2019 – Page 3 – American ME and CFS Society

Understanding neuromuscular disorders in chronic fatigue syndrome

Abstract:

Muscle failure has been demonstrated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Neurophysiological tools demonstrate the existence of both central and peripheral fatigue in these patients. Central fatigue is deduced from the reduced amplitude of myopotentials evoked by transcranial magnetic stimulation of the motor cortex as well as by the muscle response to interpolated twitches during sustained fatiguing efforts. An impaired muscle membrane conduction velocity assessed by the reduced amplitude and lengthened duration of myopotentials evoked by direct muscle stimulation is the defining feature of peripheral fatigue.

Some patients with ME/CFS show an increased oxidative stress response to exercise. The formation of lipid hydroperoxides in the sarcolemma, which alters ionic fluxes, could explain the reduction of muscle membrane excitability and potassium outflow often measured in these patients. In patients with ME/CFS, the formation of heat shock proteins (HSPs) is also reduced. Because HSPs protect muscle cells against the deleterious effects of reactive oxygen species, the lack of their production could explain the augmented oxidative stress and the consecutive alterations of myopotentials which could open a way for future treatment of ME/CFS.

Source: Jammes Y, Retornaz F. Understanding neuromuscular disorders in chronic fatigue syndrome.F1000Res. 2019 Nov 28;8. pii: F1000 Faculty Rev-2020. doi: 10.12688/f1000research.18660.1. eCollection 2019. https://www.ncbi.nlm.nih.gov/pubmed/31814961

Efficacy and safety of Sijunzi Decoction for chronic fatigue syndrome with spleen deficiency pattern: study protocol for a randomized, double-blind, placebo-controlled trial

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS), which is characterized by severe and disabling fatigue, has become an extensively concerned medical disorder in clinical practice. Due to the unclear etiology, current treatments are symptomatic or need assistance from psychology and kinesiology. Under the immature conditions in China, many patients would seek help from traditional Chinese medicine (TCM), in which Chinese herbal medicine (CHM) is one of the main interventions. Sijunzi Decoction (SJZD) is a classical formula and has been utilized in improving fatigue symptoms for a long time. However, lack of rigorously-designed randomized controlled trial limits its application and generalization in CFS management. Hence, we design this clinical trial to assess the effectiveness and safety of SJZD for CFS.

METHODS: This is a single-center, randomized, double-blind, placebo-controlled trial. Two hundred and twelve patients with CFS will be recruited from public and equally allocated to SJZD group and placebo group. Based on the general education, these two groups will receive corresponding drugs twice a day for consecutive 2 months. The follow-up period will be 1 month. The primary outcome will be the change of Chalder fatigue scoring after treatment. Secondary outcomes include the short form-36 physical function subscale (SF36-PF), spleen deficiency rating scale, quality of life and self-rated clinical global impression (CGI) scales.

DISCUSSION: The four ingredients of SJZD are Renshen (Radix Ginseng), Baizhu (Rhizoma Atractylodis Macrocephalae), Fulin (Poria) and Zhigancao (Radix Glycyrrhizae Preparata), which show potential to alleviate CFS on the foundation of available studies. The results of this trial will provide high-quality clinical evidence for the application of SJZD, and hope to further support a new TCM choice in CFS treatment.

TRIAL REGISTRATION: ISRCTN23930966 (ISRCTN registry, registered on 28th May, 2019).

Source: Dai L, Zhou WJ, Wang M, Zhou SG, Ji G. Efficacy and safety of Sijunzi Decoction for chronic fatigue syndrome with spleen deficiency pattern: study protocol for a randomized, double-blind, placebo-controlled trial. Ann Transl Med. 2019 Oct;7(20):587. doi: 10.21037/atm.2019.09.136. https://www.ncbi.nlm.nih.gov/pubmed/31807568

Intimate Partner Violence and the Risk of Developing Fibromyalgia and Chronic Fatigue Syndrome

Abstract:

Intimate partner violence (IPV) is a global public health issue with a variety of ill health consequences associated with exposure. Due to the stimulation of chronic stress and inflammatory pathways, childhood abuse has been associated with the subsequent development of functional syndromes such as fibromyalgia and chronic fatigue syndrome (CFS). Although IPV in women appears to elicit similar biochemical responses, this association has not been tested thoroughly in IPV survivors. These functional syndromes are complex in etiology and any indication of their risk factors would benefit health care professionals managing this population. Therefore, we aimed to investigate the association between exposure to IPV with functional syndromes: fibromyalgia and CFS.

