Number 3 |
1st September 2005 |
IMMUNOLOGY
|
Fremont, M., El Bakkouri, K., Vaeyens, F., Herst, CV., De Meirleir, K and Englebienne, P. 2'5'-Oligoadenylate size is critical to protect RNase L against proteolytic cleavage in chronic fatigue syndrome. Experimental and Molecular Pathology, 2005, 78, 3, 239-246.
A dysregulation in the 2',5'-oligoadenylate (2-5A)-dependent RNase L antiviral pathway has been detected in peripheral blood mononuclear cells (PBMC) of CFS patients, which is characterized by upregulated 2-5A synthetase and RNase L activities, as well as by the presence of a low molecular weight (LMW) 2-5A-binding protein of 37-kDa related to RNase L. This truncated protein has been shown to originate from proteolytic cleavage of the native 83-kDa RNase L by m-calpain and human leukocyte elastase (HLE).
We investigated the possible role of 2-5A oligomers in the proteolytic action toward the endonuclease and show that incubation of PBMC extracts with 2-5A trimer and tetramer, but not with the dimer, results in a significant protection of the native 83-kDa RNase L against cleavage by endogenous and purified proteases. Similar results are obtained with a purified recombinant RNase L.
An analysis of the size of 2-5A oligomers produced by the catalytic activity of the 2-5A synthetase present in PBMC extracts further shows that samples containing the 37-kDa RNase L preferentially produce 2-5A dimers instead of higher oligomers.
Taken together, our results indicate that homodimerization of RNase L by 2-5A oligomers higher than the dimer prevents its cleavage by proteolytic enzymes. The presence of the truncated 37-kDa RNase L in PBMC extracts is therefore likely to result, not only from the abnormal activation of inflammatory proteases, but also from a dysregulation in 2-5A synthetase induction or activation towards the preferential production of 2-5A dimers.
Robertson, MJ., Schacterle, RS., Mackin, GA., Wilson, SN., Bloomingdale, KL., Ritz, J and Komaroff, AL. Lymphocyte subset differences in patients with chronic fatigue syndrome, multiple sclerosis and major depression. Clinical and Experimental Immunology, 2005, 141, 2, 326-332.
CFS is a heterogeneous disorder of unknown aetiology characterized by debilitating fatigue, along with other symptoms, for at least 6 months. Many studies demonstrate probable involvement of the central and autonomic nervous system, as well as a state of generalized immune activation and selective immune dysfunction in patients with CFS.
The aim of this study was to compare the lymphocyte subsets of patients with CFS (n=23, CDC criteria '88) those of patients with major depression (n=24) and multiple sclerosis (n=22) as well as those of healthy control subjects (n=25).
No differences were found in total numbers of T cells, B cells or natural killer (NK) cells. However, differences were found in T, B and NK cell subsets. Patients with major depression had significantly fewer resting T (CD3+/CD25-) cells than the other groups. Patients with major depression also had significantly more CD20+/CD5+ B cells, a subset associated with the production of autoantibodies.
Compared to patients with multiple sclerosis, patients with CFS had greater numbers of CD16+/CD3- NK cells. Further study will be required to determine whether these alterations in lymphocyte subsets are directly involved in the pathophysiology of these disorders, or are secondary effects of the causal agent(s).
White, PD., Nye, KE., Pinching, AJ., Yap, TM., Power, N., Vleck, V., Bentley, DJ., Thomas, JM., Buckland, M and Parkin, JM. Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. Journal of Chronic Fatigue Syndrome, 2004, 12, 2, 51-66.
We designed this pilot study to explore whether the illness was associated with alterations in immunological markers following exercise. We measured immunological markers before and up to three days after either a sub-maximal or maximal bicycle exercise test. We studied nine patients with CFS (CDC criteria '94) and nine age and sex-matched healthy but sedentary controls. We also studied 7 of the same patients with CFS at home after a night's sleep and then after travelling to the study center.
There were no significant differences in any of the cell markers after a sub-maximal exercise test compared to a maximal test. However, we found elevated concentrations of plasma transforming growth factor beta (TGF-ß), even before exercise, in subjects with CFS (median (IQR) of 904 (182-1072) pg/ml) versus controls (median (IQR) of 50 (45-68) pg/ml) (p<.001). Travelling from home to the hospital significantly elevated TGF-ß concentrations from a resting median (IQR) concentration of 1161 (130-1246) pg/ml to a median (IQR) concentration of 1364 (1155-1768) pg/ml (p<.02).
There was also a sustained increase in plasma tumor necrosis factor a (TNF-a) after exercise in CFS patients, but not in controls (p= .004 for the area under the curve), although travelling had no such effect. CD3, CD4 and HLA DR-expressing lymphocyte counts were lower in CFS patients, but exercise had the same effect in both groups, causing an immediate increase in circulating cell numbers that lasted less than three hours.
These results suggest that the relationship between physical activity and both pro-inflammatory and anti-inflammatory cytokines merits other investigation in patients with CFS. The results also emphasize the importance of defining a truly resting baseline condition in such studies.
De Lange, FP., Kalkman, JS., Bleijenberg, G., Hagoort, P., van der Meer, JWM and Toni, I. Gray matter volume reduction in the chronic fatigue syndrome. NeuroImage, 2005, 26, 3, 777-781.
