Multiple sclerosis (MS) misdiagnosis may cause physical and emotional damage to patients. The objective of this study is to determine the frequency and characteristics of MS misdiagnosis in patients referred to the Multiple Sclerosis Centre of Catalonia. We designed a prospective study including all new consecutive patients referred to our centre between July 2017 and June 2018. Instances of misdiagnosis were identified, and referral diagnosis and final diagnosis were compared after 1 year of follow-up. Association of misdiagnosis with magnetic resonance imaging (MRI) findings, presence of comorbidities and family history of autoimmunity were assessed. A total of 354 patients were referred to our centre within the study period, 112 (31.8%) with ‘established MS’. Misdiagnosis was identified in eight out of 112 cases (7.1%). MRI identified multifocal white matter lesions, deemed non-specific or not suggestive of MS in all misdiagnosed cases. Patients with MS misdiagnosis had more comorbidities in general than patients with MS (p = 0.026) as well as a personal history of autoimmunity (p < 0.001). A low frequency of MS misdiagnosis was found in our clinical setting. Multifocal non-specific white matter lesions in referral MRI examinations and the presence of comorbidities, including a personal history of autoimmunity, seem to be contributing factors to misdiagnosis.

Importance: Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay.Objective: To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment.Design, Setting, and Participants: This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023.Exposures: Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year).Main Outcomes and Measures: Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed.Results: Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment.Conclusions and Relevance: The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

Invasive procedures may delay the diagnostic process in multiple sclerosis (MS). We investigated the added value of serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), chitinase-3-like 1 (sCHI3L1), and the immune responses to the Epstein-Barr virus-encoded nuclear antigen 1 to current MS diagnostic criteria. In this multicentric study, we selected patients from 2 prospective cohorts presenting a clinically isolated syndrome (CIS). Patients were classified as (1) not presenting dissemination in space (DIS) nor dissemination in time (DIT) (noDIS and noDIT); (2) presenting DIS without DIT (DIS and noDIT); and (3) presenting both (DIS and DIT), which were used as a reference. sNfL, sGFAP, and sCHI3L1 levels were measured with single-molecule array immunoassays and EBNA1-specific IgG levels with ELISA. Biomarker levels were compared between groups using linear regression models. Receiver operating characteristic curve analyses and Youden Index were used to determine cutoff values associated with MS diagnosis during follow-up. We included 181 patients (66.3% females, mean [SD] age of 35.0 [9.7] years). At baseline, 25 (13.8%) were classified as noDIS and noDIT, 62 (34.3%) as DIS and noDIT, and 94 (51.9%) as DIS and DIT. Only sNfL Z-scores discriminated between groups (DIS and DIT vs DIS and noDIT [p = 0.002], DIS and DIT vs noDIS and noDIT [p < 0.001], and DIS and noDIT vs noDIS and noDIT [p = 0.026]). In noDIS and noDIT patients (median interquartile range [IQR] follow-up of 8.1 [5.0-11.7] years), high sNfL Z-scores best predicted MS diagnosis (specificity [SP] and 95% CI of 93.3% [68.1-99.8] and positive predictive value [PPV] of 87.5% [47.3-99.7]). Among DIS and noDIT patients (median [IQR] follow-up of 6.8 [4.0-9.1] years), high sNfL Z-scores best predicted MS diagnosis (SP of 80% [28.4-99.5] and PPV of 97.3% [85.8-99.9]) without considering oligoclonal band (OB) status. In the subset of patients of this group with negative OBs, a combination of high sNfL Z-scores and sGFAP levels predicted MS diagnosis (SP of 100% [39.8-100] and PPV of 100% [54.1-100]). These results suggest that sNfL and sGFAP may be incorporated in particular scenarios to diagnose MS in patients with CIS not fulfilling current diagnostic criteria.

Emerging concepts in the early detection of multiple sclerosis (MS) progression reveal that disability accumulation can start early in the disease course. Aging in MS is increasingly recognized as a key factor for disease progression and disability accrual. We evaluate the prognostic impact of age in a cohort of patients experiencing a first demyelinating event (FDE), using a variety of disability outcomes, including some not previously assessed in age-specific studies. Patients aged 18-50 years, assessed within 3 months from the FDE, were prospectively included since 1994 and categorized into 3 age groups: 18-29, 30-39, and 40-50 years. Relapse-associated worsening (RAW) at FDE, annualized relapse rate, and EDSS trajectories during follow-up were compared across age groups. Cox regression analyses adjusted for sex, comorbidities, and time exposed to very high-efficacy drugs were performed to assess the risk of achieving the following outcomes: time to reach McDonald 2017 criteria, first relapse, recurrent RAW, >2 new T2 brain lesions/year, first progression independent of relapse activity (PIRA), confirmed disability accumulation (CDA), and confirmed EDSS score 3.0. Patient-reported outcome measures were also analyzed. A total of 1,170 patients were included (median age 32 years; 69% female). The 40-50 group had a higher proportion of RAW at FDE (34% vs 25% and 29%; p = 0.031) and less time exposed to very high-efficacy treatments (p < 0.001) than the 30-39 and 18-29 groups, respectively. EDSS trajectories in the 40-50 group displayed a greater annual increase in the EDSS score compared with the 18-29 group (β 0.019 [95% CI 0.0001; 0.0387]). Cox analyses (HR; 95% CI) showed that the 40-50 group was at lower risk to reach McDonald 2017 criteria (0.80; 0.67-0.96), first relapse (0.59; 0.47-0.74), recurrent RAW (0.51; 0.31-0.86), or >2 new T2 brain lesions/year (0.39; 0.30-0.52), but at a higher risk of CDA (1.49; 1.16-1.97), PIRA (2.48; 1.88-3.27), and EDSS score 3.0 (1.50; 1.05-2.12), than the 18-29 group. Different functional and well-being variables were more affected in the 40-50 group, compared with 30-39 and 18-29 groups (p values< 0.05). Patients with a FDE at 40-50 years exhibit less inflammatory outcomes compared with younger patients and reach outcomes more closely related to neurodegeneration despite the lower disease activity.