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IMMUNOLOGY
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Natelson, BH., Weaver, SA., Tseng, C-L and Ottenweller, JE. Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clinical and Diagnostic Laboratory Immunology, 2005, 12, 1, 52-55.
Arguments exist as to the cause of CFS. Some think that it is an example of symptom amplification indicative of functional or psychogenic illness, while our group thinks that some CFS patients may have brain dysfunction. To further pursue our encephalopathy hypothesis, we did spinal taps on 44 patients (31 women and 13 men) fulfilling the 1994 CDC criteria for CFS and on 8 women and 5 men serving as healthy controls. Our outcome measures were white blood cell count, protein concentration in spinal fluid, and cytokines detectable in spinal fluid.
We found that significantly more CFS patients had elevations in either protein levels or number of cells than healthy controls (30% versus 0%), and 13 CFS patients had protein levels and cell numbers that were higher than laboratory norms; patients with abnormal fluid had a lower rate of comorbid major depression than those with normal fluid (0 vs 27%, p<.04). In addition, of the 11 cytokines detectable in spinal fluid, (i) levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) were lower in patients than controls (p<.03), (ii) levels of interleukin-8 (IL-8) were higher in patients with sudden, influenza-like onset than in patients with gradual onset or in controls (p<.007 for both comparisons), and (iii) IL-10 levels were higher in the patients with abnormal spinal fluids than in those with normal fluid or controls (p<.025).
The presence or absence of FM did not alter the outcome.
The results support two hypotheses: that some CFS patients have a neurological abnormality that may contribute to the clinical picture of the illness and that immune dysregulation within the central nervous system may be involved in this process. Lower levels of GM-CSF (a growth factor) in the presence of IL-10 and IL-8 can lead to a downregulation of the immune response to certain bacterial infections. Alternatively, IL-10 may have downregulated the GM-CSF in these patients.
[Ed. Note. See Glaser et al, below].
Suhadolnik, RJ., Peterson, DL., Reichenbach, NL., Roen, G., Metzger, M., McCahan, J., O'Brien, K., Welsch, S., Gabriel, J., Gaughan, JP and McGregor, NR. Clinical and biochemical characteristics differentiating chronic fatigue syndrome from major depression and healthy control populations: relation to dysfunction and RNase L pathway. Journal of Chronic Fatigue Syndrome, 2004, 12, 1, 5-35.
Patterns of immune dysfunction have emerged in CFS that include an immune activation state (evidenced by increased activated T lymphocytes and circulating cytokines) and poor cellular function (low natural killer (NK) cell cytotoxicity and impaired T lymphocyte response to mitogens). Therefore, the aim of the current study was to examine the relationship between clinical and functional characteristics, immune abnormalities and status of the RNase L pathway in CFS compared with healthy control and depression control populations.
All study participants were assessed with respect to their general health, functional status, blood count and chemistry, biochemical and immune parameters.
The CFS group (CDC criteria ’88 and ’94, Karnofsky Performance score <60, n=66) demonstrated clinical, functional and biochemical abnormalities distinct from the healthy (n=62) and depression (n=51) control groups. The CFS group showed marked functional impairment compared with both control groups (p<.001) as measured by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) (p<.001). The CFS group also showed decreased cognitive performance on a computerized test battery compared to healthy (p<.001) and depression controls (p<.009) and significantly higher 37/80 kDa RNase L ratio (p<.001) compared with both control groups. The odds ratios of a 37/80 kDa RNase L ratio >2 compared with the CFS patients were 3.9 for the healthy controls (p<.05) and 65.8 for the depression controls (p<.001). The CFS group demonstrated low NK cell cytotoxicity compared to healthy controls (p=.045).
The correlation between abnormalities in the RNase L pathway and impaired NK cell function (r=.21, p<.006) suggests that both may be part of the same underlying disease mechanism, at least in this homogeneous population of very disabled CFS patients. Healthy contact-control subjects who had exposure to CFS patients showed a number of characteristics similar to the CFS patients, including an increased mean 37/80 kDa RNase L ratio (p<.04) and prevalence of the 37/80 kDa RNase L ratio >2 (<.03). In these contact-control subjects, the 37/80 kDa RNase L ratio was correlated with the interferon-α levels (r=.58, p<.02), suggestive of activation of the interferon pathway.
The results of the present study support the cytokine/immune activation model in this well-characterized CFS patient group.
