Research Volunteers’ Attitudes Toward Chronic Fatigue Syndrome and Myalgic Encephalomyelitis

Abstract:

Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are stigmatizing illnesses characterized by cognitive difficulties, post-exertional malaise, unrefreshing sleep, and other symptoms. Patients are often incapacitated and stigmatized as having a psychological disorder.

The Chronic Fatigue Attitudes Test (CAT) assesses stigmatizing views toward individuals with Chronic Fatigue Syndrome, however, there is little research examining factors that may account for variation in stigmatizing attitudes toward this group. We examined CAT scores among college age research volunteers (N = 90), hypothesizing that exposure to information about ME and CFS as a result of volunteering on a ME and CFS-related research project would be associated with less stigmatizing attitudes compared to volunteers on unrelated projects.

Findings indicated that ME and CFS research volunteers expressed less stigmatizing attitudes. Educational efforts aiming to disseminate accurate information about ME and CFS may mitigate stigma and the experience of stigma among individuals with ME and CFS.

Source: Nehrke PI, Fox PA, Jason LA. Research Volunteers’ Attitudes Toward Chronic Fatigue Syndrome and Myalgic Encephalomyelitis. Neurology (ECronicon). 2017;7(4):172-178. Epub 2017 Aug 16.  https://www.ncbi.nlm.nih.gov/pubmed/29662969

Abnormal rheological properties of red blood cells as a potential marker of Gulf War Illness: A preliminary study

Editor’s comment: In the 1980s, L. O. Simpson studied abnormally shaped red blood cells in patients with ME, which he published in a paper, “Nondiscocyte Erythrocytes in Myalgic Encephalomyelitis.” He later summarized his findings in a paper entitled “The Results from Red Cell Shape Analyses of Blood Samples From Members of Myalgic Encephalomyelitis Organisations in Four Countries.” You can read it HERE.

Abstract:

BACKGROUND: Veterans with Gulf War Illness (GWI) experience chronic symptoms that include fatigue, pain, and cognitive impairment. This symptom cluster may be the consequence of impaired tissue oxygen delivery due to red blood cell (RBC) dysfunction.

OBJECTIVE: The purpose of this preliminary study was to determine whether the microrheological behavior of RBCs is altered in GWI.

METHODS: We recruited 17 cases of GWI (GWI+) and 10 age matched controls (GWI-), and examined RBC deformability and aggregation via ektacytometry along with measurement of complete blood counts.

RESULTS: RBCs were more deformable in GWI+, as indicated by higher elongation indices particularly at higher shear stress values (5.33, 9.49, and 16.89) when compared to GWI-. Aggregation formation, stability and kinetics were similar between GWI+and GWI-. Complete blood counts were also similar, with the exception of mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and RBC distribution width (RDW) which was elevated in GWI+.

CONCLUSIONS: In this preliminary study, we observed increased deformability along with increased MCH, MCHC and RDW in veterans with GWI+, which may contribute to the symptomatology of GWI. Further research is required to confirm our findings and the role of RBC microrheology in GWI.

Source: Falvo MJ, Chen Y, Klein JC, Ndirangu D, Condon MR. Abnormal rheological properties of red blood cells as a potential marker of Gulf War Illness: A preliminary study. Clin Hemorheol Microcirc. 2018;68(4):361-370. doi: 10.3233/CH-170262. https://www.ncbi.nlm.nih.gov/pubmed/29660926

Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review

Abstract:

Chronic fatigue syndrome (CFS), commonly known as myalgic encephalomyelitis (ME), is a debilitating disease of unknown etiology. CFS/ME is a heterogeneous disease associated with a myriad of symptoms but with severe, prolonged fatigue as the core symptom associated with the disease. There are currently no known biomarkers for the disease, largely due to the lack of knowledge surrounding the eitopathogenesis of CFS/ME. Numerous studies have been conducted in an attempt to identify potential biomarkers for the disease.

This mini-review offers a brief summary of current research into the identification of metabolic abnormalities in CFS/ME which may represent potential biomarkers for the disease. The progress of research into key areas including immune dysregulation, mitochondrial dysfunction, 5′-adenosine monophosphate-activated protein kinase activation, skeletal muscle cell acidosis, and metabolomics are presented here. Studies outlined in this mini-review show many potential causes for the pathogenesis of CFS/ME and identify many potential metabolic biomarkers for the disease from the aforementioned research areas.

The future of CFS/ME research should focus on building on the potential biomarkers for the disease using multi-disciplinary techniques at multiple research sites in order to produce robust data sets. Whether the metabolic changes identified in this mini-review occur as a cause or a consequence of the disease must also be established.

Source: Cara Tomas; Julia Newton. Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review. Biochemical Society Transactions Apr 17, 2018; DOI: https://doi.org/10.1042/BST20170503. http://www.biochemsoctrans.org/content/early/2018/04/16/BST20170503

KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial

Abstract:

Mitochondrial dysfunction and a hypometabolic state are present in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). KPAX002 consists of low-dose methylphenidate hydrochloride to treat a hypometabolic state combined with key micronutrients intended to broadly support mitochondrial function.

