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Lerner, AM., Dworkin, HJ., Sayyed, T., Chang, CH., Fitzgerald, JT., Beqaj, S., Deeter, RG., Goldstein, J., Gottipolu, P and O'Neill, W. Prevalence of abnormal cardiac wall motion in the cardiomyopathy associated with incomplete multiplication of Epstein-Barr Virus and/or cytomegalovirus in patients with chronic fatigue syndrome. In Vivo, 2004, 18, 4, 417-424.
We reported unique incomplete herpesvirus (Epstein-Barr Virus (EBV) and/or nonstructural (HCMV) cytomegalovirus) multiplication in 2 distinct subsets of CFS patients. The CFS subsets were identified by: a) presence of IgM serum antibodies to HCMV non-structural gene products p52 and CM2(UL44 and UL57), and/or b) IgM serum antibodies to Epstein-Barr virus viral capsid antigen (EBV, VCA IgM). Diagnostic IgM serum antibodies were found in two independent blinded studies involving 49 CFS patients, but the same antibodies were absent in 170 control patients (p<0.05). Abnormal 24 Hr-electrocardiographic monitoring, tachycardias at rest and, in severe chronic cases, abnormal cardiac wall motion (ACWM) were seen in these same CFS patients.
We now report a prospective consecutive case control study from 1987-1999 of cardiac dynamics as measured by radionuclide ventriculography in 98 CFS patients. All patients met the 1988 and 1994 CDC criteria and all had abnormal Holter monitoring. None had been depressed prior to the onset of CFS but 11% had reactive depressions since. The mean age was 42.3 years. Controls were patients with various malignancies who were evaluated in protocols requiring radionuclide ventriculography before initiation of cardiotoxic chemotherapeutic agents. Mean age was 48.9 years.
The prevalence of abnormal cardiac wall motion (ACWM) at rest in CFS patients was 10 out of 87 patients (11.5%). With stress exercise, 21 patients (24.1%) demonstrated ACWM. Cardiac biopsies in 3 of these CFS patients with ACWM showed a cardiomyopathy. Among the controls, ACWM at rest was present in 4 out of 191 patients (2%)(p=0.0018), even though they were slightly older. ”Abnormal cardiac wall motion at rest indicates severe cardiac dysfunction” A progressive cardiomyopathy caused by incomplete virus multiplication of EBV and/or HCMV in CFS patients is present.
Kennedy, G., Spence, V., Underwood, C and Belch JJF. Increased neutrophil apoptosis in chronic fatigue syndrome. Journal of Clinical Pathology, 2004, 57, 8, 891-893.
Many patients with CFS have symptoms that are consistent with an underlying viral or toxic illness. Because increased neutrophil apoptosis occurs in patients with infection, this study examined whether this phenomenon also occurs in patients with CFS. Apoptosis was assessed in patients with CFS (CDC criteria ’94) in conjunction with concentrations of the anti-inflammatory cytokine, transforming growth factor-b1 (TGFb1).
The 47 patients with CFS had higher numbers of apoptotic neutrophils, lower numbers of viable neutrophils, increased annexin V binding, and increased expression of the death receptor, tumour necrosis factor receptor-I (TNFRI), on their neutrophils than did the 34 healthy controls. Patients with CFS also had raised concentrations of active TGFb1 (p<0.005).
These findings provide new evidence that patients with CFS have an underlying detectable abnormality in their immune cells.
From the discussion: We have shown that there are a greater proportion of apoptotic cells among neutrophils isolated from patients with CFS and that these cells are significantly less viable when compared with those from healthy subjects. The same neutrophils expressed more TNFRI death receptor molecules and had increased binding of annexin V, indicative of phosphatidylserine exposure…
The data presented here are consistent with the fact that many patients with CFS have an underlying, detectable abnormality in the behaviour of their immune cells, consistent with an activated inflammatory process.
In addition, we found that the concentrations of activated TGFb1 were significantly raised in the PPP (platelet poor plasma, Ed) of patients with CFS. An increase in activated TGFb1 in conjunction with neutrophil apoptosis is an important process in the downregulation of cytokines and eicosanoid production during the chronic inflammatory process. TGFb1 is also crucial in the apoptotic process because it curbs leucocyte adhesion and transmigration, and this impairment of the transmigratory process of neutrophils may independently promote apoptosis. Neutrophils that transmigrate across the endothelium lose TNF receptors and this loss of receptor density is necessary for the survival of the neutrophil. The fact that neutrophils from patients with CFS have increased surface expression of TNFRI is a further indication that such cells are more susceptible to apoptosis.
The neutrophils of patients with CFS have an increased rate of apoptosis and this may impact on the innate immune system of these patients, given that neutrophils are the major effector cells of this system. The control of apoptosis is complex, and the increased rate of apoptosis in patients with CFS may be a consequence of several factors. Accelerated apoptosis is indicative of a persistent or reactivating viral infection or a toxic state, reprogramming of apoptotic pathways by an infectious or toxic agent, or quicker neutrophil turnover, secondary to an abnormal host response to noxious stimuli.
…The data presented here are consistent with the fact that many patients with CFS have an underlying, detectable abnormality in the behaviour of their immune cells, consistent with an activated inflammatory process.
[Ed. Note: This study was funded by MERGE, suggesting patients also met the criteria for ME.]
Chaudhuri, A and Behan, PO. In vivo magnetic resonance spectroscopy in chronic fatigue syndrome. Prostaglandins, Leukotrines and Essential Fatty Acids, 2004, 71, 3, 181-183.
Short discussion paper noting that the pathogenic mechanisms of CFS are not clearly known. Research data on magnetic resonance spectroscopy (MRS) of muscles and brain in CFS patients suggest a cellular metabolic abnormality in some cases. 31P MRS of skeletal muscles in a subset of patients indicate early intracellular acidosis in the exercising muscles. 1H MRS of the regional brain areas in CFS have shown increased peaks of choline derived from the cell membrane phospholipids. Cell membrane oxidative stress may offer a common explanation for the observed MRS changes in the muscles and brain of CFS patients and this may have important therapeutic implications.
As a research tool, MRS may be used as an objective outcome measure in the intervention studies. In addition, regional brain 1H MRS has the potential for wider use to substantiate a clinical diagnosis of CFS from other disorders of unexplained chronic fatigue.
