Abstract Background Neuromyelitis optica spectrum disorders (NMOSD) are associated with a high burden of depression, pain, and physical disability, all of which significantly impair quality of life. At the same time, discussions on the cost-effectiveness of treatment strategies are gaining importance. However, it is not yet known whether specific symptom burdens are particularly cost-driving. This study aims to provide a comprehensive cost analysis considering depression and pain to optimise future healthcare strategies. Methods This prospective cross-sectional multicentre study was conducted at twelve centres of the Neuromyelitis Optica Study Group (NEMOS). Over a three-year period, 115 NMOSD patients were recruited. Disease-related costs, pain, and depression were assessed using standardised questionnaires. A generalised linear model analysis and graphical sub-cost analysis were performed to identify key cost drivers. The robustness of our findings was confirmed using two independent depression rating scales. Results In our sample of 115 patients, 77% suffered from chronic pain with a median pain intensity of 4.0 on the numeric rating scale (NRS). Moreover, 56% of patients reported depressive symptoms. In multivariate regression analysis, depression emerged as a significant predictor of total costs (p < 0.001) alongside the EDSS score (p < 0.001) and age (p = 0.004). In contrast, pain was not significantly influencing total costs (p = 0.057), despite being reported by the majority of patients. Graphical analyses highlighted informal costs as the main cost driver in patients with increasing depressive symptoms. Conclusions Depressive symptoms are not only common in NMOSD patients but also represent a major cost driver alongside neurological disability. Addressing these symptoms is essential for optimal patient care and may help reduce the socioeconomic burden.

Purpose To assess the feasibility of an optical coherence tomography (OCT)-based radiomics approach in optic neuritis (ON) and determine whether peripapillary retinal nerve fiber layer (pRNFL) OCT-derived radiomic features could help differentiate between multiple sclerosis–associated optic neuritis (MS-ON) and myelin oligodendrocyte glycoprotein antibody–associated disease optic neuritis (MOGAD-ON). Design Retrospective cohort study. Participants Patients with ON associated with either multiple sclerosis (MS-ON) or MOGAD-ON were selected from the existing ONET (Optic Neuropathies of la Timone) cohort. Forty-five patients (61 eyes with optic neuritis; 28 MS and 17 MOGAD) contributing 266 OCT examinations were included. Methods A radiomics pipeline was applied to pRNFL OCT data to extract quantitative imaging features. A total of 102 radiomic features were generated and reduced using feature selection methods. Unsupervised and supervised machine-learning approaches were used to identify relevant radiomic patterns and evaluate their ability to discriminate MS-ON from MOGAD-ON. Models were trained using radiomic features alone, clinical variables alone, and a combination of both. Main Outcome Measures The primary outcome measure was the diagnostic performance of machine-learning models in distinguishing MS-ON from MOGAD-ON, assessed using the area under the receiver operating characteristic curve (AUC). Results Among the 102 extracted radiomic features, 62 were retained after feature reduction, and three features were selected through machine-learning–based analysis. Supervised machine learning models (Logistic Regression) using radiomic features outperformed models based on clinical variables alone (AUC 0.763 vs 0.584, p = 0.001). Combining radiomics with clinical variables yielded a numerically higher AUC of 0.788 compared with radiomics alone (0.763), but without statistical significancy (p = 0.361). The combined model remained significantly better than the clinical-variable-only model (p < 0.001). Conclusions This study establishes a reproducible OCT radiomics pipeline and demonstrates the feasibility of applying unsupervised and supervised machine-learning approaches to pRNFL OCT data. Radiomic features show promising potential for improving the differentiation between MOGAD-ON and MS-ON.

Intermittent hypoxia intervention may provide an alternative therapeutic approach to enhance neuroprotection in people with multiple sclerosis (pwMS). However, clinical data on its safety and feasibility in pwMS are lacking. In this prospective single-arm safety and feasibility trial, individuals with primarily progressive MS (18-60 years; Expanded Disability Status Scale ≤6.5) were recruited from the MS outpatient clinic of the University Medical Center Hamburg-Eppendorf and underwent a 12-week repetitive continuous hypoxia (RCH). Participants completed two to three standardized 2-hour sessions per week simulating altitudes of up to 4,500 meters, corresponding to a minimum fraction of inspired oxygen of 11%. The primary outcome was the occurrence of acute high-altitude sickness, assessed using the Lake Louise Score (LLS). Secondary outcomes included systemic adverse events, adherence, disability measures, patient-reported outcomes, neuropsychological screening tests, MRI disease activity, immune cell subpopulations in peripheral blood, serum neurofilament light chain levels, and serum metabolomic profiles. Twelve pwMS were enrolled, and ten completed the intervention. No participant developed moderate or severe symptoms of high-altitude illness, and no systemic safety concerns or worsening of clinical, radiological, or laboratory parameters were observed over the intervention period. Exploratory analyses suggested improvements in disability-related outcomes. These findings indicate that a 12-week RCH is safe and feasible in pwMS and support further investigation in larger, controlled trials.

