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Lerner, AM., Beqaj, SH., Deeter, RG and Fitzgerald, JT. IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. In Vivo, 2004, 18, 2, 101-106.
A unique subset of patients with CFS and IgM serum antibodies to cytomegalovirus (HCMV) non-structural gene products p52 and CM2 (UL 44 and UL 57) has been described.
Fifty-eight patients with CFS (CDC criteria '88 and '94) and 68 non-CFS matched controls were studied. Serum antibodies to EBV viral capsid antigen (VCA) IgM and EBV Early Antigen, diffuse (EA, D) as well HVCMV(V), IgM and IgG; VP (sucrose, density purified V); p52 and CM2 IgM serum antibodies were assayed. Tests on the CFS patients were repeated every 6-12 weeks.
Mean age of CFS patients was 44 years (75% women). Control patients were 9 years older (73% women). Serum EBV VCA IgM positive antibody titers were identified in 33 CFS patients (Group A subset EBV VCA IgM 62.3+/-8.3, neg. <20), but were not present in other CFS patients, (group B subset, n=22, EBV VCA IgM 6.8+/-0.7) and controls: group C (50 random patients from a clinical laboratory) and group D (18 non-fatigued patients from a physician's practice, p<0.0001). EBV VCA IgM titers remained positive in CFS patients from Group A for 24-42 months. Serum EBV EA (D) IgG antibody titers were not different in the CFS groups and controls.
Serum antibody to EBV VCA IgM may be a specific diagnostic test for a second subset of CFS patients. "Except as reported in the CFS subset, EBV IgM VCA serum antibodies are not demonstrable in the general population and their 'presence' is virtually diagnostic of acute infection".
Schacterle, RS., Milford, EL and Komaroff, AL. The frequency of HLA Class II antigens in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2003, 11, 4, 33-42.
CFS is a condition characterized by unexplained, persistent fatigue in conjunction with other generalized symptoms. However, the patients as a group are more likely to have objective abnormalities of the immune system than control subjects. We measured the frequency of certain HLA antigens in a representative group of 35 patients (CDC criteria '94). We restricted our analysis to class II molecules as these appear to be more specific predictors of susceptibility to immunologically-based disorders.
The frequency of the HLA-DQ1 antigen was increased in patients compared to general population Caucasian controls. This association between CFS and the HLA-DQ1 antigen translates into a relative risk of 3.2. This association has not been reported previously in CFS. Differences in the ethnic sub-grouping of patients in this study and in previous studies also could have contributed to the difference between our findings and those of previous investigators. Conversely, this study did not find HLA associations that have been reported by previous studies. There was no clear HLA association with fibromyalgia (FM). The sample size of this study could have led to type II statistical errors and a failure to recognize certain HLA associations as significant.
De Lange, FP., Kalkman, JS., Bleijenberg, G., Hagoort, P., vd Werf, SP., van der Meer, JWM and Toni, I. Neural correlates of the chronic fatigue syndrome - an fMRI study. Brain, 2004 Jul 7 [Epub ahead of print]
Patients who suffer from CFS report a variety of physical complaints as well as neuropsychological complaints. Therefore, it is conceivable that the CNS plays a role in the pathophysiology of CFS. The purpose of this study was to investigate neural correlates of CFS, and specifically whether there exists a linkage between disturbances in the motor system and CFS.
We measured behavioural performance and cerebral activity using rapid event-related functional MRI in 16 CFS patients (CDC criteria '94, no depression) and 16 matched healthy controls while they were engaged in a motor imagery task and a control visual imagery task.
CFS patients were considerably slower on performance of both tasks, but the increase in reaction time with increasing task load was similar between the groups. Both groups used largely overlapping neural resources. However, during the motor imagery task, CFS patients evoked stronger responses in visually related structures. Furthermore, there was a marked between-groups difference during erroneous performance.
In both groups, dorsal anterior cingulate cortex was specifically activated during error trials. Conversely, ventral anterior cingulate cortex was active when healthy controls made an error, but remained inactive when CFS patients made an error. Our results support the notion that CFS may be associated with dysfunctional motor planning. Furthermore, the between-groups differences observed during erroneous performance point to motivational disturbances as a crucial component of CFS.
Crofford, LJ., Young, EA., Engleberg, NC., Korszun, A., Brucksch, CB., McClure, LA., Brown, MB and Demitrack MA. Basal circadian and pulsatile ACTH and cortisol secretion in patients with fibromyalgia and/or chronic fatigue syndrome. Brain, Behavior and Immunology, 2004, 18, 4, 314-325.
The objective of this study was to evaluate and compare the basal circadian and pulsatile architecture of the HPA axis in groups of patients with fibromyalgia syndrome (FMS), CFS, or both syndromes with individually matched control groups. Forty patients with either FMS (n=13), FMS and CFS (n=12), or CFS (CDC criteria '94, n=15) were matched by sex, age (18-65) and menstrual status to healthy (sedentary) controls. Subjects were excluded if they met criteria for major Axis I psychiatric disorders by structured clinical interview (SCID). Subjects were admitted to the General Clinical Research Center where meals and activities were standardized. Blood was collected from an intravenous line every 10min over 24h for analysis of ACTH and cortisol. Samples were evaluable for ACTH in 36 subject pairs and for cortisol in 37 subject pairs.
Patients with CFS had lower cortisol levels than controls between 5 and 7.00 am. (20% had an anxiety disorder). The depressed cortisol levels were not seen in those with FM alone. There was a significant delay in the rate of decline from acrophase to nadir for cortisol levels in patients with FMS (p<.01). Elevation of cortisol in the late evening quiescent period was evident in half of the FMS patients compared with their control group, while cortisol levels were numerically, but not significantly, lower in the overnight period in patients with CFS compared with their control group. Pulsatility analyses did not reveal statistically significant differences between patient and control groups.