Okada, T., Tanaka, M., Kuratsune, H., Watanabe, Y and Sadato N. Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome. BMC Neurology, 2004, 4(1):14. URL: http://www.biomedcentral.com/1471-2377/4/14
Fatigue is a crucial sensation that triggers rest, yet its underlying neuronal mechanisms remain unclear. Intense long-term fatigue is a symptom of CFS, which is used as a model to study the mechanisms underlying fatigue. Using magnetic resonance imaging, we conducted voxel-based morphometry of sixteen patients with CFS (CDC criteria ’94) and 49 age-matched healthy control subjects.
We found that patients with CFS had reduced gray-matter volume in the bilateral prefrontal cortex. Within these areas, the volume reduction in the right prefrontal cortex paralleled the severity of the fatigue, as measured by performance-status scores.
These results are consistent with previous reports of an abnormal distribution of acetyl-L-carnitine, which is one of the biochemical markers of CFS, in the prefrontal cortex. Thus, the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue.
[Ed. Note: The authors also discuss similar findings relating to MS.]
Pazderka-Robinson, H., Morrison, JW and Flor-Henry, P. Electrodermal dissociation of chronic fatigue and depression: evidence for distinct physiological mechanisms. International Journal of Psychophysiology, 2004, 53, 3, 171-82.
Our primary goal was dissociation of these disorders using psychophysiological methods. As previous research has implicated the autonomic nervous system in CFS, we conducted what we believe to be the first analysis of bilateral electrodermal and skin temperature responses of dextral females in a cross-modal orienting task, to investigate differences between these two patient groups. The subject pool comprised 45 people with CFS (CDC criteria ’94, no current depression), 25 patients with major depressssion and 44 healthy controls.
A multivariate analysis of variance (MANOVA) examining three measures of electrodermal activity revealed prestimulus tonic skin conductance levels (SCLs) were markedly lower for the CFS group, with no difference between controls and depressives. Concurrent skin temperature levels were higher for the CFS group than the other two groups.
These findings indicate that, despite overtly similar cognitive and symptom profiles, depression and CFS patients can be differentiated with psychophysiological measures. This study adds to the growing body of evidence demonstrating that CFS and depresssion have distinct neurobiological profiles, consistent with unique aetiologies.
[Ed. Note: The researchers acknowledge that patients often report decreased body temperature. Moreover, several authors have observed that ‘cold extremities’ are common in ME. It is unclear how this relates to the findings of higher temperatures above.]
Siemionow, V., Fang, Y., Calabrese, L., Sahgal, V and Yue, GH. Altered central nervous system signal during motor performance in chronic fatigue syndrome. Clinical Neurophysiology, 2004, 115, 10, 2372-2381.
The purpose of this study was to determine whether brain activity of CFS patients during voluntary motor actions differs from that of healthy individuals.
Eight CFS patients (CDC criteria ’88) and 8 age- and gender-matched healthy volunteers performed isometric handgrip contractions at 50% maximal voluntary contraction level. They first performed 50 contractions with a 10 second rest between adjacent trials - the 'Non-Fatigue' (NFT) task. Subsequently, the same number of contractions was performed with only a 5 second rest between trials - the 'Fatigue' (FT) task. Fifty-eight channels of surface EEG were recorded simultaneously from the scalp. Spectrum analysis was performed to estimate power of EEG frequency indifferent tasks. Motor activity-related cortical potential (MRCP) was derived by triggered averaging of EEG signals associated with the muscle contractions.
Major findings include:
(i) Motor performance of the CFS patients was poorer than the controls. The handgrip strength was 26% lower than that of the controls. As a whole, the CFS patients were ‘weaker’ and fatigued significantly whereas the healthy controls did not. The patients were more severely fatigued by the motor tasks, especially by the FT task. These findings could reflect inactivity.
(ii) Relative power of EEG theta frequency band (4-8 Hz) during the NFT and FT tasks was significantly greater in the CFS than control group (p<.05).
(iii) The amplitude of MRCP negative potential (NP) for the combined NFT and FT tasks was higher in the CFS than control group (p<.05).
(iv) Within the CFS group, the NP was greater for the FT than NFT task (p<.01) whereas no such difference between the two tasks was found in the control group. Stronger voluntary efforts were needed by patients to perform the same motor tasks. There were no group differences in EMG.
To conclude: these results clearly show that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue. Physical activity-induced EEG signal changes may serve as physicological markers for more objective diagnosis of CFS.
Yoshiuchi, K., Quigley, KS., Ohashi, K., Yamamoto, Y and Natelson, BH. Use of time-frequency analysis to investigate temporal patterns of cardiac autonomic response during head-up tilt in chronic fatigue syndrome. Autonomic Neuroscience, 2004, 113(1-2), 55-62.
Although a number of studies have reported alterations in cardiac
autonomic nervous system function in CFS, the results are not consistent across studies. Reasons for these discrepancies include (1) the use of a heterogeneous patient sample that included those with orthostatic postural tachycardia (POTS), a condition with autonomic changes, and (2) the use of frequency domain techniques which require a stationary signal and averaging data across relatively long epochs.
To deal with these shortcomings, we used the smoothed pseudo-Wigner-Ville transform (SPWVT) to analyze heart rate variability (HRV) and blood pressure variability (BPV) during head-up tilt (HUT) by separating CFS patients into those with and without POTS. SPWVT has the advantage of providing instantaneous information about autonomic function under nonstable physiological conditions.
We studied 18 CFS patients without POTS, eight CFS patients with POTS and 25 sedentary healthy controls during supine rest and during the first 10 minutes after HUT. All patients with CFS met the 1988 and 1994 CDC criteria. The controls did not exercise regularly.
While we found significant effects of postural change in both groups for all autonomic variables, there were significant group x time interactions between CFS without POTS and controls for only instant center frequency (ICF) within the low frequency region both from HRV (p=0.02) and from BPV (p=0.01). Although the physiological meaning of ICF still remains unknown, the data suggest that even CFS patients without POTS may have a subtle underlying disturbance in autonomic function.
Gaab, J., Rohleder, N., Heitz, V., Engert, V., Schad, T., Schurmeyer, TH and Ehlert, U. Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology, 2005 30, 2, 188-198.
