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Myalgic Encephalomyelitis/Chronic Fatigue SyndromeClinical Working Case Definition, Diagnostic and Treatment Protocols
Abstract and Figures
Recent years have brought growing recognition of the need for clinical criteria for myalgic encephalomyelitis (ME), which is also called chronic fatigue syndrome (CFS). An Expert Subcommittee of Health Canada established the Terms of Reference, and selected an Expert Medical Consensus Panel representing treating physicians, teaching faculty and researchers. A Consensus Workshop was held on March 30 to April 1,2001 to culminate the review process and establish consensus for a clinical working case definition, diagnostic protocols and treatment protocols. We present a systematic clinical working case definition that encourages a diagnosis based on characteristic patterns of symptom clusters, which reflect specific areas of pathogenesis. Diagnostic and treatment protocols, and a short overview of research are given to facilitate a comprehensive and integrated approach to this illness. Throughout this paper, “myalgic encephalomyelitis” and “chronic fatigue syndrome” are used interchangeably and this illness is referred to as “ME/CFS.”
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... Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating medical condition characterized by persistent and severe post-exertional malaise (PEM) accompanied with symptoms related to dysautonomia, cognitive, immune, and endocrine dysfunction (1). ME/CFS can lead to a considerable loss of physical and mental function with many patients becoming house-or bed-bound (2). ...
... Guidelines regarding pharmacologic treatments for ME/CFS remain variable and indecisive. Many of these recommendations have not been verified through controlled clinical trials but are rather based on the clinical experience of experts in the field (1). Although there is insufficient supporting evidence for such treatments, individuals with ME/CFS still commonly report using a wide array of medications (5). ...
... ME/CFS is a severe, debilitating illness affecting millions of people worldwide, with women being 1.5 to 2 times more likely to be diagnosed than men (3). It is marked by persistent, unexplained fatigue lasting over 6 months and is often accompanied by a complex array of symptoms linked to neurological, autonomic, immune, and endocrine dysfunction (1). Alarmingly, the level of disability caused by ME/CFS frequently exceeds that of other chronic conditions, including multiple sclerosis and cancer (15,16). ...
Background
There are no known curative treatments for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and current therapeutic regimens often yield inconsistent results. Despite the profound physical and mental burden experienced by those living with ME/CFS, patients often face a trial-and-error process in finding medications that offer some relief.
Method
The current study surveyed 135 North American women diagnosed with ME/CFS to characterize medication use in relation to disease features, symptomology, and function. Medications were classified into 9 categories according to their primary mechanism of action and therapeutic use.
Results
Participants were primarily middle-aged (47.1 ± 15.3 years) and were diagnosed for a mean duration of 8.4 ± 9.5 years (mean ± SD). Responses showed 68.6% of participants reported taking medications specifically for ME/CFS. Of those taking ME/CFS-related symptom medications, the average use was 3.0 medications per patient, with higher use in US compared to Canadian participants. Analgesic medications (31.7%) were the most frequently used, followed by psychotropic (26.4%), and immune-related medications (10.6%). These trends persisted across different symptom profiles, apart from gastrointestinal associated medication use replacing immune-related medications in those with gastrointestinal, neurological, and psychiatric symptoms. There was no significant correlation found between the number of medications used with disease duration, age, or age at diagnosis. However, a U-shaped relationship between ME/CFS-related symptom medication use and functional capacity as assessed by self-reported physical movement (hours/week) was evident.
Conclusion
Our study highlights the diverse and complex patterns in pharmacological treatment regimens for ME/CFS in women, while also underscoring the need for more tailored and evidence-based therapeutic strategies to address the varied symptom profiles.
... Diagnosis criteria for ME/CFS rely on clinical symptoms [2][3][4], as no validated biomarker exists, with post-exertional malaise or PEM playing a significant role, including fatigue, pain, and cognitive, intestinal, and sleep disturbances, among others, limiting a patient's daily performance in mildly affected patients and driving bed confinement in ...
