Management Questionnaire (Ray) and CES-D for depression. Testing was repeated six weeks later, primarily to assess predictors of fatigue.
Accommodating to the illness (incorporates pacing, Ed) was related to less fatigue at the later testing point, though not significantly except in those fatigued from 1-6 months. Ignoring fatigue ('maintaining activity') was significantly associated with increased fatigue, in those ill for 6-12 months. More chronic cases showed little influence of coping, but depression increased fatigue (12-24 months fatigue).
Powell, P., Bentall, RP, Nye, FJ and Edwards, RHT. Patient education to encourage graded exercise in chronic fatigue syndrome. 2-year follow-up of randomised controlled trial. British Journal of Psychiatry, 2004, 184, 142-146.
Background: An earlier trial demonstrated good outcomes after 1 year for patients with CFS (Oxford criteria, all ambulatory) who received an educational intervention designed to encourage graded activity.
Aims: To determine 2-year outcomes for the same treated patients and the response to treatment of patients formerly in the control condition.
Method: Patients in the treatment groups (n=114) were followed up at 2 years; 32 patients from the control group were offered the intervention after 1 year and were assessed 1 year later. Assessments were the self-rated measures used in the original trial.
Results: At 2 years, 63 of the treated patients (55%) no longer fulfilled the trial criteria for CFS compared with 64 patients (56%) at 1 year. Fourteen of 30 crossover patients (47%) achieved a good outcome at 1 year and seven (23%) no longer fulfilled criteria for CFS.
Conclusions: Benefits of the intervention were maintained at 2 years. Delaying treatment (as in the control group) is associated with reduced efficacy and required more intensive therapy.
[Ed. note: There is no evidence that any of the patients had an illness resembling ME. The average fatigue score in all groups was above 4, scores over 3 indicated "excessive fatigue". The lack of a significant group effect for the duration of treatment is noteworthy.]
Shin, HY., Shin, CH., Shin, TY., Lee, EJ and Kim, HM. Effect of bojungikki-tang on lipopolysaccharide-induced cytokine production from peripheral blood mononuclear cells of chronic fatigue syndrome patients. Immunopharmacology and Immunotoxicology, 2003, 25, 4, 491-501.
Bojungikki-tang (BIT) has been widely used to treat patients suffering from CFS. However, its effect has not been yet investigated experimentally. Based upon the clinical presentation of CFS, we hypothesized that cytokines may play a role in the pathogenesis of the disease. We studied the effect of BIT on lipopolysaccharide (LPS)-induced cytokines production in peripheral blood mononuclear cells (PBMC) of patients with CFS (CDC criteria '94).
Bojungikki-tang (1 mg/mL) significantly inhibited LPS-induced tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, transforming growth factor (TGF)-β1 production by 63.55%, 55.06%, 48.23%, 54.09%, respectively (p<0.05). Bojungikki-tang showed a slightly lower inhibitory effect of LPS-induced Interferon (IFN)-γ production. These results suggest that BIT may be useful in treating fatigue associated with chronic diseases.
The, GK., Prins, J., Bleijenberg, G and van der Meer, JW. The effect of granisetron, a 5-HT3 receptor antagonist, in the treatment of chronic fatigue syndrome patients - a pilot study. Netherlands Journal of Medicine, 2003, 61, 9, 285-289.
OBJECTIVE: To explore the effect of granisetron, a 5-HT3 antagonist, on fatigue and functional impairment in patients with CFS.
METHODS: Five female patients were eligible to receive oral granisetron for one month (1 mg a day for the first two weeks and 2 mg a day for the second two weeks). The patients had to be between 18 and 65 years of age and suffering from CFS according to the CDC criteria. The effect was assessed by pre- and post-testing, using validated instruments designed to assess the different dimensions of CFS. Treatment response was also evaluated by visual analogue scales (VAS) for fatigue.
RESULTS: Treatment with granisetron resulted in significant improvement in fatigue severity and functional impairment. Activity levels showed no significant increase.
CONCLUSION: The promising results of this study have encouraged us to perform a placebo-controlled, double-blind study to evaluate the efficacy of 5-HT3 receptor antagonists in the treatment of CFS.
