Tag: 2025

Autonomic phenotyping, brain blood flow control, and cognitive-motor-integration in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and the prolonged sequelae after COVID-19 (>3 months; Long COVID) have similar symptomology, are both associated with autonomic dysfunction, and a growing proportion of Long COVID patients are developing ME/CFS. We aimed to determine an autonomic phenotype of patients with ME/CFS vs Long COVID. We hypothesized that the groups would differ from controls yet be similar to one another.

We recruited sedentary controls (n = 10), mild/moderate ME/CFS patients (n = 12), and Long COVID patients (n = 9) to undergo 1) breathing 5 % CO2, 2) breathing 10 % O2, and 3) 5-minutes of 70° head-up tilt. Respiratory, hemodynamic, and cerebrovascular variables were measured throughout the 3 trials. Resting vascular function and cognitive-motor-integration were also assessed. ME/CFS and Long COVID were similar to the healthy controls and each other with regard to resting vascular function and the hemodynamic responses to hypoxia, hypercapnia, and head-up tilt (p > 0.05). However, in ME/CFS we observed a greater reduction of cerebrovascular resistance (p = 0.041) and impaired autoregulation (p = 0.042) during hypercapnia alongside impaired cognitive-motor integration (p < 0.02), and in Long COVID we observed reduced peripheral and end-tidal oxygen (p < 0.04) and less vagal withdrawal during tilt (p = 0.028).

Our findings suggest unique phenotypes when comparing ME/CFS and Long COVID whereby we have shown that Long COVID patients experience hypoxia while upright contributing to less vagal withdrawal, and ME/CFS patients experience impaired cerebrovascular control during potentially leading to reduced cognitive-motor integration. These differences could stem from disease severity/duration or some unique aspect of the COVID-19 virus.

Source: Badhwar S, Pereira TJ, Kerr K, Bray R, Tabassum F, Sergio L, Edgell H. Autonomic phenotyping, brain blood flow control, and cognitive-motor-integration in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study. Auton Neurosci. 2025 Oct 14;262:103358. doi: 10.1016/j.autneu.2025.103358. Epub ahead of print. PMID: 41138391. https://www.autonomicneuroscience.com/article/S1566-0702(25)00120-1/fulltext (Full text)

HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions

Abstract:

Viral infections have been widely implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) pathogenesis. Recent evidence has also identified certain Human Leukocyte Antigen (HLA) alleles that are significantly associated with ME/CFS risk/protection. Here we tested the hypothesis that ME/CFS risk or protection conferred from those HLA alleles is associated with binding affinity to antigens of HHV viruses, a critical step in initiating the adaptive immune system response to foreign antigens.

Specifically, we determined in silico the predicted binding affinity of two susceptibility alleles (C*07:04, DQB1*03:03) and two protective alleles (B*08:01, DPB1*02:01) to > 10,000 antigens of the 9 Human Herpes Viruses (HHV1, HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8) which have been implicated in the etiology of ME/CFS. We found that the binding affinity of all HHV antigens to the susceptibility alleles was significantly weaker than the binding affinity to the protective alleles (P < 0.001). In fact, none of the HHV antigens showed strong binding to the susceptibility alleles, in contrast to the strong bindings showed by the protective alleles. These findings are in keeping with the hypothesis that the effect of a putative HHV insult in contributing to ME/CFS is modulated by the host’s HLA immunogenetic makeup.

We speculate that strong HLA-antigen binding likely protects against ME/CFS via elimination of virus antigens; conversely, weak HLA-antigen binding may permit persistence of foreign antigens, contributing to ME/CFS and other chronic conditions. Finally, with respect to the latter, we determined the binding affinities to the 4 HLA alleles above to pathogens causing two chronic diseases with very similar symptomatology to ME/CFS, namely Long COVID and post-treatment Lyme disease syndrome (PTLDS).

We found that the 2 ME/CFS susceptibility HLA alleles above had very weak binding with SARS-CoV-2 virus glycoprotein (involved in Long COVID) and 5 proteins of Borrelia burgdorferi (involved in PTLDS), in contrast to the ME/CFS protective alleles that showed strong bindings. These findings support the hypothesis that ME/CFS, long COVID and PTLDS are caused by persistent pathogenic antigens that could not be eliminated due to inadequate protection by the patient’s HLA makeup.

