Category: Symptoms

Actigraphic and Genetic Characterization of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Phenotypes in the UK Biobank (P10-9.007)

Abstract:

Objective: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often experience debilitating fatigue and autonomic dysregulation, yet objective measurements of these symptoms are limited. This study utilized actigraphic data from the United Kingdom Biobank (UKBB) to investigate (1) reduced activity in those with CFS, (2) decreased amplitudes of daily temperature rhythms as a potential indicator of autonomic dysregulation, and (3) the impact of specific single nucleotide polymorphisms (SNPs) associated with CFS on these actigraphic parameters.

Background: ME/CFS is a complex and poorly understood condition characterized by profound fatigue, postural orthostasis, and temperature dysregulation. Objective metrics reflecting these fatigue-related symptoms are scarce. Previous research explored small-scale actigraphic analyses, shedding light on movement and temperature patterns in CFS, but large-scale investigations remain limited. Genetic factors have also emerged as potential contributors to CFS risk, although how they affect phenotypic manifestations remains unclear.

Design/Methods: Actigraphic data from the UKBB were analyzed to compare those with CFS (n = 295) to controls (n = 63,133). Movement parameters, acceleration amplitudes, and temperature amplitudes were assessed. Additionally, the impact of specific SNPs associated with CFS on actigraphic measurements and subjective fatigue experiences was examined.

Results: In addition to profound fatigue, those with CFS exhibited significantly reduced overall movement (Cohen’s d = −0.220, p-value = 2.42 × 10–15), lower acceleration amplitudes (Cohen’s d = −0.377, p-value = 1.74 × 10−6), and decreased temperature amplitudes (Cohen’s d = −0.173, p-value = 0.002) compared to controls. Furthermore, certain SNPs associated with CFS were found to significantly influence both actigraphic measurements and subjective fatigue experiences.

Conclusions: This study provides valuable insights into the objective characterization of CFS using actigraphy, shedding light on the interaction between genetics and symptomatology in CFS. The findings offer avenues for further research into the pathophysiology of CFS and may contribute to a better understanding of fatigue-related conditions in general.

Source: Patrick Liu, David Raizen, Carsten Skarke, Thomas Brooks, and Ron Anafi. Actigraphic and Genetic Characterization of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Phenotypes in the UK Biobank (P10-9.007). Neurology, April 9, 2024 issue
102 (17_supplement_1) https://doi.org/10.1212/WNL.0000000000204829 https://www.neurology.org/doi/abs/10.1212/WNL.0000000000204829

The influence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) family history on patients with ME/CFS

Abstract:

Aim: It is unclear if individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with family histories of ME/CFS differ from those with ME/CFS without this family history. To explore this issue, quantitative data from patients with ME/CFS and controls were collected, and we examined those with and without family histories of ME/CFS.

Methods: The samples included 400 patients with ME/CFS, and a non-ME/CFS chronic illness control group of 241 patients with multiple sclerosis (MS) and 173 with post-polio syndrome (PPS).

Results: Confirming findings from prior studies, those with ME/CFS were more likely to have family members with ME/CFS than controls. We found family histories of ME/CFS were significantly higher (18%) among the ME/CFS group than the non-ME/CFS controls (3.9%). In addition, patients with ME/CFS who had family histories of ME/CFS were more likely to have gastrointestinal symptoms than those with ME/CFS without those family histories.

Conclusions: Given the recent reports of gastrointestinal difficulties among those with ME/CFS, our findings might represent one predisposing factor for the emergence of ME/CFS.
Source: Jason LA, Ngonmedje S. The influence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) family history on patients with ME/CFS. Explor Med. 2024;5:185–92. https://doi.org/10.37349/emed.2024.00215 https://www.explorationpub.com/Journals/em/Article/1001215 (Full text)

Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis

Abstract:

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

Source: Yi-Dan Zhang, Li-Na Wang. Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis. Front. Endocrinol., 09 April 2024, Sec. Neuroendocrine Science, Volume 15 – 2024 | https://doi.org/10.3389/fendo.2024.1373748 https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1373748/full

Do people with ME/CFS and joint hypermobility represent a disease subgroup? An analysis using registry data

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, multifaceted disease that affects millions globally. Despite its significant impact, the disease’s etiology remains poorly understood, and symptom heterogeneity poses challenges for diagnosis and treatment. Joint hypermobility, commonly seen in hypermobile Ehlers-Danlos Syndrome (hEDS), has been observed in ME/CFS patients but its prevalence and clinical significance within this population are not well-characterized.

