ME and CFS References

Burton C, Knoop H, Popovic N, Sharpe, M and Bleijenberg, G. Reduced complexity of activity patterns in patients with chronic fatigue syndrome: a case control study. Biopsychosocial Medicine, 2009 Jun 2;3(1):7. [Epub ahead of print]

CFS is an illness characterised by pervasive physical and mental fatigue without specific identified pathological changes. Many patients with CFS show reduced physical activity which, though quantifiable, has yielded little information to date. Nonlinear dynamic analysis of physiological data can be used to measure complexity in terms of dissimilarity within timescales and similarity across timescales. A reduction in these objective measures has been associated with disease and ageing. We aimed to test the hypothesis that activity patterns of patients with CFS would show reduced complexity compared to healthy controls.

We analysed continuous activity data over 12 days from 42 patients with CFS (CDC criteria '94) and 21 matched healthy controls. We estimated complexity in two ways, measuring dissimilarity within timescales by calculating entropy after a symbolic dynamic trans-formation of the data and similarity across timescales by calculating the fractal dimension using allometric aggregation.

CFS cases showed reduced complexity compared to controls, as evidenced by reduced dissimilarity within timescales (mean (SD) Renyi(3) entropy 4.05 (0.21) vs. 4.30 (0.09), t=-6.6, p<0.001) and reduced similarity across timescales (fractal dimension 1.19 (0.04) vs. 1.14 (0.04), t = 4.2, p<0.001). This reduction in complexity persisted after adjustment for total activity.

Patients with CFS show evidence of reduced complexity of activity patterns. Measures of complexity applied to activity have potential value as objective indicators for CFS.

http://www.bpsmedicine.com/content/pdf/1751-0759-3-7.pdf

Hurwitz, BE., Coryell, VT., Parker, M., Martin, P., Laperriere, A., Klimas, NG., Sfakianakis, GN and Bilsker, MS. Chronic fatigue syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function. Clinical Science, 2009. May 26th. [Epub ahead of print]. doi:10.1042/CS20090055.

This study examined whether deficits in cardiac output and blood volume in a CFS cohort were present and linked to illness severity and sedentary lifestyle. Follow-up analyses assessed whether differences between CFS and control groups in cardiac output levels were corrected by controlling for cardiac contractility and total blood volume (TBV). The 146 participants were subdivided into two CFS groups based on symptom severity data, severe (n=30) vs. non-severe (n=26), and two healthy non-CFS control groups based on physical activity, sedentary (n=58) vs. non-sedentary (n=32). Controls were matched to CFS participants using age, sex, ethnicity and body mass.

Echocardiographic measures indicated that the severe CFS participants displayed 10.2% lower cardiac volume (i.e., stroke index and end diastolic volume) and 25.1% lower contractility (velocity of circumferential shortening corrected by heart rate) than the control groups. Dual tag blood volume assessments indicated that CFS groups had lower TBV, plasma volume (PV) and red blood cell volume (RBCV) than control groups. Of the CFS subjects with a TBV deficit (i.e., >8% below ideal levels), the mean +SD percent deficit in TBV, PV and RBCV were 15.4+4.0, 13.2+5.0, and 19.1+6.3, respectively. Lower CFS cardiac volume levels were substantially corrected by controlling for prevailing TBV deficits, but were not affected by controlling for cardiac contractility.

Analyses indicated that the TBV deficit explained 91-94% of the group differences in cardiac volume indices. Group differences in cardiac structure were offsetting and hence no differences emerged for LV mass index. Therefore, the findings indicate that lower cardiac volume levels, displayed primarily by persons with severe CFS, were not linked to diminished cardiac contractility levels, but were likely a consequence of a comorbid hypovolemic condition. Further study is needed to address the extent to which the CFS cardiac and blood volume alterations have physiological and clinical significance.

Jammes, Y, Steinberg, JG., Delliaux, S and Brégeon, F. Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. Journal of Internal Medicine, 2009, doi: 10.1111/j.1365-2796.2009.02079.x. 19th May.

As heat shock proteins (Hsp) protect the cells against the deleterious effects of oxidative stress, we hypothesized that Hsp expression might be reduced in patients suffering from CFS who present an accentuated exercise-induced oxidative stress. This case–control study com-pared nine CFS (CDC criteria '94) patients to a gender-, age- and weight-matched control group of nine healthy sedentary subjects.

All subjects performed an incremental cycling exercise continued until exhaustion. We mea-sured ventilation and respiratory gas exchange and evoked compound muscle potential (M-wave) recorded from vastus lateralis. (M-wave: muscle membrane excitability. Ed.) Repetitive venous blood sampling allowed measurements of two markers of oxidative stress [thiobarbituric acid reactive substances (TBARS) and reduced ascorbic acid (RAA)], two cytokines (IL-6 and TNF-α) and two Hsp (Hsp27 and Hsp70) at rest, during maximal exercise and the 60-min recovery period.

Compared with controls, resting CFS patients had low baseline levels of RAA and Hsp70. Their response to maximal exercise associated (i) M-wave alterations indicating reduced muscle membrane excitability, (ii) early and accentuated TBARS increase accompanying reduced changes in RAA level, (iii) absence of significant increase in IL-6 and TNF-α, and (iv) delayed and marked reduction of Hsp27 and Hsp70 variations. The post-exercise increase in TBARS was accentuated in individuals having the lowest variations of Hsp27 and Hsp70.

The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress, which might result from delayed and insufficient Hsp production.

