Myalgic encephalomyelitis: International Consensus Criteria
Université libre de Bruxelles1, University of Miami2, University of Alberta3, Suffolk University4, Bond University5, St. Joseph's Healthcare Hamilton6, Durham University7, Salt Lake Regional Medical Center8, University of Utah9, Oslo University Hospital10, State University of New York System11, University of California, Los Angeles12, University of Limerick13, Konyang University14, University of Nevada, Reno15, Washington State University16, University of the Pacific (United States)17
TL;DR: Myalgic encephalomyelitis: International Consensus Criteria (Review).
Abstract: 12 FatigueConsultationClinic,SaltLake RegionalMedicalCenter; 13 InternalMedicine,FamilyPractice,UniversityofUtah,SaltLakeCity,UT,USA; 14 ME ⁄CFSCenter,OsloUniversity HospitalHF,Norway; 15 DepartmentofPaediatrics,StateUniversityofNewYork,Buffalo,NY,USA; 16 Independent,Pavia,Italy; 17 Harbor-UCLA MedicalCenter,UniversityofCalifornia,LosAngeles,CA; 18 EVMedResearch,Lomita,CA,USA; 19 UniversityofLimerick,Limerick,Ireland; 20 Pain Clinic,KonyangUniversityHospital,Daejeon,Korea; 21 DonvaleSpecialistMedicalCentre,Donvale,Victoria,Australia; 22 Departmentsof Anesthesiology,NeurobiologyandAnatomy,UniversityofUtah,SaltLakeCity,UT,USA; 23 DepartmentofMedicinaNuclear,ClinicaLasCondes, Santiago,Chile; 24 WhittemorePetersonInstitute,UniversityofNevada,Reno,NV,USA; 25 MiwaNaikaClinic,Toyama,Japan; 26 A.Kirchenstein InstituteofMicrobiologyandVirology,RigaStradinsUniversity,Riga,Latvia; 27 DepartmentofBiochemistryBand 28 DepartmentofSportsSciences,UniversityofthePacific,Stockton,CAUSA
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TL;DR: The effects of exercise therapy for patients with CFS as compared with any other intervention or control was determined, with seven studies consistently showed a reduction in fatigue following exercise therapy at end of treatment, even though the fatigue scales used different scoring systems.
Abstract: Background
Chronic fatigue syndrome (CFS) is characterised by persistent, medically unexplained fatigue, as well as symptoms such as musculoskeletal pain, sleep disturbance, headaches and impaired concentration and short-term memory. CFS presents as a common, debilitating and serious health problem. Treatment may include physical interventions, such as exercise therapy, which was last reviewed in 2004.
Objectives
The objective of this review was to determine the effects of exercise therapy (ET) for patients with CFS as compared with any other intervention or control.
• Exercise therapy versus 'passive control' (e.g. treatment as usual, waiting-list control, relaxation, flexibility).
• Exercise therapy versus other active treatment (e.g. cognitive-behavioural therapy (CBT), cognitive treatment, supportive therapy, pacing, pharmacological therapy such as antidepressants).
• Exercise therapy in combination with other specified treatment strategies versus other specified treatment strategies (e.g. exercise combined with pharmacological treatment vs pharmacological treatment alone).
Search methods
We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL) and SPORTDiscus up to May 2014 using a comprehensive list of free-text terms for CFS and exercise. We located unpublished or ongoing trials through the World Health Organization (WHO) International Clinical Trials Registry Platform (to May 2014). We screened reference lists of retrieved articles and contacted experts in the field for additional studies
Selection criteria
Randomised controlled trials involving adults with a primary diagnosis of CFS who were able to participate in exercise therapy. Studies had to compare exercise therapy with passive control, psychological therapies, adaptive pacing therapy or pharmacological therapy.
Data collection and analysis
Two review authors independently performed study selection, risk of bias assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) and standardised mean differences (SMDs). We combined serious adverse reactions and drop-outs using risk ratios (RRs). We calculated an overall effect size with 95% confidence intervals (CIs) for each outcome.