We conducted a retrospective open cohort study using “The Heath Improvement Network” database between January 1, 1995 and December 1, 2017. A total of 18,547 women who were exposed to IPV were each matched by age to four controls who were not exposed (n = 74,188). The main outcome measures were the risk of developing fibromyalgia and CFS. These were presented as adjusted incidence rate ratios (aIRR) with 95% confidence intervals (CIs).

We found that 97 women in the exposed group developed fibromyalgia (incidence rate [IR] = 1.63 per 1,000 person-years) compared to 239 women in the unexposed group (IR = 0.83 per 1,000 person-years). Following adjustment, this translated to an IRR of 1.73 (95% CI = [1.36, 2.22]). Similarly, 19 women developed CFS in the exposed group (IR = 0.32 per 1,000 person-years), compared to 53 in the unexposed group (0.18 per 1,000 person-years), which translates to an aIRR of 1.92 (95% CI = [1.11, 3.33]).

Therefore, we have identified an association between a history of IPV in women and the development of these functional syndromes, which may provide more information to inform the biopsychosocial pathway precipitating the development of fibromyalgia and CFS.

Source: Chandan JS, Thomas T, Raza K, Bradbury-Jones C, Taylor J, Bandyopadhyay S1, Nirantharakumar K. Intimate Partner Violence and the Risk of Developing Fibromyalgia and Chronic Fatigue Syndrome. J Interpers Violence. 2019 Dec 6:886260519888515. doi: 10.1177/0886260519888515. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31805821

Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union

Abstract:

ME/CFS is a chronic, complex, multisystem disease that often limits the health and functioning of the affected patients. Diagnosing patients with ME/CFS is a challenge, and many different case definitions exist and are used in clinical practice and research. Even after diagnosis, medical treatment is very challenging. Symptom relief and coping may affect how patients live with their disease and their quality of life. There is no consensus on which diagnostic criteria should be used and which treatment strategies can be recommended for patients.

The purpose of the current project was to map the landscape of the Euromene countries in respect of national guidelines and recommendations for case definition, diagnosis and clinical approaches for ME/CFS patients. A 23 items questionnaire was sent out by email to the members of Euromene. The form contained questions on existing guidelines for case definitions, treatment/management of the disease, tests and questionnaires applied, and the prioritization of information for data sampling in research. We obtained information from 17 countries. Five countries reported having national guidelines for diagnosis, and five countries reported having guidelines for clinical approaches.

For diagnostic purposes, the Fukuda criteria were most often recommended, and also the Canadian Consensus criteria, the International Consensus Criteria and the Oxford criteria were used. A mix of diagnostic criteria was applied within those countries having no guidelines. Many different questionnaires and tests were used for symptom registration and diagnostic investigation. For symptom relief, pain and anti-depressive medication were most often recommended. Cognitive Behavioral Therapy and Graded Exercise treatment were often recommended as disease management and rehabilitative/palliative strategies.

The lack of consistency in recommendations across European countries urges the development of regulations, guidance and standards. The results of this study will contribute to the harmonization of diagnostic criteria and treatment for ME/CFS in Europe.

Source: Strand EB, Nacul L, Mengshoel AM, Helland IB, Grabowski P, Krumina A, Alegre-Martin J, Efrim-Budisteanu M, Sekulic S, Pheby D, Sakkas GK, Sirbu CA, Authier FJ; European Network on ME/CFS (EUROMENE). Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union. PLoS One. 2019 Dec 5;14(12):e0225995. doi: 10.1371/journal.pone.0225995. eCollection 2019. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225995 (Full article)

Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterised by fatigue and post-exertional malaise. Its pathogenesis is poorly understood. GDF15 is a circulating protein secreted by cells in response to a variety of stressors. The receptor for GDF15 is expressed in the brain, where its activation results in a range of responses. Among the conditions in which circulating GDF15 levels are highly elevated are mitochondrial disorders, where early skeletal muscle fatigue is a key symptom. We hypothesised that GDF15 may represent a marker of cellular stress in ME/CFS.

METHODS: GDF15 was measured in serum from patients with ME/CFS (n = 150; 100 with mild/moderate and 50 with severe symptoms), “healthy volunteers” (n = 150) and a cohort of patients with multiple sclerosis (n = 50).

RESULTS: Circulating GDF15 remained stable in a subset of ME/CFS patients when sampled on two occasions ~ 7 months (IQR 6.7-8.8) apart, 720 pg/ml (95% CI 625-816) vs 670 pg/ml (95% CI 598-796), P = 0.5. GDF15 levels were 491 pg/ml in controls (95% CI 429-553), 546 pg/ml (95% CI 478-614) in MS patients, 560 pg/ml (95% CI 502-617) in mild/moderate ME/CFS patients and 602 pg/ml (95% CI 531-674) in severely affected ME/CFS patients. Accounting for potential confounders, severely affected ME/CFS patients had GDF15 concentrations that were significantly increased compared to healthy controls (P = 0.01). GDF15 levels were positively correlated (P = 0.026) with fatigue scores in ME/CFS.