Extracts from discussion:

As the Hsp response to exercise protects the cells against the deleterious effects of oxidative stress, the present data corroborate our primary hypothesis that a reduced Hsp production in CFS patients might explain their accentuated exercise induced oxidative stress. The severe and prolonged exercise-induced oxidative stress in CFS patients might explain their altered muscle excitability, both events have been already reported in our previous CFS study... The relatively high VO2max in our CFS patients corroborates numerous previous studies. Indeed, VO2 measurement in exercising CFS patients indicated normal or increased aerobic function, especially the relationship between the concomitant increases in VO2 and work rate, which were similar to that expected in healthy subjects... Thus, the depressed cytokine response to exercise in CFS patients might have dual consequences: there may be some benefits of the absence of a post-exercise TNF-α increase, through the reduction of inflammatory reaction, whilst the reduced IL-6 response might attenuate the anti-inflammatory actions. The present observations of a dissociation between an accentuated exercise-induced oxidative stress and absent inflammatory response to exercise in CFS patients are not surprising...

PSYCHOLOGY AND PSYCHIATRY

Dennison, L., Stanbrook, R., Moss-Morris, R., Yardley L and Chalder, T. Cognitive behavioural therapy and psycho-education for chronic fatigue syndrome in young people: Reflections from the families' perspective. British Journal of Health Psychology, Epub. 6th May 2009. doi: 10.1348/135910709X440034

Abstract will be included when the article is available.

Thomas, M and Smith, A. An investigation into the cognitive deficits associated with chronic fatigue syndrome. The Open Neurology Journal, 2009, 3, 13-23.

This study addresses, among other things, the debate as to whether cognitive deficits do occur with a diagnosis of CFS. Previous studies have indicated a potential mismatch between subjective patient ratings of impairment and clinical assessment. In an attempt to tackle some of the methodological problems faced by previous research in this field, this study recruited a large sample of CFS patients (CDC criteria '94, n=307) and administered an extensive battery of measures. Healthy controls (n=126) were used to compare the results. Patients were recruited from a hospital clinic, and 68% had a provisional diagnosis of CFS. However, not all attributed their illness to infection. Indeed, 25% cited stress as a possible cause.

The design meant that the study was able to replicate previous published evidence of clear cognitive impairment in this group and demonstrate also that these deficits occurred independent of psychopathology. Moreover, the results indicated that patients were able to assess their cognitive performance accurately.

The conclusion drawn is that cognitive impairments can be identified if appropriate measures are used. Furthermore, the authors have shown that performance changes in these measures have been used to assess both efficacy of a treatment regime and rates of recovery.

http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2682840&blobtype=pdf

Van Houdenhove, B., Van Hoof, E., Becq, K., Kempke, S., Luyten, P and De Meirleir, K. A comparison of patients with chronic fatigue syndrome in two "ideologically" contrasting clinics. Journal of Nervous and Mental Disease, 2009, 197, 5, 348-353.

Aim of the present study was to compare CFS patients, attending 2 "ideologically" contrasting clinics for CFS, on various patient and illness characteristics. Fifty-nine CFS patients of each clinic, located in Leuven and Brussels (Belgium), participated. Patients did not differ with regard to age, levels of fatigue, psychopathology, and self-efficacy. However, patients from the psychosocially-oriented clinic (Leuven) had a lower level of education, reported more progressive illness onset (9% vs 31%), higher levels of depression, and attributed their illness more to psychological causes. Patients in the biologically-oriented clinic (Brussels) reported more pain, and showed higher levels of social functioning, motivation and vitality, as well as fewer limitations related to emotional problems.

It is concluded that CFS patients attending the 2 clinics could not be distinguished along dualistic biological/psychosocial lines, but those reporting sudden illness onset and making somatic attributions were more likely to be represented in the biologically-oriented clinic.

Jason, L., Benton, M., Torres-Harding, S and Muldowney, K. The impact of energy modulation on physical functioning and fatigue severity among patients with ME/CFS. Patient Education and Counseling, 2009, 10.1016/j.pec.2009.02.015. Published online 8 April.

The Energy Envelope postulates that patients with ME/CFS will improve functioning when maintaining expended energy levels at the same level as available energy level. Estimated weekly energy quotients were established by dividing expended energy level by perceived energy level and multiplying by 100.

Two groups of patients were identified following participation in a non-pharmacologic intervention trial. Some were able to keep expended energy close to available energy (n=49) and others were not successful at this task (n=32). Those who were able to stay within their energy envelope had significant improvements in physical functioning and fatigue severity.

Findings suggest that helping patients with ME/CFS maintain appropriate energy expenditures in coordination with available energy reserves can help improve functioning over time. Health care professionals that treat patients with ME/CFS might incorporate strategies that help patients self-monitor and self-regulate energy expenditures.

http://www.sciencedirect.com/science/journal/07383991

[Ed. Note: This study supports pacing.]

Jason, L., Porter, N., Shelleby, E., Till, L., Bell, DS., Lapp, CW., Rowe, K and De Meirleir, K. Severe versus moderate criteria for the new pediatric case definition for ME/CFS Child Psychiatry and Human Development, 2009, doi: 10.1007/s10578-009-0147-8. Published online 10 June.

The new diagnostic criteria for pediatric ME/CFS are structurally based on the Canadian Clinical Adult case definition, and have more required specific symptoms than the CDC '94 adult case definition. Physicians specializing in pediatric ME/CFS referred 33 pediatric patients with ME/CFS and 21 youths without the illness. Those who met ME/CFS criteria were separated into Severe (n=16) and Moderate (n=14) categories. Results were available for 20 controls.