Van Hoof, E., Coomans, D., De Becker, P., Meeusen, R., Cluydts, R and De Meirleir, K. Hyperbaric therapy in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2003, 11, 3, 37-49.
The aim of this study was to determine if hyperbaric oxygen treatment (HBOT) could be used as adjunctive therapy and if HBOT could increase the quality of life in such a way that the functional status would improve in patients with an infection. A randomized, controlled trial was conducted on 15 Mycoplasma sp. infected patients with CFS (CDC criteria '94) and 14 CFS patients with no evidence of a Mycoplasma infection [who] were enrolled in a convenience randomization sample from our referral clinic. No statistical differences were found by use of univariate repeated measures although Bodily Pain as measured by the SF-36 seems to decrease after hyperbaric therapy (p=.010).
Trends were found using paired t-testing for Mycoplasma infected CFS patients. The general perceived fatigue seemed to decrease after hyperbaric therapy (p=.06). Directly after one week of hyperbaric therapy, general fatigue improved (p=.03) but there was a reduction of activity (p=.05) and general perceived health (p=.04). One month later the physical role scores increased (p=.07). More marked improvements were found in the subset with mycoplasma.
Jones, JF., Nisenbaum, R and Reeves, WC. Medication use by persons with chronic fatigue syndrome: results of a randomized telephone survey in Wichita, Kansas. Health and Quality of Life Outcomes, 2003, 1:74. Epub Dec 02 2003.
Patients with CFS use a variety of prescribed and self-administered medications, vitamins, and supplements for relief of their symptoms. The objective of this study was to describe utilization of medications and supplements by persons with CFS and non-fatigued individuals representative of the general population of Wichita, Kansas.
Methods: We used a random-digit dialing telephone survey to identify persons with CFS in the general population of Wichita, Kansas. Subjects who on the basis of telephone interview met the CFS case definition, and randomly selected non-fatigued controls, were invited for a clinic evaluation that included self-reported use of medications and supplements.
Results: We clinically evaluated and classified 90 subjects as CFS during the study and also collected clinical data on 63 who never described fatigue. Subjects with CFS reported using 316 different drugs compared to 157 reported by non-fatigued controls. CFS subjects were more likely to use any drug category than controls (p=0.0009). Pain relievers and vitamins/supplements were the two most common agents listed by both groups. In addition CFS persons were more likely to use pain relievers, hormones, antidepressants, benzodiazepines, gastro-intestinal, and central nervous system medications (Sex-adjusted odds ratios range = 2.97-12.78).
Conclusion: Although the reasons for increased use of these agents were not elucidated, the data indicated the CFS patients' need for symptom relief.
[Ed. note: The full text of this article is available for free in PDF format at: http://www.hqlo.com/content/pdf/1477-7525-1-74.pdf]
Schmaling, KB., Fiedelak, JI., Katon, WJ., Bader, JO and Buchwald, DS. Prospective study of the prognosis of unexplained chronic fatigue in a clinic-based cohort. Psychosomatic Medicine, 2003, 65, 6, 1047-1054.
OBJECTIVES: To determine prospective changes in clinical status related to chronic fatigue over an 18-month period, and to test demographic and clinical predictors of outcome.
METHODS: A cohort of 100 patients with unexplained chronic fatigue (UCF), which encompasses both CFS and idiopathic chronic fatigue (ICF), completed questionnaire measures and medical and psychiatric evaluations on four occasions, each six months apart.
RESULTS: The response was good, with data for 86 patients at time 4. Approximately 21% of the sample did not meet criteria for either CFS (CDC criteria '94) or ICF at their last research appointment 1.5 years after their index visit. (93% were cases at the initial visit). Vitality increased over time, and physical functioning tended to improve, but UCF symptoms did not decrease significantly. Less education, being unemployed, worse mental health, more use of sedating and antidepressant medications, and more somatic attributions for their symptoms were associated with worsening symptom severity over time. Older age, current depression, and more somatic attributions predicted worsening physical functioning. Better mental health, less use of sedating medications, and fewer somatic attributions for illness were significant predictors of increases in vitality.
CONCLUSIONS: Demographic and clinical variables predict outcomes over time among a cohort of patients with unexplained chronic fatigue.
