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Lane, RJM., Soteriou, BA., Zhang, H and Archard, LC. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 2003, 74, 1382-1386
Objective: To detect and characterise enterovirus RNA in skeletal muscle from patients with CFS and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients.
Methods: Quadriceps muscle biopsy samples from 48 patients with CFS (Oxford criteria but many with muscle symptoms) were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 healthy people or patients with muscle diseases. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points.
Results: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 abnormal respondents to SATET (SATET+ 32.1%), compared with only one (5%) of the 20 SATET-patients. PCR products were most closely related to coxsackie B virus.
Conclusions: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients
Extracts from the discussion: "We reported previously that a subset of CFS patients had abnormal lactate responses to exercise at work rates below the predicted anaerobic threshold. Such cases proved less likely to have evidence of psychiatric disorder than cases with normal lactate responses, and the finding could not be explained satisfactorily by the effects of deconditioning or muscle disuse, either on the basis of heart rate responses to exercise or from a subsequent analysis of muscle fibre sizes and fibre type proportions. Further studies using phosphorus magnetic resonance spectroscopy have shown that some CFS patients have defective muscle energy metabolism, notably reduced ATP resynthesis rates following exercise, suggestive of mitochondrial dysfunction.
....No mechanistic link between defective muscle energy metabolism and enterovirus infection has been established by the present study. Indeed, two patients had identical enteroviral RNA sequence changes but only one had an abnormal lactate response to exercise; mutations at other sites in the viral RNA might therefore determine viral persistence and effects on mitochondrial function. However, the observations presented here support the view that CFS is heterogeneous, and that some cases have a peripheral component to their fatigue related to muscle dysfunction. While the effects of 'disuse' and lack of fitness cannot be excluded, previous studies, supported by the evidence presented here, show that some CFS patients have abnormal muscle energy metabolism which is related statistically to the presence of enterovirus sequences in muscle, and that the viruses involved are predominantly coxsackie-B-like. The data support the concept of a true postviral fatigue syndrome following enterovirus infection."
With editorial comment by Dalakas, MC (p. 1361-2).
"The paper raises a fundamental question: can enteroviruses infect human muscle and cause persistent infection that affects only the metabolic machinery of the cells without muscle destruction? If so, is this clinically relevant to CFS patients?... The findings of Lane et al are theoretically relevant to CFS even though a causal relationship between viral persistence and reduced muscle endurance was not demonstrated. In the past, such findings have turned out to be epiphenomena because enteroviruses are ubiquitous in humans and technical flaws inherently connected to contamination in laboratories working with these viruses are inevitable. Lane et al have performed a careful study and their findings deserve attention because, if proved to be specific, they will provide the first indirect indication of a viral related fatigue in a subset of CFS patients.
...The authors need...to demonstrate enterovirus within the muscle fibres by in-situ PCR; prove that viral persistence alters the metabolic machinery of the cell and show that such abnormalities cause clinical symptomatology. This is a laborious, but worthwhile effort that may prove rewarding for the millions of CFS patients because anti-enteroviral agents are now available (pleconaril) or in the offing. The authors may be on the right target but there are no shortcuts in pursuing it."
Vernon, SD., Shukla, SK and Reeves, WC. Absence of Mycoplasma species DNA in chronic fatigue syndrome. Journal of Medical Microbiology, 2003, 52, 11, 1027-1028.
In this study, we used Mycoplasma species-specific primer pairs for direct amplification of these microbes from plasma DNA. As part of a population-based study of CFS in Wichita, Kansas, USA, peripheral blood was collected during the clinical evaluation of 34 subjects with CFS (CDC criteria '94) and a random selection of 55 non-fatigued subjects. Primer pairs for Mycoplasma fermentans, Mycoplasma hominis, Mycoplasma penetrans and Mycoplasma pneumoniae were synthesized according to published sequences. As it has been shown that Mycoplasma species exist at relatively high rates in the peripheral blood of CFS patients in both the USA and Europe, it seems plausible that these microbial sequences should have been detected in plasma, reflecting death and lysis of infected cells. Whilst a variety of bacterial sequences were detected in both fatigued and non-fatigued groups, no Mycoplasma sp. 16S rDNA sequences were found.
Our goal was to reproduce the results of Nasralla et al. (1999) and Nijs et al. (2002) in a systematic way... Our study tested persons with CFS identified in the general population. Previous studies did not include appropriate controls, thus reported associations may be spurious. Our study enrolled non-fatigued controls from the same population as CFS cases. Finally, neither previous studies that reported an association nor our study, which shows no association, have been replicated independently. Independent reproducibility of PCR-based detection methods for infectious agents by other laboratories is an important factor for establishing an infectious cause of disease.
Nicolson, GL., Nasralla, MY., De Meirleir, K., Gan, R and Haier, J. Evidence for bacterial (Mycoplasma, Chlamydia) and viral (HHV-6) co-infections in chronic fatigue syndrome patients. Journal of Chronic Fatigue Syndrome, 2003, 11, 2, 7-19.
Using the blood of 100 CFS patients (CDC criteria '94) and forensic PCR, we have found that a majority of CFS patients show evidence of multiple, systemic bacterial and viral infections (p<0.001) that could play an important role in CFS morbidity.
CFS patients had a high prevalence (51%) of one of four Mycoplasma species (p<0.001) and often showed evidence of co-infections with different Mycoplasma species, chlamydia pneumoniae (p<0.01) and/or active Human Herpes Virus-6 (HHV-6) (p<0.001). We found that 8% of the CFS patients showed evidence of C. pneumoniae and 31% of active HHV-6 infections.
Since the presence of one or more chronic systemic infections may predispose patients to other infections, we examined the prevalence of C. pneumoniae and active HHV-6 infections in mycoplasma-positive and -negative patients. The incidence of C. pneumoniae or HHV-6 was similar in mycoplasma-positive and -negative patients, suggesting that such infections occur independently in CFS patients. Also, the incidence of C. pneumoniae in active HHV-6-positive and -negative patients was similar. Healthy control subjects (N=100) had low rates of mycoplasma (6%), active HHV-6 (9%) or chlamydia (1%) infections, and there were no co-infections in control subjects.
Differences in bacterial and/or viral infections in CFS patients compared to control subjects were significant. The results indicate that a relatively large subset of CFS patients show evidence of bacterial and viral co-infections.
Nijs, J., De Meirleir, K., Coomans, D., De Becker, P and Nicolson, GL. Deregulation of the 2,5A synthetase RNase L antiviral pathway by mycoplasma spp in subsets of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2003, 11, 2, 37-50.
