The T1-dark-rim: A novel imaging sign for detecting smoldering inflammation in multiple sclerosis.

PURPOSE: Paramagnetic rim lesions (PRLs), usually identified in susceptibility-weighted imaging (SWI), are a promising prognostic biomarker of disability progression in multiple sclerosis (MS). However, SWI is not routinely performed in clinical practice. The objective of this study is to define a novel imaging sign, the T1-dark rim, identifiable in a standard 3DT1 gradient-echo inversion-recovery sequence, such as 3D T1 turbo field echo (3DT1FE) and explore its performance as a SWI surrogate to define PRLs. METHODS: This observational cross-sectional study analyzed MS patients who underwent 3T magnetic resonance imaging (MRI) including 3DT1TFE and SWI. Rim lesions were evaluated in 3DT1TFE, processed SWI, and SWI phase and categorized as true positive, false positive, or false negative based on the value of the T1-dark rim in predicting SWI phase PRLs. Sensitivity and positive predictive values of the T1-dark rim for detecting PRLs were calculated. RESULTS: Overall, 80 rim lesions were identified in 63 patients (60 in the SWI phase and 78 in 3DT1TFE; 58 true positives, 20 false positives, and two false negatives). The T1-dark rim demonstrated 97% sensitivity and 74% positive predictive value for detecting PRLs. More PRLs were detected in the SWI phase than in processed SWI (60 and 57, respectively). CONCLUSION: The T1-dark rim sign is a promising and accessible novel imaging marker to detect PRLs whose high sensitivity may enable earlier detection of chronic active lesions to guide MS treatment escalation. The relevance of T1-dark rim lesions that are negative on SWI opens up a new field for analysis.

Baseline serum neurofilament light chain levels differentiate aggressive from benign forms of relapsing-remitting multiple sclerosis: a 20-year follow-up cohort.

BACKGROUND AND OBJECTIVES: Serum biomarkers are emerging as useful prognostic tools for multiple sclerosis (MS); however, long-term studies are lacking. We aimed to evaluate the long-term prognostic value of the serum levels of neurofilament light chain (NfL), total tau, glial fibrillary acidic protein (GFAP), and chitinase 3-like-1 (CHI3L1) measured close to the time of MS onset. METHODS: In this retrospective, exploratory, observational, case and controls study, patients with relapsing-remitting MS (RRMS) with available baseline serum samples and prospectively follow-up in our MS unit for a long time were selected based on their clinical evolution to form two groups: (1) a benign RRMS (bRRMS) group, defined as patients with an Expanded Disability Status Scale (EDSS) score of ≤ 3 at ≥ 10 years of follow-up; (2) an aggressive RRMS (aRRMS) group, defined as patients with an EDSS score of ≥ 6 at ≤ 15 years of follow-up. An age-matched healthy control (HC) group was selected. NfL, total tau, and GFAP serum levels were quantified using a single-molecule array (SIMOA), and CHI3L1 was quantified using ELISA. RESULTS: Thirty-one patients with bRRMS, 19 with aRRMS, and 10 HC were included. The median follow-up time from sample collection was 17.74 years (interquartile range, 14.60-20.37). Bivariate and multivariate analyses revealed significantly higher NfL and GFAP levels in the aRRMS group than in the bRRMS group. A receiver operating characteristic curve analysis identified serum NfL level as the most efficient marker for distinguishing aRRMS from bRRMS. DISCUSSION: This proof-of-concept study comparing benign and aggressive RRMS groups reinforces the potential role of baseline NfL serum levels as a promising long-term disability prognostic marker. In contrast, serum GFAP, total tau, and CHI3L1 levels demonstrated a lower or no ability to differentiate between the long-term outcomes of RRMS.

Kappa free light chains index in multiple sclerosis very long-term prognosis.

