Improving Diagnostic Accuracy of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Through a Point-of-Care Clinical Algorithm

Abstract:

Despite the increasing prevalence and median severity of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), medical education on the disease is scant, leading to a diagnostic crisis in which the majority of people with ME/CFS are undiagnosed. We created a care process algorithm in AskMayoExpert accessible to all Mayo Clinic medical providers as a source for information on diagnosis and management of ME/CFS.

To evaluate whether the algorithm was associated with improved diagnostic accuracy, we compared concordance before versus after the algorithm was introduced, where concordance was defined as agreement between an appropriately coded referral to Mayo Clinic’s Chronic Fatigue Specialty Clinic and the specialty clinic with an expert diagnosis of ME/CFS.

Referrals to the Chronic Fatigue Specialty Clinic increased overall and were more likely to show concordance between specialist diagnosis and referral after the introduction of the ME/CFS AskMayoExpert algorithm. Particularly in diseases that are prevalent and poorly understood, a point-of-care clinical tool may offer just-in-time opportunities to improve diagnosis and management.

Source: Seltzer J, Grach SL, Eggers SD, Redetzke MM, Mau KJ, Chon TY, Ganesh R. Improving Diagnostic Accuracy of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Through a Point-of-Care Clinical Algorithm. Int J Environ Res Public Health. 2026 Apr 3;23(4):460. doi: 10.3390/ijerph23040460. PMID: 42074399. https://www.mdpi.com/1660-4601/23/4/460 (Full text)

Digital Approaches for Managing Brain Fog in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Interventions, Monitoring, and Future Directions

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a high-burden, under-researched condition characterized by heterogeneous and fluctuating symptoms, including cognitive dysfunction commonly described by patients as “brain fog”. Despite growing interest in digital health technologies for symptom monitoring and personalized care, their application to the assessment and management of cognitive dysfunction in ME/CFS remains unclear. This descriptive review aimed to examine the current scientific evidence on digital approaches related to brain fog in ME/CFS.

A structured literature search following PRISMA guidance was conducted to identify relevant studies. The available literature remains limited in scope and methodological maturity. During synthesizing across studies, three main functional domains of digital application become apparent: (1) digital tools for cognitive assessment, which have the strongest evidence base; (2) digital platforms for longitudinal monitoring; and (3) digitally mediated interventions or rehabilitation approaches, both of which are less well studied.

Simultaneously, the findings suggest that patient-reported brain fog may represent a visible component of the broader ME/CFS disease spectrum and could serve as an early clinical indicator guiding diagnosis and management. Interpreting these symptoms within a biopsychosocial framework may facilitate understanding of the complex nature of the disease and optimize the use of digital technologies for monitoring cognitive dysfunction and supporting patient-centered care in ME/CFS.

Source: Araja D, Murovska M, Krumina A, Eory A, Berkis U. Digital Approaches for Managing Brain Fog in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Interventions, Monitoring, and Future Directions. Life (Basel). 2026 Apr 1;16(4):571. doi: 10.3390/life16040571. PMID: 42073381. https://www.mdpi.com/2075-1729/16/4/571 (Full text)

3D Virtual Reality Performance Metrics as a Future Fatigue Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder, characterized by symptoms such as post-exertional malaise (PEM) and cognitive impairments. This study assessed reaction time (RT) metrics in three-dimensional (3D) visual tasks with the aim of objectively quantifying the cognitive impairments in ME/CFS patients compared to controls.

Methods: A total of 120 participants (60 ME/CFS patients and 60 controls) were recruited at the Department of Ophthalmology, Universität of Erlangen-Nürnberg. RT was assessed using a virtual reality-oculomotor test system, presenting 3D stimuli at three disparity levels (275″, 550″, and 1100″) within three gaming repetitions (R1, R2, and R3). Mixed-effects models were used to evaluate group differences, with age and gender as covariates. Pairwise contrasts were calculated to assess changes across repetitions. Fatigue self-assessments were recorded by validated questionnaires, (FACIT Fatigue Scale, Chalder Fatigue Scale, Bell Score and Health Assessment Questionnaire), and their correlation with RT metrics was portrayed using a Spearman correlation matrix.