The deregulation of the 2,5A synthetase RNase L antiviral pathway and the prevalence of Mycoplasma spp. in subsets of CFS have been separately reported in the scientific literature. We hypothesised that a co-morbid pathophysiological mechanism involving infection by Mycoplasma spp. and the deregulation of the 2,5A synthetase RNase L antiviral pathway may exist in CFS. Therefore, 186 consecutive patients with CFS (CDC criteria '94) were enrolled. Mycoplasma detection was performed using forensic PCR. For RNase L determination, a radio-active probe was used to label 2,5A binding proteins in unfractionated peripheral blood mononuclear cell (PBMC) extracts. Mycoplasma-infected CFS patients (n=131, 70.4%) presented with significantly elevated RNase L-ratio, compared to non-infected age- and sex-matched patients (p=0.016). These results suggest that mycoplasma infections may cause deregulation of the 2,5A synthetase RNase L antiviral pathway in patients with CFS.
Nijs, J., Coomans, D., Nicolson, GL., De Becker, P., Demanet, C and De Meirleir, K. Immunophenotyping predictive of mycoplasma infection in patients with chronic fatigue syndrome? Journal of Chronic Fatigue Syndrome, 2003, 11, 2, 51-69.
An impaired immune system and opportunistic infections are considered important characteristics in the pathophysiology of CFS. Using immunofluorescence we examined healthy subjects (n=35) and two subsets of CFS patients: those without evidence of Mycoplasma (n=55) and those with evidence of a Mycoplasma infection in their blood (n=131). Using monoclonal antibodies and forensic PCR for detection of M. hominis, M. fermentans, M. pneumoniae and M. penetrans, we examined leukocytes in peripheral blood samples. Both patient groups presented with significantly elevated CD25+ (activated) cells as compared to healthy volunteers. CFS patients without evidence of mycoplasma infection(s) had increased amounts of CD5+ B-cells. Stepwise discriminant analysis indicated the number of activated cells, number of memory CD4+ cells and percentage of suppressor T-cells (lower in Mycoplasma+ patients as compared to Mycoplasma- patients) as the discriminant variables. A classification tree, for predicting the presence of Mycoplasma species in CFS patients, was constructed. Taken together, these data confirm earlier reports on immune activation among CFS patients, but this does not appear to be specific for Mycoplasma-infected CFS patients.
Khan, F., Spence, V., Kennedy, G and Belch, JJ. Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clinical Physiology and Functional Imaging, 2003, 23, 5, 282-285.
Although the aetiology of CFS is unknown, there have been a number of reports of blood flow abnormalities within the cerebral circulation and systemic blood pressure defects manifesting as orthostatic intolerance. Neither of these phenomena has been explained adequately, but recent reports have linked cerebral hypoperfusion to abnormalities in cholinergic metabolism.
Our group has previously reported enhanced skin vasodilatation in response to cumulative doses of transdermally applied acetylcholine (ACh), implying an alteration of peripheral cholinergic function. To investigate this further, we studied the time course of ACh-induced vasodilatation following a single dose of ACh in 30 patients with CFS (CDC criteria '94)* and 30 age- and gender-matched healthy control subjects.
No differences in peak blood flow was seen between patients and controls, but the time taken for the ACh response to recover to baseline was significantly longer in the CFS patients than in control subjects. The time taken to decay to 75% of the peak response in patients and controls was 13.7 +/- 11.3 versus 8.9 +/- 3.7 min (p=0.03), respectively, and time taken to decay to 50% of the peak response was 24.5 +/- 18.8 versus 15.1 +/- 8.9 min (p=0.03), respectively.
Prolongation of ACh-induced vasodilatation is suggestive of a disturbance to cholinergic pathways, perhaps within the vascular endothelium of patients with CFS, and might be related to some of the unusual vascular symptoms, such as hypotension and orthostatic intolerance, which are characteristic of the condition.
[Ed. note: This study was funded by MERGE suggesting that patients also met criteria for ME.]
Khan, F., Kennedy, G., Spence, VA., Newton, DJ and Belch, JJ. Peripheral cholinergic function in humans with chronic fatigue syndrome, gulf war syndrome, and with illness following organophosphate exposure. Clinical Science (Lond), 2003, Sep 23 [Epub ahead of print].
We investigated whether the peripheral cholinergic abnormalities we previously reported in patients with CFS are also present in those with Gulf War syndrome (GWS) and agricultural workers exposed to organophosphate pesticides, where cholinesterase inhibition is specifically implicated. We also looked at whether these abnormalities might be due to a reduction in the activity of cholinesterase expressed on the vascular endothelium. We used laser Doppler imaging to measure the forearm skin blood flow responses to iontophoresis of acetylcholine and of methacholine (which is resistant to breakdown by cholinesterase) in patients with CFS, GWS, and those with a history of ill health after definite organophosphate exposure, as well as in matched, healthy controls.
The response to acetylcholine was significantly higher in patients with CFS than in controls (p=0.029), but was normal in those with GWS and those exposed to organophosphates. The methacholine response was higher than the acetylcholine response in all patient groups except for CFS, where there was no difference between the responses.
Although there are many clinical similarities between these three illnesses, our results indicate peripheral cholinergic abnormalities in the vascular endothelium of only patients with CFS, suggesting that this syndrome has a different aetiology, which might involve inhibition of vascular cholinesterase.
McCully, KK., Smith, S., Rajaei, S., Leigh, Jr JS and Natelson, BH. Muscle metabolism with blood flow restriction in chronic fatigue syndrome. Journal of Applied Physiology, 2003, Oct 24 [Epub ahead of print].
The purpose of this study was to determine if CFS is associated with reduced blood flow and muscle oxidative metabolism. Patients with CFS (CDC criteria '94, n=19) were compared to normal sedentary subjects (n=11). Muscle blood flow was measured in the femoral artery with Doppler ultrasound after exercise. Muscle metabolism was measured in the medial gastrocnemius muscle using 31P magnetic resonance spectroscopy (MRS). Muscle oxygen saturation and blood volume were measured using near-infrared spectroscopy.
CFS and controls were not different in hyperemic blood flow or phosphocreatine recovery rate. Cuff pressures of 50, 60, 70, 80, and 90 mmHg were used to partially restrict blood flow during recovery. All pressures reduced blood flow and oxidative metabolism, with 90 mmHg reducing blood flow by 46% and oxidative metabolism by 30.7% in CFS patients. Hyperemic blood flow during partial cuff occlusion was significantly reduced in CFS patients (p<0.01), and recovery of oxygen saturation was slower (p<0.05). No differences were seen in the amount of reduction in metabolism with partially reduced blood flow.
In conclusion, CFS patients showed evidence of reduced hyperemic flow and reduced oxygen delivery, but no evidence that this impaired muscle metabolism. Thus, CFS patients might have altered control of blood flow, but this is unlikely to influence muscle metabolism. Further, abnormalities in muscle metabolism do not appear to be responsible for the CFS symptoms.