Significant differences were found for symptoms within each of the six major categories: fatigue, post-exertional malaise, autonomic/neuroendocrine/immune manifestations, neurocognitive difficulties, and sleep, pain. In general, the results showed participants who met the Severe ME/CFS criteria reported the highest scores, the Moderate ME/CFS group show scores that were a little lower, and the control group evidenced the lowest scores. Findings indicate that the Pediatric Case Definition for ME/CFS can distinguish between those with this illness and controls, and between those with Severe versus Moderate manifestations of the illness.

EPIDEMIOLOGY

Goudsmit, EM., Ho-Yen, DO and Dancey, CP. Learning to cope with chronic illness. Efficacy of a multi-component treatment for people with chronic fatigue syndrome. Patient Education and Counseling, 2009. doi: 10.1016/j.pec.2009.05.015. 2nd July.

REVIEWS

Belgamwar, RB., Jorsh, MS., Knisely-Marpole, A., Snowden, H., Mayall, E., Singhal, A and Jones, JM. Multidisciplinary group treatment for chronic fatigue syndrome. Progress in Neurology and Psychiatry, 2009, 13, 1, 27-29.

It is estimated that between 0.2 and 0.4 per cent of the population suffer from CFS/ME. Service provision varies across the UK, and while there is a good evidence for the efficacy of cognitive behavioural therapy and graded exercise programmes, the evidence for group inter-ventions is still limited. Here, the authors describe the results of their service evaluation of a group treatment programme for CFS/ME.

[Ed. Note: This is an uncontrolled study using patients selected using the Oxford criteria only.]

Byrnes, A., Jacks, A., Dahlman-Wright, K., Evengard, B., Wright, FA., Pedersen, NL and Sullivan, PF. Gene expression in peripheral blood leukocytes in monozygotic twins discordant for chronic fatigue: No evidence of a biomarker. PLoS ONE, 2009, 4(6):e5805. doi:10.1371/journal.pone.0005805.

Chronic fatiguing illness remains a poorly understood syndrome of unknown pathogenesis. We attempted to identify biomarkers for chronic fatiguing illness using microarrays to query the transcriptome in peripheral blood leukocytes.

Cases were 44 individuals who were clinically evaluated and met the criteria for CFS (CDC '94 or 2003, 73%) or idiopathic chronic fatigue (27%), and controls were their monozygotic co-twins who were clinically evaluated and never had even one month of impairing fatigue. Biological sampling conditions were standardized and RNA stabilizing media were used. These methodological features provide rigorous control for bias resulting from case-control mismatched ancestry and experimental error. Individual gene expression profiles were assessed using Affymetrix Human Genome U133 Plus 2.0 arrays.

There were no significant differences in gene expression for any transcript. Contrary to our expectations, we were unable to identify a biomarker for chronic fatiguing illness in the transcriptome of peripheral blood leukocytes suggesting that positive findings in
prior studies may have resulted from experimental bias.

[Ed. Note: Study involving rats. Results are therefore difficult to extrapolate to humans.]

Maloney, EM., Boneva, R., Nater, UM and Reeves, WC. Chronic fatigue syndrome and high allostatic load: results from a population-based case-control study in Georgia. Psychosomatic Medicine, 2009, 71, 549-556.

The objective of this study was to confirm the association of CFS with high allostatic load (AL) level, examine the association of subsyndromal CFS with AL level, and investigate the effect of depression on these relationships and the association of AL with functional impairment, fatigue, symptom severity, fatigue duration, and type of CFS onset. AL represents the cumulative physiologic effect of demands to adapt to stress ('wear and tear on the body due to repeated cycles of inadequate adaptation to stress, resulting in dysregulation of the HPA axis etc).

Population-based case-control study of 83 persons with CFS (CDC criteria '94, 2003, 2005), 202 persons with insufficient symptoms or fatigue for CFS (ISF), and 109 well controls living in Georgia. Unconditional logistic regression was used to generate odds ratios (ORs) as measures of the association of AL with CFS.

Relative to well controls, each 1-point increase in allostatic load index (ALI) was associated with a 26% increase in likelihood of having CFS (ORadjusted = 1.26, 95% Confidence Interval (CI) = 1.00, 1.59). This association remained in the presence and absence of depression (ORadjusted = 1.35, CI = 1.07, 1.72; ORadjusted = 1.35, CI = 1.10, 1.65). Compared with the ISF group, each 1-point increase in ALI was associated with a 10% increase in likelihood of
having CFS (ORadjusted = 1.10, CI = 0.93, 1.31). After adjusting for covariates, including BMI, insulin was the only AL factor significantly correlated with CFS. Among persons with CFS, the duration of fatigue was inversely correlated with ALI (r = -.26, p = .047).

Compared with well controls, persons with CFS were significantly more likely to have a high AL. AL increased in a gradient across well, ISF, and CFS groups.

[Ed. Note: The original group tested comprised 113 patients with CFS (CDC 2003), although information relating to ALI was incomplete, and 30 were therefore excluded from analysis. Cases had a higher BMI index compared to well controls, 82.9% had a gradual onset but there is no information on sugar intake, which might explain the raised insulin levels. Impairment (SF-36) and fatigue were not correlated with ALI and depression was only weakly correlated with ALI. Mean cortisol levels were similar in all three groups. Reduced motivation was significantly correlated with ALI, however. Given all the findings, a further study including a post-viral comparison group and data on sugar and fat intake is warranted.]

Nater, UM., Lin, JMS., Maloney, EM., Jones, JF., Tian, H., Boneva, RS., Raison, CL., Reeves, WC and Heim, C. Psychiatric comorbidity in persons with chronic fatigue syndrome identified from the Georgia population. Psychosomatic Medicine, 2009, 71, 557-565.

