The recent SARS-CoV-2 pandemic and related vaccines have raised several issues. Among them, the potential role of the viral infection (COVID-19) or anti-SARS-CoV-2 vaccines as causal factors of dysimmune CNS disorders, as well as the safety and efficacy of vaccines in patients affected by such diseases and on immune-active treatments have been analyzed. The aim is to better understand the relationship between SARS-CoV-2 infection/vaccines with dysimmune CNS diseases by describing 12 cases of multiple sclerosis/myelitis onset or reactivation after exposure to SARS-CoV-2 infection/vaccines and reviewing all published case reports or case series in which MS onset or reactivation was temporally associated with either COVID-19 (8 case reports, 3 case series) or anti-SARS-CoV-2 vaccines (13 case reports, 6 case series). All the cases share a temporal association between viral/vaccine exposure and symptoms onset. This finding, together with direct or immune-based mechanisms described both during COVID-19 and MS, claims in favor of a role for SARS-CoV-2 infection/vaccines in unmasking dysimmune CNS disorders. The most common clinical presentations involve the optic nerve, brainstem and spinal cord. The preferential tropism of the virus together with the presence of some host-related genetic/immune factors might predispose to the involvement of specific CNS districts.

In the 2023 diagnostic criteria, supporting clinical/MRI features are required to diagnose myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in patients at high risk of false MOG-IgG positivity (low/unavailable titer, cerebrospinal fluid-restricted), to help differentiation from multiple sclerosis (MS). However, overlap is possible and determining the frequency of the MOGAD supporting features at MS onset may help prevent misdiagnosis. We assessed the frequency of the MOGAD supporting features and potential risk of misdiagnosis at first attack of MS/clinically isolated syndrome (CIS). In this observational study, we retrospectively identified consecutive patients hospitalized between 2021 and 2024 at 2 Italian centers, with: (1) relapsing-remitting MS/CIS, and (2) first attack MRI available. The frequency of the MOGAD supporting features was assessed at MS/CIS presentation, and potential risk of misdiagnosis determined based on the probability of concurrent false MOG-IgG positivity. Other clinical-MRI features typical of MOGAD but not included in the 2023 diagnostic criteria were also evaluated. A total of 244 patients with MS/CIS were included (median age, 34 [range, 13-78] years; 66% were female). Overall, 65/244 (27%) patients with MS/CIS showed at least 1 MOGAD supporting feature during the presenting attack. "Central cord lesion" (27/82 [33%]) and "deep gray nuclei involvement" (24/86 [28%]) were more represented than other supporting features (0%-7%); p < 0.001. MOG-IgG was tested in 207/244 (85%) patients, showing false positivity in 3 (1.4%) patients. The combined probability of detecting a false MOG-IgG positivity and meeting 1 of the MOGAD supporting features was 0.4%. Among other typical MOGAD features not included in the diagnostic criteria, the following had a 0% frequency at MS/CIS presentation: (1) encephalopathy, (2) marked CSF pleocytosis (>50 cells/mm³), (3) wheelchair need during myelitis, and (4) MRI T2-lesion resolution postattack. Although the MOGAD supporting features can be met in one-fourth of patients at MS/CIS presentation, the risk of misdiagnosis in similar unselected cohorts remains low. Future refinements of the MOGAD supporting features should take into account their relative frequency in MS/CIS and possible integration with additional clinical-MRI features that are more specific for MOGAD.

Cerebrospinal fluid (CSF) oligoclonal IgM bands (OCMBs) have been suggested as prognostic biomarkers in MS, but serum OCMBs meaning is still uncertain. We aimed to assess frequency and clinical relevance of all OCMB patterns. In this retrospective cohort study, 136 paired sera-CSF from consecutive persons with MS (pwMS) were tested in 2 centers for OCMBs using isoelectric focusing-immunoblotting. Active disease was defined as clinical or radiological relapse occurring during two-year follow-up. Predictors of active disease were analyzed with logistic regressions and Kaplan-Meier survival curves. OCMBs were found in 6.6 % of pwMS as unique-to-CSF (pattern #2), and in 20.6 % as identical in serum-CSF (pattern #4), without between-cohort difference. Active disease was more frequent in those with pattern #2 (88.9 %) and #4 (64.3 %) than in those OCMB-negative (33.3 %, p < 0.001). In multivariate analysis, pattern #2 (OR: 15.9; 95 % CI [1.8-136]), and pattern #4 (OR: 3.3 95 % CI [1.3-8.3]) were independent predictors of active disease. In survival analysis, pattern #2 (p < 0.001) and #4 (p = 0.017) predicted radiological relapses. Our data confirm that CSF OCMB marks poor prognosis in MS. However, both OCMB pattern #4 and pattern #2, with different strength prediction, might be useful to stratify pwMS deserving more aggressive treatments, although the stratification could be achieved in the near future with more standardized and easily measurable biomarkers (e.g., serum neurofilaments).

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for both Relapsing and Primary Progressive forms of Multiple Sclerosis (MS) treatment. OCR is postulated to act via rapid B cell depletion; however, by analogy with other anti-CD20 agents, additional effects can be envisaged, such as on Protein Kinase C (PKC). Hence, this work aims to explore novel potential mechanisms of action of OCR in peripheral blood mononuclear cells from MS patients before and after 12 months of OCR treatment. We first assessed, up-stream, PKCβII and subsequently explored two down-stream pathways: hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF), and human antigen R (HuR)/manganese-dependent superoxide dismutase (MnSOD) and heat shock proteins 70 (HSP70). At baseline, higher levels of PKCβII, HIF-1α, and VEGF were found in MS patients compared to healthy controls (HC); interestingly, the overexpression of this inflammatory cascade was counteracted by OCR treatment. Conversely, at baseline, the content of HuR, MnSOD, and HSP70 was significantly lower in MS patients compared to HC, while OCR administration induced the up-regulation of these neuroprotective pathways. These results enable us to disclose the dual positive action of OCR: anti-inflammatory and neuroprotective. Therefore, in addition to B cell depletion, the effect of OCR on these molecular cascades can contribute to counteracting disease progression.

Background: Visual evoked potentials (VEPs) are commonly used in the assessment of optic neuritis (ON) but were not included in the International Consortium for ON (ICON) 2022 diagnostic criteria as supporting tests. Objectives: We aimed to assess VEPs diagnostic performances and their addition to the ICON criteria in a large consecutive cohort of patients with suspected ON. Methods: We screened 207 patients with suspected ON and included 71 who performed MRI, OCT, and VEPs within 30 days from symptoms onset. We calculated diagnostic performances for each test and for the ICON 2022 criteria with and without the addition of VEPs. Results: VEPs had high overall accuracy (88.7%; 95% confidence interval [CI]: 79.0–95.0) and area under the curve in the ROC analysis (0.89, CI: 0.82–0.97]). The addition of VEPs to the ICON 2022 criteria led to an improvement in sensitivity (100.0%, CI: 92.5–100.0), PPV (88.7%, CI: 79.6–94.0) and NPV (100%, CI: 78.2–100.0), maintaining the same specificity (75.0%, CI: 53.2–90.2), improving diagnostic accuracy to 91.5% (CI: 82.5–96.8). Conclusions: VEPs are reliable for the assessment of suspected ON, and they could be considered as a further paraclinical test in the ICON criteria.