Vaccine Safety and Immunogenicity in Patients With Multiple Sclerosis Treated With Natalizumab.

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.

Prediction of disease activity and treatment failure in relapsing-remitting MS patients initiating daily oral DMTs.

BACKGROUND: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS). OBJECTIVES: We assessed the capacity of available scoring systems to anticipate disease activity parameters in naïve relapsing-remitting MS (RRMS) patients initiating daily oral DMTs, hypothesizing that they exhibit different predictive potentials. METHODS: We conducted a retrospective study and applied the Rio Score (RS), modified Rio Score (mRS), and MAGNIMS Score 12 months after DMT initiation. At 36 months, we examined their ability to predict evidence of disease activity (EDA) components and treatment failure by logistic regression analysis. RESULTS: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7-36.9]) and treatment failure (OR 10.6 [3.4-32.5]) but did not predict radiological activity (OR 1.9 [0.7-5]). The mRS non-responders group did not predict EDA and treatment failure. RS, mRS, and MAGNIMS 0 categories showed significantly lower EDA and treatment failure than the remainder. CONCLUSION: Scoring systems present different predictive abilities for disease activity parameters at 36 months in MS patients initiating daily oral therapies, warranting further adjustments (i.e. introduction of fluid biomarkers) to depict disease activity status fully.

Trans-Synaptic Degeneration in the Visual Pathway in Patients With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

BACKGROUND AND OBJECTIVES: We aimed to assess the presence of retinal neurodegeneration independent of optic neuritis (ON) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to investigate the development of trans-synaptic anterograde degeneration in these patients after ON. METHODS: Cross-sectional, retrospective study of 34 adult patients with MOGAD and 23 healthy controls (HC). Clinical, optical coherence tomography (OCT), and MRI data were collected. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell inner plexiform layer (GCIPL) were obtained using Heidelberg Spectralis. FreeSurfer7 was used to obtain the lateral geniculate nucleus (LGN), occipital volume fractions (to total estimated intracranial volume), and occipital cortical thickness. For the anterior visual pathway, the analysis was conducted using eyes, classified based on the history of ON (Eye-ON and Eye-NON) and compared with Eye-HC. The analysis of OCT and brain volumetric measures was conducted comparing MOGAD-ON, MOGAD-NON, and HC groups. The analysis of covariance with a Bonferroni-adjusted post hoc test was used to test differences between groups and linear regression analysis to evaluate OCT/MRI associations; age and sex were considered as covariates. RESULTS: 24 (70.5%) patients had a prior ON. Median pRNFL and GCIPL thickness (um) was significantly reduced in Eye-ON vs EyeNON and HC (pRNFL: 69.4 (17.3), 89.6 (13.7), 98.2 (11.7), p < 0.001; GCIPL: 55.8 (8.7), 67.39 (8.7), 72.6 (4.5), p < 0.001). pRNFL and GCIPL thickness had a negative correlation with the number of ON episodes (p = 0.025 and p = 0.031, respectively). LGN volume fraction was significantly lower in patients with MOGAD-ON than in HC (0.33 (0.05) vs 0.39 (0.04), p = 0.002). The occipital cortical thickness was lower in MOGAD-ON compared with MOGAD-NON and HC (p = 0.010). In patients with MOGAD-ON, pRNFL correlated with LGN volume (p = 0.006), occipital thickness (p = 0.002), and the medial occipital cortex (p = 0.002), but not the lateral occipital lobe. DISCUSSION: Compared with HC, MOGAD-ON exhibits reduced retinal thickness, primarily influenced by the presence and the number of prior ON episodes. Moreover, MOGAD-ON demonstrates significant atrophy in the retinal, subcortical, and cortical regions of the visual pathway, distinguishing them from MOGAD-NON and HC. These findings suggest that in patients with MOGAD neurodegeneration is tightly correlated with damage to the involved pathway.

Optic nerve topography in multiple sclerosis diagnostic criteria: Existing knowledge and future directions.

Current diagnostic criteria for multiple sclerosis (MS) do not consider the optic nerve as a typical topography for establishing the diagnosis. Recent studies have proved the utility of optic nerve magnetic resonance imaging, optical coherence tomography and visual evoked potentials in detecting optic nerve lesions during the early stages of MS. In addition, emerging evidence supports the inclusion of optic nerve topography as a fifth region to fulfil the dissemination in space criteria. Anticipating a modification in the McDonald criteria, it is crucial for neurologists to familiarize with the diagnostic properties of each test in detecting optic nerve lesions and understand how to incorporate them into the MS diagnostic process. Therefore, the objective of this article is to review the existing evidence supporting the use of these tests in the diagnostic process of MS and provide a practical algorithm that can serve as a valuable guide for clinical practice.

Adding the Optic Nerve in Multiple Sclerosis Diagnostic Criteria: A Longitudinal, Prospective, Multicenter Study

