Hypothesis: ME/CFS as an immune & oxidative stress disorder

Posted on 10/28/2021 by wames

The reification of the clinical diagnosis of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) as an immune and oxidative stress disorder: construction of a data-driven nomothethic network and exposure of ME/CFS subgroups, by Michael Maes, Marta Kubera, Kristina Stoyanova, Jean-Claude Leunis in Current Topics in Medicinal Chemistry, Vol 21 , Issue 16 , 2021 [DOI : 10.2174/1568026621666210727170147]

 

Article abstract:

The approach towards myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) remains in a permanent state of crisis with fierce competition between the psychosocial school, which attributes ME/CFS to the perception of effort, and the medical approach (Maes and Twisk, BMC Med, 2010,8,35).

The aim of this paper is to review how to construct a nomothetic model of ME/CFS using Partial Least Squares (PLS) path analysis and ensembling causome (bacterial) translocation as assessed with IgM/IgA responses to LPS), protectome (lowered coenzyme Q10), adverse outcome pathways (AOP) including increased lysozyme, CD38+ T cell activation, cell-mediated immune activation (CMI), and IgM responses to oxidative specific epitopes and NO-adducts (IgM OSENO).

Using PLS, we trained, tested and validated this knowledge- and data-driven causal ME/CFS model, which showed adequate convergence, construct and replicability validity. This bottom-up explicit data model of ME/CFS objectivates the descriptive narratives of the ME/CFS phenome, using causome-protectome-AOP data, whereby the abstract concept ME/CFS is translated into pathways, thereby securing the reification of the ME/CFS phenome.

We found that 31.6% of the variance in the physiosomatic symptom dimension of ME/CFS was explained by the cumulative effects of CMI and CD38+ activation, IgM OSENO, IgA LPS, lysozyme (all positive) and coenzyme Q10 (inversely).

Cluster analysis performed on the PLS-generated latent vector scores of all feature sets exposed three distinct immune groups of ME/CFS, namely:

  • one with increased lysozyme,
  • one with increased CMI + CD38 activation + depressive symptoms,
  • and another with increased bacterial translocation + autoimmune responses to OSENO [OSEs and NO-adducts].

Excerpt from paper:

…the nomothetic network exposed new drug targets to treat ME/CFS. Moreover, the latent variable scores shape an idiomatic feature set profile that is specific for every patient and may be exploited for a personalized treatment.

Download full paper [preprint pdf]

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Research: Impact of life stressors on ME/CFS symptoms

Posted on 10/27/2021 by wames

Impact of life stressors on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome symptoms: An Australian longitudinal study, by  Cassandra Balinas, Natalie Eaton-Fitch, Rebekah Maksoud, Donald Staines, and Sonya Marshall-Gradisnik in Int. J. Environ. Res. Public Health 2021, 18(20) [10.3390/ijerph182010614] (This article belongs to the Special Issue Chronic Fatigue Syndrome: Medical, Nursing and Public Health Management)

 

Research abstract:

(1) Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multifaceted illness. The pathomechanism, severity and progression of this illness is still being investigated. Stressors have been implicated in symptom exacerbation for ME/CFS, however, there is limited information for an Australian ME/CFS cohort. The aim of this study was to assess the potential effect of life stressors including changes in work, income, or family scenario on symptom severity in an Australian ME/CFS cohort over five months;

(2) Methods: Australian residents with ME/CFS responded to questions relating to work, income, living arrangement, access to healthcare and support services as well as symptoms experienced;

(3) Results: thirty-six ME/CFS patients (age: 41.25 ± 12.14) completed all questionnaires (response rate 83.7%). Muscle pain and weakness, orthostatic intolerance and intolerance to extreme temperatures were experienced and fluctuated over time. Sleep disturbances were likely to present as severe. Work and household income were associated with worsened cognitive, gastrointestinal, body pain and sleep symptoms. Increased access to healthcare services was associated with improved symptom presentation;

(4) Conclusions: life stressors such as work and financial disruptions may significantly contribute to exacerbation of ME/CFS symptoms. Access to support services correlates with lower symptom scores.

Conclusions from full paper:

This longitudinal study identified a group of Australian ME/CFS patients who reported significantly reduced levels of full-time employment and financial instability.

Access to healthcare and professional and unpaid services were positively correlated to symptom scores, whereas financial and work-related parameters were negatively correlated with symptom scores. Although significant symptom improvements and exacerbations were reported between some months, clinical symptoms fluctuated throughout the study. Symptom fluctuation is a consistent pattern for ME/CFS and may be due to the heterogenous nature of this disease.

Importantly, as there were significant negative associations found between stressors such as financial and work-related parameters and symptom scores, this study highlights the importance of stress mitigation and delivery of resources aimed at supporting patients with chronic illnesses who are unable to work, as financial stability may improve symptom experience of ME/CFS.