CFS is a disabling disorder of unknown etiology. The symptomatology of CFS (central fatigue, impaired concentration, attention and memory) suggests that this disorder could be related to alterations at the level of the central nervous system (CNS). In this study, we have used an automated and unbiased morphometric technique to test whether CFS patients (CDC criteria '94) display structural cerebral abnormalities.
We mapped structural cerebral morphology and volume in two cohorts of CFS patients (in total 28 patients, one group younger than the other, all female, none with psychiatric disorders) and healthy controls (in total 28 controls) from high-resolution structural magnetic resonance images, using voxel-based morphometry. Additionally, we recorded physical activity levels to explore the relation between severity of CFS symptoms and cerebral abnormalities. Severity of illness was measured using the CIS. Activity was measured using an actometer.
We observed significant reductions in global gray matter volume in both cohorts of CFS patients (8%), as compared to matched control participants. Moreover, the decline in gray matter volume was linked to the reduction in physical activity, a core aspect of CFS (r=.39, p=.026). There was no correlation between GM volume and age, duration or the CIS scores.
These findings suggest that the CNS plays a key role in the pathophysiology of CFS and point to a new objective and quantitative tool for clinical diagnosis of this disabling disorder.
[Ed. Note: If the lack of physical activity caused the GM volume reduction, one might expect a stronger correlation between the two variables and between GM volume and duration. If CFS plays a significant causal role, then one would expect a strong correlation with illness severity, but there was no adequate assessment of this (the CIS only measures fatigue). It might have been useful to include a measure of anxiety or cortisol, to assess the possible confounding effect of stress.]
Lange, G., Steffener, J., Cook, DB., Bly, BM., Christodoulou, C., Liu, WC., Deluca, J and Natelson, BH. Objective evidence of cognitive complaints in chronic fatigue syndrome: A BOLD fMRI study of verbal working memory. NeuroImage, 2005, 26, 2, 513-524.
Individuals with CFS often have difficulties with complex auditory information processing. In a series of two Blood Oxygen Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) studies, we compared BOLD signal changes between healthy controls and individuals with CFS (CDC criteria '94) who had documented difficulties in complex auditory information processing (Study 1) and those who did not (Study 2) in response to performance on a simple auditory monitoring and a complex auditory information processing task (mPASAT). We hypothesized that under conditions of cognitive challenge: (1) individuals with CFS who have auditory information processing difficulties will utilize frontal and parietal brain regions to a greater extent than controls and (2) these differences will be maintained even when objective difficulties in this domain are controlled for.
Using blocked design fMRI paradigms in both studies, we first presented the auditory monitoring task followed by the mPASAT. Within and between regions of interest (ROI), group analyses were performed for both studies with statistical parametric mapping (SPM99).
Findings showed that individuals with CFS are able to process challenging auditory information as accurately as controls but utilize more extensive regions of the network associated with the verbal WM system. Individuals with CFS appear to have to exert greater effort to process auditory information as effectively as demographically similar healthy adults. Our findings provide objective evidence for the subjective experience of cognitive difficulties in individuals with CFS.
[Ed. Note: the CFS group had significantly higher STAI anxiety and BDI depression scores than the controls. This was taken into account in study 2 but may still have led to some confounding given the somatic symptom score of the BDI was not included in the analysis of covariance.]
Badawy, AA., Morgan, CJ., Llewelyn, MB., Albuquerque, SR and Farmer A. Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome. Journal of Psychopharmacology, 2005, 19, 4, 385-391.
We assessed the serotonin status of patients with the CFS. Tryptophan (Trp) availability to the brain, expressed as the ratio of concentration of serum Trp to the sum of those of its five com-petitors (CAA), and other parameters of Trp disposition were compared in 23 patients with the CFS (CDC criteria '94) and 42 healthy controls.
The serum [free Trp]/[CAA] ratio was 43% higher in CFS patients, due to a 48% higher level of free tryptophan. Total tryptophan levels were also significantly higher (by 19%) in CFS patients, and, although the [total Trp]/[CAA] ratio did not differ significantly between the control and patient groups, the difference became significant when the results were co-varied with age and gender. [CAA] was not significantly different between groups, but was significantly lower in females, compared to males, of the CFS patient group. There were no differences in levels of cortisol.
We have established normal ranges for tryptophan disposition parameters and propose criteria for defining the serotonin-biosynthetic status in humans. We have provisionally identified two subgroups of CFS patients, one with normal serotonin (n=13) and the other with a high serotonin status (n=10).
The relevance of our findings to, and their implications for, the pharmacological and other therapies of the CFS are discussed.
Chalmers, RA., Jones, MG., Goodwin, CS and Amjad, S. CFSUM1 and CFSUM2 in urine from patients with chronic fatigue syndrome are methodological artefacts. Clinica Chimica Acta, 2005 Aug 8 [Epub ahead of print].
McGregor et al. reported increased levels of an unidentified urinary compound (CFSUM1) in patients with CFS, with reduced excretion of another unidentified compound (CFSUM2), and suggested the possibility of chemical or metabolic 'markers' for CFS. The identity of CFSUM1 as reported was erroneous and the identities of these compounds have remained unknown until now.
Urine samples were obtained from 30 patients with ME/CFS (Oxford and CDC criteria '94), 30 age- and sex-matched healthy controls, 20 control patients with depression and 22 control patients with rheumatoid arthritis. Samples were prepared using the published methods of McGregor et al.