[Ed. note: physical functioning scores changed very little, from 43.5 (T1) to 49.4 (T4). It is not clear why. Vitality scores were also disappointing. The changes in those who improved may have counterbalanced the reverse changes in those who did not. At time 3, only 9 patients had improved. There is no data relating to virological or immunological status. The association between anti-depressants and poor outcome is significant. Sedating drugs were associated with more symptoms and less vitality.]
Baschetti, R. Chronic fatigue syndrome: an endocrine disease off limits for endocrinologists. European Journal of Clinical Investigation, 2003, 33, 12, 1029-1031.
Endocrinologists were not included in the multidisciplinary working groups that prepared two recent reports on CFS, despite its unequalled clinical overlap with Addison's disease, which is a classic endocrine disorder. The failure to include at least one endocrinologist in those panels may explain why in their extensive reports there is not a single word about the 42 clinical features that CFS shares with Addison's disease, including all the signs and symptoms listed in the case definition of this syndrome.
Fulle, S., Belia, S., Vecchiet, J., Morabito, C., Vecchiet, L and Fano, G. Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome. Neuromuscular Disorders, 2003, 13, 6, 479-484.
In CFS, several reported alterations may be related to specific oxidative modifications in muscle. Since sarcoplasmic reticulum membranes are the basic structures involved in excitation-contraction coupling and the thiol groups of Ca2+ channels of SR terminal cisternae are specific targets for reactive oxygen species, it is possible that excitation-contraction coupling is involved in this pathology. We investigated the possibility that abnormalities in this compartment are involved in the pathogenesis of CFS and consequently responsible for characteristic fatigue. The data presented here, from 4 patients with CFS (CDC criteria '88) and 3 patients with FM support this hypothesis and indicate that the sarcolemmal conduction system and some aspects of Ca2+ transport are negatively influenced in CFS.
In fact, both deregulation of pump activities (Na+/K+ and Ca2+-ATPase) and alteration in the opening status of ryanodine channels may result from increased membrane fluidity involving sarcoplasmic reticulum membranes.
Hokama, Y., Whang, C., Chun, KF., Suma, C., Higa, N., Or, BFW., Cocchetto, A and Kansky, G. Chronic phase lipids in sera of several chronic diseases reacting with MAB CTX (Antibody to Ciguatoxin). Journal of Toxicology: Toxin Reviews, 2003, 22, 4, 547-554.
The membrane immunobead assay results on the acetone lipid fraction of serum from CFS patients (60 samples) and normal individuals (with no clinical CFS or other disease symptoms) showed significant differences with 4 exceptions (4 normals showed 1:40 and 1:80 titres). This represented approximately 10.8% of the normal sam-ples, with 3 samples at 1:20, the majority of the CFS titred 1:40 through 1:160. This represented 95% of the samples. The small numbers of hepatitis patients and chronic ciguatera fish poisoning patients also had titres of 1:40 to 1:80 in all of the serum samples examined. The weights of the lipids in mg/ml serum essentially are very similar, except 1 or 2 of CFS and hepatitis B showed values at the upper level. Comparison of sexes showed 65% females and 35% men with CFS, representing a ratio of approximately 2:1 (female/male). It is concluded that certain disease conditions and environmental exposures to deleterious factors (toxin, chemicals, microorganisms) trigger the release of lipids (probably by the liver) with similar epitopes to ciguatoxin, and that they react with MAb CTX. We designate these lipids as chronic phase lipids comparable to acute phase protein in inflammatory and traumatic diseases.
Kennedy, G., Spence, V., Khan, F and Belch, JFF. Plasma endothelin-1 levels in chronic fatigue syndrome. Rheumatology (Oxford), 2004, 43, 252-253.
Letter responding to Pache et al (ibid, 2003, 42, 493) who found increased endothelin-1 (ET-1) levels in patients with a diagnosis of fibromyalgia syndrome (FMS) and concluded that elevated ET-1 levels might contribute to some of the apparent vascular disturbances that characterize the syndrome (see below). Pache et al. also discussed the apparent overlap between the clinical presentation of FMS, CFS and depression.
Kennedy et al note some of the differences, e.g. while many FMS patients experience fatigue, it has been estimated that only about one-fifth fulfil the specific criteria required for CFS.