Yamamoto, S., Ouchi, Y., Onoe, H., Yoshikawa, E., Tsukada, H., Takahashi, H., Iwase, M., Yamaguti, K., Kuratsune, H and Watanabe, Y. Reduction of serotonin transporters of patients with chronic fatigue syndrome. Neuroreport, 2004, 15, 17, 2571-2574.
To assess the involvement of serotonin in the symptoms of CFS, we investigated the serotonergic neurotransmitter system of 10 CFS patients (CDC criteria ’94) using positron emission tomography (PET). The density of serotonin transporters (5-HTTs) in the brain, as determined by using a radiotracer, [11C](+)McN5652, was significantly reduced in the rostral subdivision of the anterior cingulate as compared with that in the ten normal volunteers.
This subdivision is different from that in the dorsal anterior cingulate in which binding potential values of individual patient showed a weak negative correlation with self-reported pain score of the patients. Therefore, an alteration of serotonergic system in the rostral anterior cingulate may play a key role in pathophysiology of CFS.
Burnet, RB and Chatterton, BE. Gastric emptying is slow in chronic fatigue syndrome. BMC Gastroenterology, 2004, 4, 1, 32 [Epub ahead of print] 26th December.
Gastrointestinal symptoms are common in patients with CFS. The objective of this study was to determine the frequency of these symptoms and explore their relationship with objective (radionuclide) studies of upper GI function.
Thirty-two patients with CFS (CDC criteria ’94) and 45 control subjects completed a questionnaire on upper GI symptoms, and the CFS patients underwent oesophageal clearance and simultaneous liquid and solid gastric emptying studies using radionuclide techniques compared with non-fatigued controls not taking medication for GI symptoms.
The questionnaires showed a significant difference in gastric symptoms and swallowing difficulty. Nocturnal diarrhoea was a significant symptom not previously reported. 5/32 CFS subjects showed slightly delayed oesophageal clearance, but overall there was no significant difference from the control subjects, nor correlation of oesophageal clearance with symptoms. 23/32 patients showed a delay in liquid gastric emptying, and 12/32 a delay in solid gastric emptying with the delay significantly correlated with the mean symptom score (for each p<0.001).
GI symptoms in patients with CFS are associated with objective changes of upper GI motility.
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Casado, B., Zanone, C., Annovazzi, L., Iadarola, P., Whalen, G and Baraniuk, JN. Urinary electrophoretic profiles from chronic fatigue syndrome and chronic fatigue syndrome/fibromyalgia patients: a pilot study for achieving their normalization. Journal of Chromatography B (Analyt Technol Biomed Life Sci), 2005, 814, 1, 43-51.
The aim of our study was to determine if there are distinct, disease-related patterns of urinary analytes in CFS (n=11, own criteria) and CFS/fibromyalgia (n=8, CFS/FM) compared to normal controls (n=20, NC). The subjects included 2 people with Gulf War Syndrome. Urine was collected for two consecutive 24h periods and aliquots were submitted to micellar electrokinetic chromatography (MEKC).
There were a number of ‘peaks’ in people with CFS and CFS/FM which differed from those seen in controls. There were also two peaks which differed between CFS and CFS/FM. Creatinine concentrations in 24 hr urine samples were lower in people with CFS/FM compared to CFS and controls.
CFS/FM and CFS patients had significant differences in peaks compared to NC that may be of significance as biomarkers of illnesses.
Gallagher, AM., Thomas, JM., Hamilton, WT and White, PD. Incidence of fatigue symptoms and diagnoses presenting in UK primary care from 1990 to 2001. Journal of the Royal Society of Medicine, 2004, 97, 571-575.
Little is known about whether the incidence of symptoms of fatigue presented in primary care, and the consequent diagnoses made, change over time. The UK General Practice Research Database was used to investigate the annual incidence of both fatigue symptoms and diagnoses recorded in UK primary care from 1990 to 2001.
The overall incidence of all fatigue diagnoses decreased from 87 per 100000 patients in 1990 to 49 in 2001, a reduction of 44%, while postviral fatigue syndromes (PVFS) decreased from 81% of all fatigue diagnoses in 1990 to 60% in 2001. CFS (a code introduced only relatively recently) and myalgic encephalomyelitis (ME) together increased from 9% to 26% of all fatigue diagnoses. The incidence of FM increased from less than 1 per 100000 to 35 per 100000. In contrast, there was no consistent change in the incidence of all recorded symptoms of fatigue, with an average of 1503 per 100000, equivalent to 1.5% per year. CFS/ME and FM were rarely diagnosed in children and were uncommon in the elderly. All symptoms and diagnoses were more common in females than in males.