BACKGROUND:Primary progressive multiple sclerosis (PPMS) involves gradual disability accumulation driven by neurodegeneration. Standard outcomes, including the Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW), lack sensitivity to subtle functional changes. Real-life walking speed (RWS) measured with wearable sensors may offer a more responsive marker of progression. OBJECTIVES:In a prospective cohort (2012-2022) at the University Medical Center Hamburg-Eppendorf, adults with PPMS (18-65 years, EDSS ⩽7.0) underwent repeated EDSS, T25FW, Nine-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT). RWS was recorded using an accelerometer. Disease progression was defined as ⩾20% worsening in T25FW/9HPT, ⩾8-point SDMT decline, EDSS increase (⩾1.0 or ⩾0.5 if >5), or RWS reduction >0.08 m/s. RESULTS:Among 110 participants (mean age: 52 years; baseline EDSS: 3.5) followed for a median of 3 years, RWS showed a symmetric distribution and declined steadily with increasing EDSS, unlike the skewed T25FW distribution. Annual progression was detected in >30% of participants using RWS, compared with <20% for EDSS/SDMT and <10% for T25FW/9HPT. Composite endpoints including RWS identified earlier and more frequent disease progression (p < 0.01). CONCLUSION:Continuous RWS monitoring is more sensitive than conventional metrics for detecting functional decline in PPMS and may strengthen progression endpoints.

BACKGROUND AND OBJECTIVES:Severe optic neuritis (ON) is a common clinical manifestation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD). Given distinct prognoses and often the necessity of early plasma exchange in NMOSD, prompt differentiation is crucial. In this study, we investigated the utility of optical coherence tomography (OCT) in differentiating between first acute NMOSD-ON and MOGAD-associated optic neuritis (MOGAD-ON), as well as specific factors associated with disc edema. METHODS:In this retrospective multicenter study, 111 adult patients with MOGAD or aquaporin-4 antibody-positive NMOSD who experienced a first ON and underwent OCT within 2 weeks of symptom onset were included from 14 centers across 8 countries. Peripapillary retinal nerve fiber layer (pRNFL) thickness in µm was analyzed, including the average of both eyes in cases of bilateral manifestation. RESULTS:Eighty-three patients with MOGAD (51 women; 124 ON eyes; bilateral ON 48.2%) and 28 with NMOSD (24 women; 36 ON eyes; bilateral ON 21.4%) were enrolled. A significant increase in pRNFL thickness (>2SD), suggestive of disc edema, was observed in 73.4% of MOGAD-ON eyes and 11.1% of NMOSD-ON eyes (p < 0.001). The pRNFL thickness cutoff of 117.5 µm provided 92.9% specificity and 71.1% sensitivity in distinguishing between MOGAD-ON and NMOSD-ON (area under the curve = 0.838). There was no association between pRNFL thickening and MOG-IgG titer (high vs low), body mass index, or the delay between ON onset and OCT. Simultaneous bilateral MOGAD-ON was associated with significantly more pronounced pRNFL thickening. DISCUSSION:Acute-stage OCT contributes to the rapid and accurate differentiation between MOGAD-ON and NMOSD-ON prior to antibody confirmation, which can be critical for timely therapeutic decisions.

