ME, CFS & chronic fatigue: three distinct entities requiring complete different approaches

Myalgic Encephalomyelitis, Chronic Fatigue Syndrome, and Chronic Fatigue: three distinct entities requiring complete different approaches, by Frank NM Twisk in Current Rheumatology Reports June 2019, 21:27 [https://doi.org/10.1007/s11926-019-0823-z]

 

Letter abstract:

Purpose of Review:
A recent review implicates that myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue are part of the “fatigue spectrum” and recommends “longitudinal studies integrating biopsychosocial approaches to inform early management and targeted rehabilitation strategies.”

Recent Findings:
ME is a neuromuscular disease distinguished by muscle fatigability (prolonged muscle weakness after minor exertion) and specific signs of neurological dysfunction. ME is not equivalent to CFS, as proposed by the authors. CFS is defined as unexplained chronic fatigue accompanied by at least four out of a list of eight specific symptoms. CFS is a distinct clinical entity and not merely a severe variant of CF, as suggested.

Proof that CF, CFS, and ME are part of a “fatigue continuum” and that CF can convert to CFS at a later stage is lacking. Biopsychosocial approaches for early management and rehabilitation of CF, as promoted by the authors, are at odds with the current understandings of ME, CFS, and CF. The (bio)psychosocial explanatory models for ME and CFS have proven to be invalid, and the associated interventions, cognitive behavioral therapy and graded exercise therapy, have shown to be ineffective and even potentially harmful.

Summary:
ME, CFS, and CF are three very distinct clinical entities. Interventions justified by (bio)psychosocial models appear to be unsuccessful and potentially noxious. To develop effective treatments, it is crucial to make a clear distinction between ME, CFS, and CF and to leave the (bio)psychosocial explanations and therapies behind us.

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Increased risk of CFS following psoriasis in Taiwan

Increased risk of chronic fatigue syndrome following psoriasis: a nationwide population-based cohort study, by Shin-Yi Tsai, Hsuan-Ju Chen, Chi Chen, Chon-Fu Lio, Chien-Feng Kuo, Kam-Hang Leong, Yu-Ting Tina Wang, Tse-Yen Yang, Ching-Hui You and Wei-Sheng Wang in Journal of Translational Medicine 2019 May 17:154
[https://doi.org/10.1186/s12967-019-1888-1]

 

Research abstract:

Background:
The onset of chronic fatigue syndrome (CFS) has been shown to be associated with several immunological conditions such as infections or atopy. The aim of this study was to clarify the risk of chronic fatigue syndrome following the diagnosis of psoriasis, an immune-related dermatological disease, by analyzing the National Health Insurance Research Database of Taiwan.

Method:
2616 patients aged 20 years or older with newly diagnosed psoriasis during 2004–2008 and 10,464 participants without psoriasis were identified. Both groups were followed up until the diagnoses of CFS [Fukuda] were made at the end of 2011.

Results:
The relationship between psoriasis and the subsequent risk of CFS was estimated through Cox proportional hazards regression analysis, with the incidence density rates being 2.27 and 3.58 per 1000 person-years among the non-psoriasis and psoriasis populations, respectively (adjusted hazard ratio [HR] = 1.48, with 95% confidence interval [CI] 1.07–2.06). In the stratified analysis, the psoriasis group were consistently associated with a higher risk of CFS in male sex (HR = 2.05, 95% CI 1.31–3.20) and age group of ≥ 60 years old (HR = 2.32, 95% CI 1.33–4.06). In addition, we discovered that the significantly increased risk of CFS among psoriasis patients is attenuated after they receive phototherapy and/or immunomodulatory drugs.

Conclusions:
The data from this population-based retrospective cohort study revealed that psoriasis is associated with an elevated risk of subsequent CFS, which is differentiated by sex and age.

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Validation of impaired TRPM3 ion channel activity in natural killer cells from CFS/ME

Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients, by H Cabanas, K Muraki, C Balinas, N Eaton-Fitch, D Staines, S Marshall-Gradisnik in Mol Med. 2019 Apr 23;25(1):14. doi: 10.1186/s10020-019-0083-4

 

Research abstract:

BACKGROUND:

Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations. Although the aetiology of CFS/ME remains elusive, immunological dysfunction and more particularly reduced cytotoxic activity in natural killer (NK) cells is the most consistent laboratory finding.