The overall incidence of fatigue diagnoses in general has fallen, but the incidence rates of the specific diagnoses of CFS/ME and FM have risen, against a background of little change in symptom reporting. This is likely to reflect changes in diagnostic labelling rather than true changes in incidence.
Mears, CJ., Taylor, RR., Jordan, KM and Binns, HJ. Sociodemographic and symptom correlates of fatigue in an adolescent primary care sample. Journal of Adolescent Health, 2004, 35, 6, 528, e21-26.
The aim of this study was to describe the prevalence of prolonged fatigue, chronic fatigue syndrome (CFS)-like illness, and associated symptom patterns in adolescents attending primary care.
The design was cross-sectional. A questionnaire designed by the authors assessing fatigue and associated symptoms was administered to 901 adolescents (aged 11-18 years) attending 12 primary care clinics in the Chicago area. Prevalence rates for prolonged fatigue and CFS-like illness were calculated. Univariate comparisons involving socio-demographic data and fatigue severity were made between adolescents with and without prolonged fatigue, and socio-demographic and symptom predictors of prolonged fatigue were identified using logistic regression analysis.
Prolonged fatigue (>/= 1 month) occurred at a rate of 8.0% and CFS-like illness occurred at a rate of 4.4%. Adolescents with prolonged fatigue were significantly older and also reported greater fatigue severity than those without fatigue. Findings from logistic regression indicated that, in addition to increasing age, headaches, muscle pains, fever, and fatigue made worse by exercise were significantly associated with prolonged fatigue. Gender and ethnic background were not. Only 38.2% reported that exercise worsened their fatigue.
Abnormal fatigue is a disabling and prevalent condition in adolescents in primary care. It is associated with a number of additional symptoms, many of which may have viral origins.
Solomon, L and Reeves, WC. Factors influencing the diagnosis of chronic fatigue syndrome. Archives of Internal Medicine, 2004, 164, 2241-2245.
Most of what is believed about CFS is based on clinic-based studies. We used data from a population-based study of CFS to identify factors associated with receiving a CFS diagnosis.
Residents from Wichita, Kan, were screened by random-digit dialling. Eligible individuals completed a telephone interview. Respondents meeting CFS criteria (CDC ‘94) were invited for a clinical evaluation to confirm CFS. We analyzed all persons with confirmed CFS. The main outcomes of this study, prevalence and incidence of CFS, are published elsewhere. Herein, we present an exploratory analysis with previous CFS diagnosis as the outcome, predicted by demographic and symptom characteristics.
We confirmed CFS in 90 subjects; only 14 (16%) had been previously diagnosed as having CFS. All were women. Persons in the middle- vs the higher-income group were more likely to have been diagnosed as having CFS (9 [29%] of 31 subjects vs 3 [8%] of 39 subjects; p=.03), as were those with sudden vs gradual fatigue onset (7 [41%] of 17 subjects vs 4 [6%] of 64 subjects; p<.01), those reporting tender lymph nodes (7 [33%] of 21 subjects vs 7 [10%] of 69 subjects; p=.02), and those reporting a sore throat (6 [35%] of 17 subjects vs 8 [11%] of 73 subjects; p=.02). Only 17 (21%) of 81 subjects had sudden fatigue onset, and tender lymph nodes (reported in 21 [23%] of 90 subjects) and a sore throat (reported in 17 [19%] of 90 subjects) were the least common symptoms. 81% reported post-exertional fatigue.
Most cases of CFS in the population are unrecognized by the medical community; persons diagnosed as having CFS may be different from persons with CFS in the general population.
Jason, LA., Torres-Harding, SR., Jurgens, A and Helgerson, J. Comparing the Fukuda et al. criteria and the Canadian case definition for chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2004, 12, 1, 37-52.
Because the pathogenesis of CFS has yet to be determined, case definitions have relied on clinical observation in classifying signs and symptoms for diagnosis. The selection of diagnostic signs and symptoms has major implications for which individuals are diagnosed with CFS and how seriously the illness is viewed by health care providers, disability insurers and rehabilitation planners, and patients and their families and friends. Diagnostic criteria also have implications for whether research based on varying definitions can be synthesized.
The current investigation examined differences between CFS as defined by Fukuda et al. (1994) and a set of criteria that has been proposed for a clinical Canadian Case definition.
There were 23 participants who met the Canadian criteria for ME/CFS, 12 met the CFS criteria devised by Fukuda et al, and 33 had a psychiatric explanation for their chronic fatigue (CF-psychiatric group). Dependent measures included: work status, psychiatric comorbidity, symptoms, and functional impairment (measured by the Medical Outcomes Study).