Background Neuroaxonal and synaptic loss are hallmarks of multiple sclerosis (MS), the most common autoimmune disorder of the central nervous system. However, it remains unclear at which disease stages synaptic pathology occurs. We hypothesised that synaptic proteins in plasma and cerebrospinal fluid (CSF) reflect synaptic injury in MS. Methods To identify synaptic proteins lost during neuroinflammation, we performed proteomic analysis of synaptoneurosomes from mice with experimental autoimmune encephalomyelitis (EAE), the model of MS. The findings were validated by histology in the cortex of EAE mice and postmortem MS tissue. Next, we developed an ELISA with knockout-validated antibodies for the presynaptic protein Bassoon (BSN) and quantified BSN in the cortex, spinal cords and plasma of EAE mice and in the CSF (total n = 30) and serum (total n = 146) of an observational cohort study with people with MS (pwMS) and controls. We further compared longitudinal trajectories of serum BSN (sBSN) and serum neurofilament light chain (sNfL) in a cohort of people with primary progressive MS (PPMS) (n = 26) using linear mixed-effects models. Findings The synaptoneurosome screen revealed reduced levels of several presynaptic proteins, including BSN, in the cortex of EAE mice. The loss of synaptic BSN was validated in EAE and human postmortem tissues of pwMS. Notably, BSN simultaneously accumulated in neuronal soma during EAE and MS, suggesting that BSN may serve as a suitable biomarker for monitoring disease pathology. Our ELISA showed a gradual loss of BSN in the cortex of EAE mice and consistently, plasma BSN levels were elevated in two independent acute and chronic EAE cohorts. In pwMS, BSN was detectable in all CSF samples and in 81% of the serum samples. CSF BSN levels were higher in both relapsing and PPMS compared with controls, whereas sBSN was elevated in secondary progressive MS (SPMS) and PPMS. In the longitudinal PPMS cohort, sBSN and sNfL remained unchanged over an average follow-up of 37 months and did not correlate with each other. Interpretation In conclusion, the presynaptic protein BSN can be quantified in plasma and CSF to assess synaptic pathologies. BSN elevation was already detectable at the earliest disease stages and persisted in progressive MS, underscoring continuous neurodegeneration in MS. Measuring synaptic proteins may complement established biomarkers of neuronal injury to enhance our understanding of neurodegeneration in MS. Funding This work was funded by the Hamburg Innovation Call for Transfer (C4T959 to M.A.F.), Deutschen Multiple Sklerose Gesellschaft (V6.2 to M.A.F.). This work is supported by the Deutsche Forschungsgemeinschaft (FOR 5705, 523862973 to M.A.F., S.C.R., J.B.E.; 247354600, 247377969, 426788273, 518551069, 516868494 to H.S.).

Purpose:To explore the relationship between visual performance and retinal morphology as assessed by optical coherence tomography (OCT), and the ability of OCT to reflect visual impairment in people with multiple sclerosis (PwMS) compared with healthy controls (HC). Methods:We gathered data from two neurology referral centers on PwMS and HC. Neurological and ophthalmological assessments, including OCT, high-contrast visual acuity (HCVA) and low-contrast visual acuity (LCVA), area under the log contrast sensitivity function (AULCSF), and vision-related quality of life (National Eye Institute Visual Function Questionnaire), were conducted between 2018 and 2020, with follow-up at 1 year. Results:A total of 137 PwMS (271 eyes) and 118 HC (236 eyes) were available for analysis. The peripapillary retinal nerve fiber layer (pRNFL) and the macular ganglion cell layer and inner plexiform layer volume (mGCIPL) volume were both reduced in PwMS (92 µm in PwMS vs 98 µm in HC [P < 0.001], 0.55 mm3 vs 0.62 mm3 [P < 0.001], respectively). A cutoff effect for visual impairment was observed in PwMS when pRNFL fell below 68.8 µm (HCVA), 71.4 µm (LCVA), and 72.6 µm (AULCSF). Using mixed effects models, the mGCIPL volume emerged as the variable most strongly associated with the AULCSF (P < 0.001). The AULCSF showed the strongest correlation with both pRNFL and mGCIPL (P < 0.001), with optic neuritis being a significant contributing factor (P < 0.001). Conclusions:AULCSF outperformed standard HCVA and LCVA, closely reflecting retinal atrophy. mGCIPL loss showed stronger associations with vision tests and detected neurodegeneration without the cutoff effect seen in pRNFL, making it the best marker for neuronal atrophy.

