Tag: 2021

Our Evolving Understanding of ME/CFS

Abstract:

The potential benefits of the scientific insights gleaned from years of treating ME/CFS for the emerging symptoms of COVID-19, and in particular Longhaul- or Longhauler-COVID-19 are discussed in this opinion article. Longhaul COVID-19 is the current name being given to the long-term sequelae (symptoms lasting beyond 6 weeks) of SARS-CoV-2 infection. Multiple case definitions for ME/CFS exist, but post-exertional malaise (PEM) is currently emerging as the ‘hallmark’ symptom. The inability to identify a unique trigger of ME/CFS, as well as the inability to identify a specific, diagnostic laboratory test, led many physicians to conclude that the illness was psychosomatic or non-existent. However, recent research in the US and the UK, championed by patient organizations and their use of the internet and social media, suggest underlying pathophysiologies, e.g., oxidative stress and mitochondrial dysfunction. The similarity and overlap of ME/CFS and Longhaul COVID-19 symptoms suggest to us similar pathological processes.

We put forward a unifying hypothesis that explains the precipitating events such as viral triggers and other documented exposures: For their overlap in symptoms, ME/CFS and Longhaul COVID-19 should be described as Post Active Phase of Infection Syndromes (PAPIS). We further propose that the underlying biochemical pathways and pathophysiological processes of similar symptoms are similar regardless of the initiating trigger. Exploration of the biochemical pathways and pathophysiological processes should yield effective therapies for these conditions and others that may exhibit these symptoms. ME/CFS patients have suffered far too long. Longhaul COVD-19 patients should not be subject to a similar fate. We caution that failure to meet the now combined challenges of ME/CFS and Longhaul COVID-19 will impose serious socioeconomic as well as clinical consequences for patients, the families of patients, and society as a whole.

Source: Friedman KJ, Murovska M, Pheby DFH, Zalewski P. Our Evolving Understanding of ME/CFS. Medicina (Kaunas). 2021 Feb 26;57(3):200. doi: 10.3390/medicina57030200. PMID: 33652622. https://www.mdpi.com/1648-9144/57/3/200 (Full text)

Cost-effectiveness of Interventions for Chronic Fatigue Syndrome or Myalgic Encephalomyelitis: A Systematic Review of Economic Evaluations

Abstract:

Introduction: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has profound quality of life and economic consequences for individuals, their family, formal services and wider society. Little is known about which therapeutic interventions are more cost-effective.

Objective: A systematic review was carried out to identify and critically appraise the evidence on the cost-effectiveness of CFS/ME interventions.

Methods: The review protocol was prespecified (PROSPERO: CRD42018118731). Searches were carried out across two databases-MEDLINE (1946-2020) and EMBASE (1974-2020). Additional studies were identified by searching reference lists. Only peer-reviewed journal articles of full economic evaluations examining CFS/ME interventions were included. Trial- and/or model-based economic evaluations were eligible. Data extraction and screening were carried out independently by two reviewers. The methodological quality of the economic evaluation and trial were assessed using the Consensus Health Economic Criteria checklist (CHEC-list) and Risk of Bias-2 (RoB-2) tool, respectively. A narrative synthesis was used to summarise the economic evidence for interventions for adults and children in primary and secondary care settings.

Results: Ten economic evaluations, all based on data derived from randomised controlled trials, met our eligibility criteria. Cognitive behavioural therapy (CBT) was evaluated across five studies, making it the most commonly evaluated intervention. There was evidence from three trials to support CBT as a cost-effective treatment option for adults; however, findings on CBT were not uniform, suggesting that cost-effectiveness may be context-specific. A wide array of other interventions were evaluated in adults, including limited evidence from two trials supporting the cost effectiveness of graded exercise therapy (GET). Just one study assessed intervention options for children. Our review highlighted the importance of informal care costs and productivity losses in the evaluation of CFS/ME interventions.

Conclusions: We identified a limited patchwork of evidence on the cost-effectiveness of interventions for CFS/ME. Evidence supports CBT as a cost-effective treatment option for adults; however, cost-effectiveness may depend on the duration and frequency of sessions. Limited evidence supports the cost effectiveness of GET. Key weaknesses in the literature included small sample sizes and short duration of follow-up. Further research is needed on pharmacological interventions and therapies for children.

