Background:Telehealth can improve access to care for people living with multiple sclerosis (MS), but information on its acceptance is limited in Switzerland. Objective:This study aimed to determine the proportion of people living with MS willing to accept telehealth as a new default and the factors associated with their acceptance. Methods:We conducted a cross-sectional analysis using survey data from the Swiss Multiple Sclerosis Registry. We defined "telehealth as a default" as a health care model where remote consultations (telephone and/or video calls) are the primary mode of interaction between patients and their physicians, with in-person visits based on clinical necessity. Multivariable logistic regression was performed to evaluate the association between telehealth acceptance and sociodemographic and health-related factors. Telehealth acceptance was described in relation to 3 survey variables that mirrored key constructs from the Non-Adoption, Abandonment, Scale-Up, Spread, and Sustainability (NASSS) framework. The variables were digital communication preferences, internet use for health provider searches, and experience with telemedicine. Results:Among 427 respondents, 15.5% (66/427) reported a willingness to accept telehealth as their default. In this group, only 21.2% (14/66) had experience using telemedicine. A descriptive analysis of our 3 NASSS-derived key constructs showed that among the 78.5% (335/427) respondents who generally agreed to digital access to health data, only 17.0% (57/335) accepted telehealth as a default. Notably, 30.7% (129/427) of participants stated a wish for support for using devices or the internet. Among those 129 individuals, 17.1% (22/129) were willing to accept telehealth as a default. Of the 89 people with prior telehealth experience, 15.7% (14/89) were willing to accept telehealth. In multivariable analysis, digital communication with health care providers (adjusted odds ratio [aOR] 14.56, 95% CI 6.18-39.04; P<.001), current internet use for health care provider search (aOR 7.78, 95% CI 1.34-45.32; P=.021), and a secondary progressive MS diagnosis (aOR 0.22, 95% CI 0.05-0.72; P=.021) were independently associated with accepting telehealth as a default. Conclusions:Our findings suggest a low acceptance of telehealth as a default among people living with MS in Switzerland. While our 3 postulated NASSS-derived key constructs were not associated with telehealth acceptance, we noted additional behavioral factors, including previous digital communication with health care providers and using the internet to search for health care provider information, which were associated with telehealth acceptance. Moreover, advanced disease states like secondary progressive MS were negatively associated with telehealth acceptance. Thus, telehealth as a default will be most acceptable in people living with MS who already use the internet for their health, and those with less severe disease. Future research should explore provider perspectives and evaluate long-term strategies for the acceptance of telehealth in MS care.

BackgroundIdentification of fatigue in people with Multiple Sclerosis (pwMS) is still mainly based on subjective assessments due to the lack of objective diagnostic tools. We aimed to identify vocal biomarkers to differentiate between pwMS with and without fatigue.MethodsThis COMMITMENT trial was a prospective, observational study recruiting healthy controls (HCs, n = 20) and relapsing MS (RMS) patients (n = 50, EDSS <4.0) at University Hospital of Bern. The primary objective was to predict fatigue in pwMS by means of automated artificial intelligence (AI)-based speech analysis. An exploratory objective was to differentiate between pwMS and HCs.FindingsParticipants had a mean age of 36.0 years, and 73% were female, with no significant group differences. Median EDSS in pwMS was 1.0 (range 0–3.0). Motor fatigue affected 50% and cognitive fatigue 40% of pwMS. Five acoustic features were associated with general fatigue, independently of depression and sleepiness. Further, five features were associated with motor-, and 12 with cognitive fatigue. The best-performing classification and regression models [Leave-One-Speaker-Out (LOSO) paradigm] achieved specificities of 0.68–0.94, whereas sensitivity remained lower (0.38–0.90). Speech biomarkers distinguished pwMS from HCs with a specificity of 0.90 but only a sensitivity of 0.3.InterpretationSpeech in pwMS may serve as a potential biomarker for MS-associated fatigue and might help to differentiate between pwMS and HC. Our findings suggest that AI-assisted speech analysis could complement existing fatigue assessments.

