Research: Neurochemical abnormalities in CFS

Posted on 10/14/2021 by wames

Neurochemical abnormalities in chronic fatigue syndrome: a pilot magnetic resonance spectroscopy study at 7 Tesla, by Beata R Godlewska, Stephen Williams, Uzay E Emir, Chi Chen, Ann L Sharpley, Ana Jorge Goncalves, Monique I Andersson, William Clarke, Brian Angus, Philip J Cowen in Psychopharmacology, October 5, 2021

 

Research abstract: 

Rationale

Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction.

Methods

We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference.

Results

Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants.

Conclusions

The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample.

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Legal challenge to NICE ME/CFS Guideline delay

Posted on 10/14/2021 by wames

Legal challenge to NICE ‘pause in publication’

 

On the 1st October a legal action was launched against NICE, claiming the failure to publish the final guideline for ME/CFS was unlawful – that NICE failed to follow it’s own rules – and it should be published by Wed 6 October.

When NICE failed to publish, instead insisting they would aim to make a decision following the 18 October Roundtable discussion, the legal team obtained legal aid to begin the process of applying to take NICE to a Judicial Review.

Who is behind the legal action?

A child diagnosed with post-viral CFS/ME in December 2013 ‘was given treatments according to the current NICE guidelines: CBT where he was instructed not to talk about his symptoms but just push through them and Graded Exercise Therapy [GET] which was a continual gradual increase in activity, regardless of the state he was in. This treatment caused him significant harm… [his] post-exertional malaise [PEM] was ignored… [He] is worried that if he seeks treatment from the NHS he will be further subject to the harmful regimen specified in the NHS by the current NICE guidance.’

The 2021 unpublished  guideline no longer recommends the treatments many say has harmed them, so that is not the focus of the legal action.

Barrister Valerie Elliot Smith says:

“It’s important to remember that this action is concerned with a judicial review of due process, not of the scientific evidence.”

Why is NICE accused of acting unlawfully?

The accusation is based on two principles:

1. Procedural impropriety

“NICE has adopted its manual of methods and procedures for developing its guidelines. It has followed those procedures scrupulously to this point. However, NICE has broken out of its prescribed procedures and now intends to repudiate its procedures and engage in politics. This is a fundamental betrayal of NICE’s constitutional role and prescribed methods. The Claimant intends to ask the court to intervene to prevent this unlawful use of NICE’s powers.”

2. Irrationality

“… In this case it is contended that NICE have acted irrationally in that they have ceased to have regard to scientific evidence, but instead are being materially influenced by irrelevant factors such as whether those who may have commercial interests need to be persuaded to support a change which will adversely affect those interests.”

NICE’s defence

NICE’s lawyers replied late on Wed 6th October to deny the claims because:

  • they have wide discretion
  • ‘NICE guidelines are not binding. They inform the judgement of bodies providing NHS services and their clinicians, nothing more.’
  • ‘The Manual does not expressly provide circumstances justifying a pause in publication of guidelines, but nor does it expressly exclude this possibility’
  • ‘the express purpose of the meeting is to gain support for the Guideline’.

The Lawyers fail to explain why it was necessary to pause publication if all they intend to do is to gather support for the guideline. The unanswered question is whether they are open to making changes before finally publishing. The ME community knows the guideline is not perfect but believes it is a more ‘evidence based’ document than the 2007 guideline. The Royal Colleges and NHS England have said they want some reversal to the treatment recommendations so they can continue to deliver controversial treatments to people with ME.

Should the UK Government intervene?

Steve Topple, in his online article in ‘the Canary’ says the government could intervene if an MP raises the issue formally via an “urgent question” in parliament because:

  • Under the Health and Social Care Act 2012. NICE has an agreement with the Department of Health and Social Care (DHSC) its work is commissioned by ministers or by NHS England several years in advance and the development of individual pieces of guidance can take between 6 months to 2 years.
  • the DHSC secretary of state (currently Sajid Javid) is “accountable to parliament” for NICE and its “performance”. And the DHSC permanent secretary (currently Chris Wormals is responsible for making sure “arrangements are in place” to address significant problems and bring concerns about the activities of NICE to the DHSC board and give assurances that appropriate action has been taken.