[Ed. note: The negative findings are consistent with the view that broad definitions of CFS select a different, more heterogeneous population and is not equivalent to ME or strictly-defined CFS].
Peckerman, A., LaManca, JJ., Qureishi, B., Dahl, KA., Golfetti, R., Yamamoto, Y and Natelson, BH. Baroreceptor reflex and integrative stress responses in chronic fatigue syndrome. Psychosomatic Medicine, 2003, 65, 889-895.
Altered cardiovascular responses to mental and postural stressors have been reported in CFS. This study examined whether those findings may involve changes in baroreceptor reflex functioning.
Chronotropic baroreceptor reflex (by sequential analysis) and cardiovascular stress responses were recorded during postural (5-minute of standing) and cognitive (3 minute speech task) stress testing in patients with CFS grouped into cases with severe illness (n=21, met CDC '88 criteria, at least 7 symptoms worse or substantial in the previous month) or less severe illness (n=22, criteria '94 or '88), and in 29 matched (sedentary) controls. The testing session also included a two-minute cold pressor test, which is a stressor condition which does not involve high-level cognitive functioning (cf. speech task).
The average Karnofsky score for the severe group was 38, for the less severe group 47. The mean MOS score for physical functioning for the severe group was 36, for the less severe group was 47.
Patients with CFS had a greater decline in baroreceptor reflex sensitivity (BRS) during standing, although only those with severe CFS were significantly different from the controls. Systolic blood pressure (SBP) declined during standing in the control group but was maintained in the CFS patients. In contrast, the patients with less severe CFS had blunted increases in blood pressure during the speech task, which could not, however, be explained by inadequate inhibition of the baroreceptor reflex, with all groups showing an appropriate reduction in BRS during the task. There was no significant relationship between symptoms and blood pressure responses in the severe CFS group.
These results indicate that in CFS, deficiencies in orthostatic regulation, but not in centrally mediated stress responses, may involve the baroreceptor reflex. This study also suggests that classifying patients with CFS on illness severity may discriminate between patients with abnormalities in peripheral vs. central mechanisms of cardiovascular stress responses.
Extracts from discussion:
This study indicates that CFS alters baroreceptor reflex functioning... The effect of illness was accentuated in the patients with severe CFS and was associated with a deviation from the normal pattern of SBP response to standing. There were no discernible effects of illness on the baroreflex modulation by stressors, however.
...This study replicated our previous findings of blunted blood pressure responses to cognitive stressors in civilian patients with CFS and in Gulf War veterans. An important new finding of this study is that this abnormality may be specific to a less severe form of illness. Although patients with CFS in our earlier report were not classified on illness severity, the reported mean symptom severity rating (+2.0) was similar to that obtained in the less severe CFS group in this study (1.9). This finding indicated that the subjects in that study were mainly patients with less severe CFS. Similarly, review of the patients' records from our study of Gulf War veterans revealed that 85% of them had less severe CFS according to our case definition. This study also replicated in civilian patients with CFS the pattern of disturbed regulation of responses to cognitive but not sensory (the cold pressor test) challenges that we previously reported in Gulf War veterans, suggesting a similar underlying pathology. As in our previous studies, hyporeactivity to mental stress was not explainable by the lack of engagement and low motivational state, and indeed, this would not be plausible in patients with less severe CFS.
...We have previously shown that blood pressure hyporesponsiveness in CFS is symptom-related. However, CFS symptoms vary considerably from day to day, and it cannot be assumed that the short-term and long-term patterns of illness have the same underlying pathology. Using energy scores on the day of testing and average 1-week symptom severity ratings as measures of short-term and long-term trends, we found each to be uniquely related to a different aspect of blood pressure hyporeactivity-SBP [and diastolic BP], respectively. Thus, it would appear that acute and chronic illness processes may selectively impair activity in cardiac and vasomotor regulatory pathways. This finding lends further support to a view that reduced responsiveness of the brain mechanisms mediating cardiovascular responses to mental challenges is an integral part of the pathophysiology of CFS in its less severe form. A broad literature review by Chrousos and Gold suggested that reduced stress responsiveness may be the basis of symptoms in a number of unexplained illness conditions. This study provides a partial support for this view in CFS.
[Note - baroreceptor: A sensory nerve ending that is stimulated by changes in pressure. Baroreceptors are found in the walls of the atria of the heart, vena cava, aortic arch, and carotid sinus.]
Peckerman, A., LaManca, JJ., Dahl, KA., Chemitiganti, R., Qureishi, B and Natelson, BH. Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome. American Journal of Medical Science, 2003, 326, 2, 55-60.
Background: Findings indicative of a problem with circulation have been reported in patients with CFS. We examined this possibility by measuring the patient's cardiac output and assessing its relation to presenting symptoms.
Methods: Impedance cardiography and symptom data were collected from 38 patients with CFS grouped into cases with severe (n=18, all meeting the CDC '88 criteria plus reporting symptoms which were substantial or worse in the previous month) and less severe illness (n=20 using CDC criteria '88 or '94, no severity requirement) and compared with those from 27 matched, sedentary control subjects.
Results: The patients with severe CFS rated their symptoms of post-exertional fatigue, flu-like infection (sore throat, fever-chills, and swollen lymph nodes), and headaches as substantial or worse significantly more often than the patients with less severe CFS. Conversely, the mean severity ratings for sore throat and fever-chills in the less severe CFS group were not significantly different from those in the control group (p>0.05) Moreover, there was no significant difference between the two patient groups in terms of muscle pain, memory-concentration, sleep and general weakness. The fatigue scores on the day (AD ACL) were only slightly higher in the severe group (ns). Depression scores (BDI) were higher in the less severely affected.
The patients with severe CFS had significantly lower stroke volume and cardiac output than the controls and less ill patients. Post-exertional fatigue and flu-like symptoms of infection differentiated the patients with severe CFS from those with less severe CFS (88.5% concordance) and were predictive (R2 =0.46, p<0.0002) of lower cardiac output. In contrast, neuropsychiatric symptoms (i.e. memory problems) showed no specific association with cardiac output.
Extracts from the discussion: These results provide initial evidence of reduced cardiac output in severe CFS. They suggest that in some patients with CFS, blood pressure is maintained at the cost of restricted flow, possibly resulting in a low flow circulatory state. Thus, there might be periods in daily activities when demands for blood flow are not adequately met, compromising metabolic processes in at least some vascular compartments. If confirmed, this finding would signify that some cases of CFS might be explained and potentially treated as low circulation problems.
...Notably, the reduction in stroke volume in these patients was more clearly seen when they were in the supine position and tended to improve during standing, indicating worsened cardiac performance under conditions of augmented preload. Improvements in cardiac performance in cardiac patients in the upright position have been reported, indicating positive effects of preload reduction on left ventricular function of the diseased heart. An increased pre-ejection period in the supine position, when sympathetic activity is dormant, and its normalization during standing, when it is increased, may also indicate a problem with contractility or diastolic function, either of which could affect stroke volume.