Results: Estimated means (EM-means) for RT were significantly prolonged in ME/CFS patients compared to controls at disparity 275″ (1969 ms vs. 1384 ms; p = 0.0001), 550″ (1409 vs. 1071 ms; p = 0.0012) and 1100″ (1126 ms vs. 891 ms; p = 0.00223). Age was a significant covariate (p < 0.001), while gender showed no effect. Both groups demonstrated improvements in RT over repetitions; however, ME/CFS patients showed a significantly lower improvement compared to controls, reaching significance in R3 (p = 0.0042). RT metrics did not correlate with patients’ self-assessment scores.

Conclusions: ME/CFS patients showed consistently slower RTs compared to controls, particularly in later, easier gaming repetitions, potentially reflecting the impact of fatigue.

Source: Ladek AM, Priebe L, Harrer T, Harrer E, Michelson G, Knauer TS, Dias-Nunes DX, Mardin CY, Bergua A, Hohberger B. 3D Virtual Reality Performance Metrics as a Future Fatigue Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Biomedicines. 2026 Apr 9;14(4):855. doi: 10.3390/biomedicines14040855. PMID: 42072397. https://www.mdpi.com/2227-9059/14/4/855 (Full text)

 

Underuse of Pharmacologic Therapies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Before Specialist Evaluation

Abstract:

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem neurologic disease characterized by profound fatigue and decreased functional capacity, postexertional malaise, and unrefreshing sleep, along with cognitive impairment and/or orthostatic intolerance. Its prevalence has risen exponentially with the COVID-19 pandemic. Pharmacologic therapies have been used successfully by ME/CFS specialists but may be underused by the general medical field.

Methods: To assess this potential practice gap, we retrospectively analyzed the records of 571 patients with an ME/CFS diagnosis referred to our ME/CFS specialty clinic in Minnesota during 2018-2022. We ascertained medications that had already been tried at the time of consultation and also ascertained supplement use.

Results: With the exception of medications primarily used for pain and anxiety, use of pharmacotherapy for ME/CFS symptom management as proposed by specialists was limited. Overall, 68.3% of patients had had at least 1 medication potentially prescribed for ME/CFS; the most common were serotonin-norepinephrine reuptake inhibitors, gabapentin, and tricyclic antidepressants. A slightly larger share of patients, 72.2%, reported having taken at least 1 dietary supplement; the most common were vitamin D, vitamin B12 and B complex, and fish oil.

Conclusion: Our findings suggest that potentially helpful medications for ME/CFS are being underprescribed in the general medical field and that patients may resort to supplements to manage symptoms. Better education of clinicians about available treatment options and treatment guides may improve management of this debilitating disease.

Source: Grach SL, Seltzer J, Mueller MR, Aakre CA, Natividad LT, Lawson DK, Ganesh R, Hurt RT. Underuse of Pharmacologic Therapies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Before Specialist Evaluation. Ann Fam Med. 2026 Apr 29:250266. doi: 10.1370/afm.250266. Epub ahead of print. PMID: 42055743. https://www.annfammed.org/content/early/2026/04/24/afm.250266-0 (Full text available as PDF file)

Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem disease characterized by heterogeneous symptom patterns. Previous work suggested that specific symptoms tend to co‑occur, pointing toward underlying biological mechanisms. This study aimed to empirically validate literature‑based, hypothesis‑driven symptom clusters and assess whether they reflect distinct neuroimmune and autonomic pathophysiological pathways.

Methods: Symptom data from 748 adults with ME/CFS (≥20 years) participating in the APAV‑ME/CFS study were analyzed. Symptoms were assigned to predefined mechanistic groups informed by current pathophysiological hypotheses. Exploratory and Confirmatory Factor Analyses, followed by Structural Equation Modeling (SEM), evaluated the coherence, distinctiveness, and hierarchical structure of each cluster. Robustness was tested using a stratified, randomized training dataset.

Results: A coherent Brain factor (brain fog, sensory hypersensitivity, visual disturbances, sleep disturbances, headaches) showed excellent fit (RMSEA = 0.021; CFI = 0.996). Gastrointestinal symptoms demonstrated stronger internal consistency than Immune symptoms, and model comparisons supported a two‑factor Gut–Immune structure. Across all analyses, symptom groups emerged as internally consistent and statistically distinct. A higher‑order SEM including a common latent factor yielded excellent fit for the Autonomic symptom complex.