Raised cortisol levels were associated with raised ACTH levels.
We conclude that the pattern of differences for basal circadian architecture of HPA axis hormones differs between patients with FMS and CFS compared to their matched control groups. The abnormalities in FMS patients are consistent with loss of HPA axis resiliency.
Naschitz, JE., Yeshurun, D and Rosner, I. Dysautonomia in chronic fatigue syndrome: facts, hypotheses, implications. Medical Hypotheses, 2004, 62, 2, 203-206.
There is increasing evidence that dysautonomia occurs in CFS manifest primarily as disordered regulation of cardiovascular responses to stress. We impart our experience relating to diagnosis, monitoring, and treatment of CFS based on identification and management of dysautonomia. Recently proposed methods for assessment of the cardiovascular reactivity, the 'hemodynamic instability score' (HIS) and the 'Fractal and Recurrence Analysis-based Score' (FRAS), served for this purpose.
On HUTT, a particular dysautonomia is revealed in CFS patients that differ from dysautonomia in several other disorders. This distinct abnormality in CFS can be identified by HIS and FRAS. Therefore, the HIS and FRAS may be used, in the appropriate clinical context, to support the diagnosis of CFS, which until now, could only be subjectively inferred.
A pilot study suggested that midodrine treatment, directed at the autonomic nervous system in CFS, results first in correction of dysautonomia followed by improvement of fatigue. This finding implies that dysautonomia is pivotal in the pathophysiology CFS, at least in a large part of the patients, and that manipulating the autonomic nervous system may be effective in the treatment of CFS.
Whiteside, A., Hansen, S and Chaudhuri, A. Exercise lowers pain threshold in chronic fatigue syndrome. Pain, 2004, 109, 3, 497-499.
Post-exertional muscle pain is an important reason for disability in patients who are diagnosed to have CFS. We compared changes in pain threshold in five CFS patients (CDC criteria '94) with five age and sex matched controls following graded exercise. All pain related treatment and antidepressants with analgesic effects were withdrawn 48 hours before testing and subjects were asked not to undertake physical exertion for 24 hours prior to the investigation. The exercise consisted of three 5-minute periods on a treadmill, set to a speed of 5 km h-1, with an increasing incline of 5, 10 and 15. at each stage of the graded exercise test.
Pain thresholds, measured in the skin web between thumb and index finger, increased in control subjects with exercise while it decreased in the CFS subjects. Increased perception of pain and/or fatigue after exercise may be indicative of a dysfunction of the central anti-nociceptive mechanism in CFS patients.
Cleare, AJ., O'Keane, V and Miell, JP. Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome. Psychoneuroendocrinology, 2004, 29, 6, 724-732.
An association between CFS and abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis has been described, and other adrenal steroid abnormalities have been suggested. Dehydroepiandrostenedione (DHEA) and its sulphate (DHEA-S), apart from being a precursor of sex steroids, have other functions associated with memory, depression and sleep. It has been suggested that CFS may be associated with a state of relative DHEA(-S) deficiency. Therefore we investigated basal levels of DHEA(-S), the cortisol/DHEA molar ratio and the responsiveness of DHEA to stimulation by corticotrophin releasing hormone (CRH). Recent studies have also suggested that low dose hydrocortisone may be effective at reducing fatigue in CFS. We therefore also assessed these parameters prior to and following treatment with low dose oral hydrocortisone.
Basal levels of serum DHEA, DHEAS and cortisol were measured in 16 patients with CFS (Oxford and CDC criteria '94) without depression and in 16 healthy controls matched for age, gender, weight, body mass index and menstrual history. CRH tests were carried out on all subjects and DHEA measured at 0, +30 and +90 min. In the patient group, CRH tests were repeated on two further occasions following treatment with hydrocortisone (5 or 10 mg, PO) or placebo for 1 month each in a double-blind cross over study protocol.
Basal levels of DHEA were higher in the patient group compared to the controls (p=0.04), while levels of DHEAS in patients were not different from controls. Higher DHEA levels were correlated with higher disability scores. Basal cortisol levels were higher in patients, and consequently the cortisol/DHEA molar ratio did not differ between patients and controls. Levels of DHEA (p=0.015) and DHEAS (p=0.03) were lower in patients following treatment with hydrocortisone. There was a rise in DHEA responsiveness to CRH in the patients after treatment but this did not attain significance (AUC(c) pre vs post-hydrocortisone). However, those patients who responded fully to hydrocortisone in terms of reduced fatigue scores did show a significantly increased DHEA responsiveness to CRH (AUC(c): baseline vs post-treatment, p=0.029).
DHEA levels are raised in CFS and correlate with the degree of self-reported disability. Hydrocortisone therapy leads to a reduction in these levels towards normal, and an increased DHEA response to CRH, most marked in those who show a clinical response to this therapy.
Gur, A., Cevik, R., Nas, K., Colpan, L and Sarac, S. Cortisol and hypothalamic-pituitary-gonadal axis hormones in follicular-phase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these hormones. Arthritis Research and Therapy, 2004, 6, 3: R232-R238
We investigated abnormalities of the hypothalamic-pituitary-gonadal axis and cortisol concentrations in women with FM and CFS who were in the follicular phase of their menstrual cycle, and whether their scores for depressive symptoms were related to levels of these hormones. A total of 176 subjects participated - 46 healthy volunteers, 68 patients with FM, and 62 patients with CFS (CDC criteria '94, no comorbid psychiatric disorders). We examined concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, prolactin, and cortisol (all am). Depressive symptoms were assessed using the Beck Depression Inventory (BDI).
Cortisol levels were significantly lower in patients with FM or CFS than in healthy controls (p<0.05); there were no significant differences in other hormone levels between the three groups.