Source: Georgopoulos AP, James LM, Peterson PK. HLA and pathogens in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other post-infection conditions. Sci Rep. 2025 Oct 24;15(1):37303. doi: 10.1038/s41598-025-21230-z. PMID: 41136524. https://www.nature.com/articles/s41598-025-21230-z (Full text)

Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome

Abstract:

Background: Hypermobility Spectrum Disorders (HSD) and hypermobile Ehlers-Danlos syndrome (h-EDS) are multisystemic connective tissue disorders involving joint hypermobility and numerous other manifestations. Autonomic dysfunction, chronic pain, and chronic fatigue are known comorbidities of HSD and h-EDS that can affect patient quality of life (QoL), but there are limited data on the severity of autonomic symptoms, prevalence of comorbid conditions and QoL in patients with HSD/h-EDS.

Methods: We utilized the Composite Autonomic Symptom Scale (COMPASS-31) to assess autonomic symptom severity, Short-Form 36 (SF-36) to assess QoL, and the Beck Depression Inventory Second Edition (BDI-II) in a cohort of women with physician-diagnosed HSD or h-EDS, who completed these questionnaires anonymously.

Results: 84 women (mean age of 37.1 ± 8.4 years) completed the study. 58.3 % reported having physician-diagnosed postural orthostatic tachycardia syndrome (POTS), 32.1 % had mast cell activation syndrome (MCAS), 54.8 % had migraine, 26.2 % had myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 98.8 % reported experiencing chronic pain. Importantly, 25 % of patients reported having all three diagnoses: HSD/h-EDS, POTS and MCAS. Mean COMPASS-31 score was 54.45 (range 18.79-80.93), indicating severe autonomic dysfunction, which was significantly higher than in patients with multiple sclerosis, diabetic neuropathy, scleroderma, and psoriatic arthritis as shown in prior studies. Mean SF-36 score was 32.38 (SD = 22.91) indicating poor QoL, which was worse than in patients with POTS, multiple sclerosis, rheumatoid arthritis, and lupus as determined by prior studies.

Conclusions: This study demonstrates that women with HSD/h-EDS experience severe autonomic dysfunction, chronic pain, chronic comorbid conditions and reduced QoL. More than half of participants in this cohort had POTS and migraine, with one in four having a clinical triad of HSD/h-EDS, POTS and MCAS.

Source: Collins Hutchinson ML, Liang E, Fuster E, Blitshteyn S. Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome. Auton Neurosci. 2025 Oct 14;262:103356. doi: 10.1016/j.autneu.2025.103356. Epub ahead of print. PMID: 41118678. https://pubmed.ncbi.nlm.nih.gov/41118678/

A Case of Psoriasis Concurrently Complicated by Sacroiliitis and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a systemic chronic disorder characterized by persistent and unexplained severe fatigue. Recent population-based studies have revealed that patients with chronic inflammatory skin dermatoses, including psoriasis, are more likely to develop ME/CFS.

Here, we report a case of psoriasis, whose exacerbation occurred concurrently with the development of sacroiliitis and the onset of ME/CFS. The pathogenesis of ME/CFS has not yet been fully elucidated, while inflammatory cytokines are involved in dysregulated interactions among the nervous, immune, and endocrine systems in the disease.

We discussed the shared immunological abnormalities of psoriasis and ME/CFS based on previous literature. Our case contributes to the understanding of the association between psoriasis and ME/CFS.

Source: Iijima M, Miyagaki T, Nakajima K, Kadono T, Watabe H. A Case of Psoriasis Concurrently Complicated by Sacroiliitis and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Cureus. 2025 Sep 16;17(9):e92435. doi: 10.7759/cureus.92435. PMID: 41111852; PMCID: PMC12529862. https://pmc.ncbi.nlm.nih.gov/articles/PMC12529862/ (Full text)

Altered effort and deconditioning are not valid explanations of myalgic encephalomyelitis/chronic fatigue syndrome

Letter:

Response to B. Walitt et al. Nature Communications https://doi.org/10.1038/s41467-024-45107-3 (2024)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, systemic disease with significant pathophysiological uncertainties and variable presentations1. Here, we challenge Walitt et al.’s2 conclusion that post-infectious (PI) ME/CFS is a disorder defined by altered effort preference, leading to activity avoidance and subsequent deconditioning. We believe this interpretation risks reinforcing skepticism about the serious biological nature of ME/CFS and its hallmark of post-exertional malaise (PEM), as well as its potential misclassification as a mental health condition.

