The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).
RESEARCH INDEX
The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.
Audio Commentary by Dr Katrina Pears
ME/CFS Research Published 10 – 16 May 2022
There have been eight new ME/CFS studies and sixteen studies on Long Covid.
I have included a range of published research this week, including a PhD thesis (paper six (6)). Several papers in this weeks roundup are not directly on ME/CFS but are related: papers four (4) and five (5) are on Functional Neurological Disorders and paper seven (7) is on the use of MitoQ for mitochondrial diseases.
We have highlighted two of the studies below:
Paper one (1) is in support of the new NICE guideline and is in response to the previously published research by Flottorp et al. who claimed that the guideline committee came to the wrong conclusion (article commissed by the Lancet).
This study reviews the studies used by Flottorp et al. which claims the efficacy of CBT and GET, concluding that they show the opposite and also show problems with the studies included, such as: the design, reporting of results (e.g. selective results, ignoring and/or not publishing the insignificant results), relying on subjective primary outcomes in non-blinded studies, extensive endpoint changes, selecting patients who didn’t have the disease under investigation or had a self-limiting disease and labelling the severely ill as recovered.
This piece of research is well presented and easy to read, including understanding which studies were included in the previous review. It is really encouraging to see a study strongly in favour of the NICE guideline dropping CBT and GET as treatments for ME/CFS. Although I am supportive of the findings in this study, I also feel it is written in a very personal way and feels a little bit like an attack on a piece of research!
Paper eight (8) is on immune dysfunction in adolescents, particularly looking at the relationship between cytokines. Cytokines are small proteins that are crucial in cell signalling, controlling the growth and activity of other immune system cells and blood cells. The study looked at the patterns of plasma cytokines in three different groups: ME/CFS, severe ME/CFS and controls.
The study reports a range of connections between the cytokines in the three different groups:
- the ME/CFS group results suggested activation of inflammatory mechanisms,
- the severe ME/CFS group shows chronic inflammation,
- these findings together suggest pro-inflammatory responses in two different ME/CFS groups studied.
Unfortunately, we cannot access the full study, so we do not know the significance of these findings between the groups, i.e. are the findings between ME/CFS and severe ME/CFS group significantly different allowing for differentiation between the groups. The findings in the abstract (summary) only talk about within the groups, therefore, we do not know how these findings will aid a biomarker. There are also other unknowns, as we also do not know how the study distinguished between ME/CFS and severe ME/CFS, as in the previous research by this group severe ME/CFS was classified where patients had not recovered at a 6- month follow-up appointment and had more than one symptom listed in the case definition (Jason et al., 2021). However, I think we are likely to see more studies of this nature from this research group which will hopefully lead to some promising findings.
ME/CFS Research References and Abstracts
Vink, M.; Vink-Niese, A.
Healthcare 2022, 10, 898.
Abstract
The British National Institute for Health and Care Excellence (NICE) recently published its updated guidelines for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
NICE concluded, after an extensive review of the literature, that graded exercise therapy (GET) is harmful and should not be used, and that cognitive behavioural therapy (CBT) is only an adjunctive and not a curative treatment.
Leading proponents of the cognitive behavioural model (CBmodel) find it difficult to accept this paradigm shift. In, for example, an article in The Lancet, they try to argue that the new NICE guideline is based on ideology instead of science.
In this article we reviewed the evidence they used to support their claims.
Our analysis shows that the trials they used in support suffered from serious flaws which included badly designed control groups, relying on subjective primary outcomes in non-blinded studies, including patients in their trials who didn’t have the disease under investigation or had a self-limiting disease, selective reporting, outcome switching and making extensive endpoint changes, which created an overlap in entry and recovery criteria, using a post-hoc definition of recovery which included the severely ill, not publishing results that contradict their own conclusion, ignoring their own (objective) null effect, etc.
The flaws in these trials all created a bias in favour of the interventions. Despite all these flaws, treatments that are said to lead to recovery in reality do not lead to objective improvement. Therefore, these studies do not support the claim that CBT and GET are effective treatments.
Moreover, the arguments that are used to claim that NICE was wrong, in reality, highlight the absence of evidence for the safety and efficacy of CBT and GET and strengthen the decision by NICE to drop CBT and GET as curative treatments for ME/CFS.
2. NICE sets out steps NHS must take to implement ME/CFS guidelines
Ingrid Torjesen
BMJ 2022;377:o1221
Abstract
The National Institute for Health and Care Excellence has issued an unprecedented implementation statement setting out the practical steps needed for its updated guideline on the diagnosis and management of myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) to be implemented by the NHS.