CFSUM2 was identified as being partially derivatised [isobutyl ester-mono-heptafluorobutyryl (HFB)] serine. CFSUM1 was identified as partially derivatised pyroglutamic acid, being the isobutyl ester without formation of a HFB derivative. Both CFSUM1 and CFSUM2 are artefacts of the sample preparation procedure and previously reported quantitative abnormalities of CFSUM1 and CFSUM2 in urine from patients with ME/CFS are also artefactual. Pyroglutamic acid may be of primarily dietary origin.
The methods used cannot provide reliable qualitative or quantitative data on urinary metabolites. No clinical or biochemical significance can be drawn between these compounds in ME/CFS or any other clinical conditions.
Jones, MG., Goodwin, CS., Amjad, S and Chalmers, RA. Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome. Clinical Chimica Acta, 2005, Jun 18 [Epub ahead of print].
Contradictory reports have suggested that serum free carnitine and acylcarnitine concentrations are decreased in patients with CFS and that this is a cause of the muscle fatigue observed in these patients. Others have shown normal serum free carnitine and acylcarnitines in similar patients. We report here studies on free, total and esterified (acyl) carnitines in urine and blood plasma from UK patients with CFS and three control groups.
Plasma and timed urine samples were obtained from 31 patients with CFS (Oxford and CDC criteria '94), 31 healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Samples were analysed using an established radioenzymatic procedure for total, free and esterified (acyl) carnitine.
There were no significant differences in plasma or urinary total, free or esterified (acyl) carnitine between UK patients with CFS and the control groups or in renal excretion rates of these com-pounds.
The data presented here show that, in the CFS patients studied, there are no significant abnormalities of free or esterified (acyl) carnitine. It is thus unlikely that abnormalities in carnitine homeostasis have any significant role in the aetiology of their chronic fatigue.
Jones, MG., Cooper, E., Amjad, S., Goodwin, SC., Barron, JL and Chalmers, RA. Urinary and plasma organic acids and amino acids in chronic fatigue syndrome. Clinica Chimica Acta, 2005 Jun 28 [Epub ahead of print].
Previous work by others have suggested the occurrence of one or more chemical or metabolic 'markers' for ME/CFS including specific amino acids and organic acids and a number of unidentified compounds (CFSUM1, CFSUM2). We have shown elsewhere that CFSUM1 is partially derivatised pyroglutamic acid and CFSUM2 partially derivatised serine and have suggested and demonstrated that the analytical methods used were unsuitable to identify or to accurately quantify urinary metabolites. We have now made a detailed analysis of plasma and urinary amino acids and of urinary organic acids from patients with ME/CFS and from three control groups. Fasting blood plasma and timed urine samples were obtained from 31 patients with CFS (Oxford and CDC criteria '94), 31 age and sex-matched healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Plasma and urinary amino acids and urinary organic acids were determined using established and validated methods and data compared by statistical analysis. None of the previously reported abnormalities in urinary amino acids or of organic acids could be confirmed. Results however provide some evidence in patients with ME/CFS for underlying inflammatory disease and for reduced intramuscular collagen with a lowered threshold for muscle micro-injury. These factors in combination may provide a basis for the fatigue and muscle pain that are the major symptoms in these patients.
Kennedy, G., Spence, VA., McLaren, M., Hill, A., Underwood, C and Belch, JJ. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radical Biology & Medicine, 2005, 39, 5, 584-589.
The aetiology of CFS is unknown; however, recent evidence suggests excessive free radical (FR) generation may be involved. This study investigated for the first time levels of 8-iso-prostaglandin-F2a-isoprostanes alongside other plasma markers of oxidative stress in CFS patients and control subjects.
Forty-seven patients (18 males, 29 females, mean age 48 [19-63] years) with CFS (CDC criteria '94) and 34 healthy volunteers (13 males, 21 females, 46 [19-63] years) were enrolled in the study. The CFS patients were divided into two groups; one group had previously defined cardiovascular (CV) risk factors of obesity and hypertension (group 1) and the second were nor-motensive and nonobese (group 2).
Patients had significantly increased levels of isoprostanes (group 1, p=0.007; group 2, p=0.03, unpaired t test compared to controls) and oxidised low-density lipoproteins (group 2, p=0.02) indicative of a FR attack on lipids. CFS patients also had significantly lower high-density lipoproteins (group 1, p= 0.011; group 2, p= 0.005). CFS symptoms correlated with isoprostane levels, but only in group 2 low CV risk CFS patients (isoprostanes correlated with; total symptom score p = 0.005; joint pain p= 0.002; postexertional malaise p= 0.027, Pearson).
This is the first time that raised levels of the gold standard measure of in vivo oxidative stress (isoprostanes) and their association with CFS symptoms have been reported.
[Ed. Note: This study was funded by MERGE, suggesting that the subjects may also have fulfilled additional criteria for ME.]
Di Giorgio, A., Hudson, M, Jerjes, W and Cleare, A. 24-hour pituitary and adrenal hormone profiles in chronic fatigue syndrome. Psychological Medicine, 2005, 67, 3, 433-440.
Disturbances of neuroendocrine function, particularly the hypothalamo-pituitary-adrenal (HPA) axis, have been implicated in the pathophysiology of CFS. However, few studies have attempted to measure blood levels of pituitary or adrenal hormones across a whole 24-hour period in CFS, and those that did so have used infrequent sampling periods. Our aim was to assess 24-hour pituitary and adrenal function using frequent blood sampling.
