Not what it seems to be: Depression versus periodic limb movement disorder

Abstract:

Sleep disorders often disturb sleep. Daytime symptoms of disturb sleep mimic that of depression, somatoform disorder, fibromyalgia and chronic fatigue syndrome. We are presenting a case of depression who was not responding to antidepressant therapy. Based on clinical history, diagnosis was changed to chronic fatigue syndrome and in view of prominent sleep disturbances, polysomnography was done. Based on sleep study data, diagnosis of periodic limb movement disorder was made and he was started on ropinirole, that improved his symptoms.

Source: Gupta R, Kundu K, Khayyam K, Saini LK. Not what it seems to be: Depression versus periodic limb movement disorder. Indian J Psychiatry. 2020 Jul-Aug;62(4):437-439. doi: 10.4103/psychiatry.IndianJPsychiatry_450_19. Epub 2020 Jul 27. PMID: 33165358; PMCID: PMC7597704. https://pubmed.ncbi.nlm.nih.gov/33165358/

Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study.

Results: DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity. Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls.

Conclusions: Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.

Source: Helliwell AM, Sweetman EC, Stockwell PA, Edgar CD, Chatterjee A, Tate WP. Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions. Clin Epigenetics. 2020 Nov 4;12(1):167. doi: 10.1186/s13148-020-00960-z. PMID: 33148325; PMCID: PMC7641803. https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-020-00960-z  (Full study)

The negative impact of the psychiatric model of chronic fatigue syndrome on doctors’ understanding and management of the illness

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling condition that greatly impacts the lives of sufferers. Many sufferers report problems getting a confirmatory diagnosis and difficulties getting doctors to believe them and offer support. Objective: This paper explores this issue by examining a biopsychosocial (BPS) model of ME/CFS promoted within psychiatry and its potential influence on how doctors might view and manage the illness.

Method: A narrative literature review is undertaken to identify salient theory and discourse for consideration.

Findings: Psychiatrists proffer a hypothetical model of ME/CFS aetiology and continuance, that instructs doctors to view the illness as a syndrome perpetuated by psycho-social factors that sustain unexplained symptoms such as fatigue, pain and post-exertional malaise, rather than symptoms being related to biological disease processes. The psychiatric model theorises that patients’ symptoms are maintained by their maladaptive beliefs and behaviours, requiring psychotherapy.

Conclusion: The psychiatric BPS model of ME/CFS may negatively bias how physicians approach the illness, with doctors directed to view patients’ complaints as manifestations of psychological distress, rather than physical symptoms that require medical investigation or intervention. This finding may help explain why many ME/CFS patients feel disbelieved and unsupported after seeking medical care. Psychiatric theory fails to acknowledge or incorporate a substantial body of evidence showing biological deficits associated with ME/CFS. Medical trainees and physicians need more training and clinical exposure to ME/CFS patients, armed with better awareness of misleading and unproven claims associated with the BPS model.

Source: Keith Geraghty (2020) The negative impact of the psychiatric model of chronic fatigue syndrome on doctors’ understanding and management of the illness, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2020.1834295 https://www.tandfonline.com/doi/abs/10.1080/21641846.2020.1834295?journalCode=rftg20

Circulating leptin levels in patients with myalgic encephalomyelitis, chronic fatigue syndrome or fibromyalgia: a systematic review protocol

Abstract:

Objective: The objective of the review is to evaluate circulating levels of leptin in people diagnosed with myalgic encephalomyelitis chronic fatigue syndrome or fibromyalgia syndrome and to investigate the differences compared with healthy controls.

Introduction: Myalgic encephalomyelitis chronic fatigue syndrome is a condition that has major symptoms, including self-reported fatigue, post-exertional malaise, and unexplained pain across the body. The widespread pain is measured in a systematic way and is often referred to as fibromyalgia. The two disorders have many similarities, but their association with leptin has indicated that leptin may affect the role of pro-inflammatory cytokines and symptom severity.

Inclusion criteria: This review will consider observational studies of varying study designs including prospective and retrospective cohort studies, case-control studies, time-series, and analytical cross-sectional studies that include both cases and healthy comparators. Cases will include a diagnosis of myalgic encephalomyelitis, chronic fatigue syndrome, and/or fibromyalgia. Controls are people without this diagnosis, usually healthy participants. Only studies published in English will be included due to limited resources for translation.