It has been suggested that a hypofunctional hypothalamic-pituitary-adrenal (HPA) axis in CFS could result in an exaggerated release of pro-inflammatory cytokines during stress. As pro-inflammatory cytokines are involved in the induction of sickness behavior and thus constitute a potential physiological correlate of stress-induced symptom exacerbation in CFS, we set out to evaluate the LPS-induced production of pro-inflammatory cytokines during psychosocial stress in CFS and healthy controls.
Twenty-one CFS patients (Oxford and CDC criteria ’94, 14 post-infectious onset) and 20 healthy controls matched for age and gender underwent a standardized psychosocial stress test (Trier social stress test, TSST). Adrenocorticotropine hormone (ACTH), salivary cortisol and plasma cortisol levels were measured before and repeatedly following exposure to the stressor. Lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-a (TNF-a) were assessed at baseline as well as 10 and 60 min after the stress test.
There were no stress-related changes in monocyte or leukocyte numbers. CFS patients showed an inverse stress-induced response pattern of LPS-stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were significantly associated for TNF-a in controls and for both cytokines in CFS patients. Stress-induced changes in stimulated cytokine production were not associated with general fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines. However, partial correlations revealed that these results were due to the high correlations with basal LPS-induced cytokine levels. There were no differences in cortisol levels.
CFS patients do not show an exaggerated secretion of LPS-induced cytokines. Although cortisol responses to stress were normal, pro-inflammatory cytokine levels in CFS patients were significantly attenuated. Possible intracellular mechanisms, such as for example an enhanced sensitivity to inhibitory effects of glucocorticoids, a diminished responsivity to catecholaminergic stimulation, and a disruption of intracellular activation are discussed. Basal levels of stimulated pro-inflammatory IL-6 levels are generally related to fatigue scores. However, in CFS patients this association is of greater magnitude and can also be observed for TNF-a.
Huibers, MJ., Kant, IJ., Knottnerus, JA., Bleijenberg, G., Swaen, GMH and Kasl, SV. Development of the chronic fatigue syndrome in severely fatigued employees: predictors of outcome in the Maastricht cohort study. Journal of Epidemiology and Community Health, 2004, 58, 10, 877-882.
The aim of this study was to identify risk factors of the development of CFS, the persistence or recurrence of fatigue, or recovery from fatigue in a large sample of fatigued employees. Analyses were based on the Maastricht cohort study (MCS), a prospective population based cohort study among more than 12,000 employees. Multiple regression models were used to identify predictors of CFS-like caseness (meeting symptom criteria for CFS), non-CFS fatigue caseness, or no fatigue caseness. Subjects were 1143 employees with medically unexplained fatigue who were followed up prospectively for 44 months.
At 44 month follow up, 8% of the employees were CFS-like cases (none of whom were reported to have received a CFS diagnosis), 40% were non-CFS fatigue cases, and 52% were no longer fatigue cases. (At baseline, none were CFS-like.)
Baseline factors that predicted CFS-like caseness at follow-up compared with non-CFS fatigue caseness were: high age, exhaustion, female sex, low education, and visits to the general practitioner. Baseline factors that predicted non-CFS fatigue caseness compared with no fatigue caseness were fatigue, low self perceived activity, exhaustion, anxious mood, and bad self rated health.
Unexplained fatigue among employees in some instances is a precursor of the development of CFS. The prognostic role of self rated health suggests that prevention and treatment of chronic fatigue should be aimed at changing the perception of health or illness. Less clear is the role of health care seeking or receiving a CFS diagnosis.
[Ed. Note: The criteria for CFS tend to refer to new onset fatigue so it is difficult to generalise the findings of this study (on patients with ongoing fatigue) to people with well-defined CFS. There was no medical examination.]
Blacker, CVR., Greenwood, DT., Wesnes, KA, Wilson, R., Woodward, C., Howe, I and Ali, T. Effect of Galantamine Hydrobromide in chronic fatigue syndrome. A randomized controlled trial. JAMA, 2004, 292, 1195-1204.
There is no established pharmacological treatment for the core symptoms of CFS. Galantamine hydrobromide, an acetyl cholesterone inhibitor, has pharmacological properties that might benefit patients with CFS. The aim here was to compare the efficacy and tolerability of galantamine hydrobromide in patients with CFS.
This was a randomized, double-blind trial conducted June 1997 through July 1999 at 35 outpatient centers in the United Kingdom (n=17), United States (n=14), the Netherlands (n=2), Sweden (n=1), and Belgium (n=1) involving 434 patients with a clinical diagnosis of CFS with or without FM (modified CDC criteria ‘94).
Interventions: A total of 89 patients were randomly assigned to receive 2.5 mg of galantamine hydrobromide; 86 patients, 5.0 mg; 91 patients, 7.5 mg; and 86 patients, 10 mg (these patients received medicine in the tablet form 3 times per day); a total of 82 patients received matching placebo tablets 3 times per day.
Main outcome measures: The primary efficacy variable was the global change on the Clinician Global Impression Scale after 4, 8, 12, and 16 weeks of treatment. Secondary outcomes were changes in core symptoms of CFS on the Chalder Fatigue Rating Scale, the Fibromyalgia Impact Questionnaire, and the Pittsburgh Sleep Quality Index; changes in quality of life on the Nottingham Health Profile; and assessment of plasma-free cortisol levels and cognitive performance on a computer-based battery of tests.
Results: After 16 weeks, there were no statistically significant differences between any of the galantamine or placebo groups in clinical condition on the Clinician Global Impression Scale, or for any of the secondary end points. Exploratory regression analysis failed to detect any consistent prognostic factor that might have influenced the primary or any secondary outcome measures.
Conclusion: This trial did not demonstrate any benefit of galantamine over placebo in the treatment of patients with CFS.
[Ed. Note: The patients had modest Fatigue Scale scores. It is not clear how many subjects also met the criteria for FM.]
See also Straus, SE. Editorial. Pharmacotherapy of chronic fatigue syndrome. Another gallant attempt JAMA, 2004, 292, 1234-1235.
King, C and Jason, LA. Improving the diagnostic criteria and procedures for chronic fatigue syndrome. Biological Psychology, 2005, 68, 87-106.
Since the publication of the case definition for CFS in 1988 the diagnostic criteria have been revised twice in the U.S. None of the case definitions were derived empirically. As a result, there is concern regarding the sensitivity, specificity, and reliability of the criteria. The goal of the present study was to identify methods for improving the diagnostic criteria for CFS.
