Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome

Abstract:

Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors. Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases.

Here, serum samples from a patient cohort from Berlin (n=268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and β adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108).

Antibodies against β2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls. A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high β2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies.

In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated β2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.

We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and β adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing β adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

 

Source: Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Fluge Ø, Mella O, Scheibenbogen C. Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. 2016 Feb;52:32-9. doi: 10.1016/j.bbi.2015.09.013. Epub 2015 Sep 21. https://www.ncbi.nlm.nih.gov/pubmed/26399744

 

Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis

Abstract:

Patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and multiple sclerosis (MS) suffer from debilitating fatigue which is not alleviated by rest. In addition to the fatigue-related symptoms suffered by patients with CFS/ME and MS, dysfunction of the immune system and, in particular, reduced natural killer (NK) cell cytotoxic activity has also been reported in CFS/ME and MS. The purpose of this pilot study was to compare NK cellular mechanisms in patients with CFS/ME and MS to investigate potential dysfunctions in the NK cell activity pathway. Flow cytometry protocols assessed CD56(dim) CD16(+) and CD56(bright) CD16(+/-) NK cell expression of adhesion molecules, NK activating and inhibiting receptors, NK cell maturation and lytic proteins.

All participants in this study were female and included 14 patients with CFS/ME, nine patients with MS and 19 non-fatigued controls. The patient groups and the non-fatigued controls were not taking any immunosuppressive or immune-enhancing medications. In the MS cohort, KIR2DL5 was significantly increased on CD56(bright) CD16(+/-) NK cells and expression of CD94 was significantly increased on CD56(dim) CD16(+) NK cells in comparison with the controls. Co-expression of CD57 and perforin was significantly increased on CD56(dim) CD16(+) NK cells from patients with CFS/ME compared to the MS and non-fatigued control participants.

The results from this pilot study suggest that NK cells from patients with CFS/ME and MS may have undergone increased differentiation in response to external stimuli which may affect different mechanisms in the NK cell cytotoxic activity pathway.

© 2015 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Foundation for the Scandinavian Journal of Immunology.

 

Source: Huth TK, Brenu EW, Ramos S, Nguyen T, Broadley S, Staines D, Marshall-Gradisnik S. Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis. Scand J Immunol. 2016 Jan;83(1):44-51. doi: 10.1111/sji.12388. http://onlinelibrary.wiley.com/wol1/doi/10.1111/sji.12388/full (Full article)

 

Selective serotonin reuptake inhibitor combined with dengzhanshengmai capsule improves the fatigue symptoms: a 12-week open-label pilot study

Abstract:

OBJECTIVE: This study was to assess the efficacy and safety of selective serotonin reuptake inhibitor (SSRI) plus Dengzhanshengmai capsule in patients with chronic fatigue syndrome (CFS).

METHODS: SSRI at a moderate dose plus Dengzhanshengmai (n = 134) with SSRI alone (n = 134) were compared for the efficacy and safety in the treatment of CFS. The therapeutic efficacy and safety were evaluated.

RESULTS: As compared to monotherapy group, the efficacy in combined therapy group was better and characterized by the improvement of general fatigue (0.8±0.6 vs. 1.3±0.7), physical fatigue (0.6±0.3 vs. 1.0±0.4) and reduced activity (1.0±0.5 vs. 1.3±0.6) since the 2nd week (P<0.01) and in reduced motivation (2.1±0.8 vs. 2.4±1.0) since the 8th week (P<0.01) and the improvement continued thereafter. The mental fatigue score and HAD score were comparable between two groups (P>0.05). No significant difference was found in the drop-out rate between SSRI group (15.7%) and SSRI plus Dengzhanshengmai group (18.0%). The reasons for drop out were adverse events (7.5% vs. 9.7%), requests of the patients or career requirement (3.7% vs. 4.5%), loss to follow-up and others (2.2% vs. 3.0%) and lack of efficacy (2.2% vs. 0.7%). Although the patients in combined therapy group experienced a higher rate of hypertension than (5.8% vs. 1.5%), no significant difference was observed (P = 0.08).

