Tag: treatment

No consistent evidence for the anti-inflammatory effect of vagus nerve stimulation in humans: A systematic review and meta-analysis

Abstract

Vagus nerve stimulation (VNS) has been identified as an innovative immunosuppressive treatment strategy in rodent studies. However, its’ clinical potential is still unclear. Therefore, we aimed to assess whether VNS can reduce inflammatory proteins and/or immune cells in humans, through a pre-registered systematic review and meta-analysis according to PRISMA guidelines. The databases Cochrane, Pubmed and World of Knowledge were searched in duplicate up to the 3rd of March 2022 and publications from identified clinical trial registrations were identified until 20th of August 2023. Studies were included if they provided peer-reviewed data for humans who received VNS as short-term (<=1 day) or long-term (>=2 days-365 days) stimulation and reported at least one cytokine or immune cell after treatment.

Screening of title, abstract, full text, and data extraction was performed in duplicate by two independent reviewers. Data were pooled using a random-effects model and meta-regression was performed for moderating factors. Reporting bias was assessed. The standardized mean difference (Hedge’s g) was used to indicate overall differences of cytokine data (mean and standard deviation or median and interquartile range at the study level) to test our a-priori hypothesis.

The systematic review of 36 studies with 1135 participants (355 receiving a control/sham condition and 780 receiving VNS) revealed anti-inflammatory effects of VNS for cytokines in several reports, albeit often in subgroup analyses, but our meta-analyses of 26 studies did not confirm these findings. Although most cytokines were numerically reduced, the reduction did not reach statistical significance after VNS: not in the between-group comparisons (short-term: TNF-α: g = -0.21, p = 0.359; IL-6: g = -0.94, p = 0.112; long-term: TNF-α: g = -0.13, p = 0.196; IL-6: g = -0.67, p = 0.306); nor in the within-study designs (short-term: TNF-α: g = -0.45, p = 0.630; IL-6: g = 0.28, p = 0.840; TNF-α: g = -0.53, p = 0.297; IL-6:g = -0.02, p = 0.954). Only the subgroup analysis of 4 long-term studies with acute inflammation was significant: VNS decreased CRP significantly more than sham stimulation. Additional subgroup analyses including stimulation duration, stimulation method (invasive/non-invasive), immune stimulation, and study quality did not alter results. However, heterogeneity was high, and most studies had poor to fair quality. Given the low number of studies for each disease, a disease-specific analysis was not possible.

In conclusion, while numeric effects were reported in individual studies, the current evidence does not substantiate the claim that VNS impacts inflammatory cytokines in humans. However, it may be beneficial during acute inflammatory events. To assess its full potential, high-quality studies and technological advances are required.

Source: Schiweck C, Sausmekat S, Zhao T, Jacobsen L, Reif A, Edwin Thanarajah S. No consistent evidence for the anti-inflammatory effect of vagus nerve stimulation in humans: A systematic review and meta-analysis. Brain Behav Immun. 2024 Feb;116:237-258. doi: 10.1016/j.bbi.2023.12.008. Epub 2023 Dec 7. PMID: 38070618. https://www.sciencedirect.com/science/article/abs/pii/S0889159123003793

Multi-Strain Probiotic Improves Tryptophan Metabolism and Symptoms in Chronic Fatigue Syndrome Patients with Co-Occurring Irritable Bowel Syndrome: An Open-Label Pilot Study

Simple Summary:

Chronic Fatigue Syndrome (CFS) is a debilitating condition often accompanied by gut health issues, but effective treatments are scarce. Recent research suggests that an imbalance in gut bacteria (dysbiosis) may contribute to CFS symptoms by producing harmful substances that affect the nervous system. We investigated whether a specific multi-strain probiotic (CDS22-formula) could improve symptoms in women with CFS and co-occurring IBS. Over 12 weeks, patients took a high-dose probiotic supplement. We monitored their fatigue levels and analyzed urine samples to track changes in tryptophan metabolism—a key pathway linking the gut to the brain. The results showed that the probiotic intervention was associated with an improved gut bacteria profile. Importantly, this coincided with a reduction in neurotoxic metabolites and a significant decrease in fatigue severity. Our findings suggest that targeting the gut microbiome can be a valuable strategy for managing chronic fatigue, potentially by modulating the production of metabolites that affect brain function.
Abstract:

Background/Objectives: Gut dysbiosis in Chronic Fatigue Syndrome (CFS) drives low-grade inflammation and shifts tryptophan metabolism toward neurotoxic pathways. The causal link between bacterial translocation, kynurenine pathway dysregulation, and symptom severity remains under-defined. We evaluated the impact of a high-concentration multi-strain probiotic on the “gut-kynurenine axis” and clinical status in CFS patients with co-morbid IBS-U and confirmed dysbiosis.
Methods: Forty female patients with confirmed dysbiosis (GA-map™ Dysbiosis Index > 2) received the CDS22 formula (450 billion CFU/day) for 12 weeks. We compared urinary tryptophan metabolite profiles (LC-MS/MS), gut dysbiosis markers (3-indoxyl sulfate), and fatigue severity (FSS) against 40 age-matched healthy controls.
Results: Baseline analysis revealed profound metabolic perturbations: elevated bacterial proteolytic markers (3-IS), substrate depletion (low tryptophan), and a neurotoxic signature (high quinolinic acid [QA], low kynurenic acid [KYNA]). Following the intervention, fatigue scores declined by 40.3%, with 97.5% of patients reaching the remission threshold (FSS < 36). Biochemically, 3-IS levels decreased to the range observed in healthy controls and attenuated xanthurenic acid levels. Although absolute QA concentrations remained elevated compared to controls, the neuroprotective KYNA/QA ratio increased significantly (+45%). Increased systemic tryptophan availability correlated directly with clinical symptom reduction (Spearman’s rho = −0.36, p = 0.024).
Conclusions: The CDS22 formulation was associated with a restoration of intestinal eubiosis and functional tryptophan partitioning. Clinical remission coincides with a metabolic shift favoring neuroprotection (increased KYNA/QA ratio), validating the gut–kynurenine axis as a modifiable therapeutic target. Peripheral metabolic improvement relative to the healthy baseline appeared sufficient for symptom relief in this specific phenotype, despite incomplete clearance of neurotoxic metabolites.
Source:

Editorial: Exploring chronic fatigue: neural correlates, mechanisms, and therapeutic strategies

Introduction:

Fatigue and weariness have been universal experiences throughout human history, coexisting with humanity since its earliest days across all cultures and times. It occurs in ancient stories, including Genesis, in which Adam’s fatigue was linked to the toil imposed upon him as part of the consequences of disobedience, a condition that made sustaining life a laborious task. Acute fatigue, which arises naturally in response to stress or work, is a normal physiological process experienced by all humans regardless of era or place. It signals the body’s need to rest and adapt, playing a vital role in maintaining health and balance.

In contrast, chronic fatigue, as seen in aging populations and conditions like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a complex and often debilitating disorder that extends beyond normal tiredness. It involves sustained disruption of metabolic, neurological, and immune functions, resisting typical recovery mechanisms. The 14 papers in this Research Topic collectively explore the multifaceted nature of fatigue, presenting advances in mechanistic research, epidemiology, clinical interventions, rehabilitation techniques, and innovative monitoring technologies aimed at improving diagnosis, treatment, and management of this persistent condition.

Source: Kujawski S, Hodges L, Morten KJ, Zalewski P. Editorial: Exploring chronic fatigue: neural correlates, mechanisms, and therapeutic strategies. Front Neurosci. 2025 Dec 10;19:1751667. doi: 10.3389/fnins.2025.1751667. PMCID: PMC12728026. https://pmc.ncbi.nlm.nih.gov/articles/PMC12728026/ (Full text)

The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background/Objectives: Growing evidence suggests that mast cell activation (MCA) may contribute to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating disorder characterized by persistent fatigue and post-exertional malaise (PEM). Particularly in relation to orthostatic intolerance (OI), including postural orthostatic tachycardia syndrome (POTS), this study aimed to investigate the prevalence and clinical relevance of MCA in an Austrian ME/CFS patient cohort.

Methods: Two data sets were analyzed. The CCCFS data set, a comprehensive, patient-centered online questionnaire consisting of 687 filled surveys, focuses on patient stratification. Self-reported clinical features, disease progression, and treatment responses were analyzed. Preliminary findings were validated in a second, retrospective study, analyzing data of 383 Austrian ME/CFS patients with regard to MCA involvement and OI.