FM patients with high BDI scores had significantly lower cortisol levels than controls (p<0.05), and so did CFS patients, regardless of their BDI scores (p<0.05). Among patients without depressive symptoms, cortisol levels were lower in CFS than in FM (p<0.05). Our study suggests that in spite of low morning cortisol concentrations, the only abnormalities in hypothalamic-pituitary-gonadal axis hormones among follicular-phase women with FM or CFS are those of LH levels in FM patients with a low BDI score. Depression "may lower cortisol" and LH levels, or, alternatively, low morning cor-tisol may be a biological factor that contributes to depressive symptoms in FM. These parameters therefore must be taken into account in future.
Carrico, AW., Jason, LA., Torres-Harding, SR and Witter, EA. Disability in chronic fatigue syndrome and idiopathic chronic fatigue. Review of Disability Studies, 1, 1, 79-88.
The current investigation classified 31 people with CFS (CDC criteria '94) and 44 people with idiopathic chronic fatigue (ICF) into mild, moderate, and severe/very severe categories of self reported functional impairment. Differences in sociodemographic characteristics, symptom frequency, symptom severity, and functional impairment were examined between individuals with CFS and ICF, and were examined among the three categories of functional impairment.
Impairment was assessed with three measures: the MOS-SF (giving global scores for physical and mental impairment), and scales of impairment in daily activities (0-100) while the impact of fatigue scale (1-7) was used to classify patients into groups according to severity.
Results indicated that there were no differences between the CFS and ICF groups in their functional impairment classification (mild/moderate/severe). However, there were differences between the mild/moderate and severe groups for the MOS physical composite score and self-rated impairment of daily activities (p<.01).
People who were classified into the more disabled categories also reported more severe symptoms. There were no group differences in levels of fatigue (Chalder scale) or for headaches. However, the less affected patients reported less post-exertional fatigue.
[Ed. note: Patients classified as mild were still able to work full-time. This may not be consistent with the requirement in the 1994 guidelines in relation to the effect of fatigue on severity or occupational activities.]
Jones, JF., Nisenbaum, R., Solomon, L., Reyes, M and Reeves, WC. Chronic fatigue syndrome and other fatiguing illnesses in adolescents: a population-based study. Journal of Adolescent Health, 2004, 35, 1, 34-40.
PURPOSE: To estimate the prevalence of CFS and describe characteristics of other fatiguing illnesses in adolescents (aged 12 through 17 years).
METHODS: We conducted a random digit dialing survey of the residents of Wichita, Kansas. Adults identified fatigued adolescents in the household and answered questions relating to the child's health. Selected adolescents were invited to attend a clinic with a parent/guardian. After clinical evaluation they were classified as CFS or another fatigue state as defined in the 1994 CFS definition. Annual telephone interviews and clinical evaluations monitored subjects' fatigue status.
RESULTS: The survey contacted 34,018 households with 90,316 residents. Of 8586 adolescents, 138 had fatigue for >=1 month and most (107 or 78%) had chronic fatigue (>=6 months) at some point during the 3-year follow-up. Twenty-eight had exclusionary diagnoses. Thirty-one were considered to have a CFS-like illness and were invited for clinical evaluation. Eleven agreed to participate but none met the CFS case definition.
The baseline weighted prevalence of CFS-like illness was 338 per 100,000. Significant differences existed between parental and adolescents' descriptions of illness. There were also differences in symptoms between the CFS-like and CF groups e.g. in the percentage with fatigue not alleviated by rest.
CONCLUSIONS: The prevalence of CFS among adolescents was considerably lower than among adults. Evaluation of CFS in adolescents must consider both parent and patient perception of fatigue and other illnesses that might explain the symptom complex.
Boye, B., Malt, EA., Heldal, A., Dahlstrom, A., Lundin, K and Malt UF. Selective monocyte and granulocyte apheresis as a possible new treatment for chronic fatigue syndrome. Journal of Psychosomatic Research, 2004, 56, 6, 633.
Immune dysfunction in patients with CFS has been widely reported, and in some patients you may find cytokine abnormalities that in-clude perturbations in plasma levels of proinflammatory cytokines and decrease in the ratio of Type I to Type 2 cytokines produced by lymphocytes in vitro. Selective monocyte and granulocyte apheresis (M-GCAP) is a device that is approved for treatment of certain immune disorders in Europe and Japan, and the treatment has been shown to normalize cytokine imbalance and improve symptoms in disorders as inflammatory bowel disorders, rheumatoid arthritis, Bechet disease and cancer. Many CFS patients do not respond to medical or behavioral therapy, and new treatment options are needed for the severely affected patients with chronic disability.
The primary objective was to evaluate therapeutic efficacy of M-GCAP in patients with CFS. The secondary objective was to assess abnormalities in cytokine balance and changes in these markers after treatment.
We aim at including patients with CFS assumed to be related to a previous infection. The patients do not have major psychopathology explaining the symptoms. All will be nonresponders to different treatment efforts. Each patient receives one M-GCAP session per week for five consecutive weeks. The duration of one M-GCAP session is 60 minutes, flow rate 30 mL per minute. The outcome of the treatment is assessed 2 weeks and 7 weeks after the end of treatment. Changes in chronic fatigue symptoms measured by Chronic Fatigue Scale and somatic symptoms is the primary efficacy variable.
Clinical observation and assessment of vital signs (heart rate, blood pressure, and body temperature) for the first 4 patients (January 2004) indicated that the patients showed greater autonomic instability than other patient groups that have received this treatment. The study still recruits patients. The results regarding clinical improvement and cytokine balance alterations of the whole group will be presented at the meeting.
