Q. What is ME?
A. There is an uneven blood flow to the brain. The brain then sends altered signals to the body and the body reacts abnormally to physical & mental stimuli.
![ME-CFS-Awarenes-May-12th-by-Abbey-Wilkins[1]](https://i0.wp.com/wames.org.uk/cms-english/wp-content/uploads/2016/05/ME-CFS-Awarenes-May-12th-by-Abbey-Wilkins1.jpg?resize=851%2C315)
ME Awareness week 2016: 11-17 May
ME Awareness day: 12 May
Awareness and fundraising activities will be taking place around the world during the month of May. Tell us what you are doing and how you would answer the question: What is ME?
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is comparable to multiple sclerosis, diabetes or rheumatoid arthritis in prevalence (∼0.2% to 1%), long-term disability, and quality of life,[1–5] yet the scale of biomedical research and funding has been pitifully limited, as the recent National Institutes of Health (NIH) and Institute of Medicine reports highlight.[6]
Recently in the USA, NIH Director Francis Collins has stated that the NIH will be ramping up its efforts and levels of funding for ME/CFS,[8] which we hope will greatly increase the interest in, and resources for researching this illness. Despite scant funding to date, researchers in the field have generated promising leads that throw light on this previously baffling illness. We suggest the key elements of a concerted research programme and call on the wider biomedical research community to actively target this condition.
[The article outlines biological questions, potential models and a discussion of practicalities.]
The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem, by Jonathan C.W. Edwards, Simon McGrath, Adrian Baldwin, Mark Livingstone & Andrew Kewley
a) Division of Medicine, University College London, London, UK
b) Monmouth, UK
c) Bristol, UK
d) Cognac, France
e) Adelaide, Australia
in Fatigue: Biomedicine, Health & Behavior, published online 28 April 2016
The Phoenix Rising forum provided facilities for these authors to collaborate on this editorial.
Q. What is ME?
A. It is an injury to the Central Nervous System, (which controls how the body works) that is usually triggered by an infectious disease process, e.g. a virus, or by chemicals over stimulating the immune system.
![bm0tunoimaavnh2-1[1]](https://i0.wp.com/wames.org.uk/cms-english/wp-content/uploads/2016/05/bm0tunoimaavnh2-11-300x152.jpg?resize=300%2C152)
ME Awareness week 2016: 11-17 May
ME Awareness day: 12 May
Awareness and fundraising activities will be taking place around the world during the month of May. Tell us what you are doing and how you would answer the question: What is ME?
Q. What is ME?
A. ME can be called a “neuro- immune-endocrine” condition because it affects many of the body’s systems. (Classified by the WHO as neurological)
ME Awareness week 2016: 11-17 May
ME Awareness day: 12 May
Awareness and fundraising activities will be taking place around the world during the month of May. Tell us what you are doing and how you would answer the question: What is ME?
PURPOSE:
There is increasing evidence of immune system dysfunction in Chronic Fatigue Syndrome (CFS) but little is known of the regular exercise effects on immune cell parameters. This pilot study investigated the effects of graded and intermittent exercise on CD4 lymphocyte subset counts and activation compared to usual care.
METHODS
24 CFS patients (50.2 ± 10 yr) were randomised to Graded exercise (GE), Intermittent exercise (IE) or usual care (UC) groups; 18 sedentary non-CFS participants (50.6 ± 10 yr) were controls (CTL) for blood and immunological comparisons.
Outcome measures were pre- and post-intervention flow cytometric analyses of circulating lymphocyte subset cell counts, expression of CD3, CD4, CD25 and CD134, full blood counts and V[Combining Dot Above]O2peak
RESULTS
Pre-intervention, CD3 cell counts and expression of CD4, CD25, CD134 and CD4CD25CD134 were significantly lower in GE, IE and UC compared to CTL (f < 0.05). Total lymphocyte concentration was significantly lower in GE and IE groups compared to CTL.
There were significant post-intervention increases in (i) expression of CD4 and CD4CD25CD134 for GE and IE, but CD25 and CD134 for IE only; (ii) circulating counts of CD3 and CD4 for GE, and CD3, CD4, CD8, CD3CD4CD8, CD3CD16CD56, CD19 and CD45 for IE; (iii) neutrophil concentration for GE; (iv) V[Combining Dot Above]O2peak and elapsed test time for IE and GE, V[Combining Dot Above]Epeak for IE.
