Number 3 |
1st September 2007 |
PHYSIOLOGY AND BIOCHEMISTY
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Javierre, C., Alegre, J., Ventura, JL., García-Quintana, A., Segura, R., Suarez, A., Morales, A., Comella, A and De Meirleir, K. Physiological responses to arm and leg exercise in women patients with chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2007, 14, 1, 43-53.
Patients affected by CFS characteristically show easy and unexplained fatigue after minimal exertion that does not resolve with rest and is associated with specific symptoms lasting for more than six months. Cardiopulmonary exercise testing is a valid procedure for determining functional capacity in patients with CFS. We compare cardioventilatory adaptation to exercise between a group of 85 women patients affected by CFS (CDC criteria ’88 confirmed by two physicians, no other disorders) and a group of 15 healthy, age, gender-matched, extremely sedentary individuals, with the use of maximum incremental exercise testing on a cycle ergometer and arm ergometer, assessing possible differences.
The majority of values achieved at peak exhaustive exercise were significantly lower in CFS patients than controls, including the percentage of maximum oxygen uptake in arm physical test (37.4 ± 10.0% in CFS vs. 58.9 ± 15.8% in controls) and leg physical test (53.4 ± 15.0% in CFS patients vs. 76.2 ± 18.0% in controls).
“In the group with an extremely sedentary life style for more than one year (virtually the entire group had a similar lifestyle throughout their entire adult life), there was a 24% decrease in 02 uptake with respect to predicted values. This could result from a "hypoactivity syndrome" and its deconditioning-related effects on physiological responses and exercise capacity. In contrast, the CFS patients showed a decrease of 47% in 02 uptake with respect to predicted values which, although partly explained by the above reasons, should be considered along with the CFS diagnosis to justify a 23% higher decrease with respect to predicted values than in the control group. It should be considered that there is a CFS-dependent decrease in performance.”
In conclusion, the CFS group shows a lower work capacity in arm or leg exercise that would not be justified exclusively by their personal characteristics or deconditioning.
[Ed. Note: There are no data assessing post-exertional recovery which is typically delayed in ME.]
Newton, JL., Okonkwo, O., Sutcliffe, K., Seth, A., Shin, J and Jones, DEJ. Symptoms of autonomic dysfunction in chronic fatigue syndrome. Quarterly Journal of Medicine, 2007, 100, 519-526.
The aim of this study was to examine the prevalence of autonomic dysfunction in CFS, and to develop diagnostic criteria. It was a cross-sectional study with independent derivation and validation phases.
Symptoms of autonomic dysfunction were assessed using the Composite Autonomic Symptom Scale (COMPASS). Fatigue was assessed using the Fatigue Impact Scale (FIS). Subjects were studied in two groups: phase 1 (derivation phase), 40 CFS patients (CDC criteria ’94, recruited from patient groups) and 40 age- and sex-matched controls; phase 2 (validation phase), 30 CFS patients, 37 normal controls and 60 patients with primary biliary cirrhosis.
Symptoms of autonomic dysfunction were strongly and reproducibly associated with the presence of CFS or primary biliary cirrhosis (PBC), and correlated with severity of fatigue. Total COMPASS score >32.5 was identified in phase 1 as a diagnostic criterion for autonomic dysfunction in CFS patients, and was shown in phase 2 to have a positive predictive value of 0.96 (95%CI 0.86-0.99) and a negative predictive value of 0.84 (0.70-0.93) for the diagnosis of CFS.
Autonomic dysfunction is strongly associated with fatigue in some, but not all, CFS and PBC patients. We postulate the existence of a 'cross-cutting' aetiological process of dysautonomia-associated fatigue (DAF). COMPASS >32.5 is a valid diagnostic criterion for autonomic dysfunction in CFS and PBC, and can be used to identify patients for targeted intervention studies.
Cameron, B., Galbraith, S., Zhang, Y, Davenport, T., Vollmer-Conna U, Wakefield, D., Hickie, I., Dunsmuir, W., Whistler, T., Vernon, S., Reeves, WC and Lloyd, AR, for the Dubbo Infection Outcomes Study. Gene expression correlates of postinfective fatigue syndrome after infectious mononucleosis. Journal of Infectious Diseases, 2007, 196, 1, 56-66.
Infectious mononucleosis (IM) commonly triggers a protracted postinfective fatigue syndrome (PIFS) of unknown pathogenesis.
Seven subjects with PIFS with 6 or more months of disabling symptoms and meeting the CDC criteria for CFS and 8 matched control subjects who had recovered promptly from documented IM were studied. The expression of 30,000 genes was examined in the peripheral blood by microarray analysis in 65 longitudinally collected samples. Gene expression patterns associated with PIFS were sought by correlation with symptom factor scores.
Differential expression of 733 genes was identified when samples collected early during the illness and at the late (recovered) time point were compared. Of these genes, 234 were found to be significantly correlated with the reported severity of the fatigue symptom factor, and 180 were found to be correlated with the musculoskeletal pain symptom factor. Validation by analysis of the longitudinal expression pattern revealed 35 genes for which changes in expression were consistent with the illness course. These genes included several that are involved in signal transduction pathways, metal ion binding, and ion channel activity. Cluster analysis of the Time 3 data set, which included the subjects with 6 or more months of illness and the recovered subjects, did not provide a coherent gene expression signature for PIFS.
Gene expression correlates of the cardinal symptoms of PIFS after IM have been identified. Further studies of these gene products may help to elucidate the pathogenesis of PIFS.
With editorial commentary by PD White. What causes prolonged fatigue after Infectious Mononucleosis - and does it tell us anything about chronic fatigue syndrome? (ibid, 4-5).
