RIP Dr. Jay A. Goldstein

I was deeply saddened to learn that Dr. Jay Goldstein had passed away on March 4, 2021. Dr. Goldstein was a pioneer among ME/CFS researchers and clinicians. He rose to prominence in the 1990s through his clinical practice, and through the publication of several seminal works, chief among them: Betrayal by the Brain : The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders, Tuning the Brain : Principles and Practice of Neurosomatic Medicine, and Chronic Fatigue Syndromes : The Limbic Hypothesis. In addition to his books, Dr. Goldstein was also one of the editors, along with Dr. Byron Hyde, of The Clinical and Scientific Basis of Myalgic Encephalomyelitis–Chronic Fatigue Syndrome, a collection of papers on clinical practice and research that remains unsurpassed in both depth and scope.

Dr. Goldstein believed that ME/CFS was the result of an insult to the limbic system, located deep within the brain. The limbic system is involved with memory, emotion, and regulation of the autonomic nervous system. This last function is of critical importance to maintaining homeostasis in the body, as the autonomic nervous system regulates appetite, body temperature, blood pressure, blood sugar, sleep, wakefulness, heart rate, digestion – in short, nearly every physiological function necessary for maintaining life.

Dr. Goldstein’s theory, as laid out in his book, Betrayal by the Brain, was that ME/CFS is essentially a communication problem between the limbic system and the rest of the nervous system. His “limbic hypothesis” essentially states that no matter what the underlying cause of ME/CFS, the result is an injury to the limbic system, which subsequently causes widespread neuroimmune dysfunction. He identified ME/CFS as a “neurosomatic” illness, that is, a disorder of central nervous system processing. Dr. Goldstein based his theory on what he knew of the brain, which was substantial, as well as what he had observed of his patients’ reactions to various psychotropic medications. Recent studies have shown that in his approach Dr. Goldstein was  far ahead of his time.

Dr. Goldstein will be sorely missed, not just for his tremendous insights but for his compassion and commitment to his patients. There will never be another like him. RIP Dr. Jay A. Goldstein.

Dissecting the nature of post-exertional malaise

Abstract:

Background: Post-exertional malaise (PEM) is a defining characteristic of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) but there is insufficient research dissecting the nature of PEM from the patients’ perspective.

Methods: A PEM questionnaire administered to 150 ME/CFS patients. It included open-ended questions about triggers, experiences, recovery, and prevention. Responses were re-coded into concise, representative topics. Chi-Square tests of independence were then used to test for differences and relationships between duration of ME/CFS illness (<4 years and >10 years), PEM onset and duration, and gender with PEM trigger, experience, recovery, and prevention.

Results: Physical exertion was the most common trigger of PEM. The onset of PEM occurred within minutes after physical exertion compared to within hours after cognitive exertion (<0.05). ME/CFS patients sick for <4 years reported stress as a trigger significantly more often than those sick for >10 years (<0.001). ME/CFS patients sick for <4 years experienced more orthostatic symptoms during PEM than those sick for >10 years. ME/CFS patients sick for >10 years reported using medications to recover from PEM significantly more that those sick for <4 years (<0.01). Pacing and avoiding specific triggers were common approaches to prevent PEM.

Conclusions: There are differences in PEM triggers, experiences and recovery based on duration of illness. Asking about PEM is important for diagnosis and to understand how to manage PEM. Given that PEM occurs more quickly after physical versus cognitive exertion, these results should instigate research on the relationship of upright posture, hypoperfusion and PEM.

Source: Megan Hartle, Lucinda Bateman & Suzanne D. Vernon (2021) Dissecting the nature of post-exertional malaise, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2021.1905415 https://www.tandfonline.com/doi/full/10.1080/21641846.2021.1905415 (Full text)

Medical School Education on Myalgic Encephalomyelitis

Abstract:

Background and objectives: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS is a common complex multi-system disease with a significant impact on the quality of life of patients and their families, yet the majority of ME/CFS patients go unrecognised or undiagnosed. For two decades the medical education establishment in the UK has been challenged to remedy these failings, but little has changed. This study was designed to ascertain the current UK medical school education on ME/CFS and to identify challenges and opportunities to inform the future of medical education.

Materials and methods: A questionnaire, developed under the guidance of the Medical Schools Council, was sent to all 34 UK Medical Schools to collect data for the academic year 2018-2019.

Results: Responses were provided by 22 out of a total of 34 medical schools (65%). 59% of respondents taught ME/CFS, led by specialists drawn from 6 medical disciplines. Teaching delivery was usually by lecture; however, discussion case studies and e-learning were used. 7 schools included questions on ME/CFS in their examinations and 3 schools reported likely clinical exposure to ME/CFS patients. 64% of respondents were interested in receiving further teaching aids in ME/CFS. None of the schools shared details of their teaching syllabus so it was not possible to ascertain what students were being taught.