CONCLUSIONS: Severe ME/CFS is associated with increased levels of GDF15, a circulating biomarker of cellular stress that appears which stable over several months.

Source: Melvin A, Lacerda E, Dockrell HM, O’Rahilly S, Nacul L. Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2019 Dec 4;17(1):409. doi: 10.1186/s12967-019-02153-6. https://www.ncbi.nlm.nih.gov/pubmed/31801546

Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is hallmarked by a significant reduction in natural killer (NK) cell cytotoxicity, a mechanism tightly regulated by calcium (Ca2+). Interestingly, interleukin-2 (IL-2) increases NK cell cytotoxicity. Transient receptor potential melastatin 2 (TRPM2) ion channels are fundamental for Ca2+ signalling in NK cells. This pilot investigation aimed to characterise TRPM2 and CD38 surface expression in vitro on NK cells in ME/CFS patients. This investigation furthermore examined the pharmaceutical effect of 8-bromoadenosine phosphoribose (8-Br-ADPR) and N6-Benzoyladenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP) on TRPM2 and CD38 surface expression and NK cell cytotoxicity between ME/CFS and healthy control (HC) participants.

METHODS: Ten ME/CFS patients (43.45 ± 12.36) and 10 HCs (43 ± 12.27) were age and sex-matched. Isolated NK cells were labelled with fluorescent antibodies to determine baseline and drug-treated TRPM2 and CD38 surface expression on NK cell subsets. Following IL-2 stimulation, NK cell cytotoxicity was measured following 8-Br-ADPR and N6-Bnz-cAMP drug treatments by flow cytometry.

RESULTS: Baseline TRPM2 and CD38 surface expression was significantly higher on NK cell subsets in ME/CFS patients compared with HCs. Post IL-2 stimulation, TRPM2 and CD38 surface expression solely decreased on the CD56DimCD16+ subset. 8-Br-ADPR treatment significantly reduced TRPM2 surface expression on the CD56BrightCD16Dim/- subset within the ME/CFS group. Baseline cell cytotoxicity was significantly reduced in ME/CFS patients, however no changes were observed post drug treatment in either group.

CONCLUSION: Overexpression of TRPM2 on NK cells may function as a compensatory mechanism to alert a dysregulation in Ca2+ homeostasis to enhance NK cell function in ME/CFS, such as NK cell cytotoxicity. As no improvement in NK cell cytotoxicity was observed within the ME/CFS group, an impairment in the TRPM2 ion channel may be present in ME/CFS patients, resulting in alterations in [Ca2+]i mobilisation and influx, which is fundamental in driving NK cell cytotoxicity. Differential expression of TRPM2 between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in ME/CFS.

Source: Balinas C, Cabanas H, Staines D, Marshall-Gradisnik S. Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2019 Dec 3;17(1):401. doi: 10.1186/s12967-019-02155-4. https://www.ncbi.nlm.nih.gov/pubmed/31796045

Myalgic encephalomyelitis and chronic fatigue syndrome case definitions: effects of requiring a substantial reduction in functioning

Abstract:

BACKGROUND: Current case definitions for myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) require an individual to report a ‘substantial reduction’ in activity levels, when compared to premorbid functioning. However, little guidance is provided on how to measure these reductions, as well as what level of reduction should be deemed ‘substantial,’ leading to inconsistencies in how this criterion is applied across research settings.

PURPOSE: The current study examined the influence of substantial reduction criterion on case definitions.

METHOD: The current study analyzed an international convenience sample of 1002 individuals with ME or CFS, 53 healthy controls, and 260 controls with other chronic illnesses.

RESULTS: Findings indicated that the utility of the substantial reduction criterion varied by case definition, with more stringent case definitions not needing this criterion to identify cases.

CONCLUSION: These results suggest that the requirement of a substantial reduction in functioning may be redundant when case definitions specify that individuals must endorse a set of core symptoms at specified frequency and severity levels.

Source: Scartozzi S, Sunnquist M, Jason LA. Myalgic encephalomyelitis and chronic fatigue syndrome case definitions: effects of requiring a substantial reduction in functioning. Fatigue. 2019;7(2):59-68. doi: 10.1080/21641846.2019.1600825. Epub 2019 Apr 1. https://www.ncbi.nlm.nih.gov/pubmed/31788347

A laboratory approach for characterizing chronic fatigue: what does metabolomics tell us?