Extracts (minus references):
“One successful way of sorting fact from fiction has been through the use of cohort studies of populations at high risk for developing prolonged fatigue. Perhaps one of the most fruitful areas of research has involved postinfectious cohorts, particularly following Epstein-Barr virus (EBV) infections presenting as infectious mononucleosis (IM) in adults. Five such cohort studies have been published. These studies have demonstrated that a discrete postinfectious fatigue syndrome exists, one that is not a mood disorder. In fact, there seems to be not 1 but 2 postinfectious fatigue syndromes, one characterized by excessive sleep and the other characterized by insomnia associated with muscle and joint pain. Both syndromes also include poor concentration, irritability, and psychomotor retardation... What cofactors make CFS happen after IM? A systematic review of all studies of prolonged fatigue found that physical inactivity was the most replicated predictor. Of particular interest, the first reported cohort study showed that neither premorbid mood disorder nor recent stressful life events predicted post-IM CFS, once comorbid mood disorder had been controlled for. By contrast, these same factors did predict depressive illness after IM, reinforcing the contrast with mood disorders. Predictors of prolonged fatigue 6 months after onset were early positivity for heterophil antibody and evidence of physical deconditioning 4 months earlier. There were no significant associations with any other immune response to EBV. No other cohort has shown convincing associations with the immune response to EBV... The weaknesses of the study include the small number of subjects (with type I errors likely), the lack of matching by sex, and the lack of validation by real-time polymerase chain reaction analysis of messenger RNA. We cannot be sure that gene expression in lymphocytes reflects gene expression in other tissues, such as the brain. Because gene expression changes rapidly and in response to behavioral changes, the lack of replication of the results of previous studies is no surprise.”
Bennett, B., Goldstein, D., Friedlander, M., Hickie, I and Lloyd, A. The experience of cancer-related fatigue and chronic fatigue syndrome: A qualitative and comparative study. Journal of Pain and Symptom Management, 2007, May 31, doi:10.1016/j.jpainsymman.2006.10.014.
Cancer-related fatigue (CRF) is a common and disabling symptom complex reported by survivors. This study aimed to better understand the manifestations of CRF in women treated for breast cancer, and to compare them with those of women diagnosed with CFS (CDC criteria ’94).
Women with CRF persisting 6 months after treatment for early stage breast cancer, and women with CFS participated in separate, audiotaped focus groups. Transcripts of the sessions were analyzed using the NUD*IST software (
Non-numerical Unstructured Data Indexing, Searching, and Theorising), and interpreted using grounded theory. Twenty-eight women participated, 16 with CRF and 12 with CFS.Analysis of transcripts from both groups revealed a similar core set of symptoms, featuring fatigue, neurocognitive difficulties, and mood disturbances. Women with CFS reported additional symptoms including musculoskeletal pain and influenza-like manifestations. Both groups suffered disabling behavioral consequences of the symptom complex.
Qualitatively, CRF appears closely related to CFS. These findings raise the emergent hypothesis of a conserved neurobehavioral symptom complex, which results from diverse triggering insults.
Claypoole, KH., Noonan, C., Mahurin, RK., Goldberg, J., Erickson, T and Buchwald, D. A twin study of cognitive function in chronic fatigue syndrome: The effects of sudden illness onset. Neuropsychology, 2007, 21, 4, 507-513.
Variable reports of neuropsychological deficits in individuals with CFS may, in part, be attributable to methodological limitations. In this study, these limitations were addressed by controlling for genetic and environmental influences and by assessing the effects of comorbid depression and mode of illness onset.
Specifically, the researchers conducted a co-twin control study of 22 pairs of monozygotic twins, in which 1 twin had CFS (CDC criteria ’94, no medical examination) and the co-twin was healthy. Twins underwent a structured psychiatric interview and comprehensive neuropsychological assessment evaluating 6 cognitive domains. Ten reported a sudden onset with flu-like symptoms, 9 reported a gradual onset.
Results indicated that twin groups had similar intellectual and visual memory functioning, but fatigued twins exhibited decreases in motor functions (p=.05), speed of information processing (p=.02), verbal memory (p=.02), and executive functioning (p=.01). Major depression did not affect neuro-psychological functioning among fatigued twins, although twins with sudden illness onset (with a flu, cold, virus) demonstrated slowed information processing compared with those with gradual onset (p=.01).
“
In conclusion, CFS is associated with neuropsychological deficits across multiple cognitive domains, and in some domains — notably speed of information processing — individuals with a sudden onset of illness may be more impaired than those with a gradual onset. The reasons behind this are unclear, but they may reflect an infectious trigger and involvement of the central nervous system. In addition, our findings may have clinical implications for determining disability among individuals with CFS, a process that is complicated by the absence of accepted guidelines for physical and cognitive disability (Hickie et al., 1995). We suggest that neuropsychological evaluations could describe vocational capacity and the potential benefit of cognitive rehabilitation and workplace accommodation. Future studies should examine the functional and anatomical aspects of cognitive deficits associated with CFS and distinguish participants with sudden and gradual onset of illness.”
Le Bon, O., Cappeliez, B., Neu, D., Stulens, L., Hoffmann, G., Hansenne, M., Lambrecht, L., Ansseau, M and Linkowski, P. Personality profile of patients with chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2007, 14, 1, 55-68.
Personality may play a role in the predisposition, the precipitation and/or the maintenance of the CFS. Thirty-six consecutively examined female patients hospitalised for a medical and sleep workup for fatigue, all meeting the CDC criteria ’94, filled out a Temperament and Character Inventory (TCI) questionnaire. A MANOVA compared the patients with a control group of 72 females matched for age.
Significant scores were obtained for dimensions such as Harm Avoidance, Reward Dependence, and Self-Directedness. However, the only subdimension of Harm Avoidance that proved significantly higher in CFS than in controls was "Fatigability," which is likely to overlap with the core CFS symptom.