The Transient Receptor Potential (TRP) superfamily of cation channels play a pivotal role in the pathophysiology of immune diseases and are therefore potential therapeutic targets. We have previously identified single nucleotide polymorphisms in TRP genes in peripheral NK cells from CFS/ME patients. We have also described biochemical pathway changes and calcium signaling perturbations in NK cells from CFS/ME patients. Notably, we have previously reported a decrease of TRP cation channel subfamily melastatin member 3 (TRPM3) function in NK cells isolated from CFS/ME patients compared with healthy controls after modulation with pregnenolone sulfate and ononetin using a patch-clamp technique.

In the present study, we aim to confirm the previous results describing an impaired TRPM3 activity in a new cohort of CFS/ME patients using a whole cell patch-clamp technique after modulation with reversible TRPM3 agonists, pregnenolone sulfate and nifedipine, and an effective TRPM3 antagonist, ononetin. Indeed, no formal research has commented on using pregnenolone sulfate or nifedipine to treat CFS/ME patients while there is evidence that clinicians prescribe calcium channel blockers to improve different symptoms.

METHODS:

Whole-cell patch-clamp technique was used to measure TRPM3 activity in isolated NK cells from twelve age- and sex-matched healthy controls and CFS/ME patients, after activation with pregnenolone sulfate and nifedipine and inhibition with ononetin.

RESULTS:

We confirmed a significant reduction in amplitude of TRPM3 currents after pregnenolone sulfate stimulation in isolated NK cells from another cohort of CFS/ME patients compared with healthy controls.

The pregnenolone sulfate-evoked ionic currents through TRPM3 channels were again significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients. In addition, we used nifedipine, another reversible TRPM3 agonist to support the previous findings and found similar results confirming a significant loss of the TRPM3 channel activity in CFS/ME patients.

CONCLUSIONS:

Impaired TRPM3 activity was validated in NK cells isolated from CFS/ME patients using different pharmacological tools and whole-cell patch-clamp technique as the gold standard for ion channel research. This investigation further helps to establish TRPM3 channels as a prognostic marker and/ or a potential therapeutic target for CFS/ME.

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Treatment avenues in ME/CFS: a split-gender pharmacogenomic study of gene-expression

Treatment avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a split-gender pharmacogenomic study of gene-expression modules, by Mary G Jeffrey, Lubov Nathanson, Kristina Aenlle, Zachary M Barnes, Mirza Baig, Gordon Broderick, Nancy G Klimas, Mary Ann Fletcher, Travis JA Craddock in Clinical Therapeutics vol 41, issue 5, May 2019, pages 815-835.e6 [https://doi.org/10.1016/j.clinthera.2019.01.011]

 

Research abstract:

doctor holding tabletPurpose:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.

Methods:
Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics.

Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database.

Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.

Findings:
The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147<Cohen delta<0.532).

Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor alpha, transforming growth factor beta, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.

Implications:
The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies.

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Comparison of differential metabolites in urine of the middle school students with CFS before & after exercise

Comparison of differential metabolites in urine of the middle school students with chronic fatigue syndrome before and after exercise [Article in Chinese], by Chi AP, Wang ZN, Shi B, Yang XF, Min RX, Song J in Zhongguo Ying Yong Sheng Li Xue Za Zhi. [Chinese journal of applied physiology] 2018 Apr 8;34(4):340-344 349.

Research abstract:

OBJECTIVE:

To study the differential metabolites in urine and the characteristics of metabolic pathway of middle school students with chronic fatigue syndrome (CFS) before and after exercise, and then explain the metabolic mechanism of CFS.

METHODS:

Eight male middle school students (age:17-19) with CFS were selected as the CFS group according to CFS screening criteria of the U.S. centers. At the same time, 8 male health students of the same age from the same school were selected as the control group. They were administrated to do one-time exercise on the improved Harvard step (up and down steps 30 times/min for 3 minutes).