CONCLUSION: SSRI combined with Dengzhanshengmai capsule may significantly improve the general fatigue, physical fatigue, reduced activity and reduced motivation of CFS patients as compared to monotherapy with SSRI. Furthermore, this combined therapy is safe and tolerable.

 

Source: Li DQ, Li ZC, Dai ZY. Selective serotonin reuptake inhibitor combined with dengzhanshengmai capsule improves the fatigue symptoms: a 12-week open-label pilot study. Int J Clin Exp Med. 2015 Jul 15;8(7):11811-7. eCollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565405/ (Full article)

 

A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome

Abstract:

Stimulant drugs and various micronutrient interventions have previously been studied in chronic fatigue syndrome (CFS) but they have never been studied in combination. This proof of concept investigation seeks to examine the clinical effects and safety profile of KPAX002 (a combination of methylphenidate hydrochloride and mitochondrial support nutrients) in patients with CFS.

Fifteen patients diagnosed with CFS by 1994 Fukuda criteria were recruited and treated with KPAX002 to explore a potential synergistic effect of this combination. Fatigue and concentration disturbance symptoms were measured at baseline, 4 weeks, and 12 weeks using two clinically validated tools: Checklist Individual Strength (CIS) and Visual Analog Scale (VAS).

The primary outcome objective was a decrease in the total CIS score of ≥25% in at least 50% of the subjects. The mean total CIS score decreased by 36.4 points (34%) at 12 weeks (P<0.0001), corresponding to a ≥25% decrease in 87% of the participants.

Treatment with KPAX002 was well tolerated and significantly improved fatigue and concentration disturbance symptoms in greater than 50% of patients with CFS. These results were statistically significant. This combination treatment is worthy of additional investigation.

 

Source: Kaiser JD. A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome. Int J Clin Exp Med. 2015 Jul 15;8(7):11064-74. eCollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4565289/ (Full article)

 

Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance

Abstract:

Central nervous system dysfunction with myalgic encephalomyelitis (ME) has been suggested as the main cause of chronic fatigue syndrome. Fluctuation of the symptom severity and hierarchy is a characteristic feature in ME patients. The characteristics of the sympathetic activation may differ between the “good days” and “bad days” in them.

Twenty-four ME patients with orthostatic intolerance underwent a conventional 10-min active standing test and echocardiography both on a “good day” and a “bad day”, defined according to the severity of their symptoms. The mean heart rate at rest was significantly higher on the “bad days” than on the “good days”. During the standing test on a “bad day”, 5 patients (21 %) failed to maintain an upright posture for 10 min, whereas on a “good day” all the 24 patients maintained it.

Postural orthostatic tachycardia (POT) (increase in heart rate ≥30 beats/min) or severe POT (heart rate ≥120 beats/min) was observed on the “bad days” in 10 patients (43 %) who did not suffer from the severe tachycardia on the “good days”, suggesting the exaggerated sympathetic nervous activation.

In contrast, POT did not occur or severe POT was attenuated on the “bad days” in 5 patients (21 %) who developed POT or severe POT on the “good days”, suggesting the impaired sympathetic activation. Echocardiography revealed significantly lower mean values of both the left ventricular end-diastolic diameter and stroke volume index on the “bad days” compared with the “good days”.

In conclusion, in ME patients with orthostatic intolerance, the exaggerated activation of the sympathetic nervous system while standing appears to switch to the impaired sympathetic activation after the system is loaded with the additional accentuated stimuli associated with the preload reduction.

 

Source: Miwa K. Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance. Heart Vessels. 2016 Sep;31(9):1522-8. doi: 10.1007/s00380-015-0744-3. Epub 2015 Sep 15. https://www.ncbi.nlm.nih.gov/pubmed/26374335

 

Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients

Abstract:

BACKGROUND: Research has identified immunological abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), a heterogeneous illness with an unknown cause and absence of diagnostic test. There have been no CFS/ME studies examining innate and adaptive immune cells longitudinally in patients with varying severities. This is the first study to investigate immune cells over 6 months while also examining CFS/ME patients of varying symptom severity.

METHODS: Participants were grouped into 18 healthy controls, 12 moderate and 12 severe CFS/ME patients and flow cytometry was used to examine cell parameters at 0 and 6 months.