Patients with CFS were mostly shown to be (slightly) more dependent than controls, and more perfectionist. Patients without psychiatric comorbidity even showed higher scores than controls on usually well-considered subdimensions such as those included in dimensions Self-Directedness and Cooperativeness. “As personality is supposed to exist before the beginning of the disorder symptoms and to remain stable along life, it is believed that it does not play a major role in the predisposition, the precipitation or the perpetuation of chronic fatigue.” All in all, the personality structure does not appear to play a major role in the CFS.
Brown, MM and Jason, LA. Functioning in individuals with chronic fatigue syndrome: increased impairment with co-occurring multiple chemical sensitivity and fibromyalgia. Dynamic Medicine, 2007, May 31, 6:6. doi:10.1186/1476-5918-6-6.
CFS, multiple chemical sensitivity (MCS), and fibromyalgia (FM) commonly co-occur. Some propose that CFS, MCS, and FM are manifestations of the same illness based on high rates of co-occurrence and overlapping diagnostic criteria. This study seeks to differentiate these diagnoses by comparing individuals with one or more illness on functioning, psychiatric comorbidity, co-ping style, and in vivo physical measures.
Participants included 114 men and women who met the CDC ’94 criteria for CFS. [Not all reported post-exertional malaise. Mean MOS-PF score for the CFS group was 53.61. Ed.] Less than a half were referred by physicians; others were recruited by media or from other sources. FM was diagnosed during a physical examination, and MCS was assessed using a questionnaire. Participants were divided into four groups: CFS alone, CFS-MCS, CFS-FM, and CFS-MCS-FM. Self-report measures, a psychiatric interview, and in vivo physical measures (e.g. actigraph) were employed.
In this sample, 43.9% met criteria for CFS alone, 23.7% met criteria for CFS-MCS, 15.8% met criteria for CFS-FM, and 16.7% met criteria for CFS-MCS-FM. The CFS-MCS-FM group was more disabled than the CFS alone group on measures of physical functioning, general health, and bodily pain. In vivo measures (e.g. strength, tolerance) did not differ, but the CFS-MCS-FM group rated exertion higher than the CFS alone group.
Individuals with CFS alone were the highest functioning group across several domains, such as disability, depression, and severity of symptoms. Participants with three diagnoses experienced the greatest amount of disability. There were no differences between the groups in current psychiatric diagnoses or lifetime psychiatric diagnoses. While substantial co-occurrence of these illnesses was found, this study provides evidence that having more than one illness exacerbates one's disability beyond CFS alone.
http://www.dynamic-med.com/content/pdf/1476-5918-6-6.pdf
Reeves, WC., Jones, JF., Maloney, E., Heim, C., Hoaglin, DC., Boneva, RS., Morrissey, M and Devlin, R. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Population Health Metrics, 2007, 5:5. doi:10.1186/1478-7954-5-5.
CFS is a debilitating illness with no known cause or effective therapy. Population-based epidemiologic data on CFS prevalence are critical to put CFS in a realistic context for public health officials and others responsible for allocating resources.
Based on a random-digit dialing survey we ascertained CFS cases and controls to estimate the prevalence of CFS in metropolitan, urban, and rural populations of Georgia. This report focuses on the 5,623 of 19,381 respondents ages 18 to 59 years old. Fatigued (2,438), randomly selected unwell not fatigued (1,429) and randomly selected well (1,756) respondents completed telephone questionnaires concerning fatigue, other symptoms, and medical history. Subsets of those identified by interview as having CFS-like illness (292), chronic unwellness which was not CFS-like (268-randomly selected), and well subjects (223, matched to those with CFS-like illness on sex, race, and age) completed a clinical evaluation. Among the measures to aid diagnosis was the MOS-SF. For example, “For classification as CFS, those with a score <25th percentile of population norms in the physical function or role physical, or social function, or role emotional subscales of the SF-36 were considered to have substantial reduction in activities as specified in the 1994 definition.”
We estimated that 2.54% of persons 18 to 59 years of age suffered from CFS based on the new, empiric case definition. There were no significant differences in prevalence of CFS between metropolitan, urban or rural populations or between white and black residents of the three regions. However, there were significant differences in female-to-male ratios of prevalence across the strata (metropolitan female : male 11.2:1, urban 1.7:1, rural 0.8:1).
We estimated that 2.54% of the Georgia population suffers from CFS, which is 6 to 10 fold higher than previous population-based estimates in other geographic areas. These differences may reflect broader screening criteria and differences in the application of the case definition, however we cannot exclude the possibility that CFS prevalence may be higher in Georgia than other areas where it has been measured. Although the study did not identify differences in overall prevalence between metropolitan, urban, and rural Georgia populations, it did suggest the need for additional stratified analyses by geographic strata.
http://www.pophealthmetrics.com/content/pdf/1478-7954-5-5.pdf
[Ed. Note: Others have argued that clinical judgement and assessment of intensity, frequency and duration of symptoms should be used for greater diagnostic precision. The cut-off points on some measures may have led to the inclusion of people who would otherwise not have met the criteria as interpreted previously, and identifies people with high chronic distress and illness, rather than CFS or ME.]
See also White, PD. How common is chronic fatigue syndrome; how long is a piece of string? Ibid, 5:6. doi:10.1186/1478-7954-5-6.
http://www.pophealthmetrics.com/content/5/1/6
The, GKH., Bleijenberg, G and Van der Meer, JWM. The effect of acclydine in chronic fatigue syndrome: a randomized controlled trial. PLoS Clinical Trials, 2007, 2(5): e19. doi:10.1371/journal.pctr.0020019.
This RCT found that a food supplement which increases biologically active IGF1 levels, Acclydine, plus amino acids, was not effective in alleviating fatigue in 22 patients recruited from the Dutch ME Association, and there were no differences between the group and neighbourhood controls (placebo plus amino-acids) on any measure. There was no change in IGF1 status.
http://clinicaltrials.plosjournals.org/archive/1555-5887/2/5/pdf/10.1371_journal.pctr.0020019-L.pdf
Goudsmit, EM and Howes, S. Pacing: An additional strategy to manage fatigue in chronic fatigue syndrome. May, 2007. http://freespace.virgin.net/david.axford/pacing.htm
The first academic review of this strategy to manage limited energy.