Naschitz, J., Dreyfuss, D., Yeshurun, D and Rosner, I. Case Report: Midodrine treatment for chronic fatigue syndrome. Postgraduate Medical Journal, 2004, 80, 230-232.
The long term results of midodrine treatment in a patient having debilitating CFS (CDC criteria '94) are reported. Midodrine treatment (starting with 2.5 mg bd to 10 mg per day), directed at the autonomic nervous system, resulted in correction of the dysautonomia followed by improvement of fatigue. Stopping medication led to a return of the fatigue.
This finding is consistent with the hypothesis that dysautonomia plays a major part in the pathophysiology of CFS and that therapies directed at the autonomic nervous system may be effective in the treatment of CFS.
Puri, BK., Holmes, J and Hamilton, G. Eicosapentaenoic acid-rich essential fatty acid supplementation in chronic fatigue syndrome associated with symptom remission and structural brain changes. International Journal of Clinical Practice, 2004, 58, 3, 297-299.
Lateral ventricular enlargement has been reported in CFS, while cerebral neurospectroscopy has recently indicated that essential fatty acid treatment may be of value in this condition.
An essential fatty acid supplement rich in eicosapentaenoic acid (EPA) was therefore given daily to a female patient with a 6-year history of unremitting symptoms of CFS. Cerebral magnetic resonance scanning was carried out at baseline and 16 weeks later. The EPA-rich essential fatty acid supplementation (Eye q, five caps bd) led to a marked clinical improvement in her symptoms of CFS, starting within 6-8 weeks. However, there was no reduction in muscle pain.
Accurate quantification of the lateral ventricular volumes in the baseline and 16-week follow-up registered images of high-resolution magnetic resonance imaging structural scans showed that the treatment was accompanied by a marked reduction in the lateral ventricular volume during this period, from 28,940-23,660 mm3. The authors note that EFAs have "direct anti-viral actions".
Viner, R., Gregorowski, A., Wine, C., Bladen, M., Fisher, D., Miller, M and El Neil, S. Outpatient rehabilitative treatment of chronic fatigue syndrome (CFS/ME). Archives of Diseases in Childhood, 2004, 89, 7, 615-619.
Aims: To assess the outcome of outpatient multidisciplinary rehabilitative treatment (graded activities/exercise programme, family sessions) compared with supportive care alone (with advice on pacing, symptom control and school reintragration) for children and adolescents with CFS/ME.
Methods: Fifty six young people (aged 9-17 years) with CFS/ME by standard 1994 criteria (min duration three months) were followed up for 3-24 months. All subjects received supportive care. Families additionally opted to either enter the rehabilitation programme (supportive care plus graded activities/exercise programme and family sessions) or have no additional treatment.
Results: Twenty two (39%) subjects had supportive care alone and 26 (46%) entered the programme. Treatment groups were comparable at baseline in terms of age, severity and duration of illness, Wellness score, and school attendance. At end of follow up, those in the programme group had significantly higher Wellness scores and school attendance than those having supportive care alone. The programme significantly reduced the overall severity of illness: after the programme, 43% had complete resolution of CFS/ME compared to only 4.5% of those having supportive care alone. The presence of depressed mood and family beliefs about the aetiology of CFS/ME were not significantly associated with outcomes. Positive outcome was correlated with a shorter duration of illness.
Conclusions: Outpatient rehabilitative treatment offers significant potential to improve the prognosis of CFS/ME in childhood and adolescence.
[Ed. note: Little is known about the type of symptoms experienced, e.g. neurological problems, immune related symptoms. There was no objective measure of activity.]
Wallman, KE., Morton, AR, Goodman, C., Grove, R and Guilfoyle, AM. Randomised controlled trial of graded exercise in chronic fatigue syndrome. Medical Journal of Australia, 2004, 180, 9, 444-448.
Objective: To investigate whether 12 weeks of graded exercise with pacing would improve specific physiological, psychological and cognitive functions in people with CFS (CDC criteria '94).
Design: Randomised controlled trial.
Setting: Human performance laboratory at the University of Western Australia.
Participants: 61 patients with CFS aged between 16 and 74 years, six of whom had had major depression in the previous six months. Two had dysthymia.
Interventions: Either graded exercise with pacing (32 patients) or relaxation/flexibility therapy (29 patients) performed twice a day over 12 weeks. Pacing meant that if patients relapsed, or the symptoms worsened, they could cancel or shorten the next exercise session.
Main Outcome Measures: Changes in any of the physiological, psychological or cognitive variables assessed.
Results: Following the graded exercise intervention, scores were improved for resting systolic blood pressure (p=0.018), work capacity (W.kg-1) (p=0.019), net blood lactate production (p=0.036), depression (p=0.027) and performance on a modified Stroop Colour Word test (p=0.029).
Rating of perceived exertion scores, associated with an exercise test, was lower after graded exercise (p=0.013). No such changes were observed in the relaxation/flexibility condition, which served as an attention-placebo control. The greatest reductions were for mental fatigue and depression. The mean scores for physical fatigue were 8.1 and 9.6 respectively (p=0.074).
91% of the exercise group rated themselves as better, as did 76% of the controls. No one in the exercise rated themselves as worse.
Conclusions: Graded exercise was associated with improvements in physical work capacity, as well as in specific psychological and cognitive variables. Improvements may be associated with the abandonment of avoidance behaviours.
With editorial by Lloyd, A, p 437-438.
[Ed. Note: There is no data on symptom other than fatigue and emotional distress and there were no objective measures of activity. Levels of physical fatigue at baseline were modest (11.6 and 11.4 where the maximum score is 21).]
Bobo, WV and Hall, WC. On chronic fatigue syndrome. American Journal of Psychiatry, 2004, 161, 6, 1132-1133.
Letter responding to Afari and Buchwald (ibid, 2003, 160, 2, 221) describing a patient who benefited from modafinil 200 mg/day.