RESULTS: Over time, iNKT CD62L expression significantly increased in moderate CFS/ME patients and CD56(bright) NK receptors differed in severe CFS/ME. Naïve CD8(+)T cells, CD8(-)CD4(-) and CD56(-)CD16(-) iNKT phenotypes, γδ2T cells and effector memory subsets were significantly increased in severe CFS/ME patients at 6 months. Severe CFS/ME patients were significantly reduced in CD56(bright)CD16(dim) NKG2D, CD56(dim)CD16(-) KIR2DL2/DL3, CD94(-)CD11a(-) γδ1T cells and CD62L(+)CD11a(-) γδ1T cells at 6 months.

CONCLUSIONS: Severe CFS/ME patients differed from controls and moderate CFS/ME patients over time and expressed significant alterations in iNKT cell phenotypes, CD8(+)T cell markers, NK cell receptors and γδT cells at 6 months. This highlights the importance of further assessing these potential immune biomarkers longitudinally in both moderate and severe CFS/ME patients.

 

Source: Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Ramos S, Staines D, Marshall-Gradisnik S. Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. J Transl Med. 2015 Sep 14;13:299. doi: 10.1186/s12967-015-0653-3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568602/ (Full article)

 

Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial

Abstract:

BACKGROUND: Cognitive behaviour therapy (CBT) added to specialist medical care (SMC), or graded exercise therapy (GET) added to SMC, are more effective in reducing fatigue and improving physical function than both adaptive pacing therapy (APT) plus SMC and SMC alone for chronic fatigue syndrome. We investigate putative treatment mechanisms.

METHODS: We did a planned secondary mediation analysis of the PACE trial comparing SMC alone or SMC plus APT with SMC plus CBT and SMC plus GET for patients with chronic fatigue syndrome. 641 participants were recruited from six specialist chronic fatigue syndrome clinics in the UK National Health Service between March 18, 2005, and Nov 28, 2008. We assessed mediation using the product of coefficients method with the 12 week measure of the mediators and the 52 week measure of the outcomes. The primary outcomes were fatigue measured by the Chalder fatigue scale and physical function measured by the physical function subscale of the SF-36. We included confounder covariates and used treatment by mediator interaction terms to examine differences in mediator-outcome relations by treatment group.

FINDINGS: The largest mediated effect for both CBT and GET and both primary outcomes was through fear avoidance beliefs with an effect of larger magnitude for GET (standardised effects ×10, CBT vs APT, fatigue -1.22, 95% CI -0.52 to -1.97, physical function 1.54, 0.86 to 2.31; GET vs APT, fatigue -1.86, -0.80 to -2.89, physical function 2.35, 1.35 to 3.39). Increase in exercise tolerance (6 min walk distance) was a potent mediator of the effect of GET (vs APT, fatigue -1.37, 95% CI -0.76 to -2.21, physical function 1.90, 1.10 to 2.91), but not CBT.

INTERPRETATION: Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET. Changes in both beliefs and behaviour mediated the effects of both CBT and GET, but more so for GET. The results support a treatment model in which both beliefs and behaviour play a part in perpetuating fatigue and disability in chronic fatigue syndrome.

FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, and Institute of Psychiatry, Psychology, and Neuroscience, King’s College London.

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

Source: Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry. 2015 Feb;2(2):141-52. doi: 10.1016/S2215-0366(14)00069-8. Epub 2015 Jan 28. https://www.ncbi.nlm.nih.gov/pubmed/26359750

Comment in

COMMENTS

  • Robert Courtney 2016 Feb 16 10:20 a.m

    A study that uses questionable assumptions rather than empirical evidence leads to conclusions that stretch credibility.

    Chalder et al. [1] used the “single mediation model” for their methodology, which is explained in detail in a book by MacKinnon [2]. Explaining the methodology MacKinnon says a temporal separation between variables must be observed (i.e. changes in mediating variable must occur before changes in the mediated variable) for a mediation effect to be empirically and robustly established.

    Chalder et al. were working to this model and acknowledged that they failed to establish a clear temporal separation between variables, and therefore did not empirically establish a causal mediation effect: “Given the pattern of change in the mediators was similar to the pattern of change in the outcomes it is possible that the variables were affecting each other reciprocally”.