CONCLUSIONS
Twelve weeks of GE and IE training significantly improved CD4 lymphocyte activation and aerobic capacity without exacerbating CFS symptoms. IE may be a more effective exercise modality with regard to enhanced CD4 activation in CFS patients.
Graded vs Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue Syndrome, by S Broadbent, R Coutts in Medicine & Science in Sports & Exercise, April 26, 2016
Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR).
In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring.
We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS.
Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter.
Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations.
This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.
Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome, by LR Barnden, R Kwiatek, B Crouch, R Burnet, P Del Fante in Neuroimage Clin. 2016 Mar 31;11:530-7
Thesis abstract:
There is growing recognition in psychology that wellness is more than the absence of disease and distress. Well-being has been defined in numerous ways. Two dominant models include Diener, Eunkook, Suh, Lucas & Smith’s (1999) Hedonic model of Subjective Well-Being (SWB) and Ryff’s (1989) Eudiamonic model of Psychological Well-Being (PWB). There has been insufficient research into positive mental processes and well-being in Chronic Fatigue Syndrome (CFS), in contrast to the abundance of research emphasising psychopathology and dysfunction.
This study’s first aim was to examine PWB and SWB and their relationship to symptoms in
individuals with CFS (N = 60). Participants completed self-report scales of PWB, SWB, fatigue, pain, anxiety and depression.
The second aim was to compare PWB scores in a subgroup of the CFS sample (N=42) to a
matched non-clinical control group (N=42). Correlations between scales of symptoms and well-being were found to be complex. Well-being dimensions were largely independent of physical symptoms (Pain intensity, Physical Fatigue, Reduced Activity and General Fatigue) but strongly related to psychological components of fatigue (Mental Fatigue
and Reduced Motivation) and psychological distress (Depression and Anxiety).
Multiple regression analyses indicated that five dimensions of well-being uniquely predicted symptomatology in CFS. Compared to the control group, the CFS group scored significantly lower on five of Ryff ‘s six PWB dimensions, with particularly marked deficits in Personal Growth, Environmental Mastery and Self-Acceptance.
No significant difference was found between the CFS and control groups on the Autonomy
subscale. This multi-dimensional assessment of well-being advances our understanding of CFS; it highlights the burden of CFS beyond symptoms, challenges the over emphasis on maladaptive cognitive and personality traits in previous research and offers several new treatment targets.
Future research must investigate whether interventions targeting these well-being deficits can boost the efficacy of symptom focused treatments, which currently produce unsatisfactory recovery rates in this client group.
Well-being in Chronic Fatigue Syndrome: Relationship to symptoms and psychological distress, by Hannah Jackson. Research submitted in partial fulfillment of the requirements for the degree of Doctor in Clinical Psychology, Royal Holloway, University of London, June 2015
Contains post-mortem results of somebody who had the diagnosis of “post viral syndrome”
BACKGROUND:
In a previous study of a Q fever outbreak in Birmingham, our group identified a non-infective complex of Coxiella burnetii (C.b.) antigens able to survive in the host and provoked aberrant humoral and cell-mediated immunity responses.
The study led to recognition of a possible pathogenic link between C.b. infection and subsequent long-term post Q fever fatigue syndrome (QFS).
This report presents an unusually severe case of C.b. antigen and DNA detection in post-mortem specimens from a patient with QFS.
CASE PRESENTATION:
We report a 19-year old female patient who became ill with an acute unexplained febrile encephalitis-like illness, followed by increasingly severe multisystem dysfunction and death 10 years later.
During life, extensive clinical and laboratory investigations from different disciplinary stand points failed to deliver a definitive identification of a cause.
Given the history of susceptibility to infection from birth, acute fever and the diagnosis of “post viral syndrome”, tests for infective agents were done starting with C.b. and Legionella pneumophila.
The patient had previously visited farms a number of times.
Comprehensive neuropathological assessment at the time of autopsy had not revealed gross or microscopic abnormalities.
The aim was to extend detailed studies with the post-mortem samples and identify possible factors driving severe disturbance of homeostasis and organ dysfunction exhibited by the course of the patient’s ten-year illness.