Relapsing multiple sclerosis (RMS) is a chronic inflammatory disease usually diagnosed at a young age. Most patients receive several disease-modifying therapies (DMTs) over time, but evidence-based guidelines to support treatment sequencing are limited, particularly for switches between high-efficacy DMTs. An international group of experts in the care of RMS reviewed the current evidence and their clinical practice in order to provide recommendations on the optimal therapeutic use of cladribine tablets (CladT, an immune reconstitution therapy for RMS) in patients previously managed on anti-trafficking agents (S1P modulators, natalizumab) or an anti-CD20 agent. Recommendations relate to switching due to breakthrough RMS disease activity or safety/tolerability issues, to reduce the risk of safety concerns, including de-risking in older people with stable RMS, and to facilitate family planning. We propose that CladT is a rational option for people with RMS presenting with intractable safety/tolerability issues during treatment with a high-efficacy DMT, for older patients with stable RMS who have received long-term DMT, or for patients with breakthrough RMS disease activity despite treatment with an S1P modulator. In selected cases, CladT may be considered for patients with breakthrough RMS disease activity on anti-CD20 treatment. It is important to keep the interval between withdrawal of a previous anti-trafficking DMT (especially S1P modulators) and initiation of CladT as short as possible if the switch is intended to address breakthrough RMS disease activity, especially with regard to the prevention of rebound RMS disease activity. Immune reconstitution therapy with CladT may also provide an opportunity to plan for pregnancy in the absence of continuous DMT.

Multiple sclerosis (MS) is an immune-mediated chronic neuroinflammatory and neurodegenerative disorder. Inflammation in MS disrupts the barriers between blood and central nervous system and affects transport and diffusion of metabolites between blood and cerebrospinal fluid (CSF). In this exploratory retrospective case–control study, we used targeted metabolomics to evaluate differences in serum and CSF amino acid and neurotransmitter levels between patients with MS (n = 73) and non-neuroinflammatory controls (n = 78). The influence of patient characteristics, including sex, age, disease duration, severity and treatment status, was also analzyed. Although no significant differences in serum and CSF metabolite levels were found between MS and control patients, a stratification by sex uncovered significantly reduced metabolites in male MS patients compared to male controls in CSF but not in serum. While in male MS patients CSF histidine levels were decreased, female MS patients showed increased levels. Further, sex-specific associations of amino acids and neurotransmitters with disease duration and disability were observed. MS patients exhibited enhanced positive correlations between CSF and serum analyte levels. In serum, only a few amino acids, along with serotonin and glutathione, were associated with MS disease duration. Overall, this study suggests that targeted metabolomics of selected analytes in matched CSF and serum samples is a valuable approach for assessing alterations in CSF–serum metabolite associations in MS, as well as sex-specific imbalances between excitatory and inhibitory neurotransmitters across disease duration. Our findings further highlight the importance of considering sex as a key biological factor in MS.

BACKGROUND:The Phase IV MAGNIFY-MS Extension study evaluated the long-term efficacy and durability of cladribine tablets (CladT) in participants with highly active relapsing multiple sclerosis (RMS) during treatment-free Years (Y) 3 and 4. METHODS:Data were analysed for all participants and by subgroups (treatment-naïve vs experienced). Time to no evidence of disease activity (NEDA-3) and first confirmed Symbol Digit Modalities Test (SDMT) score change (⩾4/8 point improvement or ⩽4/8 point worsening) were assessed using Kaplan-Meier analysis. SDMT changes were confirmed if sustained across two visits ⩾166 days apart; others were classified as stable. Percentage brain volume change (PBVC) was analysed using the SIENA-XL method. RESULTS:Of 270 MAGNIFY-MS participants, 219 entered MAGNIFY-MS Extension (64.8% female; mean age ± standard deviation: 40.4 ± 9.45 years). NEDA-3 rates were 78.6% (Y3), 79.2% (Y4) and 54.2% (Y3-Y4 combined). At Y4, 83.1% had no T1 gadolinium-enhancing lesions, 67.4% had no active T2 lesions, and the annualised relapse rate was 0.09. Mean annualised PBVC was <0.4% in Y4. SDMT scores were 4/8-point stable or improved in 79.0%/88.1% of participants, and 84.5% had no 6-month confirmed disability progression. CONCLUSION:Two years of short-course CladT provided sustained clinical and cognitive benefits, supporting the potential for treatment-free remission in RMS. CLINICALTRIALS:gov Identifier: NCT04783935. Date registered: 3 March, 2021.