"Our group has previously demonstrated that CFS patients have a significantly increased microcirculatory blood flow response to the endothelium-dependent vasodilator acetylcholine (ACh) but not to the endothelium-independent vasodilator sodium nitroprusside (SNP)-a unique phenomenon that we believe may be related to a disturbance of endothelial acetylcholinesterase expression in these patients. Similar experiments carried out by us on patients with FMS and matched control subjects failed to demonstrate any significant difference in either the ACh or SNP responses, nor did these patients show increased baseline vasoconstriction...
As part of an investigation into specific vascular risk factors in CFS, we have recently completed a study in our Vascular Diseases Research Unit on 47 patients who, on clinical examination", fulfilled the CDC 1994 criteria for CFS, "and 34 age- and sex-matched healthy controls... Supine blood pressure measurements were obtained after a standard rest period of 20 min. ET-1 levels were measured from a morning blood sample..."
No differences in plasma ET-1 levels were found between CFS patients and their control group (p=0.30). CFS patients had a mean ET-1 level of 0.49 pg/ml (range 0.11-1.02) and the control group had a mean ET-1 level of 0.44 pg/ml (range 0.16-0.92). "We also found no differences in blood pressure between CFS patients and control subjects. The mean and range for systolic blood pressure were 125 mmHg (90-198) in CFS patients and 123 mmHg (100-180) in controls (p=0.50); for diastolic blood pressure the results for CFS patients and control subjects were 74 mmHg (50-108) and 72 mmHg (50-88) respectively (p=0.36).
Taken together, these experimental data challenge the concept that CFS and FMS are part of the same spectrum of illness. Normal ET-1 levels in CFS patients in conjunction with an enhanced endothelial response to ACh may predispose these patients to abnormal cardiovascular responses to orthostatic challenge. While there have been reports of impaired activation of the hypothalamic-pituitary-adrenal (HPA) axis in both CFS and FMS patients that is clearly dissimilar to that seen in depression, caution is required about assuming that FMS and CFS are aetiologically analogous disorders of the stress response axis. Our results show no elevation of ET-1 in CFS, in contrast to the data of Pache et al."
With response by Pache et al (p. 253-4).
From the original letter by Pache et al:
The peptide endothelin-1 (ET-1), mainly produced by epithelial cells, is one of the most potent physiological vasoconstrictors known so far. Increased plasma levels of ET-1 could explain some of the above-mentioned symptoms of vascular dysregulation occurring in patients with FMS. Elevated ET-1 plasma levels have already been demonstrated in various other rheumatological diseases, such as rheumatoid arthritis, giant cell arteritis and lupus erythematosus. Therefore, in this study, we evaluated whether plasma ET-1 levels of patients with FMS differ from those of healthy controls...
Apart from its direct vasoconstrictive effect, ET-1 also increases the sensitivity of blood vessels to the action of other vasoconstrictive circulating hormones such as noradrenaline, serotonin and angiotensin II. In some vascular beds such as the heart and kidney, an increased production of ET-1 after tissue ischaemia has been demonstrated. As mentioned above, FMS patients frequently show a distinctive vascular cold-response. It is therefore conceivable that a repeated relative ischaemia due to a vascular dysregulation might increase the ET-1 levels in FMS patients. An elevated ET-1 level in turn might further enhance vasospasm, thereby creating a vicious circle.
Koelle, DM., Barcy, S., Huang, M-L., Ashley, RL., Corey, L., Zeh, J., Ashton, S and Buchwald, D. Markers of viral infection in monozygotic twins discordant for chronic fatigue syndrome. Clinical Infectious Diseases, 2002, 35, 518-525.
The researchers conducted a co-twin control study of 22 monozygotic twin pairs, of which one twin met the criteria for CFS and the other twin was healthy. Levels of antibodies to human herpesvirus (HHV)-8, cytomegalovirus, herpes simplex virus 1 and 2, and hepatitis C virus were measured. Polymerase chain reaction (PCR) assays for viral DNA were performed on PBMC cell specimens to detect infection with HHV-6, HHV-7, HHV-8, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, varicella zoster virus, JC virus, BK virus, and parvovirus B19. To detect lytic infection, plasma was tested by PCR for HHV-6, HHV-8, cytomegalovirus, and Epstein-Barr virus DNA, and saliva was examined for HHV-8 DNA. For all assays, results did not differ between the group of twins with CFS and the healthy twins.
