Overview/Epidemiology Studies

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Extended List of Studies (by year)

2019

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop? [PDF]
Morris G, Maes M, Berk M, Puri BK. Metabolic Brain Disease. 2019
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation...

In this paper, it has been shown that, while the aetiology of CFS/ME is currently unknown, there is strong evidence of this illness being associated with a wide range of biological abnormalities, most notably in the neuroendocrine, autonomic, neurological, bioenergetic, redox and immunological domains. It has also been seen that epigenetic variation in immune response genes plays a major role in determining the development of DAMPs post-infection, which is pertinent from the perspective of the aetiology of the illness as the production or presence of these molecules can ‘convert’ an acute pathogenic infection into a state of escalating chronic systemic inflammation, which in turn can give rise to many of the reported symptoms and biological abnormalities. It has further been demonstrated in this paper how this relatively simple concept does indeed lead to a novel explanatory model which explains the major biological observations.

Estimating Prevalence, Demographics, and Costs of ME/CFS Using Large Scale Medical Claims Data and Machine Learning. [PDF]
Valdez AR, Hancock EE, Adebayo S, Kiernicki DJ, Proskauer D, Attewell JR, Bateman L, DeMaria Jr. A, Lapp CW, Rowe PC, Proskauer C. Front. Pediatr. 2019
ME/CFS is an acquired, chronic, multi-systemic disease characterized by significant relapse after physical, cognitive, or emotional exertion of any sort. The disease includes immune, neurological and cognitive impairment, sleep abnormalities, and autonomic dysfunction, resulting in significant functional impairment accompanied by a pathological level of fatigue...Annual direct medical costs for ME/CFS patients are three to four times higher than average of the reference population and fifty percent higher than for multiple sclerosis or lupus, diseases with similar characteristics...Based on our results and analysis, ME/CFS should get more attention in research and provider communities, and warrants more education to providers (primary care, specialties, and allied health sciences) to improve the quality of healthcare and quality of life for affected individuals.

2015-2018

Myalgic Encephalomyelitis (ME) or What? An Operational Definition. [PDF]
Twisk F. Diagnostics (Basel). 2018
This article proposes an operational definition based on the most recent formal definitions and symptoms observed in ME. ME is a multi-systemic illness, which (1) often has a sudden onset, in most cases a respiratory and/or gastro-intestinal infection, but a gradual or more dramatic onset is also possible; (2) has an epidemic and an endemic form; (3) has an unique clinical pattern deviating from other post-viral states; (4) is distinguished by muscle fatigability/prolonged muscle weakness after trivial exertion; (5) is accompanied by symptoms relating to neurological disturbance, especially of cognitive, autonomic, and sensory functions; (6) can be accompanied by symptoms associated with cardiac and other systems; (7) is characterized by fluctuation of symptoms (within and between "episodes"); (8) has a prolonged relapsing course; and (9) has a tendency to become chronic.

In conclusion, a discriminative definition for ME contains four mandatory elements: (1) muscle fatigability/post-exertional muscle weakness lasting for days; (2) operational criteria for "neurological disturbance, especially of cognitive, autonomic and sensory functions"; (3) fluctuation of symptoms; and (4) a prolonged relapsing course. This tentative definition of ME justifies the qualification "neuromuscular disease".

Regulation of Endotoxin Tolerance and Compensatory Anti-inflammatory Response Syndrome by Non-coding RNAs. [PDF]
Vergadi E, Vaporidi K, Tsatsanis C. Front Immunol. 2018.
Endotoxin tolerance and compensatory anti-inflammatory response syndrome (CARS) describe a state of hypo-responsiveness characterized by reduced capacity of myeloid cells to respond to inflammatory stimuli, particularly those initiated by bacterial lipopolysaccharide (LPS). To achieve endotoxin tolerance, extensive reprogramming otherwise termed as “innate immune training”, is required that leads to both modifications of the intracellular components of TLR signaling and also to alterations in extracellular soluble mediators. Non-coding RNAs (ncRNAs) have been recognized as critical regulators of TLR signaling.

Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review. [PDF]
Vink M, Vink-Niese A. Sage Journal. 2018
The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome.