Multiple sclerosis (MS) is a chronic central nervous system disease with heterogeneous symptoms, including gait disturbances and motor fatigue, affecting daily functioning and quality of life. Episodic assessments may miss within-day functional fluctuations, whereas home-like monitoring may characterize them. This technical proof-of-concept case study quantified gait parameters (velocity, step length, and variability) during natural walking, explored temporal changes in gait and activity as potentially fatigue-relevant motor-performance patterns, and examined the feasibility of deriving candidate digital measures in MS. Three individuals with MS (one EDSS 1; two EDSS 3) were monitored in an instrumented apartment for 6.5-9.0 h using three LiDAR sensors. Gait parameters, region transitions, activity patterns, EDSS, FSMC, VAS-F, and available data-yield indicators were summarized descriptively. Compared with published healthy-adult references, P01 and P03 showed lower walking velocity, and P03 showed reduced step length. P01 maintained stable gait, P02 increased afternoon walking velocity, and P03 showed an afternoon velocity decline and a smaller step length decrease. The behavioral profiles described different spatial activity patterns, and the activity levels remained low during monitoring. LiDAR-based monitoring may provide a privacy-preserving approach to capture gait and activity variations as candidate variables for future validation without establishing fatigue specificity, clinical validity, or diagnostic thresholds.

Importance:Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation. Objective:To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA). Design, Setting, and Participants:This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements). Exposures:Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months. Main Outcomes and Measures:Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC). Results:The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively. Conclusions and Relevance:In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.

In multiple sclerosis (MS) patients under therapy, the increase of serum glial fibrillary acidic protein (sGFAP) concentrations is associated with the course of 'progression in absence of relapse' (PIRA). While serum neurofilament light chain (sNfL) reflects both response as well as insufficient or lack of efficiency of disease-modifying therapies (DMT), the longitudinal course of sGFAP levels as a drug response marker for future PIRA in relation to specific types of DMT is less clear. We aimed to compare the predictive capacity of sGFAP and sNfL for PIRA and relapse activity and the longitudinal course in people with MS (PwMS) treated with fingolimod, based on Z scores derived from normative values. Overall, 420 PwMS under fingolimod treatment with follow-up of 9.1 years (interquartile range: 7.0-11.0) from the Swiss MS Cohort, contributing 2935 longitudinal serum samples, were included. A reference data set for sGFAP established from 4297 healthy controls across three European and North American cohorts was used to calculate Z scores. The longitudinal course and the predictive capacity of biomarkers for time to PIRA and relapse were assessed by Cox proportional hazards and linear mixed-effects models. In controls, sGFAP concentrations were 13.6% higher in females than males and increased exponentially with age. Altogether, 31.0% of PwMS experienced ≥1 PIRA event. Elevated sGFAP Z scores (>0.75) were associated with increased risk of PIRA [hazard ratio (HR): 1.64; 95% confidence interval (CI): 1.16-2.32; P = 0.006], while this was not the case for sNfL. Conversely, elevated sNfL predicted relapses (HR: 1.58; 95% CI: 1.13-2.23; P = 0.008), while sGFAP did not. Both biomarkers decreased under treatment: sGFAP by 0.19 Z score units (ZSU)/10 years (95% CI: -0.27 to -0.11; P < 0.001) and sNfL by 0.16 ZSU/10 years (95% CI: -0.27 to -0.06; P = 0.002). Serum GFAP remained elevated in PwMS with future PIRA events (estimate: 0.29; 95% CI: 0.07-0.50; P = 0.009); no such association was found for sNfL. Serum GFAP and sNfL Z scores provide complementary predictive capacity for PIRA and relapse risk. The decrease of sGFAP under fingolimod is a feature not observed with other types of DMT and may hint to a specific anti-neurodegenerative effect of Sphingosine-1-phosphate-receptor modulators on astrocytes.