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Research: CAN connectivity predicts symptoms in ME/CFS

Posted on 10/26/2021 by wames

Cortical autonomic network connectivity predicts symptoms in myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), by Mark A Zinn, Leonard A Jason in International Journal of Psychophysiology Vol 170, Dec 2021, Pages 89-101 [doi.org/10.1016/j.ijpsycho.2021.10.004]

 

Highlights

  • The findings of this study contribute to the understanding of unexplained symptoms in patients with ME/CFS.
  • Graph theoretical analysis revealed topological differences between groups that were associated with patient symptoms.
  • Results suggest that cortical dysregulation with this network may serve as a therapeutic target for patients.

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) represents a significant public health challenge given the presence of many unexplained patient symptoms. Research has shown that many features in ME/CFS may result from a dysfunctional autonomic nervous system (ANS).

We explored the role of the cortical autonomic network (CAN) involved in higher-order control of ANS functioning in 34 patients with ME/CFS and 34 healthy controls under task-free conditions. All participants underwent resting-state quantitative electroencephalographic (qEEG) scalp recordings during an eyes-closed condition.

Source analysis was performed using exact low-resolution electromagnetic tomography (eLORETA), and lagged coherence was used to estimate intrinsic functional connectivity between each node across 7 frequency bands: delta (1–3 Hz), theta (4–7 Hz), alpha-1 (8–10 Hz), alpha-2 (10–12 Hz), beta-1 (13–18 Hz), beta-2 (19–21 Hz), and beta-3 (22–30 Hz).

Symptom ratings were measured using the DePaul Symptom Questionnaire and the Short Form (SF-36) health survey.

Graph theoretical analysis of weighted, undirected connections revealed significant group differences in baseline CAN organization. Regression results showed that cognitive, affective, and somatomotor symptom cluster ratings were associated with alteration to CAN topology in patients, depending on the frequency band. These findings provide evidence for reduced higher-order homeostatic regulation and adaptability in ME/CFS. If confirmed, these findings address the CAN as a potential therapeutic target for managing patient symptoms.

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Healthcare: Caring for the patient with severe or very severe ME/CFS

Posted on 10/22/2021 by wames

Caring for the patient with severe or very severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Jose G Montoya, Theresa G Dowell, Amy E Mooney, Mary E Dimmock, Lily Chu in Healthcare Vol 9, #10, p 1331, 6 Oct 2021 [doi.org/10.3390/healthcare9101331] (This article belongs to the Special Issue ME/CFS – the Severely and Very Severely Affected)

 

Article abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can cause a wide range of severity and functional impairment, leaving some patients able to work while others are homebound or bedbound. The most severely ill patients may need total care.

Yet, patients with severe or very severe ME/CFS struggle to receive appropriate medical care because they cannot travel to doctors’ offices and their doctors lack accurate information about the nature of this disease and how to diagnose and manage it.

Recently published clinical guidance provides updated information about ME/CFS but advice on caring for the severely ill is limited. This article is intended to fill that gap. Based on published clinical guidance and clinical experience, we describe the clinical presentation of severe ME/CFS and provide patient-centered recommendations on diagnosis, assessment and approaches to treatment and management.

We also provide suggestions to support the busy provider in caring for these patients by leveraging partnerships with the patient, their caregivers, and other providers and by using technology such as telemedicine. Combined with compassion, humility, and respect for the patient’s experience, such approaches can enable the primary care provider and other healthcare professionals to provide the care these patients require and deserve.

Recommendations include:

6.1.Recommendations for Minimizing Post-Exertional Malaise and Sensory Sensitivities
6.2. Recommendations for Treatment and Management Approaches
6.3. Recommendations for Follow-Up Visits, Advance Care Directives, and Hospitalization

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NICE will announce guideline decision next week

Posted on 10/21/2021 by wames

NICE announces next steps for publication of its guideline on ME/CFS

 

NICE has today (20 October 2021) announced the next steps for publication of its updated guideline on the diagnosis and management of myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS).

 

NICE will publish the guideline following a meeting of its Guidance Executive next week.

Today’s announcement follows a roundtable meeting held earlier this week involving representatives from a range of patient and professional organisations, to discuss concerns raised about some aspects of the guideline that had led to the publication of the guideline being paused.

Professor Gillian Leng, NICE chief executive, said:

“We would like to thank all those who took part in the meeting earlier this week for their contributions to what was an extremely open and positive discussion. During the meeting we had a constructive conversation about all the key issues that had been raised – those concerning the criteria for diagnosing ME/CFS, the decision not to recommend graded exercise therapy, the role of CBT, and the particular challenges of treating children and young people with the condition, as well as the approach taken to identifying and considering the evidence.

“We are now confident that the guideline can be effectively implemented across the system and we will discuss the input from the meeting at our Guidance Executive next week with a view to publication of the guideline.”