Three groups of 15 participants each were recruited: participants with (1) CFS, (2) major depressive disorder (MDD), and (3) healthy controls. Measures included the Beck Depression Inventory, the MOS SF-36 scale and physical, cognitive, and emotional symptom checklist. For the latter, participants were asked to indicate whether or not they had a number of symptoms commonly experienced by people with CFS. Included in this list were fatigue and the eight diagnostic symptoms specified by Fukuda et al (1994). Participants were asked to report if each symptom had been present for 6 months or longer, began before the onset of their fatigue or health problems, how often it is experienced, and rate the intensity of each symptom on a scale of 0-100. Subjects were also interviewed using the structured clinical interview for the DSM-IV (SCID). Using statistical procedures, three methods for improving the diagnostic criteria were explored: identification of new diagnostic symptoms, the use of severity ratings for symptomatology, and the identification of standardized measures that differentiate cases of CFS from other conditions.
None of the 66 symptoms from the physical, cognitive, and emotional symptom checklist were found to separate all three groups when looking at symptom occurrence. However, 37 of the 66 symptoms were more common in the CFS patients compared to controls and 16 were more common in the former than in the MDD group. Indeed, three symptoms in the fatigue/weakness group (post-exertional malaise, muscle weakness, feeling unsteady on feet), five symptoms in the neuropsychological category (need to focus on one thing at a time, confusion/disorientation, difficulty finding the right word, frequently losing train of thought, slowness of thought), three symptoms in the infectious category (hot and cold spells, feeling like having a temperature, feeling chilled/shivery), one in the cardiopulmonary (chest pain), and one in the gastrointestinal category (upset stomach), were found to occur significantly more in the CFS group than either the MDD or control group. In terms of severity, 31 of the 66 symptoms were rated as more severe by people with CFS compared to controls. In comparison to the MDD group, 17 symptoms were reported as being significantly more severe in the CFS group. Only three symptoms were reported as being significantly more severe in the MDD group in comparison to the control group.
Muscle weakness was reported by 93% of the CFS group and was found to occur significantly more in the CFS than either the MDD or controls groups. Muscle weakness was also significantly more severe in the CFS group in comparison to the MDD or control groups. Muscle weakness was therefore found to be a good discriminator among the three groups.
In comparing the CFS and control group, fatigue and all eight CDC symptoms were found to be significantly more severe in the CFS group. Comparisons between the MDD and control group revealed that two symptoms were reported as significantly more severe in the MDD group: unrefreshing sleep and impaired memory and concentration. Only one symptom, unrefreshing sleep, was found to be significantly different across all three groups.
When looking at symptom occurrence alone, some individuals in the MDD group met the inclusionary criteria for the current CDC definition for CFS. Taken together, these findings strongly suggest that when using symptom occurrence alone, there is a strong potential for individuals with MDD to be misclassified as having CFS. Six CDC symptoms were reported as being significantly more severe in the CFS group than the MDD group: fatigue, post-exertional malaise, unrefreshing sleep, sore throat, tender/sore lymph nodes, muscle pain, and pain in multiple joints without swelling or redness.
With regard to the MOS SF-36, CFS participants were found to have significantly lower scores on the physical functioning subscale (M= 44) in comparison to the MDD group (M= 70.33, p= 0.01) and the control group (M= 88.0, p= 0.01). Significant differences were not found between the MDD and control group on this scale. The mean BDI score of the CFS patients (14.53) fell between those of the other groups and indicated mild depression. Using SCID-IV, three (20%) met the DSM-IV criteria for dysthymia. No other psychiatric disorders were identified in the patients with CFS.
Results of the present study suggest that these three methods hold promise for improving the sensitivity, specificity, and reliability of the diagnostic criteria for CFS. The analyses examining differences in symptom severity ratings for fatigue and the eight symptoms of the CDC definition amongst individuals with CFS, MDD, and healthy controls demonstrated an improved ability to distinguish the CFS group from the MDD group than when symptom occurrence was used.
[Ed. Note: The findings contribute to the discussion of the validity of the CDC case definition but there are no figures for specificity and sensitivity.]
Edmonds, M., McGuire, H and Price, J. Exercise therapy for chronic fatigue syndrome. (Cochrane Review). In The Cochrane Library, issue 3, 2004. Chichester, UK: John Wiley & Sons Ltd.
Objectives: To investigate the relative effectiveness of exercise therapy and control treatments for CFS.
Search strategy: CCDANCTR-Studies and CENTRAL were searched using "Chronic Fatigue" and Exercise. The Journal of Chronic Fatigue Syndrome and CFS conferences were hand-searched. Experts in the field were contacted. Clinicaltrials.gov and controlled-trials.com were searched. Only Randomised Controlled Trials (RCT) including participants with a clinical diagnosis of CFS and of any age were included.
Data collection and analysis: The full articles of studies identified were inspected by two reviewers (ME and HMG). Continuous measures of outcome were combined using standardised mean differences. An overall effect size was calculated for each outcome with 95% confidence intervals. One sensitivity analysis was undertaken to test the robustness of the results.
Main results: Nine studies were identified for possible inclusion in this review, and five of those studies were included. At 12 weeks, those receiving exercise therapy were less fatigued than the control participants (SMD -0.77, 95% CIs -1.26 to -0.28). Physical functioning was significantly improved with exercise therapy group (SMD -0.64, Cis -0.96 to -0.33) but there were more dropouts with exercise therapy (RR 1.73, CIs 0.92 to 3.24). Depression was non-significantly improved in the exercise therapy group compared to the control group at 12 weeks (WMD -0.58, 95% CIs -2.08 to 0.92). Participants receiving exercise therapy were less fatigued than those receiving the antidepressant fluoxetine at 12 weeks (WMD -1.24, 95% CIs -5.31 to 2.83). Participants receiving the combination of the two interventions, exercise + fluoxetine, were less fatigued than those receiving exercise therapy alone at 12 weeks, although again the difference did not reach significance (WMD 3.74, 95% CIs -2.16 to 9.64). When exercise therapy was combined with patient education, those receiving the combination were less fatigued than those receiving exercise therapy alone at 12 weeks (WMD 0.70, 95% CIs -1.48 to 2.88).