Source: Cochrane M, Mitchell E, Hollingworth W, Crawley E, Trépel D. Cost-effectiveness of Interventions for Chronic Fatigue Syndrome or Myalgic Encephalomyelitis: A Systematic Review of Economic Evaluations. Appl Health Econ Health Policy. 2021 Mar 1:1–14. doi: 10.1007/s40258-021-00635-7. Epub ahead of print. PMID: 33646528; PMCID: PMC7917957. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917957/ (Full text)

Chronic fatigue syndrome: Abnormally fast muscle fiber conduction in the membranes of motor units at low static force load

Abstract:

Objective: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are disorders of unknown etiology and unclear pathophysiology, with overlapping symptoms of – especially muscular -fatigue and pain. Studies have shown increased muscle fiber conduction velocity (CV) in the non-painful muscles of FM patients. We investigated whether CFS patients also show CV abnormalities.

Methods: Females with CFS (n = 25), with FM (n = 22), and healthy controls (n = 21) underwent surface electromyography of the biceps brachii, loaded up to 20% of maximum strength, during short static contractions. The mean CV and motor unit potential (MUP) velocities with their statistical distribution were measured.

Results: The CV changes with force differed between CFS-group and both FM-group and controls (P = 0.01). The CV of the CFS-group increased excessively with force (P < 0.001), whereas that of the controls increased only slightly and non-significantly, and that of the FM-group did not increase at all. In the CFS-group, the number of MUPs conveying very high conduction velocities increased abundantly with force and the MUPs narrowed.

Conclusion: Our results suggest disturbed muscle membrane function in CFS patients, in their motor units involved in low force generation. Central neural deregulation may contribute to this disturbance.

Chronic fatigue syndrome (CFS)/Myalgic Encephalomyelitis (ME) and Fibromyalgia (FM): the foundation of a relationship

Abstract:

Introduction: Chronic fatigue syndrome (CFS)/Myalgic Encephalomyelitis (ME) and fibromyalgia (FM) are both debilitating syndromes with complex polysymptomatology. Early research infers that a relationship may exist even though the diagnosis provided may influence the management trajectory. In the absence of a diagnostic test and treatment, this study aims to confirm the symptoms and their severity, which may infer a relationship and influence future research.

Method: A quasi-experimental design was utilised, using Internet-based self-assessment questionnaires focusing on nine symptom areas: criteria, pain, sleep, fatigue, anxiety and depression, health-related quality of life, self-esteem and locus of control. The questionnaires used for data collection are as follows: the American Centre for Disease Control and Prevention Symptom Inventory for CFS/ME (American CDC Symptom Inventory); the American College of Rheumatology (ACR) Criteria for FM; Fibromyalgia Impact Questionnaire (FIQ); McGill Pain Questionnaire (MPQ); Multidimensional Fatigue Inventory (MFI); Pittsburgh Sleep Quality Index (PSQI); Health-Related Quality of Life SF-36 V2 (HRQoL SF-36 V2); Hospital Anxiety and Depression Scale (HADS); Multidimensional Health Locus of Control (MHLOC) and the Rosenberg Self-Esteem Scale (RSES).

Setting and participants: Participants were recruited from two distinct community groups, namely CFS/ME (n = 101) and FM (n = 107). Participants were male and female aged 17 (CFS/ME mean age 45.5 years; FM mean age 47.2 years).

Results: All participants in the CFS/ME and FM groups satisfied the requirements of their individual criteria. Results confirmed that both groups experienced the debilitating symptoms measured, with the exception of anxiety and depression, impacting on their quality of life. Results suggest a relationship between CFS/ME and FM, indicating the requirement for future research.

Source: Mckay PG, Martin CR, Walker H, Fleming M. Chronic fatigue syndrome (CFS)/Myalgic Encephalomyelitis (ME) and Fibromyalgia (FM): the foundation of a relationship. Br J Pain. 2021 Feb;15(1):26-39. doi: 10.1177/2049463719875164. Epub 2019 Oct 5. PMID: 33633851; PMCID: PMC7882776. https://pubmed.ncbi.nlm.nih.gov/33633851/

Historical Insight into Infections and Disorders Associated with Neurological and Psychiatric Sequelae Similar to Long COVID

Abstract:

Long-term sequelae of coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are now recognized. However, there is still a lack of consensus regarding the terminology for this emerging chronic clinical syndrome, which includes long COVID, chronic COVID syndrome, post-COVID-19 syndrome, post-acute COVID-19, and long-hauler COVID-19. In this review, I will use the term “long COVID”. A review of the medical history and epidemiology of past pandemics and epidemics in modern literature review identifies common long-term post-infectious disorders, with the common finding of altered cognition.