The Canadian criteria group, in contrast to the Fukuda et al. CFS group, had more variables that statistically significantly differentiated them from the psychiatric comparison group. Overall, there were 17 symptom differences between the Canadian and CF-psychiatric group, but only 7 symptom differences between the CFS and CF-psychiatric group. The Canadian group had lower rates of psychiatric diagnoses, with 47.5% meeting criteria for current psychiatric disorders (SCID) compared to 75% of the CFS group and 87.9% of the CF-Psychiatric group.
The findings suggest that both the Canadian and Fukuda et al. case definitions select individuals who are statistically significantly different from psychiatric controls with chronic fatigue, with the Canadian criteria selecting cases with less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms. The CFS group differed from the CF-psychiatric group in reporting more rheumatological and gastrointestinal complaints. The Canadian group showed similarities with the patients who met criteria for ME in an earlier study by the authors*. Both reported more neurological and neuropsychiatric symptoms, as well as muscle weakness.
[Ed. Note: In the introduction (p. 39), the authors refer to the clinical criteria for ME devised by Dowsett et al 1990 and Lloyd et al 1990 and claim that these “stipulate that both post exertional malaise as well as memory and concentration difficulties are central to diagnosis” (p. 39). In fact, Dowsett et al’s criteria refer to “a complaint of general or local muscular fatigue following minimal exertion with prolonged recovery time”, and to “neurological disturbance, especially of cognitive, autonomic and sensory functions”.
Thus it is possible to be diagnosed with ME without memory or concentration problems and in the paper by Dowsett et al, not every patient reported these. Moreover, their definition of cognitive disturbance extended beyond memory and concentration problems. Dowsett et al’s criteria are consistent with the concept of ME as a post-viral neurological disease involving cardiac and other systems. Lloyd et al’s criteria from 1990 do not mention muscle fatiguability or postexertional malaise and only 66% reported “myalgia after activity”. [There appear to be no data for postexertional malaise or fatigue. Postexertional malaise\fatigue is not mentioned either in their stricter criteria 1988, JNNP. Ed.] Dowsett and Ramsay’s definition emphasises muscle fatiguability and delayed recovery from minimal exertion plus the involvement of the CNS. This also differentiates their criteria from recent definitions of CFS which focus on more general fatigue, ‘malaise’ and cognitive complaints, as reported in neurasthenia.
*The study referred to here compared people with CFS and ME using a definition of the latter based on the ‘London criteria’. If one compares the results of the patients diagnosed using the Canadian criteria with data from patients with ME, it appears that the former report less intolerance to alcohol (47.8% vs ~90%), and fewer cognitive difficulties. Ed.]
Stulemeijer, M., de Jong, LWAM., Fiselier, TJW., Hoogveld, SWB and Bleijenberg, G. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ, 2005, 330, 14-17. Also bmj.com (corrected version), December 14th, 2004. The abstract below was published online 7th December 2004.
The aim of this study was to evaluate the efficacy of cognitive behaviour therapy (CBT) for adolescents aged 10-17 years with CFS. It was a randomised controlled trial in the Department of child psychology.
The participants were 69 consecutively referred patients with CFS (CDC criteria ’94); 36 were randomly assigned to immediate CBT and 35 to the waiting list for therapy [error: 36+35=71]. They were given 10 sessions of therapy over five months. Treatment protocols depended on the type of activity pattern (relatively active or passive). All participants were assessed again after five months.
Outcome measures included fatigue severity (checklist individual strength), functional impairment (SF-36 physical functioning), and school attendance. Two subjects were excluded, one from each group. Six did not start CBT or withdrew. Only one withdrew from the control group.
There were complete data for 58 patients at five months (29 in the immediate therapy group and 33 on the waiting list) [Error: 29+33=62]. Patients in the therapy group reported significantly greater decrease in fatigue severity (difference in decrease on checklist individual strength was 14.5, 95% confidence interval 7.4 to 21.6) and functional impairment (difference in increase on SF-36 physical functioning was 17.3, 6.2 to 28.4) and their attendance at school increased significantly (difference in increase in percentage school attendance was 18.2, 0.8 to 35.5). They also reported a significant reduction in several accompanying symptoms. Self reported improvement was largest in the therapy group. “CBT is an effective treatment for CFS in adolescents.”