Main results
We have included eight randomised controlled studies and have reported data from 1518 participants in this review. Three studies diagnosed individuals with CFS using the 1994 criteria of the Centers for Disease Control and Prevention (CDC); five used the Oxford criteria. Exercise therapy lasted from 12 to 26 weeks. Seven studies used variations of aerobic exercise therapy such as walking, swimming, cycling or dancing provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, whilst one study used anaerobic exercise. Control groups consisted of passive control (eight studies; e.g. treatment as usual, relaxation, flexibility) or CBT (two studies), cognitive therapy (one study), supportive listening (one study), pacing (one study), pharmacological treatment (one study) and combination treatment (one study). Risk of bias varied across studies, but within each study, little variation was found in the risk of bias across our primary and secondary outcome measures.
Investigators compared exercise therapy with 'passive' control in eight trials, which enrolled 971 participants. Seven studies consistently showed a reduction in fatigue following exercise therapy at end of treatment, even though the fatigue scales used different scoring systems: an 11-item scale with a scoring system of 0 to 11 points (MD -6.06, 95% CI -6.95 to -5.17; one study, 148 participants; low-quality evidence); the same 11-item scale with a scoring system of 0 to 33 points (MD -2.82, 95% CI -4.07 to -1.57; three studies, 540 participants; moderate-quality evidence); and a 14-item scale with a scoring system of 0 to 42 points (MD -6.80, 95% CI -10.31 to -3.28; three studies, 152 participants; moderate-quality evidence). Serious adverse reactions were rare in both groups (RR 0.99, 95% CI 0.14 to 6.97; one study, 319 participants; moderate-quality evidence), but sparse data made it impossible for review authors to draw conclusions. Study authors reported a positive effect of exercise therapy at end of treatment with respect to sleep (MD -1.49, 95% CI -2.95 to -0.02; two studies, 323 participants), physical functioning (MD 13.10, 95% CI 1.98 to 24.22; five studies, 725 participants) and self-perceived changes in overall health (RR 1.83, 95% CI 1.39 to 2.40; four studies, 489 participants). It was not possible for review authors to draw conclusions regarding the remaining outcomes.
Investigators compared exercise therapy with CBT in two trials (351 participants). One trial (298 participants) reported little or no difference in fatigue at end of treatment between the two groups using an 11-item scale with a scoring system of 0 to 33 points (MD 0.20, 95% CI -1.49 to 1.89). Both studies measured differences in fatigue at follow-up, but neither found differences between the two groups using an 11-item fatigue scale with a scoring system of 0 to 33 points (MD 0.30, 95% CI -1.45 to 2.05) and a nine-item Fatigue Severity Scale with a scoring system of 1 to 7 points (MD 0.40, 95% CI -0.34 to 1.14). Serious adverse reactions were rare in both groups (RR 0.67, 95% CI 0.11 to 3.96). We observed little or no difference in physical functioning, depression, anxiety and sleep, and we were not able to draw any conclusions with regard to pain, self-perceived changes in overall health, use of health service resources and drop-out rate.
With regard to other comparisons, one study (320 participants) suggested a general benefit of exercise over adaptive pacing, and another study (183 participants) a benefit of exercise over supportive listening. The available evidence was too sparse to draw conclusions about the effect of pharmaceutical interventions.
Authors' conclusions
Patients with CFS may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes. A positive effect with respect to sleep, physical function and self-perceived general health has been observed, but no conclusions for the outcomes of pain, quality of life, anxiety, depression, drop-out rate and health service resources were possible. The effectiveness of exercise therapy seems greater than that of pacing but similar to that of CBT. Randomised trials with low risk of bias are needed to investigate the type, duration and intensity of the most beneficial exercise intervention.
469 citations
TL;DR: In this article, the authors discuss the mechanisms by which RNA viruses beyond just SARS-CoV-2 have been connected to long-term health consequences, and review literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Abstract: The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of coronavirus disease 2019 (COVID-19). Across the globe, a subset of patients who sustain an acute SARS-CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months. These patients are being given the diagnosis Long COVID or Post-acute sequelae of COVID-19 (PASC). It is likely that individual patients with a PASC diagnosis have different underlying biological factors driving their symptoms, none of which are mutually exclusive. This paper details mechanisms by which RNA viruses beyond just SARS-CoV-2 have be connected to long-term health consequences. It also reviews literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to discuss different scenarios for PASC symptom development. Potential contributors to PASC symptoms include consequences from acute SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, re-activation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage care for specific patients with the diagnosis.