The objective of this study was to compare the prevalence of psychiatric disorders in persons with CFS identified from the general population and a chronically ill group of people presenting with subsyndromic CFS-like illness ("insufficient symptoms or fatigue" (ISF)). Previous studies in CFS patients from primary and tertiary care clinics have found high rates of psychiatric disturbance, but this may reflect referral bias rather than true patterns of comorbidity with CFS.

We used random digit dialing to identify unwell individuals. A detailed telephone interview identified those with CFS-like illness. These individuals participated in a 1-day clinical evaluation to confirm CFS or ISF status. We identified 113 cases of CFS (CDC '03) and 264 persons with ISF. To identify current and lifetime psychiatric disorders, participants completed the Structured Clinical Interview for DSM-IV (SCID).

Sixty-four persons (57%) with CFS had at least one current psychiatric diagnosis, in contrast to 118 persons (45%) with ISF. One hundred one persons (89%) with CFS had at least one lifetime psychiatric diagnosis compared with 208 persons (79%) with ISF. Of note, only 11 persons (9.8%) with CFS and 25 persons (9.5%) with ISF reported having seen a mental healthcare specialist during the past 6 months.

Our findings indicate that current and lifetime psychiatric disorders commonly accompany CFS in the general population. Most CFS cases with comorbid psychiatric conditions had
not sought appropriate help during the past 6 months. These results demonstrate an urgent need to address psychiatric disorders in the clinical care of CFS cases.

[Ed. Note: If the sample was largely identical to that described in a separate study (Maloney et al, above), the patients with CFS had a higher BMI index compared to well controls, and most had a gradual onset. The high insulin levels in the absence of other measures of stress or impairment suggest a metabolic/nutritional problem and possible misdiagnosis. Details of diet are not given but a high sugar intake could add to the porosity of the blood brain barrier as well as increase fatigue and the other symptoms included as criteria for diagnosis. The higher rate of eating disorders are noteworthy. Amongst people with CFS, 22.1% had major depressive disorder and a current anxiety disorder was diagnosed in 45.9%. Both may explain the symptoms of CFS. Comparison with a group diagnosed with another chronic, neuro-logical condition matched for BMI, and/or ME using the new criteria might have been useful. Given the flaws, the findings of the above study should be interpreted with caution.]

Neu, D., Cappeliez, B., Hoffmann, G., Verbanck, P., Linkowski, P and Le Bon, O. High slow-wave sleep and low-light sleep: Chronic fatigue syndrome is not likely to be a primary sleep disorder. Journal of Clinical Neurophysiology, 2009 May 6. [Epub ahead of print].

The status of CFS is still under debate. Mainstream views still often consider it as an undetected primary sleep disorder or as the psychosomatic expression of a related anxiety or depression syndrome. Both primary sleep disorder and CFS are often related to unrefreshing sleep and affective daytime symptoms. The present study compares nonrapid eye movement sleep distribution between patients with a primary sleep disorder and "pure" CFS patients without sleep or mood disorders.

Intensity measures of affective symptoms are also analyzed. Sleep variables of 32 pure CFS patients (mean age, 41.9 + 8.7 years; 25 women), 30 Sleep Apnea Hypopnea Syndrome patients (mean age, 43.7 + 6.7 years; 13 women), and 14 healthy controls (mean age, 40.2 + 7.6 years; 9 women) were compared. Related affective symptoms were assessed using
the self-reported Zung anxiety and depression scales.

The study confirms previous reports on increased slow-wave sleep in CFS patients. Both pa-tient groups showed similar sleep duration and efficiency. Sleep efficiency was lower in both patient groups compared with controls. CFS patients showed a higher microarousal index than controls. Anxiety, but not depression symptoms were more intense in the CFS group.

The distribution of nonrapid eye movement sleep in CFS differs sizeably from what can be observed in a primary sleep disorder.

Newton, JL., Sheth, A., Shin, J., Pairman, J., Wilton, K., Burt, JA and Jones, DE. Lower ambulatory blood pressure in chronic fatigue syndrome. Psychosomatic Medicine, 2009, 71, 3, 361-365.

The objective was to examine blood pressure circadian rhythm in subjects with CFS and appropriate normal and fatigued controls to correlate parameters of blood pressure regulation with perception of fatigue in an observational cohort study. The cause of CFS remains unknown and there are no effective treatments.

To address whether inactivity was a confounder, we performed a 24-hour ambulatory blood pressure monitoring in the following three subject groups: 1) CFS patients (CDC criteria '94) (n = 38); 2) normal controls (n = 120); and 3) a fatigue comparison group (n = 47) with the autoimmune liver disease primary biliary cirrhosis (PBC). All patients completed a measure of fatigue severity (Fatigue Impact Scale). In view of the different demographics between the
patient groups, patients were age- and sex-matched on a case-by-case basis to normal controls and blood pressure parameters were compared.

Compared with the control population, the CFS group had significantly lower systolic blood pressure (p<.0001) and mean arterial blood pressure (p=.0002) and exaggerated diurnal variation (p=.009). There was a significant inverse relationship between increasing fatigue and diurnal variation of blood pressure in both the CFS and PBC groups (p<.05).

Lower blood pressure and abnormal diurnal blood pressure regulation occur in patients with CFS. We would suggest the need for a randomized, placebo-controlled trial of agents to increase blood pressure such as midodrine in CFS patients with an autonomic phenotype.