The objective of this study was to evaluate KPAX002 as a treatment for fatigue and concentration disturbance symptoms in ME/CFS subjects. This phase 2 randomized, double-blinded, placebo-controlled trial was conducted at 4 sites in the United States. A total of 135 subjects with ME/CFS were randomly assigned to either KPAX002 (n=67) or placebo (n=68) for 12 weeks of treatment. The primary endpoint was change in the Checklist Individual Strength (CIS) total score from baseline to Week 12. Secondary measurements included visual analog scales for fatigue and concentration disturbance symptoms.

In the intent-to-treat population, the mean reduction in the CIS total score from baseline to week 12 for the KPAX002 and placebo groups was -16.9 (± 23.52) and -13.8 (± 22.15), respectively (95% confidence interval, -11.1, 4.0; P=0.359). On the visual analog scale for fatigue, the mean reduction from baseline to week 12 was -18.2 mm (± 25.05) and -11.1 mm (± 22.08) for the KPAX002 and placebo groups, respectively (95% confidence interval, -11.5, 2.3; P=0.189). The two groups demonstrating the most robust response to KPAX002 were subjects with more severe ME/CFS symptoms at baseline (P=0.086) and subjects suffering from both fatigue and pain (P=0.057). The incidence of adverse events was not statistically different between the two groups.

Treatment with KPAX002 resulted in a reduction in fatigue and concentration disturbance symptoms in multiple analyses. Two key subgroups of patients whose response approached statistical significance were identified.

Source: Jose G Montoya, Jill N Anderson, Danya L Adolphs, Lucinda Bateman, Nancy Klimas, Susan M Levine, Donn W Garvert, Jon D Kaiser. KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med 2018;11(3):2890-2900 www.ijcem.com /ISSN:1940-5901/IJCEM0065685 (Full article)

Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS

Abstract:

Background: Skeletal muscle fatigue and post-exertional malaise are key symptoms of Myalgic Encephalomyelitis (ME/CFS). We have previously shown that AMPK activation and glucose uptake are impaired in primary human skeletal muscle cell cultures derived from patients with ME/CFS in response to electrical pulse stimulation, a method which induces contraction of muscle cells in vitro. The aim of this study was to assess if AMPK could be activated pharmacologically in ME/CFS.

Methods: Primary skeletal muscle cell cultures from patients with ME/CFS and healthy controls were treated with either metformin or 991. AMPK activation was assessed by Western blot and glucose uptake measured.

Results: Both metformin and 991 treatment significantly increased AMPK activation and glucose uptake in muscle cell cultures from both controls and ME/CFS. Cellular ATP content was unaffected by treatment although ATP content was significantly decreased in ME/CFS compared to controls.

Conclusions: Pharmacological activation of AMPK can improve glucose uptake in muscle cell cultures from patients with ME/CFS. This suggests that the failure of electrical pulse stimulation to activate AMPK in these muscle cultures is due to a defect proximal to AMPK. Further work is required to delineate the defect and determine whether pharmacological activation of AMPK improves muscle function in patients with ME/CFS.

Source: Brown AE, Dibnah B, Fisher E, Newton JL, Walker M. Pharmacological activation of AMPK and glucose uptake in cultured human skeletal muscle cells from patients with ME/CFS. Biosci Rep. 2018 Apr 13. pii: BSR20180242. doi: 10.1042/BSR20180242. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/29654166/

 

Metabolic features of the cell danger response

Editor’s note: Dr. Naviaux has theorized that the cell danger response lies at the heart of ME/CFS pathophysiology.

Abstract:

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal.

When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development.

An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette’s syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis.

Source: Robert K.Naviaux. Metabolic features of the cell danger response. Mitochondrion. Volume 16, May 2014, Pages 7-17. https://www.sciencedirect.com/science/article/pii/S1567724913002390 (Full article)

Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment.

METHODS: This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed.

RESULTS: WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines.

CONCLUSIONS: The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.

Source: Richardson AM, Lewis DP, Kita B, Ludlow H, Groome NP, Hedger MP, de Kretser DM, Lidbury BA. Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection. J Transl Med. 2018 Apr 12;16(1):97. doi: 10.1186/s12967-018-1473-z. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1473-z (Full article)

Changes in fatigue, autonomic functions, and blood biomarkers due to sitting isometric yoga in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: In a previous randomized controlled trial, we found that sitting isometric yoga improves fatigue in patients with chronic fatigue syndrome (CFS) who are resistant to conventional therapy. The aim of this study was to investigate possible mechanisms behind this finding, focusing on the short-term fatigue-relieving effect, by comparing autonomic nervous function and blood biomarkers before and after a session of isometric yoga.