[Ed. Note: Written for health psychologists, this paper was rejected by all three British/European journals because it was deemed too clinical. As it does not aim to treat behavioural/psychological problems, it is not suitable for clinical psychology journals. Given the urgent need for clarity in relation to definition, rationale and limitations, it was decided to submit the paper to a site specialising in ME and make it available to a wider readership. The review includes a summary of the research showing why graded activity is not appropriate for many patients with CFS and gives details of the four controlled trials supporting the use of pacing as part of a flexible, tailor-made, multi-dimensional programme.]
Van den Eede, F, Moorkens, G., Van Houdenhove, B., Cosyns, P and Claes. SJ. Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology, 2007, 55, 2, 112-120.
There is evidence for a hypofunction of the hypothalamic-pituitary-adrenal (HPA) axis in a proportion of the patients with CFS, despite the negative studies and methodological difficulties. In this review, we focus on challenge studies and on the role of the HPA axis in the pathogenesis of CFS. Mild hypocortisolism, blunted adrenocorticotropin response to stressors and enhanced negative feedback sensitivity to glucocorticoids are the main findings. Several underlying mechanisms have been proposed. Currently, it is a matter of debate whether these disturbances have a primary role in the pathogenesis of CFS. However, even if the HPA axis dysfunctions are secondary to other factors, they are probably a relevant factor in symptom propagation in CFS.
Armitage, R., Landis, C., Hoffmann, R., Lentz, M., Watson, NF., Goldberg, J and Buchwald, D. The impact of a 4-hour sleep delay on slow wave activity in twins discordant for chronic fatigue syndrome. Sleep, 2007, 30, 5, 657-662.
CFS has been associated with altered amounts of slow wave sleep, which could reflect reduced delta electroencephalograph (EEG) activity and impaired sleep regulation. To evaluate this hypothesis, we examined the response to a sleep regulatory challenge in CFS.
The first of 3 consecutive nights of study served as laboratory adaptation. Baseline sleep was assessed on the second night. On the third night, bedtime was delayed by 4 hours, followed by recovery sleep. Total available sleep time was held constant on all nights. The setting was a research sleep laboratory. Subjects were 13 pairs of monozygotic twins discordant for CFS.
Power spectral analysis quantified slow wave activity (SWA) in the 0.5-3.9 Hz band in successive NREM periods (stage 2, 3, or 4) on each night. To ensure comparability, analyses were restricted to the first 4 NREM periods on each night. Data were coded for NREM period and twin pair. Repeated-measures analysis of variance (ANOVA) contrasted sleep delay effects across NREM periods between twin pairs. A second ANOVA calculated the SWA in each NREM period in recovery sleep relative to baseline SWA. The 2 groups of twins were similar on baseline SWA power. After sleep delay, CFS twins exhibited significantly less SWA power in the first NREM period of recovery sleep and accumulated a smaller percentage of SWA in the first NREM period than their co-twins.
CFS is associated with a blunted SWA response to sleep challenge, suggesting that the basic sleep drive and homeostatic response are impaired.
Friedberg, F., Sohl, S and Schmeizer, B. Publication trends in chronic fatigue syndrome: Comparisons with fibromyalgia and fatigue: 1995–2004. Journal of Psychosomatic Research, 2007, 63, 143-146.
In order to identify publishing patterns in CFS, we compared the annual number of peer review articles for CFS, FM, and non-CFS fatigue over a recent decade (1995–2004). Citations were drawn from Ovid/Medline, PsychInfo, and the Journal of Chronic Fatigue Syndrome for peer review articles focusing on CFS, FM, and fatigue for each year of the decade ending in 2004. Statistics included chi-square, tests for differences in proportions, and regression-based curve estimation.
The frequency of CFS peer review articles did not significantly change from the first half to the second half of the decade (1995–2004). By comparison, the output of both FM and fatigue articles significantly increased (p<.0001). A quadratic model (inverted U shape; p<.02) best fit the data for CFS annual publication frequency. By comparison, exponential models best fit the data for both FM (p<.0001) and fatigue (p<.0001) citations. The highest percentage of citations (15–16%) for both CFS and FM fell within the domains of diagnosis, physiopathology, and psychology. For fatigue, almost one third (31.4%) of the citations were focused on etiology, while psychology (11.5%) and physiopathology (10.4%) articles were the next most cited. Based on first-author affiliation, CFS articles were most likely to originate in the United States (37.7%), England (31.4%), and the Netherlands (4.9%).
The output of CFS peer review articles has not increased over the past decade, while the number of FM and fatigue articles has increased substantially.
Larun, L and Malterud, K. Identity and coping experiences in chronic fatigue syndrome: A synthesis of qualitative studies. Patient Education and Counselling. 2007 Aug 14; [Epub ahead of print]. doi:10.1016/j.pec.2007.06.008.
The objective of this review was to provide insight into patients’ and doctors’ experiences with CFS. We compiled available qualitative studies and applied meta-ethnography to identify and translate across the studies. Analysis provided second-order interpretation of the original findings and developed third-order constructs from a line of arguments.
Twenty qualitative studies on CFS experiences were identified. Symptom experiences and the responses from significant others could jeopardise the patients’ senses of identity. They felt severely ill, yet blamed and dismissed. Patients’ beliefs and causal attributions oppose the doctor's understanding of the condition. For the patient, getting a diagnosis and knowing more was necessary for recovery. Doctors were reluctant towards the diagnosis, and struggle to maintain professional authority. For patients, experience of discreditation could lead to withdrawal and behavioural disengagement.
The identities of CFS patients are challenged when the legitimacy of their illness is questioned. This significant burden adds to a loss of previously established identity and makes the patient more vulnerable than just suffering from the symptoms. CFS patients work hard to cope with their condition by knowing more, keeping a distance to protect themselves and learning more about their limits.