Conclusions: The findings support ME/CFS as a complex neuroimmune–autonomic multisystem disorder and suggest that symptom clusters align with functional biological systems. Mechanism-aligned symptom subgrouping may enable pathophysiology-guided diagnostics, patient stratification, and targeted therapeutic development. The proposed interpretations of underlying mechanisms derive from the integration of existing literature and were not directly measured in this study. The identified clusters therefore indicate mechanistic alignment rather than direct mechanistic validation.

Source: Habermann-Horstmeier L, Horstmeier LM. Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model. J Transl Med. 2026 Apr 28;24(1):606. doi: 10.1186/s12967-026-08159-1. PMID: 42050709; PMCID: PMC13126800. https://pmc.ncbi.nlm.nih.gov/articles/PMC13126800/ (Full text)

Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes

Abstract:

Post-viral syndromes are heterogeneous multisystem diseases without a uniform etiology that occur as a result of acute viral infections. During the COVID-19 pandemic, the number of patients increased dramatically due to infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This is known as post-acute sequelae of COVID-19 (PASC), with many cases also meeting the criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the most severe form of a post-viral disease, characterized by severe fatigue, post-exertional malaise (PEM), unrefreshing sleep, neurocognitive impairment, and autonomic and immune dysregulation.

Orexin (OX) neuropeptides, which regulate arousal, metabolism, and neuroendocrine functions, may serve as a central link between stress, immune activation, and metabolic changes in these syndromes. Notable phenotypic similarities between OX system dysfunction and core features of PASC and ME/CFS, including fatigue, sleep issues, impaired glucose metabolism, and neuropsychiatric symptoms, support a mechanistic model in which impaired OX signaling contributes to post-viral endocrine and metabolic dysfunction.

This review examines the role of OX in regulating glucose metabolism, HPA axis activity, and systemic homeostasis, with a specific focus on sexually dimorphic expression and function in relation to post-viral syndromes. We also highlight the effect of glucagon-like peptide-1 (GLP-1), another key player in metabolism, which also has neuroprotective, anti-inflammatory, vasoprotective, and immunomodulatory effects. We further emphasize emerging therapeutic strategies, such as GLP-1 receptor agonists (GLP-1RAs) and drugs targeting the OX system.

Together, these insights provide an integrated framework for understanding and targeting the neuroendocrine-metabolic underpinnings of PASC, ME/CFS, and other post-viral syndromes.

Source: Ruhrländer J, Schieffer E, Schieffer B. Regulatory Cycles of Orexin and Glucagon-Like Peptide-1 in Post-Viral Syndromes. Endocr Rev. 2026 Apr 27:bnag009. doi: 10.1210/endrev/bnag009. Epub ahead of print. PMID: 42037238. https://pubmed.ncbi.nlm.nih.gov/42037238/

A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in myalgic encephalomyelitis/chronic fatigue syndrome: lessons learned from long-COVID

Abstract:

Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a neuroimmune disease characterized by debilitating post-exertional malaise (PEM), brain-fog/cognitive problems, and dysregulation of the autonomic nervous system. Currently, there are no objective biomarkers for ME/CFS despite decades of research.

Here, we compile evidence from literature that supports taste dysfunction, particularly alterations of taste perception mediated by Type II taste receptor cells, may be a critical underrecognized feature of ME/CFS. The impetus is drawn from the emerging evidence of clinicopathological similarities between long-COVID and ME/CFS. We discuss in parallel the mechanisms of cellular metabolism, inflammation, vascular dysfunction, and autonomic dysregulation in ME/CFS and long-COVID pathophysiology.

We postulate that mechanistically, dysregulation of ATP signaling through P2X2/P2X3 purinergic receptors underlies both gustatory impairment and core ME/CFS symptoms. Adopting information from the NIH-RECOVER shared resources, we present evidence that suggests chemosensory dysfunction as a potential indicator of progression/severity of PEM. We discuss standardized taste testing as a non-invasive screening tool complementary to molecular biomarkers for ME/CFS.

Notwithstanding, we acknowledge the limitations, confounding and contributing factors such as medications and deficiencies that may exacerbate or independently cause taste-related symptoms in ME/CFS.

In conclusion, we present a compelling case for the multi-factorial role of taste dysfunction in ME/CFS and suggest specific research priorities for investigating the relationship between chemosensory function and post-viral chronic illness.

