MAGENTA trial comment: ‘Targeting activity levels in ME/CFS

Michiel Tack queries some conclusions of the recently published MAGENTA trial paper.

Physical activity patterns among children and adolescents with mild-to-moderate chronic fatigue syndrome/myalgic encephalomyelitis, by Emma Solomon-Moore, Russell Jago, Lucy Beasant, Amberly Brigden, Esther Crawley in BMJ Paediatrics Open Volume 3, Issue 1, 2019

The study concludes:

  • Children and adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are less active than the general child population, but not all are inactive. 9.4% of participants met physical activity recommendations.
  • Compared with being ‘inactive’, ‘active’ children reported greater physical function but increased anxiety, while ‘lightly’ active children reported greater physical function and reduced fatigue.
  • Paediatricians need to recognise that physical activity varies between patients with CFS/ME when they recommend treatment.

Comment: Targeting activity levels in ME/CFS,  by Michiel Tack in BMJ Paediatrics Open [Published on: 15 July 2019]

Contrary to what is claimed by Solomon-Moore et al., [1] the study by Van der Werf et al., (reference 17) [2] found little evidence of a boom and bust activity pattern in adult patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The Dutch researchers measured physical activity using actimeters worn for 12 consecutive days. There was no significant difference in day-to-day fluctuations in physical activity between ME/CFS patients and controls. The peak amplitude and peak duration of physical activity were larger in controls than in ME/CFS patients while the latter had longer rest duration after an activity peak. Another actimeter study [3] found no supporting evidence of a more fluctuating activity pattern in patients with ME/CFS compared to controls, during the day, nor during consecutive days.

Now, Solomon-Moore et al. report that in children and adolescents with ME/CFS, no fluctuating active or boom-bust physical activity pattern could be identified.

It would be helpful if the authors could clarify how the actimeter data impacted the treatments in the MAGENTA trial. According to the trial protocol [4], one of the interventions aimed to “convert a boom–bust pattern of activity (lots 1 day and little the next) to a baseline with the same daily amount”. Was this aspect removed from the intervention now that participants showed little indication of a boom–bust activity pattern? Or were young ME/CFS patients instructed to correct illness behavior they did not display when tested objectively?

Solomon-Moore et al., [1] also report that 9.4% of participants achieved government recommended levels of physical activity for children and adolescents, namely a minimum of 60 minutes of moderate to vigorous physical activity per day. This is of interest given that approximately half of healthy children and adolescents do not reach this target. [1] These results indicate that activity patterns are unlikely to be a key factor in perpetuating ME/CFS symptoms, at least for this subgroup. Nonetheless, one of the interventions in the MAGENTA trial aims for a gradual increase in physical activity by prescribing exercise targets. Were ME/CFS patients who already met government health recommendations for physical activity also instructed to increase their amount of exercise by 10-20% a week or were they exempted?

I look forward to reading the authors’ response to these questions.

References

[1] Solomon-Moore E, Jago R, Beasant L, Brigden A, Crawley E. Physical activity patterns among children and adolescents with mild-to-moderate chronic fatigue syndrome/myalgic encephalomyelitis. BMJ Paediatr Open. 2019 May 2;3(1):e000425. 2019.

[2] van der Werf SP, Prins JB, Vercoulen JH, et al. Identifying physical activity patterns in chronic fatigue syndrome using actigraphic assessment. J Psychosom Res 2000;49:373–9.

[3] Meeus M, van Eupen I, van Baarle E, De Boeck V, Luyckx A, Kos D, et al. Symptom fluctuations and daily physical activity in patients with chronic fatigue syndrome: a case-control study. Arch Phys Med Rehabil. 2011 Nov;92(11):1820-6.

[4] Brigden A, Beasant L, Hollingworth W, et al. Managed activity graded exercise iN teenagers and pre-Adolescents (magenta) feasibility randomised controlled trial: study protocol. BMJ Open 2016;6:e011255.

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Intro to Mindfulness course begins in Neath, 6 Aug 2019

Introduction to mindfulness course, Neath

Location: Tonna Hospital, Pant –Y-Coed Café, Tonna Uchaf, Neath SA11 3LX
Room: Canteen
Date: Tuesday 6th, 13th & 20th August 2019
Time: 5.30 – 7.30 pm

What is Mindfulness?
Paying more attention to the present moment – to your own thoughts and feelings, and to the world around you – can improve your mental wellbeing.