[Ed. Note: In the section on the interventions, there is a lack of information on CBT. There is no information as to how they dealt with the beliefs thought to be maladaptive. The reference given for the passive patients refers to a book, where the authors imply that that a degree of pacing was used. If true, this deserved to be mentioned here.
The CBT arm had more 'tiredness after exercise' than the controls at baseline. Patients recorded very low physical functioning scores (42 and 45), which in adults, is usually matched by similar scores on other disability scales, reflecting severe illness. However, many were able to attend school and 70% and 79% in each group were relatively active. This is also relevant in relation to the high fatigue scores and suggest that the measure used to assess fatigue has a low ceiling (cf Stouten, in press).
In terms of the results, the CBT group ended up with a physical functioning score of 69.4, still below normal (defined here as >75, elsewhere as >80). The drop out rate from treatment was given as 19%. (Possible error. 6/35=17% from the CBT arm.) There are no data for those who completed the trial i.e. minus last scores of those who didn't, cf Deale et al 1997. 71% given CBT felt improved, but so did 44% in the waiting list controls. The actometer scores are not given but a member of the Nijmegen team has publicly admitted that none of the studies carried out by them showed increases in activity levels. This means that the aim of increasing activity was not achieved.
There is no information as to the type of onset or any subgrouping as suggested by the 1994 guidelines. There are no data on the correlation between attribution, considered important, and outcome. The authors conclude that CBT is an effective treatment for CFS in adolescents but for 29%, it wasn't, and for the group as a whole, the average physical functioning score remained below normal. The data from the follow-up of the CBT group are not included in this report.
In a rapid response on bmj.com dated 20th January 2005, Stulemeijer et al wrote: “In contrast to what Table 1 perhaps suggests there were 13 youngsters (6 in the CBT condition and 7 in the waiting list condition) who did not attend school at all at the first assessment; these youngster were included in the group ‘partial school attendance’, which might be confusing”.
The various mathematical errors identified by the editors of the ME and CFS References, e.g. in the abstract above, were passed on to the BMJ in time for amendments to be made to the paper version. They include the error in the trial profile. The error relating to the drop out rate was identified at a later stage and at the time of writing, has not yet been corrected.]
Glaser, R., Padgett, DA., Litsky, ML., Baiocchi, RA., Yang, EV., Chen, M., Yeh, P-E., Klimas, NG., Marshall, GD., Whiteside, T., Herberman, R., Kiecolt-Glaser, J and Williams, MV. Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer. Brain, Behavior, and Immunity, 2005, 19, 2, 91-103.
Antibodies to several Epstein-Barr virus (EBV)-encoded enzymes are observed in patients with different EBV-associated diseases. The reason for these antibody patterns and the role these proteins might play in the pathophysiology of disease, separate from their role in virus replication, is unknown.
In this series of studies, we found that purified EBV deoxyuridine triphosphate nucleotidohydrolase (dUTPase) can inhibit the replication of human peripheral blood mononuclear cells in vitro and upregulate the production of TNF-α, IL-1β, IL-6, IL-8, and IL-10. It also enhanced the ability of natural killer cells to lyse target cells. The EBV dUTPase also significantly inhibited the replication of mitogen-stimulated lymphocytes and the synthesis of IFN-γ by cells isolated from lymph nodes and spleens obtained from mice inoculated with the protein. It also produced sickness behaviors known to be induced by some of the cytokines that were studied in the in vitro experiments. These symptoms include an increase in body temperature, a decrease in body mass and in physical activity.
The data provide a new perspective on how an early nonstructural EBV-encoded protein can cause immune dysregulation and produce clinical symptoms observed in patients with CFS separate from its role in virus replication and may serve as a new approach to help identify one of the etiological agents for CFS. The data also provide additional insight into the pathophysiology of EBV infection, inflammation, and cancer.
[Ed. Note: IL-10 may allow the replication of EBV, perhaps by downregulating the host-specific cytotoxic T-cell response, and is associated with poor prognosis in patients with chronic lymphocytic leukaemia (CLL) who have raised levels of IL-10 and IL-6. CLL has been linked to EBV. IL-10 can also inhibit the production of IFN-γ and IL-1.]
Kop, WJ., Lyden, A., Berlin, AA., Ambrose, K., Olsen, C., Gracely, RH., Williams, DA and Clauw, DJ. Ambulatory monitoring of physical activity and symptoms in fibromyalgia and chronic fatigue syndrome. Arthritis and Rheumatism, 2005, 52, 1, 296-303
Determinants of self-reported physical disability are poorly understood. This investigation uses objective ambulatory activity monitoring to compare patients with FM and/or CFS with controls, and examines associations of ambulatory activity levels with both physical function and symptoms during activities of daily life.