Next steps:

Lawyer Peter Todd is preparing papers to file and serve proceedings in the High Court after the Round Table discussion.  Ian Wise QC is being instructed to settle the statement of facts and grounds. 

More information:

Letter before action to NICE

Letter of response from NICE legal team

Valerie Eliot Smith: NICE developments: preparatory action for a judicial review of the decision to pause publication of the new guideline for “ME/CFS”

Steve Topple: NICE will now face court over the ME guidelines debacle, in the Canary

See also

NICE publishes ME/CFS guideline: evidence says GET & CBT cannot cure!

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Dr Muirhead: “the medical profession have massively underestimated hidden disease”

Posted on 10/12/2021 by wames

What long COVID awareness means for people with chronic illnesses

 

Dr Nina Muirhead is quoted in an article by Rachel Charlton-Dailey on the Verywell Health website, September 29, 2021

 

Hopeful for more acceptance and understanding

There is hope in the chronic illness community that interest in long COVID will also trickle down into more acceptance and a better understanding of other illnesses.

“Whilst it feels frustrating…I think that the wave of interest in long COVID will pull up all the little boats of chronic conditions,” Nina Muirhead, MRCS, DOHNS, director of Doctors with M.E., tells Verywell.

Muirhead hopes that long COVID will make “patient experts more culturally acceptable.”

What Is a Patient Expert?
Patient experts are those who have significant knowledge of their disease and treatment in addition to self-management skills. Medical teams will sometimes lean on patient experts as educators for other patients and as a person to provide feedback on care delivery.

“Doctors can’t be expected to know everything,” Muirhead says. But at the same time, once they’ve done all the tests and ruled out what they think a patient’s options might be, healthcare providers shouldn’t “turn around and tell the patient they’re making up [their condition],” she adds.

As a doctor who has a chronic illness herself, Muirhead acknowledges she is in a unique position.

“It was only by being on the patient side that I realized the medical profession have massively underestimated hidden disease,” she says. “I was completely ignorant to the knowledge gap between where I stood, and where [the patient] sat.”

Though it has been difficult for disabled and chronically ill people to see long COVID garner attention and resources their illnesses have never received, the prevailing sentiment is one of goodwill.

Read the full article for more views from a researcher about long COVID and other people with ME.

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Research review: ME/CFS: a neurological entity?

Posted on 10/05/2021 by wames

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A neurological entity?, by Inigo Murga Gandasegui, Larraitz Aranburu Laka, Pascual-Angel Gargiulo, Juan-Carlos Gomez-Esteban, Jose-Vicente Lafuente Sanchez in Medicina Vol 57, #10, p 1030, Sep 27, 2021 [doi.org/10.3390/medicina57101030]

 

Review abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disorder of unknown physiopathology with multisystemic repercussions, framed in ICD-11 under the heading of neurology (8E49). There is no specific test to support its clinical diagnosis.

Our objective is to review the evidence in neuroimaging and dysautonomia evaluation in order to support the neurological involvement and to find biomarkers serving to identify and/or monitor the pathology. The symptoms typically appear acutely, although they can develop progressively over years; an essential trait for diagnosis is ‘central’ fatigue together with physical and/or mental exhaustion after a small effort.

Neuroimaging reveals various morphological, connectivity, metabolic, and functional alterations of low specificity, which can serve to complement the neurological study of the patient. The COMPASS-31 questionnaire is a useful tool to triage patients under suspect of dysautonomia, at which point they may be redirected for deeper evaluation.

Recently, alterations in heart rate variability, the Valsalva maneuver, and the tilt table test, together with the presence of serum autoantibodies against adrenergic, cholinergic, and serotonin receptors were shown in a subgroup of patients. This approach provides a way to identify patient phenotypes. Broader studies are needed to establish the level of sensitivity and specificity necessary for their validation.

Neuroimaging contributes scarcely to the diagnosis, and this depends on the identification of specific changes. On the other hand, dysautonomia studies, carried out in specialized units, are highly promising in order to support the diagnosis and to identify potential biomarkers. ME/CFS orients towards a functional pathology that mainly involves the autonomic nervous system, although not exclusively.