Reviewers' conclusions: There is encouraging evidence that some patients may benefit from exercise therapy and no evidence that exercise therapy may worsen outcomes on average. However the treatment may be less acceptable to patients than other management approaches, such as rest or pacing. Patients with CFS who are similar to those in these trials should be offered exercise therapy, and their progress monitored. Further high quality randomised studies are needed.
[Ed. Note: this review has not taken significant factors into account, such as the limited assessment of symptoms (tiredness and emotional distress only), the lack of objective measures to ascertain that any improvements can be correlated with increases in activity, the low ceiling of the Chalder Fatigue scale (as a result of which baseline scores tend to be high and a worsening of fatigue can therefore not be recorded) and the fact that one of the studies assessed a mixture of GET and pacing, not ‘exercise’ as in the other trials. The authors refer to validated criteria when in fact, none have yet been validated (see above). In addition, they do not acknowledge important findings such as the limited number of significant group differences. Finally the higher drop out rates documented in the review may signify the fact that in some, exercise does worsen outcomes, though this is not perceived as an ‘adverse effect’ and therefore denied in the conclusions.]
<http://www.cochrane.org/cochrane/revabstr/ab003200.htm>
Baschetti, R. Chronic fatigue syndrome, pregnancy, and Addison’s Disease. Archives of Internal Medicine, 2004, 164, 2026.
Letter responding to Schacterle and Komaroff (ibid, 164, 401) and discussing the possible role of hypocorticolism.
Bazelmans, E., Prins, JB., Hoogveld, S and Bleijenberg, G. Manual-based cognitive behaviour therapy for chronic fatigue syndrome: therapists' adherence and perceptions. Cognitive Behaviour Therapy, 2004, 33, 3, 143-150.
Several randomized controlled trials have indicated that cognitive behaviour therapy (CBT) is an effective treatment for CFS. In one of these studies 13 therapists applied CBT for CFS in 83 patients. In the present study, therapists' adherence and perceptions of the manual are studied. Following completion of the study the therapists were asked to complete a questionnaire. Audiotaped sessions were conducted to verify the therapists' adherence. Analyses of the audiotapes showed that in 87% of the sessions this appeared to be the case. The questionnaire revealed that the therapists found it more difficult to treat patients with CFS than to treat patients with psychological or other physical problems. Treatment aspects posing the most problems were integrating individual problems into the standardized treatment, dealing with the patients' lack of confidence in the treatment and handling insufficient motivation.
Binder, LM and Campbell, KA. Medically unexplained symptoms and neuropsychological assessment. Journal of Clinical and Experimental Neuropsychology, 2004, 26, 369-392.
[Ed. Note: Discussion article with selective and unreliable information, which help to psychologise CFS. In relation to the results of brain scans, for example, the paper mentions that “a study using the same technique (as Tirelli et al, Ed.) found no difference between a group with CFS and a group with somatization disorder.” The study cited, Hakala et al 2002, does not compare SD with CFS but with healthy controls. Furthermore, it did not assess or report results in the brainstem, where Tirelli et al found hyperfusion. The authors do not mention the results of Costa et al which challenges their view. They would have known of the study as it was discussed in a paper which they cite (Lange et al 1998). They claim that according to Lange et al, “the abnormalities are nonspecific and similar to those found in psychiatric groups”. However, the paper points out that while some findings are similar to patients with psychiatric disorders and to controls, some are not. In fact, Lange et al found that patients with CFS but without psychiatric disorders, had “a significantly higher prevalence of white matter lesions than controls” and they mention abnormalities which differ from those documented in depression. There have been no reports, to my knowledge, of hypoperfusion in the brainstem in patients with psychiatric disorders.]
McCue, P., Martin, CR., Buchanan, T., Rodgers, T and Scholey, AB. An investigation into the psychometric properties of the Hospital Anxiety and Depression Scale in individuals with chronic fatigue syndrome. Psychology, Health & Medicine, 2003, 8, 425-439.
The study sought to determine the psychometric properties of the Hospital Anxiety and Depression Scale (HADS) in individuals with CFS assessed using a web-based data collection tool. Exploratory and confirmatory factor analyses were conducted on the HADS to determine its psychometric properties in 117 individuals with CFS (CDC criteria ’94). Seven models were tested to determine model fit to the data. Internal reliability estimations of the anxiety and depression subscales were found to be acceptable, however, a three-factor model was found to provide a significantly better fit to the data when compared to the bi-dimensional two-factor structure previously assumed to underpin the HADS’ construct validity (anhedonic depression, autonomic anxiety and negative affectivity).
The clinical utility of the HADS in the assessment of anxiety and depression in CFS appears to be fundamentally compromised by the presence of a three-dimensional underlying factor structure. Future revision of the HADS is recommended if the instrument is to be used reliably to screen CFS patients.
[Ed. Note: The patients represented a community, not clinical sample and were screened using items from the CDC and London criteria.]
Miike, T., Tomoda, A., Jhodoi, T., Iwatani, N and Mabe, H. Learning and memorization impairment in childhood chronic fatigue syndrome manifesting as school phobia in Japan. Brain and Development, 2004, 26, 7, 442-447.
For the last 15 years, we have tried to understand the pathophysiology of childhood CFS in Japan. In this condition, two major symptoms are important: easy fatigability and disturbed learning and memorization.
In CFS patients, we clinically evaluated autonomic nervous system function, circadian rhythm of hormonal secretion (melatonin, cortisol and 3-endorphin), core body temperature, and sleep-wake pattern. Most patients showed autonomic nervous system dysfunction and circadian rhythm disturbances, similar to those observed in jet lag.
Radiological imaging studies (SPECT, Xe-CT, and MRS) revealed decreased blood flow in the frontal and thalamic areas (N=167, patients versus controls p=.03), and accumulation of choline in the frontal lobe (N=42, patients versus controls: p<.05). In 81 patients, glucose was measured and cumulative blood glucose was significantly higher than in controls (p<.01). In addition, serum pyruvic acid was high.
The authors speculate that a problem is the disappearance of the biological clock and rhythms of activity and rest due to life-style.
[Ed, note: It is not clear how many, if any, patients met standardised criteria for CFS.]
Naschitz, JE., Rozenbaum, M., Shaviv, N., Fields, MC., Enis, S., Babich, JP., Manor, H., Yeshurun, D., Sabo, E and Rosner, I. The feeling of fatigue - fatigue severity by unidimensional versus composite questionnaires. Behavioral Medicine, 2004, 29, 4, 167-172.