In Multiple Sclerosis, inflammation and neurodegeneration disrupt structural and functional brain networks. While the association between structural connectivity and disability is rather clear, functional connectivity changes are not yet characterised as a physiological response to the disease, as functionally meaningful adaptation or as a deceptive response. We explored the topology of brain networks of 65 Multiple Sclerosis patients over up to seven years in comparison to 59 controls. Connectomes based on probabilistic tractography from diffusion weighted imaging and resting-state MRI, were analysed with graph theory. The hub disruption index estimated connectivity perturbation in relation to the network hierarchy. In controls, we observed a transient increase in functional hub connectivity in the 5th and 6th age decade as a response to a subtle diffuse loss of structural connectivity, before structural and functional connectomes show a pronounced loss of hub connectivity. In Multiple Sclerosis, structural hub disruption was present from the disease onset while the transient upregulation of functional hub connectivity in the middle age was lacking. Patients seem to transition directly into an exhausted hub connectivity configuration. However, we observed the transient functional reorganisation of hubs in the first years after disease onset. Multiple Sclerosis patients present a probable physiological response to structural connectivity loss very early in the disease, potentially leading to an accelerated hub overload with accelerated neurodegeneration. The onset of chronic progression in the 5th age decade might be partially driven by the absence of the physiological increased hub connectivity observed in healthy individuals.

The potential benefits of extended-interval dosing (EID) of rituximab (RTX) or ocrelizumab (OCR) in mitigating the reduction of immunoglobulin levels and decreasing the risk of infection in persons with relapsing-remitting multiple sclerosis (pwRRMS) remain largely unknown. We retrospectively analyzed two structured data collections including pwRRMS who were prescribed RTX/OCR using different interval dosing regimens, a 6-month standard-interval dosing (SD) or EID. The SD and EID cohorts included 88 and 271 pwRRMS, respectively, with a mean (SD) treatment duration of 3.5 (1.3) and 4.4 (1.5) years, and a mean (SD) interval between infusions of 6.4 (1.7) and 19.2 (11.9) months. After RTX/OCR initiation, the two cohorts did not differ in time to first relapse (p = 0.83), time to first sustained accumulation of disability (p = 0.98) and incidence of MRI activity (p = 0.91). The time to first severe infectious event (SIE) was shorter in the SD cohort (p = 0.005). The effect of treatment duration on reduction of serum IgG level was lower in the EID cohort (Estimate = 0.15 g/L per year of follow-up, 95 % CI -0.06, -0.23, p = 0.001). In the entire patient group, higher serum IgG levels at the last infusion were associated with a lower risk of SIE between two visits (HR = 0.77 per g/L of serum IgG; 95 % CI: 0.66-0.91; p = 0.006). This study suggests that EID of RTX/OCR may reduce the risk of serum IgG decline in pwRRMS without a loss of efficacy and may mitigate the risk of severe infections. These results must be confirmed by future randomized studies.

Objective:This study analyzed clinical characteristics, attack recovery and long-term disability accumulation in late-onset (LO ≥ 50 years at onset) versus early-onset (EO < 50 years) NMOSD. Methods:This multicenter cohort study included demographic and clinical data from 446 NMOSD patients collected from 35 German Neuromyelitis Optica Study Group (NEMOS) centers. Time to disability milestones was estimated through Kaplan-Meier analysis and Cox proportional hazard regression models adjusted for sex, year of onset, immunotherapy exposure and antibody status. Generalized estimating equations (GEE) were used to compare attack outcomes. Results:Of the 446 NMOSD patients analyzed (83.4% female, 85.4% AQP4-IgG-positive, median age at disease onset = 43 years), 153 had a late-onset (34.3%). AQP4-IgG+ prevalence was higher in LO- than in EO-NMOSD (94.1% vs. 80.9%, p<0.001). Optic neuritis at onset was more frequent in EO-NMOSD (27.4% vs. 42.6%, p<0.002), whereas myelitis was more common in LO-NMOSD (58.4% vs. 37.9%, p<0.001). Both groups had similar annualized attack rates (AAR, 0.51 vs. 0.54, p=0.352), but attack recovery was poorer (complete remission in 15.6% vs. 27.4%, p<0.001) and relapse-associated worsening (RAW) was higher in LO-NMOSD (RAW: 3 vs. 0.5, p<0.001). Long-term immunotherapy use was comparable. LO-NMOSD exhibited faster progression to disability endpoints (EDSS 4: HR = 2.64, 95% CI=1.81-3.84). Interpretation:LO-NMOSD patients presented more often with myelitis, experienced worse attack outcomes and faster disability accumulation, despite comparable AAR, acute attack treatment and long-term treatment regimens. Accordingly, therapeutic strategies for attack and prophylactic treatment in LO-NMOSD have to be improved.

BACKGROUND:Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD. METHODS:The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses. RESULTS:At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance. CONCLUSIONS:Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions.