Pae, CU., Marks, DM., Patkar, AA., Masand, PS., Luyten, P and Serretti, A. Pharmacological treatment of chronic fatigue syndrome: Focusing on the role of antidepressants. Expert Opinion on Pharmacotherapy, 2009 Jun 11. [Epub ahead of print].

Review focusing on antidepressants and other psychotropic agents in CFS to provide a platform for clinicians to make decisions in their treatment of this challenging syndrome.

Rao, AV., Bested, AC., Beaulne, TM., Katzman, MA., Iorio C., Berardi, JM and Logan, AC. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathogens, 2009, 1:6. Mar 19.

CFS is complex illness of unknown etiology. Among the broad range of symptoms, many patients report disturbances in the emotional realm, the most frequent of which is anxiety. Research shows that patients with CFS and other so-called functional somatic disorders have
alterations in the intestinal microbial flora. Emerging studies have suggested that pathogenic and non-pathogenic gut bacteria might influence mood-related symptoms and even behavior in animals and humans. In this pilot study, 39 CFS patients (Canadian criteria) were randomized to receive either 24 billion colony forming units of Lactobacillus casei strain Shirota (LcS) or a placebo daily for two months. Patients provided stool samples and completed the Beck Depression and Beck Anxiety Inventories before and after the inter-vention.

35 patients completed the trial. We found a significant rise in both Lactobacillus and Bifidobacteria in those taking the LcS, and there was also a significant decrease in anxiety symptoms among those taking the probiotic vs controls (p = 0.01). These results lend further support to the presence of a gut-brain interface, one that may be mediated by microbes that reside or pass through the intestinal tract.

Free full text at: http://www.gutpathogens.com/content/1/1/6

Pietrangelo T, Toniolo L, Paoli A, Fulle S, Puglielli C, Fano G, Reggiani C. Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study. International Journal of Immunopathology and Pharmacology, 2009, 22, 2, 427-436.

[Ed. Note: Abstract will be included in a future issue when full article is available.]

Robinson, M., Gray, SR., Watson, MS., Kennedy, G., Hill, A., Belch, JJ and Nimmo, MA. Plasma IL-6, its soluble receptors and F-isoprostanes at rest and during exercise in chronic fatigue syndrome. Scandinavian Journal of Medicine & Science in Sports, 2009 Apr 13. [Epub ahead of print]. doi: 10.1111/j.1600-0838.2009.00895.x.

The aim of the current study was to investigate the levels of interleukin-6 (IL-6), its soluble receptors (sIL-6R and sgp130) and F2-isoprostanes, at rest and during exercise, in patients with CFS.

Six male CFS patients (CDC criteria '94) and six healthy controls performed an incremental exercise test to exhaustion and a submaximal exercise bout to exhaustion. Blood samples taken in the submaximal test at rest, immediately post-exercise and 24 hours post-exercise were analyzed for IL-6, sIL-6R, sgp130 and F2-isoprostanes. A further 33 CFS and 33 healthy control participants gave a resting blood sample for IL-6 and sIL-6R measurement.

During the incremental exercise test only power output at the lactate threshold was lower (p<0.05) in the CFS group. F2-isoprostanes were higher (p<0.05) in CFS patients at rest and this difference persisted immediately and 24 hours post-exercise. The exercise study found no
differences in IL-6, sIL-6R or sgp130 at any time point between groups. In the larger resting group, there were no differences in IL-6 and sIL-6R between CFS and control groups.

This investigation has demonstrated that patients with CFS do not have altered plasma levels of IL-6, sIL-6R or sgp130 either at rest or following exercise. F2-isoprostanes, however, were consistently higher in CFS patients.

[Ed. Note: the failure to find additional differences after exercise supports the notion that ME differs from CFS.]

Scheeres, K., Knoop, H., van der Meer, J and Bleijenberg, G. Clinical assessment of the physical activity pattern of chronic fatigue syndrome patients: a validation of three methods. Health and Quality of Life Outcomes, 2009, 7:29. doi:10.1186/1477-7525-7-29.

This article posits that infection of the peripheral ganglia causes at least some cases of CFS, with a neurotropic herpesvirus, particularly varicella-zoster virus (VZV), as the most likely cause of the infection. Virtually all CFS symptoms could be produced by an infection of the peripheral ganglia, with infection of the autonomic ganglia causing fatigue, postural hypotension, and sleep disturbances, and infection of the sensory ganglia causing sensory symptoms such as chronic pain. Furthermore, infections of the peripheral ganglia are known to cause long-term nerve dysfunction, which would help explain the chronic course of CFS. Herpesviruses have long been suspected as the cause of CFS; this theory has recently been supported by studies showing that administering antiherpes agents causes substantial improvement in some CFS patients. VZV is known to frequently reactivate in the peripheral ganglia of previously healthy adults and cause sudden, debilitating illness, making it a likely candidate as a cause of CFS. Moreover, many of the symptoms of CFS overlap with those of herpes zoster (shingles), with the exception that painful rash is not one of the symptoms of CFS. A model is therefore proposed in which CFS is one of the many manifestations of zoster sine herpete; that is, herpes zoster without rash. Furthermore, re-exposure to VZV in the form of chickenpox has become less common in the past few decades; without such re-exposure, immunity to VZV drops, which could explain the increased incidence of CFS. Co-infection with multiple herpesviruses is a possibility, as some CFS patients show signs of infection with other herpesviruses including Epstein-Barr, Cytomegalovirus, and HHV6. These three herpesviruses can attack immune cells, and may therefore promote neurotropic herpesvirus reactivation in the ganglia. The possibility of VZV as the causal agent in CFS has previously received almost no attention; the possibility that CFS involves infection of the peripheral ganglia has likewise been largely overlooked. This suggests that the search for a viral cause of CFS has been far from exhaustive. Several antiherpes drugs are available, as is a vaccine for VZV; more research into such agents as possible treatments for CFS is urgently needed.