    However, despite the lack of robust empirical evidence to support a mediation effect, the investigators concluded that they had established mediation effects, e.g: “Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET.”

    The study’s conclusion relied upon an assumption that the investigators’ favoured hypothetical model of illness for ME/CFS has a robust empirical evidence base and is applicable to this study. The hypothesis is based upon the idea that symptoms and disability in ME/CFS are perpetuated by unhelpful or maladaptive illness beliefs, fear, and an avoidance of activity.

    However, the prestigious National Academy of Medicine (formerly known as the Institute of Medicine) recently released a comprehensive report [3] into ME/CFS that rejected such a hypothetical model of illness, and unambiguously concluded that ME/CFS does not have a psychological or cognitive-behavioural basis, but is an organic illness that requires biomedical research.

    Chalder et al. discussed the possibility that more frequent measurements may have potentially demonstrated a temporal separation between the variables, and therefore a mediation effect. However, this raises the possibility of whether changes in the primary outcome variables (self-report physical function and fatigue) may, in fact, have occurred before changes in the presumed mediator variables. Such an outcome would entirely contradict the investigators’ premature conclusions. According to MacKinnon [2] and Wiedermann et al. [4], unexpected outcomes should not be ruled out.

    Chalder et al. concluded that symptoms and physical impairment, in ME/CFS patients, are mediated by activity avoidance and other factors. (e.g. This would mean that a decrease in activity would cause an increase in symptoms.) However, from a common sense point of view, this seems like rather a convoluted conclusion, and it seems more likely that increased symptoms would be the direct cause of activity avoidance in any illness, rather than vice versa. To conclude that activity avoidance causes fatigue (rather than fatigue being a direct cause of activity avoidance), is similar to concluding that a person has flu because they’ve taken a day off work, rather than the obvious conclusion that they’ve taken a day off work because they have flu.

    In the case of fatigue, flu-like malaise and other symptoms of ME/CFS, it seems reasonable to consider the possibility that, as the symptoms fluctuate, patients may intuitively or rationally adapt their activity levels according to what is comfortable and safe. i.e. patients reduce activity levels because they are fatigued. The investigators have concluded that patients are fatigued because they have reduced activity levels.

    Perhaps patients’ perspectives and insights would help clarify the issues but, unfortunately, patients were not consulted for this study.

    References:

    1. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 2015; 2: 141–52.
    2. MacKinnon DP. Introduction to Statistical Mediation Analysis. Taylor and Francis: New York 2008.
    3. IOM (Institute of Medicine). 2015. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. Washington, DC: The National Academies Press. http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx
    4. Wiedermann W, von Eye A. Direction of Effects in Mediation Analysis. Psychol Methods 2015; 20: 221-44.
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    Tom Kindlon 2015 Sep 15 09:53 a.m.

    Objective measures found a lack of improvement for CBT & GET in the PACE Trial: subjective improvements may simply represent response biases or placebo effects in this non-blinded trial

    [Originally posted here: http://www.bmj.com/content/350/bmj.h227/rr-10]

    This BMJ article and a flurry of articles in the lay media this week followed the publication in Lancet Psychiatry of an analysis of the mediators of change in the important PACE Trial, a chronic fatigue syndrome (CFS) trial which cost UK taxpayers £5 million[1,2]. What seems to have been lost in the coverage is that, although there were some modest improvements in the self-report measures, there was an almost complete absence of improvements in objectively measured outcomes for cognitive behavioural therapy (CBT) and graded exercise therapy (GET) compared to the control group (specialist medical care only (SMC)).

    This is a non-blinded trial, where participants were told CBT and GET had previously been found to be effective in CFS and other conditions[3,4]: one way to look at the mediation results for subjective measures when there was a lack of objective improvements is that they may merely tell us how response biases and/or placebo effects are mediated[5].

    The focus on subjective measures in some CFS studies was previously criticised in a systematic review published back in 2001 (long before the PACE Trial started)[6]. They suggested instead “a more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities.”