Immunohistochemistry for C.b. antigen and PCR for DNA were tested on paraffin embedded blocks of autopsy tissues from brain, spleen, liver, lymph nodes (LN), bone marrow (BM), heart and lung. Standard H&E staining of brain sections was unrevealing.
Immuno-staining analysis for astrocyte cytoskeleton proteins using glial fibrillary acidic protein (GFAP) antibodies showed a reactive morphology.
Coxiella antigens were demonstrated in GFAP immuno-positive grey and white matter astrocytes, spleen, liver, heart, BM and LN. PCR analysis (COM1/IS1111 genes) confirmed the presence of C.b. DNA in heart, lung, spleen, liver & LN, but not in brain or BM.
CONCLUSION:
The study revealed the persistence of C. b. cell components in various organs, including astrocytes of the brain, in a post-infection QFS.
The possible mechanisms and molecular adaptations for this alternative C.b. life style are discussed.
Funding: The authors are grateful to Mrs C. Hunter and Alison Hunter Memorial Foundation in Partnership with the National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffith University, Queensland, Australia for generous financial support of this.
Coxiella burnetii dormancy in a fatal ten-year multisystem dysfunctional illness: case report, by Olga A. Sukocheva, Jim Manavis, Tuck-Weng Kok, Mark Turra, Angelo Izzo,
Peter Blumbergs and Barrie P. Marmion in BMC Infect Dis. 2016 Apr 18;16(1):165
Chronic fatigue syndrome (CFS) is a debilitating illness, but it is unclear if patient age and illness duration might affect symptoms and functioning of patients.
In the current study, participants were categorized into four groups based upon age (under or over age 55) and illness duration (more or less than 10 years). The groups were compared on functioning and symptoms.
Findings indicated that those who were older with a longer illness duration had significantly higher levels of mental health functioning than those who were younger with a shorter or longer illness duration and the older group with a shorter illness duration.
The results suggest that older patients with an illness duration of over 10 years have significantly higher levels of mental health functioning than the three other groups. For symptoms, the younger/longer illness duration group had significantly worse immune and
autonomic domains than the older/longer illness group. In addition, the younger patients with a longer illness duration displayed greater autonomic and immune symptoms in comparison to the older group with a longer illness duration.
These findings suggest that both age and illness duration need to be considered when trying to understand the influence of these factors on patients.
The relationship between age and illness duration in Chronic Fatigue Syndrome, by Elizabeth Kidd, Abigail Brown, Stephanie McManimen, Leonard A. Jason, Julia L. Newton, Elin Bolle Strand in Diagnostics Vol. 6, #2, page 16 [Published: 22 April 2016]
Blog post by Prof James C Coyne, 23 April 2016: Probing an untrustworthy Cochrane review of exercise for “chronic fatigue syndrome”
From my work in progress:
My ongoing investigation so far has revealed that the 2016 Cochrane review misrepresents what was done and what was found in a key meta analysis . These problems are related to an undeclared conflict of interest.
The first author and spokesperson for the review, Lillebeth Larun was also the first author on the protocol for a Cochrane review that is not-yet published.
Larun L, Odgaard-Jensen J, Brurberg KG, Chalder T, Dybwad M, Moss-Morris RE, Sharpe M, Wallman K, Wearden A, White PD, Glasziou PP.
Exercise therapy for chronic fatigue syndrome (individual patient
data) (Protocol). Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD011040.
At a meeting organized and financed by PACE investigator Peter White, Larun obtained privileged access to data that the PACE investigators have spent tens of thousands of pounds to keep most of us from viewing. Larun used this information to legitimize outcome switching or p-hacking favorable to the PACE investigators’ interests. The Cochrane review misled readers in presenting how some analyses were conducted that were crucial to its conclusions.
One of the crucial function of Cochrane reviews is to protect policymakers, clinicians, researchers, and patients from the questionable research practices utilized by trial investigators to promote particular interpretation of their results. This Cochrane review fails miserably in this respect. The Cochrane is complicit in endorsing the PACE investigators’ misinterpretation of their findings.