Source: Srinivasan M, Joseph PV. A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in myalgic encephalomyelitis/chronic fatigue syndrome: lessons learned from long-COVID. Front Med (Lausanne). 2026 Apr 8;13:1808646. doi: 10.3389/fmed.2026.1808646. PMID: 42040552; PMCID: PMC13107777. https://pmc.ncbi.nlm.nih.gov/articles/PMC13107777/ (Full text)

Cardiopulmonary Exercise Testing Reveals Functional Limitations and Work Disability in Severe Post-COVID-19 and ME/CFS Patients

Abstract:

Background: Patients severely affected by post-COVID-19 condition (PCC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often experience long-term work incapacity, contributing to a growing economic burden. Organ-centered clinical diagnostics frequently fail to explain their work disability.

Objectives: We aimed to objectively assess physical work ability using cardiopulmonary exercise testing (CPET) in a cohort of long-standing and severely affected PCC patients. We hypothesized: (1) patients with ME/CFS exhibit lower peak oxygen uptake (VO₂peak [mL/min/kg]) and peak power output (PPO [W/kg]) than those without; (2) most patients demonstrate objective work disability, closely aligned with subjective perception of disability; (3) oxygen pulse (O2 pulse [mL/bpm]) is reduced in ME/CFS, independent of comorbidity.

Methods: The study was conducted in the Department of Sports Medicine, Prevention and Rehabilitation at Johannes Gutenberg-University Mainz (Mainz, Germany). Between July 31, 2023, and March 31, 2025, a total of 92 PCC patients with suspected occupational disease underwent symptom-limited CPET and completed the Canadian Consensus Criteria, Bell Disability Scale (Bell-Score), and DePaul Symptom Questionnaire (Post-Exertional Malaise) Short Form (DSQ-PEM).

Results: Nearly half of the patients (49%) met ME/CFS criteria and 79% screened positive on the DSQ-PEM. ME/CFS patients showed significantly lower VO₂peak (13.0 ± 3.1 vs. 15.4 ± 4.9, p = 0.012), PPO (0.9 ± 0.3 vs. 1.1 ± 0.5, p = 0.014), and O₂ pulse (7.7 ± 2.0 vs. 8.5 ± 1.9, p = 0.047) compared to those without ME/CFS. Overall, 66% of patients met objective thresholds for work disability (VO₂peak < 15 mL/min/kg or PPO < 1 W/kg). Forty-five patients (51%) had a Bell-Score ≤ 30 and 82% from those had VO₂peak < 15 and/or PPO < 1. VO₂peak and PPO significantly correlated with Bell-Score (r = 0.3, p = 0.005 and r = 0.3, p = 0.003) and were the lowest among patients on medical sick leave (13.3 ± 3.3 and 0.9 ± 0.3), compared to those in occupational reintegration (16.0 ± 3.9, p = 0.04 and 1.2 ± 0.5, p = 0.024) or currently working (18.0 ± 7.1, p = 0.036 and 1.2 ± 0.5, p = 0.015).

Conclusions: Severely affected PCC patients exhibit objective work disability, particularly those with ME/CFS. VO₂peak and PPO are associated with subjective disability and occupational status. Therefore, early integration of CPET into clinical and occupational evaluations can inform individualized therapy planning and return-to-work decisions.

Trial registration DRKS, DRKS00032394. Registered 28 July 2023, https://drks.de/search/de/trial/DRKS00032394.

Source: Tomaskovic A, Weber V, Ochmann DT, Hillen B, Neuberger EWI, Brahmer A, Lachtermann E, Lieb K, Simon P. Cardiopulmonary Exercise Testing Reveals Functional Limitations and Work Disability in Severe Post-COVID-19 and ME/CFS Patients. Sports Med Open. 2026 Apr 27;12(1):50. doi: 10.1186/s40798-026-00995-1. PMID: 42043742. https://link.springer.com/article/10.1186/s40798-026-00995-1 (Full text)

Health, labour market, and social service outcomes for people with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome on a health or disability related benefit: an Aotearoa | New Zealand nationwide cross-sectional study using the integrated data infrastructure

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating chronic condition characterised by persistent fatigue and multisystem symptoms, often leading to long-term disability and socioeconomic disadvantage. In Aotearoa New Zealand (NZ), little is known about the health, labour market, and social service outcomes of people with ME/CFS.