    The model presented for cognitive behaviour therapy (CBT) in the PACE Trial manuals posits that the impairments and symptoms are reversible with the therapy[3,7]. However, the latest paper shows that fitness, as measured by a step test, didn’t improve following CBT[2]. An earlier PACE Trial publication reported that the addition of CBT to SMC did not result in an improvement in 6-minute walking test scores compared to SMC alone[8].

    The PACE Trial was part funded by the UK Department of Work and Pensions, a rare move for them, presumably done due to an expectation that the therapies would improve measures of employment and levels of benefit receipt. However, again CBT brought about no improvement using objective measures, such as days of employment lost, levels of disability benefits received and levels of receipt of insurance payments[9].

    These results are in line with earlier studies of CBT. For example, an analysis of three randomized controlled trials of CBT interventions for CFS found no improvement in objectively measured activity, despite participants reporting a reduction in (self-reported) fatigue and (sometimes) functional impairments[10]. Similar results were found in another uncontrolled trial where changes in objectively measured activity did not predict fatigue levels, and objectively measured activity on completion remained low compared to population norms[11]. An uncontrolled study found improvements in self-reported physical functioning and fatigue were reported despite a numerical decrease in (objectively measured) activity[12]. In another study, the level of self-reported cognitive impairment in CFS patients decreased significantly after CBT, however, cognition had not improved when it was measured objectively using neuropsychological test performance[13].

    It is unsurprising that 15 sessions of CBT (and the associated homework exercises and management program) might alter how participants respond to self-report questionnaires. A PACE Trial manual itself says “the essence of CBT is helping the participant to change their interpretation of symptoms”: this could lead to altered or biased fatigue scores, one of the two primary outcome measures[14]. Also, one of the aims of CBT (for CFS) has been said to be “increased confidence in exercise and physical activity”[15]. The possible responses for the other primary outcome measure, the SF-36 physical functioning subscale, are “yes, limited a lot”, “yes, limited a little” and “no, not limited at all” to questions on a range of physical activities. Such responses could be easily be artificially altered following a therapy like CBT for CFS.

    The results were not that different with the GET cohort in the PACE Trial. Again the manuals predicted that the impairments and symptoms are reversible using the intervention[4,15]. The model said there was no reason participants should not be able to get back to full functioning. Deconditioning was posited to be an important maintaining factor. However, GET did not result in an improvement in fitness, as measured by the step test. GET did result in a small improvement on the six minute walking test to a final distance of 379 metres, or 35 metres more than the SMC-only group[7]. However, as Knoop and Wiborg commented in an accompanying editorial in Lancet Psychiatry: “an increase in distance walked during a test situation without an increased fitness suggests that patients walk more because of a change in cognitive processes (eg, daring to do more or an increased self-efficacy with respect to activity), not because of a change in physiological capacity”[16]. The result remained very poor given that normative data would suggest a group of similar age and gender should walk an average of 644 or so metres[17]. The distance walked remained comparable to people with many serious conditions[18-21], and considerably worse than the distance walked by healthy elderly adults[22,23], despite the PACE trial cohort having a mean age of only 40[8]. Also, to be allowed entry into CFS research studies such as the PACE Trial one can not have a range of chronic illnesses so with genuine recovery one would expect results comparable to healthy people[8].

    As with CBT, measures relating to employment showed no improvement following GET in days of work missed, which remained very high, nor a reduction in levels of benefits (financial support from the state) or payments from insurance companies[9].

    These results are in line with an audit of Belgian rehabilitation centres for CFS offering CBT and GET[24-26]. Some improvements in subjective measures were found, but there was no improvement in the results of the exercise test and hours in employment actually decreased.

    Probably the main contribution of the PACE Trial has been to add to a growing body of evidence that while CBT and GET for CFS have resulted in some changes on subjective measures, they haven’t lead to improvements on objective measures.

    Competing interests: I am a committee member of the Irish ME/CFS Association and perform various types of voluntary work for the Association.

    (continues)

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    • Tom Kindlon 2015 Sep 15 09:55 a.m.

      (Contd.)

      References:

      1 Torjesen I. Tackling fears about exercise is important for ME treatment, analysis indicates. BMJ 2015;350:h227 http://www.bmj.com/content/350/bmj.h227

      2 Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry 14 Jan 2015, doi:10.1016/S2215-0366(14)00069-8.

