Review Chronic Fatigue Syndrome: Diagnosis, Treatment, and Future Direction, 2024, Graves et al

Wyva

Senior Member (Voting Rights)
B. Sue Graves Mitsu PatelHailey NewgentGauri ParvathyAhmad NasriJillene MoxamGurnoor S. GillVivek SawhneyManish Gupta

Abstract

Myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a complex, chronic condition marked by persistent, debilitating fatigue that is not alleviated by rest and often worsens with physical or mental exertion. Along with fatigue, patients experience various symptoms, including cognitive impairments, post-exertional malaise, muscle and joint pain, sleep disturbances, and immune system dysfunction.

Diagnosing CFS/ME is challenging due to the absence of definitive biomarkers, the overlap of symptoms with other conditions, and the lack of standardized diagnostic criteria. This comprehensive literature review aims to contribute to the understanding of CFS/ME, including its diagnosis, pathophysiology, differential diagnosis, treatment, and future directions.

Open access: https://www.cureus.com/articles/299...e-diagnosis-treatment-and-future-direction#!/
 
Just skimmed through it to see what it says about GET for example.

GET and Pacing Controversy

The use of GET for CFS/ME has been a subject of controversy. While some studies suggest potential benefits, patient experiences vary widely, with some reporting improvement and others experiencing worsened symptoms.

The quality of evidence regarding GET for CFS/ME is a contentious issue [47]. Many studies supporting GET have been criticized for methodological flaws, including small sample sizes, lack of appropriate control groups, and potential biases in patient selection [47,48]. Additionally, some studies rely on subjective outcome measures, such as self-reported improvement in symptoms, which can introduce bias and limit the reliability of findings. Moreover, there are concerns about patient adherence to GET protocols. Due to the nature of CFS/ME, patients may experience fluctuating levels of fatigue and post-exertional malaise, making it difficult for them to adhere to a structured exercise regimen [47,48]. This variability in adherence further complicates the interpretation of study results, as it becomes challenging to differentiate between the effects of the therapy and the natural course of the illness.

Critics also point out that many studies do not adequately address the potential harms of GET, such as exacerbation of symptoms [47,48]. As a result, the controversy surrounding GET is fueled not only by conflicting study outcomes but also by limitations in the design and execution of these studies. Therefore, more rigorous, patient-centered research is needed to provide clearer guidance on the use of GET in CFS/ME management [47,48].
 
CFS/ME appears to have a genetic component, supported by higher concordance rates in identical twins and the increased prevalence of certain gene variants related to autoimmunity in post-infectious CFS/ME patients. Specific single nucleotide polymorphisms (SNPs), such as PTPN22 rs2476601 and CTLA4 rs3087243, are associated with infection-triggered CFS/ME, while other SNPs, such as IRF5 rs3807306 and TNF rs1799724, have decreased allele frequencies in CFS/ME patients who do not have infection-triggered onset [38]. These genetic variants may contribute to impaired mucosal immunity, potentially increasing susceptibility to CFS/ME following infection. However, more research is necessary to fully elucidate the genetic factors involved.

38: Circulating microRNA expression signatures accurately discriminate [ME] from fibromyalgia and comorbid conditions 2023 Moreau et al

They cite one paper for all these claims, but that paper doesn't talk about any of these claims, as far as I can tell.

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Edit: Also from this thread's paper:
Advances in genomics have enabled researchers to study the genetic basis of CFS/ME more comprehensively [37]. Genome-wide association studies (GWAS) and transcriptomic analyses can help identify genetic variants and gene expression patterns associated with CFS/ME, providing insights into underlying molecular mechanisms [37].
37: Neuroimaging characteristics of ME/CFS: a systematic review. Shan et al. 2020

37 doesn't have anything to do with genetics, except for one sentence: "Several recent studies have demonstrated that Ca2+ mobilisation is impaired in ME/CFS from genetic [78, 79], molecular biological [80], and electrophysiological aspects [81]."

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Edit 2: Where they cited 38, they probably meant to cite 33, which says this:
2.6.3 Genetic Predisposition
Some studies provide support for the suggestion that genes might play a role in ME/CFS (54), as the disease shows higher concordance in identical monozygotic twins (127). The rates of ME/CFS for first-degree relatives vary from 2.7% (128) to 13% (54). A monozygotic twin study in which more than half (55%) of both identical twin pairs showed ME/CFS symptoms support the evidence of a genetic component, at least in a subgroup of ME/CFS (127). A recent study showed a significantly higher prevalence of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles in post-infectious ME/CFS, but not in ME/CFS patients without infection-triggered onset. For the IRF5 rs3807306 risk allele and the TNF rs1799724 we observed a significantly lower allele frequency in ME/CFS patients without infection-triggered onset (129). Interestingly, these SNPs are associated with enhanced serum levels of TNF-α and IFN-α and are frequently associated with autoimmune diseases of mucosal sites (130134). It is tempting to speculate that patients who can produce less TNF-α and IFN-α have impaired mucosal immunity and are therefore more prone to develop infection-triggered ME/CFS.
33: The Gut Microbiome in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS), 2022, Scheibenbogen et al
 
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Specific single nucleotide polymorphisms (SNPs), such as PTPN22 rs2476601 and CTLA4 rs3087243, are associated with infection-triggered CFS/ME, while other SNPs, such as IRF5 rs3807306 and TNF rs1799724, have decreased allele frequencies in CFS/ME patients who do not have infection-triggered onset [38].
In terms of these four SNPs, @Chris Ponting on the paper this is based on:
Can these SNPs be replicated? The answer is "no". I went back to the UK Biobank CFS findings (far more than 305 ME/CFS patients) and asked what is the association (what are the p-values?) of these SNPs to CFS status? The answers are: p = 0.43, 0.41, 0.56, 0.92 and 0.17. None of the 5 are replicated. So the paper's results are not replicated with a far larger number of CFS cases.
 
Therefore, more rigorous, patient-centered research is needed to provide clearer guidance on the use of GET in CFS/ME management
Yes. By all means, let's have another wasted decade, probably more, of terrible biased studies from biased ideologues while the current flawed guidance remains in place and continues to harm people. Good grief this profession is such a mess.

Even in LC all the trials are tiny pilot/feasibility studies. They're actually even lower quality, and the quality was already beneath consideration. Absolutely maddening disregard for patients yet again.
 
Moreover, there are concerns about patient adherence to GET protocols. Due to the nature of CFS/ME, patients may experience fluctuating levels of fatigue and post-exertional malaise, making it difficult for them to adhere to a structured exercise regimen [47,48]. This variability in adherence further complicates the interpretation of study results, as it becomes challenging to differentiate between the effects of the therapy and the natural course of the illness.

I would have said unknown level of adherence rather than variability. But otherwise pleased to see this very critical issue being raised.

Also critical is that adherence measures need to account for patients trading off adherence to therapy with reducing normal daily/weekly activities. Merely adhering to treatment protocol is meaningless if patients are not doing more than their normal levels of overall activity.
 
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