Patients with FM and/or CFS (n=38, mean age 41.5 years, of whom 9 had CFS and 8 had FM only) completed a 5-day program of ambulatory monitoring of physical activity and symptoms (pain, fatigue, and distress) and results were compared with those in age-matched controls (n=27, mean age 38.0 years). Activity levels were assessed continuously using an actigraph, ambulatory symptoms were determined using electronically time-stamped recordings at 5 time points during each day, and physical function was measured with the 36-item Short Form health survey at the end of the 5-day monitoring period.
Patients had significantly lower peak activity levels than controls (mean 8,654 versus 12,913 units; p=0.003) and spent less time in high-level activities compared with controls (p=0.001). In contrast, patients had similar average activity levels as those of controls (mean 1,525 versus 1,602, p=0.47). Among patients, low activity levels were associated with worse self-reported physical function over the preceding month. Activity levels were inversely related to concurrent ambulatory pain (p=0.031) and fatigue (p<0.001). Pain and fatigue were associated with reduced subsequent ambulatory activity levels, whereas activity levels were not predictive of subsequent symptoms.
Patients with FM and/or CFS engaged in less high-intensity physical activities than that recorded for sedentary control subjects. This reduced peak activity was correlated with measures of poor physical function. The observed associations may be relevant to the design of behavioral activation programs, because activity levels appear to be contingent on, rather than predictive of, symptoms.
[Ed. Note: The researchers did not find a consistent exacerbation of symptoms following increased activity, suggesting that the sample did not include people with ME, or that they were pacing themselves successfully. The percentage of patients with FM in Table 1 should be 21%, not 27%.]
Looper, KJ and Kirmayer, LJ. Perceived stigma in functional somatic syndromes and comparable medical conditions. Journal of Psychosomatic Research, 2004, 57, 4, 373-378.
The aim was to determine if patients with functional somatic syndromes (FSS) perceive greater levels of stigma than patients with comparable medical conditions that have a clear medical pathology. Patients with CFS (CDC criteria ’94, n=42), FM, or irritable bowel syndrome (IBS), categorised here as FSS, were compared to people with multiple sclerosis (MS), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), respectively.
There were greater levels of perceived stigma in the combined group of FSS compared to the medical control group. When each FSS was compared to its matched control group, only CFS had a higher level of perceived stigma. These results remained when controlling for other variables relevant to stigma. There was a positive correlation between depression and stigma in both CFS and MS. The higher level of perceived stigma in CFS may be due to the ambiguity of its status as a medical condition. The absence of this effect in FM and IBS is consistent with a greater level of acceptance of these disorders as medical illnesses. The authors argue against the term FSS.
Madill, PV. Chronic fatigue syndrome and the cholinergic hypothesis. JAMA, 2004, 292, 22, 2723.
Letter discussing the cholinergic hypothesis following the trial of galantamine (see also reply by Blacker).
Nijs, J., Van de Velde, B and De Meirleir, K. Pain in patients with chronic fatigue syndrome: Does nitric oxide trigger central sensitisation? Medical Hypotheses 2005, 64, 3, 558-562.
Previous studies have provided evidence supportive of the clinical importance of widespread pain in patients with CFS: pain severity may account for 26-34% of the variability in the CFS patient's activity limitations and participation restrictions. The etiology of widespread pain in CFS remains to be elucidated, but sensitisation of the central nervous system has been suggested to take part of CFS pathophysiology.
It is hypothesised that a nitric oxide (NO) - dependent reduction in inhibitory activity of the central nervous system and consequent central sensitisation accounts for chronic widespread pain in CFS patients. In CFS patients, deregulation of the 2',5'-oligoadenylate synthetase/RNase L pathway is accompanied by activation of the protein kinase R enzyme. Activation of the protein kinase R and subsequent nuclear factor-kappaβ activation might account for the increased production of NO, while infectious agents frequently associated with CFS (Coxsackie B virus, EBV, Mycoplasma) might initiate or accelerate this process. In addition, the evidence addressing behavioural changes in CFS patients fits the central sensitisation-hypothesis: catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by sensitisation of the central nervous system.
Nijs, J and De Meirleir, K. Prediction of peak oxygen uptake in patients fulfilling the 1994 CDC criteria for chronic fatigue syndrome. Clinical Rehabilitation, 2004, 18, 7, 785-792.