History of Researches on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Watanabe Y, Kuratsune H. Brain Nerve. 2018

Chronic fatigue syndrome prevalence is grossly overestimated using Oxford criteria compared to Centers for Disease Control (Fukuda) criteria in a U.S. population study. [PDF]
Baraniuk, J.N. Fatigue: Biomedicine, Health & Behavior. 2017

The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE [PDF]
Scheibenbogen & Freitag, et al. Journal of Translational Medicine. 2017

Oxford Criteria.
Sharpe M, Archard L, Banatvala J, Borysiewicz L, Clare A,  David A, Edwards R, Hawton K, Lambert H, Lane R. MEpedia. 2017

Subtyping Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) By Course
of Illness [Full Text] [PDF]
Stoothoff & Gleason et al. Center for Community Research, DePaul University, Chicago. 2017

A Comparison of Case Definitions for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome.
[Full Text] [PDF]
Sunnquist M, Jason LA, Nehrke P, Goudsmit EM. J Chronic Dis Manag. 2017

The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem. [PDF]
Edwards JCW, McGrath S, Baldwin A, Livingstone M, Kewley A. Fatigue: Biomedicine, Health & Behavior. 2016
Considering both the clinical picture itself (with widespread cognitive and other global problems such as pain and fatigue), and the likelihood that the chronic disease state may involve a complex regulatory system shifting to an abnormal equilibrium state, it is likely that the pathophysiology involves the central nervous system (CNS), plus or minus the immune system (both with complex regulatory dynamics) in some or all cases. The autonomic nervous system is another potential site for dysregulation. Generalised metabolic abnormalities have been proposed by others.

[HIGHLIGHT] Are Myalgic Encephalomyelitis and chronic fatigue syndrome different illnesses? A preliminary analysis.
[Full Text] [PDF]
Jason LA, Sunnquist M, Brown A, Evans M, Newton JL. J Health Psychol. 2016
Considerable discussion has transpired regarding whether chronic fatigue syndrome is a distinct illness from Myalgic Encephalomyelitis. A prior study contrasted the Myalgic Encephalomyelitis International Consensus Criteria (ME-ICC; Carruthers et al., 2011) with the Fukuda et al. (1994) CFS criteria and found that the ME-ICC identified a subset of patients with greater functional impairment and physical, mental, and cognitive problems than the larger group who met Fukuda et al. (1994) criteria (Brown et al., 2013). The current study analyzed two discrete data sets and found that the ME-ICC identified more impaired individuals with more severe symptomatology.

Notes:

The term Myalgic Encephalomyelitis (ME) was first used in an anonymous editorial in an issue of the Lancet (Anonymous Editorial, 1956). Using this term, Ramsay (1988) published a case definition for ME (Hyde et al., 1992). Subsequently, a case definition was developed utilizing the term Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS; Carruthers et al., 2003), known as the 2003 Canadian Clinical ME/CFS case definition. These criteria required the occurrence of seven specific ME/CFS symptoms. Several of the individuals who were involved in creating the ME/CFS criteria, along with other scientists and clinicians, recently published the International Consensus Criteria for Myalgic Encephalomyelitis (ME-ICC; Carruthers et al., 2011). In addition to requiring the presence of eight symptoms from four domains, these criteria specify that the impact of the illness must result in a 50% or greater reduction in the patient’s premorbid activity level.

In contrast, most scientists have used the Fukuda et al. (1994) case definition in researching chronic fatigue syndrome (CFS). This case definition requires an individual to experience six or more months of chronic fatigue of a new or definite onset that is not substantially alleviated by rest, not the result of ongoing exertion, and results in substantial reductions in occupational, social, and personal activities (Fukuda et al., 1994: 956). The Fukuda et al. case definition employs a polythetic approach for assessing symptomatology. Thus, in contrast to the ME/CFS (Carruthers et al., 2003) and ME-ICC (Carruthers et al., 2011) case definitions, the Fukuda et al. criteria require any four symptoms out of a possible eight, so individuals who meet Fukuda et al. criteria may not have core CFS symptoms such as post-exertional malaise.

In a study of individuals who had been diagnosed using the Fukuda et al. (1994) CFS criteria, Brown et al. (2013) examined whether these participants also met the ME-ICC (Carruthers et al., 2011). Findings indicated that the ME-ICC identified individuals with more serious symptomatology and functional disability than those who met only the Fukuda et al. criteria. Unfortunately, there were two limitations in this initial effort to compare the CFS and ME-ICC. First, individuals recruited into the sample had to have been diagnosed with CFS, so this requirement may have led to a selection bias. Second, the instrument used to measure ME-ICC symptoms was created prior to the criteria’s publication, so a number of the symptoms could only be assessed indirectly. The present study used a new instrument that better assessed ME-ICC symptoms and examined two groups of participants who were recruited using different case ascertainment methods to reduce selection bias. We hypothesized that the ME-ICC would identify a more impaired, symptomatic group than the Fukuda et al. criteria.