Methods: This protocol will be reported based on the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist and will follow the JBI methodology for systematic reviews of etiology and risk. A comprehensive search strategy will include PubMed, Embase, Scopus, Science Direct, and PsycINFO. Two reviewers will screen, critically appraise eligible articles, and extract data using a standardized data extraction tool informed by JBI SUMARI. The authors will complete a quantitative analysis that synthesizes findings across studies using pooled effect sizes and confidence intervals of the measures provided.

Source: Musker M, McArthur A, Munn Z, Wong ML. Circulating leptin levels in patients with myalgic encephalomyelitis, chronic fatigue syndrome or fibromyalgia: a systematic review protocol. JBI Evid Synth. 2020 Oct 30. doi: 10.11124/JBIES-20-00125. Epub ahead of print. PMID: 33136710. https://pubmed.ncbi.nlm.nih.gov/33136710/

Systematic Review of Primary Outcome Measurements for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in Randomized Controlled Trials

Abstract:

Background: Due to its unknown etiology, the objective diagnosis and therapeutics of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are still challenging. Generally, the patient-reported outcome (PRO) is the major strategy driving treatment response because the patient is the most important judge of whether changes are meaningful.

Methods: In order to determine the overall characteristics of the main outcome measurement applied in clinical trials for CFS/ME, we systematically surveyed the literature using two electronic databases, PubMed and the Cochrane Library, throughout June 2020. We analyzed randomized controlled trials (RCTs) for CFS/ME focusing especially on main measurements.

Results: Fifty-two RCTs out of a total 540 searched were selected according to eligibility criteria. Thirty-one RCTs (59.6%) used single primary outcome and others adapted ≥2 kinds of measurements. In total, 15 PRO-derived tools were adapted (50 RCTs; 96.2%) along with two behavioral measurements for adolescents (4 RCTs; 7.7%). The 36-item Short Form Health Survey (SF-36; 16 RCTs), Checklist Individual Strength (CIS; 14 RCTs), and Chalder Fatigue Questionnaire (CFQ; 11 RCTs) were most frequently used as the main outcomes. Since the first RCT in 1996, Clinical Global Impression (CGI) and SF-36 have been dominantly used each in the first and following decade (26.1% and 28.6%, respectively), while both CIS and Multidimensional Fatigue Inventory (MFI) have been the preferred instruments (21.4% each) in recent years (2016 to 2020).

Conclusions: This review comprehensively provides the choice pattern of the assessment tools for interventions in RCTs for CFS/ME. Our data would be helpful practically in the design of clinical studies for CFS/ME-related therapeutic development.

Source: Kim DY, Lee JS, Son CG. Systematic Review of Primary Outcome Measurements for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in Randomized Controlled Trials. J Clin Med. 2020 Oct 28;9(11):E3463. doi: 10.3390/jcm9113463. PMID: 33126460. https://pubmed.ncbi.nlm.nih.gov/33126460/

The antinuclear antibody dense fine speckled pattern and possible clinical associations: An indication of a proinflammatory microenvironment

Abstract:

Background: Indirect immunofluorescence (IIF) is the most prevalent screening antinuclear antibody test for systemic autoimmune rheumatic disease (SARD). Certain IIF patterns have known antibody and disease associations, but the dense fine speckled (ANA-DFS) pattern has no confirmed clinical associations. Our objective was to determine the prevalence of SARD among a group of ANA-DFS positive individuals and to identify final diagnoses among non-SARD individuals in order to determine possible clinical associations with the ANA-DFS pattern.

Methods: A retrospective study of 425 patients from a university health care system with a positive ANA-DFS pattern consecutively between August 2017 and September 2018. Sera samples underwent ANA testing by IIF on HEp-2 cell substrates (Euroimmun, Germany). Clinical information was retrieved from electronic health records and stored in a de-identified database.

Results: The prevalence of SARD was 24%. Undetermined diagnosis (17%), skin disorders (12.1%), and fibromyalgia/chronic pain syndrome/chronic fatigue syndrome (11.8%) were the most common non-SARD diagnoses. Taking into account past medical history, the most common non-SARD were atopic disorders (21.2%), fibromyalgia/chronic pain syndrome/chronic fatigue syndrome (17.6%), and skin disorders (16.7%).

