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Background: A randomized trial of phenytoin in acute optic neuritis (ON) demonstrated a 30% reduction in retinal nerve fiber layer (RNFL) loss with phenytoin versus placebo. Here we present the corresponding serum neurofilament analyses. Methods: Eighty‐six acute ON cases were randomized to receive phenytoin (4–6 mg/kg/day) or placebo for 3 months, and followed up for 6 months. Serum was collected at baseline, 3 and 6 months for analysis of neurofilament heavy chain (NfH) and neurofilament light chain (NfL). Results: Sixty‐four patients had blood sampling. Of these, 58 and 56 were available at 3 months, and 55 and 54 were available at 6 months for NfH and NfL, respectively. There was no significant correlation between serum NfH and NfL at the time points tested. For NfH, the difference in mean placebo – phenytoin was −44 pg/ml at 3 months (P = 0.019) and −27 pg/ml at 6 months (P = 0.234). For NfL, the difference was 1.4 pg/ml at 3 months (P = 0.726) and −1.6 pg/ml at 6 months (P = 0.766). Conclusions: At 3 months, there was a reduction in NfH, but not NFL, in the phenytoin versus placebo group, while differences at 6 months were not statistically significant. This suggests a potential neuroprotective role for phenytoin in acute ON, with the lower NfH at 3 months, when levels secondary to degeneration of the anterior visual pathway are still elevated, but not at 6 months, when levels have normalized. [ABSTRACT FROM AUTHOR]

Background and purpose: To investigate the relation of age at disease onset and clinical outcomes across the lifespan from adolescence in patients with multiple sclerosis (MS) on disease‐modifying therapy (DMT). Methods: We analysed data from the Swiss Association for Joint Tasks of Health Insurers database containing data from 14 718 patients with MS. Patients were included in this analysis when they were on DMT for at least 1 year. The influence of age at disease onset on future relapses and disability worsening was explored using multivariable Cox proportional hazard regression models. Results: Data from 9705 patients with MS were analysed. Pediatric‐onset MS patients (n = 236) had higher relapse rates and marginally slower disability worsening rates compared with adult‐onset MS (n = 9469). The risk of relapses was highest in childhood and decreased continuously to about 35 years of age. It remained stable for about a decade and then again continuously decreased. In contrast, disability worsening hazards remained stable from childhood to about 32 years of age and then increased sharply around the age of 45 years. Conclusions: Age is an important factor independently affecting clinical outcomes in MS. This should be considered when designing clinical trials or choosing DMT. [ABSTRACT FROM AUTHOR]

Background and purpose: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti‐inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti‐inflammatory disease‐modifying treatment on disability outcomes in PPMS. Methods: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease‐modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention‐to‐treat and an as‐treated approach in paired, pairwise‐censored analyses. Results: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on‐study pairwise‐censored follow‐up was 3.4 years (quartiles 1.2–5.5). No difference in the hazard of experiencing 3‐month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6–1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6–1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7–1.6, P = 0.69). Conclusion: Our pooled analysis of disease‐modifying agents suggests that these therapies have no substantial effect on short‐ to medium‐term disability outcomes in PPMS. [ABSTRACT FROM AUTHOR]

Background and purpose N-acetyl aspartate ( NAA) assessed using proton magnetic resonance spectroscopy (1H MRS) has a high pathological specificity for axonal density. Retinal nerve fibre layer thickness ( RNFLT) measured by using optical coherence tomography is increasingly used as a surrogate marker of neurodegeneration in multiple sclerosis ( MS). Our aim was to investigate the relation between RNFLT and NAA/creatine in brain normal-appearing white matter ( NAWM), their dynamics over time and the association with clinical outcome measures in relapsing MS. T2 WM lesions served as control tissue. Methods Forty-three MS patients underwent standardized neurological examination including the Expanded Disability Status Scale ( EDSS), Multiple Sclerosis Functional Composite ( MSFC) score, optical coherence tomography and magnetic resonance imaging including 1H MRS at baseline and after 1 year. Results At baseline, NAA/creatine level was lower in T2 WM lesions than in NAWM (1.64 ± 0.16 vs. 1.88 ± 0.24, P < 0.001). Lowest levels were found in secondary progressive MS ( SPMS). Mean RNFLT was higher in clinically isolated syndrome than in the combined group of relapsing−remitting MS and SPMS (99.8 ± 12.3 μm vs. 92.4 ± 12.8 μm, P = 0.038). In all patients, mean RNFLT decreased by 1.4% during follow-up. At baseline, MSFC z-scores correlated with NAA/creatine levels both in NAWM ( r = 0.42; P = 0.008) and T2 WM lesions ( r = 0.52, P = 0.004). NAWM NAA/creatine variation correlated with the RNFLT change over 1 year ( ρ = 0.43, P = 0.046). Conclusions N-acetyl aspartate/creatine level reduction correlated with RNFLT thinning over 1 year in an EDSS stable MS cohort suggesting that these techniques might be sensitive to detect subclinical disease progression. [ABSTRACT FROM AUTHOR]