Torres-Harding, S., Sorenson, M., Jason, LA., Reynolds, N., Brown, M, Maher, K and Fletcher, MA., The associations between basal salivary cortisol levels and illness symptomatology in chronic fatigue syndrome. Journal of Applied Biobehavioral Research, 2008, 13, 157-180.

Hypocortisolism has been reported in CFS, with the significance of this finding to disease etiology unclear. This study examined cortisol levels and their relationships with symptoms in a group of 108 individuals with CFS.

CFS symptoms examined included fatigue, pain, sleep difficulties, neurocognitive functioning, and psychiatric status. Alterations in cortisol levels were examined by calculation of mean daily cortisol, and temporal variation in cortisol function was examined by means of a regression slope. Additionally, deviation from expected cortisol diurnal pattern was deter-mined via clinical judgment.

Results indicated that fatigue and pain were associated with salivary cortisol levels. In particular, variance from the expected pattern of cortisol was associated with increased levels of fatigue. The implications of these findings are discussed.

Van Campen, E., Van Den Eede, F., Moorkens, G., Schotte, C., Schacht, R., Sabbe, BG., Cosyns, P and Claes, SJ. Use of the Temperament and Character Inventory (TCI) for assessment of personality in chronic fatigue syndrome. Psychosomatics, 2009, 50, 2, 147-54.

The study examined whether CFS is associated with specific dimensions of Cloninger's psychobiological model of personality. Personality profiles were compared between 38 CFS patients (CDC criteria '94, 29% with anxiety disorders, 21% with somatisation disorder) and 42 control subjects by means of the Temperament and Character Inventory (TCI).

The CFS group showed significantly higher scores on Harm-Avoidance and Persistence.
The current study shows a significant association between specific personality characteristics and CFS. These personality traits may be implicated in the onset and/or perpetuation of CFS and may be a productive focus for psychotherapy.

[Ed. Note: The high incidence of anxiety disorders may explain the results. The lack of a chronically ill control group also means that the findings cannot be attributed to CFS per se. The personality variables may represent the result of illness. In the discussion, the authors argue the case for pacing.]

Wang, JH., Chai, TQ., Lin, GH and Luo, L. Effects of the intelligent-turtle massage on the physical symptoms and immune functions in patients with chronic fatigue syndrome. Journal of Traditional Chinese Medicine, 2009, 29, 1, 24-28.

To evaluate the effects of the intelligent-turtle massage on the physical symptoms and immune functions in patients with CFS, the authors selected 182 cases of CFS who were randomly divided into an experimental group of 91 cases treated by the intelligent-turtle massage, and a control group of 91 cases treated with the conventional massage method. After 2 courses of treatment, the therapeutic effects were statistically analyzed with the accumulated score for the improved clinical symptoms; and the changes of IgA, IgM and IgG were compared in 96 cases.

There was a significant difference between the two groups in the accumulated scores for improvement of the symptoms (p<0.05). A remarkable difference was found in the therapeutic effect and there was a significant difference in the IgA, IgM and IgG levels between the two groups (p<0.05). The intelligent-turtle massage is an effective therapy for relieving the physical symptoms of CFS, and it may show certain effects on the immune functions.

Barlow, J., Turner, A., Edwards, R and Gilchrist, M. A randomised controlled trial of lay-led self-management for people with multiple sclerosis. Patient Education and Counseling, 2009, in press. doi:10.1016/j.pec.2009.02.009. Available online 24 March.

The objective was to determine the impact of the Chronic Disease Self-Management Course (CDSMC) on people with multiple sclerosis (MS). This was a 2-group, randomised, con-trolled trial with Intervention Group (IG) and Waiting-List Control Group (WLCG). Ad-ditional data were collected from a Comparison Group (CG) who chose not to attend the CDSMC. Participants completed baseline questionnaires; IG participants attended the CDSMC immediately; all participants were assessed at 4-months and 12-months.

216 baseline questionnaires were returned; 73% were female, mean age 51.1 years, mean disease duration 12.0 years. Results showed that the CDSMC had an impact on self-management self efficacy (ES 0.30, p=0.009 for the IG) and MSIS physical status (ES 0.12 for the IG, p=0.005). There were no other statistically significant changes. However, trends towards improvement on depression (ES 0.21 for the IG, p=0.05) and MS self-efficacy (ES 0.16 for the IG, p=0.04) were noted. All improvements were maintained at 12-months. At baseline, CG participants were older, had longer disease duration (p<0.01) and less anxiety (p=0.009) compared to RCT participants.

To conclude: The CDSMC provides some small positive effects for people with MS. Motivation to attend may be linked to psychological dis-tress and disease duration. Practice implications: The CDSMC may be of value for those with mild anxiety/depression who need extra support. Attendance early in the disease course is recommended.

Deluca, J., Genova, HM., Capili, EJ and Wylie, GR. Functional neuroimaging of fatigue. Physical Medicine and Rehabilitation Clinics of North America, 2009, 20, 2, 325-337.

Recent studies employing functional neuroimaging provide new insights into the elusive construct of fatigue. Studies have been conducted primarily in persons with MS and CFS. These studies outline the key role of the basal ganglia and frontal lobes in understanding the neural mechanisms associated with fatigue. The lack of a relationship between self-reported fatigue and objectively measured fatigue is outlined, and new functional imaging paradigms may lead to significant advances in relating cognitive fatigue to functional cerebral activity.