[Ed. note: These results are consistent with other studies on broadly-defined CFS. There are no data for the percentage of patients with a post-viral onset, or symptoms suggestive of a post-viral syndrome.]
Full article at:
http://www.cfsresearch.org/cfs/research/viruses/15nf.htm
Le Bon, O., Minner, P., Van Moorsel, C., Hoffmann, G., Gallego, S.,Lambrecht, L., Pelc, I and Linkowski, P. First-night effect in the chronic fatigue syndrome. Psychiatry Research, 2003, 120, 2, 191-199.
Since the magnitude of the first-night effect has been shown to be a function of medical conditions and of settings in which polysomnographies are performed, it is essential to evaluate the habituation phenomenon in each case in order to determine the optimal recording methodology.
A first-night effect was evidenced in certain cases of CFS, but not in others. To clarify this issue, a large group of patients with CFS who had no primary sleep disorders were selected and recorded for two consecutive nights in a hospital sleep unit. Several parameters, frequently associated with the first-night effect, were found to be influenced by the recording methodology...
Factorial analysis grouped the difference scores into three factors. No significant difference was observed between patients with generalized anxiety comorbidity and those with no psychiatric co-morbidity, or between those with and without psychiatric comorbidity. CFS must thus be added on the list of conditions where a clinically significant habituation effect takes place.
Lim, BR., Tan, SY., Zheng, YP., Lin, KM., Park, BC and Turk, AA.Psychosocial factors in chronic fatigue syndrome among Chinese Americans: a longitudinal community-based study. Transcultural Psychiatry, 2003, 40, 3, 429-441.
For 57 Chinese American individuals initially diagnosed with CFS, those who recovered after one year reported lower levels of life stress than those who did not recover. Effects of changes in perceived social support also appeared to be mediated by life stress.
Murdoch, JC. Chronic fatigue syndrome: The patient centered clinical method - a guide for the perplexed. Australian Family Physician, 2003, 32, 883-887.
[Ed. note: Article reflecting the confusion about the concept of CFS, and the role of deconditioning (author suggests that it is a risk but without reference that anyone has actually found it to be a risk). Case history does not indicate typical CFS but the author implies that it is.]
Narita, M., Nishigami, N., Narita, N., Yamaguti, K., Okado, N., Watanabe, Y and Kuratsune, H. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochemical and Biophysical Research Communications, 2003, 311, 2, 264-266.
Interaction between the HPA axis and the serotonergic system is thought to be disrupted in CFS patients. We examined a serotonin transporter (5-HTT) gene promoter polymorphism, which affects the transcriptional efficiency of 5-HTT, in 78 CFS patients (CDC criteria '94) using PCR amplification of the blood genomic DNA. A significant increase of longer (L and XL) alleic variants was found in the CFS patients compared to the controls both by the genotype-wise and the allele-wise analyses (both p<0.05). Attenuated concentration of extracellular serotonin due to longer variants may cause higher susceptibility to CFS.
Pearson Murphy, BE., Abbott, FV., Allison, CM., Watts, C and Ghadirian, AM. Elevated levels of some neuroactive progesterone metabolites, particularly isopregnanolone, in women with chronic fatigue syndrome. Psychoneuroendocrinology, 2004, 29, 2, 245-268.
In this study we have explored the possibility that progesterone metabolites may be involved in CFS. Plasma levels of the progesterone precursor pregnenolone, progesterone itself, and five ring A-reduced metabolites of progesterone were measured in 20 women with CFS (CDC criteria '94) and in 13 age-matched (working full-time, so not sedentary) controls. To minimize the contribution of the ovary, women were either post-menopausal or in the follicular phase of the menstrual cycle (day 4-8), and progesterone levels were all well within the expected range (<3.5 nmol/l). (Two patients and 2 controls were taking oral contraceptives. 12 patients were taking anti-depressants. Ed.)