We recruited 15 medication-free patients with CFS (CDC criteria '94) without comorbid psychiatric disorder and 10 healthy control subjects. Blood samples were collected over 24 hours and assayed for cortisol, corticotropin (ACTH), growth hormone (GH), and prolactin (PRL) levels on an hourly basis during daytime hours (10 am to 10 pm) and every 15 minutes thereafter (10 pm to 10 am).
Repeated-measures analyses of variance were undertaken using hormone levels averaged over 2-hour blocks to smooth curves by reducing the influence of sample timing relative to secretory burst. For ACTH, there was both a main effect of group, suggesting reduced mean ACTH secretion in patients with CFS over the whole monitoring period, and a group-by-time interaction, suggesting a differential pattern of ACTH release. Post hoc analysis showed reduced ACTH levels in CFS during the 8 am to 10 am period. In contrast, there were no significant abnormallities in the levels of cortisol, GH, and PRL in patients with CFS over the full cycle compared with control subjects. Cosinor analysis found no differences in the cortisol circadian rhythm parameters, but the ACTH rhythm did differ, patients with CFS showing an earlier acrophase.
Patients with CFS demonstrated subtle alterations in HPA axis activity characterized by reduced ACTH over a full circadian cycle and reduced levels during the usual morning physiological peak ACTH secretion. This provides further evidence of subtle dysregulation of the HPA axis in CFS. Whether this dysregulation is a primary feature of the illness or instead represents a biologic effect secondary to having the illness itself (e.g. as a result of stress, inactivity, early life trauma) remains unclear.
Jerjes, WK., Cleare, AJ., Wessely, S., Wood, PJ and Taylor, NF. Diurnal patterns of salivary cortisol and cortisone output in chronic fatigue syndrome. Journal of Affective Disorders, 2005, 87, 2-3, 299-304.
The aim of the present study was to obtain a naturalistic measure of diurnal HPA axis output in CFS patients unaffected by medication or comorbid psychiatric disorder likely to influence the axis. Cortisol and cortisone levels were measured in saliva samples collected from 0600 h to 2100 h at 3-h intervals in 15 CFS patients (CDC criteria '94) and 20 healthy controls.
Mean cortisol and cortisone concentrations were significantly lower in patients than controls across the whole day, as were levels at each individual time point except 2100 h. Cosinor analysis showed a significant diurnal rhythm of cortisol and cortisone that was not phase-shifted in CFS compared to controls. However, there was a lower rhythm-adjusted mean and a lower amplitude in CFS patients. The cortisol/cortisone ratio showed no diurnal rhythm and did not differ between CFS subjects and controls.
The sample size was relatively small, and drawn from specialist referral patients who had been ill for some time; generalisation of these results to other populations is therefore unwarranted.
The main findings of this study are to provide further evidence for reduced basal HPA axis function in at least some patients with CFS and to show for the first time that salivary cortisone is also reduced in CFS and has a diurnal rhythm similar to that of cortisol. We have also demonstrated that the cortisol/cortisone ratio remains unchanged in CFS, suggesting that increased conversion of cortisol to cortisone cannot account for the observed lowering of salivary cortisol.
Kaushik, N., Fear, D., Richards, SCM., McDermott, CR., Nuwaysir, EF., Kellam, P., Harrison, TJ., Wilkinson, RJ., Tyrrell, DAJ., Holgate, ST and Kerr, JR. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. Journal of Clinical Pathology, 2005, 58, 826-832.
The aim of this study was to test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. Gene expression was analysed in PBMC from 25 patients with CFS (CDC criteria '94) and 25 normal blood donors matched for age, sex, and geographical location, using a single colour microarray representing 9522 human genes. After normalisation, average difference values for each gene were compared between test and control groups using a cutoff fold difference of expression > 1.5 and a p value of 0.001. Genes showing differential expression were further analysed using Taqman real time polymerase chain reaction (PCR) in fresh samples.
Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were upregulated (ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1) and one of which was downregulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Upregulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively.
These results suggest that patients with CFS have reproducible alterations in gene regulation.
Smith, J., Fritz, EL., Kerr, JR., Cleare, AJ., Wessely, S and Mattey, DL. Association of chronic fatigue syndrome with human leucocyte antigen class II alleles. Journal of Clinical Pathology, 2005, 58, 860-863.
A genetic component to the development of CFS has been proposed, and a possible association between human leucocyte antigen (HLA) class II antigens and chronic fatigue immune dysfunction has been shown in some, but not all, studies. The aim of this study was to investigate the role of HLA class II antigens in CFS.
Forty nine patients with CFS (CDC criteria '94, 25 with depression) were genotyped for the HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles and the frequency of these alleles was compared with a control group comprising 102 normal individuals from the UK. All patients and controls were from the same region of England.
Analysis by 2 x 2 contingency tables revealed an increased frequency of HLA-DQA1*01 alleles in patients with CFS (51.0% v 35%; p=0.008). HLA-DQB1*06 was also increased in the patients with CFS (30.2% v 20.0%; p=0.052). Only the association between HLA-DQA1*01 and CFS was significant in logistic regression models containing HLA-DQA1*01 and HLA-DRQB1*06, and this was independent of HLA-DRB1 alleles. There was a decreased expression of HLA-DRB1*11 in CFS, although this association disappeared after correction for multiple comparisons.