A number of remedies should be implemented. The first could be for Cochrane Editor in Chief and Deputy Chief Director Dr. David Tovey to call publicly for release for independent reanalysis of the PACE trial data from The Lancet original outcomes paper and the follow-up data reported in Lancet Psychiatry.
Given the breach in trust with the readership of Cochrane that has occurred, Dr. Tovey should announce that the individual patient-level data used in the ongoing review will be released for independent re-analysis.
Larun should be removed from the Cochrane review that is in progress. She should recuse herself from further comment on the 2016 review. Her misrepresentations and comments thus far have tarnished the Cochrane’s reputation for unbiased assessment and correction when mistakes are made.
An expression of concern should be posted for the 2016 review.
The 2016 Cochrane review of exercise for chronic fatigue syndrome:
Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2016; CD003200.
Added only three studies that not included in a 2004 Cochrane review of five studies:
Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, et al. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ 2010; 340 (1777):1–12. [DOI: 10.1136/bmj.c1777]
Hlavaty LE, Brown MM, Jason LA. The effect of homework compliance on treatment outcomes for participants with myalgic encephalomyelitis/chronic fatigue syndrome. Rehabilitation Psychology 2011;56(3):212–8.
White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 2011; 377:611–90.
This blog post concentrates on a sub analysis that is crucial to the conclusions of the 2016 review reported on page 68. I welcome others to extend this scrutiny to other analyses in the review, especially that for the SF-36.
Analysis 1.1. Comparison 1 Exercise therapy versus treatment as usual, relaxation or flexibility, Outcome 1 Fatigue (end of treatment).
The only sub analysis that involves new studies includes Wearden et al FINE trial, White et al PACE trial and an earlier study, Powell et al. The meta-analysis gives 27.2% weight to Wearden et al and 62.9% weight to White et al.
https://jcoynester.files.wordpress.com/2016/04/wearden-selective-reporting.png?w=615
Inclusion of the Wearden et al FINE trial in the meta-analysis
Concerning Wearden et al, the Cochrane review states on page 49:
This is untrue.
Cochrane used a ‘Likert’ scoring method (0,1,2,3), but the original Wearden et al. paper reports using the…
11 item Chalder et al fatigue scale,19 where lower scores indicate better outcomes. Each item on the fatigue scale was scored dichotomously on a four point scale (0, 0, 1, or 1).
This would seem a trivial difference, but this outcome switching will take on increasing importance as we proceed.
Based on a tip from Robert Courtney. I found the first mention of a re-scoring of the Chalder fatigue scale in the Weardon study in a BMJ Rapid Response:
Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, et al. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ, Rapid Response 27 May 2010.
The excuse that was offered for the rescoring in the Rapid Response was:
“Following Bart Stouten’s suggestion that scoring the Chalder fatigue scale (1) 0123 might more reliably demonstrate the effects of pragmatic rehabilitation, we recalculated our fatigue scale scores.”
“Might reliably demonstrate…”? Where I come from, we call this outcome switching, p-hacking, a questionable research practice, or simply cheating.
In the original reporting of the trial, effects of exercise were not significant at follow-up. With the rescoring of the Chalder fatigue scale, these results are now significant.
Inclusion of the White et al PACE trial in the meta-analysis
A physician who suffers from myalgic encephalomyelitis (ME) – what both the PACE investigators and Cochrane review term “chronic fatigue syndrome” – sent me the following comment:
I have recently published a review of the PACE trial and follow-up articles and according to the Chalder Fatigue Questionnaire, when using the original bimodal scoring I only score 4 points, meaning I was not ill enough to enter the trial, despite being bedridden with severe ME. After changing the score in the middle of the trial to Likert scoring, the same answers mean I suddenly score the minimum number of 18 to be eligible for the trial yet that same score of 18 also meant that without receiving any treatment or any change to my medical situation I was also classed as recovered on the Chalder Fatigue Questionnaire, one of the two primary outcomes of the PACE trial.
So according to the PACE trial, despite being bedridden with severe ME, I was not ill enough to take part, ill enough to take part and recovered all 3 at the same time …
Yet according to Larun et al. there’s nothing wrong with the PACE trial.