Some people call this awareness “mindfulness”. Mindfulness can help us enjoy life more and understand ourselves better.

Living life well programme

The Living Life Well Programme runs this taught course which is delivered in a lecture style (not a group therapy); as such they contain no discussion of personal problems. This allows people who feel uncomfortable talking in front of others to attend without any concerns; however you are more than welcome to speak to the facilitators of the course either during the break or at the end of the sessions if you have any questions.

Open access –  turn up on the day, no need to book.

Run by Abertawe Bro Morgannwg University Health Board (ABMU)

NB  Some people with ME may find this course helpful. Please check the details carefully to make sure it is suitable for you and you are well enough to attend

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MESiG ME support group meets in Cardiff 5 Aug 2019

MESiG Support Group invites you to join them from 2 – 4 pm on Monday 5 August 2019 for tea and cake in Roath Park Cafe, Roath Park, Cardiff, CF23 5PH

It is easily accessible for those unable to walk far.  A beautiful setting. This is an opportunity to meet up with old friends and an informal setting for new folk to find out a bit more about the group.

All are welcome, please note that people with similar conditions are also welcome to come along.

 

More info: mesigwales@gmail.com      website

Next meeting: 2 September

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Acceptance, fatigue severity & self-reported physical activity in individuals with CFS/ME

Acceptance, fatigue severity and self-reported physical activity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis, by Neil Chapman, Suzanne Broadbent, Rosanne Coutts in Fatigue: Biomedicine, Health & Behavior, Volume 7, 2019, Issue 2, Pages 102-115 [Preprint June 28, 2019]

 

Abstract:

Background
Acceptance is a coping strategy associated with chronic pain management, but its effectiveness is unclear for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

Objective
The aim of the study was to investigate the relationship between acceptance, fatigue severity, pain and self-reported physical activity in individuals with CFS/ME.

Method
Ten females and seven males diagnosed with CFS/ME (51.9  p/m  8.8 years), and gender, age-matched sedentary controls, completed self-reported measures of acceptance, fatigue severity and physical activity. Acceptance was measured using the Chronic Pain Acceptance Questionnaire and Acceptance and Action Questionnaire-II. Fatigue was assessed with the Fatigue Severity Scale, and Physical Activity using the International Physical Activity Questionnaire – Short Form. Self-reported physical activity was calculated using categorical and continuous measures (MET-minutes).

Result
CFS/ME and control groups were compared using Independent t-tests and Spearman’s Rho correlations. The CFS/ME group reported significantly greater fatigue severity and psychological inflexibility, and lower pain willingness and time spent sitting than controls. However, no between-group differences for activity engagement or physical activity. The CFS/ME group showed a negative relationship between pain willingness and psychological inflexibility, and a positive relationship between walking time and the time since symptom onset, and time since diagnosis.

Conclusion
Despite reporting greater fatigue and less acceptance of their illness, CFS/ME patients had comparable levels of physical activity to controls, possibly due to pacing their activity to avoid symptom exacerbation. CFS/ME patients with an older diagnosis walked further than the newly diagnosed, suggesting the development of better coping skills and management strategies over time.

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ACTivate your life wellbeing course, Pontardawe, 5 Aug 2019

ACTivate your life courses

The course is based on Acceptance and Commitment Therapy which teaches people how to reduce their suffering and how to lead a richer, more fulfilling life by accepting the things they cannot control and making a commitment to do the things that they really care about.

We all experience suffering, pain and distress at some point in our lives, whether this be psychological or physical, so anyone and everyone is welcome to attend.

The course is run weekly over four sessions for approximately 2 hours with a break halfway through the session.

The four sessions:

  • ACT 1- You are not your mind
  • ACT 2- Facing up to your life
  • ACT 3- Being mindful
  • ACT 4- Living wisely, living well

Pontardawe

  • Trebanos Community Centre, Swansea Road, Pontardawe SA8 4BN
  • Room: Hall
  • Mondays 5th August – 2nd September 2019     2-4 pm

Self help material can be used to improve feelings of stress, low mood, anxiety and other wellbeing difficulties.