Walitt et al.2 utilized a single CPET to evaluate systems-level physiological responses to exercise. However, this methodology does not allow for measuring responses after an initial exertion, which is critically important for fully understanding PEM3. Over the past two decades, 2-day CPET has been used to characterize the systems-level metabolism of ME/CFS3. This paradigm uses an initial maximal CPET to establish the individual’s baseline performance and as a participant-referenced method to induce PEM4. A second maximal CPET is then conducted 24 h later to measure physiological and perceptual responses to exercise during the post-exertional state4. Standard objective criteria to evaluate effort are used to ensure maximal testing, including the respiratory exchange ratio at peak exertion4. This removes uncertainty related to effort. Meta-analyses involving participants with ME/CFS who have completed 2-day CPET indicate characteristic declines in the volume of oxygen consumed, work rate, and heart rate (HR) at submaximal exertion on the second CPET. These findings are reliably observed in people with ME/CFS but not deconditioned individuals5,6,7. Accordingly, the Institute of Medicine (IOM) cautioned that “a single CPET may be insufficient to document the abnormal response of ME/CFS patients to exercise.”1 (p. 106)

Using a single CPET introduces a threat to validity in Walitt et al.’s study2, as it did not allow for the measurement of submaximal performance decrement in the post-exertional state1,3,4,5,6. This is important because deconditioning and PEM are not mutually exclusive. Special care must be taken when applying and interpreting CPET results1. Failure to use 2-day CPET prevented the authors from adequately testing their conclusion that PEM is related to participants’ effort preference, as they did not evaluate physiological performance under conditions involving objective, standardized criteria for maximal exertion. Unfortunately, the use of a single CPET in this study contributed to the authors’ misinterpretation that PEM is synonymous with reduced effort and deconditioning.

Read the rest of this letter here: https://www.nature.com/articles/s41467-025-64538-0

Source: Davenport, T.E., Scheibenbogen, C., Zinn, M.A. et al. Altered effort and deconditioning are not valid explanations of myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun 16, 9176 (2025). https://doi.org/10.1038/s41467-025-64538-0 https://www.nature.com/articles/s41467-025-64538-0 (Full text)

Understanding concussion in myalgic encephalomyelitis/chronic fatigue syndrome: Findings from the 2023 National Health Interview study

Abstract:

Background: Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms (dysautonomia, dizziness, balance impairments) may theoretically contribute to an association with concussion, the nature of this association has not been determined. This study explored the association between ME/CFS and concussion, as well as risk factors for concussion, history of recent falls, and feelings of being dizzy or off balance.

Method: 2023 National Health Interview Survey data were utilized. United States adults (unweighted N = 29,373) responded to items regarding sociodemographic factors, ME/CFS status, and history of concussion, falls, and feeling off balance or dizzy. Logistic regression analyses assessed the association between ME/CFS and concussion, falls, and feeling dizziness or balance problems within the past year, adjusting for sociodemographic factors.

Results: Individuals with ME/CFS had 4.89 times greater odds of reporting concussion in the past year compared to individuals without ME/CFS. Individuals with ME/CFS also had 2.86 times greater odds of having fallen within the past year and 5.88 times greater odds of reporting feeling dizzy or off balance in the past year.

Conclusions: ME/CFS status may be associated with concussion status. Healthcare practitioners should improve concussion screening and referrals for reducing concussion risk among individuals with ME/CFS.

Source: Sirotiak Z, Adamowicz JL, Thomas EBK. Understanding concussion in myalgic encephalomyelitis/chronic fatigue syndrome: Findings from the 2023 National Health Interview study. Brain Inj. 2025 Oct 16:1-8. doi: 10.1080/02699052.2025.2575479. Epub ahead of print. PMID: 41103060. https://pubmed.ncbi.nlm.nih.gov/41103060/

The association of fatigue and pain with cognitive test performance in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Objectives: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) typically perform worse on cognitive tasks compared to controls. The present study explored the independent associations of fatigue and pain symptoms with cognitive performance in a large sample of patients who met CDC criteria of CFS (n = 1375), of whom most also met NICE/ IOM criteria (n = 1072). Moreover, we tested the hypothesis that these associations become stronger with older age and longer symptom duration.