Such statements are only issued when a guideline is expected to have a “substantial” impact on NHS resources, and this is thought to be the first. It outlines the additional infrastructure and training that will be needed in both secondary and primary care to ensure that the updated ME/CFS guideline, published in October 2021, can be implemented.
The statement is necessary because the 2021 guideline completely reversed the original 2007 guideline recommendations that people with mild or moderate ME/CFS be treated with cognitive behavioural therapy (CBT) and graded exercise therapy (GET). Instead, the 2021 guideline says that CBT should be only offered to support patients to manage their symptoms and that any exercise programme should be overseen by an ME/CFS specialist team.
Many areas have no or very limited specialist ME/CFS services, meaning that services must be commissioned, specialist health professionals need to be trained to deliver these services, and GPs need training in how to care for their patients. “With no nationally commissioned service for ME/CFS in either primary or secondary care, it will be for local systems to determine how to structure their services to achieve the aims of the guideline,” said Paul Chrisp, director of the Centre for Guidelines at NICE.
The 2007 recommendations were overturned during a long and difficult guideline development process. Patient groups had long argued that the recommendations were inappropriate, ineffective, and potentially harmful, and hindered research into the disease. But health professionals raised concerns about the proposed guidelines and the process that underpinned them. Just weeks before the final guideline was due to be published three members of the development committee resigned, royal colleges and other professional bodies signalled that they would not support it, and NICE had to delay publication. The guideline was finally published after a meeting was arranged with stakeholders to iron out differences, but concerns among medical leaders persisted.
When the 2021 guideline was published, Charles Shepherd, honorary medical adviser of the ME Association, told The BMJ that the recommendations were “something that currently cannot be coped with.” After publication of the implementation statement, he said, “I think NICE have gone as far as they can. It is now up to individual clinical services to reposition what they do in order to comply with the recommendations and for commissioners to start setting up new clinical services where none currently exist—especially in Wales and Northern Ireland.
“A lot of people with ME/CFS are clearly not getting the medical care and support that they need in both primary care and secondary care, especially those who are severely affected and do not have access to any form of domiciliary service or a dedicated inpatient facility.” He added: “It would obviously be helpful if the royal colleges could also express their support for implementation of the changes, as it’s not clear whether they remain unhappy with the recommendations downgrading CBT and the removal of GET.”
The same day NICE published its implementation statement, Sajid Javid, health and social care secretary, announced the publication of research priorities for ME/CFS by Action for ME, a charity that supports people with ME. “We are committed to funding research into this important area,” he said. Javid and his chief scientific adviser, Lucy Chappell, will co-chair an advisory board of experts on ME/CFS, including patients, to discuss what needs to happen next and liaise with the devolved nations.
“We will be developing our own delivery plan later this year and will be working with stakeholders to understand how we can improve experiences and outcomes for people with these debilitating conditions,” he said. “At the heart of the delivery plan will be two core principles. Firstly, that we do not know enough about ME/CFS, which must change if we are to improve experiences and outcomes. Secondly, we must trust and listen to those with lived experience of ME/CFS.”
The BMJ asked three royal colleges for a response to the implementation statement, but none responded before publication.
Hughes BM, Tuller D.
J Health Psychol. 2022 Jun;27(7):1783-1789
Abstract
In a paper published in the Journal of the Royal Society of Medicine, Adamson et al. (2020) interpret data as showing that cognitive behavioural therapy leads to improvement in patients with chronic fatigue syndrome and chronic fatigue.
Their research is undermined by several methodological limitations, including: (a) sampling ambiguity; (b) weak measurement; (c) survivor bias; (d) missing data and (e) lack of a control group.
Unacknowledged sample attrition renders statements in the published Abstract misleading with regard to points of fact. That the paper was approved by peer reviewers and editors illustrates how non-rigorous editorial processes contribute to systematic publication bias.
4. Functional neurological disorder and other unexplained syndromes
Kanaan RA
The Lancet- Neurology 21 (6):499-500
Abstract
Functional neurological disorder is a syndrome of medically unexplained neurological symptoms. In The Lancet Neurology, Mark Hallett and colleagues review some of the potential explanations for functional neurological disorder and the evidence that supports these explanations.
The paper by Hallett and colleagues, however, is more than a Review: it is also a territorial claim, seeking to expand the boundaries of what should be considered functional neurological disorder. The details of this claim are unlikely to be controversial to any clinician working in the field: the presentations Hallett and colleagues describe are not new, even if they do not fall within the current classifications of the disorder. But the claim is nonetheless remarkable, as even a decade ago it would have been thought to be sheer folly. A good argument could then have been made that functional neurological disorder (or conversion disorder, as it was more formally known) was the most stigmatised of all disorders, even compared with other unexplained syndromes. What would have been the point of expanding the scope of a diagnosis that patients went to such lengths to avoid?