METHODS: Fifteen patients with CFS who remained symptomatic despite at least 6 months of conventional therapy practiced sitting isometric yoga (biweekly 20 min practice with a yoga instructor and daily home practice) for eight weeks. Acute effects of sitting isometric yoga on fatigue, autonomic function, and blood biomarkers were investigated after the final session with an instructor. The effect of a single session of sitting isometric yoga on fatigue was assessed by the Profile of Mood Status (POMS) questionnaire immediately before and after the session. Autonomic nervous function (heart rate (HR) variability) and blood biomarkers (cortisol, DHEA-S, TNF-α, IL-6, IFN-γ, IFN-α, prolactin, carnitine, TGF-β1, BDNF, MHPG, and HVA) were compared before and after the session.

RESULTS: Sitting isometric yoga significantly reduced the POMS fatigue score (p < 0.01) and increased the vigor score (p < 0.01). It also reduced HR (p < 0.05) and increased the high frequency power (p < 0.05) of HR variability. Sitting isometric yoga increased serum levels of DHEA-S (p < 0.05), reduced levels of cortisol (p < 0.05) and TNF-α (p < 0.05), and had a tendency to reduce serum levels of prolactin (p < 0.1). Decreases in fatigue scores correlated with changes in plasma levels of TGF-β1 and BDNF. In contrast, increased vigor positively correlated with HVA.

CONCLUSIONS: A single session of sitting isometric yoga reduced fatigue and increased vigor in patients with CFS. Yoga also increased vagal nerve function and changed blood biomarkers in a pattern that suggested anti-stress and anti-inflammatory effects. These changes appear to be related to the short-term fatigue-relieving effect of sitting isometric yoga in patients with CFS. Furthermore, dopaminergic nervous system activation might account for sitting isometric yoga-induced increases in energy in this patient population.

TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN CTR) UMIN000009646. Registered Dec 27, 2012.

Source: Oka T, Tanahashi T, Sudo N, Lkhagvasuren B, Yamada Y. Changes in fatigue, autonomic functions, and blood biomarkers due to sitting isometric yoga in patients with chronic fatigue syndrome. Biopsychosoc Med. 2018 Apr 10;12:3. doi: 10.1186/s13030-018-0123-2. eCollection 2018. https://www.ncbi.nlm.nih.gov/pubmed/29643935

SEID diagnostic criteria applied on an adolescent cohort: evaluation of subgroup differences and prognostic utility

Systemic exertion intolerance disease diagnostic criteria applied on an adolescent chronic fatigue syndrome cohort: evaluation of subgroup differences and prognostic utility

Abstract:

OBJECTIVE: Existing case definitions for chronic fatigue syndrome (CFS) all have disputed validity. The present study investigates differences between adolescent patients with CFS who satisfy the systemic exertion intolerance disease (SEID) diagnostic criteria (SEID-positive) and those who do not satisfy the criteria (SEID-negative).

METHODS: 120 adolescent patients with CFS with a mean age of 15.4 years (range 12-18 years) included in the NorCAPITAL project (ClinicalTrials ID: NCT01040429) were post-hoc subgrouped according to the SEID criteria based on a comprehensive questionnaire. The two subgroups were compared across baseline characteristics, as well as a wide range of cardiovascular, inflammatory, infectious, neuroendocrine and cognitive variables. Data from 30-week follow-up were used to investigate prognostic differences between SEID-positive and SEID-negative patients.

RESULTS: A total of 45 patients with CFS were SEID-positive, 69 were SEID-negative and 6 could not be classified. Despite the fact that clinically depressed patients were excluded in the NorCAPITAL project, the SEID-positive group had significantly higher score on symptoms suggesting a mood disorder (Mood and Feelings Questionnaire): 23.2 vs 13.4, difference 9.19 (95% CI 5.78 to 12.6). No other baseline characteristics showed any group differences. When accounting for multiple comparisons, there were no statistically significant differences between the groups regarding cardiovascular, inflammatory, infectious, neuroendocrine and cognitive variables. Steps per day and Chalder Fatigue Questionnaire at week 30 showed no differences between the groups.

CONCLUSION: The findings question the discriminant and prognostic validity of the SEID diagnostic criteria in adolescent CFS, and suggest that the criteria tend to select patients with depressive symptoms.

Source: Asprusten TT, Sulheim D, Fagermoen E, Winger A, Skovlund E, Wyller VB. Systemic exertion intolerance disease diagnostic criteria applied on an adolescent chronic fatigue syndrome cohort: evaluation of subgroup differences and prognostic utility. BMJ Paediatr Open. 2018 Mar 16;2(1):e000233. doi: 10.1136/bmjpo-2017-000233. eCollection 2018.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887832/ (Full article)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology.

In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients.

Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Source: Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S1, Murovska M, Scheibenbogen C; European Network on ME/CFS (EUROMENE). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease. Autoimmun Rev. 2018 Apr 7. pii: S1568-9972(18)30088-0. doi: 10.1016/j.autrev.2018.01.009. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29635081