Although this pattern is consistent with cardiac dysfunction, a number of other circulatory, neurogenic, and endocrinologic abnormalities could explain the present findings. [The authors mention a number of variables including deconditioning. "However, this seems unlikely, because there seem to be no significant differences in the physical fitness between patients with CFS and sedentary control subjects".]
...Although the reduction in cardiac output in CFS is not likely to fall within the range that would be considered abnormal, this should not detract from its physiological significance. Even marginal reduction in cardiac output can result in selective underperfusion during activities that increase demand for blood flow.
Conclusions: These results provide a preliminary indication of reduced circulation in patients with severe CFS. Further research is needed to confirm this finding and to define its clinical implications and pathogenetic mechanisms.
[Ed. Note: A number of patients were on SSRIs which may have influenced some of the results, though there was no evidence of this in relation to the lower cardiac output.]
Powell, R., Ren, J., Lewith, G., Barclay, W., Holgate, S and Almond, J. Identification of novel expressed sequences, up-regulated in the leucocytes of chronic fatigue syndrome patients. Clinical & Experimental Allergy, 2003, 33, 10, 1450-1456.
BACKGROUND: Of the many hypotheses that purport to explain CFS, immune system activation, as a central feature, has remained prominent but unsubstantiated. Supporting this, a number of important cytokines have previously been shown to be over-expressed in disease subjects. The diagnosis of CFS is highly problematic since no biological markers specific to this disease have been identified.
OBJECTIVE: The aim of this study was to screen for changes in gene expression in the lymphocytes of CFS patients.
METHODS: 'Differential Display' is a method for comparing mRNA populations for the induction or suppression of genes. In this technique, mRNA populations from control and test subjects can be 'displayed' by gel electrophoresis and screened for differing banding patterns. These differences are indicative of altered gene expression between samples, and the genes that correspond to these bands can be cloned and identified. Differential display has been used to compare expression levels between four control subjects and seven CFS patients (CDC criteria '94, acute onset (post-viral), duration >2years).
RESULTS: Twelve short expressed sequence tags have been identified that were over-expressed in lymphocytes from CFS patients. Two of these correspond to cathepsin C and MAIL1 - genes known to be upregulated in activated lymphocytes. The expression level of seven of the differentially displayed sequences have been verified by quantifying relative level of these transcripts using TAQman quantitative PCR.
CONCLUSION: Taken as a whole, the identification of novel gene tags up-regulated in CFS patients adds weight to the idea that CFS is a disease characterized by subtle changes in the immune system.
Clarke, JN and James, S. The radicalized self: the impact on the self of the contested nature of the diagnosis of chronic fatigue syndrome. Social Science & Medicine, 2003, 57, 8, 1387-1395.
CFS is a contested disease immersed in dispute about whether it is a physical or psychiatric reality. Sufferers often claim to experience not only the physical challenges of the disease, and these can be extensive, but also, initially, the anomie of suffering from a condition whose very reality is debated both in the medical and in the wider communities. Theories of self in illness emphasize how people who are diagnosed as chronically ill work hard as they seek to maintain previous, or to develop supernormal, selves... This paper raises questions about the constraints and liberties, power and powerlessness associated with a clear and undisputed medical diagnosis. It suggests a model of the self in chronic illness that considers not only changes in body and biography but also the availability of an uncontested diagnosis.
Hatcher, S and House, A. Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study. Psychological Medicine, 2003, 33, 7, 1185-1192.
BACKGROUND: The role of stress in the onset of CFS is unclear. Our objectives in this study were first, to determine the relation between the onset of CFS and stressful life events and difficulties. Secondly, we examined the role of a particular type of problem, dilemmas, in the onset of CFS.
METHOD: We used a case-control design with 64 consecutive referrals from an Infectious Diseases/Liaison Psychiatry Fatigue clinic and 64 age- and sex-matched controls from a general practice population control group in Leeds. We had two main outcome measures; the odds ratios of the risk of developing CFS after experiencing a severe life event, severe difficulties or both in the year and 3 months preceding onset; and the proportion of subjects in each group who experienced a dilemma prior to onset.
RESULTS: Patients with CFS were more likely to experience severe events and difficulties in the 3 months (OR=9, 95% CI 3.2 to 25.1) and year (OR=4.3, 95% CI 1.8 to 10.2) prior to onset of their illness than population controls. In the 3 months prior to onset 19 of the 64 patients (30%) experienced a dilemma compared to none of the controls.
CONCLUSIONS: CFS is associated with stressful events and difficulties prior to onset. Those events and difficulties characterized as being dilemmas seem to be particularly important.
[Ed. note: From a health psychology perspective, the central issue is not so much the relationship between stressful life events and illness, but between coping with the distress of those events and illness. (This is because people perceive stressors in different ways.) There is also the issue of the retrospective design and the influence of illness on memory. (Similar findings have been documented for MS and cancer but inconsistent results and methodological flaws have made it difficult to draw firm conclusions). It is not clear if there is a similar relationship between ME\PVFS and stress. If stress is followed by the symptoms of CFS, one might also argue that the illness is explained and the diagnosis of CFS is inappropriate.]
Moss-Morris, R and Chalder, T. Illness perceptions and levels of disability in patients with chronic fatigue syndrome and rheumatoid arthritis. Journal of Psychosomatic Research, 2003, 55, 4, 305-308.
Objective: To investigate the strength of CFS patients' negative illness perceptions by comparing illness perceptions and self-reported disability in patients with CFS and rheumatoid arthritis (RA).
Methods: Seventy-four RA patients and 49 CFS patients (CDC criteria '94) completed the Illness Perception Questionnaire-Revised and the 36-item Short-Form Health Survey. [The groups were not matched on some variables which might influence perceptions, e.g. 'vitality'. Ed.].
Results: When compared to the RA group, the CFS group attributed a wider range of everyday somatic symptoms to their illness, perceived the consequences of their illness to be more profound and were more likely to attribute their illness to a virus or immune system dysfunction. Both groups reported equivalent levels of physical disability* but the CFS group reported significantly higher levels of role and social disability.
Conclusion: Although the symptoms of CFS are largely medically unexplained, CFS patients have more negative views about their symptoms and the impact that these have had on their lives than do patients with a clearly defined and potentially disabling medical condition. The data support the cognitive behavioural models of CFS that emphasise the importance of patients' illness perceptions in perpetuating this disorder.
