Background: The optic nerve has been recommended as an additional region for demonstrating dissemination in space (DIS) in diagnostic criteria for multiple sclerosis (MS). Objective: To investigate whether adding the optic nerve region as determined by optical coherence tomography (OCT) as part of the DIS criteria improves the 2017 diagnostic criteria. Methods: From a prospective observational study, we included patients with a first demyelinating event who had complete information to assess DIS and a spectral-domain OCT scan obtained within 180 days. Modified DIS criteria (DIS+OCT) were constructed by adding the optic nerve to the current DIS regions based on validated thresholds for OCT inter-eye differences. Time to second clinical attack was the primary endpoint. Results: We analyzed 267 MS patients (mean age 31.3 years [SD 8.1], 69% female) during a median observation period of 59 months (range: 13 - 98). Adding the optic nerve as a fifth region improved the diagnostic performance by increasing accuracy (DIS+OCT 81.2% vs. DIS 65.6%,) and sensitivity (DIS+OCT 84.2% vs. DIS 77.9%) without lowering specificity (DIS+OCT 52.2% vs. DIS 52.2%). Fulfilling DIS+OCT criteria (≥2 of 5 DIS+OCT regions involved) indicated a similar risk of a second clinical attack (HR 3.6, CI 1.4 – 14.5) compared to a 2.5-fold increased risk when fulfilling DIS criteria (HR 2.5, CI 1.2 – 11.8). When the analysis was conducted according to topography of the first demyelinating event, DIS+OCT criteria performed similarly in both optic neuritis and non–optic neuritis. Conclusions: Addition of the optic nerve, assessed by OCT, as a fifth region in the current DIS criteria improves diagnostic performance by increasing sensitivity without lowering specificity. Classification of Evidence: This study provides Class II evidence that adding the optic nerve as determined by optical coherence tomography (OCT) as a fifth dissemination in space (DIS) criterion to the 2017 McDonald criteria improves diagnostic accuracy.

Background and purpose: Long‐term outcome after COVID‐19 in patients with multiple sclerosis (pwMS) has scarcely been studied, and controlled data are lacking. The objective of this study was to compare long‐term outcome after COVID‐19 in pwMS to a matched control group of pwMS without COVID‐19.Methods: We included pwMS with polymerase chain reaction‐confirmed diagnosis of COVID‐19 and ≥6 months of follow‐up and, as a control group, pwMS matched 1:1 for age, sex, disability level, and disease‐modifying treatment type.Results: Of 211 pwMS with COVID‐19 (mean age = 42.6 years [SD = 12.2], 69% female, median Expanded Disability Status Scale = 1.5 [range = 0–7.5], 16% anti‐CD20), 90.5% initially had a mild COVID‐19 course. At follow‐up, 70% had recovered completely 3 months (M3) after COVID‐19, 83% after 6 months (M6), and 94% after 12 months (M12). Mild initial COVID‐19 course was the only significant predictor of complete recovery (odds ratio [OR] = 10.5, p < 0.001). The most frequent residual symptoms were fatigue (M3: 18.5%, M6: 13.7%, M12: 7.3%), hyposmia (M3: 13.7%, M6: 5.2%, M12: 1.7%), and dyspnea (M3: 7.1%, M6: 6.6%, M12: 2.8%). Compared to matched controls, fatigue, hyposmia, and dyspnea were significantly more frequent at M3 and still slightly more frequent at M6, whereas there was no difference at M12. pwMS with COVID‐19 had neither a significantly increased risk for relapses (OR = 1.1, p = 0.70) nor disability worsening (OR = 0.96, p = 0.60).Conclusions: Long‐term outcome of COVID‐19 is favorable in a large majority of pwMS, with only a small proportion of patients suffering from persistent symptoms usually resolving after 3–6 months. COVID‐19 is not associated with increased risk of relapse or disability.

Background: Paramagnetic rim lesions (PRLs) are an imaging biomarker in multiple sclerosis (MS), associated with a more severe disease. Objectives: To determine quantitative magnetic resonance imaging (MRI) metrics of PRLs, lesions with diffuse susceptibility-weighted imaging (SWI)-hypointense signal (DSHLs) and SWI-isointense lesions (SILs), their surrounding periplaque area (PPA) and the normal-appearing white matter (NAWM). Methods: In a cross-sectional study, quantitative MRI metrics were measured in people with multiple sclerosis (pwMS) using the multi-dynamic multi-echo (MDME) sequence post-processing software “SyMRI.” Results: In 30 pwMS, 59 PRLs, 74 DSHLs, and 107 SILs were identified. Beside longer T1 relaxation times of PRLs compared to DSHLs and SILs (2030.5 (1519–2540) vs 1615.8 (1403.3–1953.5) vs 1199.5 (1089.6–1334.6), both p < 0.001), longer T1 relaxation times were observed in the PRL PPA compared to the SIL PPA and the NAWM but not the DSHL PPA. Patients with secondary progressive multiple sclerosis (SPMS) had longer T1 relaxation times in PRLs compared to patients with late relapsing multiple sclerosis (lRMS) (2394.5 (2030.5–3040) vs 1869.3 (1491.4–2451.3), p = 0.015) and also in the PRL PPA compared to patients with early relapsing multiple sclerosis (eRMS) (982 (927–1093.5) vs 904.3 (793.3–958.5), p = 0.013). Conclusion: PRLs are more destructive than SILs, leading to diffuse periplaque white matter (WM) damage. The quantitative MRI-based evaluation of the PRL PPA could be a marker for silent progression in pwMS.