336 citations
TL;DR: High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease.
Abstract: Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.
255 citations
TL;DR: Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.
Abstract: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (11C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used 11C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients. Methods: Nine CFS/ME patients and 10 healthy controls underwent 11C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BPND) values were determined using linear graphical analysis with the cerebellum as a reference region. Results: The BPND values of 11C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%–199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BPND values of 11C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BPND values in the cingulate cortex and thalamus positively correlated with pain score, and the BPND value in the hippocampus positively correlated with depression score. Conclusion: Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments.
252 citations
TL;DR: In this paper, the authors identify case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and explore how the validity of case definitions can be evaluated in the absence of a reference standard.
Abstract: Objective To identify case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and explore how the validity of case definitions can be evaluated in the absence of a reference standard. Design Systematic review. Setting International. Participants A literature search, updated as of November 2013, led to the identification of 20 case definitions and inclusion of 38 validation studies. Primary and secondary outcome measure Validation studies were assessed for risk of bias and categorised according to three validation models: (1) independent application of several case definitions on the same population, (2) sequential application of different case definitions on patients diagnosed with CFS/ME with one set of diagnostic criteria or (3) comparison of prevalence estimates from different case definitions applied on different populations. Results A total of 38 studies contributed data of sufficient quality and consistency for evaluation of validity, with CDC-1994/Fukuda as the most frequently applied case definition. No study rigorously assessed the reproducibility or feasibility of case definitions. Validation studies were small with methodological weaknesses and inconsistent results. No empirical data indicated that any case definition specifically identified patients with a neuroimmunological condition. Conclusions Classification of patients according to severity and symptom patterns, aiming to predict prognosis or effectiveness of therapy, seems useful. Development of further case definitions of CFS/ME should be given a low priority. Consistency in research can be achieved by applying diagnostic criteria that have been subjected to systematic evaluation.
224 citations
References
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TL;DR: A conceptual framework and a set of research guidelines for use in studies of the chronic fatigue syndrome are developed that cover the clinical and laboratory evaluation of persons with unexplained fatigue; the identification of underlying conditions that may explain the presence of chronic fatigue; revised criteria for defining cases of the Chronic fatigue syndrome; and a strategy for dividing the chronic Fatigue syndrome and other unexplained cases of Chronic fatigue into subgroups.
Abstract: The complexities of the chronic fatigue syndrome and the methodologic problems associated with its study indicate the need for a comprehensive, systematic, and integrated approach to the evaluation, classification, and study of persons with this condition and other fatiguing illnesses. We propose a conceptual framework and a set of guidelines that provide such an approach. Our guidelines include recommendations for the clinical evaluation of fatigued persons, a revised case definition of the chronic fatigue syndrome, and a strategy for subgrouping fatigued persons in formal investigations.
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TL;DR: Dorland's illustrated medical dictionary as discussed by the authors, a dictionary for illustrated medical dictionaries, is a good starting point for any medical dictionary, and it can be found online here.