... Magnetic resonance imaging (MRI) in 2016, at age 26, revealed a small demyelinating juxtacortical lesion in the left temporal pole, but other investigations were unremarkable, leading to a diagnosis of ME/CFS. The patient met the 2011 International Consensus Criteria [2], as well as Canadian [3] and IOM (Institute of Medicine) 2015 criteria [4]. Prescribed supplements, including magnesium, NADH, D-ribose, L-carnitine, ubiquinol, melatonin, vitamin B1, alpha-lipoic acid, vitamin D, and LDN (Low-Dose Naltrexone), failed to improve his symptoms. ...
This article summarizes the case of 30-year-old male diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and its longitudinal follow-up, which provided a secondary diagnosis of Multiple Sclerosis (MS) eight years later. The most impactful result was his response to rituximab treatment after the systematic failure of prior treatments. Although the expression of endogenous retroviral proteins has been associated with autoimmunity, the patient did not show increased expression of the toxic protein HERV (human endogenous retrovirus)-W ENV, a target of the ongoing clinical trials with temelimab in MS and long COVID-19 cases. However, genome-wide HERV transcriptome analysis by high density microarrays clearly revealed a distinct profile in the patient’s blood supportive of an altered immune system. Limitations of the study include sub-optimal frequency of magnetic resonance imaging to monitor lesion progression, and similarly for reassessment of HERV profiles after rituximab. Overall, the coincidence of HERV alterations and the impactful response to rituximab presents the possibility of additional, more specific, therapeutic targets encoded by other HERV elements yet to be discovered.
... All ME/CFS cases were diagnosed by expert physicians according to the 2003 Canadian consensus criteria. 38 Participants in both groups were excluded if they were diabetic, smoked cigarettes, consumed excessive amounts of alcohol, had an orthopaedic limitation preventing them from performing the cardiopulmonary exercise test (CPET), or had any of the following diagnoses: an autoimmune disease, schizophrenia, major depressive disorder, bipolar disorder, or an anxiety disorder. Healthy subjects included in the present study were categorized as "low-active": they had a sedentary job and no regular organized physical activity in the past 6 months. ...
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating illness characterized by post‐exertional malaise (PEM), a worsening of symptoms following exertion. The biological mechanisms underlying PEM remain unclear. Extracellular vesicles (EVs) play a key role in cell–cell communication and may provide insight into ME/CFS pathophysiology post‐exertion. Emerging evidence suggests similarities between ME/CFS and Long COVID, including PEM and overlapping immune and metabolic dysfunctions, highlighting the need for deeper mechanistic understanding.
Methods
This study explores the EV proteome response to exercise in 10 males with ME/CFS and 12 well‐matched sedentary male controls. Participants underwent a maximal cardiopulmonary exercise test, and plasma samples were collected at baseline, 15 min, and 24 h postexercise. EVs were isolated from plasma using size‐exclusion chromatography and characterized with nanoparticle tracking analysis. EV protein abundance was quantified with untargeted proteomics (nanoLC‐MS/MS). Comprehensive analyses included differential abundance, pathway enrichment, protein–protein interaction networks, and correlations between EV protein dynamics and clinical or exercise physiology data.
Results
ME/CFS patients exhibited many significantly altered EV proteomic responses compared with controls, including downregulation of TCA cycle‐related proteins and upregulation of complement system proteins at 15 min postexercise. Changes in proteins involved in protein folding and the endoplasmic reticulum (ER) stress response during recovery were highly correlated with PEM severity, highlighting their potential as therapeutic targets. EV protein changes postexercise were also associated with disease severity and unrefreshing sleep. Correlations between EV protein levels and the exercise parameters VO₂ peak and ventilatory anaerobic threshold were observed in controls but were absent in ME/CFS patients, suggesting disrupted EV‐mediated physiological processes.
Conclusions
ME/CFS patients exhibit a maladaptive EV proteomic response to exercise, characterized by metabolic impairments, immune overactivation, and ER stress response dysregulation. These findings provide insight into the molecular basis of PEM and suggest promising targets for improving recovery and energy metabolism in ME/CFS.
Key points
EVs were isolated from plasma of ME/CFS patients and healthy controls at baseline, and 15 min and 24 h postexercise.
Untargeted proteomics revealed dysregulation in energy metabolism, the complement system, and the endoplasmic reticulum stress response.
Changes in EV protein levels postexercise are associated with post‐exertional malaise.
These findings suggest promising therapeutic targets for post‐exertional malaise and ME/CFS pathophysiology.
... Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with key symptoms including (but not limited to) unrefreshing sleep, post-exertional malaise, and cognitive impairment [1][2][3]. Sleep difficulties are some of the most common symptoms experienced by patients with ME/CFS [4,5]. There are different subtypes of sleep disorders for those with ME/CFS [3,4,6], and suboptimal sleep quality is related to more frequent and severe ME/CFS symptoms [7]. ...
Background/objectives:
Impaired sleep is one of the core symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), yet the mechanisms and impact of sleep-related issues are poorly understood. Sleep dysfunctions for patients with ME/CFS include frequent napping, difficulties falling asleep, waking up early, and sleep reversal patterns (e.g., sleeping throughout the day and staying awake throughout the night). The current study focuses on sleep reversal for patients with ME/CFS.
Methods:
We explored the symptoms and functional impairment of those with and without sleep reversal by analyzing the responses of a large international sample (N = 2313) using the DePaul Symptom Questionnaire (DSQ) and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36).
Results:
We found that those in our Sleep Reversal group (N = 327) compared to those without sleep reversal (N = 1986) reported higher symptom burden for 53 out of 54 DSQ symptoms and greater impairments for all six SF-36 subscales. The most accurate predictors of sleep reversal included age (p < 0.05), body mass index (p < 0.05), eleven DSQ symptoms (p < 0.01), and two SF-36 subscales (p < 0.01).
Conclusions:
These features provide clues regarding some of the possible pathophysiological underpinnings of sleep reversal among those with ME/CFS.
... This definition of ME/CSF symptoms conformed to the essential symptoms of Canadian consensus criteria for ME/CSF. 16 It was unnecessary to strictly meet the diagnostic criteria for ME/CFS because our goal was not to diagnose ME/CFS, but only to collect the primary symptoms of ME/CFS. The severity of acute COVID-19 was classified according to World Health Organization guidelines. ...
Background
Long‐COVID is a significant global health concern, regardless of age. However, few reports have longitudinally evaluated the characteristics, prevalence, and risk factors of long‐COVID in children.
Methods
Participants were Japanese children younger than 18 years hospitalized for COVID‐19 between November 2021 and October 2022, along with their COVID‐19 affected parents. During hospitalization and at 1‐, 3‐, and 6‐month follow‐ups, participants completed age‐appropriate questionnaires on long‐COVID symptoms. The quality of life (QOL) score was assessed in children older than 2 years. The prevalence of long‐COVID symptoms by age group was compared. Multivariable logistic regression analysis was conducted to investigate risk factors affecting long‐COVID. Analysis of covariance adjusted for potential confounders was conducted to determine which symptoms affect QOL score.
Results
Of 108 children enrolled, the prevalence of long‐COVID was 44.9%, 37.8%, and 22.8% at 1, 3, and 6 months, respectively, after SARS‐CoV‐2 infection. There were no specific risk factors for long‐COVID. Cough, fatigue, and sleep disturbance were the most common long‐COVID symptoms, with sleep disturbance associated with a change in lower QOL score from admission at all three follow‐ups (mean difference 9.25, 20.15, and 19.81; 95% CI, 1.58–16.91, 3.38–36.92, and 5.51–34.11). The prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms among 0–6 years was significantly lower than among 7–17 years and parents; there was no significant difference between 7 and 17 years and parents.
Conclusion
Even 6 months after SARS‐CoV‐2 infection, 22.8% of pediatric patients still had long‐COVID symptoms. Some of these symptoms were similar to those of ME/CFS, potentially affecting children's QOL.