Abstract:

INTRODUCTION: Manifestations of fatigue range from chronic fatigue up to a severe syndrome and myalgic encephalomyelitis. Fatigue grossly affects the functional status and quality of life of affected individuals, prompting the World Health Organization to recognize it as a chronic non-communicable condition.

OBJECTIVES: Here, we explore the potential of urinary metabolite information to complement clinical criteria of fatigue, providing an avenue towards an objective measure of fatigue in patients presenting with the full spectrum of fatigue levels.

METHODS: The experimental group consisted of 578 chronic fatigue female patients. The measurement design was composed of (1) existing clinical fatigue scales, (2) a hepatic detoxification challenge test, and (3) untargeted proton nuclear magnetic resonance (1H-NMR) procedure to generate metabolomics data. Data analysed via an in-house Matlab script that combines functions from a Statistics and a PLS Toolbox.

RESULTS: Multivariate analysis of the original 459 profiled 1H-NMR bins for the low (control) and high (patient) fatigue groups indicated complete separation following the detoxification experimental challenge. Important bins identified from the 1H-NMR spectra provided quantitative metabolite information on the detoxification challenge for the fatigue groups.

CONCLUSIONS: Untargeted 1H-NMR metabolomics proved its applicability as a global profiling tool to reveal the impact of toxicological interventions in chronic fatigue patients. No clear potential biomarker emerged from this study, but the quantitative profile of the phase II biotransformation products provide a practical visible effect directing to up-regulation of crucial phase II enzyme systems in the high fatigue group in response to a high xenobiotic-load.

Source: Erasmus E, Mason S, van Reenen M, Steffens FE, Vorster BC, Reinecke CJ. A laboratory approach for characterizing chronic fatigue: what does metabolomics tell us? Metabolomics. 2019 Nov 27;15(12):158. doi: 10.1007/s11306-019-1620-4. https://www.ncbi.nlm.nih.gov/pubmed/31776682

Parasympathetic activity is reduced during slow-wave sleep, but not resting wakefulness, in patients with chronic fatigue syndrome

Abstract:

STUDY OBJECTIVES: Physiological dearousal characterized by an increase in parasympathetic nervous system activity is important for good-quality sleep. Previous research shows that nocturnal parasympathetic activity (reflected by heart rate variability [HRV]) is diminished in individuals with chronic fatigue syndrome (CFS), suggesting hypervigilant sleep. This study investigated differences in nocturnal autonomic activity across sleep stages and explored the association of parasympathetic activity with sleep quality and self-reported physical and psychological wellbeing in individuals with CFS.

METHODS: Twenty-four patients with medically diagnosed CFS, and 24 matched healthy control individuals participated. Electroencephalography and HRV were recorded during sleep in participants’ homes using a minimally invasive ambulatory device. Questionnaires were used to measure self-reported wellbeing and sleep quality.

RESULTS: Sleep architecture in patients with CFS differed from that of control participants in slower sleep onset, more awakenings, and a larger proportion of time spent in slow-wave sleep (SWS). Linear mixed-model analyses controlling for age revealed that HRV reflecting parasympathetic activity (normalized high frequency power) was reduced in patients with CFS compared to control participants, particularly during deeper stages of sleep. Poorer self-reported wellbeing and sleep quality was associated with reduced parasympathetic signaling during deeper sleep, but not during wake before sleep, rapid eye movement sleep, or with the proportion of time spent in SWS.

CONCLUSIONS: Autonomic hypervigilance during the deeper, recuperative stages of sleep is associated with poor quality sleep and self-reported wellbeing. Causal links need to be confirmed but provide potential intervention opportunities for the core symptom of unrefreshing sleep in CFS.

Source: Fatt SJ, Beilharz JE, Joubert M, Wilson C, Lloyd AR, Vollmer-Conna U, Cvejic E. Parasympathetic activity is reduced during slow-wave sleep, but not resting wakefulness, in patients with chronic fatigue syndrome. J Clin Sleep Med. 2019 Nov 27. pii: jc-19-00271. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31771749

Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/ chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS.

We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers.

Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.

Source: Eguchi A, Fukuda S, Kuratsune H, Nojima J, Nakatomi Y, Watanabe Y, Feldstein AE. Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/ chronic fatigue syndrome. Brain Behav Immun. 2019 Nov 20. pii: S0889-1591(19)30762-7. doi: 10.1016/j.bbi.2019.11.015. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31759091