Third vaccination against SARS-CoV-2 is recommended for patients with multiple sclerosis (pwMS), usually six months after the last vaccination. In this prospective multicenter study on 292 pwMS and 46 healthy controls (HC), who had all received two vaccinations prior to study enrollment, SARS-CoV-2 IgG response was measured in the month before and 2–4 months after third vaccination. PwMS were categorized as follows: untreated (N-DMT, n = 32), receiving disease-modifying therapy (DMT) with expected humoral response (er-DMT: interferon-beta preparations, glatiramer acetate, dimethyl fumarate, teriflunomide, natalizumab, cladribine, alemtuzumab; n = 120) or no expected humoral response (nr-DMT: S1PMs, CD20mAb; n = 140). PwMS on nr-DMT had significantly lower median antibody levels before (12.1 U/ml [0.4–2500]) and after third vaccination (305 U/ml [0.4–2500]) in comparison to other groups (p<0.001). We did not find differences in antibody levels after homologous (n = 281; 2500 [0.4–2500]) and heterologous (n = 57; 2500 [0.4–2500]) vaccination regime regardless of the DMT group. The DMT group ($\beta$= –0.60; 95% CI –1195.73, –799.10; p<0.001) was associated with antibody levels after third vaccination, while time to revaccination (6 months [1–13]) was not. After third vaccination, seropositivity was reached in 75.8% and 82.2% of pwMS on anti-CD20 mAbs and S1PMs, respectively. Complete B-cell depletion significantly decreased the probability of seroconversion even after the third vaccination (OR 0.14; p = 0.021), whereas time interval to last DMT intake and time to revaccination did not. Twenty-two patients reported a SARS-CoV-2 infection (3 N-DMT, 9 er-DMT, 10 nr-DMT), one being asymptomatic and the rest having a mild course. Humoral response to SARS-CoV-2 third vaccination in pwMS is excellent. While reduced by S1PMs and CD20mAb, protective response is still expected in the majority of patients

Background: Peripapillary retinal nerve fibre layer and macular ganglion cell plus inner plexiform layer thinning are markers of neuroaxonal degeneration in multiple sclerosis. Objective: We aimed to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning for prediction of long-term disability. Methods: This is a 6-year prospective longitudinal study on 93 multiple sclerosis patients. Optical coherence tomography scans were performed at baseline, after 1, 2 and 6 years. Primary endpoint was disability progression after 6 years, defined as expanded disability status scale worsening and/or cognitive deterioration. Univariate and multivariate analysis was used to investigate the value of peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer to predict the primary endpoint. Results: A total of 57 (61.3%) patients had disability worsening, 40 (43.0%) expanded disability status scale worsening and 34 (36.6%) cognitive deterioration. Mean peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness were 93.0 and 75.2 µm, and mean annualised peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer thinning rates over 6 years were 1.3 and 1.6 µm, respectively. Univariate and multivariate analysis revealed lower peripapillary retinal nerve fibre layer and ganglion cell plus inner plexiform layer baseline thickness and higher annualised thinning rates in patients with disability progression after 6 years. Effects were more pronounced for ganglion cell plus inner plexiform layer and expanded disability status scale worsening than for peripapillary retinal nerve fibre layer models and cognitive deterioration. Conclusion: Ganglion cell plus inner plexiform layer and peripapillary retinal nerve fibre layer measurements depict neurodegeneration and predict disability progression in multiple sclerosis.

Progression independent of relapse activity (PIRA) is increasingly recognized as a key driver of disability in multiple sclerosis (MS). However, the concept of PIRA remains elusive, with uncertainty surrounding its definition, underlying mechanisms, and methods of quantification. This review examines the current landscape of biomarkers used to predict and measure PIRA, focusing on clinical, imaging, and body fluid biomarkers. Clinical disability scores such as the Expanded Disability Status Scale (EDSS) are widely used, but may lack sensitivity in capturing subtle relapse-independent progression. Imaging biomarkers, including MRI-derived metrics (brain and spinal cord volume loss, chronic active lesions) and optical coherence tomography (OCT) parameters (retinal nerve fiber layer and ganglion cell-inner plexiform layer thinning), offer valuable insights, but often reflect both inflammatory and neurodegenerative processes. Body fluid biomarkers, such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), are promising indicators of axonal damage and glial activation, but their specificity for PIRA remains limited. This review emphasizes the distinction between predicting PIRA—identifying individuals at risk of future progression—and measuring ongoing PIRA-related disability in real time. We highlight the limitations of current biomarkers in differentiating PIRA from relapse-associated activity and call for a clearer conceptual framework to guide future research. Advancing the precision and utility of PIRA biomarkers will require multimodal approaches, longitudinal studies, and standardized protocols to enable their clinical integration and to improve personalized MS management.