Results: Among followed-up ME/CFS patients, MCA prevalence increased over the disease course, with up to 25.3% meeting the criteria for clinically relevant MCA. ME/CFS patients with Mast Cell Activation Syndrome (MCAS) and OI reported symptom alleviation significantly more often following mast cell-targeted treatment than those without MCAS (p < 0.0001). With regard to IF-channel inhibitors, ME/CFS patients diagnosed with MCAS responded more frequently than those without MCAS (p = 0.076), while no significant differences were observed in response to beta blockers (p = 0.637). In both cohorts, OI, particularly POTS, was significantly more common in patients with MCA involvement.

Conclusions: MCA appears to be a frequent and clinically relevant comorbidity in ME/CFS and is associated with a higher prevalence of OI, particularly POTS. Stratifying patients based on MCA involvement may support personalized treatment approaches and improve clinical outcomes.

Source: Rohrhofer J, Ebner L, Schweighardt J, Stingl M, Untersmayr E. The Clinical Relevance of Mast Cell Activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Diagnostics (Basel). 2025 Nov 7;15(22):2828. doi: 10.3390/diagnostics15222828. PMID: 41300853; PMCID: PMC12651186. https://pmc.ncbi.nlm.nih.gov/articles/PMC12651186/ (Full text)

Systematic literature review: treatment of postural orthostatic tachycardia syndrome (POTS)

Abstract:

Postural orthostatic tachycardia syndrome (POTS) is a condition defined by symptoms of orthostatic intolerance and a sustained heart rate (HR) increment of ≥ 30 beats per minute (bpm) upon postural change to the upright position in the absence of orthostatic hypotension, defined as a sustained decrease in systolic blood pressure (SBP) of ≥ 20 mmHg or a decrease in diastolic blood pressure (DBP) of ≥ 10 mmHg within 3 min of standing. In children, a sustained HR increment of at least 40 bpm is required for diagnosis of POTS. POTS is a common condition in adults and children suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In daily clinical practice, therapeutic recommendations are rare and evidence is missing.

The objective of this review is to present the current knowledge on non-pharmacological and pharmacological approaches in POTS with a special focus on POTS therapy in children and people with ME/CFS. Of 3853 studies, 45 studies were included in the systematic review.

on therapy in POTS is rare and large randomized controlled trials (RCT) on single interventions are needed. Non-pharmacological approaches such as the use of compression garments, physical training, salt supplementation and transdermal vagal nerve stimulation could be possible treatment options in POTS because they are easy to implement as first-line therapeutic measures in clinical practice. For pharmaceuticals, several studies showed significant effects following therapy with ivabradine and β-adrenergic blocking agents. There are single studies which imply that midodrine (hydrochloride) and pyridostigmine seem to have a beneficial effect on hemodynamics in POTS.

Source: Schiweck N, Langer K, Maier A, Vilser D, Spiegler J. Systematic literature review: treatment of postural orthostatic tachycardia syndrome (POTS). Clin Auton Res. 2025 Nov 12. doi: 10.1007/s10286-025-01172-2. Epub ahead of print. PMID: 41225175. https://link.springer.com/article/10.1007/s10286-025-01172-2 (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)

Relationships between fatigue, cognitive function, and upright activity in a randomized trial of oxaloacetate for myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition characterized by fatigue, cognitive impairment, and reduced physical function. Oxaloacetate (OAA), a metabolic compound with potential mitochondrial and neuroprotective effects, has shown promise in reducing fatigue symptoms in ME/CFS. However, the interrelationships between fatigue, cognitive performance, and physical activity and their responsiveness to treatment remain poorly understood in ME/CFS.

Methods: This 90-day randomized, double-blind, controlled trial evaluated the effects of 2,000 mg/day OAA or a control of 2,000 mg rice flour in 82 adults with ME/CFS. Self-reported fatigue (Chalder Fatigue Questionnaire), cognitive function (DANA Brain Vital), and upright activity time (UP Time) were assessed at baseline and three follow-up visits. Linear mixed-effects models examined associations between fatigue severity and cognitive/physical function, with treatment group interactions. Responder status at the last visit (Visit 4) was classified based on ≥15% fatigue reduction and/or ≥10% cognitive improvement.

Results: The OAA group showed greater cognitive improvement over time, with a significant between-group difference at Visit 3, 60 days into the trial, (p = 0.034) and trends at other visits. Higher fatigue was significantly associated with reduced cognitive gains in the OAA group (β = −0.34, p < 0.0001), but not in controls. UP Time increased modestly in the OAA group, reaching significance at Visit 2, day 30 (p = 0.044), though fatigue was not a strong predictor of UP Time in either group. At Visit 4, day 90, Global and Fatigue Only Responders were more frequent in the OAA group, while Cognitive Only Responders were more frequent in controls, though group differences did not reach statistical significance (p = 0.10).