Background: The treatment landscape for myasthenia gravis (MG) has evolved with the introduction of novel therapies. An international consensus on patient selection criteria and optimal time to initiate these therapies could improve clinical outcomes and reduce delays for likely beneficiaries. Objective: This Delphi consensus was undertaken by MG specialists from selected European countries to explore gaps in the application of national guidelines and elicit expert opinion in practice. Design: A mixed-method approach was used; qualitative and quantitative study phases were combined to explore key concepts and reach consensus. Methods: The qualitative first phase involved seven healthcare professionals (HCPs) and two patient advocacy group representatives who participated in idea generation. Findings from this phase supported the development of a Delphi survey, which was completed by 16 HCPs in two rounds. This constituted the quantitative second phase of the study. Consensus was defined as ⩾70% agreement or disagreement on a 6-point Likert scale. Results: In total, 65% of statements achieved consensus. Key findings include—HCPs highly regard international guidelines but find critical discrepancies between the “ideal” scenario and current clinical practices. Consensus was achieved on the importance of incorporating patient-related quality of life in decision-making, despite limited current methods. Consensus was obtained on steroid tapering and treatment-switch criteria based on steroid dose and duration. Consensus was also achieved on suitable patient profiles, including those with persistent symptoms, severe side effects, or needing rapid control. Conclusion: This study recognized that guidelines offer valuable direction but do not replace individualized treatment decisions. This study identified the areas of alignment and opportunities to refine patient selection criteria and treatment-switch categories, particularly to integrate novel therapy use in MG management, highlighting a path to a more patient-centric approach.

Background Complementary therapies (CTs) are widely used among persons with multiple sclerosis (MS). Patients’ expectations of treatment effectiveness are linked to CT use in the general population. However, little is known about how such expectations vary among people with MS or whether they are associated with CT use.Objectives To identify expectation-based clusters among adults with MS, describe their characteristics and assess associations with current CT use.Methods We conducted a cross-sectional analysis of Swiss MS Registry follow-up survey data collected between October 2022 and October 2023, exploring expectations regarding manual, mind–body, natural product-based and dietary therapies. K-means clustering was applied to eight variables assessing participants’ expectations of each therapy’s effectiveness for physical and psychological symptoms. Clusters were described, and associations with current CT use were analysed using log-binomial regression.Results A total of 753 participants were classified into three expectation clusters: low (20.3%), moderate (47.6%) and high (32.1%). The low-expectation cluster included more individuals with progressive MS, severe gait disability and lowest CT use. Expectation clusters were significantly associated with current CT use. In unadjusted analyses, inclusion of the cluster variable significantly improved model fit (likelihood ratio test (LRT)=31.25, p<0.001), and participants in the moderate-expectation and high-expectation clusters were more likely to use CT compared with the low-expectation cluster (relative risk (RR) 1.60, 95% CI 1.26 to 2.04; RR: 1.80, 95% CI 1.42 to 2.30). After adjustment, the association remained significant (LRT=29.01, p<0.001), with higher likelihoods of CT use in the moderate-expectation and high-expectation clusters (adjusted RR: 1.58, 95% CI 1.24 to 2.00; RR: 1.80, 95% CI 1.41 to 2.30, respectively). Sensitivity analyses using an alternative CT outcome variable yielded consistent results.Conclusions Expectation profiles are independently associated with CT use in MS. Addressing misalignments between patient expectations and evidence may help promote informed, evidence-based decision-making about CTs.