Introduction: The role of the kappa-free light chain (kFLC) in the diagnosis of multiple sclerosis (MS) and, to a lesser extent, its role as a medium-term prognostic marker have been extensively studied. This study aimed to explore its potential as a long-term prognostic marker for MS. Methods: We performed an exploratory retrospective observational study by selecting patients systemically followed up in our MS unit with available cerebrospinal fluid and serum samples at the time of initial evaluation. Two groups were defined: benign MS (bMS), defined as patients with Expanded Disability Status Scale (EDSS) ≤ 3 at 10 years of follow-up, and aggressive MS (aMS), defined as patients with EDSS ≥ 6 at 15 years of follow-up. Clinical variables were collected, and the immunoglobulin G (IgG) index, kFLC index, and oligoclonal bands (OCB) were determined for all patients and compared between the groups. Results: Twenty bMS and 15 aMS patients were included in this study. Sixty percent (21/35) were female, and the mean age at the time of the first symptom was 31.5 ± 9.45 years, with no statistical differences between groups. Median follow-up time was 19.8 years (Interquartile range, IQR 15.9-24.6). The median EDSS scores at the last follow-up were 1.5 and 7.5 in the bMS and the aMS group, respectively. No statistically significant differences were found in the kFLC index between the two groups (136.6 vs. 140.27, p=0.59). The IgG index was positive in 62.9% of patients (55% bMS vs. 73.3% aMS, p>0.05), and OCB was positive in 88.6% (90% bMS vs. 86.7% aMS, p>0.05). A significant positive correlation was found between IgG and kFLC indices (rs = 0.85, p<0.001). Conclusion: Given the absence of differences between the two groups with opposite disease courses, it is unlikely that the kFLC index is a reliable and powerful marker of long-term prognosis in MS.

Natalizumab continuation versus switching to ocrelizumab after PML risk stratification in RRMS patients: a natural experiment.

BACKGROUND: Natalizumab (NTZ) and ocrelizumab (OCR) can be used for the treatment of relapsing-remitting multiple sclerosis (RRMS). In patients treated with NTZ, screening for JC virus (JCV) is mandatory, and a positive serology usually requires a change in treatment after 2 years. In this study, JCV serology was used as a natural experiment to pseudo-randomize patients into NTZ continuation or OCR. METHODS: An observational analysis of patients who had received NTZ for at least 2 years and were either changed to OCR or maintained on NTZ, depending on JCV serology status, was performed. A stratification moment (STRm) was established when patients were pseudo-randomized to either arm (NTZ continuation if JCV negativity, or change to OCR if JCV positivity). Primary endpoints include time to first relapse and presence of relapses after STRm and OCR initiation. Secondary endpoints include clinical and radiological outcomes after 1 year. RESULTS: Of the 67 patients included, 40 continued on NTZ (60%) and 27 were changed to OCR (40%). Baseline characteristics were similar. Time to first relapse was not significantly different. Ten patients in the JCV + OCR arm presented a relapse after STRm (37%), four during the washout period, and 13 patients in the JCV-NTZ arm (32.5%, p = 0.701). No differences in secondary endpoints were detected in the first year after STRm. CONCLUSIONS: The JCV status can be used as a natural experiment to compare treatment arms with a low selection bias. In our study, switching to OCR versus NTZ continuation led to similar disease activity outcomes.

Influence of Cardiovascular Risk Factors in Early Relapsing-Remitting Multiple Sclerosis: A Retrospective Analysis.

INTRODUCTION: Prior studies have suggested that cardiovascular risk factors (CVRFs) can affect the prognosis of multiple sclerosis (MS). The aim of this study was to assess if CVRFs affect the early course of MS. METHODS: A retrospective observational study was performed, including patients diagnosed with relapsing-remitting MS (RRMS) from 2010 to 2020, with at least 2 years of disease and 6 months follow-up. Age at onset, disease duration, number of relapses, time to confirmed Expanded Disability Status Scale (EDSS) 3.0 and 6.0, and time to secondary progressive MS (SPMS) were collected. Presence and date at onset of hypertension (HT), diabetes mellitus (DM), high low-density lipoprotein cholesterol (LDLc), and smoking during the study period were collected. The primary objective was to assess if CVRFs at the onset of MS are associated with lower time to EDSS 3.0, time to EDSS 6.0, and time to SPMS, using bivariate and multivariate analysis. RESULTS: 281 RRMS patients were included; median age at onset was 33 (IQR 26-39); 69.4% were female. Median EDSS at onset was 1.5 (IQR 1-2.5). Nine patients reached SPMS; 24 patients were diagnosed with HT, 9 with DM, 109 with high LDLc, and 123 were smokers during follow-up. No statistically significant association was found between the presence of CVRF at MS onset and the mentioned clinical outcomes during the MS course. CONCLUSION: No association was found between CVRFs and the early course of MS in our cohort.