Post-acute infection syndromes (PAIS), i.e., long-lasting pathologies subsequent to infections that do not properly resolve, have both a common core and a broad diversity of manifestations. PAIS include a group of core symptoms (pathological fatigue, cognitive problems, sleep disorders and pain) accompanied by a large set of diverse symptoms. Core and diverse additional symptoms, which can persist for years, exhibiting periods of relapses and remissions, usually start suddenly after an apparently common infection. PAIS display highly variable clinical features depending on the nature of the initial pathogen, and to an even larger extent, on the diversity of preexisting individual terrains in which PAIS are rooted. In a first part, I discuss biological issues related to the persistence of microbial antigens, dysregulated immune responses, reactivation of latent viruses, different potential self-sustained inflammatory loops, mitochondrial dysfunction, metabolic disorders in the tryptophan- kynurenin pathway (TKP) with impact on serotonin, and consequences of a dysfunctional bidirectional microbiota-gut-brain axis. The second part deals with the nervous system dependence of PAIS. I rely on the concept of interoception, the process by which the brain senses, integrates and interprets signals originating from within the body, and sends feebacks aimed at maintaining homeostasis. Interoception is central for understanding the origin of fatigue, dysautonomia, dysfunctioning of the hypothalamus-pituitary-adrenal (HPA) axis, and its relation with stress, inflammation or depression. I propose that all individual predispositions leading to self-sustained vicious circles constitute building blocks that can self-assemble in many possible ways, to give rise to both core and diverse features of PAIS. A useful discrimination between different PAIS subtypes should be obtained with a composite profiling including biomarkers, questionnaires and functional tests so as to take into account PAIS multidimensionality.
Post-exertional malaise is a cardinal symptom present in 95% of individuals with myalgic encephalomyelitis (ME/CFS). Repeated cardiopulmonary exercise testing has been momentous in revealing that the physiological systems of those with ME/CFS are impaired or damaged and do not respond to exercise/physical activity like those without the condition. The 24-h repeated exercise test may demonstrate a reduction in peak oxygen consumption (VO2 peak), VO2 at ventilatory threshold, power output at both peak and ventilatory threshold, along with a reduction/diminished maximal heart rate commensurate with chronotropic intolerance. In this chapter, I describe the process and methods of repeated cardiopulmonary exercise testing, used to assess exercise tolerance in individuals with ME/CFS.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex heterogeneous multiorgan disease that can have severe impact on individuals' quality of life. Diagnosis of ME/CFS is based on symptom presentation, and a significant goal for the field is to establish meaningful subtypes. The heterogeneity in the literature suggests that individuals living with ME/CFS may suffer from overlapping but different underlying pathophysiological mechanisms. We enrolled 40 participants with ME/CFS and 41 matched healthy control subjects at the Bragée Clinic in Sweden. We assessed plasma samples from both ME/CFS cases and control groups and cerebrospinal fluid (CSF) samples from individuals with ME/CFS. We investigated dysregulated pathways and disease profiles through clinical questionnaires; multiplex analyses of cytokines, hormones, and matrix metalloproteinases; pathogen seroreactivity through peptide display bacteria libraries; and high-throughput microarray for autoantibodies. All samples used were from humans. We show altered interaction patterns between circulating biological factors in plasma of ME/CFS participants. Our analysis of CSF from individuals with ME/CFS revealed different immunotypes of disease. We found 2 patient clusters based on matrix metalloproteinases profiles. The subgroups had similar clinical presentation but distinct pathogen exposure and CSF inflammatory profiles. Our findings shed light on ME/CFS immune phenotypes and generate hypotheses for future research in disease pathogenesis and treatment development by exploring disease subgroups.
Background:
Disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to: (1) low circulating cortisol; (2) disturbance of central neurotransmitters; or (3) disturbance of the relationship between cortisol and central neurotransmitter function. Accumulating evidence of the complex relationship between cortisol and 5-HT function, make some form of hypothesis (3) most likely. We review the methodology and results of studies of the HPA and other neuroendocrine axes in CFS.
Method:
Medline, Embase and Psychlit were searched using the Cochrane Collaboration strategy. A search was also performed on the King's College CFS database, which includes over 3000 relevant references, and a citation analysis was run on the key paper (Demitrack et al. 1991).
Results:
One-third of the studies reporting baseline cortisol found it to be significantly low, usually in one-third of patients. Methodological differences may account for some of the varying results. More consistent is the finding of reduced HPA function, and enhanced 5-HT function on neuroendocrine challenge tests. The opioid system, and arginine vasopressin (AVP) may also be abnormal, though the growth hormone (GH) axis appears to be intact, in CFS.
Conclusions:
The significance of these changes, remains unclear. We have little understanding of how neuroendocrine changes relate to the experience of symptoms, and it is unclear whether these changes are primary, or secondary to behavioural changes in sleep or exercise. Longitudinal studies of populations at risk for CFS will help to resolve these issues.