BACKGROUND AND OBJECTIVES:Multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are autoimmune disorders of the CNS causing severe neurologic impairment. Evidence suggests that extracellular vesicles (EVs) may play a disease-specific role in the orchestration of the immune cell response of MS, NMOSD, and MOGAD. In addition, EVs are considered as a potential source of biomarkers that may allow us to establish molecular signatures for these diseases and perhaps as well to follow treatment effects and disease progression. The aim of this study was to analyze the composition of EVs in patients with relapsing-remitting MS (RRMS) (n = 52), NMOSD (n = 19), and MOGAD (n = 10) and healthy controls ([HCs], n = 15). METHODS:The concentrations of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were determined in plasma using single-molecule array (SIMOA). The size and concentration of tetraspanin-presenting EVs were evaluated in plasma samples with a single-particle interferometric resonance imaging sensor (SP-IRIS). Tetraspanin-independent analyses were performed by nanoparticle-tracking analysis (NTA) after EV isolation by size exclusion (SmartSEC) and cryo-electron microscopy observations. EV epitopes were analyzed by extended multiplex analysis using flow cytometry. RESULTS:The plasma concentration of NfL and GFAP was significantly higher in patients with RRMS than in HCs. For patients with NMOSD, only GFAP increased. The density of EVs assessed by NTA was lower in plasma of patients with RRMS than in HC plasma. In addition, the 3 disease groups presented increased mean EV sizes in comparison with HCs. Tetraspanin-based EV analyses by SP-IRIS allowed us to observe a modest difference in the level of CD81 in RRMS EVs. In patients with RRMS, but not in those with NMOSD and MOGAD, multiplex/flow cytometry analyses revealed changes in the EV levels of CD29, CD31, and CD69 associated with the time elapsed since the last relapse. The negative correlations established between the vesicular levels of CD31, CD40, CD44, CD49c, CD69, and NfL or GFAP z-scores suggest a negative relationship specifically in RRMS. DISCUSSION:We speculate that the higher release of EVs containing CD29, CD31, CD40, CD44, CD49c, and CD69 in plasma, at low levels of circulating NfL/GFAP, may be associated with reduced immune cell activity in RRMS. These EV markers may characterize patients with RRMS in disease stabilization.

Introduction Following the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), post-COVID-19 syndrome (PCS) has emerged as a major health concern, affecting approximately 3.0-11.7% of infected individuals. While neuropsychiatric symptoms such as fatigue, pain, and sleep disturbances dominate the clinical picture, recent evidence suggests a pivotal role for immune dysregulation in the pathophysiology of PCS. This study aimed to analyze the clinical course and laboratory features of patients with PCS. Methods In this retrospective single-center study, 74 patients with PCS were evaluated between November 2020 and June 2022 at the Department of Neurology, University Hospital Bern. Clinical assessments included standardized questionnaires [Fatigue Severity Scale (FSS), Fatigue Scale of Motor and Cognitive Function (FSMC), Beck Depression Index II (BDI-II), Epworth Sleepiness Scale (ESS)] and laboratory investigations at two timepoints. Particular focus was placed on immune-related biomarkers, including ferritin and antinuclear antibodies (ANA). Results Fatigue, sleep disturbances, and pain were the most frequently reported symptoms. At follow-up (a mean duration of 14.4 weeks after the first consultation), both symptom burden and severity scores decreased significantly. Nevertheless, 82.4% of patients continued to report fatigue. Elevated ferritin levels were found in 78.1% of tested patients (mean: 306.9 µg/l), and ANA titres ≥1:160 were observed in 40% of patients without known autoimmune disease. At follow-up, 80% of patients with initially elevated ferritin and 68% with elevated ANA remained above normal thresholds, suggesting ongoing immune activation. Conclusions While symptom burden declined over time, most PCS patients continued to experience clinically relevant symptoms. The persistence of elevated ferritin and ANA levels underscores possible immune dysregulation and highlights the potential of these biomarkers in characterizing PCS. These findings underline the need for further studies investigating their diagnostic and therapeutic relevance.