[Ed. note: *Here, disability appears to be defined as the score on physical functioning subscale of the MOS. Patients were not matched for severity of symptoms, especially fatigue (apparently not measured). Consequently, the interpretations of the findings are limited in scope and negative perceptions could reflect more disabling and unpleasant symptoms (e.g. nausea). To define CFS in terms of a lack of vitality is limited. These findings therefore do not support any model. Speculation about fearful cognitions relating to activity is unhelpful as these variables could, and should have been measured and to rely so long on speculation instead of research is hard to justify.]
Diaz-Mitoma, F., Turgonyi, E., Kumar, A., Lim, W., Larocgue, L and Hyde, BM. Clinical improvement in chronic fatigue syndrome is associated with enhanced natural killer cell-mediated cytotoxicity: the results of a pilot study with Isoprinosine. Journal of Chronic Fatigue Syndrome, 2003, 11, 2, 71-95.
CFS is associated with systemic and cognitive symptoms and with several immune abnormalities. The clinical impact of Isoprinosine was evaluated in 16 CFS patients (CDC criteria '88 and '94, two with depression), followed for 28 weeks in a single-blind, placebo controlled trial. Patients were also monitored for various immune parameters. Improvement based on clinical staging was observed in six of ten treated patients (60%). Clinically improved patients showed significantly enhanced natural killer (NK) cell activity, which correlated with the duration of Isoprinosine treatment (p<0.03). Treatment with Isoprinosine resulted in significantly increased numbers of CD4+ T helper cells (p<0.03). Treatment with Isoprinosine for 12 weeks did not appreciably influence the in- vitro production of IFN-ã, IL-1á, IL-10 or IL-12. However, IL-12 was significantly increased at week 28 (p<0.02) in patients who improved after treatment with Isoprinosine. These results suggest that taking Isoprinosine may benefit a subgroup of patients with CFS, and this clinical improvement is associated with enhanced NK cell function and IL-12 levels. Further trials to evaluate the use of Isoprinosine in the treatment of CFS patients are warranted.
Kawamura, Y., Kihara, M., Nishimoto, K and Taki, M. Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology, 2003, 9, 3, 189-194.
We describe three cases who fulfil the definition of CFS (Dyck et al 1996), in whom a defect of neuromuscular transmission and dysautonomia are present and who respond to acetylcholine-esterase inhibition.
Case 1: 18-year-old female with a 3-year history of CFS. Response of compound-muscle-action potential, recorded using surface recording electrode, over left abductor pollicis brevis muscle, to repetitive nerve stimulation (RNS) at a rate of 10 Hz showed a 42% incremental response. Composite autonomic scoring system (CASS) showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2). Serological tests for Epstein-Barr virus (EBV) revealed positive antiviral capsid antigens (anti-VCA) immunoglobulins G (IgG). Oral pyridostigmine therapy (30 mg) resulted in marked improvement in symptoms.
Case 2: 28-year-old female with 10-year history of CFS. RNS, using identical protocol, showed a 60% incremental response over the same muscle. CASS showed mild cholinergic impairment (cardiovagal score: 1; sudomotor score: 2) and this patient was also positive for EBV. This patient responded dramatically to 10-mg pyridostigmine.
Case 3: 29-year-old female with a history of CFS for longer than 15 years. Repetitive stimulation, using identical paradigm to left abductor pollicis brevis muscle, showed a 42% incremental response. CASS showed mildly cholinergic impairment (cardiovagal score: 2; sudomotor score: 1). EBV antibody titers were positive. Patient responded to 30-mg pyridostigmine with an improvement in her fatigue. These three cases generate the hypothesis that the fatigue in some patients with clinical CFS might be due to a combination of mild neuromuscular transmission defect combined with cholinergic dysautonomia. Support for this thesis derives from the improvement with cholinesterase inhibition.
Chalder, T., Goodman, R., Wessely, S., Hotopf, M and Meltzer, H. Epidemiology of chronic fatigue syndrome and self reported myalgic encephalomyelitis in 5-15 year olds: cross sectional study. BMJ, 2003, 327, 654-655.
The researchers conducted interviews with 10438 children. Measures included the GHQ (12?). Logistic regression was used to examine associations between independent and dependent variables.
Parental report of ME (not defined) or CFS (CDC criteria '94) was associated with maternal distress on the general health questionnaire. Female sex was not a risk factor for any outcomes.
The authors comment that symptomatic fatigue in children is common, but chronic fatigue and CFS are relatively rare. "The rates of the syndrome that we report are lower than those found in equivalent surveys in adults. Cases where children are labelled as having myalgic encephalomyelitis or chronic fatigue syndrome are even less common." Given the small numbers, the results obtained in the subsequent analysis cannot be precise. We found no concordance between parental labelling that a child had myalgic encephalomyelitis and operationally defined chronic fatigue syndrome. We found a strong association between psychiatric disorder and these outcomes, which is a consistent finding among adults with CFS. Maternal psychological distress was associated with parental report of myalgic encephalomyelitis or CFS, but given the cross sectional nature of the data it is impossible to determine the direction of causality.
[Ed. note: It has been known for many years that ME and CFS are less common amongst younger people. But as this study shows, it does exist. There are no details for the percentage of patients with 'psychiatric disorder' or whether this preceded or followed diagnosis of CFS. Findings were obtained using an interview without medical examinations which means that the prevalence figures should be interpreted with caution.]
Jason, L.A., Plioplys, A.V., Torres-Harding, S., and Corradi, K. Comparing symptoms of chronic fatigue syndrome in a community-based versus tertiary care sample. Journal of Health Psychology, 2003, 8, 459-464.
Almost all studies of samples with patients with CFS have relied on referrals from physicians or health facilities. Underserved minorities, who not only tend to manifest higher levels of chronic illness, but are also less likely to seek and receive adequate medical care, have not been adequately represented in these studies. The present study compared two groups of individuals with CFS, one from a community-based sample and another from a tertiary-based sample. Findings indicate that patients with CFS from tertiary care settings have a higher frequency of symptoms than those in the general population who have CFS and suggest that they are "more impaired".
Solomon, L., Nisenbaum, R., Reyes, M., Papanicolaou, DA and Reeves, WC. Functional status of persons with chronic fatigue syndrome in the Wichita, Kansas, population. Health & Quality of Life Outcomes, 2003, 1, 1, 48. Epub 2003 Oct 03.
BACKGROUND: Scant research has adequately addressed the impact of CFS on patients' daily activities and quality of life... This study addresses issues of functional status in persons with CFS and other fatiguing illnesses in a population based sample, which can be generalized to all persons with chronic fatigue.