Conclusions: UK medical school teaching in ME/CFS is shown to be inadequate. Several medical disciplines, with known differences about the disease, need to set these aside to give greater clarity in teaching undergraduates so they can more easily recognise and diagnose ME/CFS. Improvements are proposed in ME/CFS medical education consistent with the international paradigm shift in biomedical understanding of this disease. Many medical schools (64% of respondents) acknowledge this need by expressing a strong appetite for the development of further teaching aids and materials. The GMC and MSC are called upon to use their considerable influence to bring about the appropriate changes to medical school curricula so future doctors can recognise, diagnose and treat ME/CFS. The GMC should also consider creating a registered speciality encompassing ME/CFS, post viral fatigue and Long Covid.

Source: Muirhead, N.; Muirhead, J.; Lavery, G.; Marsh, B. Medical School Education on Myalgic Encephalomyelitis. Preprints 2021, 2021030420 https://www.preprints.org/manuscript/202103.0420/v1

We Already Know Enough to Avoid Making the Same Mistakes Again With Long COVID

Based on experience with past coronaviruses, the emerging challenge of prolonged symptoms after infection with the novel coronavirus 2019 (SARS-CoV-2) is unsurprising. Data from a large international web-based patient survey indicate substantial symptom overlap between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) at 6 months following the onset of first symptoms, including three quarters of participants suffering from fatigue and postexertional malaise, and over half with cognitive dysfunction.4 Apparent similarities between the presentations of long COVID and ME/CFS suggest that we may apply what we have learned from ME/CFS to long COVID.

Source: Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness. We Already Know Enough to Avoid Making the Same Mistakes Again With Long COVID. Journal of Orthopedic & Sports Physical Therapy. Published online on March 10, 2021
https://doi.org/10.2519/jospt.blog.20210310

Understanding the economic impact of myalgic encephalomyelitis/chronic fatigue syndrome in Ireland: a qualitative study

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling and complex chronic disease of unknown origin, whose symptoms, severity, and progression are extremely variable. Despite being relatively common, the condition is poorly understood and routine diagnostic tests and biomarkers are unavailable. There is no evidence on the economic impact of ME/CFS in Ireland.

Methods: Adopting a patient and public involvement approach, we undertook three semi-structured focus groups, which together included 15 ME/CFS patients and 6 informal carers, to consider costs related to ME/CFS in Ireland, including how and why they arise. Focus groups were audio-recorded and transcribed verbatim, and we employed thematic analysis following the approach set out in Braun and Clarke (2006).

Results: Themes from the data were: (1) Healthcare barriers and costs; (2) Socioeconomic costs; (3) Costs of disability; and, (4) Carer-related costs. Patient participants described a range of barriers to effective healthcare that led to extra costs, including delays getting a diagnosis, poor awareness/understanding of the condition by healthcare professionals, and a lack of effective treatments. These were linked to poor prognosis of the illness by participants who, as a result, faced a range of indirect costs, including poorer labour market and education outcomes, and lower economic well-being. Direct extra costs of disability were also described, often due to difficulties accessing appropriate services and supports. Informal carer participants described a range of impacts, including time costs, burnout, and impacts on work and study.

Conclusions: The data suggests that ME/CFS patients face a wide range of costs, while there are also wider societal costs in the form of costs to the health service, lost productivity, and impacts on informal carers. These results will inform ongoing research that aims to quantify the economic burden of ME/CFS in Ireland and raise awareness of the illness amongst healthcare providers and policymakers.

Source: Cullinan J, Ní Chomhraí O, Kindlon T, Black L, Casey B. Understanding the economic impact of myalgic encephalomyelitis/chronic fatigue syndrome in Ireland: a qualitative study. HRB Open Res. 2020 Dec 4;3:88. doi: 10.12688/hrbopenres.13181.1. PMID: 33659857; PMCID: PMC7898356. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898356/ (Full text)

COVID-19: A methyl-group assault?

Abstract:

The socio-economic implications of COVID-19 are devastating. Considerable morbidity is attributed to ‘long-COVID’ – an increasingly recognized complication of infection. Its diverse symptoms are reminiscent of vitamin B12 deficiency, a condition in which methylation status is compromised. We suggest why SARS-CoV-2 infection likely leads to increased methyl-group requirements and other disturbances of one-carbon metabolism. We propose these might explain the varied symptoms of long-COVID. Our suggested mechanism might also apply to similar conditions such as myalgic encephalomyelitis/chronic fatigue syndrome. The hypothesis is evaluable by detailed determination of vitamin B12 and folate status, including serum formate as well as homocysteine and methylmalonic acid, and correlation with viral and host RNA methylation and symptomatology. If confirmed, methyl-group support should prove beneficial in such individuals.

Source: McCaddon A, Regland B. COVID-19: A methyl-group assault? Med Hypotheses. 2021 Feb 18;149:110543. doi: 10.1016/j.mehy.2021.110543. Epub ahead of print. PMID: 33657459; PMCID: PMC7890339. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890339/ (Full text)

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/