The authors' purpose was to compare the perception of fatigue severity as measured by different fatigue questionnaires. The authors evaluated 3 groups of patients in a cross-sectional study: CFS (n=20), non-CFS fatigue (n=20), and familial Mediterranean fever (FMF n=25). In addition, the authors tracked 7 patients with CFS longitudinally for severity of fatigue. The severity of fatigue-related symptoms was assessed with 2 questionnaires: the unidimensional Chalder's Fatigue Severity Scale (CH) and the composite Fatigue Impact Scale (FI) which has 3 subscales -cognitive, physical, and social- and a total score.
In the cross-sectional study, correlations between CH and FI cognitive scores were r=.78 (p<.0001), CH versus FI physical scores r=.603 (p<.0001), CH versus FI social scores r=.66 (p<.0001), and CH versus FI total scores r=.74 (p<.0001). In the longitudinal survey of CFS patients, the authors compared 30 questionnaires revealing correlations of CH versus FI cognitive scores r=.64 (p=.0004), CH versus FI physical r=.68 (p=.0001), CH versus FI social r=.87 (p<.0001), and CH versus FI total r=.90 (p< .0001).
Fatigue severity as assessed by the unidimensional CH scale and the composite FI scale is comparable. The simple CH scale may be adequate for the assessment of the feeling of fatigue, in general, and for monitoring the severity of fatigue in CFS, in particular.
[Ed. Note: There is no data on the performance of the scales in differentiating the mild, moderate and severely affected patients. Correlations with another measure of fatigue checks only one type of validity.]
Nijs, J., Vanherberghen, K., Duquet, W and De Meirleir, K. Chronic fatigue syndrome: lack of association between pain-related fear of movement and exercise capacity and disability. Physical Therapy, 2004, 84(8): 696-705.
Patients who experience pain, a symptom of CFS, often exhibit kinesiophobia (irrational fear of movement or activity). The purpose of this study was to examine whether pain-related fear of movement is associated with exercise capacity, activity limitations, or participation restrictions in patients with CFS who experience widespread pain.
64 subjects met the inclusion criteria. All subjects fulfilled the 1994 CDC definition for CFS and experienced widespread myalgias or arthralgias. The subjects completed the Tampa Scale for Kinesiophobia-Dutch Version (TSK-DV) and the Dutch Chronic Fatigue Syndrome-Activities and Participation Questionnaire (CFS-APQ). They then performed a maximal exercise test on a bicycle ergometer. Heart rate was monitored continuously by use of an electrocardiograph. Ventilatory factors were measured through spirometry. Correlations between the TSK-DV scores and both the exercise capacity data and the CFS-APQ scores were assessed using the Spearman rank correlation coefficient. Using the Mann-Whitney U test, the TSK-DV scores were compared between subjects who performed a maximal exercise stress test and those who did not perform the test.
Forty-seven subjects (73.4%) attained a total score of greater than 37 on the TSK-DV, indicating high fear of movement. Neither the exercise capacity data nor the CFS-APQ scores indicated a correlation with the TSK-DV scores (n=64). Subjects who did not perform a maximal exercise capacity test had more fear of movement (median TSK-DV score=43.0) compared with those who did perform a maximal exercise capacity test (median TSK-DV score=38.0, z=-1.974, p=.048), but the correlation analysis was unable to reveal an association between exercise capacity and kinesiophobia in either subgroup.
These results indicate a lack of correlation between kinesiophobia and exercise capacity, activity limitations, or participation restrictions, at least in patients with CFS who are experiencing widespread muscle or joint pain.
Nijs, j., De Meirleir, K and Duquet, W. Kinesiophobia in chronic fatigue syndrome: Assessment and associations with disability. Archives of Physical Medicine and Rehabilitation, 2004, 85, 10, 1586-1592.
The aim of this study was to investigate aspects of the validity of the total scores of the Tampa Scale for Kinesiophobia (TSK), Dutch Version, which was modified to make it an appropriate questionnaire for the assessment of kinesiophobia (fear of movement) in CFS patients (the Dutch TSK-CFS), and, using this assessment tool, to examine the associations between kinesiophobia, exercise capacity, and activity limitations and participation restrictions in patients with CFS.
In the first study, 40 patients with CFS (CDC criteria ’94) were enrolled. The sample of the second study consisted of 51 CDC-defined patients with CFS. All were from a specialist fatigue clinic.
Study 1: Subjects completed a set of questionnaires; the Utrechtse Coping List (UCL), the Dutch TSK-CFS, and the Dutch Baecke Questionnaire of Habitual Physical Activity. Study 2: All patients completed 2 questionnaires (Chronic Fatigue Syndrome Activities and Participation Questionnaire [CFS-APQ], Dutch TSK-CFS) and performed a maximal exercise stress test on a bicycle ergometer. The heart rate was monitored continuously by use of an electrocardiograph. Metabolic and ventilatory parameters were measured through spirometry.
Study 1: The total scores on the Dutch TSK-CFS showed a statistically significant correlation with both the avoidance/abide subscale of the UCL (Spearman rho=.35, p=.029) and the total score of the Baecke Questionnaire (rho=-.45, p=.004).
Study 2: The total scores on the Dutch TSK-CFS showed a statistically significant correlation with the total scores on the CFS-APQ showing a link between the fear of activity and self-reported activity (rho=.39, P=.004). No statistically significant associations were observed between the exercise capacity parameters e.g. heart rate during testing and the total scores on the Dutch TSK-CFS.
Kinesiophobia appears to be associated with activity limitations/participation restrictions but not with actual exercise capacity in patients with CFS.
[Ed. Note: there is no data on the number of patients with post-exertional malaise, and no assessment of symptoms following exertion, to see if fears of post-exertional fatigue are realistic.]
Santaella, ML., Font, I and Disdier, OM. Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. Puerto Rico Health Science Journal, 2004, 23, 2, 89-93.
The aim was to compare effectiveness of oral therapy with reduced nicotinamide adenine dinucleotide (NADH) to conventional modalities of treatment in patients with CFS.
A total of 31 patients fulfilling the CDC criteria for CFS, were randomly assigned to either NADH or nutritional supplements and psychological therapy for 24 months. A thorough medical history, physical examination and completion of a questionnaire on the severity of fatigue and other symptoms were performed each trimester of therapy. In addition, all of them underwent evaluation in terms of immunological parameters and viral antibody titers. Statistical analysis was applied to the demographic data, as well as to symptoms scores at baseline and at each trimester of therapy.