UK tribunal orders release of data from controversial chronic fatigue syndrome study.
McCook, A. Retraction Watch. 2016

Illness progression in chronic fatigue syndrome: a shifting immune baseline. [PDF]
Russell L, et al. BMC Immunol. 2016

Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians.
Bested AC, et al. Rev Environ Health. 2015

Request for information under the Freedom of Information Act 2000 (“the Act”). [PDF]
Daly, B. (n.d.) [Letter written December 11, 2015 to James Coyne]

[HIGHLIGHT] Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. [Full Text] [PDF]
IOM (Institute of Medicine). Washington (DC): National Academies Press (US). 2015
Myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are serious, debilitating conditions that affect millions of people in the United States and around the world. ME/CFS can cause significant impairment and disability. Despite substantial efforts by researchers to better understand ME/CFS, there is no known cause or effective treatment. Diagnosing the disease remains a challenge, and patients often struggle with their illness for years before an identification is made. Some health care providers have been skeptical about the serious physiological — rather than psychological — nature of the illness. Once diagnosed, patients often complain of receiving hostility from their health care provider as well as being subjected to treatment strategies that exacerbate their symptoms.

Chronic fatigue syndrome versus sudden onset myalgic encephalomyelitis. [Full Text] [PDF]
Jason LA, Evans M, Brown A, Sunnquist M, Newton JL. J Prev Interv Community. 2015

Myalgic Encephalomyelitis: Symptoms and Biomarkers. [PDF]
Jason LA, Zinn ML, Zinn MA. Current Neuropharmacology. 2015
The authors summarize advances in the physiological and neurological approaches to understanding, diagnosing, and treating ME.

[HIGHLIGHT] Accurate diagnosis of myalgic encephalomyelitis and chronic fatigue syndrome based upon objective test methods for characteristic symptoms. [PDF]
Twisk FN. World Journal of Methodology. 2015
Although myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are considered to be synonymous, the definitional criteria for ME and CFS define two distinct, partially overlapping, clinical entities. ME, whether defined by the original criteria or by the recently proposed criteria, is not equivalent to CFS, let alone a severe variant of incapacitating chronic fatigue. Distinctive features of ME are: muscle weakness and easy muscle fatigability, cognitive impairment, circulatory deficits, a marked variability of the symptoms in presence and severity, but above all, post-exertional “malaise”: a (delayed) prolonged aggravation of symptoms after a minor exertion. In contrast, CFS is primarily defined by (unexplained) chronic fatigue, which should be accompanied by four out of a list of 8 symptoms, e.g., headaches.

Due to the subjective nature of several symptoms of ME and CFS, researchers and clinicians have questioned the physiological origin of these symptoms and qualified ME and CFS as functional somatic syndromes. However, various characteristic symptoms, e.g., post-exertional “malaise” and muscle weakness, can be assessed objectively using well-accepted methods, e.g., cardiopulmonary exercise tests and cognitive tests. The objective measures acquired by these methods should be used to accurately diagnose patients, to evaluate the severity and impact of the illness objectively and to assess the positive and negative effects of proposed therapies impartially.

2010-2014

Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. [PDF]
Brurberg KG, Sporstøl Fønhus M, Larun L, Flottorp S, Malterud K. BMJ Open. 2014
The objectives of our study were to explore strategies for evaluation of accuracy and concept validity of different case definitions for CFS/ME in the absence of a reference standard. First, we wanted to conduct a systematic review to identify and describe different case definitions (sets of diagnostic criteria) for CFS/ME. Second, we wanted to explore differences between various case definitions by identifying and reviewing validation studies.

Chronic Fatigue Syndrome: The Current Status and Future Potentials of Emerging Biomarkers. [PDF]
Fischer DB, William AH, Strauss AC, Unger ER, Jason L, Marshall GD Jr, Dimitrakoff JD. Fatigue. 2014
The authors review potential CFS biomarkers related to neurological and immunological components of the illness.