Objective: To compare the characteristics of ME/CFS patients with and without joint hypermobility (JH+ and JH-) as assessed using the Beighton scoring system, and to explore whether JH+ ME/CFS patients exhibit distinct disease characteristics, comorbidities, and health-related quality of life (HRQOL).

Methods: The study used cross-sectional, self-reported data from 815 participants of the You + ME Registry. Participants were categorized as JH+ or JH- based on self–assessed Beighton scores and compared across demographics, comorbidities, family history, and symptoms. HRQOL was assessed using the Short Form-36 RAND survey and Karnofsky Performance Status.

Results: 15.5% (N = 126) of participants were classified as JH+. JH+ participants were more likely to be female, report Ehlers-Danlos Syndrome (EDS), Postural Orthostatic Tachycardia Syndrome (POTS), and a family history of EDS. They experienced worse HRQOL, particularly in physical functioning and pain, and a higher number of autonomic, neurocognitive, headache, gut, and musculoskeletal symptoms. Sensitivity analysis suggested that ME/CFS with concurrent JH+ and EDS was associated with more severe symptoms and greater functional impairment.

Conclusion: ME/CFS patients with joint hypermobility, particularly those with EDS, demonstrate distinct clinical characteristics, including more severe symptomatology and reduced HRQOL. These findings highlight the need for comprehensive clinical assessments of ME/CFS patients with joint hypermobility. Understanding these relationships could aid in subgroup identification, improving diagnosis, and informing targeted therapeutic approaches. Further research is warranted to explore these associations and their implications for clinical practice.

Source: Kathleen Mudie, Allison Ramiller, Sadie Whittaker, Leslie E. Phillips. Do people with ME/CFS and joint hypermobility represent a disease subgroup? An analysis using registry data. Front. Neurol., 12 March 2024, Sec. Autonomic Disorders, Volume 15 – 2024 | https://doi.org/10.3389/fneur.2024.1324879 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1324879/full (Full text)

The effect of comorbid medical diagnoses on disturbed sleep in chronic fatigue syndrome

Abstract:

Background: Chronic fatigue syndrome [CFS] may occur alone or with fibromyalgia. This has led some to believe the two occur along a common illness spectrum. Evaluating whether this is the case is important as differences in burden or severity of CFS with fibromyalgia (FM) would suggest different underlying pathophysiological processes.

Objective: To determine if Insomnia Severity Index [ISI] scores differ between patients with CFS and those with CFS plus FM. In addition, we aim to determine if insomnia severity is impacted by other comorbid medically unexplained diagnoses.

Methods: 247 patients with CFS completed the ISI and the Centers for Epidemiological Study – Depression. Patient groups were stratified on CFS severity and the presence of FM. A secondary analysis was conducted to evaluate insomnia severity related to the number of comorbid medically unexplained diagnoses including, FM, multiple chemical sensitivity and/or irritable bowel syndrome.

Results: When controlling for depressed mood, ISI did not differ significantly across patient groups defined by CFS severity and FM status. However, independent of mood, ISI was sensitive to multiple diagnoses showing a significant increasing trend from CFS alone to CFS plus one, two or three comorbid diagnoses.

Conclusion: Although CFS severity and FM status do not impact insomnia severity, increased illness burden as manifested by multiple medically unexplained diagnoses does appear to influence insomnia. In contrast to our earlier studies, this study did not find that a comorbid diagnosis of FM in patients with CFS is related to a worse outcome in the variable of interest.