Practice implications: Doctors can support patients’ coping by supporting the strong sides of the patients instead of casting doubt upon them.
Maes, M., Mihaylova, I and Bosmans, E. Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuroendocrinology Letters,2007, 28, 4, [Epub ahead of print].
There is now some evidence that CFS is accompanied by an activation of the inflammatory response system and by increased oxidative and nitrosative stress. Nuclear factor kappa beta (NFκβ) is the major upstream, intracellular mechanism which regulates inflammatory and oxidative stress mediators. In order to examine the role of NFκβ in the pathophysiology of CFS, this study examines the production of NFκβ p50 in unstimulated, 10 ng/mL TNF-α (tumor necrosis factor alpha) and 50 ng/mL PMA (phorbolmyristate acetate) stimulated peripheral blood lymphocytes of 18 unmedicated patients with CFS and 18 age-sex matched controls. The unstimulated (F=19.4, df=1/34, p=0.0002), TNF-α-(F=14.0, df=1/34, p=0.0009) and PMA-(F=7.9, df=1/34, p=0.008) stimulated production of NFκβ were significantly higher in CFS patients than in controls. There were significant and positive correlations between the production of NFκβ and the severity of illness as measured with the FibroFatigue scale and with symptoms, such as aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection. The results show that an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiogy of CFS and that previous findings on increased oxidative stress and inflammation in CFS may be attributed to an increased production of NFκβ. The results suggest that the symptoms of CFS, such as fatigue, muscular tension, depressive symptoms and the feeling of infection reflect a genuine inflammatory response in those patients. It is suggested that CFS patients should be treated with antioxidants, which inhibit the production of NFκβ, such as curcumin, N-Acetyl-Cysteine, quercitin, silimarin, lipoic acid and omega-3 fatty acids.
http://node.nel.edu/?node_id=5953
Maes, M., Mihaylova, I., Kubera, M and Bosmans, E. Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome. Neuroendocrinology Letters,2007, 28, 4, [Epub ahead of print].
CFS is a medically unexplained disorder, characterized by profound fatigue, infectious, rheumatological and neuropsychiatric symptoms. There is, however, some evidence that CFS is accompanied by signs of increased oxidative stress and inflammation in the peripheral blood. This paper examines the role of the inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) in the pathophysiology of CFS. Toward this end we examined the production of COX-2 and iNOS by peripheral blood lymphocytes (PBMC) in 18 CFS patients and 18 normal volunteers and examined the relationships between those inflammatory markers and the severity of illness as measured by means of the FibroFatigue scale and the production of the transcription factor nuclear factor kappa beta (NFκβ). We found that the production of COX-2 and iNOS was significantly higher in CFS patients than in normal controls. There were significant and positive intercorrelations between COX-2, iNOS and NFκβ and between COX-2 and iNOS, on the one hand, and the severity of illness, on the other. The production of COX-2 and iNOS by PBMCs was significantly related to aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, sadness and a subjective experience of infection. The results suggest that a) an intracellular inflammatory response in the white blood cells plays an important role in the pathophysiology of CFS; b) the inflammatory response in CFS is driven by the transcription factor NFκβ; c) symptoms, such as fatigue, pain, cognitive defects and the subjective feeling of infection, indicates the presence of a genuine inflammatory response in CFS patients; and d) CFS patients may be treated with substances that inhibit the production of COX-2 and iNOS.
http://node.nel.edu/?node id=5956
Malaguarnera, M., Gargante, MP., Cristaldi, E., Colonna, V., Messano, M., Koverech, A., Neri, S., Vacante, M., Cammalleri, L and Motta, M. Acetyl l-carnitine (ALC) treatment in elderly patients with fatigue. Archives of Gerontology and Geriatrics, 2007, Jul 19. doi:.1016/j.archger.2007.03.012.
Fatigue is one of the conditions most frequently complained of by the elderly. There are few effective treatment options for patients with CFS. To determine the efficacy, tolerability and impact on the fatigue, as well as on cognitive and functional status of acetyl l-carnitine (ALC), 2 g b.d., for 180 days, we tested 96 aged subjects (>70 years, range 71-88) of which 50 were females and 46 were males; mean age 76.2+7.6 and 78.4+6.4 years, respectively). They met four or more of the Holmes major criteria or at least six of Fukuda minor criteria. Fatigue was measured with the measure described by Wessely and Powell, and with the fatigue severity scale.
At the end of the treatment, we observed a decrease of physical fatigue: 6.2 (p<0.001), mental fatigue: 2.8 (p<0.001), severity fatigue: 21.0 (p<0.001) and improvements in functional status: 16.1 (p<0.001) and cognitive functions: 2.7 (p<0.001). By the end of the treatment, significant differences between the two groups were found for the following parameters: muscle pain -27% versus -3% (p<0.05); prolonged fatigue after exercise: 51% versus -4% (p<0.0001); sleep disorders: 28% versus 4% (p<0.05); physical fatigue: 7 versus -0.5 (p<0.0001); mental fatigue: -3.3 versus 0.6 (p<0.0001); fatigue severity scale: -22.5 versus 1.2 (p<0.0001); functional status 17.1 versus 0.6 (p<0.0001); mini mental state examination (MMSE) improvements: 3.4 versus 0.5 (p<0.0001). Our data show that administering ALC may reduce both physical and mental fatigue in elderly and improves both the cognitive status and physical functions.
Matthews, RM and Komaroff, AL. Changes in functional status in chronic fatigue syndrome over a decade: Do age and gender matter? Journal of Chronic Fatigue Syndrome, 2007, 14, 1, 33-42.
Patients with CFS have substantial deficits in functional capacity, but the course of these deficits over time has not often been studied. This study measured functional capacity on three occasions over a decade, in 99 patients with CFS (CDC criteria ’94), who completed the assessments in 1993, 1995 and 2002 using the Medical Outcomes Study Short Form-36 (SF-36).
