Tag: 2015

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)

      25 Evaluatierapport (2002-2004) met betrekking tot de uitvoering van de revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging (ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra voor het Chronisch vermoeidheidssyndroom (CVS). 2006. Available online:https://drive.google.com/file/d/0BxnVj9ZqRgk0QTVsU2NNLWJSblU/edit (accessed: January 17, 2015) (Dutch language version)

      26 Stordeur S, Thiry N, Eyssen M. Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie. Health Services Research (HSR). Brussel: Federaal Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE reports 88A (D/2008/10.273/58)https://kce.fgov.be/sites/default/files/page_documents/d20081027358.pdf (accessed: January 17, 2015)

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)

 

Chronic Fatigue Syndrome versus Systemic Exertion Intolerance Disease

Abstract:

BACKGROUND: The Institute of Medicine has recommended a change in the name and criteria for Chronic Fatigue Syndrome (CFS), renaming the illness Systemic Exertion Intolerance Disease (SEID). The new SEID case definition requires substantial reductions or impairments in the ability to engage in pre-illness activities, unrefreshing sleep, post-exertional malaise, and either cognitive impairment or orthostatic intolerance.

PURPOSE: In the current study, samples were generated through several different methods and were used to compare this new case definition to previous case definitions for CFS, Myalgic Encephalomyelitis (ME-ICC), Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), as well as a case definition developed through empirical methods.

METHODS: We used a cross-sectional design with samples from tertiary care settings, a biobank sample, and other forums. 796 patients from the US, Great Britain, and Norway completed the DePaul Symptom Questionnaire.

RESULTS: Findings indicated that the SEID criteria identified 88% of participants in the samples analyzed, which is comparable to the 92% that met the Fukuda criteria. The SEID case definition was compared to a four item empiric criteria, and findings indicated that the four item empiric criteria identified a smaller, more functionally limited and symptomatic group of patients.

CONCLUSION: The recently developed SEID criteria appears to identify a group comparable in size to the Fukuda et al. criteria, but a larger group of patients than the Canadian ME/CFS and ME criteria, and selects more patients who have less impairment and fewer symptoms than a four item empiric criteria.

 

Source: Jason LA, Sunnquist M, Brown A, Newton JL, Strand EB, Vernon SD. Chronic Fatigue Syndrome versus Systemic Exertion Intolerance Disease. Fatigue. 2015 Jul;3(3):127-141. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556426/ (Full article)

 

Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial

Abstract:

Milnacipran, a serotonin/norepinephrine reuptake inhibitor, has been approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that a) similar to patients with chronic fatigue syndrome, patients with FM have increased ventricular lactate levels at baseline; b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared with baseline levels and with ventricular lactate levels after placebo; and c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared with placebo. In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging was found to be higher in patients with FM than in healthy controls (F1,37 = 22.11, P < .0001, partial η(2) = .37). Milnacipran reduced pain in patients with FM relative to placebo but had no effect on cognitive processing.

At the end of the study, ventricular lactate levels in the milnacipran-treated group had decreased significantly compared with baseline and after placebo (F1,18 = 8.18, P = .01, partial η(2) = .31). A significantly larger proportion of patients treated with milnacipran showed decreases in both ventricular lactate and pain than those treated with placebo (P = .03). These results suggest that proton magnetic resonance spectroscopic imaging measurements of lactate may serve as a potential biomarker for a therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation.

PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate levels compared with those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01108731.

Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

 

Source: Natelson BH, Vu D, Mao X, Weiduschat N, Togo F, Lange G, Blate M, Kang G, Coplan JD, Shungu DC. Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial. J Pain. 2015 Nov;16(11):1211-9. doi: 10.1016/j.jpain.2015.08.004. Epub 2015 Aug 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630071/ (Full article)

 

The impact of chronic fatigue syndrome on cognitive functioning in adolescents

Abstract:

Chronic fatigue syndrome (CFS) is characterized by persistent fatigue and severe disability. Most adolescent patients report attention and concentration problems, with subsequent poor performance at school. This study investigated the impact of CFS on intellectual capacity by (1) assessing discrepancies between current intelligence quotient (IQ) and school level and (2) exploring differences in current IQ and pre-CFS school performance, compared with healthy individuals. Current data was cross-sectionally gathered and compared with retrospective pre-CFS school performance data. Fifty-nine CFS adolescents and 40 controls were evaluated on performance on age-appropriate intelligence tests and school level. Current IQ scores of CFS adolescents were lower than expected on the basis of their school level. Furthermore, there was a difference in intelligence performance across time when current IQ scores were compared with pre-CFS cognitive achievement. Healthy controls did not show any discrepancies.

CONCLUSION: According to their pre-CFS intelligence assessments, CFS patients started with appropriate secondary school levels at the age of 12. Our data suggest that CFS may be accompanied by a decline in general cognitive functioning. Given the critical age for intellectual development, we recommend a timely diagnosis followed by appropriate treatment of CFS in adolescents.

WHAT IS KNOWN: Adolescent chronic fatigue syndrome (CFS) is a debilitating condition with major impact on social and intellectual development. Most patients report concentration problems, with subsequent poor performance at school. Little is known about the influence of CFS on intellectual performances.

WHAT IS NEW: IQ scores of CFS adolescents are lower than the IQ scores of healthy peers with an equivalent school level. There is a decrease in intelligence performance across time when current IQ scores are compared with pre-CFS cognitive achievement. Healthy controls do not show any discrepancies between their current IQ, school level and previous cognitive functioning. This suggest that adolescent CFS may be accompanied by a decline in general cognitive functioning.

 

Source: Nijhof LN, Nijhof SL, Bleijenberg G, Stellato RK, Kimpen JL, Hulshoff Pol HE, van de Putte EM. The impact of chronic fatigue syndrome on cognitive functioning in adolescents. Eur J Pediatr. 2016 Feb;175(2):245-52. doi: 10.1007/s00431-015-2626-1. Epub 2015 Sep 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724362/ (Full article)

 

Mitoprotective dietary approaches for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Caloric restriction, fasting, and ketogenic diets

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is an idiopathic illness characterized by debilitating fatigue and neuro-immune abnormalities. A growing body of evidence proposes mitochondrial dysfunction as a central perpetrator of the illness due to activation of immune-inflammatory pathways that burden the mitochondria.

Under a model of mitochondrial dysfunction, this paper explores dietary strategies that are mitoprotective. Studied for decades, the cellular mechanisms of ketogenic diets, fasting, and caloric restriction now reveal mitochondria-specific mechanisms which could play a role in symptom reduction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Future research should examine the physiological effects of these dietary strategies in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Copyright © 2015 Elsevier Ltd. All rights reserved.

 

Source: Craig C. Mitoprotective dietary approaches for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Caloric restriction, fasting, and ketogenic diets. Med Hypotheses. 2015 Nov;85(5):690-3. doi: 10.1016/j.mehy.2015.08.013. Epub 2015 Aug 21. https://www.ncbi.nlm.nih.gov/pubmed/26315446