Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians.

There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2-3 years that promise new leads towards an effective clinical diagnostic test that may have a general application.

Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.

Source: Sweetman E, Noble A, Edgar C, Mackay A, Helliwell A, Vallings R, Ryan M, Tate W. Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Diagnostics (Basel). 2019 Jul 10;9(3). pii: E73. doi: 10.3390/diagnostics9030073. https://www.mdpi.com/2075-4418/9/3/73 (Full article)

Biomarker Test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

By Jennifer Abbasi

Myalgic encephalomyelitis/chronic fatigue syndrome affects at least 2 million people in the United States. Despite its prevalence, there’s no laboratory test for the disease, and its diagnosis is based on symptoms like exhaustion, unrefreshing sleep, and light sensitivity. For patients with this debilitating condition, getting a diagnosis is often a long and expensive process. Now, a long-awaited biomarker-based test for the mysterious disease could be on the horizon.

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JAMA. 2019;322(2):107. doi:10.1001/jama.2019.8890

MicroRNAs as biomarkers of pain intensity in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Numerous experimental models have shown that microRNAs play an important role in regulating pain-processing in clinical pain disorders. In this study, we evaluated a set of micro-RNAs as diagnostic biomarkers of pain intensity in adolescents with chronic fatigue syndrome (CFS). We then correlated the expression of these microRNAs with the levels of inflammatory markers and pain-related comorbidities in adolescents with CSF and healthy controls (HCs).

METHODS: A total of 150 adolescents, aged 12-18 years, participated in this study between April 2016 and April 2017. The participants were classified into two groups: adolescents with CFS (n=100) and HCs (n=50). RT-PCR was used to evaluate the expression of miR-558, miR-146a, miR-150, miR-124, and miR-143. Immunoassay analysis was used to assess the levels of immune inflammatory markers IL-6, TNF-α, and COX-2.

RESULTS: Adolescents with CFS showed significantly higher pain thresholds than comparable non-fatigued HCs. Also, enjoy of life and relation to others as the life domains, showed lower pain interference in CFS patients. Differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143 was significantly down regulated and notably interfered with pain intensity and frequency in patients with CFS. Also, the expression of these miRNAs was significantly correlated with that of IL-6, TNF-α, and COX-2, which have been shown to mediate pain intensity in patients with CFS.

Girls with CSF showed significantly decreased expression levels of these miRNAs compared with the levels of boys with CSF. Girls with CSF also showed increased expression of inflammatory pain-related markers IL-6, TNF-α, and COX-2, compared with the levels of boys with CSF

CONCLUSIONS: The intensity and consequences of pain were influenced by differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143, which was directly, associated with higher expression of immune inflammatory related genes TNFα, IL-6, and COX-2 in adolescences with CFS. Further studies of larger patient cohorts will help clarify the role of miRNAs in the pathogenesis of CFS.

This article is protected by copyright. All rights reserved.

Source: Al-Rawaf HA, Alghadir AH, Gabr SA. MicroRNAs as biomarkers of pain intensity in patients with chronic fatigue syndrome. Pain Pract. 2019 Jul 8. doi: 10.1111/papr.12817. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31282597

Myalgic encephalomyelitis or chronic fatigue syndrome

Abstract:

In this review, we discuss the myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is characterised by extreme mental and physical fatigue with associated symptoms of pain, disturbed sleep, cognitive and autonomic dysfunction, as well as post-exertional malaise. This condition is often preceded by an infection, severe physiological and/or psychological strain. Over the last decades, research has demonstrated mitochondrial, neuroendocrine, immunological, and metabolic perturbations in patients with ME/CFS, giving hope for the development of new biomarkers and new treatment modalities.

Source: Brinth L, Nielsen H, Varming K, Boonen SE, Ebsen ACG, Fernández-Guerra P, Schou AS, Mehlsen J, Gregersen N, Brandslund I, Olsen RKJ. Myalgic encephalomyelitis or chronic fatigue syndrome. Ugeskr Laeger. 2019 Jun 10;181(24). pii: V08180570. [Article in Danish] https://www.ncbi.nlm.nih.gov/pubmed/31267953

Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases

Abstract:

Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months. The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period.

Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group.

The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly. Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event.

These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation. These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response.

Source: Neil R. McGregor, Christopher W. Armstrong , Donald P. Lewis and Paul R. Gooley. Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases. Diagnostics 2019, 9(3), 70; https://doi.org/10.3390/diagnostics9030070 https://www.mdpi.com/2075-4418/9/3/70/htm (Full article)

Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome

Introduction:

The illness now called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was first described in the mid-1980s. At that time, nothing was known about its underlying biology. Indeed, because many standard laboratory test results were normal, some clinicians explained to patients that “there is nothing wrong.” There was, of course, an alternative explanation: the standard laboratory tests might not have been the right tests to identify the underlying abnormalities.

Over the past 35 years, thousands of studies from laboratories in many countries have documented underlying biological abnormalities involving many organ systems in patients with ME/CFS, compared with healthy controls: in short, there is something wrong. Moreover, most of the abnormalities are not detected by standard laboratory tests. In 2015, the Institute of Medicine of the National Academy of Sciences concluded that ME/CFS “is a serious, chronic, complex systemic disease that often can profoundly affect the lives of patients,” affects up to an estimated 2.5 million people in the United States, and generates direct and indirect expenses of approximately $17 billion to $24 billion annually.

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Source: Anthony L. Komaroff, MD. Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome. JAMA. Published online July 5, 2019. doi:10.1001/jama.2019.8312 https://jamanetwork.com/journals/jama/fullarticle/2737854 (Full article)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Induced by Repeated Forced Swimming in Mice

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue of at least 6 months, in addition to symptoms such as muscle pain and muscle weakness. There is no treatment provides long-term benefits to most patients. Recently, clinical research suggested the involvement of pyruvate dehydrogenase (PDH) in ME/CFS. PDH is a crucial enzyme in the mitochondria matrix that links glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. However, it is little known whether PDH could be a therapeutic target. The purpose of this study was to establish ME/CFS in mice and to investigate the involvement of PDH in ME/CFS.