METHODS: We conducted a random telephone survey in Wichita, Kansas to identify persons with CFS and other fatiguing illnesses. Respondents reporting severe fatigue of at least 1 month's duration and randomly selected non-fatigued respondents were asked to participate in a detailed telephone interview. Participants were asked about symptoms, medical and psychiatric illnesses, and about physical, social, and recreational functioning. Those meeting the 1994 CFS case definition, as determined on the basis of their telephone responses, were invited for clinical evaluation to confirm a diagnosis of CFS. For this analysis, we evaluated unemployment due to fatigue, number of hours per week spent on work, chores, and other activities (currently and prior to the onset of fatigue), and energy level.
RESULTS: There was no difference between persons with CFS and persons with a CFS-like illness that could be explained by a medical or psychiatric condition for any of the outcomes we measured except for unemployment due to fatigue (15% vs. 40%, p<.01). Persons with CFS and other fatiguing illnesses had substantially less energy and spent less time on hobbies, schooling, or volunteer work than did non-fatigued controls (p<.01).
CONCLUSIONS: Persons with CFS are as impaired as persons whose fatigue could be explained by a medical or psychiatric condition, and they have less energy than non-fatigued controls.
Englebienne, P. RNase L in health and disease - what did we learn recently? Journal of Chronic Fatigue Syndrome, 2003, 11, 2, 97-109.
Lyall, M., Peakman, M and Wessely, S. A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. Journal of Psychosomatic Research, 2003, 55, 2, 79-90.
Objective: Immune dysfunction in patients with CFS has been widely but inconsistently reported. Traditional reviews of the literature have produced a variety of conclusions. We present the results of the first systematic review of the subject.
Methods: EMBASE, MEDLINE and PSYCHINFO databases were searched, and leading researchers in the field were contacted. Inclusion criteria were applied*, and studies were then divided into groups based on the quality of their methodology. Study results were collated and described.
Results: Studies ranged widely in quality. There was an inverse association between study quality and finding low levels of natural killer cells, suggesting that the association may be related to study methodology. On the other hand, reports of abnormalities in T cells and cytokine levels were not related to study quality.
Conclusions: The conclusions of this systematic review differ from a recent traditional narrative review of the immunology of CFS. No consistent pattern of immunological abnormalities is identified.
[Ed. note: the assessment of quality does not appear to have included the use of valid diagnostic criteria. Thus the apparent association between the use of stricter criteria and immunological abnormalities was not detected or discussed.]
Van Hout, MSE., Wekking, EM., Berg, IJ and Deelman, BG. Psychological treatment of patients with chronic toxic encephalopathy: lessons from studies of chronic fatigue and whiplash. Psychotherapy and Psychosomatics, 2003, 72, 5, 235-244.
BACKGROUND: Chronic toxic encephalopathy (CTE), which can result from long-term exposure to organic solvents, is characterized by problems of attention and memory, fatigue and affective symptoms. There is little experience with (neuro)psychological treatment in this patient group. We reviewed treatment outcome studies of CTE and comparable syndromes, namely, chronic whiplash-associated disorder (WAD) and CFS, with a view to providing recommendations for the psychological treatment of patients with CTE.
METHODS: PubMed and PsychLIT were systematically searched and reference lists of retrieved articles were studied. The articles were classified according to study design and level of evidence.
RESULTS: The studies of CFS provided high-level evidence for the effectiveness of cognitive-behavior therapy (CBT) in challenging dysfunctional cognitions regarding the effectiveness of rest and in stimulating graded activity. The studies of WAD were methodologically weaker, and most evaluated a combination of CBT and graded activity training. There was some evidence that changing fatigue- or pain-related behaviors may result in cognitive improvement. Two uncontrolled studies of CTE evaluated cognitive rehabilitation techniques but yielded inconsistent findings.
CONCLUSIONS: CBT techniques focusing on changing illness attributions and on stimulating graded activity might be useful for patients with CTE, diminishing fatigue-related problems of concentration and memory. Future studies should evaluate whether cognitive deficits of CTE patients as a result of neurotoxic effects of exposure should be treated by cognitive rehabilitation.
[Ed. note: The authors do not recognise the influence of different diagnostic criteria, nor do they note flaws such as the use of unvalidated definitions cf Prins et al, and the limited assessment of symptoms. As a result, their conclusions may not be reliable.]
Ahlberg, K., Ekman, T., Gaston-Johansson, F and Mock, V. Assessment and management of cancer-related fatigue in adults. Lancet, 2003, 362, 640-650.
Review of cancer-related fatigue with a discussion of the benefits of activity.
Candy, B., Chalder, T., Cleare, AJ., Peakman, A., Skowera, A., Wessely, S., Weinman, J., Zucherman, M and Hotopf, M. Predictors of fatigue following the onset of infectious mononucleosis. Psychological Medicine, 2003, 33, 847-855.
Infectious mononucleosis (IM)is a risk factor for chronic fatigue. However, little is known about the biological mechanisms involved in the pathogenesis of chronic fatigue following IM and no study, so far, has examined the relation between certain illness beliefs and poor outcome. This study explored immunological, endocrine, behavioural and cognitive responses to the acute illness and assessed which components of these groups of risk factors predicted a chronic course.
Using a prospective cohort design, 71 primary care patients with IM were enrolled into the study and interviewed. Their recovery was explored by postal questionnaire up to 1 year later (n=19). In the univariate analysis, increased baseline levels of immune activation were associated with fatigue at baseline and 3 months. Cortisol levels were not associated with fatigue at any point. Using multi-variate models of clinical and psychosocial baseline factors, severity of symptoms and illness perceptions were found to predict fatigue 3 months later. At 6 months, fatigue was best predicted by female gender and [various, ed.] illness perceptions, and at 12 months by female gender and a symptoms-disability factor. To conclude, in the multivariate analysis no factors were found to predict poor outcome at all time-points. Instead the pattern of predictors changed over time.
[Ed. Note: Cases were defined as having a certain score on the Chalder Fatigue Scale. The normal cortisol levels in the first six months of illness support the view that low values are not a cause of fatigue or related directly to fatigue, and may reflect chronic stress.]
Matano, S., Kinoshita, H., Tanigawa, K., Terahata, S and Sugimoto, T. Acute parvovirus B19 infection mimicking chronic fatigue syndrome. Internal Medicine, 2003, 42, 9, 903-905.
A Japanese woman developed prolonged fatigue, neck and shoulder pain, headache, pyrexia, insomnia, anorexia, lymphadenopathy, and diarrhea for two months. She had experienced various stressors before these symptoms developed. Serological test demonstrated that she had acute parvovirus B19 infection. Major depressive disorder was also diagnosed by a psychiatrist. Her symptoms disappeared after administration of selective serotonin reuptake inhibitors and oriental herbs, although human parvovirus B19 viral genome has been present in her serum for nine months.
These findings suggest that parvovirus B19 causes clinical features similar to those of CFS in cases who have prior life stressors.
Carlsen, B. Professional support of self-help groups: a support group project for chronic fatigue syndrome patients. British Journal of Guidance & Counselling, 2003, 31, 3, 289-303.