CFS may be associated with HLA-DQA1*01, although a role for other genes in linkage disequilibrium cannot be ruled out.
Gallagher, AM., Coldrick, AR., Hedge, B., Weir, WRC and White, PD. Is the chronic fatigue syndrome an exercise phobia? A case control study. Journal of Psychosomatic Research, 2005, 58, 4, 367-373.
The aim was to test whether patients with CFS have an exercise phobia, by measuring anxiety-related physiological and psychological reactions to ordinary activity and exercise.
Patients (n=41 from two clinics) and healthy but sedentary controls (n=42) were assessed over 8 hours of an ordinary day, and before, during and after an incremental exercise test on a motorised treadmill. To avoid confounding effects, those with a comorbid psychiatric disorder were excluded. All patients with CFS met the Oxford criteria, 57% met the CDC criteria and 38% met the criteria for idiopathic chronic fatigue. Data for others were missing. Heart rate, galvanic skin resistance (GSR) and the amount of activity undertaken were measured, along with state and trait measures of anxiety.
Patients with CFS were more fatigued and sleep disturbed than were the controls and noted greater effort during the exercise test. No statistically significant differences were found in either heart rate or GSR both during a normal day and before, during and after the exercise test. Patients with CFS were more symptomatically anxious at all times, but this did not increase with exercise.
The data suggest that CFS patients without a comorbid psychiatric disorder do not have an exercise phobia. "Fatigue was not caused by current levels of inactivity".
Song, S and Jason, LA. A population based study of CFS experienced in differing patient groups. An effort to replicate Vercoulen et al.'s model of CFS Journal of Mental Health, 2005, 14, 3, 277-289.
Vercoulen et al.'s model characterizes patients with CFS as having insufficient motivation for physical activity or recovery, lacking an internal locus of control, and maintaining a self-defeating preoccupation with symptoms. However, this model has only been tested in a poorly specified group using a single comparison sample.
The aim of this study was to investigate whether Vercoulen's model provides an adequate description of CFS in a community-based sample. A community based sample recruited through telephone interviewing (N=28,763) produced five groups (CFS, CF-psychiatrically explained symptoms, CF-medically unexplained symptoms, CF-Substance misuse, Idiopathic CF). The data were analysed using path analysis with the endo-genous (dependent) variables, fatigue severity, physical activity, and impairment, were ratio-level measurements and consisted of at least four values. The exogenous (independent) variables except for causal attribution of fatigue were also ratio-level measurements.
The current investigation found that the Vercoulen et al model adequately represented chronic fatigue secondary to psychiatric conditions but not CFS. This finding points to important differences between CFS and psychiatrically explained chronic fatigue which may have an impact on the development of therapy as well as explanatory models.
Bazelmans, E., Prins, JB., Lulofs, R., van der Meer, JWM and Bleijenberg, G. Cognitive behaviour group therapy for chronic fatigue syndrome: A non-randomised waiting list controlled study. Psychotherapy and Psychosomatics, 2005, 74, 4, 218-224.
It has been demonstrated that individual cognitive behaviour therapy (CBT) is an effective treatment for CFS. The aim of the present study was to investigate the effectiveness of CBT for groups (CBGT) in an unselected group of CFS patients (65 meeting CDC '94 criteria for CFS, 2 with idiopathic chronic fatigue). Additionally, pretreatment characteristics of CFS patients who improve after CBGT were explored.
In a non-randomised waiting list controlled design, 31 patients were allocated to CBGT and 36 to the waiting list condition. CBGT consisted of 12 two-hour sessions during 6 months. Main out-come measures were fatigue (Checklist Individual Strength) and functional impairment (Sick-ness Impact Profile).
A "moderate" effect on fatigue in favour of CBGT was found. Indeed, 37% of the group considered themselves improved. For functional impairment, the effect was opposite to what was expected. Patients who improved after CBGT had less complaints at baseline compared to patients who did not improve. CGBT did not improve functional impairment. At baseline, those who did not improve had higher levels of fatigue and pain. Comparing those who improved with those who did not showed no differences for baseline measures for self-efficacy, physical attributions or avoidance of activity, duration of illness or depression. However, using a repeated-measures ANOVA, an effect was found for both attributions and avoidance. Avoidance of activity increased after CBT but physical attributions decreased.
An explanation for the moderate effect might be that during CBGT, rest and relaxation were too much emphasised. Furthermore, an unselected group of CFS patients and therapists inexperienced in CB(G)T for CFS participated. Suggestions to improve CBGT for future research are given.
Beverley, DW. Chronic fatigue syndrome in children. Current Paediatrics, 2005, 15, 246-252.
[Ed. Note: Selective discussion of the research plus factual errors, e.g. the claim that C. Shepherd advocates "total rest".]
Baumer, JH. Management of chronic fatigue syndrome/myalgic encephalopathy (CFS/ME). Archives of Diseases in Childhood, 2005, 90, ep46-50.
Guideline review.
Bentler, SE., Hartz, AJ and Kuhn, EM. Prospective observational study of treatments for unexplained chronic fatigue. Journal of Clinical Psychiatry, 2005, 66, 5, 625-632.
Unexplained chronic fatigue is a frequent complaint in primary care. A prospective observational study design was used to evaluate whether certain commonly used therapies for unexplained chronic fatigue may be effective.