See also Berger, J (p. 1133), arguing that CFS is a functional somatic syndrome, and that patient groups are often ill-informed. With reply from Afari and Buchwald (p. 1133-1134), focusing on the uncertainties surrounding this condition.
Chatterjee, T. Chronic fatigue syndrome or myalgic encephalomyelitis in children and adolescents. Journal of the Indian Medical Association, 2003, 101, 9: 544.
Very short summary of the illness, prognosis and treatment.
Farmer, A., Fowler, T., Scourfield, J and Thapar, A. Prevalence of chronic disabling fatigue in children and adolescents. British Journal of Psychiatry, 2004, 184, 477-481.
Study using information from parents of twins, focusing on chronic fatigue in 8-17 year olds, identified 1.29% who had ever had symptoms "resembling operationally defined" CFS. None of the parents attributed the fatigue of the child to CFS or ME. Children were not medically examined or interviewed.
[Ed. note: Results were based on questionnaires and telephone interviews. Medical examinations in other studies have found that up to a half of those with CFS-like symptoms have medical and psychiatric conditions which are inconsistent with a diagnosis of CFS. This should be taken into account when interpreting the above findings.]
Huibers, MJH., Kant, IJ., Swaen, GMH and Kasl, SV. Prevalence of chronic fatigue syndrome-like caseness in the working population: results from the Maastricht cohort study. Occupational and Environmental Medicine, 2004, 61, 464-466
Aim: To determine the prevalence of CFS-like caseness in the working population.
Methods: Using data from the prospective Maastricht Cohort Study on Fatigue at Work, the prevalence and incidence of CFS-like cases (employees meeting research criteria for CFS) were determined among 5499 employees who responded to the follow up assessment 3 years and 8 months after baseline. One of the criteria used was a score on the MOS-SF36 physical functioning subscale of 60 or lower. The mean was 44.
Results: Of the 5499 employees, 199 (3.6%) were identified as CFS-like cases. By deleting possible CFS-like cases at baseline, the annual incidence of CFS-like caseness was estimated to be 85 per 10000. Twenty employees (0.36%) reported having been diagnosed with CFS by a physician.
Conclusions: The prevalence of CFS-like cases (3.6%) was considerably higher than the prevalence of CFS reported in previous studies (0.006-3%)*. These findings suggest that the CFS-like caseness may be underdetected in the working population and perhaps in other populations as well.
*[Ed. note: According to Jason, the higher rate may be due to the lack of a medical examination to exclude other conditions, plus the use of broad interpretation of the 1994 criteria.]
Jason, LA., Holbert, C., Torres-Harding, S., Taylor, RR., Le Vasseur, JJ., Breitinger, P., LaBarbera, D and Siegel, L. Chronic fatique syndrome versus neuroendocrineimmune dysfunction syndrome: differential attributions. Journal of Health & Social Policy, 2004, 18, 1, 43-55.
Since 1988, when the term CFS was coined, considerable discussion has occurred about stigma associated with this diagnostic term. In particular, patients with CFS have felt that this term trivializes the serious nature of this disorder.
A Name Change Work group, appointed by the CFS Coordinating Committee, developed an umbrella term: chronic neuroendocrineimmune dysfunction syndrome (CNDS), and proposed that there would be sub-types under this term, one being CFS. The present study examined attributions of this new umbrella term when compared with CFS. 208(?) Nurses and physician assistants (PAs) were presented a case study of a patient with symptoms of CFS. They were told that the patient had either CFS, chronic neuroendocrineimmune dysfunction syndrome, or chronic neuroendocrineimmune dysfunction syndrome, which had formerly been called CFS. The different terms led to different attributions, with PA respondents rating the CNDS label as more severe.
Results suggest that a more medical sounding term (CNDS) may lead to attributions that this syndrome is a more serious, disabling illness. The policy implications of these findings are discussed.
Mahurin, RK., Claypoole, KH., Goldberg, JH., Arguelles, L., Ashton S and Buchwald, D. Cognitive processing in monozygotic twins discordant for chronic fatigue syndrome. Neuropsychology, 2004, 18, 2, 232-239.
Twenty-one pairs of monozygotic twins discordant for CFS and 21 matched healthy control (HC) subjects were assessed with 5 untimed tests and 5 timed tests from the computer-based NeuroCognitive Assessment Battery. Random effects regression showed no difference between CFS and healthy twins on any of the cognitive tests. Further, the twin groups did not differ from the HC group on any content-dependent measure.
In contrast, both sets of twins performed worse than the HC group on all speed-dependent tests except Finger Tapping. Self-rated fatigue and dysphoric mood were only weakly correlated with cognitive performance. These data point toward a shared genetic trait related to information processing that is manifest in the CFS context. The findings have implications for differentiating genetic and acquired vulnerability in the symptomatic expression of the disorder.
Nijs, J., De Meirleir, K., Meeus, M., McGregor, NR and Englebienne, P. Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Medical Hypotheses, 2004, 2, 5, 759-765.
The exacerbation of symptoms after exercise differentiates CFS from several other fatigue-associated disorders. Research data point to an abnormal response to exercise in patients with CFS compared to healthy sedentary controls, and to an increasing amount of evidence pointing to severe intracellular immune deregulations in CFS patients. This manuscript explores the hypothetical interactions between these two separately reported observations. First, it is explained that the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduction of maximal oxygen uptake, as typically seen in CFS patients.
Second, the activation of the protein kinase R enzyme, a characteristic feature in at least subsets of CFS patients, might account for the observed excessive nitric oxide (NO) production in patients with CFS. Elevated NO is known to induce vasodilation, which may limit the capacity to increase blood flow during exercise, and may even cause and enhance postexercise hypotension. Finally, it is explored how several types of infections, frequently identified in CFS patients, fit into these hypothetical pathophysiological interactions.