Background and Purpose: In relapsing-remitting multiple sclerosis (RRMS), analyses from observational studies comparing dimethyl fumarate (DMF) and teriflunomide showed conflicting results. We aimed to compare the effectiveness of DMF and teriflunomide in a real-world setting, where both drugs are licensed as first-line therapies for RRMS., Methods: We included all patients who initiated DMF or teriflunomide between 2013 and 2022, listed in the Swiss National Treatment Registry. Coarsened exact matching was applied using age, gender, disease duration, baseline Expanded Disability Status Scale (EDSS) score, time since last relapse, and relapse rate in the previous year as matching variables. Time to relapse and time to 12-month confirmed EDSS worsening were compared using Cox proportional hazard models., Results: In total, 2028 patients were included in this study, of whom 1498 were matched (DMF: n = 1090, 69.6% female, mean age 45.1 years, median EDSS score 2.0; teriflunomide: n = 408, 68.9% female, mean age 45.1 years, median EDSS score 2.0). Time to relapse and time to EDSS worsening was longer in the DMF than the teriflunomide group (hazard ratio 0.734, p = 0.026 and hazard ratio 0.576, p = 0.003, respectively)., Conclusion: Analysis of real-world data showed that DMF treatment was associated with more favorable outcomes than teriflunomide treatment., (© 2023 European Academy of Neurology.)

Background: The neurofilament light chain (NfL) assay is gradually becoming an essential diagnostic tool for the diagnosis of many neurological diseases including amyotrophic lateral sclerosis (ALS). Different methods for the determination of this biomarker in serum have been developed in recent years., Methods: We measured blood NfL in 429 patients referred to the tertiary ALS center of Montpellier, France using two different ultrasensitive methods (Ella™ and Simoa™) and we compared the clinical performances of these two approaches. We also converted NfL values into age and body mass index-adjusted Z-scores to assess cut-off values of this biomarker in this clinical context., Results: We show comparable diagnostic and prognostic performance of Ella™ and Simoa™ technologies in ALS, with specificities and sensitivities exceeding 80% for both. We propose cut-off values for serum NfL in this clinical context, thus enabling the routine clinical use of this biomarker., Conclusion: The use of NfL in routine clinical practice will help predict survival and improve diagnostic accuracy by distinguishing ALS from other neurological diseases and motor neuron disease mimics., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution., Methods: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses., Results: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient βj = -0.352, p < 0.001), white matter (βj = -0.229, p = 0.007), thalamus (βj = -0.372, p = 0.004), and putamen (βj = -1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p = 0.007)., Conclusions: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: In an era of individualized multiple sclerosis (MS) patient management, biomarkers for accurate prediction of future clinical outcomes are needed. We aimed to evaluate the potential of short-term magnetic resonance imaging (MRI) atrophy measures and serum neurofilament light chain (sNfL) as predictors of the dynamics of disability accumulation in relapse-onset MS., Methods: Brain gray and white matter, thalamic, striatal, pallidal and cervical spinal cord volumes, and lesion load were measured over three available time points (mean time span 2.24 ± 0.70 years) for 183 patients (140 relapsing-remitting [RRMS] and 43 secondary-progressive MS (SPMS); 123 female, age 46.4 ± 11.0 years; disease duration 15.7 ± 9.3 years), and their respective annual changes were calculated. Baseline sNfL was also measured at the third available time point for each patient. Subsequently, patients underwent annual clinical examinations over 5.4 ± 3.7 years including Expanded Disability Status Scale (EDSS) scoring, the nine-hole peg test and the timed 25-foot walk test., Results: Higher annual spinal cord atrophy rates and lesion load increase predicted higher future EDSS score worsening over time in SPMS. Lower baseline thalamic volumes predicted higher walking speed worsening over time in RRMS. Lower baseline gray matter, as well as higher white matter and spinal cord atrophy rates, lesion load increase, baseline striatal volumes and baseline sNfL, predicted higher future hand dexterity worsening over time. All models showed reasonable to high prediction accuracy., Conclusion: This study demonstrates the capability of short-term MRI metrics to accurately predict future dynamics of disability progression in a real-world relapse-onset MS cohort. The present study represents a step towards the utilization of structural MRI measurements in patient care., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Natural killer (NK) cells may play a role in multiple sclerosis (MS). Ratios of NK cells to CD4 + T cells have been proposed as a biomarker for the therapeutic effect of stem cell transplantation in MS. The objectives here were to explore the relevance of this ratio in MS patients by analysing NK and T cell subsets, as well as their prognostic value for disease activity., Methods: Baseline peripheral blood mononuclear cells of 50 relapsing-remitting MS patients, participating in our vitamin D supplementation study (SOLARIUM), were analysed with flow cytometry. Disease activity was measured as new magnetic resonance imaging lesions, relapses and mean plasma neurofilament light chain levels after 48 weeks of follow-up., Results: The proportion of NK cells correlated negatively with CD4 + T cells (R = -0.335, p = 0.001) and interleukin 17A (IL-17A + ) CD4 + T cells (R = -0.203, p = 0.043). Participants with magnetic resonance imaging activity or relapses displayed lower NK/IL-17A +  CD4 + T cell ratios (p =0.025 and p = 0.006, respectively). The NK/IL-17A +  CD4 + T cell ratio correlated negatively with neurofilament light chain levels (R = -0.320, p = 0.050). Vitamin D supplementation did not affect these ratios., Conclusions: Our data suggest a protective role of an expanded NK cell compartment compared to the CD4 + T cell subset fractions in relapsing-remitting MS patients. NK/CD4 + T cell ratios may be a prognostic biomarker for disease activity in MS., (© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)