Conclusions: The ANA-DFS pattern may be indicative of an underlying antigen-antibody interaction that plays a role in either the initiation or propagation of immunologic reactions. DFS70/LEDGF is a transcription factor involved in cell survival and stress protection, and autoantibodies may inhibit its function. It is likely that there are other antibodies producing the ANA-DFS pattern besides anti-DFS70/LEDGF, and more research is necessary to identify additional antibody specificities. The ANA-DFS pattern may be an indicator of a proinflammatory microenvironment given the high frequency of symptomatic patients and disease processes with an immunologic basis (including SARD).

Source: Lundgren MC, Sapkota S, Peterson DJ, Crosson JT. The antinuclear antibody dense fine speckled pattern and possible clinical associations: An indication of a proinflammatory microenvironment. J Immunol Methods. 2020 Oct 26:112904. doi: 10.1016/j.jim.2020.112904. Epub ahead of print. PMID: 33121975. https://pubmed.ncbi.nlm.nih.gov/33121975/

Re-analysis of genetic risks for Chronic Fatigue Syndrome from 23andMe data finds few remain

Abstract:

It is tempting to mine the abundance of DNA data that is now available from direct-to-consumer genetic tests, but this approach has its pitfalls A recent study put forth a list of 50 single nucleotide polymorphisms (SNPs) that predispose to Chronic Fatigue Syndrome (CFS), a potentially major advance in understanding this still mysterious disease. However, only the patient cohort data came from a commercial company (23andMe) while the control was a genetic database. The extent to which 23andMe data agree with genetic reference databases is unknown. We reanalyzed the 50 purported CFS SNPs by comparing to control data from 23andMe which are available through public platform OpenSNP. In addition, large high-quality database ALFA was used as an additional control. The analysis lead to dramatic change with the top of the leaderboard for CFS risk reduced and reversed from an astronomical 129,000 times to 0.8.

Errors were found both within 23andMe data and the original study-reported Kaviar database control. Only 3 of 50 SNPs survived initial study criterion of at least twice as prevalent in patients, EFCAB4B involving calcium ion channel, LINC01171, and MORN2 genes. We conclude the reported top-50 deleterious polymorphisms for Chronic Fatigue Syndrome were more likely the top-50 errors in the 23andMe and Kaviar databases. In general, however, correlation of 23andMe control with ALFA was a respectable 0.93, suggesting an overall usefulness of 23andMe results for research purposes but only if caution is taken with chips and SNPs.

Source: Felice L Bedford, Bastian Greshake Tzovaras. Re-analysis of genetic risks for Chronic Fatigue Syndrome from 23andMe data finds few remain. Frontiers in Pediatrics, October 29. 2020. https://www.medrxiv.org/content/10.1101/2020.10.27.20220939v1.full.pdf+html  (Full study)

Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Rintatolimod is a selective TLR3 agonist, which has demonstrated clinical activity for ME/CFS in Phase II and Phase III double-blind, placebo-controlled, randomized, multi-site clinical trials.

Methods and findings: A hypothesis-based post-hoc analysis of the Intent to Treat (ITT) population diagnosed with ME/CFS from 12 independent clinical sites of a Phase III trial was performed to evaluate the effect of rintatolimod therapy based on disease duration. The clinical activity of rintatolimod was evaluated by exercise treadmill tolerance (ETT) using a modified Bruce protocol. The ITT population (n = 208) was divided into two subsets of symptom duration. Patients with symptom duration of 2-8 years were identified as the Target Subset (n = 75); the remainder (<2 year plus >8 year) were identified as the Non-Target Subset (n = 133). Placebo-adjusted percentage improvements in exercise duration and the vertical rise for the Target Subset (n = 75) were more than twice that of the ITT population. The Non-Target Subset (n = 133) failed to show any clinically significant ETT response to rintatolimod when compared to placebo. Within the Target Subset, 51.2% of rintatolimod-treated patients improved their exercise duration by ≥25% (p = 0.003) despite reduced statistical power from division of the original ITT population into two subsets.