Nijs, J., Vaes, P., McGregor, N., Lambrecht, L., Van Hoof, E and De Meirleir, K. Comparison of activity limitations/participation restrictions among Fibromyalgia and Chronic Fatigue Syndrome patients. Journal of Chronic Fatigue Syndrome, 2003, 11, 4, 3-18.
FM and CFS are related yet overlapping disorders; the current case definitions prohibit a clear-cut differential diagnosis. These diagnostic criteria mainly address the impairment level of the World Health Organization's International Classification of Functioning, Disability and Health. This study aimed at comparing activity limitations and participation restrictions in patients with FM (n=90) and CFS (CDC criteria 94, n=47). The Chronic Fatigue Syndrome Activities and Participation Questionnaire (CFS-APQ) was used for assessing functionality in both groups. The convergent validity of the scores obtained with the questionnaire with visual analogue scales for pain, fatigue and concentration was investigated in FM patients, as well as the content validity.
No differences in total scores and 25 out of 26 individual items on the CFS-APQ were observed between the 2 groups. This sample of FM patients reported to be more disabled in 'sitting for two hours' as compared to the CFS group (p=.004). Four hundred and thirty-seven of the 497 (87.9%) responses to the request to list difficult activities matched the content of the CFS-APQ. The overall scores of the CFS-APQ correlated statistically significant in respect to visual analogue scales for pain and concentration (Spearman rho for the total scores ranged between .44 and .49).
These data question the disease specificity of the CFS-APQ for CFS, but suggests its applicability in 'the Chronic Pain-Fatigue Syndromes.' The present report provides evidence for both the content and convergent validity of the CFS-APQ in FM patients.
Nijs, J., De Meirleir, K and Truyen, S. Hypermobility in patients with chronic fatigue syndrome: preliminary observations. Journal of Musculoskeletal Pain, 2004, 12, 1, 9-17.
The present report aims at examining 1. the prevalence of generalized hypermobility in patients with CFS; 2. whether hypermobile CFS patients experience more pain and have more severe activity limitations/participation restrictions compared to non-hypermobile CFS patients; and 3. whether the history of widespread pain is indicative of generalized hypermobility in patients with CFS.
Forty-four consecutive patients with CFS filled in the Chronic Fatigue Syndrome Activities and Participation Questionnaire (CFS-APQ) for the assessment of activity limitations/ participation restrictions, rated three visual analogue scales (for pain, myalgia, and arthralgia), were screened for generalized hypermobility according to the Beighton et al. (1973) criteria, and were questioned about muscle and joint aches.
Eleven of the 44 (25%) subjects met the criteria for generalized hypermobility. The Spearman Rank correlation analysis did not reveal statistically significant correlations between the Beighton et al. scores and any of the self-reported measures. No statistically significant differences in pain severity and activity limitations/participation restrictions were observed between hypermobile (n=11) and nonhypermobile (n=33) patients with CFS. The positive likelihood ratio for widespread pain in shifting the odds favoring the presence of generalized hypermobility was 1.24; the negative likelihood ratio was 0.749.
The present report suggests that a subgroup of patients with CFS present with generalized hypermobility, but questions the clinical importance of hypermobility in patients with CFS. A history of widespread pain was not predictive of generalized hypermobility in this sample of CFS patients.
Raine, R., Carter, S., Sensky, T and Black, N. General practitioners' perceptions of chronic fatigue syndrome and beliefs about its management, compared with irritable bowel syndrome: qualitative study. BMJ, 2004, 328, 1354-1357.
Objectives: To compare general practitioners' perceptions of CFS and irritable bowel syndrome (IBS) and to consider the implications of their perceptions for treatment.
Design: Qualitative analysis of transcripts of group discussions. Participants and setting A randomly selected sample of 46 general practitioners in England.
Results: The participants tended to stereotype patients with CFS as having certain undesirable traits. This stereotyping was due to the lack of a precise bodily location; the reclassification of the syndrome over time; transgression of social roles, with patients seen as failing to conform to the work ethic and "sick role"; and conflict between doctor and patient over causes and management. These factors led to difficulties for many general practitioners in managing patients with CFS. For both conditions many participants would not consider referral for mental health interventions, even though the doctors recognised social and psychological factors, because they were not familiar with the interventions or thought them unavailable or unnecessary.
Conclusions: Barriers to the effective clinical management of patients with IBS and CFS are partly due to doctors' beliefs, which result in negative stereotyping of patients with CFS and the use of management strategies for both syndromes that may not take into account the best available evidence.
With letter by C. Clark (ibid 329, 112-113), challenging the authors' reference to patient support associations as 'pressure groups'.
[Ed. note: The results are unsurprising given the biased accounts of CFS with its emphasis on misguided beliefs and behaviours and lack of attention for non-psychiatric factors, in all British mainstream journals. The confusion and helplessness expressed by some GPs is therefore not surprising. Responses on eBMJ have noted some of the flaws, e.g. comparing a complex multisystem disorder with a more localised one for which there are treatments.]
Reynolds, KJ., Vernon, SD., Bouchery, E and Reeves, WC. The economic impact of chronic fatigue syndrome. Cost effectiveness and resource allocation, 2004, 2:4 doi:10.1186/1478-7547-2-4.
CFS is a chronic incapacitating illness that affects between 400,000 and 800,000 Americans. Despite the disabling nature of this illness, scant research has addressed the economic impact of CFS either on those affected or on the national economy. We used microsimulation methods to analyze data from a surveillance study of CFS in Wichita, Kansas, and derive estimates of productivity losses due to CFS.