Methods: We conducted a nationwide cross-sectional study using the Integrated Data Infrastructure (IDI) to identify a cohort of working-age individuals (16–64 years) receiving a health or disability-related benefit with a recorded ME/CFS diagnosis. Outcomes were compared to propensity score-matched cohorts: (1) benefit recipients without ME/CFS, and (2) a general population not receiving any benefit. We examined sociodemographic characteristics, co-occurring conditions, health service utilisation, disability support use, employment and income, and benefit reliance.

Results: The study population included 1,902 individuals with ME/CFS. Compared to the general population, the ME/CFS cohort had significantly higher rates of emergency department visits (18.8% vs. 12.8%) and pharmaceutical use (32.8% vs. 14.2% for > 10 medications), and lower current employment (18.3% vs. 83.8%). Compared to other benefit recipients, those with ME/CFS had lower hospitalisation (11.2% vs. 20.9%) and disability support service use (1.6% vs. 7.2%), but higher rates of Supported Living Payment (64.7% vs. 49.0%) and long-term benefit receipt. The ME/CFS cohort was disproportionately female and European, with notable underrepresentation of Māori, Pacific, and Asian ethnic groups.

Conclusions: People with ME/CFS on a benefit in NZ, while only representative of a small fraction of those affected by ME/CFS, still face substantial health burdens, economic vulnerability, and limited access to appropriate supports. The findings highlight systemic policy exclusions that disadvantage individuals with chronic, fluctuating conditions. Improved diagnostic coding, inclusive eligibility criteria, and integrated, person-centred care models are urgently needed to address inequities and support this underserved population.

Source: Bowden N, McLeod K, Anns F, Catchpole L, Charlton F, Taylor B, Vallings R, Vu H, Tate W. Health, labour market, and social service outcomes for people with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome on a health or disability related benefit: an Aotearoa | New Zealand nationwide cross-sectional study using the integrated data infrastructure. BMC Public Health. 2026 Apr 24. doi: 10.1186/s12889-026-27499-7. Epub ahead of print. PMID: 42032509. https://link.springer.com/article/10.1186/s12889-026-27499-7 (Full text available as PDF file)

Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a major clinical challenge as a complex multisystemic disorder with no well-established pathophysiological mechanism, characterized by persistent fatigue and post-exertional malaise, along with unrefreshing sleep, cognitive impairment, and impaired stress recovery. Despite decades of investigation into the hypothalamic-pituitary-adrenal (HPA) axis, a definitive neuroendocrine hallmark has remained elusive due to inconsistent findings across various cortisol matrices. Therefore, this systematic review and meta-analysis aimed to provide an integrated understanding of HPA-axis regulation in ME/CFS.

We identified 46 case-control studies (comprising 46 independent datasets, including 12 pharmacological challenge studies), involving 1388 ME/CFS patients (71.9% female; mean age 37.3 ± 6.2 years) and 1349 matched healthy controls. Meta-analyses showed lower salivary cortisol at awakening and in the morning. Reductions were also observed in 24-h urinary cortisol and hair cortisol. In pharmacological challenge tests, patients exhibited impaired cortisol release in response to adrenocorticotropic hormone (ACTH) stimulation and exaggerated suppression following glucocorticoid administration.

Collectively, these alterations indicate reduced free cortisol availability and enhanced HPA-axis negative feedback sensitivity, consistent with a hyporeactive endocrine state in ME/CFS. This neuroendocrine hypo-reactivity may underlie hallmark clinical features such as unrefreshing sleep, post-exertional malaise, and severe fatigue, as well as cognitive slowing, emotional blunting, and diminished stress resilience frequently observed in ME/CFS and related functional disorders. Integrating neuroendocrine and psychological perspectives may help clarify mechanisms of chronic stress maladaptation and inform psychobiological interventions for fatigue syndromes.

Source: Woo TW, Choi YJ, Kim JY, Lee JS, Son CG. Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity. Mol Psychiatry. 2026 Apr 23. doi: 10.1038/s41380-026-03608-1. Epub ahead of print. PMID: 42026257. https://pubmed.ncbi.nlm.nih.gov/42026257/