NB  Some people with ME may find this course helpful, others won’t. Please check the details carefully to make sure it is suitable for you and you are well enough to attend

The courses and workshops are free, self-referral and open access, so there is no need to book on or register, simply choose what you feel is the most suitable for you and turn up; feel free to bring someone along and spread the word. There is no attendance register, but it is recommended that you attend all of the sessions to get the most out of it, although you can always switch between courses to fit in with your commitments.

For more information contact the Living Life Well programme at Abertawe Bro Morgannwg Health Board.       07967612246      living.lifewell@wales.nhs.uk

Self help material can be used to improve feelings of stress, low mood, anxiety and other wellbeing difficulties.

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Advances in understanding the pathophysiology of CFS

Advances in understanding the pathophysiology of Chronic Fatigue Syndrome, by Anthony L Komaroff in JAMA [Preprint July 5, 2019]

 

Viewpoint extracts:

When does an illness become a disease? When the underlying biological abnormalities that cause the symptoms and signs of the illness are clarified.

The illness now called myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) was first described in the mid-1980s. At that time, nothing was known about its underlying biology. Indeed, because many
standard laboratory test results were normal, some clinicians explained to patients that ‘there is nothing wrong.’ There was, of course, an alternative explanation: the standard laboratory tests might not have been the right tests to identify the underlying abnormalities.

Over the past 35 years, thousands of studies from laboratories in many countries have documented underlying biological abnormalities involving many organ systems in patients with ME/CFS, compared with healthy controls: in short, there is something wrong.  Moreover, most of the abnormalities are not detected by standard laboratory tests. In 2015, the Institute of Medicine of the National Academy of Sciences concluded that ME/CFS ‘is a serious, chronic, complex systemic disease that often can profoundly affect the lives of patients,’ affects up to an estimated 2.5 million people in the United States, and generates direct and indirect expenses of approximately $17 billion to $24 billion annually…

A 2-day conference at the NIH in April 2019 highlighted recent progress. New research was presented that both reinforced and expanded on previous reports. Equally important, several plausible models were proposed that could explain many of the abnormalities that have been described.

The Central and Autonomic Nervous System

Metabolic Changes

Immunologic Changes

Provocation Studies

Potential Unifying Models

Conclusions

A great deal more is known today than 35 years ago about the underlying biology of ME/CFS. It is clear that many biological measurements clearly distinguish patients with ME/CFS from healthy control individuals.

At the same time, some areas of ME/CFS research remain a challenge, and research has not yet given practicing physicians 2 important tools. First, there are as yet no US Food and Drug Administration-approved treatments. Second, although various biological measurements distinguish patients with ME/CFS from healthy controls, none yet have demonstrated the high sensitivity and specificity required for a good diagnostic test. However, 1 small study (20 cases and 20 controls) described at the NIH conference (and recently published9) reported perfect sensitivity; the specificity of the test in individuals with other fatiguing illnesses remains to be shown.

With growing international interest in the illness, and increased research support from the NIH, the day is coming when physicians will be able to explain to patients not only that there is something wrong but also that advances in understanding the pathophysiology have led to effective therapy.

Read full article

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ME Support Group meets in Montgomery 24 July 2019

You are invited to join people with ME and their carers for a chat and a cuppa at the Dragon Hotel, Montgomery, Powys on Wednesday 24 July 2019 between 2.30 and 3.30pm.

Contact Donna Teague beforehand to confirm the meeting is going ahead.  dateague@hotmail.co.uk

Next meeting:   21 August 2019

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Pathological mechanisms underlying ME/CFS

Pathological mechanisms underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Daniel Missailidis, Sarah Annesley, Paul Fisher in Preprints  [Published  online: 16 July 2019] doi: 10.20944/preprints201907.0196.v1

 

Review abstract

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems.

This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems.

Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition.

Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

Conclusion

ME/CFS is a heterogeneous condition that may encompass scenarios where uncertain, and possibly varying, underlying insults trigger body-wide molecular and cellular perturbations perpetuated by alternative, stable homeostatic states. Diagnostic advancement and the development of tools which objectively and accurately phenotype patients is therefore paramount for the development of mechanistic insight and effective therapeutics.

It is likely that the inflammation and immune dysfunction classically studied in ME/CFS are entangled with dysfunctional energetics, gut health, or autonomic and adrenal dysregulation. The evidence for metabolic and mitochondrial dysfunction indicates inefficient respiration, impaired provision of TCA cycle substrate, and metabolic shifts towards the utilization of alternative metabolites.