Their urine was collected before and after exercise, and the differential metabolites in urine were detected by liquid chromatography-mass spectrometry (LC-MS). The multidimensional statistical methods were used to analyze the metabolites by principal component analysis (PCA) and orthogonal projections to latent structures-discriminant analysis (OPLS-DA). Finally, MetPA database was used to analyze the metabolites and to construct the correlative metabolic pathways.

RESULTS:

Compared with the control group, the creatine, indoleacetaldehyde, phytosphingosine and pyroglutamic acid were selected as differential metabolites and the contents of those were decreased significantly (P<0.05 or P<0.01) in CFS group before the step movement.

However, 11 differential metabolites in CFS group were selected out after exercise, which were nonanedioic acid, methyladenosine, acetylcarnitine, capric acid, corticosterone, creatine, levonorgestrel, pantothenic acid, pyroglutamic acid, xanthosine and xanthurenic acid in sequence, the contents of methyladenosine and creatine were significantly increased (P<0.05) and the contents of the other 9 differential metabolites were significantly decreased (P<0.05 or P<0.01) compared with the control group.

The 15 differential metabolites mentioned above were input MetPA database in order to analyze the metabolic pathways weighted score. The results showed that the arginine-proline metabolism pathway disorders were detected in the CFS group before exercise, the marker metabolite was creatine. And 3 metabolic pathways disorder were detected in the CFS group after exercise, which were arginine-proline metabolism, biosynthesis of pantothenic acid and CoA, steroid hormone biosynthesis, and the marker metabolites, in turn, were creatine, pantothenic acid and corticosterone.

CONCLUSIONS:

The disorder of arginine-proline metabolic pathway is detected in CFS middle school students before exercise intervention. After exercise, it can be detected that the steroid hormone biosynthetic metabolic pathway, pantothenic acid and CoA metabolic pathways also have metabolic disorders.

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Altered erythrocyte biophysical properties in CFS

Altered Erythrocyte biophysical properties in Chronic Fatigue Syndrome, by Amit K Saha, Brendan R Schmidt, Julie Wilhelmy, Vy Nguyen, Justin K Do, Vineeth C Suja, Mohsen Nemat-Gorgani, Anand K Ramasubramanian, Ronald W Davis in Biophysical Journal, Vol 116, #3, Suppl 1, p 122a, February 15, 2019

Research: abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide.

In this work, we tested the hypothesis that erythrocyte [red blood cell] biophysical properties are adversely affected in ME/CFS.

We tested erythrocyte deformability using a high-throughput microfluidic device which mimics microcapillaries. We perfused erythrocytes from ME/CFS patients and from age and sex matched healthy controls (n=14 pairs of donors) through a high-throughput microfluidic platform (5μmx5μm).

We recorded cell movement at high speed (4000 fps), followed by image analysis to assess the following parameters: entry time (time required by cells to completely enter the test channels), average transit velocity (velocity of cells inside the test channels) and elongation index (ratio of the major diameter before and after deformation in the test channel).

We observed that erythrocytes from ME/CFS patients had higher entry time, lower average transit velocity and lower elongation index as compared to healthy controls. Taken together, this data shows that erythrocytes from ME/CFS patients have reduced deformability. To corroborate our findings, we measured the erythrocyte sedimentation rate for these donors which show that the erythrocytes from ME/CFS patients had lower sedimentation rates.

To understand the basis for differences in deformability, we investigated changes in the fluidity of the membrane using pyrenedecanoic acid and observed that erythrocytes from ME/CFS patients have lower membrane fluidity. Zeta potential measurements showed that ME/CFS patients had lower net negative surface charge on the erythrocyte plasma membrane.

Higher levels of reactive oxygen species in erythrocytes from ME/CFS patients were also observed. Using scanning electron microscopy, we also observed changes in erythrocyte morphology between ME/CFS patients and healthy controls.

Finally, preliminary studies show that erythrocytes from ‘recovering’ ME/CFS patients do not show such differences, suggesting a connection between erythrocyte deformability and disease severity.