BACKGROUND AND OBJECTIVES:A simple, quick, and reproducible procedure for distinguishing multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) at inaugural optic neuritis (ION) could be highly valuable in guiding early management. METHODS:We included all adults admitted to the MS center of Marseille for ION between March 2016 and April 2024, with CSF analysis including the kappa free light chain (K-FLC) index. Receiver operating characteristic curves were used to measure the diagnostic ability of the K-FLC index. RESULTS:Two hundred twenty-seven adults were admitted for ION; 210 (93%) had a K-FLC index measurement. MS was diagnosed in 84 (40%); clinically isolated syndrome suggestive of MS in 77 (36.5%), including 20 with future conversion to MS (CISwc); MOGAD in 26 (12.5%); NMOSD in 13 (6%); and other inflammatory disorders in 10 (5%). A K-FLC index ≥6.7 differentiated MS/CISwc from other diagnoses with specificity 86% and sensitivity 95% (area under the curve [AUC] 0.94). A K-FLC index <4.9 differentiated MOGAD from other diagnoses with specificity 63% and sensitivity 92% (AUC 0.78) and MOGAD from MS/CISwc with specificity 96% and sensitivity 92% (AUC 0.97). Among all patients, 93 (44%) had a K-FLC index <4.9: 24 of these (26%) had MOGAD and 5 (5.5%) MS/CISwc. Among the remaining patients with a K-FLC index ≥4.9 (n = 117), 2 (1.7%) had MOGAD (K-FLC index of 7.9 and 16.2) and 99 (85%) MS/CISwc. Among patients with normal MRI (n = 96), 73 (76%) had a K-FLC index <4.9: 22 of these (30%) had MOGAD, and none showed conversion to MS. Among the remaining patients with a K-FLC index ≥4.9 (n = 23), 2 (8.5%) had MOGAD and 7 (30.5%) showed conversion to MS. The K-FLC index did not differentiate NMOSD from other diagnoses and only moderately differentiated NMO from MS/CISwc (AUC 0.80). DISCUSSION:The K-FLC index is an accessible biomarker to guide early diagnosis in patients with ION. The probability of MOGAD in patients with ION and a K-FLC index ≥4.9 is low even in case of normal brain/spinal cord MRI. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for patients with ION, the K-FLC index can distinguish between MS/CISwc and MOGAD.

BackgroundRecurrent attacks in neuromyelitis optica spectrum disorders (NMOSDs) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can lead to severe disability. We aimed to analyse the real-world use of immunotherapies in patients with NMOSD and MOGAD, focusing on changes in treatment strategies, effects on attack rates (ARR) and risk factors for attacks.MethodsThis longitudinal registry-based cohort study included 493 patients (320 with aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive NMOSD (65%), 44 with AQP4-IgG seronegative NMOSD (9%) and 129 MOGAD (26%)) with 1247 treatments from 19 German and one Austrian centre from the registry of the neuromyelitis optica study group (NEMOS). We analysed unadjusted ARR and implemented survival analyses and Cox proportional hazard regression to assess efficiency and risk factors for subsequent attacks over time.ResultsRituximab and azathioprine are the most widely used immunotherapies in NMOSD as well as in MOGAD, with changes in distribution over the last decade. Immunotherapy demonstrated significant therapeutic effects in NMOSD but less pronounced effects in MOGAD. Risk factors for attacks included younger age and prior attacks under the same therapy. Efficacy varied among the different immunotherapies, with azathioprine, rituximab and eculizumab showing significant risk reductions in AQP4-IgG seropositive NMOSD.ConclusionsThis study provides insights into the evolving treatment landscape and effectiveness of immunotherapies in NMOSD and MOGAD. Established off-label therapies continue to play an important role, especially for patients with stable disease, with emerging evidence supporting newly approved therapies. Future studies are needed to refine treatment algorithms and address the ongoing uncertainties in MOGAD management.

Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein IgG-associated disease (MOGAD). This study evaluated the applicability of optical coherence tomography (OCT) for differentiating between both diseases in two independent cohorts. One hundred sixty two patients from seven sites underwent standard OCT and high-contrast visual acuity (HCVA) testing at least 6 months after first ON. Of these, 100 patients (32 MOGAD, 68 MS) comprised the primary investigational cohort, while 62 patients (31 MOGAD, 31 MS) formed a validation cohort. A composite score distinguishing between MOGAD and MS was developed using multivariate logistic regression. Bilateral simultaneous ON occurred more frequently in MOGAD compared to MS (46.9 vs. 11.8