The twelve patients who received NADH had a dramatic and statistically significant reduction of the mean symptom score in the first trimester (p<0.001). However, symptom scores in the subsequent trimesters of therapy were similar in both treatment groups. Elevated IgG and IgE antibody levels were found in a significant number of patients.
Observed effectiveness of NADH over conventional treatment in the first trimester of the trial and the trend of improvement of that modality in the subsequent trimesters should be further assessed in a larger patient sample.
Schillings, ML., Kalkman, JS., van der Werf, SP., van Engelen, BG.,Bleijenberg, G and Zwarts, MJ. Diminished central activation during maximal voluntary contraction in chronic fatigue syndrome. Clinical Neurophysiology, 2004, 115, 11, 2518-2524.
We have investigated whether central activation failure (CAF) is increased during local muscle fatigue in CFS.
Fourteen female CFS patients (CDC criteria ’94) and 14 age- matched healthy female controls made a 2 min sustained maximal voluntary contraction (MVC) of the biceps brachii muscle. Before, during, and after sustained MVC, electrical endplate stimulation was applied. Force and 5 channel surface EMG (sEMG) were registered.
Although force responses upon stimulation during rest did not differ between patients and controls, MVC was significantly lower in patients. Already at the beginning of sustained MVC, CFS patients showed significantly larger CAF than controls (36.5+17.0% and 12.9+13.3%, respectively). For all individual patients mean CAF over the first 45 secs was higher than 30%, while it was below 30% for all controls. Less peripheral fatigue in patients was demonstrated by the changes in muscle fibre conduction velocity and the differences between force responses before and after contraction.
Central activation is diminished in CFS patients. Possible causes include changed perception, impaired concentration, reduced effort and physiologically defined changes, e.g. in the corticospinal excitability or the concentration of neurotransmitters. As a consequence, demands on the muscle are lower, resulting in less peripheral fatigue.
CFS patients show reduced central activation during MVC. The underlying pathophysiological processes remain still to be deter-mined.
[Ed. Note: the article does not state how disabled the subjects were, nor if any had post-exertional fatigue.]
Steinau, M., Unger, ER., Vernon, SD., Jones, JF and Rajeevan, MS. Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome. Journal of Molecular Medicine, 2004, Oct 14 [Epub ahead of print]
We used differential-display PCR of peripheral blood mononuclear cells (PBMCs) to search for candidate biomarkers for CFS. PBMCs were collected from a subject with CFS (CDC criteria ’94) and an age- and sex-matched control before and 4 hours after exercise. RNA expression profiles were generated using 46 primer combinations, and the similarity between the individuals was striking. Differentially expressed bands were excised, reamplified, and sequenced, yielding 95 nonredundant sequences, of which 50 matched to known gene transcripts, 38 matched to genes with unknown functions, and 7 had no similarity to any database entry.
Most (86%) of the differences between the two subjects were present at baseline. Differential expression of ten genes was verified by real-time reverse-transcription PCR: five (cystatin F, MHC class II, platelet factor 4, fetal brain expressed sequence tag, and perforin) were downregulated, and the remaining five genes (cathepsin B, DNA polymerase epsilon4, novel EST PBMC191MSt, heparanase precursor, and ORF2/L1 element) were upregulated in the subject with CFS. Many of these genes have known functions in defense and immunity, thus supporting prior suggestions of immune dysregulation in the pathogenesis of CFS.
Differential-display PCR is a powerful tool for identification of candidate biomarkers. Investigation of these markers in samples from well-designed epidemiological studies of CFS will be required to determine the validity of these candidate biomarkers. The real-time reverse-transcription PCR assays that we developed for assay of these biomarkers will facilitate high-throughput testing of these additional samples.
Stouten, B. Chronic fatigue syndrome: a clinical and laboratory study with a well-matched control group. Journal of Internal Medicine, 2004, 256, 265-267.
Stouten notes that in the paper by Swanink et al (ibid, 1995, 237, 499-506) the ANOVA of patients who met the CDC criteria and those who did not (Oxford only) yielded significant differences (at least p<0.05) in concentration, activity, sleep and rest, ambulation, alertness behaviour, and recreation and pastimes, which means that CDC-CFS patients are significantly more impaired in daily functioning. Because of the use of ANCOVA (with number of symptoms as the covariate), it appeared that there are no clinical differences between CDC-CFS and non-CDC-CFS patients, and this study has often been cited to permit leaving out additional symptom criteria when considering CFS. However, the ANCOVA assumptions were not met (the covariate was not independent), and the results are therefore misleading. The incorrect results of the article have also been presented during a recent meeting held for revising the latest CDC-CFS definition presentation (Bleijenberg, CDC consensus meeting, Atlanta 2000).
With reply by Bleijenberg, G, Vercoulen, JHHM and Van Der Meer, JWM (268-269). This does not address the issue discussed but instead the authors argued that there was other evidence suggesting that full adherence to the 1994 criteria did not make a difference.
[Ed. Note: the authors ignored all the evidence indicating that there are differences between patients meeting the stricter and broader criteria, and between patients meeting the criteria and those who do not. Moreover, the study they cite (Wessely et al 1996) actually found differences (e.g. patients with CFS reported more myalgia, post-exertional malaise and muscle weakness than people with CF). It is difficult to understand the argument that “that there is no evidence that CDC symptoms are characteristic of CFS.” One of the authors helped to devise the criteria for CFS which they now criticise. If this point was generally accepted, the criteria would have been amended at the recent meeting of the Study Group, or they would have been scrapped (Reeves et al). They offer no support for the view that omitting the minor criteria solves any problems, e.g. this helps differentiate patients from other ill populations.]
Tryon, WW., Jason, L., Frankenberry, E and Torres-Harding, S. Chronic fatigue syndrome impairs circadian rhythm of activity level. Physiology and Behavior, 2004, 82, 5, 849-853.
Some of the symptoms of CFS are the same as for disrupted circadian rhythm. Activity level is frequently used to study circadian rhythm. Continuous waist activity measurements taken every minute 24 h/day for from 5 to 7 days in 10 controls and from 2 to 7 days in 8 patients with CFS yielded two primary findings: (a) lower daytime activity and (b) less regular activity-rest cycles in persons with CFS than in controls.