We estimated a 37% decline in household productivity and a 54% reduction in labor force productivity among people with CFS. The annual total value of lost productivity in the United States was $9.1 billion, which represents about $20,000 per person with CFS or approximately one-half of the household and labor force productivity of the average person with this syndrome.
Lost productivity due to CFS was substantial both on an individual basis and relative to national estimates for other major illnesses. CFS resulted in a national productivity loss comparable to such losses from diseases of the digestive, immune and nervous systems, and from skin disorders. The extent of the burden indicates that continued research to determine the cause and potential therapies for CFS could provide substantial benefit both for individual patients and for the nation.
Ross, SD., Estok, RP., Frame, D., Stone, LR., Ludensky, V and Levine, CB. Disability and chronic fatigue syndrome. A focus on function. Archives of Internal Medicine, 2004, 164, 1098-1107.
Evidence was sought in the published literature on how best to measure, monitor, and treat disability in patients with CFS.
Methods: A systematic review was performed of English-language literature published between January 1, 1988, and November 15, 2001. Interventional and observational studies of adults with CFS were eligible if they reported measures of disability and employment. A qualitative synthesis of results relating impairment measures to employment was performed.
Results: Of 3840 studies identified, 37 reported employment status and some measure of mental or physical impairment associated with disability. Most patients with CFS in these studies were unemployed. In 22 studies, the employment status of control subjects was also available. Only depression seemed to be associated with unemployment in patients with CFS.* No other measurable impairment seemed to be consistently associated with disability or work outcomes. Only CBT, rehabilitation, and exercise therapy interventions were associated with restoring the ability to work. No specific patient characteristics were identified as best predictors of positive employment outcomes. No quantitative syntheses of results were performed.
Conclusions: For questions of disability and employment in CFS, the limitations inherent in the current literature are extensive. Methodologically rigorous, longitudinal, and interventional studies are needed to determine baseline characteristics that are associated with the inability to work and interventions that are effective in restoring the ability to work in the CFS population. Simple and consistent evaluations of functional capacity in patients with CFS are needed.
* [Ed. note: This claim must be interpreted cautiously, owing to the often inadequate measures of disability and depression (e.g. POMS)].
Sackner, MA., Gummels EM and Adams, JA. Say NO to fibromyalgia and chronic fatigue syndrome: an alternative and complementary therapy to aerobic exercise. Medical Hypotheses, 2004, 63, 1, 118-123.
It is hypothesized that FM and CFS have chronic inflammation as their basis.
Staines, DR. Is chronic fatigue syndrome an autoimmune disorder of endogenous neuropeptides, exogenous infection and molecular mimicry? Medical Hypotheses, 2004, 62, 5, 646-652.
CFS is a disorder characterised by prolonged fatigue and debility and is mostly associated with post-infection sequelae although ongoing infection is unproven. Immunological aberration is likely and this may prove to be associated with an expanding group of vasoactive neuropeptides in the context of molecular mimicry and inappropriate immunological memory.
Vasoactive neuropeptides including vasoactive intestinal peptide (VIP) and pituitary adenylate activating polypeptide (PACAP) belong to the secretin/glucagon superfamily and act as hormones, neurotransmitters, immune modulators and neurotrophes. They are readily catalysed to smaller peptide fragments by antibody hydrolysis. They and their binding sites are immunogenic and are known to be associated with a range of autoimmune conditions.
Vasoactive neuropeptides are widely distributed in the body particularly in the central, autonomic and peripheral nervous systems and have been identified in the gut, adrenal gland, reproductive organs, vasculature, blood cells and other tissues. They have a vital role in maintaining vascular flow in organs, and in thermoregulation, memory and concentration. They are co-transmitters for acetylcholine, nitric oxide, endogenous opioids and insulin, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system to toxic assault, promotion of neural development and the maintenance of homeostasis.
This paper describes a biologically plausible mechanism for the development of CFS based on loss of immunological tolerance to the vasoactive neuropeptides following infection, significant physical exercise or de novo. It is proposed that release of these substances is accompanied by a loss of tolerance either to them or their receptor binding sites in CFS. Such an occurrence would have predictably serious consequences resulting from compromised function of the key roles these substances perform. All documented symptoms of CFS are explained by vasoactive neuropeptide compromise, namely fatigue and nervous system dysfunction through impaired acetylcholine activity, myalgia through nitric oxide and endogenous opioid dysfunction, chemical sensitivity through peroxynitrite and adenosine dysfunction, and immunological disturbance through changes in immune modulation. Perverse immunological memory established against these substances or their receptors may be the reason for the protracted nature of this condition.
The novel status of these substances together with their extremely small concentrations in blood and tissues means that clinical research into them is still in its infancy. A biologically plausible theory of CFS causation associated with vasoactive neuropeptide dysfunction would promote a coherent and systematic approach to research into this and other possibly associated disabling conditions.
Stouten, B. Cost-effectiveness of cognitive behaviour therapy for patients with chronic fatigue syndrome. Quarterly Journal of Medicine, 2004, 97, 378-379.
Letter responding to Severens et al (ibid, 153), noting the differences at baseline between the patients included and excluded from the analysis. This information was not included in the article, but in a report about the research to the Health Care Insurance Board of the Netherlands, which funded the study.
See also Baschetti, R. Letter, p 378-379 discussing the value of low dose hydrocortisone.
Tripp, J. Medically unexplained symptoms. Journal of the Royal Society of Medicine, 2004, 97, 360-361.
Letter responding to Butler et al (ibid, May), challenging the authors statement that doctors are required "to do an awkward dance of collusion with the patient" and proposing a different approach to explain how emotional variables may lead to physical symptoms. "I am at a loss to see how bringing in another dimension - ie that their symptom is somehow due to their 'reaction to the world' -helps, or how this assists patients to see their problems as unambiguously medical".