5. Conclusions
The neurobiopathological substrate of ME/CFS is unknown. There currently is no neuroimaging finding or specific laboratory test to establish the diagnosis. Changes reported in volumetry, cerebral blood flow, anatomy, and functional connectivity, at rest as well as in response to stimuli reveal the existence of brain dysfunctions, whose meaning is yet to be determined. The interpretation of findings is complicated by the lack of a consensual study protocol.

The available evidence on the involvement of the autonomic nervous system
(sympathetic/parasympathetic imbalance) indicates that the neurologist plays an essential role in the clinical evaluation of the syndrome and highlights the potential benefits of dysautonomia units for a better understanding of these dysfunctional pathologies.

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IAfME expands & relaunches as World ME Alliance

Posted on 10/05/2021 by wames

International Alliance for ME becomes the World ME Alliance

As a founding member of IAfME, WAMES is excited to be part of the development and launch of the World ME Alliance.

The Alliance is the only organisation in the world to bring together national ME/CFS organisations to advocate for better recognition and treatments for Myalgic Encephalomyelitis at an international level, with a particular aim of targeting the World Health Organization to bring greater focus to all post-viral illness.

Bringing myalgic encephalomyelitis out of the shadows

 

In addition, the World ME Alliance website and events will create a dedicated space for national ME/CFS organisation leaders to share the knowledge, experience and challenges they face in their countries.

This re-launch comes at an important time for ME/CFS globally. Long Covid has shone a light on post-viral disease that has long been missing. Other developments around ME/CFS, such as new guidance published in Mayo Clinic Proceedings and the UK’s much-anticipated National Institute for Health and Care Excellence guideline, will have an impact that reverberates around many countries.

Sonya Chowdhury, chair of the World ME Alliance, tells us:

“Our new website, name, logo and brand will help place us at the fore of international discussions around ME/CFS and other post-viral illnesses.

ME/CFS is a global health crisis, with hundreds of thousands more now being diagnosed with this illness and other post-viral illnesses in the wake of Covid-19.

By working collaboratively, we can expose the devastating impact of these illnesses, and begin to do justice to those desperately in need of research and care.”

The Alliance is currently made up of member organisations from countries including the UK, South Africa, Canada, Spain, Wales, New Zealand and the US. As part of its next steps, it is looking to expand this and bring in more organisations to help shape its future.

Find out more:

www.worldmealliance.org    Read in a variety of languages, including Welsh

Twitter: @WorldMEAlliance

Sian Leary, Communications Officer  sian@worldmealliance.org

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Research: A comprehensive examination of severely ill ME/CFS patients

Posted on 10/01/2021 by wames

A comprehensive examination of severely ill ME/CFS patients, by Chia-Jung Chang, Li-Yuan Hung, Andreas M. Kogelnik, David Kaufman, Raeka S Aiyar, Angela M Chu, Julie Wilhelmy, Peng Li, Linda Tannenbaum, Wenzhong Xiao, Ronald W Davis in Healthcare Vol 9, #10, p 1290, Sep 29, 2021 [doi.org/10.3390/healthcare9101290]

 

Research abstract:

One in four myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients are estimated to be severely affected by the disease, and these house-bound or bedbound patients are currently understudied. Here, we report a comprehensive examination of the symptoms and clinical laboratory tests of a cohort of severely ill patients and healthy controls.

The greatly reduced quality of life of the patients was negatively correlated with clinical depression. The most troublesome symptoms included fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments.

Lower morning cortisol level and alterations in its diurnal rhythm were observed in the patients, and antibody and antigen measurements showed no evidence for acute infections by common viral or bacterial pathogens. These results highlight the urgent need of developing molecular diagnostic tests for ME/CFS.

 

In addition, there was a striking similarity in symptoms between long COVID and ME/CFS, suggesting that studies on the mechanism and treatment of ME/CFS may help prevent and treat long COVID and vice versa.