      3 Burgess M, Chalder T. Manual for Participants. Cognitive behaviour therapy for CFS/ME.http://www.pacetrial.org/docs/cbt-participant-manual.pdf (accessed: January 17, 2015)

      4 Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME. Information for Participants http://www.pacetrial.org/docs/get-participant-manual.pdf (accessed: January 17, 2015)

      5 Wechsler ME, Kelley JM, Boyd IO, Dutile S, Marigowda G, Kirsch I, Israel E, Kaptchuk TJ. Active albuterol or placebo, sham acupuncture, or no intervention in asthma. N Engl J Med. 2011;365(2):119-26.

      6 Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramírez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA. 2001 Sep 19;286(11):1360-8.

      7 Burgess M, Chalder T. PACE manual for therapists. Cognitive behaviour therapy for CFS/ME.http://www.pacetrial.org/docs/cbt-therapist-manual.pdf (accessed: January 17, 2015)

      8 White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al, for the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-36.

      9 McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS One. 2012;7(8):e40808. doi: 10.1371/journal.pone.0040808

      10 Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychol Med. 2010 Aug;40(8):1281-7. doi: 10.1017/S0033291709992212. Epub 2010 Jan 5.

      11 Heins MJ, Knoop H, Burk WJ, Bleijenberg G. The process of cognitive behaviour therapy for chronic fatigue syndrome: which changes in perpetuating cognitions and behaviour are related to a reduction in fatigue? J Psychosom Res. 2013 Sep;75(3):235-41. doi: 10.1016/j.jpsychores.2013.06.034. Epub 2013 Jul 19.

      12 Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Apr;65(4):423-42. doi: 10.1002/jclp.20551.

      13 Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G. The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance. Journal of Neurology and Neurosurgery Psychiatry. 2007 Apr;78(4):434-6.

      14 Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME (Therapist manual): http://www.pacetrial.org/docs/get-therapist-manual.pdf (accessed: January 17, 2015)

      15 O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140.

      16 Knoop H, Wiborg JF. What makes a difference in chronic fatigue syndrome? Lancet Psychiatry 13 Jan 2015 DOI: http://dx.doi.org/10.1016/S2215-0366(14)00145-X

      17 Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME. 2011;19(2):59-111http://iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/ta…

      18 Lipkin DP, Scriven AJ, Crake T, Poole-Wilson PA. Six minute walking test for assessing exercise capacity in chronic heart failure. Br Med J (Clin Res Ed) 1986. 292:653–655.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1339640/pdf/bmjcred00224-001…

      19 Marin JM, Carrizo SJ, Gascon M, Sanchez A, Gallego B, Celli BR. Inspiratory Capacity, Dynamic Hyperinflation, Breathlessness, and Exercise Performance during the 6-Minute-Walk Test in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2001 63(6):1395-1399.http://171.66.122.149/content/163/6/1395.full

      20 Goldman MD, Marrie RA, Cohen JA. Evaluation of the six-minute walk in multiple sclerosis subjects and healthy controls. Multiple Sclerosis 2008. 14(3):383-390.http://pocketknowledge.tc.columbia.edu/home.php/viewfile/download/65399/The six-minute walk test.pdf

      21 Ross RM, Murthy JN, Wollak ID, Jackson AS. The six minute walk test accurately estimates mean peak oxygen uptake. BMC Pulm Med. 2010 May 26;10:31. PMID 20504351.http://www.biomedcentral.com/1471-2466/10/31

      22 Camarri B, Eastwood PR, Cecins NM, Thompson PJ, Jenkins S. Six minute walk distance in healthy subjects aged 55–75 years. Respir Med. 2006. 100:658-65 http://www.resmedjournal.com/article/S0954-6111(05)00326-4/abstract

      23 Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J. 1999. 14:270-4. http://www.ersj.org.uk/content/14/2/270.full.pdf

      24 Rapport d’évaluation (2002-2004) portant sur l’exécution des conventions de rééducation entre le Comité de l’assurance soins de santé (institué auprès de l’Institut national d’assurance maladie invalidité) et les Centres de référence pour le Syndrome de fatigue chronique (SFC), Bruxelles, juillet 2006. (French language edition)

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Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: To design and validate an instrument to capture the characteristic post-exertional exacerbation of fatigue in patients with chronic fatigue syndrome (CFS).