The expansive mood in the Review by Hallett and colleagues therefore reflects a striking transformation in the status of functional neurological disorder. Functional neurological disorder has become a diagnosis that a neurologist might be comfortable to give, and that a patient might be glad to receive.
5. Functional neurological disorder: new subtypes and shared mechanisms
Prof Mark Hallett, Selma Aybek, Prof Barbara A Dworetzky, Laura McWhirter, Prof Jeffrey P Staab, Prof Jon Stone
The Lancet- Neurology 21 (6): 537-550
Abstract
Functional neurological disorder is common in neurological practice. A new approach to the positive diagnosis of this disorder focuses on recognisable patterns of genuinely experienced symptoms and signs that show variability within the same task and between different tasks over time.
Psychological stressors are common risk factors for functional neurological disorder, but are often absent.
Four entities—functional seizures, functional movement disorders, persistent perceptual postural dizziness, and functional cognitive disorder—show similarities in aetiology and pathophysiology and are variants of a disorder at the interface between neurology and psychiatry.
All four entities have distinctive features and can be diagnosed with the support of clinical neurophysiological studies and other biomarkers. The pathophysiology of functional neurological disorder includes overactivity of the limbic system, the development of an internal symptom model as part of a predictive coding framework, and dysfunction of brain networks that gives movement the sense of voluntariness.
Evidence supports tailored multidisciplinary treatment that can involve physical and psychological therapy approaches.
Loades, M
PhD Thesis, University of Bristol
Abstract
Background: Many common mental health problems, including depression and anxiety, first emerge in adolescence. Prior work has found evidence of elevated depression and anxiety in samples of adolescents with chronic fatigue syndrome (CFS/ME).
However, this has been based on gold standard diagnostic interviews in small, self-selecting samples which may be biased or on screening questionnaires in larger, more representative samples which may be affected by symptom conflation and have not been validated for use in this population. Furthermore, few studies have investigated the prevalence of both depression and anxiety concurrently in the same adolescents with CFS/ME. Some adolescents with CFS/ME may be more likely to have co-morbid depression and/or anxiety than others and their outcomes may be different.
Identifying the demographic and clinical characteristics of those who are more likely to have co-morbid depression and/or anxiety would enable selective, targeted screening and monitoring. Negative thinking patterns are a malleable perpetuating factor in depression and anxiety. Understanding how the general and fatigue-specific negative thinking patterns of those adolescents with CFS/ME and co-morbid depression and/or anxiety compare to those with CFS/ME only would inform treatment targets.
Comparing outcomes at 6-month follow-up for those with co-morbid depression and/or anxiety to those with CFS/ME only is an important part of determining whether treatments for both CFS/ME and mental health problems need to be adapted.
My programme of work aimed to improve the identification and treatment of co-morbid depression and/or anxiety in adolescents with CFS/ME. I conducted 3 empirical studies and used the findings to inform the development of an adapted treatment for this subgroup.
Methods: Study 1: Cross-sectional clinical study using gold standard semi-structured diagnostic psychiatric diagnostic interview and screening questionnaires, N = 164 adolescents (age 12 to 18) with confirmed CFS/ME.
Study 2: Longitudinal study, 3 clinical cohorts, using questionnaire data (demographics, fatigue, functioning, depression, and anxiety symptoms) at baseline (initial clinical assessment) and 6-month follow-up, N = 490 adolescents (age 12 to 18) with confirmed CFS/ME.
Study 3: Cross-sectional study nested within the baseline of a randomised control trial, using questionnaires (depression and anxiety symptoms, general negative thinking patterns, fatigue specific thinking patterns, behavioural responses to fatigue symptoms), N = 205 adolescents (age 11 to 18) with confirmed CFS/ME.
Results: Study 1: One third of the participants met the diagnostic criteria for current depression and/or anxiety. Of these, approximately 20% met the criteria for a major depressive disorder, and 27% an anxiety disorder, with many meeting the criteria for more than one disorder concurrently. The questionnaires I tested were not sufficiently accurate for screening purposes, apart from the Revised Children's Anxiety and Depression Scale-anxiety subscale (self-report and parent versions).
Study 2: Co-morbid depression and/or anxiety symptoms were common (45.3%) and at baseline, the odds of having co-morbid depression and/or anxiety symptoms increased 1.18- fold (95% CI 1.10, 1.26, p < 0.001) for every one-point increase in baseline fatigue severity. Those with higher depression and/or anxiety symptom scores at baseline had worse fatigue severity, physical functioning, and school attendance 6 months later.