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Hypothesis: Radiation exposure & mitochondrial insufficiency in CIFDS

Posted on 09/30/2021 by wames

Radiation exposure and mitochondrial insufficiency in chronic fatigue and immune dysfunction syndrome by Andrej Rusin, Megan Li, Alan Cocchetto, Colin Seymour, Carmel Mothersill, in Medical Hypotheses, Vol 154, Sep 2021, 110647 [doi.org/10.1016/j.mehy.2021.110647]

 

Research abstract:

Chronic fatigue and Immune Dysfunction Syndrome (CFIDS) is a heterogeneous disease that may be promoted by various environmental stressors, including viral infection, toxin uptake, and ionizing radiation exposure.

Previous studies have identified mitochondrial dysfunction in CFIDS patients, including modulation of mitochondrial respiratory chain activity, deletions in the mitochondrial genome, and upregulation of reactive oxygen species (ROS).

This paper focuses on radiation effects and hypothesizes that CFIDS is primarily caused by stressor-induced mitochondrial metabolic insufficiency, which results in decreased energy production and anabolic metabolites required for normal cellular metabolism. Furthermore, tissues neighbouring or distant from directly perturbed tissues compensate for this dysfunction, which causes symptoms associated with CFIDS.

This hypothesis is justified by reviewing the links between radiation exposure and CFIDS, cancer, immune dysfunction, and induction of oxidative stress.

Moreover, the relevance of mitochondria in cellular responses to radiation and metabolism are discussed and putative mitochondrial biomarkers for CFIDS are introduced. Implications for diagnosis are then described, including a potential urine assay and PCR test for mitochondrial genome mutations.

Finally, future research needs are offered with an emphasis on where rapid progress may be made to assist the afflicted.

Full paper behind paywall

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Research: ME/CFS is not influenced by the presence or absence of joint hypermobility

Posted on 09/30/2021 by wames

The presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is not influenced by the presence or absence of joint hypermobility, by Sarah K Vogel, Isabelle R Primavera, Colleen L Marden, Marissa AK Flaherty, Richard L Violand, Peter C Rowe in the Journal of Pediatrics Sep 16, 2021 [DOI:https://doi.org/10.1016/j.jpeds.2021.09.014]

 

Research abstract:

Objective
To examine demographic and clinical characteristics of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with and without joint hypermobility We hypothesized that JH+ patients would have an earlier onset of ME/CFS symptoms as well as increased severity, greater number of co-morbid conditions, and lower health related quality of life.

Study design
From an observational cohort study of 55 individuals meeting the Fukuda criteria for ME/CFS, we compared groups using a Beighton score cut-off of 4 or higher to indicate JH. Chart data were collected to examine the age and type of onset of ME/CFS, and the presence of comorbid conditions. The impact on quality of life was assessed through questionnaires that included the Peds QL, Functional Disability Inventory, Peds QL Multidimensional Fatigue Scale, and Anxiety Subscale of the Symptom Checklist 90.

Results
There was no significant difference between groups in mean (SD) age at onset of ME/CFS (13.3 [3.3] years vs 13.3 [2.3] years; P = .92), sex, frequency, and severity of ME/CFS symptoms, orthostatic intolerance symptoms, or comorbid conditions. There was no significant difference between groups in measures of health-related quality of life using a Beighton score cut-off of 4 or a cut-off of 5 to define joint hypermobility.

Conclusions
Despite being a risk factor for the development of ME/CFS, JH as defined in this study was not associated with other clinical characteristics of the illness.

The full paper is behind a paywall.

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The ‘medically unexplained symptoms’ (MUS) concept, CBT & CFS

Posted on 09/28/2021 by wames

The ‘medically unexplained symptoms’ syndrome concept and the cognitive-behavioural treatment model, by Michael J Scott , Joan S Crawford , Keith J Geraghty , David F Marks in Journal of Health Psychology Sep 2021 [doi:10.1177/13591053211038042]

 

Article abstract:

The American Psychiatric Association’s, 2013 DSM-5 abandoned the use of the term ‘medically unexplained symptoms’ for non-neurological disorders. In the UK, treatments for various medical illnesses with unexplained aetiology, such as chronic fatigue syndrome, irritable bowel syndrome and fibromyalgia, continue to fall under an MUS umbrella with cognitive behavioural therapy promoted as a primary therapeutic approach.