Methods: Questionnaires and diaries were employed assessing fatigue and pain severity, together with the impact of health problems on daily life (using the SF-36 ‘Physical Functioning’ and ‘Bodily Pain’ subscales). Cognitive outcomes consisted of speeded performance measures, namely the Symbol Digit Test, motor speed, simple and choice reaction time (RT), and response inhibition. Categorical regression with lasso penalization was employed to identify relevant correlates of cognitive performance.

Results: Fatigue severity remained as only correlate of response inhibition. For the other cognitive outcomes, fatigue severity consistently emerged together with contributions of pain severity, bodily pain and/or physical functioning. Restricting these analyses to those patients meeting NICE/IOM criteria revealed overall similar results. Age, not symptom duration, moderated several relationships, showing more pronounced associations between cognitive performance and pain severity, physical functioning, and bodily pain with older age.

Conclusions: This study highlights that a multidimensional nature of symptoms, including fatigue and pain severity, and the impact on daily-life functioning, relate to lower cognitive performance in patients with ME/CFS. Studies are needed to identify the direction and potential causality of these associations.

Source: Oosterman JM, van der Schaaf M, de Kleijn WPE, Kuut TA, Brazil IA, Knoop H. The association of fatigue and pain with cognitive test performance in patients with myalgic encephalomyelitis/chronic fatigue syndrome. J Psychosom Res. 2025 Oct 3;199:112401. doi: 10.1016/j.jpsychores.2025.112401. Epub ahead of print. PMID: 41101039. https://www.sciencedirect.com/science/article/pii/S0022399925003654 (Full text)

Corticosteroids with low glucocorticoid activity as a potential therapeutic strategy for post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome in patients with bipolar affective disorder: A case report

Abstract:

Background: The COVID-19 pandemic has led to an increase in post-acute sequelae, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), potentially mediated by dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Corticosteroids are occasionally administered to ameliorate fatigue symptoms in ME/CFS; however, their psychiatric adverse effects, particularly in individuals with preexisting mood disorders, necessitate careful consideration.

Case presentation: We report the case of a 32-year-old woman with bipolar disorder who developed ME/CFS following COVID-19 infection. Initial corticosteroid therapy with betamethasone and prednisolone, agents with potent glucocorticoid receptor (GR) activity, resulted in a manic episode with psychotic features, necessitating psychiatric hospitalization. Although mood stabilization was achieved with olanzapine and valproate, corticosteroid withdrawal subsequently led to metabolic alkalosis and hypoxemia, secondary to hypothalamic hypoadrenalism. Following a comprehensive endocrinological assessment, physiological replacement therapy with hydrocortisone, characterized by relatively higher mineralocorticoid receptor (MR) activity and lower GR potency, was initiated, resulting in the resolution of physical symptoms without destabilization of psychiatric status.

Conclusion: The clinical course suggests that GR-dominant corticosteroids may exacerbate psychiatric instability in patients with mood disorders. Simultaneously, MR-favoring agents, such as hydrocortisone, may offer a safer therapeutic alternative for managing HPA axis dysfunction. This case underscores the critical role of receptor selectivity in corticosteroid therapy, particularly in patients with comorbid psychiatric conditions, and highlights the necessity for individualized treatment strategies that integrate both endocrine and neuropsychiatric considerations.

Source: Nakajima K, Ayani N, Matsuoka T, Kasahara K, Nakajima Y, Ikawa H, Kitaoka R, Akimoto T, Narumoto J. Corticosteroids with low glucocorticoid activity as a potential therapeutic strategy for post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome in patients with bipolar affective disorder: A case report. PCN Rep. 2025 Oct 12;4(4):e70222. doi: 10.1002/pcn5.70222. PMID: 41089430; PMCID: PMC12515714.

Effects of recumbent isometric yoga on the daily functioning level of patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, controlled trial

Abstract:

Background: Although seated isometric yoga has been shown to reduce the fatigue and pain of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), some patients who are for the most part bedridden have difficulty practicing it. Many patients with this disease also suffer from fibromyalgia (FM). We developed a recumbent isometric yoga program for patients who were for the most part bedridden, including patients with comorbid FM. The aim of this study was to investigate the effect of this recumbent isometric yoga intervention with such patients.