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.
Using magnetic resonance imaging [3 Tesla, Ed.], we conducted voxel-based morphometry of 16 patients with CFS (CDC criteria ’94) and 49 age-matched healthy control subjects. The mean duration of illness was 69.8 months.
We found that patients with CFS had reduced gray-matter volume in the bilateral prefrontal cortex. There was an average reduction of 11.8% compared to controls. Within these areas, the volume reduction in the right prefrontal cortex paralleled the severity of the fatigue of the subjects. Here the average reduction in gray-matter volume was 16.9%. There was no atrophy in white matter.
These results are consistent with previous reports of an abnormal distribution of acetyl-L-carnitine uptake, 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.
Prefrontal pathology has also been reported in cases of MS with pathological fatigue.
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Scroop, GC and Burnett, RB. To exercise or not to exercise in chronic fatigue syndrome? Medical Journal of Australia, 2004, 181, 10, 578.
Letter in response to the editorial by Lloyd (ibid, 180, 437) noting that “a fundamental flaw with most exercise studies in CFS is the use of submaximal or symptom-limited tests, which provide notoriously misleading data when compared with maximal exercise testing procedures. Wallman et al correctly identify maximal oxygen consumption as the “gold standard” measure of exercise capacity, yet such measurements were not made in the three articles they cited. When such procedures are applied, the exercise capacity of people with CFS is not significantly different from either measured or age-predicted values for healthy sedentary people. Wallman et al suggested that maximal testing procedures could favour the recruitment of “more robust or healthier” patients and provide misleading information.
In the first place this is denied by the study of Sargent et al, in which the illness status reported by patients who completed the maximal tests was similar to that in previous CFS studies. In the second place, the maximal test protocol chosen for a given population should be designed to exclude any influence of fatigue on the metabolic measurements. This is confirmed by the results from the study cited, in which the metabolic measurements met the published criteria of a maximal test.
In summary, patients with CFS are not “deconditioned”. Neither their muscle strength nor their exercise capacity is different from that of other sedentary members of the community (>70%). We remain unaware of any incontrovertible evidence that the various “exercise training” programs suggested in previous articles improve either the physiological or clinical status of people with CFS.”
A second letter by Stein and Hunter (p.579), note the generalisations in the editorial and discuss the new Canadian guidelines. In his reply (p. 579), Lloyd points out that the latter also advocate gently increasing activity and corrects an error re SPHERE.
[Ed. Note: Lloyd’s claim that muscle strength, endurance and recovery is essentially normal in patients with CFS is inconsistent with other findings e.g. Paul et al 1999 and with the reports of post-exertional malaise.]
Shepherd, C. Patients with chronic fatigue syndrome are being ignored. BMJ, 2004, 329, 1405.
Letter responding to the editorial by White (ibid 23rd October), noting the oversimplistic view of ME and CFS, the failure to acknowledge the heterogeneity of the latter, and the need for more research into neurological aspects of central fatigue.
Van Hoof, E., Coomans, D., Cluydts, R and De Meirleir, K. The Fennell Phase Inventory in a Belgian sample. Journal of Chronic Fatigue Syndrome, 2004, 12, 1, 53-69.
The present study is a follow-up of the research conducted by Jason, Fennell et al. on a multistage (four phases) theory for CFS. This multistage model is a very promising method for the evaluation of patients and could facilitate the appropriate selection of various psychosocial therapies that improve the patient's ability to cope with CFS. There were some differences between the patients from Belgium studied here, and the American patients evaluated by Jason et al. Biological parameters e.g. RNase L, varied over the different phases suggesting an important interaction between body and psyche.
Wallman, KE., Morton, AR., Goodman, C and Grove, R. Physiological responses during a submaximal cycle test in chronic fatigue syndrome. Medical & Science in Sports and Exercise, 2004, 36, 10, 1682-1688.
Numerous studies have assessed physical function in individuals suffering from CFS but neglected to match control subjects according to current activity levels, consequently casting doubt on reported results. The purpose of this study was to include current activity levels as one criterion for matching CFS subjects with healthy control subjects in order to more accurately assess physical function in these subjects.
Thirty-one healthy control subjects were matched to subjects with CFS (CDC criteria ’94) according to age, gender, body mass, height, and current activity levels. Physiological function was assessed weekly over a 4-wk period using a submaximal cycle test.