Source: Aaron J. Stegner, Michelle Blate & Benjamin H. Natelson (2024) The effect of comorbid medical diagnoses on disturbed sleep in chronic fatigue syndrome, Fatigue: Biomedicine, Health & Behavior, DOI: 10.1080/21641846.2024.2322915 https://www.tandfonline.com/doi/full/10.1080/21641846.2024.2322915

Heterogeneity in Measures of Illness among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Explained by Clinical Practice: A Study in Seven U.S. Specialty Clinics

Abstract:

Background: One of the goals of the Multi-site Clinical Assessment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (MCAM) study was to evaluate whether clinicians experienced in diagnosing and caring for patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) recognized the same clinical entity.
Methods: We enrolled participants from seven specialty clinics in the United States. We used baseline data (n = 465) on standardized questions measuring general clinical characteristics, functional impairment, post-exertional malaise, fatigue, sleep, neurocognitive/autonomic symptoms, pain, and other symptoms to evaluate whether patient characteristics differed by clinic.
Results: We found few statistically significant and no clinically significant differences between clinics in their patients’ standardized measures of ME/CFS symptoms and function. Strikingly, patients in each clinic sample and overall showed a wide distribution in all scores and measures.
Conclusions: Illness heterogeneity may be an inherent feature of ME/CFS. Presenting research data in scatter plots or histograms will help clarify the challenge. Relying on case–control study designs without subgrouping or stratification of ME/CFS illness characteristics may limit the reproducibility of research findings and could obscure underlying mechanisms.
Source: Unger ER, Lin J-MS, Chen Y, Cornelius ME, Helton B, Issa AN, Bertolli J, Klimas NG, Balbin EG, Bateman L, et al. Heterogeneity in Measures of Illness among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Explained by Clinical Practice: A Study in Seven U.S. Specialty Clinics. Journal of Clinical Medicine. 2024; 13(5):1369. https://doi.org/10.3390/jcm13051369 https://www.mdpi.com/2077-0383/13/5/1369 (Full text)

Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome

Abstract:

Background: Fatigue of unknown origin is a hallmark symptom in chronic fatigue syndrome (CFS) and is also found in 20% of hypothyroidism patients despite appropriate levothyroxine treatment. Here, we suggest that in these disorders, peripheral serotonin levels are low, and elevating them to normal range with L-carnitine is accompanied with reduced fatigue.

Methods: We conducted a retrospective analysis of follow-up clinical data (CFS N=12; hypothyroidism with fatigue N=40) where serum serotonin and fatigue levels were compared before vs. after 7 weeks of oral L-carnitine supplementation.

Results: After L-carnitine, serotonin increased (8-fold in CFS, Sig. = 0.002, 6-fold in hypothyroidism, Sig. < 0.001) whereas fatigue decreased (2-fold in both CFS and hypothyroidism, Sig. = 0.002 for CFS, Sig. < 0.001 for hypothyroidism). There was a negative correlation between serotonin level and fatigue (for CFS, rho = -0.49 before and -0.67 after L-carnitine; for hypothyroidism, rho = -0.24 before and -0.83 after L-carnitine).

Conclusions: These findings suggest a new link between low peripheral serotonin, L-carnitine, and fatigue.

Source: Tommi Raij, Kari Raij. Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome. Front. Endocrinol. Sec. Neuroendocrine Science, Volume 15 – 2024 | doi: 10.3389/fendo.2024.1358404 https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1358404/abstract

The Head-Up Tilt Table Test as a Measure of Autonomic Functioning among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often experience autonomic symptoms. In the present study, we evaluated 193 adults seeking treatment for ME/CFS, who were recruited from an outpatient clinic. The participants completed a head-up tilt table test to assess two common types of orthostatic intolerance, namely, postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH).
During the tilt test, 32.5% of the participants demonstrated POTS or OH. The participants with either of these two common types of orthostatic intolerance were found to have more problems with sleep and post-exertional malaise as assessed by the DePaul Symptom Questionnaire; these patients also reported more physical and health function limitations. The implications of the findings are discussed.
Source: Jason LA, McGarrigle WJ, Vermeulen RCW. The Head-Up Tilt Table Test as a Measure of Autonomic Functioning among Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Personalized Medicine. 2024; 14(3):238. https://doi.org/10.3390/jpm14030238 https://www.mdpi.com/2075-4426/14/3/238 (Full text)

Mixed methods system for the assessment of post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an exploratory study

Abstract:

Background A central feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is post-exertional malaise (PEM), which is an acute worsening of symptoms after a physical, emotional and/or mental exertion. Dynamic measures of PEM have historically included scaled questionnaires, which have not been validated in ME/CFS. To enhance our understanding of PEM and how best to measure it, we conducted semistructured qualitative interviews (QIs) at the same intervals as visual analogue scale (VAS) measures after a cardiopulmonary exercise test (CPET).