Conclusion/significance: Analysis of ETT from a Phase III trial has identified within the ITT population, a subset of ME/CFS patients with ≥2 fold increased exercise response to rintatolimod. Substantial improvement in physical performance was seen for the majority (51.2%) of these severely debilitated patients who improved exercise duration by ≥25%. This magnitude of exercise improvement was associated with clinically significant enhancements in quality of life. The data indicate that ME/CFS patients have a relatively short disease duration window (<8 years) to expect a significant response to rintatolimod under the dosing conditions utilized in this Phase III clinical trial. These results may have direct relevance to the cognitive impairment and fatigue being experienced by patients clinically recovered from COVID-19 and free of detectable SARS-CoV-2.

Source: Strayer DR, Young D, Mitchell WM. Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. PLoS One. 2020 Oct 29;15(10):e0240403. doi: 10.1371/journal.pone.0240403. PMID: 33119613. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240403 (Full text)

Prediction of Discontinuation of Structured Exercise Programme in Chronic Fatigue Syndrome Patients

Abstract:

Purpose: The purpose of this study was to assess differences in the physiological profiles of completers vs. non-completers following a structured exercise programme (SEP) and the ability to predict non-completers, which is currently unknown in this group.

Methods: Sixty-nine patients met the Fukuda criteria. Patients completed baseline measures assessing fatigue, autonomic nervous system (ANS), cognitive, and cardiovascular function. Thirty-four patients completed a home-based SEP consisting of 10-40 min per day at between 30 and 80% actual HR max. Exercise intensity and time was increased gradually across the 16 weeks and baseline measures were repeated following the SEP.

Results: Thirty-five patients discontinued, while 34 completed SEP. For every increase in sympathetic drive for blood pressure control as measured by the taskforce, completion of SEP decreased by a multiple of 0.1. For a 1 millisecond increase in reaction time for the simple reaction time (SRT), the probability for completion of SEP also decreases by a multiple of 0.01. For a one beat HRmax increase, there is a 4% increase in the odds of completing SEP.

Conclusion: The more sympathetic drive in the control of blood vessels, the longer the reaction time on simple visual stimuli and the lower the HRmax during physical exercise, then the lower the chance of SEP completion in ME/CFS.

Source: Kujawski S, Cossington J, Słomko J, Dawes H, Strong JW, Estevez-Lopez F, Murovska M, Newton JL, Hodges L, Zalewski P. Prediction of Discontinuation of Structured Exercise Programme in Chronic Fatigue Syndrome Patients. J Clin Med. 2020 Oct 26;9(11):E3436. doi: 10.3390/jcm9113436. PMID: 33114704. https://www.mdpi.com/2077-0383/9/11/3436 (Full text)

Early Growth Response Gene Upregulation in Epstein-Barr Virus (EBV)-Associated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease exhibiting a variety of symptoms and affecting multiple systems. Psychological stress and virus infection are important. Virus infection may trigger the onset, and psychological stress may reactivate latent viruses, for example, Epstein-Barr virus (EBV). It has recently been reported that EBV induced gene 2 (EBI2) was upregulated in blood in a subset of ME/CFS patients. The purpose of this study was to determine whether the pattern of expression of early growth response (EGR) genes, important in EBV infection and which have also been found to be upregulated in blood of ME/CFS patients, paralleled that of EBI2.

EGR gene upregulation was found to be closely associated with that of EBI2 in ME/CFS, providing further evidence in support of ongoing EBV reactivation in a subset of ME/CFS patients. EGR1, EGR2, and EGR3 are part of the cellular immediate early gene response and are important in EBV transcription, reactivation, and B lymphocyte transformation. EGR1 is a regulator of immune function, and is important in vascular homeostasis, psychological stress, connective tissue disease, mitochondrial function, all of which are relevant to ME/CFS. EGR2 and EGR3 are negative regulators of T lymphocytes and are important in systemic autoimmunity.

Source: Kerr J. Early Growth Response Gene Upregulation in Epstein-Barr Virus (EBV)-Associated Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Biomolecules. 2020 Oct 26;10(11):E1484. doi: 10.3390/biom10111484. PMID: 33114612. https://www.mdpi.com/2218-273X/10/11/1484  (Full text)