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Background: The spinal cord (SC) is a preferential target of multiple sclerosis (MS) damage highly relevant towards disability. Differential impact of such damage could be due to the initial amount of SC tissue, as described for the brain parenchyma (brain reserve concept). We aimed to test the existence of SC reserve by using spinal canal area (SCaA) as a proxy., Methods: Brain sagittal three-dimensional T1-weighted scans covering down to C5 level were acquired in 2930 people with MS and 43 healthy controls (HCs) in a cross-sectional, multicentre study. SC area (SCA) and SCaA were obtained with the Spinal Cord Toolbox. Demographical data and patient-derived disability scores were obtained. SC parameters were compared between groups with age-adjusted and sex-adjusted linear regression models. The main outcome of the study, the existence of an association between SCaA and Patient Determined Disease Steps, was tested with scaled linear models., Results: 1747 persons with MS (mean age: 46.35 years; 73.2% female) and 42 HCs (mean age: 45.56 years; 78.6% female) were analysed after exclusion of post-processing errors and application of quality criteria. SCA (60.41 mm 2 vs 65.02 mm 2 , p<0.001) was lower in people with MS compared with HC; no differences in SCaA were observed (213.24 mm 2 vs 212.61 mm 2 , p=0.125). Adjusted scaled linear models showed that a larger SCaA was significantly associated with lower scores on Patient Determined Disease Steps (beta coefficient: -0.12, p=0.0124) independently of spinal cord atrophy, brain T2 lesion volume, age and sex., Conclusions: A larger SCaA may be protective against disability in MS, possibly supporting the existence of SC reserve., Competing Interests: Competing interests: JS-G declares fees from Sanofi, Biogen, Celgene, Merck, Biopass, Novartis and Roche, outside the submitted work. AR serves on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche, Biogen and OLEA Medical, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche and Biogen. He is also member of the editorial board of Neurology and Neuroradiology, and member of the executive committee of the International Society of Radiology (ISR) and of MAGNIMS. AG-V has nothing to disclose. PC-M has nothing to disclose. MA has nothing to disclose. AV-J has received support has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organised by Roche, Novartis, Merck and Sanofi. CA declares that she has no conflict of interest. MT reports personal fees from Almirall, Bayer Healthcare, Biogen Idec, Merck-Serono, Novartis, Roche, Viela-Bio, Sanofi–Genzyme and Teva, grants from Sanofi-Genzyme, and other competing interests related to Biogen Idec, outside the submitted work. XMo reports personal fees from and other competing interests related to Actelion, Alexion, Biogen, Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Medday, Merck, Mylan, Nervgen, Novartis, Sanofi-Genzyme, Teva Pharmaceutical and TG Therapeutics and grants received through the institutions from AbbVie, Biogen, Hoffmann-La Roche, Medday, Merck, Novartis, Sanofi-Genzyme and Teva Pharmaceutical, outside the submitted work. DP reports personal fees from Novartis and Sanofi-Genzyme, outside the submitted work., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: It remains unclear whether viral infections interfere with multiple sclerosis (MS) disease progression. We evaluated the prognostic role of antibody responses toward viruses determined at disease onset on long-term disease outcomes., Methods: Humoral immune responses against Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1, viral capsid antigen (VCA) and early antigen, and toward cytomegalovirus (HCMV), human herpesvirus 6 and measles were investigated in a cohort of 143 patients with MS for their association with long-term disability and inflammation disease outcomes., Results: Median (IQR) follow-up was 20 (17.2-22.8) years. In univariable analysis, increased HCMV levels were associated with a lower risk to Expanded Disability Status Scale 4.0 (HR 0.95; 95% CI 0.91 to 0.99; p=0.03), to develop a secondary progressive MS (HR 0.94; 95% CI 0.90 to 0.99; p=0.02) and to first-line treatment (HR 0.98; 95% CI 0.96 to 0.99; p=0.04). High HCMV IgG levels were associated with a longer time to first-line treatment (p=0.01). Increased immune responses against EBV-VCA were associated with higher risk for first-line (HR 1.45; 95% CI 1.12 to 1.88; p=0.005) and second-line treatments (HR 2.03; 95% CI 1.18 to 3.49; p=0.01), and high VCA IgG levels were associated with shorter time to first-line (p=0.004) and second-line (p=0.02) therapies. EBNA1-specific IgG levels correlated with disease severity (0.17; p=0.04) and with an increased relapse rate during follow-up (relapse rate 1.26; 95% CI 1.03 to 1.56; p=0.02) that remained stable in multivariable analysis., Conclusions: These results indicate that elevated immune responses against HCMV at disease onset have protective effects on long-term disability and inflammation disease outcomes. Our data also indicate that increased immune responses against EBV in early phases may influence long-term disease prognosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

ObjectiveThere is a lack of sensitive and specific biomarkers for use in progressive multiple sclerosis (MS). The study aimed to assess the potential of serum neurofilament light chain (sNfL) levels as biomarker of disability progression in patients with progressive MS., Methods: We performed a prospective observational cohort study in 51 patients with progressive MS who participated in a 2-year phase II single-centre, randomised, double-blind, placebo-controlled trial of interferon-beta. Mean (SD) follow-up duration was 13.9 (6.2) years. Levels of sNfL were measured using a single molecule array immunoassay at baseline, 1, 2 and 6 years. Univariable and multivariable analyses were carried out to evaluate associations between sNfL levels and disability progression at short term (2 years), medium term (6 years) and long term (at the time of the last follow-up)., Results: A sNfL cut-off value of 10.2 pg/mL at baseline discriminated between long-term progressors and non-progressors with a 75% sensitivity and 67% specificity (adjusted OR 7.8; 95% CI 1.8 to 46.4; p=0.01). Similar performance to discriminate between long-term progressors and non-progressors was observed using age/body mass index-adjusted sNfL Z-scores derived from a normative database of healthy controls. A cut-off increase of 5.1 pg/mL in sNfL levels between baseline and 6 years also discriminated between long-term progressors and non-progressors with a 71% sensitivity and 86% specificity (adjusted OR 49.4; 95% CI 4.4 to 2×10 3 ; p=0.008)., Conclusions: sNfL can be considered a prognostic biomarker of future long-term disability progression in patients with progressive MS. These data expand the little knowledge existing on the role of sNfL as long-term prognostic biomarker in patients with progressive MS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)