Dennison, L., Moss-Morriss, R and Chalder, T. A review of psychological correlates of adjustment in patients with multiple sclerosis. Clinical Psychology Review, 2009, 29, 141-153.

Good review of psychological variables influencing adjustment to MS.

Harvey, SB., Wessely, S., Kuh, D and Hotopf, M. The relationship between fatigue and psychiatric disorders: Evidence for the concept of neurasthenia. Journal of Psychosomatic Research, 209, 66, 445-454.

Article on fatigue concluding that a significant proportion of the adult population will suffer from fatigue without a comorbid psychiatric disorder. The paper includes a discussion of CFS: Previous studies have shown a strong association between CFS and psychiatric disorders. The diagnosis of neurasthenia, as defined by the ICD-10 classification, is similar, although it does not stipulate the duration of fatigue and requires only two associated somatic symptoms. In addition, the current definition of neurasthenia specifically excludes any individual meeting diagnostic criteria for depression or anxiety. Within our study, we have identified a group of individuals with significant fatigue in the absence of comorbid psychiatric disorder. This definition of a fatigue state is very similar to neurasthenia (although without any assessment of accompanying somatic symptoms), but is significantly different from the current criteria for diagnosing CFS.

The exact criteria used to define syndromes such as neurasthenia and CFS are, to some degree, arbitrary. However, the differences between these definitions are important to consider, particularly when investigating the relationship between fatigue and psychiatric disorders. Previous studies have shown that as additional somatic symptoms are added to the diagnostic criteria for fatigue syndromes, the association with psychiatric disorders increases. It is therefore likely that the relative incidence of comorbid fatigue and psychiatric disorder would be significantly higher if associated somatic symptoms or disability was required for a diagnosis. As such, our results cannot be directly extrapolated to those diagnosed with CFS.

[Ed. Note: The alleged correlation between number of somatic symptoms and psychiatric disorders is based on a study of patients with chronic fatigue, only a small proportion of whom had CFS.]

Marks, D. How should psychological interventions be reported? Journal of Health Psychology, 2009, 14, 4, 475-489.

This editorial describes several problems with the reporting of psychological research. The editor notes the limitations of randomized controlled trials "which do not transfer very well to real world effectiveness" – the invalidity symptom. An additional problem is the simplicity symptom, the tendency to assess one or two treatments whereas real world interventions may use several, e.g. add music and a candle when meditating. Finally, interventions are rarely fully described, the opacity symptom. It is therefore difficult to replicate a study and identify which component of treatment was responsible for efficacy. Marks presents suggestions to improve reporting and hence, evidence-based practice (EBP).

Shevil, E and Finlayson, M. Process evaluation of a self-management cognitive program for persons with multiple sclerosis. Patient Education and Counseling, 2009, 76, 1, 77-83.

Cognitive changes are highly prevalent in MS. However, evidence-based research on cognitive rehabilitation programs for this population is only beginning to emerge. This article presents results from a process evaluation of a group-based, self-management cognitive intervention program developed specifically for people with MS.

Quantitative and qualitative data were collected using focus group interviews, facilitator reflection notes, and program evaluations. The data were used to identify the strengths and limitations of the program and to document recommendations for future development. Forty-one individuals met eligibility criteria and were enrolled in the program.

Overall, participants reported that the program had a positive impact on their ability to manage cognitive symptoms. Program components that contributed to successful application of cognitive management strategies included increasing participant’s knowledge of cognitive changes, problem solving through cognitive challenges, practicing strategies through home-work assignments, and conducting the program in a group format. Participants recommended that caregivers be included in future programs. Both content and structural components of the program facilitated participants’ ability to manage cognitive changes and contributed to behavior changes made by the participants.

Practice implications: This study points to the benefits of incorporating self-management programs into the cognitive rehabilitation process in MS.

Smith, C., Hale, L., Olson, K and Schneiders, AG. How does exercise influence fatigue in people with multiple sclerosis? Disability & Rehabilitation, 2009, 31, 9, 685–692.

This study explored the influence of an 8-week exercise programme on fatigue perceptions in people with MS. Eight women and two men with a confirmed diagnosis of MS participated three times a week in an 8-week exercise programme at a physiotherapy gymnasium. Participants were interviewed at three defined time points. Interviews were transcribed, analysed, and emergent categories were subject to verification by three independent sources.

Five interrelated categories were identified from the data. The category, 'listening to your body' evolved from the participants' 'perceived control over fatigue', which subsequently defined the 'reaching the edge'; a critical point at which the 'nature of tiredness' perceived by participants following exercise was either healthy or unhealthy. This critical point consequently explained either perceived positive 'exercise outcomes', outcomes of physical improvement and wellbeing or perceived physical deterioration and negative feelings.

This study details the positive and negative influences of exercise on fatigue perceptions in people with MS. Healthcare professionals therefore, need to be cognisant of strategies which may enhance 'perceived control over fatigue' and promote 'listening to your body', in order to maximise the benefits of exercise intervention for individuals with MS-related fatigue.

Extracts: 'Listening to your body' emerged as a key strategy used by participants' to ensure fatigue was minimised during exercise. This strategy consisted of being intuitively aware of the body's requirements and responses in the context of exercise. Participants who experienced little control over fatigue also experienced mistrust of their bodies and consequently underutilised the strategy involved in 'listening to your body'. In addition, participants with a developing sense of control were often influenced by advice from healthcare professionals which was counter-intuitive to the requirements they perceived as necessary by listening to their body... When participants exercised to 'the edge' however, they experienced a healthy tiredness which was associated with perceived physical improvements and positive feelings. This was particularly the case for participants with a strong sense of control who sometimes chose to go beyond 'the edge' as they felt this was necessary in order to improve long term fitness...