Mean values for progesterone and all of its metabolites were higher in CFS patients, the most marked being a 2.3-fold elevation in isopregnanolone (3β,5α-tetrahydroprogesterone; p<=0.001). Progesterone levels were correlated with those of its metabolites, but even after controlling for progesterone by ANCOVA, isopregnanolone levels were still elevated (p<0.001). These elevated levels of isopregnanolone could not be attributed to medications (anti-depressants and anxiolytics).
When the CFS patients were divided into two groups according to their Hamilton depression scale ratings, mean (+/-SD) isopregnanolone levels were higher (274+/-160 vs 197+/-119 pmol/l) in the less depressed group (ratings 2-14) than in the more depressed group (ratings 17-28), although this difference did not reach significance. Progesterone levels were negatively correlated with Hamilton depression rating scores (r=-0.56; p<0.01). These results suggest that increases in ring A-reduced progesterone metabolites, particularly isopregnanolone, are associated with CFS, and that the pathophysiology of CFS is unlikely to be due to depression.
Shor, S. Hypothesis paper: pathogenesis of chronic fatigue syndrome, a multisystem hypothesis. Journal of Chronic Fatigue Syndrome, 2003, 11, 3, 51-68.
This treatise explores the pathogenesis of CFS as it relates to a complex multidimensional systemic process and offers a hypothesis for the disease processes. In particular, an upregulated immune system, affecting mitochondrial dysfunction is described. These pathophysiologic mechanisms impact and in turn are being impacted by the neuroendocrine system and the HPA axis. In addition, the cardiovascular system involving blood pressure and heart rate anomalies along with neurocognitive pathology is characterized.
Sleigh, KM., Marra, FH and Stiver, HG. Influenza vaccination: is it appropriate in chronic fatigue syndrome? American Journal of Respiratory Medicine, 2002, 1, 1, 3-9.
Immunizing patients with CFS 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 118 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 ... 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 (n=21) and active groups (n=19) 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 (e.g. muscle aches, headaches).
...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 anti-body 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.
Zavestoski, S., Brown, P., McCormick, S., Mayer, B., D'Ottavi, M and Lucove, JC. Patent activism and the struggle for diagnosis: Gulf War illnesses and other medically unexplained physical symptoms in the US. Social Science & Medicine, 2004, 58, 161-175.
[Ed. note: This essay on medically unexplained symptoms is fair in relation to Gulf War illnesses but ill-informed and biased as far as CFS is concerned. The authors appear not to know the history of CFS, e.g. the fact that ME existed long before media attention and the internet.]
Wright, CC., Barlow, JH., Turner, AP and Bancroft, GV. Self-management training for people with chronic disease: an exploratory study. British Journal of Health Psychology, 2003, 8, 465-476.
Study examining efficacy of a self-management programme (psychoeducational) to enhance self-efficacy. Patients included 23% with ME. Other patients included people with diabetes, polio and endometriosis. They completed six weekly sessions, each lasting about 2 hours. Topics included self-management principles, exercise, pain management, nutrition, depression and communication with doctors and relatives.
There were small-moderate improvements on variables like fatigue, self-efficacy, communication with others etc. The four month follow-up indicated no changes in exercise behaviours, visiting GPs and specialists or male patients' anxiety and depression.
Nagelkirk, PR., Cook, DB., Peckerman, A., Kesil, W., Sakowski, T., Natelson, BH and LaManca JJ. Aerobic capacity of Gulf War veterans with chronic fatigue syndrome. Military Medicine, 2003, 168, 9, 750-755.
A large overlap exists between the diagnosis of CFS and the unexplained symptoms reported by many Gulf War veterans (GV). Previous investigations have reported reduced aerobic capacity in civilians with CFS. The present investigation examined metabolic responses to maximal exercise in GVs with CFS compared with healthy GVs.
Cardiorespiratory and metabolic responses were recorded during a maximal exercise test on a cycle ergometer. The groups were not different in any demographic category or self-reported physical activity.
No differences were observed between groups for maximal oxygen uptake, heart rate, exercise time, or workload achieved. Likewise, no differences were observed at sub-maximal intensities (p>0.05). Compared with healthy controls, GVs who report multiple medically unexplained symptoms and meet criteria for CFS do not show a decreased exercise capacity. Thus, it does not appear that the pathology of the GVs with CFS includes a deficiency with mobilizing the cardiopulmonary system for strenuous physical effort.