Chester, AC. Symptoms of rhinosinusitis in patients with unexplained chronic fatigue or bodily pain: a pilot study. Archives of Internal Medicine, 2003, 163, 15, 1832-1836.
BACKGROUND: Recent otolaryngologic studies document significant fatigue and bodily pain (BP) in patients with chronic rhinosinusitis. Studies of general medical patients are lacking.
METHODS: A case-control study of 297 consecutive general medical outpatients.
RESULTS: Sixty-five patients noted unexplained chronic fatigue (UCF) of whom 23% had CFS, 33 reported BP, and 26 had both. Compared with 232 patients without UCF, patients with UCF more frequently had the following rhinosinusitis symptoms: facial pressure (odds ratio [OR], 9.7), heavy-headedness (OR, 21.9), nasal obstruction (OR, 4.3), frontal headache (OR, 13.6), postnasal drip (OR, 2.8), sore throat (OR, 3.1), and tender cervical lymph nodes (OR, 9.2). A similar predominance of rhinosinusitis symptoms was noted in patients with BP and in 15 patients with UCF who had CFS. No increased prevalence of pollen allergy was noted in association with UCF, BP, or CFS. Gastrointestinal, sleep, and psychiatric problems were similar between patients with UCF and 38 patients with explained fatigue. Rhinosinusitis symptoms, however, were more common in UCF.
CONCLUSIONS: There is an increased prevalence of rhinosinusitis symptoms but not pollen allergy among general medical outpatients with UCF, BP, or both. Rhinosinusitis symptoms are at least as common as gastrointestinal complaints, sleep disturbance, and psychiatric problems (previously well documented complaints associated with UCF and BP). Rhinosinusitis symptoms, furthermore, are more common in UCF than in fatigue explained by a physical or mental illness.
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, 4, 540-547. Online 6.10.03.
Tests on skeletal muscle found enteroviral RNA in 4 of 30 (13%) subjects with FM\CFS and 3 of 15 (20%) of patients with inflammatory muscle disease using RT-PCR. None of the 29 healthy controls were positive. The presence of VP-1 enteroviral capsid protein was also assessed; no muscle biopsy was positive in any patient or control.
The presence of viral RNA but absence of VP-1 protein supports the notion of a persistent infection involving defective viral replication.
Ikuta, K., Yamada, T., Shimomura, T., Kuratsune, H., Kawahara, R., Ikawa, S., Ohnishi, E., Sokawa, Y., Fukushi, H., Hirai, K., Watanabe, Y., Kurata, T., Kitani, T and Sairenji, T. Diagnostic evaluation of 2', 5'-oligoadenylate synthetase activities and anti-bodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan. Microbes and Infection, 2003, 5, 1096-1102.
The aim of this study was to investigate the association of viral infections with CFS. The researchers assayed 2', 5'-oligoadenylate synthetase (2-5AS) activities in PBMCs from CFS patients, diagnosed in two hospitals, H1 and H2, located in different areas of Japan. The activities were detected in 19 (86%) and 7 (32%) of each of the 22 patients in H1 and H2, respectively, while they were detected in only four (11%) out of the 38 healthy controls. IFN-á was similarly detected in a few CFS patients and healthy controls.
We also assayed the antibody titers against Epstein-Barr virus (EBV) and Coxiella burnetii in these patients. The EBV anti-EA-IgG antibodies were detected in two (9%) and seven (32%) of each of the 22 patients in H1 and H2, respectively. Anti-C. burnetii IgG antibodies were detected in six (27%) out of 22 patients in H1 but not in 22 patients in H2, while they were detected in one (11%) of the nine healthy controls.
Some cases of CFS may be associated with EBV or C. burnetii infection. There were some statistical correlations between the 2-5AS activities and antibody titers of EA-IgG (p<0.05) but not to the antibody titers of C. burnetii. The up-regulation of 2-5AS activities suggests immunological dysfunctions with some virus infections in the CFS patients. Our results indicate that 2-5AS activities are useful for a diagnostic marker of CFS and for exploring the complicated pathogenesis of CFS.
Kakumanu, SS., Mende, CN., Lehman, EB., Hughes, K and Craig, TJ. Effect of topical nasal corticosteroids on patients with chronic fatigue syndrome and rhinitis. Journal of the American Osteopathic Association, 2003, 103, 9, 423-427.
Recent studies have shown that patients with CFS have an increased prevalence of non-allergic rhinitis. Inflammation of the nasal passages due to allergic rhinitis can cause nasal congestion resulting in an increased number of sleep disturbances and daytime fatigue. While topical nasal corticosteroids have been shown to alleviate nasal obstruction effectively in patients with rhinitis who do not have CFS, it is unknown whether topical nasal corticosteroids will reduce CFS symptoms.
METHODS: Twenty-eight of 31 subjects with rhinitis and a diagnosis of CFS completed the double-blind, randomized, placebo-controlled trial. Two subjects failed screening, and 3 subjects withdrew from the study prior to its completion. Subjects were randomized according to Balaam's crossover design, and one of the following interventions was used for each group in the study: 8-week treatment with a topical nasal corticosteroid, 8-week treatment with a placebo saline spray, 4-week treatment with a topical nasal corticosteroid followed by a 4-week treatment with a placebo saline spray, or a 4-week treatment with a placebo saline spray followed by a 4-week treatment with a topical nasal corticosteroid. Data focusing on rhinitis symptoms, severity of chronic fatigue symptoms, and quality of life were gathered at biweekly office visits and with daily diaries.
RESULTS: The results indicated that daytime sleepiness was reduced when patients with rhinitis and CFS were treated with topical nasal corticosteroids. The severity of associated CFS symptoms, specifically fatigue, muscle pain, postexertional fatigue, and daily activity, did not improve with treatment.
CONCLUSION: Treating the symptoms of rhinitis in patients with CFS does not appear to alleviate daytime fatigue or associated nasal, musculoskeletal, or cognitive complaints. Therefore, it is unlikely that aggressive treatment of such symptoms with topical nasal corticosteroids will provide significant benefit to patients with CFS who do not have allergic rhinitis. The nonallergic rhinitis seen in patients with CFS may arise from a mechanism other than chronic inflammation.
Kerr, JR and Tyrrell, DA. Cytokines in parvovirus b19 infection as an aid to understanding chronic fatigue syndrome. Current Pain and Headache Reports, 2003, 7, 5, 333-341.
Human parvovirus B19 infection has been associated with various clinical manifestations of a rheumatic nature such as arthritis, fatigue, and CFS, which can persist for years after the acute phase. The authors have demonstrated recently that acute B19 infection is accompanied by raised circulating levels of IL-1b, IL-6, TNF-á, and IFN-ã and that raised circulating levels of TNF-á and IFN-ã persist and are accompanied by MCP-1 in those patients who develop CFS. A resolution of clinical symptoms and cytokine dysregulation after intravenous immunoglobulin (IVIG) therapy, which is the only specific treatment for parvovirus B19 infection, also has been reported.