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Assessment of the scientific rigour of randomized controlled trials on the effectiveness of cognitive behavioural therapy & graded exercise therapy for patients with ME/CFS: a systematic review

Assessment of the scientific rigour of randomized controlled trials on the effectiveness of cognitive behavioural therapy and graded exercise therapy for patients with myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review, by SA Ahmed, JC Mewes, HJM Vrijhoef in Journal of Health Psychology [First Published May 10, 2019] https://doi.org/10.1177/1359105319847261

Review article abstract:

Cognitive behavioural therapy and graded exercise therapy have been promoted as effective treatments for patients with myalgic encephalomyelitis/chronic fatigue syndrome. However, criticism on the scientific rigour of these studies has been raised.

This review assessed the methodological quality of studies on the effectiveness of cognitive behavioural therapy and graded exercise therapy.

The methodological quality of the 18 included studies was found to be relatively low, as bias was prominently found, affecting the main outcome measures of the studies (fatigue, physical functioning and functional impairment/status).

Future research should focus on including more objective outcome measures in a well-defined patient population.

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Varied presentation of ME/CFS & the needs for classification & clinician education: a case series

Varied presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and the needs for classification and clinician education: a case series, by Eva Martín-Martínez, & Mercedes Martín-Martínez in Clinical Therapeutics vol 41, issue 4, pages 619–624, April 2019

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, heterogeneous and serious disease.

In this article, we analyze the cases of 3 patients with ME/CFS. Due to the disbeliefs, misconceptions, and stigmas that are attached to ME/CFS, patient diagnosis is made after years of disease progression. Over this period, physicians tried to determine the etiology of the disease, taking into account its onset and symptoms.

The suspected conditions correlated with possible subgroups that researchers speculate may exist in ME/CFS. Therefore, a registry of well-selected data on clinical history could help to cluster patients into more homogenous groups, and could be beneficial for research

Conclusions:

The three cases reported highlight the need of a better medical training to get early diagnosis and a better management of the disease, and in this way it will be also possible to get samples in the early stages of the pathology.

Interestingly, in these clinical cases, the onset correlate with several of the different approaches researches followed: immune, inflammatory, genetic or metabolic disease. Therefore, clinicians can contribute to the generation of subgroups of ME/SCF patients based on clinical presentation and the occurrence of comorbidities.

To this aim, a complete clinical history should be obtained and a minimum of variables should be registered: triggers, onset, localized or generalized affectation, existence of family history, degree of disability, and comorbidities.

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In the news: Missing from their lives, missing from healthcare services

ME Awareness week – in the BBC news in Wales

“All round the world millions of people are missing from their lives. In Wales people are also missing from the healthcare system.  When we go to the surgery we’re not always treated with respect. Sometimes our illness is dismissed. Too few GPs have the knowledge to diagnose accurately and for those who are bedbound and housebound they can’t always get anyone to come and visit them ,so basically we feel invisible and ignored.”                                                                  Jan Russell, chair of WAMES

BBC Wales featured ME on the radio, TV news and online on 10th and 11th May 2019.

BBC Radio Wales: Good Morning Wales, 11 May 2019. The programme covered the nature of ME, healthcare in Wales & the #MillionsMissing event.

  • An interview with Clare Ogden from AfME took place between 05:40 – 10:00 minutes.
  • From 36:40-43:20 Jan Russell from WAMES spoke and parent Alana Sargent from Tylerstown was interviewed.

 

BBC Wales: Wales Today on Sat evening, featured the #MillionsMissing event in Cardiff, Marian Gray from Aberystwyth,  comments from Jan Russell of WAMES and Emelyne Burkhardt from MESiG from 02:00 – 04:12.

 

BBC news online: Humanitarian crisis for ME sufferers in Wales. The online article covers how people go missing from their lives, GPs find it difficult to diagnose & little improvement has been seen in service development. Comments from Marian Gray from Aberystwyth, Jan Russell from WAMES, Miriam Wood from MESiG and Dr Peter Saul from the RCGP.

“People thought I’d moved away or joined a nunnery”, said Marian Gray, who admits going “missing from life”.

She disappeared because she was one of the 13,000 people in Wales battling ME.

Campaigners say there is a “humanitarian crisis” and promises of better support from the Welsh Government have failed to materialise.

 

 

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