Methods: This was a randomized, controlled trial of 48 adult patients (7 male, 41 female, age 20-70 years) with ME/CFS without satisfactory improvement after ≥ 3 months of conventional therapy. They were divided randomly into a yoga group (n = 24) and a control group (n = 24). The yoga group received conventional therapy with recumbent isometric yoga practice for ~ 12 weeks (25-min sessions with a yoga instructor at hospital visits and daily in-home sessions). The control group received conventional therapy alone. The effect of recumbent isometric yoga on the level of functioning was assessed by measuring Performance Status (PS). Fatigue was assessed with self-rated questionnaires, including the Chalder Fatigue Scale (FS) and Profile of Mood States (POMS). Adverse events and benefits were recorded for the yoga group.

Results: After the intervention period, the PS score of the yoga group was significantly lower than that of the control group (P < 0.001), suggesting an improvement in functioning level. The Chalder FS score decreased in both groups, but the decrease was greater in the yoga group than in the control group (P < 0.01). Subgroup analysis showed that the Chalder FS score was reduced significantly only in the yoga group in patients with severe disease (P < 0.001) and those with comorbid FM (P < 0.01), although the PS scores did not differ significantly. In the yoga group, a single practice session with a yoga instructor significantly reduced fatigue and increased vigor in patients with severe disease and patients with comorbid FM. Patients reported no serious adverse effects and many benefits of recumbent isometric yoga, including improvements in physical symptoms and brain fog, enhanced awareness of their limits to activities that cause post-exertional malaise, and promotion of behavioral changes to live better within their limits.

Conclusions: Recumbent isometric yoga is an effective adjunctive therapy for patients with ME/CFS, including those for the most part bedridden and those who have FM.

Trial registration: University Hospital Medical Information Network (UMIN CTR) UMIN000023472 (Registered Aug. 4, 2016) and UMIN000030051 (Registered Nov. 20, 2017).

Source: Oka T, Lkhagvasuren B, Yamada Y. Effects of recumbent isometric yoga on the daily functioning level of patients with myalgic encephalomyelitis/chronic fatigue syndrome: a randomized, controlled trial. Biopsychosoc Med. 2025 Oct 10;19(1):19. doi: 10.1186/s13030-025-00339-7. PMID: 41074089; PMCID: PMC12512564. https://pmc.ncbi.nlm.nih.gov/articles/PMC12512564/ (Full text)

Psychometric evaluation of the PROMIS® physical function short form 12a for use by adults with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, long-term illness that significantly impairs physical functioning. Despite its impact, the use of modern generic instruments to assess physical function in this population remains underexplored. This study aims to assess the psychometric properties of the Patient-Reported Outcome Measurement Information System® (PROMIS) Physical Function Short Form (PF-SF) 12a for use in adults with ME/CFS.

Methods: This study included 334 participants (173 with ME/CFS and 161 healthy controls) who took part in a Cognitive and Exercise sub-study of the Multi-Site Clinical Assessment of ME/CFS study from six clinics across the US. Data was used to examine the ceiling/floor effects, internal consistency reliability, known-groups validity, and convergent validity of the PROMIS PF-SF.

Results: The mean T-score of the PROMIS PF-SF was 40.5 for participants with ME/CFS, about one standard deviation below the national norm (T-score = 50). The PROMIS PF-SF showed no substantial floor/ceiling effects and high internal consistency (standardized Cronbach’s α = 0.88 and ω = 0.92). In addition, this instrument showed good known-groups validity with medium-to-large effect sizes (η2 = 0.08-0.35). A significant, monotonic increase of the physical function score was found across ME/CFS participant groups with low, medium, and high functional impairment as defined by four different measures. Participants with ME/CFS had significantly worse physical function scores than healthy controls (η2 = 0.70). The PROMIS PF-SF also demonstrated good convergent validity with high correlations (magnitude of r = 0.47-0.55) with other relevant measures.

Conclusions: The PROMIS PF-SF 12a demonstrated satisfactory reliability and validity for use in ME/CFS research and clinical practice.

Source: Yang M, Keller S, Rafiee P, Lin JS. Psychometric evaluation of the PROMIS® physical function short form 12a for use by adults with myalgic encephalomyelitis/chronic fatigue syndrome. Health Qual Life Outcomes. 2025 Oct 6;23(1):95. doi: 10.1186/s12955-025-02431-6. PMID: 41053836; PMCID: PMC12502361. https://pmc.ncbi.nlm.nih.gov/articles/PMC12502361/ (Full text)