Subjects with unexplained chronic fatigue of unknown etiology for at least 6 months were recruited from the Wisconsin CFS Association, primary care clinics, and community CFS presentations. The primary outcome measure was change in a 5-question fatigue score from 6 months to 2 years. Self-reported interventions tested included prescribed medications, non-prescribed supplements and herbs, lifestyle changes, alternative therapies, and psychological support. Linear regression analysis was used to test the association of each therapy with the outcome measure after adjusting for statistically significant prognostic factors.
155 subjects provided information on fatigue and treatments at baseline and follow-up. Of these subjects, 87% were female and 79% were middle-aged. The median duration of fatigue was 6.7 years. The percentage of users who found a treatment helpful was greatest for coenzyme Q10 (69% of 13 subjects), dehydroepiandrosterone (DHEA) (65% of 17 subjects), and ginseng (56% of 18 subjects). Treatments at 6 months that predicted subsequent fatigue improvement were vitamins (p=.08), vigorous exercise (p=.09), and yoga (p=.002). Magnesium (p=.002) and support groups (p=.06) were strongly associated with fatigue worsening from 6 months to 2 years. Yoga appeared to be most effective for subjects who did not have unclear thinking associated with the fatigue.
Certain alternative therapies for unexplained chronic fatigue, especially yoga, deserve testing in randomized controlled trials.
Cervera, C., Alegre, J., Ruiz, E., Vasquez, A., Armadans, L., Garcia-Quintana, AM., Aleman, C and Fernandez de Sevilla, T. Employment status and financial repercussions in 60 patients with chronic fatigue syndrome in Spain: utility of the Fatigue Impact Scale. Journal of Chronic Fatigue Syndrome, 2004, 12, 2, 35 - 45.
Chalder, T. Chronic fatigue syndrome: focus on the provider of care rather than the consumer. Journal of Mental Health, 2005, 14, 3, 209-211.
Clark, LV and White, PD. The role of deconditioning and therapeutic exercise in chronic fatigue syndrome (CFS). Journal of Mental Health, 2005, 14, 3, 237-252.
Dumit, J. Illnesses you have to fight to get: Facts as forces in uncertain, emergent illnesses. Social Science & Medicine, 2005 Aug 5; [Epub ahead of print].
Fowler, T., Duthie, P., Thapar, A and Farmer, A. The definition of disabling fatigue in children and adolescents. BMC Family Practice, 2005, 6, 1, 33.
Although there are accepted criteria for diagnosing chronic fatigue in adults, it remains uncertain as to how best to define disabling fatigue and CFS in children and adolescents. In this population-based study, the aim was to identify children who had experienced an episode of disabling fatigue and examine the clinical and demographic differences between those individuals who fulfilled a narrow definition of disabling fatigue and those who fulfilled broader definitions of disabling fatigue.
Participants (aged 8-17 years) were identified from a population-based twin register. Parent report was used to identify children who had ever experienced a period of disabling fatigue. Standardised telephone interviews were then conducted with the parents of these affected children. Data on clinical and demographic characteristics, including age of onset, gender, days per week affected, hours per day spent resting, absence from school, comorbidity with depression and a global measure of impairment due to the fatigue, were examined. A narrow definition was defined as a minimum of 6 months disabling fatigue plus at least 4 associated symptoms, which is comparable to the operational criteria for CFS (CDC '94) in adults. Broader definitions included those with at least 3 months of disabling fatigue and 4 or more of the associated symptoms and those with simply a minimum of 3 months of disabling fatigue. Groups were mutually exclusive.
Questionnaires were returned by 1468 families (65% response rate) and telephone interviews were completed on 99 of the 129 participants (77%) who had experienced fatigue. There were no significant differences in demographic and clinical characteristics or levels of impairment between those who fulfilled the narrower definition and those who fulfilled the broader definitions, e.g. age on onset, numbers of hours resting. The only exception was the reported number of days per week that the child was affected by the fatigue. All groups demonstrated evidence of substantial impairment associated with the fatigue.
Children and adolescents who do not fulfil the current narrow definition of CFS but do suffer from disabling fatigue show comparable and substantial impairment. In primary care settings, a broader definition of disabling fatigue would improve the identification of impaired children and adolescents who require support.
See http://www.biomedcentral.com/content/pdf/1471-2296-6-33.pdf.
Hamilton, WT., Gallagher, AM., Thomas, JM and White, PD. The prognosis of different fatigue diagnostic labels: a longitudinal survey. Family Practice, 22, 383-388.
Using electronic records from the UK General Practice Research Database, researchers examined 18,122 patients who had been diagnosed by their GP with a fatigue syndrome label - either ME, CFS, PVFS or fibromyalgia - from 1988 to 2001. The length of illness was calculated as the interval between the diagnosis and the last recorded fatigue symptom.
Patients with ME/CFS combined had a worse prognosis than either PVFS or fibromyalgia. In a subgroup analysis, ME had a worse prognosis.
Having a diagnosis of ME carried the worst prognosis and PVFS the best.
[Ed. note: The authors' suggest that the worse prognosis associated with ME was caused by giving people this label rather than patients destined to have the worst prognosis attracting this label but it not clear how they ruled out alternative explanations given the limited amount of information on the database. For example, there appears to be no data on the presence of neurological symptoms or severity, which may have differentiated the ME and CFS groups. There is also the fact that the earliest data would have been less likely to refer to CFS as the term was not generally adopted until a few years later. The finding that those with ME had a worse prognosis than those diagnosed with CFS may be a reflection of the changing criteria (cf Jason et al). This study was funded by the Department of Works and Pensions.]