Methods Ten ME/CFS and nine healthy volunteers participated in a CPET. For each volunteer, PEM symptom VAS (12 symptoms) and semistructured QIs were administered at six timepoints over 72 hours before and after a single CPET. QI data were used to plot the severity of PEM at each time point and identify the self-described most bothersome symptom for each ME/CFS volunteer. Performance of QI and VAS data was compared with each other using Spearman correlations.

Results Each ME/CFS volunteer had a unique PEM experience, with differences noted in the onset, severity, trajectory over time and most bothersome symptom. No healthy volunteers experienced PEM. QI and VAS fatigue data corresponded well an hour prior to exercise (pre-CPET, r=0.7) but poorly at peak PEM (r=0.28) and with the change from pre-CPET to peak (r=0.20). When the most bothersome symptom identified from QIs was used, these correlations improved (r=0.0.77, 0.42. and 0.54, respectively) and reduced the observed VAS scale ceiling effects.

Conclusion In this exploratory study, QIs were able to capture changes in PEM severity and symptom quality over time, even when VAS scales failed to do so. Measurement of PEM can be improved by using a quantitative–qualitative mixed model approach.

Source: Stussman B, Calco B, Norato G, et al. Mixed methods system for the assessment of post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an exploratory study. BMJ Neurology Open 2024;6:e000529. doi: 10.1136/bmjno-2023-000529  https://neurologyopen.bmj.com/content/6/1/e000529 (Full text)

Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract;
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic and incapacitating multisystem condition with unknown etiology, no cure, and no FDA- approved treatments, all of which can be attributed to historical underfunding, widespread misinformation, and the complexity of the disease. Many patients encounter several immune-related symptoms, extreme fatigue, post-exertional malaise, and a flu-like onset. Studies have documented changes in ME/CFS immune cell populations and decreased natural killer (NK) cell performance, along with aberrant cytokine production, reduced glycolysis in T cells, and altered metabolites relevant to fatty acid oxidation, implicating potential intracellular metabolic dysregulation.
This knowledge prompted me to investigate fatty acid oxidation and immune cell functional states in isolated ME/CFS lymphocytes. Using extracellular flux analysis and flow cytometry, I observed elevated fatty acid oxidation levels in ME/CFS immune cells, including NK cells, CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells compared to healthy controls, particularly during high energy demands and activation. My findings suggest a metabolic dysfunction in ME/CFS immune cells, consistent with T cell exhaustion – a state that hinders immune cell proliferation, survival, and cytokine production following persistent antigen stimulation.
Building upon these results, I further investigated immune cell exhaustion and dysfunction in isolated CD8+ and CD4+ T cells from ME/CFS and healthy samples. I analyzed T cell sub-populations, including naïve, effector, memory, regulatory, and helper T cells, for frequencies of inhibitory receptors and transcription factors associated with dysfunctional immune cell states.
I detected distinct transcription factor dynamics and elevated exhausted T cell phenotype proportions in ME/CFS CD8+ T cell populations compared to healthy controls. In ME/CFS CD4+ T cells, I also observed altered inhibitory receptor population frequencies compared to healthy control samples. Moreover, dysfunctional T cell features correlated with ME/CFS health status and symptom presentation.
Overall, my findings detect dysfunctional T cell states in specific ME/CFS cell populations, which can lead to reduced effector function that may contribute to ME/CFS symptom presentation. This work highlights the significance of assessing both metabolic components and immune cell dysfunction-associated targets in the development of potential therapeutic interventions for individuals with ME/CFS.
Source: Maya, Jessica. Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome. Cornell Theses and Dissertations. 2024. https://ecommons.cornell.edu/items/242f8723-6f87-47cc-b36d-bf51a21f4255