Viner, R and Hotopf, M. Childhood predictors of self-reported chronic fatigue syndrome/myalgic encephalomyelitis in adults: national birth cohort study. BMJ, 2004, 329, 941-943.
This study found a relationship between a comparative lack of exercise (never or hardly ever) outside of school hours (as reported by parents when children were ten years) and the development of CFS many years later (median year at onset was 24, range 14-29). Other predictors included illness during childhood and female gender. 48 (.4%) of the respondents had the condition at time of final assessment. There was no association found with maternal psychological disorder, psychological problems in child-hood, atopy, obesity or academic ability.
With editorial by White, PD (ibid, 928-929.) linking CFS to an underestimation of cognitive and physical abilities and enhanced interoception (being more aware of internal physiological state).
[Ed. Note. The findings cover ‘self-reported’ CFS. 42 of those with ‘CFS’ had often played sport in their spare time compared to 54 who did not develop CFS. Only 16 did not, or hardly ever played sport in their spare time. Indeed, for the majority, there was no link between activity at ten and the later onset of ‘CFS’. More of those who developed ‘CFS’ later played sport at school compared to those who did not become ill.
In the multivariate analysis, the presence of a longstanding illness and female gender were far more significant as predictors than activity in spare time (where p=.04). There is no information on other possible mediators, e.g. results of tests for glandular fever etc. (Given the age and the fact that only 48 participants had ‘CFS’ at the time of the assessment, this could have been checked). Despite the lack of sound information on more recent and likelier sources of illness, the authors concluded that “sedentary behaviour increased the risk”. There is no evidence that an increased awareness of one’s body, a common phenomenon in those with chronic diseases, is linked to CFS. The perception of reduced abilities is realistic, e.g. Paul et al 1999, Sandman et al 1993, Komaroff et al 1996, at least, in well-defined samples.]
Wang, XQ., Takahashi, T., Zhu, SJ., Moriya, J., Saegusa, S., Yamakawa, J., Kusaka, K., Itoh, T and Kanda, T. Effect of Hochu-ekki-to (TJ-41), a Japanese herbal medicine, on daily activity in a murine model of chronic fatigue syndrome. Evidence Based Complementary & Alternative Medicine, 2004, 1, 2, 203-206.
We aimed to evaluate the effect of a Japanese herbal medicine, Hochu-ekki-to (TJ-41), on daily activity in a murine model of CFS. CFS was induced by repeated injection of Brucella abortus (BA) antigen every 2 weeks. TJ-41 was orally administered to mice in a dose of 500 mg/kg/day for 1 week before injecting BA and for 4 weeks thereafter. We evaluated daily running activity in mice receiving TJ-41 as compared with that in untreated mice. Survival of both mouse groups was also monitored during the observation period. Body weight (BW), spleen weight (SW), SW/ BW ratio and expression levels of interleukin-10 (IL-10) mRNA in spleen were determined in both groups at the time of sacrifice.
The daily activity was significantly higher in the treated group than in the control. Two mice in the untreated group died 2 days after the second injection of BA, whereas no mice in the group treated with TJ-41 died. The SW and SW/BW ratio were significant-ly lower in the treated mice than in the control. Suppressed IL-10 mRNA levels were observed in the spleens of the mice treated with TJ-41. Our data suggest that Hochu-ekki-to might possess an inhibitory effect on the marked decrease in running activity following BA injection.
Watson, NF., Jacobsen, C., Goldberg, J., Kapur, V and Buchwald, D. Subjective and objective sleepiness in monozygotic twins discordant for chronic fatigue syndrome. Sleep, 2004, 27, 5, 973-977.
The aim of this study was to examine the association of CFS with measures of objective and subjective sleepiness. Subjects were 20 monozygotic twin pairs discordant for CFS.
CFS twins reported significantly more subjective sleepiness than their healthy co-twins despite similar nonpathologic mean sleep latencies on the Multiple Sleep Latency Test. Patients with CFS may mistake their chronic disabling fatigue for sleepiness.
Heim, C., Bierl, C., Nisenbaum, R., Wagner, D and Reeves, WC. Regional prevalence of fatiguing illnesses in the United States before and after the terrorist attacks of September 11, 2001. Psychosomatic Medicine, 2004, 66, 672-678.
Stress or emotional traumas are considered risk factors for unexplained fatiguing illnesses. From July to December 2001, the CDC conducted a multigeographical pilot study to test the feasibility of a survey to estimate the prevalence of fatiguing illnesses in the United States. We used data obtained during this survey to estimate the effect of the coincidentally occurring terrorist attacks of September 11, 2001, on the regional pre-valence of fatiguing illnesses.
Identified by random-digit dialing, 2,728 households in eight regional strata were interviewed, and 7,317 respondents were screened for severe fatigue of at least 1 month duration. Identified fatigued people of age 18 to 69 years (N=440) and a sample of nonfatigued people of the same age range (N=444) were interviewed in detail concerning fatigue, other symptoms, and medical and psychiatric histories.
Weighted prevalence estimates based on interviews performed after the attacks were significantly lower compared with estimates based on interviews performed before the attacks (prolonged fatigue: p=.010; chronic fatigue: p=.002; CFS-like illness: 2,510 vs. 960/100,000, p=.014).
Our findings suggest decreased regional prevalence of fatiguing illnesses in the aftermath of the terrorist attacks. The causes of this effect are unknown but might involve acute psychological and physiological adaptations that modify the perception or manifestation of fatigue.
[Ed. Note: There is little evidence that this study examined stress as there was no measure on how subjects felt at the time of the assessment in relation to the threat of terrorism. CFS could not be diagnosed as the patients with symptoms were not medically examined. It may have been useful to limit the analysis to people living in and around New York, and to compare those directly affected with those living in the area but not directly affected. To assess patients not living in New York or working in the Pentagon means these people may have felt distress for those affected, but only fear and anxiety about a general threat, possibly coloured by what they had seen on American TV.]
Newman, S., Steede, L and Mulligan, K. Self-management interventions for chronic illness. Lancet, 2004, 364, 1523-1537.
Useful review of self-management interventions, an alternative to CGT/GET based programmes.
The paper by Wallman et al 2004 (see issue 3) stated that they used the 14-item Chalder Fatigue Scale. In fact, they used the 11-item version. (Source: Karen Wallman).
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