In the brain, the cerebral hypoxia induced by SARS-CoV-2 infection may be caused by mitochondrial dysfunction, resulting in “brain fog”. Historically, the common symptom of altered cognition has been reported during earlier pandemics, which include the influenza pandemics of 1889 and 1892 (Russian flu), the Spanish flu pandemic (1918-1919), encephalitis lethargica, diphtheria, and myalgic encephalomyelitis (chronic fatigue syndrome or post-viral fatigue syndrome).

There are similarities between chronic fatigue syndrome and the “brain fog” described in long COVID. During past viral epidemics and pandemics, a commonality of neural targets may have increased viral survival by conformational matching. The neurological and psychiatric sequelae of SARS-CoV-2 infection, or long COVID, may have emerged from neural effects that have emerged from an invertebrate and vertebrate virosphere. This review aims to present a historical overview of infections and disorders associated with neurological and psychiatric sequelae that have shown similarities with long COVID.

Source: Stefano GB. Historical Insight into Infections and Disorders Associated with Neurological and Psychiatric Sequelae Similar to Long COVID. Med Sci Monit. 2021 Feb 26;27:e931447. doi: 10.12659/MSM.931447. PMID: 33633106; PMCID: PMC7924007. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924007/ (Full text)

A systematic review of nutraceutical interventions for mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness, characterised by persistent fatigue that is unrelieved by rest, in combination with a range of other disabling symptoms. There is no diagnostic test nor targeted treatment available for this illness. The pathomechanism also remains unclear. Mitochondrial dysfunctions have been considered a possible underlying pathology based on reported differences including structural and functional changes in ME/CFS patients compared to healthy controls. Due to the potential role that mitochondria may play in ME/CFS, mitochondrial-targeting nutraceutical interventions have been used to potentially assist in improving patient outcomes such as fatigue. The aim of this systematic review is to appraise literature assessing these nutraceuticals as a possible intervention for treating ME/CFS.

Methods: A systematic search of Pubmed, Embase, Medline (EBSCO host) and Web of Science (via Clarivate Analytics) for journal articles published between January 1995 and 10th November 2020 was conducted. Articles assessing nutraceutical interventions and ME/CFS patient outcomes were retrieved. Using specific inclusion and exclusion criteria, the list of articles was further refined. Quality was measured using the Rosendal scale.

Results: Nine intervention studies were included in this review. The studies investigated patient symptom severity changes such as altered fatigue levels in response to mitochondrial-targeting nutraceuticals. Improvements in fatigue levels were observed in six of the nine studies. Secondary outcomes assessed include biochemical, psychological, and quality of life parameters.

Conclusion: There is insufficient evidence on the effectiveness of mitochondria- targeting nutraceuticals in ME/CFS patients. Future well-designed studies are required to elucidate both the involvement of mitochondria in the pathomechanism of ME/CFS and the effect of mitochondrial-modifying agents on illness severity.

Source: Maksoud R, Balinas C, Holden S, Cabanas H, Staines D, Marshall-Gradisnik S. A systematic review of nutraceutical interventions for mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2021 Feb 17;19(1):81. doi: 10.1186/s12967-021-02742-4. PMID: 33596913; PMCID: PMC7890871. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02742-4  (Full text)

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

Abstract:

Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates.

In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10-4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10-4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10-3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.

Source: Missailidis D, Sanislav O, Allan CY, Smith PK, Annesley SJ, Fisher PR. Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts. Int J Mol Sci. 2021 Feb 19;22(4):2046. doi: 10.3390/ijms22042046. PMID: 33669532; PMCID: PMC7921983. https://www.mdpi.com/1422-0067/22/4/2046/htm (Full text)

Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Evidence is emerging that individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may suffer from chronic vascular dysfunction as a result of illness-related oxidative stress and vascular inflammation. The study aimed to examine the impact of maximal-intensity aerobic exercise on vascular function 48 and 72 h into recovery.

Methods: ME/CFS (n = 11) with gender and age-matched controls (n = 11) were randomly assigned to either a 48 h or 72 h protocol. Each participant had measures of brachial blood pressure, augmentation index (AIx75, standardized to 75 bpm) and carotid-radial pulse wave velocity (crPWV) taken. This was followed by a maximal incremental cycle exercise test. Resting measures were repeated 48 or 72 h later (depending on group allocation).