Study 3: Participants who had co-morbid depression and/or anxiety symptoms more strongly endorsed all the general negative thinking patterns than those with CFS/ME only. They also more strongly endorsed most types of unhelpful cognitive responses to fatigue, specifically damage beliefs, embarrassment avoidance, catastrophising and symptom focusing. Fear avoidance beliefs were strongly endorsed by both groups, irrespective of their co-morbid mental health status. Participants with co-morbid depression and/or anxiety symptoms also endorsed more strongly both all-or-nothing behaviours and avoidance/resting behaviours.
Conclusions: A substantial minority of adolescents with CFS/ME are likely to have co-morbid depression and/or anxiety, particularly those who are more fatigued and more impaired. They also continue to be more impaired and fatigued at follow-up.
In terms of potential treatment targets, those with comorbid depression and/or anxiety tend to endorse more negative general and fatigue-specific thinking patterns. Treatments need to be adapted for this subgroup.
My programme of work culminated in using the existing evidence and public and patient involvement from healthcare professionals and young people with lived experience of CFS/ME to describe a potential adapted treatment approach based on co-produced logic models. This approach will need to be evaluated in future and my work has laid the foundations for a clinical trial, although more work is needed.
7. Pharmacological significance of MitoQ in ameliorating mitochondria-related diseases
Lateef Adegboyega Sulaimon, Lukman Olalekan Afolabi, Rahmat Adetutu Adisa, Akinrinade George Ayankojo, Mariam Olanrewaju Afolabi, Abiodun Mohammed Adewolu, Xiaochun Wan
Advances in Redox Research, 2022 [In Press, Journal pre-proof]
Abstract
The Mitochondria is a critical sub-cellular organelle that plays an integral part in a normal cellular process.
Besides ATP production, the mitochondria participate in various key cellular processes such as cell signaling, epigenetic regulation leading to cell proliferation, migration, apoptosis, differentiation, and autophagy – highlighting their importance to cellular health.
However, mitochondrial dysfunction has serious organismal consequences, playing critical roles in the pathophysiology of many diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, pulmonary and liver diseases.
In recent years, mitochondrial dysfunction has spurred a surge of interest in developing mitochondria-targeted therapies. MitoQ is a selective antioxidant that concentrates in the mitochondria and prevents oxidative damage to the mitochondria.
The therapeutic relevance of MitoQ has been studied in various diseased conditions to determine its efficacy in either slowing disease progression or alleviating symptoms.
In this review, we discussed mitochondrial dysfunction in selected diseases and the therapeutic benefit of MitoQ in numerous studies.
Highlights
- The Mitochondria represent a critical component of the cell, they are generally essential for eukaryotic life.
- Beside ATP production, the mitochondria participate in a variety of key cellular processes such as cell signaling, epigenetic regulation and apoptosis.
- Mitochondrial dysfunction has serious organismal consequences, playing critical roles in the pathophysiology of many diseases.
- The genetic risk factors associated with mitochondrial dysfunction is increasingly associated with many human inherited disorders, such as metabolic syndrome etc.
- Mitochondrial dysfunction has spurred a surge of interest in the development of mitochondria-targeted therapies in recent years.
- MitoQ is a mitochondria-targeted antioxidant that and its therapeutic relevance has been studied in a variety of different diseased conditions.
Jason LA, Gaglio CL, Furst J, et al.
Chronic Illness. May 2022.
Abstract
Objectives: Studies have demonstrated immune dysfunction in adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); however, evidence is varied. The current study used network analysis to examine relationships between cytokines among a sample of pediatric participants with ME/CFS.
Methods: 10,119 youth aged 5–17 in the Chicagoland area were screened for ME/CFS; 111 subjects and controls were brought in for a physician examination and completed a blood draw. Youth were classified as controls (Cs, N = 43), ME/CFS (N = 23) or severe (S-ME/CFS, N = 45). Patterns of plasma cytokine networks were analyzed.
Results: All participant groups displayed a primary network of interconnected cytokines. In the ME/CFS group, inflammatory cytokines IL-12p70, IL-17A, and IFN-γ were connected and included in the primary membership, suggesting activation of inflammatory mechanisms. The S-ME/CFS group demonstrated a strong relationship between IL-17A and IL-23, a connection associated with chronic inflammation. The relationships of IL-6 and IL-8 in ME/CFS and S-ME/CFS participants also differed from Cs. Together, these results indicate pro-inflammatory responses in our illness populations.
Discussion: Our data imply biological differences between our three participant groups, with ME/CFS and S-ME/CFS participants demonstrating an inflammatory profile. Examining co-expression of cytokines may aid in the identification of a biomarker for pediatric ME/CFS.
Long-COVID Research References
Dr Katrina Pears,
Research Correspondent.
The ME Association.