BACKGROUND AND OBJECTIVES:Biologically informative markers like glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) may help predict confirmed disability worsening (CDW) in multiple sclerosis (MS). However, data on the prognostic value of their blood concentrations in progressive MS (PMS) are limited, and there are substantial discrepancies in the published literature. This international collaboration uses individual participant data to define the prognostic value of serum GFAP and NfL in people with PMS (pwPMS). METHODS:Data were collected from BioMS-eu network centres and collaborating cohorts. pwPMS with primary progressive MS (PPMS) or secondary progressive MS (SPMS) with at least one GFAP value and at least three follow-up expanded disability status scale (EDSS) scores were included. The prognostic value of serum GFAP and NfL age- and sex-adjusted Z-scores for future CDW was evaluated using Cox regression models, accounting for sex, age, baseline disease duration and EDSS, and dominant treatment during follow-up. RESULTS:1058 participants and 7530 encounters were included (median age 53 years (IQR: 44 to 59), 57% female, follow-up 4.6 years (2.9 to 8.4)) with median baseline GFAP of 0.74 (-0.10 to 1.55) and NfL of 0.64 (-0.36 to 1.51). 723 CDW events were recorded. Each GFAP Z-score increase was associated with ~10% higher CDW risk (adjusted HR (aHR) 1.107 (1.001 to 1.225), p=0.049). Results were mainly driven by SPMS participants (n=613, aHR 1.242 (1.073 to 1.438), p=0.004). Higher NfL Z-scores predicted CDW only in PPMS participants (1.236 (1.092 to 1.399), p=0.001). CONCLUSIONS:GFAP was a prognostic indicator for future CDW in pwPMS, especially in pwSPMS. On the other hand, NfL was predictive of CDW only in pwPPMS.

Fatigue is a severely disabling symptom that can substantially impair quality of life and employment prospects, and has serious socioeconomic consequences. Different individual and disease-related variables interact to generate this complex symptom, leading to clinical heterogeneity. We currently lack a common understanding and definition of fatigue and its origins, thereby impeding professional exchange among disciplines regarding diagnosis and underlying pathophysiology. To aid the development of a common language that encapsulates the heterogeneity of fatigue, we propose a taxonomy consisting of neurogenic, myogenic and systemic clusters. Each cluster comprises the same five distinct concepts and their phenotypic expression. The interplay between multifactorial pathophysiological mechanisms might vary between diseases and over time, and additional factors such as comorbidities can modulate fatigue. Understanding this complexity is essential to improve both the diagnostic process and the development of targeted therapeutic interventions. In this Review, we compare the clinical and pathophysiological characteristics of a range of neurological and non-neurological diseases within predefined clusters of fatigue origin. We propose an integrative model for fatigue of different origin and over time based on the interplay of genetics and epigenetics, immunological changes, structural and functional brain abnormalities, and behavioural alterations. Large research consortia will be required to tackle the methodological shortcomings that currently hamper our understanding of fatigue and to initiate large longitudinal cohort studies with multidimensional readouts to further explore and address this burdensome symptom. Fatigue is a burdensome symptom that is commonly encountered in people with neurological or non-neurological diseases, but it is poorly understood and lacks a common definition and conceptualization. This Review presents new a conceptual model of fatigue that is designed to improve communication between experts from different methodological and medical backgrounds.

[This corrects the article DOI: 10.3389/fimmu.2025.1512189.].