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TL;DR: Authors Dr M C Sharpe MRCPsych Clinical Lecturer, Department of Psychiatry, University of Oxford Dr L C Archard PhD Senior Lecturer , Department of Biochemistry, Charing Cross and Westminster Medical School, London
Abstract: Authors Dr M C Sharpe MRCPsych Clinical Lecturer, Department of Psychiatry, University of Oxford Dr L C Archard PhD Senior Lecturer, Department of Biochemistry, Charing Cross and Westminster Medical School, London Professor J E Banatvala MD Professor of Virology, Department of Virology, St Thomas' Hospital Medical School, London Dr L K Borysiewicz FRCP Wellcome Trust Senior Lecturer, Department of Medicine, University of Cambridge Professor A W Clare MD Clinical Professor of Psychiatry, Trinity College, Dublin Dr A David MRCPsych MRC Training Fellow, Institute of Psychiatry, London Professor R H T Edwards FRCP Professor of Medicine, Department of Medicine, University of Liverpool Dr K E H Hawton DM Consultant Psychiatrist, Department of Psychiatry, University of Oxford Professor H P Lambert MD Emeritus Professor of Microbial Disease, St George's Hospital Medical School, London Dr R J M Lane MD Consultant Neurologist, Regional Neurosciences Centre, Charing Cross Hospital, London Dr E M McDonald MRCPsych Research Psychiatrist, Institute of Psychiatry, London Professor J F Mowbray FRCP Immunopathology, Department oflmmunopathology, St Mary's Hospital Medical School, London Dr D J Pearson FRCP Senior Lecturer, Department of Medicine, University of Manchester Dr TEA Peto MRCP Consultant Physician, Department of Infectious Diseases, John Radcliffe Hospital, Oxford Dr V R Preedy PhD Research Biochemist, Department of Biochemistry, King's College Hospital, London Dr A P Smith PhD Research Psychologist, Department of Psychology, University of Sussex Dr D G Smith MB General Practitioner, Horndonon-the-Hill, Essex Dr D J Taylor DPhil MRC Staff Scientist, MRC Biochemical and Clinical Magnetic Resonance Unit, John Radcliffe Hospital, Oxford Dr D A J Tyrrell MD Director, MRC Common Cold Unit, Harvard Hospital, Salisbury Dr S Wessely MRCPsych Wellcome Training Fellow in Epidemiology, Institute of Psychiatry, London Dr P D White MRCPsych Senior Lecturer, Department of Psychological Medicine, St Bartholomew's Hospital, London Other signatories who contributed to the guidelines but who were unable to attend the meeting Professor P 0 Behan MD Professor of Neurology, Department of Neurology, University of Glasgow Dr F Clifford Rose FRCP Director, Academic Unit of Neuroscience, Charing Cross and Westminster Medical School, London Professor T J Peters FRCP Professor of Clinical Biochemistry, Department of Biochemistry, King's College Hospital, London Dr P G Wallace MRCGP Head of Research Unit, Department of General Practice, St Mary's Hospital Medical School, London Professor D A Warrell FRCP Professor of Tropical Medicine and Infectious Diseases, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford Dr D J M Wright MD Consultant Microbiologist, Department of Microbiology, Charing Cross Hospital, London
1,011 citations
"Myalgic encephalomyelitis: Internat..." refers background in this paper
...The problem with broadly inclusive criteria [15, 16] is that they do not select homogeneous sets of patients....
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TL;DR: A systematic clinical working case definition for myalgic encephalomyelitis is presented and an Ex- pert Medical Consensus Panel representing treating physicians, teaching faculty and researchers are selected.
Abstract: 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 Ex- pert 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
864 citations
"Myalgic encephalomyelitis: Internat..." refers background in this paper
...The broad spectrum of symptoms alerts medical practitioners to areas of pathology and may identify critical symptoms more accurately [18-20]....
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...Numerous papers document abnormal biological responses to exertion, such as loss of the invigorating effects of exercise [20], decreased pain threshold [48-50], decreased cerebral oxygen and blood volume/flow [51-54], decreased maximum heart rate [55], impaired oxygen delivery to muscles [56], elevated levels of nitric oxide metabolites [57], and...
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...Poor attentional capacity and working memory are prominent disabling symptoms [20, 78, 81]....
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...Structural and functional pathological abnormalities [3] within the brain and spinal cord suggest dysregulation of the CNS control system and communication network [64], which play crucial roles in cognitive impairment and neurological symptoms [20]....
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...Some symptoms of the Fukuda criteria overlap with depression whereas the Canadian Consensus Criteria [20] differentiate ME patients from those who are depressed and identify patients who are more physically debilitated and have greater physical and cognitive functional impairments [21]....
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TL;DR: Physicians seeking systematic treatments for their patients might consider testing urinary organic acids to determine how best to treat mitochondrial diseases and dysfunction, and antioxidant therapies hold promise for improving mitochondrial performance.
564 citations
"Myalgic encephalomyelitis: Internat..." refers background in this paper
...Myalgic encephalomyelitis (ME), also referred to in the literature as chronic fatigue syndrome (CFS), is a complex disease involving profound dysregulation of the central nervous system (CNS) [1-3] and immune system [4-8], dysfunction of cellular energy metabolism and ion transport [9-11], and cardiovascular abnormalities [12-14]....
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