All participants felt that it was necessary to work close to 'the edge'. Staying well away from 'the edge' or 'playing it safe' led to feelings of boredom, frustration and consequently increased negative feelings associated with an unhealthy tiredness... Level of perceived control in our study was associated with individual confidence in the ability to recognise and manage fatigue; a state more commonly described as self efficacy... Level of perceived control may also be linked to the concept of health locus of control. Health locus of control refers to an individual's perception of health behaviour and subsequent benefits, as being under the control of the individual (internal orientation), or, controlled by external factors such as fate, chance or other individuals with greater perceived power such as health care professionals. Therefore, in order for an exercise intervention to be successful it may need to be tailored in such a way which not only fosters increased levels of perceived control, but caters for contrasting health locus of control in individuals with MS. In our study, level of perceived control may also have been influenced by the nature of communication between the participant and their body and the participant and the therapist. For example, on occasion some participants, who utilised the strategy 'listening to your body', felt frustrated at not being able to exercise at a self selected level of intensity because the therapist advised otherwise. It has been shown that many individuals with MS experience frustration regarding communication with healthcare providers and it is possible therefore, that these communication difficulties may contribute to increased fatigue via mechanisms of frustration and heightened anxiety. Consequently, it is recommended that future research should explore healthcare provider perceptions regarding fatigue and exercise, and how advice regarding these strategies is communicated.

In addition to improved communication, exploration of the effectiveness of other strategies in combination with exercise, such as meditation and mindfulness, may further enhance the strategy of 'listening to your body', thereby reinforcing the positive outcomes of exercise in the MS population... In a reconceptualisation of fatigue, Olson suggested that perceived fatigue may reflect an individual's ability to adapt to a variety of internal and external stressors and may represent one point along a continuum ranging from tiredness to exhaustion, regardless of whether or not they experience chronic illness. The continuum of perceived control over fatigue in our study may reflect this continuum of adaptation to stressors in the MS population.... Healthcare professionals therefore, need to be cognisant of strategies which may enhance 'perceived control over fatigue' and promote 'listening to your body', in order to maximise the benefits of exercise intervention for individuals with MS-related fatigue.

[Ed. Note: The concept of reaching the edge is consistent with the Envelope theory and the theory underpinning pacing as developed by Goudsmit and Howes. The adverse effects of operating below one's abilities was also found in patients with CFS (Goudsmit et al, above).]

Suoyrjö, H., Oksanen, T., Hinkka, K., Pentti, J., Kivimäki, M., Klaukka, T and Vahtera, J. A comparison of two multidisciplinary inpatient rehabilitation programmes for fibromyalgia: a register linkage study on work disability. Journal of Rehabilitation Medicine, 2009, 41, 66-72.

Patients with FM have a high risk of temporary and permanent work disability. Little is known about the effects of FM rehabilitation on work disability. The aim was to determine whether a specific FM rehabilitation programme is superior to a non-specific musculoskeletal rehabilitation of patients with FM in terms of work disability.

A prospective observational study of 215 local government employees with a 6-year post-intervention follow-up to monitor the occurrence of long sick-leave and disability pensions among the participants of two different FM rehabilitation programmes.

Specific FM rehabilitation (less education, aimed at increasing self-efficacy, more aerobic exercise) was not superior to a non-specific musculoskeletal rehabilitation, with the corresponding hazard ratios (95% confidence intervals) after adjustments being 1.02 (0.75–1.40) for long sick-leave, 1.18 (0.75–1.87) for very long sick-leave, and 1.07 (0.63–1.83) for disability pension. The results suggest that in reducing work disability among patients with FM a specific multidisciplinary FM rehabilitation programme practised in Finland provides no benefit compared with non-specific multidisciplinary musculoskeletal rehabilitation.

COMPLETE REFERENCES FOR SIGNIFICANT E-PUBS

Christopher, G and Thomas, M. Social problem solving in chronic fatigue syndrome: preliminary findings. Stress and Health, 2009, 25, 2, 161-169.  

Roberts, AD., Papadopoulos, AS., Wessely, S., Chalder, T and Cleare, AJ. Salivary cortisol output before and after cognitive behavioural therapy for chronic fatigue syndrome. Journal of Affective Disorders, 2009, 115 (1-2), 280-286.

Friedberg, F and Sohl, SJ. Longitudinal change in chronic fatigue syndrome: what home-based assessments reveal. Journal of Behavioral Medicine, 2009, 32, 2, 209-218.

Goedendorp, MM., Knoop H, Schippers, GM and Bleijenberg, G. The lifestyle of patients with chronic fatigue syndrome and the effect on fatigue and functional impairments. Journal of Human Nutrition and Dietetics, 2009, 22, 3, 226-231.

Sakudo, A., Kato, YH., Tajima, S., Kuratsune, H and Ikuta, K. Visible and near-infrared spectral changes in the thumb of patients with chronic fatigue syndrome. Clinica Chimica Acta, 2009, 403 (1-2), 163-166.

Van Houdenhove., Van Den Eede, F and Luyten, P. Does hypothalamic–pituitary–adrenal axis hypofunction in chronic fatigue syndrome reflect a ‘crash’ in the stress system? Medical Hypotheses, 2009, 72, 6, 701-705.