Physical function, as reflected in several different scales, improved modestly but significantly over time, particularly for patients aged 18-60 years and for women. Mental/emotional function was not substantially impaired at the outset of the study, and did not change over time. This study found that physical function tended to improve for many patients over time, despite the fact that they were aging. Physical function did not deteriorate with time.
Mihaylova, I., Deruyter, M., Rummens, JL., Bosmans, E and Maes, M. Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. Neuroendocrinology Letters,2007, 28, 4 [Epub ahead of print].
There is some evidence that patients with CFS suffer from immune abnormalities, such as immune activation and decreased immune cell responsivity upon polyclonal stimili. This study was designed to evaluate lymphocyte activation in CFS by using a CD69 expression assay. CD69 acts as a costimulatory molecule for T- and natural killer (NK) cell activation. We collected whole blood from CFS patients, who met CDC criteria, and healthy volunteers. The blood samples were stimulated with mitogens during 18 h and the levels of activated T and NK cells expressing CD69 were measured on a Coulter Epics flow cytometer using a three color immunofluorescence staining protocol. The expression of the CD69 activation marker on T cells (CD3+, CD3+CD4+, and CD3+CD8+) and on NK cells (CD45+CD56+) was significantly lower in CFS patients than in healthy subjects. These differences were significant to the extent that a significant diagnostic performance was obtained, i.e. the area under the ROC curve was around 89%. No differences either in the number of leukocytes or in the number or percentage of lymphocytes, i.e. CD3, CD4, CD8 and CD19, could be found between CFS patients and the controls. Patients with CFS show defects in T- and NK cell activation. Since induction of CD69 surface expression is dependent on the activation of the protein kinase C (PKC) activation pathway, it is suggested that in CFS there is a disorder in the early activation of the immune system involving PKC.
http://node.nel.edu/?node_id=5962
Osaba, T., Gray, S and Duffield, J. The development of an epidemiological case definition for chronic fatigue syndrome (CFS). American Journal of Epidemiology, 2006, 163 (Suppl.): S097.
Abstract concerning research on case definitions, expert and GP diagnoses, noting the preliminary statistical analysis revealed a Cronbach’s alpha of .644. Post-exertional malaise was the strongest predictor of caseness.
Perrin RN. Lymphatic drainage of the neuraxis in chronic fatigue syndrome: a hypothetical model for the cranial rhythmic impulse. Journal of the American Osteopathic Association, 2007, 107, 6, 218-224.
The cranial rhythmic impulse is a palpable, rhythmic fluctuation believed to be synchronous with the primary respiratory mechanism. The precise physiologic mechanism of the cranial rhythmic impulse is not fully understood.
Based on traditional and current views of the cranial rhythmic impulse, animal studies, and clinical findings in patients with CFS, the author argues that the cranial rhythmic impulse is the rhythm produced by a combination of cerebrospinal fluid drainage from the neuraxis (brain and spinal cord) and pulsations of central lymphatic drainage induced by the sympathetic nervous system. In addition, evidence is provided to demonstrate that a disturbed, palpable, and visible neurolymphatic process leads to CFS. This process may also explain the pathophysiologic mechanisms leading to other disease states. Finally, the author's proposed manual treatment protocol for patients with CFS is described.
Scheeres, K., Wensing, M., Mes, C and Bleijenberg, G. The impact of informational interventions about cognitive behavioral therapy for chronic fatigue syndrome on GPs referral behavior. Patient Education and Counselling, 2007, May 21. doi:10.1016/j.pec.2007.04.002.
This study investigated the impact of an informational intervention among general practitioners (GPs) about a new treatment with cognitive behavioral therapy (CBT) for CFS in a mental health center (MHC). The outcome measures concerned GPs knowledge and attitudes towards CFS and their actual referrals of CFS patients to this new treatment setting.
Three hundred and one GPs, who all had received written information about CFS four times, and who partly had also visited an informational group session, completed a short questionnaire survey on CFS knowledge and attitudes. Referral data were obtained from the mental health center.
During 16 months, 22% of all GPs in the concerning region had referred at least one CFS patient. Concerning knowledge and attitude, the survey results showed that 70% of the GPs had remembered the intervention's main message, namely the new treatment possibility. These informed GPs reported better knowledge and more positive attitudes towards CFS than the non-informed GPs, who had not seen and read the intervention's information.
This study showed that disseminating written materials can be a useful method for stimulating GPs to refer CFS patients for CBT. In future implementation projects concerning CBT for CFS (or other 'new' treatments for a disputed illness) in a MHC or other institution, the informational intervention evaluated here can be a suitable and efficient method to inform GPs and let them refer patients.
Schur, EA., Noonan, C., Smith, WR, Goldberg, J and Buchwald, D. Body mass index and fatigue severity in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2007, 14, 1, 69-77.
It is uncertain how much fatigue is related to weight in patients with CFS. The objective of this study was to assess the association of body mass index (BMI) and fatigue in CFS patients.
Consecutive patients seen in a referral-based specialty clinic were eligible if they met the (CDC ’94) CFS criteria and had completed required measures. Fatigue measures were the vitality subscale of the Medical Outcomes Short-Form 36 and the global fatigue index from the Multidimensional Assessment of Fatigue.
In women, there was no relationship between BMI and vitality subscale or global fatigue index scores (p=0.99 and p=0.44). For men, vitality subscale scores significantly decreased as BMI increased (p=0.02).
In CFS patients, the prevalence of obesity was low despite risk factors for weight gain. Fatigue severity and BMI were unrelated in women with CFS, but this relationship may differ for men.
Ter Wolbeek, M., van Doornen, LJP., Kavelaars, A, van de Putte, EM., Schedlowski M and Heijnen, CJ. Longitudinal analysis of pro- and anti-inflammatory cytokine production in severely fatigued adolescents. Brain Behavior and Immununity, 2007, May 31. doi:10.1016/j.bbi.2007.04.007.