Comparison of absolute physiological results recorded at the end of each incremental work level of the exercise test showed that ratings of perceived effort (RPE) was the only variable that was significantly different between the two groups. Scores for RPE were significantly higher in CFS subjects for each incremental work level assessed. Conversely, results recorded on completion of the exercise test showed that the control group was capable of a greater power output than the CFS group as reflected by significantly higher scores for watts per kilogram (p<0.0005), net lactate production (p=0.003), oxygen uptake p<0.0005), respiratory exchange ratio (p=0.021), and HR values as a percentage of age predicted HRmax (p=0.001). End-point RPE scores were again significantly higher in the CFS group (p<0.0005).
It is proposed that the reduced exercise tolerance in CFS is due to impairment in the mechanisms that constitute effort sense and/or to avoidance behaviors that result in a reluctance by these subject to exercise to full capacity.
Whitely, P., Shattock, P., Todd, L and Wright, A. Correlates of overlapping fatigue syndromes. Journal of Nutritional & Environmental Medicine, 2004, 14, 3, 247-252.
This study compared 259 patients with the diagnosis of ME, CFS and/or FM, of whom 34% had more than one diagnosis, with 102 patients sent to a clinic specialising in fatigue syndromes but who had not yet received a formal diagnosis. There were 17 significant differences between the groups, including a greater percentage of muscle fatigue, auditory hyperacuity, balance problems, walking problems and history of viral infection.
Huibers, MJH., Bleijenberg, G., van Amelsvoort, LGPM., Beurskens, AJHM., van Schayck, CP, Bazelmans, E and Knottnerus, JA. Predictors of outcome in fatigued employees on sick leave. Results from a randomised trial. Journal of Psychosomatic Research, 2004, 57, 5, 443-449.
The main objective of this study was to identify predictors of fatigue caseness, work resumption and CFS-like caseness in a sample of fatigued employees on sick leave.
For 12 months, 151 fatigued employees on sick leave, 44% of whom met research (symptom) criteria for CFS at baseline, were followed. Measures included fatigue, health aspects, psychological problems, burnout, causal attributions and self-efficacy. Logistic regression analysis was used to determine associations between predictor variables at baseline and outcome at follow-up.
After 12 months, 43% of the patients were no longer fatigue cases, and 62% had resumed work. Recovery from fatigue caseness was predicted by stronger psychological attributions and other perception-related factors, whereas work resumption was predicted by lower age, male sex, CFS-like caseness and less cognitive difficulties. Lower physical functioning scores were predictive of (the development of) CFS-like caseness.
Recovering from persistent fatigue and work resumption seem to result from different underlying processes and do not necessarily fall together.
[Ed. Note: This research did not include medical examination and hence the diagnosis of CFS could not be confirmed.]
Long-term persistence of C. burnetii in infected animals was established in the 1950s and 60s, but the implications for human Q fever are not fully explored. The aim was to compare the prevalence of markers of infection in a cohort of Q fever patients in Australia (up to 5 years after infection) with those in the 1989 Birmingham cohort (12 years after infection). This was a case follow-up study.
C. burnetii was tested for by: (i) antibodies to Phase 1 and 2 antigens in the three immunoglobulin classes; (ii) detection of DNA in bone marrow and peripheral blood mononuclear cells by PCR assays directed against several different targets in the genome; and (iii) attempts to isolate coxiellas in cell culture or mice from PCR-positive samples. Amplicon specificity was verified by fluorometric probing and by sequencing. Cross-contamination was excluded by extensive use of non-template controls, and in particular by the use of certain IS1111a target sequences.
Irrespective of
clinical state, both groups remained seropositive, principally
exhibiting medium levels of IgG antibody against C. burnetii
Phase 2 antigen. C. burnetii genomic DNA was detected by PCR
in 65% of bone marrow aspirates from Australian patients and 
88%
of Birmingham patients. No coxiella were isolated from PCR positive
samples.
We propose a provisional model for persistence. In Q fever without sequelae, the process is largely confined to the bone marrow. In Q fever fatigue syndrome (QFS), it is modulated by the patient's immunogenetic background to give higher levels of coxiella genomes in bone marrow and increased shedding into the peripheral blood. In Q fever endocarditis, late pregnancy, or during iatrogenic or other immunosuppression, the multiplication cycle is prolonged, and a potential source of live organisms.
Sources used include Co-Cure and Medline. Editors: EM Goudsmit PhD, S. Howes and B. Stouten MSc. With thanks to Dr. Charles Shepherd and Ray Colliton.
This update is for personal use only. Not all abstracts were checked with the original document and there may be errors due to conversion between word processors. For reliable information, please refer to the original articles.
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