METHODS: Firstly, patients with CFS (N=19) participated in five focus group discussions to jointly explore the nature of fatigue and dynamic changes after activity, and inform development of a self-report instrument – the Fatigue and Energy Scale (FES). The psychometric properties of the FES were then examined in two case-control challenge studies: a physically-demanding challenge (moderate-intensity aerobic exercise; N=10 patients), and a cognitively-demanding challenge (simulated driving; N=11 patients). Finally, ecological validity was evaluated by recording in association with tasks of daily living (N=9).

RESULTS: Common descriptors for fatigue included ‘exhaustion’, ‘tiredness’, ‘drained of energy’, ‘heaviness in the limbs’, and ‘foggy in the head’. Based on the qualitative data, fatigue was conceptualised as consisting of ‘physical’ and ‘cognitive’ dimensions. Analysis of the psychometric properties of the FES showed good sensitivity to the changing symptoms during a post-exertional exacerbation of fatigue following both physical exercise and driving simulation challenges, as well as tasks of daily living.

CONCLUSION: The ‘fatigue’ experienced by patients with CFS covers both physical and cognitive components. The FES captured the phenomenon of a post-exertional exacerbation of fatigue commonly reported by patients with CFS. The characteristics of the symptom response to physical and cognitive challenges were similar. Both the FES and the challenge paradigms offer key tools to reliably investigate biological correlates of the dynamic changes in fatigue.

Copyright © 2015 Elsevier Inc. All rights reserved.

 

Source: Keech A, Sandler CX, Vollmer-Conna U, Cvejic E, Lloyd AR, Barry BK. Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome. J Psychosom Res. 2015 Dec;79(6):537-49. doi: 10.1016/j.jpsychores.2015.08.008. Epub 2015 Sep 2. https://www.ncbi.nlm.nih.gov/pubmed/26359713

 

Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A-adrenoceptor agonist clonidine.

METHODS: A total of 176 adolescent CFS patients (12-18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 μg or 50 μg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model.

RESULTS: A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period.

CONCLUSIONS: Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance.

TRIAL REGISTRATION: Clinical Trials ID: NCT01040429, date of registration 12/28/2009.

 

Source: Fagermoen E, Sulheim D, Winger A, Andersen AM, Gjerstad J, Godang K, Rowe PC, Saul JP, Skovlund E, Wyller VB. Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial. BMC Pediatr. 2015 Sep 10;15:117. doi: 10.1186/s12887-015-0428-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566847/ (Full article)

 

Activity Pacing Self-Management in Chronic Fatigue Syndrome: A Randomized Controlled Trial

Abstract:

OBJECTIVE: To evaluate the effectiveness of an activity pacing self-management (APSM) intervention in improving performance of daily life activities in women with chronic fatigue syndrome (CFS).

METHOD: A total of 33 women with CFS (age 41.1±11.2 yr) were randomly allocated to APSM (experimental group; n=16) or relaxation (control group; n=17). Main outcome measures included the Canadian Occupational Performance Measure (COPM; primary) and Checklist Individual Strength (CIS).

RESULTS: COPM scores changed significantly over time in both groups (p=.03). The change in Satisfaction scores showed a significant difference in favor only of APSM (effect size=0.74 [0.11, 1.4]). CIS scores decreased significantly in the experimental group only (p<.01).

CONCLUSION: APSM was found to be feasible and effective in optimizing participation in desired daily life activities in women with CFS. Replication in a larger sample with long-term follow-up is required.

Copyright © 2015 by the American Occupational Therapy Association, Inc.

 

Source: Kos D, van Eupen I, Meirte J, Van Cauwenbergh D, Moorkens G, Meeus M, Nijs J. Activity Pacing Self-Management in Chronic Fatigue Syndrome: A Randomized Controlled Trial. Am J Occup Ther. 2015 Sep-Oct;69(5):6905290020. doi: 10.5014/ajot.2015.016287. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4564796/ (Full article)