Prins, J., Bleijenberg, G., Klein Rouwelier, E and van der Meer, J. Effect of psychiatric disorders on outcome of cognitive-behavioural therapy for chronic fatigue syndrome. British Journal of Psychiatry, 2005, 187, 184-185.
This study examined the impact of psychiatric disorders on outcome of CBT. Psychiatric diagnoses were assessed with a structured psychiatric interview in a CBT trial of 270 people with CFS. The analysis of lifetime and current psychiatric disorders were found in 50 and 32% respectively (N=264). After controlling for CFS symptoms, fatigue and poor concentration, lifetime and current mood disorders were found in 26.5 and 14% of the participants respectively. The prevalence of lifetime and current psychiatric disorders was 42.8 and 28.4% respectively. No significant differences in fatigue severity and functional impairment following treatment were found between participants with and without psychiatric diagnoses. The course of CFS was not adversely affected by current psychiatric morbidity over a period of 14 months. This is consistent with research by Vercoulen et al which found that depression was not a significant factor in the persistence of CFS.
Michielsen, HJ., Van Houdenhove, B., Leirs, I., Vandenbroeck, A and Onghena, P. Depression, attribution style and self-esteem in chronic fatigue syndrome and fibromyalgia patients: is there a link? Clinical Rheumatology, 2005 Jul 12; [Epub ahead of print]
The aims of the present study were to compare a single diagnosis (CFS) and a double diagnosis (CFS + fibromyalgia, CFS+FM) group regarding depression, attribution style and self-esteem, as well as to examine whether attribution style is a mediator in the relationship between self-esteem and depression.
Eighty-five patients (CFS: 47, CFS+FM: 38) completed questionnaires on attribution style, self-esteem and depression. The single and double diagnosis groups tended to differ slightly, but the differences were never statistically significant. In addition, only one condition was met of the four conditions mentioned by Baron and Kenny to establish that mediation exists between two variables.
In conclusion, an external attribution style does not protect the CFS or CFS+FM patients with a low self-esteem from depression. The prevalence rate of depression was high in both patient samples, of which clinicians should be aware.
Masuda, A., Kihara, T., Fukudome, T., Shinsato, T., Minagoe, S and Tei, C. The effects of repeated thermal therapy for two patients with chronic fatigue syndrome. Journal of Psychosomatic Research, 58, 4, 383-387.
This paper describes the successful treatment of two patients with CFS using repeated thermal therapy. Two patients with CFS underwent treatment with prednisolone (PSL) with no satisfactory effect. They were subjected to thermal therapy that consisted of a far-infrared ray dry sauna at 60 degrees C and postsauna warming. The therapy was performed once a day for a total of 35 sessions. After discharge, these subjects continued the therapy once or twice a week on an outpatient basis for 1 year.
Symptoms such as fatigue, pain, sleep disturbance, and low-grade fever were dramatically improved after 15 to 25 sessions of thermal therapy. Although PSL administration was discontinued, the subjects showed no relapse or exacerbation of symptoms during the first year after discharge. The patients became socially rehabilitated 6 months after discharge.
These results suggest that repeated thermal therapy might be a promising method for the treatment of CFS.
Moss-Morris, R. Symptom perception, illness beliefs and coping in the chronic fatigue syndrome. Journal of Mental Health, 2005, 14, 3, 223-235.
Nicolson, GL., Gan, R and Haier, J. Evidence for Brucella spp. and Mycoplasma spp. co-infections in blood of chronic fatigue syndrome patients. Journal of Chronic Fatigue Syndrome, 2004, 12, 2, 5 - 17.
We examined the blood of 94 North American CFS patients (CDC criteria '94) using forensic polymerase chain reaction (PCR) and found that a subset (10.6%) of these patients show evidence of Brucella spp. infections compared to one of 70 control subjects (Odds Ratio = 8.2; p<.01). Rural patients showed a higher incidence of Brucella spp. infections over urban patients (OR = 5.5, p<.02).
Since CFS patients also have a high prevalence of one of four Mycoplasma species and sometimes show evidence of infections with Chlamydia pneumoniae, we examined Brucella-positive patients for other bacterial infections. Previously we found that 8% of the CFS patients showed evidence of C. pneumoniae and about 50% show evidence of Mycoplasma spp. 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 Mycoplasma spp. infections in Brucella-positive patients.
We found only one Brucella-positive patient with C. pneumoniae and four other patients with evidence of Mycoplasma spp., suggesting that such bacterial infections occur independently in CFS patients. Control subjects (N=70) had low rates of Brucella spp. (1.4%), Mycoplasma spp. (7.2%) or C. pneumoniae (1.4%) infections, and there were no co-infections in control subjects.
The results indicate that a subset of CFS patients show evidence of infection with Brucella spp., and some of these patients also have other bacterial infections.
[Ed. Note: the researchers accept that additional infections may be opportunistic but point out that they could add to the severity of the illness and should be treated.]
Sharpe, M. Psychiatric diagnosis and chronic fatigue syndrome: controversies and conflicts. Journal of Mental Health, 2005, 14, 3, 269-276.