In the adolescent population, fatigue is associated with somatic complaints, unrefreshing sleep, cognitive disturbances and symptoms of depression and anxiety. This pattern of symptoms resembles the one described in CFS. Since immunological alterations have been reported in CFS patients, we wondered whether also severely fatigued girls from a healthy population would show comparable alterations in psychological and immunological parameters.
We tested this hypothesis in a longitudinal design, allowing a reliable assessment of the participants' characteristic immune status. Groups of severely fatigued (N=67) and non-fatigued (N=61) participants were selected.
Severely fatigued girls reported more depressive symptoms, anxiety, reduced sleep quality, and somatic and CFS-related symptoms than non-fatigued participants across three measurements during 12 months (T1: spring, T2: autumn, T3: next spring). In contrast, no group differences in mitogen-induced cytokine production or T-cell proliferation in vitro or in leukocyte subset counts were observed. Although absolute cytokine production and cell counts were affected by seasonal variation, the within-subject values, relatively to the rest of the participants, were fairly stable. Data from a small group of CFS patients (CDC criteria ’94, N=11) showed similarities in self-reported complaints between CFS patients and fatigued participants. Interestingly, CFS patients showed a distinct immune profile when compared to the severely fatigued or non-fatigued participants, i.e. increased levels of anti-inflammatory cytokines (IL-10, decreased IFN-γ/IL-10 ratio) and reduced levels of pro-inflammatory cytokines (IL-6, TNF-α) over all three time points analyzed.
These results show that, although overlap in symptomatology between the general population and patients with CFS was observed, only CFS patients show a skewing of the cytokine balance towards an anti-inflammatory profile.
Thanawala, S and Taylor, RR. Service utilization, barriers to service access, and coping in adults with chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2007, 14, 1, 5–21.
In a sample of 47 adults with CFS, we aimed to describe patterns of service utilization, identify barriers to service access, and explore the relationship between service utilization and coping styles.
A questionnaire assessing service utilization frequency and barriers to service access was administered to a sample of 47 individuals with CFS. The Illness Management Questionnaire was used to assess relationships between coping styles and service utilization.
A Cochran's Q test of homogeneity revealed that medical and CFS self-help services were most frequently used and rehabilitation services were least frequently used. In terms of service accessibility, 80.9% of participants reported at least one barrier. Lack of financial (including insurance) resources and lack of knowledge about service availability were the two most frequently reported. In terms of coping styles, symptom focusing was positively associated with use of CFS self-help services and with use of in-home services and social service agencies. Information seeking was negatively associated with use of in-home and social service agencies and with use of mental health services.
These findings can be used by health-care professionals and advocacy-based organizations to develop programs focused on mass education campaigns for health-care providers, increase knowledge of service availability among individuals with CFS, and to understand relationships between certain types of coping styles and service preferences.
Weatherburn, GC., Goldsmith Lister, A and Findley, LJ. The feasibility of reviewing chronic fatigue syndrome clients at a distance: A teleconference pilot study. Journal of Chronic Fatigue Syndrome, 2007, 14, 1, 23-32.
There continues to be a shortage of clinical staff specialising in the treatment of CFS (ME). In order to access specialist care, many clients have to undertake long or difficult journeys that may exacerbate their symptoms. This exploratory study aimed to reduce these travel problems by the introduction of a Teleconference Review Clinic (TRC).
A TRC was booked for six CFS clients who would normally have face-to-face review by specialists 44 miles away. Questionnaires were used to elicit the views of both clients being reviewed and clinicians undertaking the review at a distance. Differences in distances travelled by clients for conventional face to face and telemedicine review were calculated and comments about the teleconference made by clients and therapists were noted.
There was general satisfaction with the quality of the pictures and sound during the reviews. Clinicians were able to obtain all the information required to undertake all clinical assessments. For two clients the clinical management was changed after the consultation and for one client an issue was identified that required referral to another clinician. For clients who lived nearer to the teleconference hospital, the journey saved ranged between 1 mile and 85.8 miles, the mean being 64.2 miles.
This pilot study does suggest that telemedicine in this area of medicine is logistically viable and effective, and indicates that a larger study is needed.
Wyller, VB., Saul, JP., Amlie, JP and Thaulow, E. Sympathetic predominance of cardiovascular regulation during mild orthostatic stress in adolescents with chronic fatigue. Clinical Physiology and Functional Imaging, 2007, 27, 4, 231-238.
Haemodynamic abnormalities have been documented in the CFS, indicating functional disturbances of the autonomic nervous system responsible for cardiovascular control.
This study was designed to explore the pathophysiology in adolescent CFS-patients by analysing RR-interval (RRI) variability and diastolic blood pressure (DBP) variability during mild orthostatic stress, using an algorithm which accounts for non-stationary biosignals.
A total of 27 adolescents with CFS (CDC criteria ’94, 4 months minimum) and 33 healthy control subjects having equal age- and sex distribution underwent 15 minutes of 20 degrees head-up tilt (HUT). The spectral power densities of RRI and DBP were computed in the low-frequency (LF) band (0.04-0.15 Hz) and the high-frequency (HF) band (0.15-0.4 Hz) using an adaptive autoregressive algorithm to obtain a time-varying spectrum. RMSSD, a time domain index of RRI variability, was also computed.
At rest, all indices of variability were similar in the two groups. During tilt, CFS patients had a larger increase in the LF/HF ratio (p<0.001) and normalized LF power of RRI (p<0.01), and a larger decrease in normalized HF power (p<0.01) of RRI than controls. CFS patients also had trends towards a larger decrease in absolute HF power of RRI and a larger increase in normalized LF power of DBP.
These findings suggest that adolescents with CFS have sympathetic predominance of cardiovascular regulation during very mild orthostatic stress. Possible underlying mechanisms are moderate hypovolemia, abnormalities of reflex control or physical de-conditioning.