Are Myalgic Encephalomyelitis and chronic fatigue syndrome different illnesses? A preliminary analysis. [PDF]
Jason LA, Sunnquist M, Brown A, Evans M, Newton JL. J Health Psychol. 2014

Biomarkers for chronic fatigue. [PDF]
Klimas NG, Broderick G, Fletcher MA.  Brain Behav Immun. 2012
This review is focused on the recent literature related to biomarkers for fatigue associated with CFS/ME and, for comparison, those associated with other diseases.

Chronic fatigue syndrome, the immune system and viral infection. [Full Text]
Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Brain Behavior and Immunity. 2011
The authors review what is known about the immune system in CFS. Slightly increased parameters of inflammation and pro-inflammatory cytokines such as interleukin (IL) 1, IL6 and tumour necrosis factor (TNF) α are likely present. Additionally, impaired natural killer cell function appears evident. Alterations in T cell numbers have been described by some and not others. While the prevalence of positive serology for the common herpes viruses appears no different from healthy controls, there is some evidence of viral persistence and inadequate containment of viral replication. The ability of certain herpes viruses to impair the development of T cell memory may explain this viral persistence and the continuation of symptoms.

[HIGHLIGHT] Myalgic encephalomyelitis: International Consensus Criteria. [PDF]
Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG, Broderick G, Mitchell T, Staines D, Powels ACP, Speight N, Vallings R, Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J, Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisnik S, Mena I, Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S. Journal of Internal Medicine. 2011
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]. The underlying pathophysiology produces measurable abnormalities in physical and cognitive function and provides a basis for understanding the symptomatology. Thus, the development of International Consensus Criteria that incorporate current knowledge should advance the understanding of ME by health practitioners and benefit both the physician and patient in the clinical setting as well as clinical researchers.

2005-2009

Chronic fatigue syndrome: characteristics and possible causes for its pathogenesis. [PDF]
Bassi N, Amital D, Amital H, Doria A, Shoenfeld Y. Israel Medical Association Journal. 2008
Several mechanisms have been suggested to play a role in CFS, such as excessive oxidative stress following exertion, immune imbalance characterized by decreased natural killer cell and macrophage activity, immunoglobulin G subclass deficiencies (IgG1, IgG3) and decreased serum concentrations of complement component. Autoantibodies were also suggested as a possible factor in the pathogenesis of CFS. Recent studies indicate that anti-serotonin, anti-microtubule-associated protein 2 and anti-muscarinic cholinergic receptor 1 may play a role in the pathogenesis of CFS. It has been demonstrated that impairment in vasoactive neuropeptide metabolism may explain the symptoms of CFS.

Myalgic encephalomyelitis: a review with emphasis on key findings in biomedical research. [PDF]
Hooper M. Journal of Clinical Pathology. 2007
A review of research findings in CFS, termed a “chronic multiple-symptom, multiorgan, multisystem illness.”

Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions.
Klimas NG, Koneru AO. Curr Rheumatol Rep. 2007
Studies of CFS patients show a variety of dysfunctions, including mitochondrial dysfunction and immune dysfunction.

Overview of chronic fatigue syndrome focusing on prevalence and diagnostic criteria. [PDF]
Kuratsune H. Nihon Rinsho. BMC Psychiatry. 2007
Recent studies reveal that CFS can be understood to be a special condition based on the abnormality of neuroendocrine-immunologic system caused by the psycho-social stress and some genetic components. Under these conditions, a reactivation of various kinds of herpes virus infections and/or chronic infections might occur as a result of immune dysfunction, causing the abnormal production of several cytokines. A distinctive feature of CFS is thought to be the secondary brain dysfunction caused by the abnormal production of several cytokines.

Sub-typing CFS patients on the basis of ‘minor’ symptoms.
Janal MN, Ciccone DS, Natelson BH. Biological Psychology. 2006
The authors did an analysis of a population of CFS patients and came up with musculoskeletal, infectious and neurological subtypes.

2000-2004

[HIGHLIGHT] Myalgic encephalomyelitis/chronic fatigue syndrome: clinical working case definition, diagnostic and treatment protocols. [PDF]
Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, et al. J Chronic Fatigue
Syndrome. 2003
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.”

Variability in diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns of symptoms and disability. [Full Text]
Jason LA, Helgerson J, Torres-Harding SR, Carrico AW, Taylor RR. Eval Health Prof. 2003

PRE-2000

The chronic fatigue syndrome: a comprehensive approach to its definition and study. [PDF]
Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994

A Community Based Study of Chronic Fatigue Syndrome. [PDF]
Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang C, Plioplys S.
Arch Intern Med. 1999