Results: No significant differences were found when ME/CFS were directly compared to controls at baseline. During recovery, the 48 h control group experienced a significant 7.2% reduction in AIx75 from baseline measures (p < 0.05), while the matched ME/CFS experienced no change in AIx75. The 72 h ME/CFS group experienced a non-significant increase of 1.4% from baseline measures. The 48 h and 72 h ME/CFS groups both experienced non-significant improvements in crPWV (0.56 ms−1 and 1.55 ms−1, respectively).

Conclusions: The findings suggest that those with ME/CFS may not experience exercise-induced vasodilation due to chronic vascular damage, which may be a contributor to the onset of post-exertional malaise (PEM).

Source: Bond J, Nielsen T, Hodges L. Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Environmental Research and Public Health. 2021; 18(5):2366. https://doi.org/10.3390/ijerph18052366 https://www.mdpi.com/1660-4601/18/5/2366/htm (Full text)

Three Cases of Severe ME/CFS in Adults

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, only partially understood multi-system disease whose onset and severity vary widely. Symptoms include overwhelming fatigue, post-exertional malaise, sleep disruptions, gastrointestinal issues, headaches, orthostatic intolerance, cognitive impairment, etc. ME/CFS is a physiological disease with an onset often triggered by a viral or bacterial infection, and sometimes by toxins. Some patients have a mild case and are able to function nearly on a par with healthy individuals, while others are moderately ill and still others are severely, or even, very severely ill. The cohort of moderately to very severely ill is often housebound or bedbound, has lost employment or career, and has engaged in a long, and often futile, search for treatment and relief. Here, we present three case studies, one each of a moderately ill, a severely ill, and a very severely ill person, to demonstrate the complexity of the disease, the suffering of these patients, and what health care providers can do to help.

Source: Williams LR, Isaacson-Barash C. Three Cases of Severe ME/CFS in Adults. Healthcare (Basel). 2021 Feb 16;9(2):215. doi: 10.3390/healthcare9020215. PMID: 33669438; PMCID: PMC7920463. https://www.mdpi.com/2227-9032/9/2/215 (Full text)

Perceptions of European ME/CFS Experts Concerning Knowledge and Understanding of ME/CFS among Primary Care Physicians in Europe: A Report from the European ME/CFS Research Network (EUROMENE)

Abstract:

Background and Objectives: We have conducted a survey of academic and clinical experts who are participants in the European ME/CFS Research Network (EUROMENE) to elicit perceptions of general practitioner (GP) knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and suggestions as to how this could be improved.

Materials and Methods: A questionnaire was sent to all national representatives and members of the EUROMENE Core Group and Management Committee. Survey responses were collated and then summarized based on the numbers and percentages of respondents selecting each response option, while weighted average responses were calculated for questions with numerical value response options. Free text responses were analysed using thematic analysis.

Results: Overall there were 23 responses to the survey from participants across 19 different European countries, with a 95% country-level response rate. Serious concerns were expressed about GPs’ knowledge and understanding of ME/CFS, and, it was felt, about 60% of patients with ME/CFS went undiagnosed as a result. The vast majority of GPs were perceived to lack confidence in either diagnosing or managing the condition. Disbelief, and misleading illness attributions, were perceived to be widespread, and the unavailability of specialist centres to which GPs could refer patients and seek advice and support was frequently commented upon. There was widespread support for more training on ME/CFS at both undergraduate and postgraduate levels.

Conclusion: The results of this survey are consistent with the existing scientific literature. ME/CFS experts report that lack of knowledge and understanding of ME/CFS among GPs is a major cause of missed and delayed diagnoses, which renders problematic attempts to determine the incidence and prevalence of the disease, and to measure its economic impact. It also contributes to the burden of disease through mismanagement in its early stages.

Source: Cullinan J, Pheby DFH, Araja D, Berkis U, Brenna E, de Korwin JD, Gitto L, Hughes DA, Hunter RM, Trepel D, Wang-Steverding X. Perceptions of European ME/CFS Experts Concerning Knowledge and Understanding of ME/CFS among Primary Care Physicians in Europe: A Report from the European ME/CFS Research Network (EUROMENE). Medicina (Kaunas). 2021 Feb 26;57(3):208. doi: 10.3390/medicina57030208. PMID: 33652747. https://www.mdpi.com/1010-660X/57/3/208 (Full text)