Inclusion of the White et al PACE trial in the meta-analysis
Results of the Wearden et al FINE trial were available to the PACE investigators when they performed the controversial switching of outcomes for their trial. This should be taken into account in interpreting Larun’s defense of the PACE investigators in response to a comment from Tom Kindlon. She stated:
You particularly mention the risk of bias in the PACE trial regarding not providing pre-specified outcomes however the trial did pre-specify the analysis of outcomes. The primary outcomes were the same as in the original protocol, although the scoring method of one was changed and the analysis of assessing efficacy also changed from the original protocol. These changes were made as part of the detailed statistical analysis plan (itself published in full), which had been promised in the original protocol. These changes were drawn up before the analysis commenced and before examining any outcome data. In other words they were pre-specified, so it is hard to understand how the changes contributed to any potential bias.
I think that what we have seen here so far gives us good reason to side with Tom Kindlon versus Lillebeth Larun on this point.
Also relevant is an excellent PubMed Commons comment by Sam Carter, Exploring changes to PACE trial outcome measures using anonymised data from the FINE trial. His observations about the Chalder fatigue questionnaire:
White et al wrote that “we changed the original bimodal scoring of the Chalder fatigue questionnaire (range 0–11) to Likert scoring to more sensitively test our hypotheses of effectiveness” (1). However, data from the FINE trial show that Likert and bimodal scores are often contradictory and thus call into question White et al’s assumption that Likert scoring is necessarily more sensitive than bimodal scoring.
For example, of the 33 FINE trial participants who met the post-hoc PACE trial recovery threshold for fatigue at week 20 (Likert CFQ score ≤ 18), 10 had a bimodal CFQ score ≥ 6 so would still be fatigued enough to enter the PACE trial and 16 had a bimodal CFQ score ≥ 4 which is the accepted definition of abnormal fatigue.
Therefore, for this cohort, if a person met the PACE trial post-hoc recovery threshold for fatigue at week 20 they had approximately a 50% chance of still having abnormal levels of fatigue and a 30% chance of being fatigued enough to enter the PACE trial.
A further problem with the Chalder fatigue questionnaire is illustrated by the observation that the bimodal score and Likert score of 10 participants moved in opposite directions at consecutive assessments i.e. one scoring system showed improvement whilst the other showed deterioration.
Moreover, it can be seen that some FINE trial participants were confused by the wording of the questionnaire itself. For example, a healthy person should have a Likert score of 11 out of 33, yet 17 participants recorded a Likert CFQ score of 10 or less at some point (i.e. they reported less fatigue than a healthy person), and 5 participants recorded a Likert CFQ score of 0.
The discordance between Likert and bimodal scores and the marked increase in those meeting post-hoc recovery thresholds suggest that White et al’s deviation from their protocol-specified analysis is likely to have profoundly affected the reported efficacy of the PACE trial interventions.
Compare White et al.’s “more sensitively test our hypotheses” to Weardon et al.’s ““might reliably demonstrate…” explanation for switching outcomes.
A correction is needed to this assessment of risk of bias in the review for the White et al PACE trial.
A figure on page 68 shows results of a subanalysis with the switched outcomes at the end of treatment.
This meta analyses concludes that exercise therapy produced an almost 3 point drop in fatigue on the rescored Chalder scale at the end of treatment.
Analysis 1.2. Comparison 1 Exercise therapy versus treatment as usual, relaxation or flexibility, Outcome 2 Fatigue (follow-up).
A table on page 69 shows results of a subanalysis with the switched outcomes at follow up:
This meta analysis entirely depends on the revised scoring of the Chalder fatigue scale and the FINE and PACE trial. It suggests that the three point drop in fatigue persists at followup.
But Cochrane should have stuck with the original primary outcomes specified in the original trial registrations. That would have been consistent what with the Cochrane usually does, what is says it did here, and what its readers expect.
Readers were not at the meeting that the PACE investigators financed and cannot get access to the data on which the Cochrane review depends. So they depend on Cochrane as a trusted source.
I am sure the results would be different if the expected and appropriate procedures had been followed. Cochrane should alert readers with an Expression of Concern until the record can be corrected or the review retracted.
Now what?
it too much to ask that Cochrane get out of bed with the PACE investigators?
What would Bill Silverman say? Rather than speculate about someone who neither Dr.Tovey or I have ever met, I ask Dr Tovey “What would Lisa Bero say?”