Tritt, K., Nickel, M., Mitterlehner, F., Nickel, C., Forthuber, P.,
Leiberich, P., Rother, W and Loew, T. Chronic fatigue and indicators of long-term employment disability in psychosomatic inpatients. Wiener Klinische Wochenschrift, 2004, 31, 116, (5-6), 182-189.
The major goal of this study was to determine indictors of long-term disability for psychosomatic inpatients with CFS. To this end, a cross-sectional study was performed with a random sample of patients (n=1000, response rate: 83.9%) at a psychosomatic inpatient clinic. 51.1% of the patients (n=429) reported intensely persistent exhaustion that had no logical relation to actual exertion. 159 (37.1%) patients in this group were disabled from working and these comprised the main target group of this study.
Significantly more patients in the target group worked part time, were disabled for a disproportionately long period of time (50.9% of all were disabled for more than 6 months in the previous year), and felt stressed because of conflicts with their superiors and/or colleagues (in each case, p<0.01). While more frequent psychological comorbidity was not found, they reported physical complaints more often. It was not the patients fit for work who felt more burdened with chronic fatigue, but rather the employment-disabled, who were actually exposed to fewer demands. These patients had, in comparison with those fit to work, a stronger fixation on somatic complaints, inadequate perception of physical and psychic sensations, difficulties getting along with other people and in coping with a regular job (in each case, p<0.01).
Prospective examination of these indicators could help detect predictor variables for long-term disability in chronic fatigue. Such predictors could contribute to timely social-medical assessment and treatment.
[Ed. note: Although the authors state that the patients met the 1994 criteria, the report that 94.8% mentioned hallucinations as a symptom cast some doubt on the accuracy of the diagnosis of CFS.]
Unger, ER., Nisenbaum, R., Moldofsky, H., Cesta, A., Sammut, C., Reyes, M and Reeves, WC. Sleep assessment in a population-based study of chronic fatigue syndrome. BMC Neurology, 2004 Apr 19, 4, (1), 6.
Most CFS patients complain of unrefreshing sleep and many of the postulated etiologies of CFS affect sleep. Conversely, many sleep disorders present similarly to CFS. Few studies characterizing sleep in unselected CFS subjects have been published and none have been performed in cases identified from population-based studies.
The study included 339 subjects (mean age 45.8 years, 77% female, 94.1% white) identified through telephone screening in a previously described population-based study of CFS in Wichita, Kansas. They completed questionnaires to assess fatigue and wellness and 2 self-administered sleep questionnaires. Scores for five of the six sleep factors (insomnia/hypersomnia, non-restorative sleep, excessive daytime somnolence, sleep apnea, and restlessness) in the Centre for Sleep and Chronobiology's Sleep Assessment Questionnaire(c) (SAQ(c)) were dichotomized based on threshold. The Epworth Sleepiness Scale score was used as a continuous variable.
81.4% of subjects had an abnormality in at least one SAQ(c) sleep factor. Subjects with sleep factor abnormalities had significantly lower wellness scores but statistically unchanged fatigue severity scores compared to those without SAQ(c) abnormality. CFS subjects had significantly increased risk of abnormal scores in the non-restorative (adjusted odds ratio [OR] = 28.1) and restlessness (OR = 16.0) SAQ(c) factors compared to non-fatigued, but not for factors of sleep apnea or excessive daytime somnolence. This is consistent with studies finding that, while fatigued, CFS subjects are not sleepy. A strong correlation (0.78) of Epworth score was found only for the excessive daytime somnolence factor.
SAQ(c) factors describe sleep abnormalities associated with CFS and provide more information than the Epworth score. Validation of these promising results will require formal polysomnographic sleep studies.
[The full text of this article is available in PDF format for free at http://www.biomedcentral.com/content/pdf/1471-2377-4-6.pdf .]
Van Hoof, E. Cognitive behavioural therapy as cure-all for CFS. Journal of Chronic Fatigue Syndrome, 2003, 11, 4, 43-47.
Critical discussion paper noting some of the flaws of the Prins et al study, and the fact that improvements reported by those having CBT often did not last.
Wallman, K., Goodman, C., Morton, A., Grove, R and Dawson, B. Test-retest reliability of the Aerobic Power Index test in patients with Chronic Fatigue Syndrome. Journal of Chronic Fatigue Syndrome, 2003, 11, 4, 19-32.
Use of maximal aerobic exercise testing in a chronically ill population may not only deter potential subjects from participating in trials, or returning for repeat trials, but may also result in the exacerbation of symptoms related to CFS. The Aerobic Power Index represents a submaximal exercise test that forms the aerobic component of the Tri-Level Fitness Profile. This incremental bike test has a predetermined termination point based on a target heart rate (THR) of 75% of age predicted heart rate maximum, making successful completion of the test more likely in chronically ill subjects. The aim of this study was to determine reliability of the Aerobic Power Index in 20 subjects with CFS (CDC criteria '94).
Results for the 17 subjects who reached THR for both trials, demonstrate high reliability for watts per kilogram and oxygen uptake, as demonstrated by an intraclass correlation coefficient (ICC) of .97 and .91, respectively, while RPE resulted in moderate reliability (ICC=.87). The results of this study indicate that the Aerobic Power Index is a reliable submaximal test for use in a CFS population.
Manu, P. The Psychopathology of Functional Somatic Syndromes. Neurobiology and illness behavior in chronic fatigue syndrome, fibromyalgia, Gulf War illness, irritable bowel, and premenstrual dysphoria. New York: Haworth Medical Press. Pb. 299pp. $27.96.
Account of functional somatic syndromes, which describes evidence supporting this concept, but very little of the research which does not. The one-sidedness of the discussion shows little respect for readers, or for the many researchers whose findings point to different mechanisms. Not recommended.
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