In this editorial, we comment on whether the MUS concept is a viable diagnostic term, the credibility of the cognitive-behavioural MUS treatment model, the necessity of practitioner training and the validity of evidence of effectiveness in routine practice.

As the MUS diagnostic category is alleged to include up to one-third of all patients seen in primary care on a regular basis (Nimnuan et al., 2001), the scale of the artificially created ‘syndrome’ highlights the absurdity of such a conceptualisation.

Excerpt:

Maes and Twisk (2010) provide a predominantly biological model to help explain chronic fatigue syndrome, rescuing it from the ‘unexplained’ category. Their model explains readily why immunological and endocrinological variables better predict outcome in CFS than psychological variables. By contrast, in the Harvey and Wessely (2009) model of CFS there is no specification of any key and lock mechanism that is, what precipitant, acting on which predisposing factor would usher in the said debility, nor which perpetuating factor would be pertinent to which key-lock combination.

Excerpt: 

A recurring theme among practitioners applying the CBM is the claim that dysfunctional illness beliefs (e.g. that ‘symptoms are the result of a virus’) are causally linked to deconditioning and a poor prognosis (e.g. Wessely et al., 1991). Attempting to induce patients into cognitive behaviour therapy (CBT) to change the way they are alleged to habitually think has not proved a successful strategy, as the revised NICE (2020) guidance has concluded.

Conclusions:

The MUS concept can no longer be accepted as a viable diagnostic term. The credibility of the cognitive-behavioural MUS treatment model has reached a nadir and can be given only an auxiliary role in treatment. An urgent necessity to provide practitioner training has been identified and the need for greater awareness of the misleading nature of poor quality evidence for effectiveness of the CBT approach in routine practice.

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Diagnostic test hypothesis: iP stem cells as suitable sensors for FM & ME/CFS

Posted on 09/27/2021 by wames

Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome, by Maria B Monzon-Nomdedeu, Karl J Morten, Elisa Oltra in World Journal of Stem Cells Vol 13, #8, pp 1134-1150 [DOI:10.4252/wjsc.v13.i8.1134] August 26, 2021

 

Core Tip:

Because of the special ability to sense environmental cues we propose that induced pluripotent stem cells (iPSCs) are suitable for use as a sensor system for metabolic disease. As fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome body-fluids have unique metabolic profiles, the applicability of iPSC-based bioassays for those conditions are worth investigating.

We envisage the development of iPSC platforms that allow differential diagnosis and disease-specific high-throughput drug-screening platforms. Using healthy iPSCs and patient body fluids has significant advantages over using cell lines, primary culture of patient cells or iPSCs derived from patients.

A consistent iPSC control-cell line platform will provide a robust metabolic/phenotypic model allowing faster, cost-effective, large cohort screenings.

Review abstract:

Background

Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers. Despite patient heterogeneity linked to patient subgroups and variation in disease severity, anomalies are found in the blood and plasma of these patients when compared with healthy control groups.

Stem cells are the body’s raw materials — cells from which all other cells with specialized functions are generated. Under the right conditions in the body or a laboratory, stem cells divide to form more cells called daughter cells.     Mayo Clinic

The seeming specificity of these ‘plasma factors’, as recently reported by Ron Davis and his group at Stanford University, CA, United States, and observations by our group, have led to the proposal that induced pluripotent stem cells (iPSCs) may be used as metabolic sensors for FM and ME/CFS, a hypothesis that is the basis for this in-depth review.

Aim

To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs.

Methods

A PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids. The MeSH terms ‘metabolomic’ or ‘metabolites’ in combination with FM and ME/CFS disease terms were screened against the PubMed database.

Only original studies applying omics technologies, published in English, were included. The data obtained were tabulated according to the disease and type of body fluid analyzed. Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups.

Results

Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids. In vitro cell-based assays have the potential to be developed as screening platforms, providing evidence for the existence of factors in patient body fluids capable of altering morphology, differentiation state and/or growth patterns. Moreover, they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients. The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust, reproducible reporter systems of metabolic diseases, including ME/CFS and FM.

Furthermore, culturing iPSCs, or their mesenchymal stem cell counterparts, in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies.

Conclusion

This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.

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