Immune effector cell dysfunction, chronic inflammation, defective signalling and elevated oxidative stress may interact with not only the dysfunctional energetics but also with abnormal gut physiology and microbiota composition. These effects on the gut may also tie back to mitochondrial function and vice versa.

The reciprocal interactions between these affected systems and the varied clinical presentation of relevant symptoms between individuals make it difficult to postulate cause-effect relationships with confidence. Furthermore, while disturbances to this range of interconnected systems across the body have been demonstrated, in some cases concurrently, this body of research has historically relied upon correlations, which creates the urgent need for research utilising direct experimental investigation of cause-effect relationships.

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Current research provides insight into the biological basis & diagnostic potential for ME/CFS

Current research provides insight into the biological basis and diagnostic potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), by Eiren Sweetman, Alex Noble, Christina Edgar, Angus Mackay, Amber Helliwell, Rosamund Vallings, Margaret Ryan and Warren Tate in Diagnostics 2019, 9(3), 73; [https://doi.org/10.3390/diagnostics9030073]

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person.

ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians. There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness.

Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2-3 years that promise new leads towards an effective clinical diagnostic test that may have a general application.

Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness.

These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.

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Red blood cell biomechanics in CFS

Red blood cell biomechanics in Chronic Fatigue Syndrome, by Amit K Saha, Brendan R Schmidt, Arun Kumar, Amir Saadat, Vineeth C Suja, Vy Nguyen, Justin K Do, Wendy Ho, Mohsen Nemat-Gorgani, Eric SG Shaqfeh, Anand K Ramasubramanian, Ronald W Davis in Summer Biomechanics, Bioengineering and Biotransport Conference papers, June 25 -28, Seven Springs, PA, USA, SB3C2019-221  [Published July 1, 2019]

 

Introduction:

Chronic Fatigue Syndrome (CFS) is a multi-systemic illness of unknown etiology, affecting millions worldwide, with the capacity to persist for several years. It is characterized by persistent or relapsing unexplained fatigue of at least 6 months’ duration that is not alleviated by rest.

CFS can be debilitating, and its clinical definition includes a broad cluster of symptoms and signs that give it its distinct character, and its diagnosis is based on these characteristic symptom patterns including cognitive impairment, post-exertional malaise, unrefreshing sleep, headache, hypersensitivity to noise, light or certain food items.

Although an abnormal profile of circulating proinflammatory cytokines, and the presence of chronic oxidative and nitrosative stresses have been identified and correlated with severity in CFS, there are no reliable molecular or cellular biomarkers of the disease.

In the present work, we focus on the pathophysiological changes in red blood cells (RBCs) since CFS is a systemic disease rather than of a particular organ or tissue, and RBCs, comprising ~45% of blood volume, are responsible for microvascular perfusion and tissue oxygenation.

RBCs deform and travel through microvessels smaller than their diameter to facilitate the optimal transfer of gases between blood and tissue. The usual shape of a RBC is a biconcave discoid, which is changed to an ellipsoid due to shear flow. This shape gives them a specific surface area-to-volume ratio which facilitates large reversible deformations and elastic transformation [3].

We used a high throughput microfluidic platform to assess the changes in RBC deformability between CFS patients and matching healthy controls. We also performed computational studies to have a better understanding of the cell deformation. In order to explore the mechanisms for observed changes in cell deformability, we explored the membrane fluidity, reactive oxygen species, and surface charge, of RBCs.

Erythrocyte deformability refers to the ability of erythrocytes (red blood cells, RBC) to change shape under a given level of applied stress, without hemolysing (rupturing). Wikipedia

Discussion:

Together, the various estimates show that the RBCs in CFS patients are significantly less deformable than those of healthy controls. We speculate that the larger and less deformable RBCs in CFS patients may partly explain the musculoskeletal pain and fatigue in the pathophysiology of CFS due to impaired microvascular perfusion and tissue oxygenation.

It has been shown that the quality of life of ME/CFS patients was significantly worse as compared to patients with diseases like sclerosis, cancer (multiple types, such as colon, breast and prostate), type II diabetes, rheumatoid arthritis and chronic renal failure, among others.

This work introduces a new paradigm in our understanding of the mechanistic aspects of ME/CFS. It also opens the possibility of a diagnostic platform for ME/CFS using RBC deformability as the biomarker.

 

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