Van de Putte, EM., Engelbert, RH., Kuis, W., Sinnema, G., Kimpen, JL and Uiterwaal, CS. Chronic fatigue syndrome and health control in adolescents and parents. Archives of Diseases in Childhood, 2005, Jul 27; [Epub ahead of print]
Health behaviour and beliefs about health control are known to influence the outcome of an illness. Locus of health control is defined as the source from which health related behaviour is initiated. An internal locus refers to the belief that health is determined by one's own behaviour or capacities.
The aim of this study was to explore the locus of health control in adolescents with CFS and their parents in comparison with healthy adolescents and their parents. In this cross-sectional study, 32 adolescents with CFS were compared with 167 healthy controls and their respective parents. The Multidimensional Health Locus of Control (MHLC) questionnaire was administered to all participants.
There was significantly less internal health control in adolescents with CFS than in healthy controls. An increase of internal health control of one standard deviation was associated with a 61% reduced risk for CFS. Internal health control of the parents was protective as well. The external loci of health control were higher in adolescents with CFS and in their parents. Increased levels of fatigue (56%) were found in the mothers of the adolescents with CFS, in contrast with the fathers who reported a normal percentage of 13%.
In comparison with healthy adolescents, adolescents with CFS and their respective parents show less internal locus of health control. They attribute their health more to external factors, such as chance and physicians. This outcome is of relevance for treatment strategies like cognitive behaviour therapy, for which health behaviour is the main focus.
Vernon, SD and Reeves, WC. Evaluation of autoantibodies to common and neuronal cell antigens in chronic fatigue syndrome. Journal of Autoimmune Diseases, 2005, May 25th, 2:5
The exact causes of CFS are not known, but the symptom complex resembles that of several diseases that affect the immune system and autoantibodies may provide clues to the various etiologies of CFS. We used ELISA, immunoblot and commercially available assays to test serum from subjects enrolled in a physician-based surveillance study conducted in Atlanta, Georgia and a population-based study in Wichita, Kansas for a number of common autoantibodies and antibodies to neuron specific antigens. Participants from the physician surveillance study comprised 22 patients with CFS (CDC criteria '94) and 34 age and sex matched controls from Atlanta. In the population-based study, 37 patients met the CDC criteria '94 for CFS and there were 57 non-fatigued controls from Witchita. There were more acute onset cases in the former.
Subsets of those with CFS had higher rates of antibodies to microtubule-associated protein 2 (MAP2) (p=0.03) and ssDNA (p=0.04). There was no evidence of higher rates for several common nuclear and cellular antigens in people with CFS. Autoantibodies to specific host cell antigens may be a useful approach for identifying subsets of people with CFS, identify biomarkers, and provide clues to CFS etiologies.
See: http://www.jautoimdis.com/content/2/1/5
Wagner, D., Nisenbaum, R., Heim, C., Jones, JF., Unger, ER and Reeves, WC. Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome. Population Health Metrics, 2005 Jul 22, 3, 1:8 [Epub ahead of print]
The Symptom Inventory appears to be a reliable and valid instrument to assess symptoms that accompany CFS. It is a positive addition to existing instruments measuring fatigue because it allows other dimensions of the illness to be assessed.
Wallman, KE., Morton, AR., Goodman, C and Grove, R. Exercise prescription for individuals with chronic fatigue syndrome. Medical Journal of Australia, 2005, 183, 3, 142-143.
[Ed. Note: This protocol is consistent with the strategy of graded pacing.]
Wernham, W., Pheby, D and Saffron, L. Risk factors for the development of severe ME/CFS: A pilot study. Journal of Chronic Fatigue Syndrome, 2004, 12, 2, 47-50.
The pilot phase is reported of a case-control study to determine risk factors for severe CFS/ME. One hundred fifty-seven members of the ME Association, selected at random, were sent postal questionnaires, with a 56% response rate. The Barthel index was used as a validated proxy measure to distinguish severe disease and those less severe. Thirteen of 88 respondents had severe disease, and 44 mild disease. Two matched controls from the 'mild' group were selected per case. Of possible risk factors, odds ratios greater than 2 were found for comorbidities, damaging initial treatment and occupational chemical exposure, although in this study they were not statistically significant. These data suggest that additional studies are warranted.
Wheatland, R. Chronic ACTH autoantibodies are a significant pathological factor in the disruption of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome, anorexia nervosa and major depression. Medical Hypotheses, 2005, 65, 2, 287-295.
Some symptoms of CFS, anorexia nervosa and major depression, such as anxiety, are the adverse effects of mechanisms compensating for less effective ACTH due to autoantibodies. Furthermore, these patients engage in extraordinary behaviors, such as self-injury, to increase their cortisol levels. When this compensation is inadequate, symptoms of adrenocortical insufficiency appear.
Corticosteroid supplements have been demonstrated to be an effective treatment for CFS, anorexia nervosa and major depression. It allows the patients to have the corticosteroids they require for daily functioning and daily stressors. This therapy will relieve the patients of their symptoms of adrenocortical insufficiency and permit their cortisol-stimulating mechanisms to operate at levels that will not cause pathological problems.
[Ed. Note: We are not aware of evidence of self-injury in CFS, nor of 'extraordinary behaviors'.]
Fries, E., Hesse, J., Hellhammer, J and Hellhammer, DH. A new view on hypocorticolism. Psychoneuroendocrinology, 2005, 30, 10, 1010-1016.
Good review on the relationship between cortisol and immune function.
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