Taylor, RR, Jason, LA and Jahn, SC. Chronic fatigue and sociodemographic characteristics as predictors of psychiatric disorders in a community-based sample. Psychosomatic Medicine, 2003, 65, 896-901.
A stratified random sample of 18,675 adults residing in diverse neighborhoods in Chicago completed a telephone-screening questionnaire. A control group without chronic fatigue (n=74) and a group of individuals with chronic fatigue (n=227) were identified and administered a semi-structured psychiatric interview. Stepwise logistic regression analyses predicting occurrence of current and lifetime psychiatric disorders according to chronic fatigue status and sociodemographics were conducted on this overall sample of 301 participants.
Chronic fatigue, low socioeconomic status, and unemployment were among significant predictors of overall Axis I psychiatric disorders. Chronic fatigue functioned as a predictor for mood and anxiety disorders (including posttraumatic stress disorder), but did not function as a predictor for somatoform disorders, substance abuse/dependence, and eating disorders. Low socioeconomic status and unemployment were significantly associated with current psychiatric disorder, and low socioeconomic status was also significantly associated with mood and anxiety disorders. Women were significantly more likely to experience mood disorder, and minorities (eg, African Americans, Latinos, and individuals of other ethnicity) were significantly more likely to report posttraumatic stress disorder.
CONCLUSIONS: Results support prior findings for increased rates of psychiatric disorder among individuals with chronic fatigue and highlight the roles of low socioeconomic status, unemployment, being a woman, and being classified as a minority in their association with certain psychiatric disorders.
Torres-Harding, SR., Herrell, R and Howard, C. Epidemiological research: science and community participation. In LA Jason et al (Eds.). Participatory Community Research: Theories and Methods in Action. pp 53-59. Washington DC: APA. 2004.
Chapter describing study on CFS.
Turkington, D., Hedwat, D., Rider, I and Young, AH. Recovery from chronic fatigue syndrome with modafinil. Human Psychopharmacology- Clinical and Experimental, 2004, 19, 63-64.
Case report of a person with the symptoms of CFSwhere the fatigue improved on modafinil 2000 mcg mane.
Meirleir, K., CIuydts, R and Coomans, D. The symptoms and psychiatric status of the Bijlmermeer plane crash disaster: similarities with chronic fatigue syndrome and Gulf War Syndrome. Journal of Chronic Fatigue Syndrome, 2003, 11, 3, 3-21.
On October 4, 1992, the El Al Boeing crashed in the residential quarter 'Bijimermeer' in Amsterdam (The Netherlands). In the years after the plane crash, local residents and assistance personnel began reporting a variety of unusual symptoms not unlike those reported by patients with CFS and Gulf War Syndrome (GWS). The aim of this study was to define the symptom constellations reported by 22 patients and assess the possible causes of the illness. Standardized psychological questionnaires (MMPI-II, SCL-90, KPS and a complaints checklist) were used to screen for psychological changes and to describe the symptoms reported by the patients. Differences between local residents and assistance personnel, gender differences, Mycoplasma-infected and mycoplasma non-infected patients were monitored. The major symptoms reported were extreme fatigue, non-restorative sleep, concentration-problems, memory problems and muscle and joint pains. There were no changes in the SCL-90 responses that indicated any alteration of psychological distress. Assessment using the MMPI-II revealed a profile typically seen in chronic physical illness and assessment of the Harris-Lingoes scales revealed no elevations in pathogenic scales. Twelve subjects (67%) had a positive Mycoplasma PCR response. Victims of the Bijlmermeer plane crash disaster had increases in symptoms similar to patients with Gulf War Syndrome and CFS and no evidence of somatoform disorder, anxiety or depression. Similar to patients with Gulf War Syndrome and CFS, a deregulation of the imune-competence through a combination of toxic material exposure and psychological stressors associated with increased opportunistic infections may be the most likely etiological hypothesis.
Patarca-Montero, R. Chronic Fatigue Syndrome, Genes, and Infection. The Eta-1/Op Paradigm. NY: Haworth Press. 2003. Pb. 254 pp. $39.95.
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