Conclusion: OAA supplementation was associated with improved cognitive performance and small improvement in UP Time in ME/CFS participants receiving OAA. Fatigue–cognition coupling was particularly strong in OAA-treated participants, suggesting a potentially targetable phenotype. These findings underscore the importance of multidimensional outcome measures in ME/CFS clinical trials and support the need for more research and trials of metabolic interventions in ME/CFS.

Source: Vernon Suzanne D. , Rond Candace , Sun Yifei , Roundy Shad , Bell Jennifer , Rond Bella , Kaufman David L. , Cash Alan B. , Yellman Brayden , Bateman Lucinda. Relationships between fatigue, cognitive function, and upright activity in a randomized trial of oxaloacetate for myalgic encephalomyelitis/chronic fatigue syndrome. Frontiers in Neurology, Volume 16 – 2025. DOI=10.3389/fneur.2025.1691147 ISSN=1664-2295 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1691147/full (Full text)

Specialised care for severely affected ME/CFS patients

Abstract:

Introduction: A specialised care unit for severely and very severely ill ME/CFS patients opened in 2021. The results from the first 3 years are reported.

Methods: People with ME/CFS who were diagnosed according to the Canadian Consensus Criteria, who are aged 18 or above with severe or very severe ME/CFS according to the UK NICE guidelines, are eligible to stay at Røysumtunet. The study design is a retrospective review of medical records.

Results: Between June 2021 and June 2024, 24 ME/CFS patients, 20 women and 4 men with a confirmed diagnosis of ME, were admitted to the unit for stays of at least 3 months. Seventeen were very severely affected and 7 were severely affected. Ages ranged from 18 to 68 years, with mean (SD) 37.5 (12.8) years. Seven patients showed significant improvement (p < 0.01), and five others showed some improvement. In total 50% improved (p < 0.01). Patients who improved were borderline significantly younger than those who did not, with a mean age of 30.3 (SD 12.6) years compared to 39.8 (SD 11.8) years (p = 0.06). The mean duration of disease was 2.3 (1.3) years for those who improved versus 6.7 (3.9) years for those who did not improve (p < 0.05).

Conclusion: This is the first report of a specialised care unit for the most severely ill ME/CFS patients. Fifty per cent of patients showed significant or partial improvement. The mechanisms behind these improvements are discussed but require further exploration in future studies.

Source: Saugstad, O. D., Sollie, M. G., Torp, H. A., & Storla, D. G. (2025). Specialised care for severely affected ME/CFS patients. Fatigue: Biomedicine, Health &amp; Behavior, 1–13. https://doi.org/10.1080/21641846.2025.2565101 https://www.tandfonline.com/doi/full/10.1080/21641846.2025.2565101 (Full text)

Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies

Abstract:

Although Gulf War Illness (GWI), fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID have distinct origins, in this article we have reviewed evidence that these disorders comprise a group of so-called low-energy associated disorders with overlapping common symptoms underlying pathology.

In particular, evidence for mitochondrial dysfunction, oxidative stress, inflammation, immune dysregulation, neuroendocrine dysfunction, disrupted brain-gut-microbiome axis, apoptosis/ferroptosis and telomere shortening as common features in the pathogenesis of these disorders has been identified.

Given the role of coenzyme Q10 (CoQ10) in promoting normal mitochondrial function, as an antioxidant, antiinflammatory and antiapoptotic and antiferroptotic agent, there is a rationale for supplementary CoQ10 in the management of these disorders. The reported benefits of supplementary CoQ10 administration in GWI, FM, ME/CFS and long COVID have been reviewed; the potential benefit of supplementary CoQ10 in reducing telomere shortening and improving the efficiency of stem cell transfer relevant has also been identified as promising therapeutic strategies in these disorders.

This review advances beyond previous systematic reviews and consensus statements on overlapping similar symptoms and underlying biological pathomechanisms in these complex disorders.

Source: Mantle D, Domingo JC, Golomb BA, Castro-Marrero J. Gulf War Illness, Fibromyalgia, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID Overlap in Common Symptoms and Underlying Biological Mechanisms: Implications for Future Therapeutic Strategies. Int J Mol Sci. 2025 Sep 17;26(18):9044. doi: 10.3390/ijms26189044. PMID: 41009608. https://www.mdpi.com/1422-0067/26/18/9044 (Full text)