To induce the chronic fatigue in mice, a repeated forced swimming test was conducted. To evaluate fatigue, we measured immobility time in forced swimming test and starting time of grooming. An open field test was conducted on day 8. After 25 d of the forced swimming test, the mitochondrial fraction in gastrocnemius muscle was isolated and PDH activity was measured. Moreover, we evaluated the effect of PDH activation by administering sodium dichloroacetate (DCA).

In ME/CFS mice group, the immobility time and starting time of grooming increased time-dependently. In addition, the moved distance was decreased in ME/CFS mice. PDH activity was decreased in the mitochondrial fraction of the gastrocnemius muscle of the forced swimming group. DCA treatment may be beneficial in preventing fatigue-like behavior in ME/CFS. These findings indicate that ME/CFS model was established in mice and that a decrease in mitochondrial PDH activity is involved with the symptom of ME/CFS.

Source: Ohba T, Domoto S, Tanaka M, Nakamura S, Shimazawa M, Hara H. Biol Pharm Bull. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Induced by Repeated Forced Swimming in Mice. 2019;42(7):1140-1145. doi: 10.1248/bpb.b19-00009. https://www.jstage.jst.go.jp/article/bpb/42/7/42_b19-00009/_article (Full article)

Chronic Fatigue Syndrome and chronic pain conditions – vitally protective systems gone wrong

Abstract:

Chronic Fatigue Syndrome (CFS) and chronic pain syndromes represent major health problems in society. These conditions are disabling and strongly associated with low quality of life. Even though CFS and chronic pain are separate conditions, they have strikingly much in common. Both pain and fatigue are important sensations with protective value in an acute situation. It can be life-threatening not to be aware of them.

However, as these symptoms become chronic, their protective roles decrease and instead they become health problems. Our understanding of the perception of pain and fatigue has shifted through the years, from a dualistic biomedical point of view to a holistic biopsychosocial understanding. This combined with the increasing evidence of how our brain works in a predictive/anticipatory manner, gives a deeper understanding of why treatments like cognitive behavior therapies and stress relief therapies can help these patients recover to better health.

Source: Pedersen M. Chronic Fatigue Syndrome and chronic pain conditions – vitally protective systems gone wrong. Scand J Pain. 2019 Jun 29. pii: /j/sjpain.ahead-of-print/sjpain-2019-0072/sjpain-2019-0072.xml. doi: 10.1515/sjpain-2019-0072. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31256069

Medically Documenting Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Cases

Introduction:

Patients with severe myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS) experience debilitating physical and cognitive symptoms, which often result in the need to file disability claims. A significant number of ME/CFS patients are children or adolescents. ME/CFS patients often turn to physicians who are not trained to recognize and diagnose ME/CFS, and who might or might not understand that ME/CFS is a multi-system primarily physical illness. Such misperceptions can adversely affect the doctor-patient relationship, the clinical outcomes, as well as the results of disability claims.

According to the National Academies of Science, Engineering and Medicine, “Between 836,000 and 2.5 million Americans suffer from myalgic encephalomyelitis/chronic fatigue syndrome… This disease is characterized by profound fatigue, cognitive dysfunction, sleep abnormalities, autonomic manifestations, pain, and other symptoms that are made worse by exertion of any sort. ME/CFS can severely impair patients’ ability to conduct their normal lives.1” The prevalence of MECFS among children and adolescents has been estimated variously as between 0.11 and 4% (1). A large percentage of children and adolescents with ME/CFS suffer from orthostatic intolerance due to one or both of these syndromes: Neurally Mediated Hypotension (NMH) and Postural Orthostatic Tachycardia Syndrome (POTS). These elements of ME/CFS often respond well to proper treatment (2, 3).

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Source: Barbara B. Comerford and Richard Podell. Medically Documenting Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Cases. Front. Pediatr., 02 July 2019 | https://doi.org/10.3389/fped.2019.00231 (Full article) https://www.frontiersin.org/articles/10.3389/fped.2019.00231/full

The clinical value of cytokines in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a heterogeneous disorder with uncertain pathogenesis. Without effective therapy, CFS is characterized by disabling fatigue, depression, memory loss, and somatic discomfort. This comprehensive and impartial review aimed to assess the available evidence and examined the potential clinical value of using cytokines for the monitoring of CFS and as targets for the treatment of CFS.

Inflammatory reactions and immune modulation are considered to contribute to the pathophysiology of CFS, and it is well documented that cytokines present in both blood and cerebrospinal fluid (CSF) are closely associated with the progression and severity of CFS. However, pathophysiological and methodological limitations prevent using circulating cytokines as independent diagnostic indices. Moreover, there is no evidence to support the use of CSF cytokines as independent diagnostic indices.

Nevertheless, a comprehensive evaluation of changes in circulating and CSF cytokines may improve clinical understanding of the pathophysiology of patients with CFS, aiding in the establishment of an appropriate diagnosis. Importantly, the available evidence does not support the value of cytokines as therapeutic targets. We believe that an improved understanding of cytokine-related mechanisms will be helpful to explore new cytokine-related therapeutic targets.

Source: Yang T, Yang Y, Wang D, Li C, Qu Y, Guo J, Shi T, Bo W, Sun Z, Asakawa T. The clinical value of cytokines in chronic fatigue syndrome. J Transl Med. 2019 Jun 28;17(1):213. doi: 10.1186/s12967-019-1948-6 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-019-1948-6 (Full article)