[Ed. Note: None of the participants were bed-ridden, thus deconditioning is unlikely to have played a major role. The test was performed after an overnight fast.]
Wyller, VB., Godang, K., Mørkrid, L., Saul, JP., Thaulow E and Walløe, L. Abnormal thermoregulatory responses in adolescents with chronic fatigue syndrome: Relation to clinical symptoms. Pediatrics, 2007, 120, e129-e137. doi: 10.1542/peds.2006-2759.
In CFS, accumulating evidence indicates dysfunction of the autonomic nervous system. To further explore the pathophysiology of CFS, we investigated thermoregulatory responses dependent on catecholaminergic effector systems in adolescent patients with CFS.
A consecutive sample of 15 patients with CFS (modified CDC criteria ’94, no accompanying symptoms) aged 12 to 18 years and a volunteer sample of 57 healthy control subjects of equal gender and age distribution were included. Plasma catecholamines and metanephrines were measured before and after strong cooling of one hand. Acral skin blood flow, tympanic temperature, heart rate, and mean blood pressure were measured during moderate cooling of one hand. In addition, clinical symptoms indicative of thermoregulatory disturbances were recorded.
Patients with CFS reported significantly more shivering, sweating, sudden change of skin color, and feeling unusually warm. At baseline, patients with CFS had higher levels of norepinephrine, heart rate, epinephrine, and tympanic temperature than control subjects. During cooling of one hand, acral skin blood flow was less reduced, vasoconstrictor events occurred at lower temperatures, and tympanic temperature decreased more in patients with CFS compared with control subjects. Catecholamines increased and metanephrines decreased similarly in the 2 groups.
Adolescent patients with CFS have abnormal catecholaminergic-dependent thermoregulatory responses both at rest and during local skin cooling, supporting a hypothesis of sympathetic dysfunction and possibly explaining important clinical symptoms.
[Ed. Note: The paper gives no information on type of onset, and other relevant measures e.g. history of stress. The latter may have confounded the results.]
Yoshiuchi K, Cook DB, Ohashi K, Kumano H, Kuboki T, Yamamoto Y, Natelson BH. A real-time assessment of the effect of exercise in chronic fatigue syndrome. Physiology & Behavior, 2007, Jul 24. doi: 10.1016/j.physbeh.2007.07.001.
Patients with CFS report substantial symptom worsening after exercise. However, the time course over which this develops has not been explored. Therefore, the objective of this study was to investigate the influence of exercise on subjective symptoms and on cognitive function in CFS patients in natural settings using a computerized ecological momentary assessment method, which allowed us to track the effects of exercise within and across days. Subjects were 9 female patients with CFS (CDC criteria ’88 and 94, 7 symptoms rated substantial to severe, <6 years duration) and 9 healthy women. A watch-type computer was used to collect real-time data on physical and psychological symptoms and cognitive function for 1 week before and 2 weeks after a maximal exercise test. For each variable, we investigated temporal changes after exercise using multilevel modeling.
Following exercise, physical symptoms did get worse but not until a five-day delay in CFS patients. Despite this, there was no difference in the temporal pattern of changes in psychological symptoms or in cognitive function after exercise between CFS patients and controls. In conclusion, physical symptoms worsened after several days delay in patients with CFS following exercise while psychological symptoms or cognitive function did not change after exercise.
[Ed. Note: These results may not be reliable as CFS is defined in terms of worsening of symptoms following minimal exertion. Exercise must lead to an exacerbation within a short period of time, e.g. Jason et al, although it is well-documented that there is often an additional reaction after a delay, particularly in those who do not pace their activities, or following an event which requires the person to operate well beyond his or her limits. Although the absence of an immediate reaction (lasting up to 24 hours) may reflect effective pacing, the rating of perceived exertion (RPE) was the same as in the controls, which is surprising and inconsistent with reports of “substantial” and “severe” symptoms. Objective measures of activity would have been helpful in clarifying the post-exertion activity levels, and accordingly, the diagnosis. The relative stability of post-testing psychological symptoms supports the view that the physical symptoms are not a result of altered mood. The small sample and lack of data regarding onset etc limits the interpretation of results.]
Ledina, D., Bradaric, N., Milas, I., Ivic, I., Brncic, N and Kuzmicic, N. Chronic fatigue syndrome after Q Fever. Medical Science Monitor, 2007, 13, 7, CS88-92.
Q fever is a common and acute but rare chronic zoonosis caused by Coxiella burnetii. Its acute form manifests as atypical pneumonia, flu-like syndrome, or hepatitis. Some authors observed symptoms of chronic fatigue in a small number of patients after the acute phase of Q fever; in many cases serological assay confirmed the activity of Coxiella burnetii infection. The effect of antibiotic therapy on post-Q-fever fatigue syndrome has not been studied in south-east Europe thus far.
Case Reports: Three patients are presented with post-Q-fever fatigue syndrome. All fulfilled the CDC criteria for CFS. IgA antibodies to phase I of the growth cycle of Coxiella burnetii were positive in two patients and negative in one. Two patients were treated with doxycycline for two weeks in the acute phase of illness and one with a combination of erythromycin and gentamycin. After 4-12 months they developed post-Q-fever fatigue syndrome and were treated with intracellular active antibiotics (fluoroquinolones and tetracycline) for 3-12 months. Efficacy of the treatment was observed in two patients, but in one patient the results were not encouraging.
These results suggest the possibility of the involvement of Coxiella burnetii infection in the evolution of CFS. This is the first report on post-Q-fever fatigue syndrome in Mediterranean countries. Evidence of IgA antibodies to phase I of the growth cycle of Coxiella burnetii is not a prerequisite for establishing a diagnosis of CFS. The recommendation of antibiotic treatment in post-Q-fever fatigue syndrome requires further investigation.
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