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Research review: Potential implications of TRPM7 in ME/CFS

Posted on 10/21/2021 by wames

Potential implications of mammalian Transient Receptor Potential Melastatin 7 in the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a review, by  Stanley Du Preez, Helene Cabanas, Donald Staines and Sonya Marshall-Gradisnik in Int. J. Environ. Res. Public Health 2021, 18(20), 10708  [doi.org/10.3390/ijerph182010708] 2 October 2021 (This article belongs to the Special Issue Chronic Fatigue Syndrome: Medical, Nursing and Public Health Management)

 

Research abstract:

The transient receptor potential (TRP) superfamily of ion channels is involved in the molecular mechanisms that mediate neuroimmune interactions and activities. Recent advancements in neuroimmunology have identified a role for TRP cation channels in several neuroimmune disorders including amyotropic lateral sclerosis, multiple sclerosis, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

ME/CFS is a debilitating disorder with an obscure aetiology, hence considerable examination of its pathobiology is warranted. Dysregulation of TRP melastatin (TRPM) subfamily members and calcium signalling processes are implicated in the neurological, immunological, cardiovascular, and metabolic impairments inherent in ME/CFS.

In this review, we present TRPM7 as a potential candidate in the pathomechanism of ME/CFS, as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes. A focused examination of the biochemistry of TRPM7, the role of this protein in the aforementioned systems, and the potential of TRPM7 as a molecular mechanism in the pathophysiology of ME/CFS will be discussed in this review.

TRPM7 is a compelling candidate to examine in the pathobiology of ME/CFS as TRPM7 fulfils several key roles in multiple organ systems, and there is a paucity of literature reporting on its role in ME/CFS.

Excerpt from 4. Conclusions

Of particular interest is elucidating the role of TRPM7 in NK cell function in both healthy individuals and ME/CFS patients. Specifically, identifying the importance of TRPM7 in Ca2+ and kinase signalling cascades, as well as regulating intracellular Mg2+ homeostasis and metabolism, in NK cells may serve to facilitate the identification of additional diagnostic and treatment targets to relieve the burden of illness in ME/CFS.

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Diagnostic test research: Autoantibodies & receptors correlate with symptom severity, autonomic dysfunction & disability in ME/CFS

Posted on 10/19/2021 by wames

Autoantibodies to vasoregulative G-Protein-Coupled receptors correlate with symptom severity, autonomic dysfunction and disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Helma Freitag, Marvin Szklarski, Sebastian Lorenz, Franziska Sotzny, Sandra Bauer, Aurélie Philippe, Claudia Kedor, Patricia Grabowski, Tanja Lange, Gabriela Riemekasten, Harald Heidecke and Carmen Scheibenbogen in J. Clin. Med. 2021, 10(16), 3675; 19 August 2021  (This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)

 

Research abstract:

Background:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an acquired complex disease with patients suffering from the cardinal symptoms of fatigue, post-exertional malaise (PEM), cognitive impairment, pain and autonomous dysfunction. ME/CFS is triggered by an infection in the majority of patients. Initial evidence for a potential role of natural regulatory autoantibodies (AAB) to beta-adrenergic (AdR) and muscarinic acetylcholine receptors (M-AChR) in ME/CFS patients comes from a few studies.

Methods:

Here, we analyzed the correlations of symptom severity with levels of AAB to vasoregulative AdR, AChR and Endothelin-1 type A and B (ETA/B) and Angiotensin II type 1 (AT1) receptor in a Berlin cohort of ME/CFS patients (n = 116) by ELISA. The severity of disease, symptoms and autonomic dysfunction were assessed by questionnaires.

Results:

We found levels of most AABs significantly correlated with key symptoms of fatigue and muscle pain in patients with infection-triggered onset. The severity of cognitive impairment correlated with AT1-R- and ETA-R-AAB and severity of gastrointestinal symptoms with alpha1/2-AdR-AAB. In contrast, the patients with non-infection-triggered ME/CFS showed fewer and other correlations.

Conclusion:

Correlations of specific AAB against G-protein-coupled receptors (GPCR) with symptoms provide evidence for a role of these AAB or respective receptor pathways in disease pathomechanism.

Excerpts from: 4. Discussion

There is increasing evidence for a role of vascular dysfunction in ME/CFS that shows associations with key symptoms [11]. In this study, we found several remarkable correlations of vasoregulative AAB with clinical symptoms in ME/CFS.

In conclusion, our study provides evidence that AAB and/or the receptor pathways of AdR, AChR as well as AT1-R and ET-R play a role in ME/CFS due to the association with symptom severity. Thus, it is conceivable that various symptoms of ME/CFS, including fatigue, muscle pain, cognitive impairment and autonomic dysregulation, could be mediated or aggravated by these AAB.

Further studies are required to decipher the mechanism and binding specificity of these GPCR-AAB, and their effect of on vascular function in ME/CFS, and how this may be translated into therapeutic concepts. In the case of dysfunctional AAB, therapies targeting AAB, such as immunoadsorption or rituximab, would be warranted and were shown to be effective in a subset of ME/CFS patients (reviewed in [5]).

Further specific targeting of dysfunctional or regulative AAB may be developed as treatment strategies in ME/CFS.

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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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