Although CFS may be caused by various microbial and other triggers, that triggered by B19 virus is clinically indistinguishable from idiopathic CFS and exhibits similar cytokine abnormalities and may represent an accessible model for the study of CFS.
Morrison, MCT. Medically unexplained symptoms. Journal of the Royal Society of Medicine, 2003, 96, 520.
Letter responding to an article by Page and Wessely (ibid, 223-7) noting that a doctor's ignorance may be one cause of medically unexplained symptoms.
Nicolson, GL., Nasralla, MY., Nicolson, NL and Haier, J. High prevalence of mycoplasma infections in symptomatic (chronic fatigue syndrome) family members of mycoplasma-positive Gulf War illness patients. Journal of Chronic Fatigue Syndrome, 2003, 11, 2, 21-36.
Immediate family members of veterans diagnosed with Gulf War llnesses (GWI) often complain of fatiguing illnesses, and upon analysis they report similar signs and symptoms as their veteran family members. The researchers examined military families (149 patients, 42 veterans, 40 spouses, 32 other relatives, and 35 children) selected from a group of 110 veterans of GWI who tested positive for at least one of mycoplasma species (fermentans, hominis, pneumoniae or genetalium).
Consistent with previous results, over 80% of Gulf War illness patients who were positive for blood mycoplasma infections had only one Mycoplasma spp., in particular M. fermentans. 53% of symptomatic family members were found to have symptoms of CFS and\or FM. In the few mycoplasma-positive, non-symptomatic family members, the mycoplasma species was often different from the species found in GWI patients. The findings suggest that there is a subset of patients with GWI who have mycoplasma infections and that in some cases, this is transmitted to family members who then develop symptoms of CFS and\or FM.
Nisenbaum, R., Jones, JF., Unger, ER., Reyes, M and Reeves, WC. A population-based study of the clinical course of chronic fatigue syndrome. Health and Quality of Life Outcomes, 2003, 1, 1:49 (published 3 October 2003, www.hqlo.com/content/1/1/49/0)
We conducted a longitudinal population-based study to characterize the clinical course of CFS.
Methods. Sixty-five CFS subjects were identified from a random-digit-dialing survey of Wichita, Kansas residents and followed for up to 3 years. We evaluated changes in CFS classification (partial or total remission, alternative medical or psychiatric diagnoses), CFS case-defining criteria, wellness scores, hours of activities and sleep, and treatments used to reduce fatigue. Associations between risk factors and outcomes were determined by use of logistic regression and generalized estimating equations models.
Results. About 30% had been diagnosed as depressed but only 16.9% had a lifetime history of MD (DIS). None had current or lifetime somatisation. 77% had a gradual onset. 20%-33% of the subjects were classified as having CFS at follow-up, 56.9% experienced partial or total remission, 10% sustained total remission, and 23.1% received alternative diagnoses, of which 20% were sleep disorders. Higher fatigue severity scores and total number of symptoms were negatively associated with any remission. Duration of illness <2 years was positively associated with sustained remission. Unrefreshing sleep persisted in more than 80% of the subjects across all periods but, as with most of the CFS symptoms, tended to be less frequent over time. The number of activities affected by fatigue decreased over time, while wellness scores increased. At any follow-up, more than 35% of subjects reporting reduced fatigue used complementary and alternative medicine therapies, and of those subjects, at least 50% thought these therapies were responsible for reducing their fatigue.
Conclusions. The clinical course of CFS was characterized by an intermittent pattern of relapse and remission. Remission rates documented by our population-based study were similar to those reported in clinical studies. Shorter illness duration was a significant predictor of sustained remission, and thus early detection of CFS is of utmost importance. The persistence of sleep complaints and identification of sleep disorders suggest that CFS subjects be evaluated for sleep disturbances, which could be treated.
See also editorial by G. Bleijenberg, ibid, 1, 1:52, published online 6th October.
Patel, MX., Smith, DG., Chalder, T and Wessely, S. Chronic fatigue syndrome in children: a cross sectional survey. Archives of Diseases in Childhood, 2003, 88, 10, 894-898.
METHODS: Cross sectional survey of 36 children attending a GP specialist interest clinic in southeast England.
RESULTS: Patient sociodemographics and clinical morbidity were largely comparable to the literature from tertiary referral research centres. Some prognostic indicators for adults did not readily transfer to this younger age group, although several children had a positive family psychiatric history. Receiving treatment (consistent with the CBT\GET regimes for adults) was associated with increased school attendance, but one third of subjects obtained no qualifications. Return to normal health or significant overall improvement was reported by 29/36 subjects.
CONCLUSIONS: The outcomes in this setting are favourable and comparable to those seen in a controlled setting; this study supports the concept that the prognosis for CFS in children and adolescents is generally good. However, the impact of the illness is significant and this is perhaps most evident in terms of education. Current methods of reporting educational outcomes in the literature are varied and merit development of standardised tools.
[Ed. note: It is unclear how many, if any, children fulfilled the standard criteria for CFS. 36.1% of the children considered emotional upset as a causal factor. 33.3% highlighted school stress as a definite factor. There is no information on symptoms other than fatigue, anxiety and depression.]
Singh, A., Garg, V., Gupta, S and Kulkarni, SK. Role of antioxidants in chronic fatigue syndrome in mice. Indian Journal of Experimental Biology, 2002, 40, 11, 1240-1244.
The present study was carried out using mice model of CFS in which mice were forced to swim everyday for 7 days for a 6 minute session. There was a significant increase in despair behavior (immobility period) in saline treated mice on successive days. Treatment with potent antioxidants carvedilol (5 mg/kg, i.p.) and melatonin (10 mg/kg, i.p.) produced a significant reduction in immobility period. Similar results were observed with herbal products St. John's Wort (Hypericum perforatum L., 10 mg/kg, p.o.) and GS-02 (20 mg/kg, p.o.). Fluoxetine, a selective serotonin reuptake inhibitor produced a significant effect only on first and second day of its treatment.
Biochemical analysis revealed that the swim test significantly increased lipid peroxidation and catalase levels in whole brains of mice. Administration of carvedilol, melatonin, GS-02 and St. John's Wort restored the levels of lipid peroxidation and glutathione. The enzymes SOD and catalase were also restored. Fluoxetine affected the biochemical variables not to the same extent as other treatments. The findings of the present study suggest that oxidative stress might play a significant role in the pathophysiology of CFS.
[Ed. note: It may be argued that these findings apply to 'stress-related' fatigue, rather than CFS.]
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