BACKGROUND AND OBJECTIVES: The optic nerve is not one of the areas of the CNS that can be used to demonstrate dissemination in space (DIS) within the 2017 McDonald criteria for the diagnosis of multiple sclerosis (MS). Objectives were (1) to assess whether optic nerve-MRI (ON-MRI), optical coherence tomography (OCT), and visual evoked potentials (VEP) detect optic nerve involvement in clinically isolated syndrome (CIS) and (2) to evaluate the contribution of the optic nerve topography to the current diagnostic criteria in a prospective, multicenter cohort. METHODS: MAGNIMS centers were invited to provide prospective data on patients with CIS who underwent a visual assessment with at least 2 of 3 investigations (ON-MRI, OCT, or VEP) within 6 months of onset. Modified DIS criteria were constructed by adding the optic nerve topography, defined by each investigation separately and any combination of them, as the fifth area of the CNS. A risk assessment analysis and the performance of the different DIS criteria were analyzed using the diagnosis of MS according to the 2017 McDonald criteria as the primary outcome and new T2 lesions and/or a second relapse as the secondary outcome. RESULTS: We included 157 patients with CIS from 5 MAGNIMS centers; 60/157 (38.2%) patients presented with optic neuritis. Optic nerve involvement on ON-MRI was found in 40.2% patients at study entry and in 72.5% of those with optic neuritis.At follow-up (mean 27.9 months, SD 14.5), 111/157 patients (70.7%) were diagnosed with MS according to the 2017 McDonald criteria. Fulfilling either 2017 DIS or any modified DIS criteria conferred a similar high risk for reaching primary and secondary outcomes. The modified DIS criteria had higher sensitivity (92.5% [with ON-MRI] vs 88.2%), but slightly lower specificity (80.0% [with GCIPL IEA ≥4 µm] vs 82.2%), with overall similar accuracy (86.6% [with ON-MRI] vs 86.5%) than 2017 DIS criteria. Consistent results were found for secondary outcomes. DISCUSSION: In patients with CIS, the presence of an optic nerve lesion defined by MRI, OCT, or VEP is frequently detected, especially when presenting with optic neuritis. Our study supports the addition of the optic nerve as a fifth topography to fulfill DIS criteria.

Optic chiasm manual and automated measurements in sub-acute optic neuritis with OCT and MRI correlations.

PURPOSE: The optic chiasm (OC) is a central structure in the visual pathway and can be visualized in conventional MRI, but no consensus regarding its measurement has been defined. We aim to investigate the most reproducible manual approach to OC measurement and to explore associations of OC with optical coherence tomography (OCT) parameters, and automatic brain segmentation (FreeSurfer) in subacute optic neuritis (sON), multiple sclerosis without optic neuritis (MSwoON), and healthy subjects (HS). MATERIALS AND METHODS: We reproduced two previously reported methodologies and implemented a new proposed simplified approach, entitled optic chiasm mean area (OCMA). The intra and inter-rater reliability and reproducibility were assessed through the intraclass correlation (ICC) and Dice similarity (DSC) coefficients. Partial correlations were calculated to gauge the associations between OCMA fraction (OCMA divided by total intracranial volume), brain regional segmentations derived from FreeSurfer, and OCT parameters. RESULTS: We have analysed 43 sON, 20 MSwoON, and 20 HS. OCMA presented better results for reliability in both intra- and inter-rater analysis (excellent ICC and DSC with over 80% overlap between masks), as compared to the other two approaches. OCMA fraction was associated with OC volume fraction obtained with Freesurfer in all groups, brain parenchymal fraction, and OCT parameters in MSwoON. CONCLUSIONS: The OCMA is a simplified approach to measure OC atrophy, has a higher reliability than the current approaches and shows association with an automated method. OC-derived measures seem to reflect diffuse neurodegenerative damage, whereas, in patients with subacute ON, it may be associated with local damage.

Hepatitis B reactivation is a rare event among patients with resolved infection undergoing anti-CD20 antibodies in monotherapy without antiviral prophylaxis: results from the HEBEM study.

INTRODUCTION: Prospective data on the risk of hepatitis B reactivation (HBVr) among patients with resolved HBV infection undergoing anti-CD20 antibodies monotherapy is scarce. We aimed to assess the risk of HBVr in patients with resolved HBV infection treated with rituximab or ocrelizumab in monotherapy for multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) without antiviral prophylaxis. METHODS: HEBEM is a prospective study that included all consecutive adults HBsAg-negative/anti-HBc-positive who initiated anti-CD20 antibodies for MS or NMOSD at Cemcat. Inclusion criteria encompassed undetectable HBV-DNA, absence of other immunosuppressants or antiviral therapy. Every 6 months HBsAg, ALT and HBV-DNA were performed to rule out HBVr (defined by 2-log increase in HBV-DNA or seroconversion to HBsAg+). RESULTS: From August/2019 to August/2022, 540 subjects initiated anti-CD20 antibodies, 28 (5.2%) were anti-HBc-positive and were included. Twenty-two received rituximab and 6 ocrelizumab. The majority (89.3%) had previously received ≥ 1 immunomodulatory drug, with corticosteroids (82.1%) and interferon (42.9%) as the most common. At inclusion, all presented normal transaminases and undetectable HBV-DNA. Median anti-HBs levels were 105.5 mIU/mL (IQR 0-609). Median follow-up was 3.1 years (2.1-4.0). Median number of cycles of anti-CD20 antibodies was 6 (3-7), with a cumulative dose of 8.5 g (5.8-11.2) of rituximab and 3 g (1.8-3.8) of ocrelizumab. Neither cases of HBVr nor changes in anti-HBs titers were observed per 83.6 patient-years treated with monotherapy with anti-CD20 antibodies. CONCLUSIONS: In this cohort of patients with MS or NMOSD and resolved HBV infection, anti-CD20 monotherapy was not associated with detectable risk of HBV reactivation despite the lack of antiviral prophylaxis.

The OSCAR-MP Consensus Criteria for Quality Assessment of Retinal Optical Coherence Tomography Angiography.

BACKGROUND AND OBJECTIVES: Optical coherence tomography angiography (OCTA) is a noninvasive high-resolution imaging technique for assessing the retinal vasculature and is increasingly used in various ophthalmologic, neuro-ophthalmologic, and neurologic diseases. To date, there are no validated consensus criteria for quality control (QC) of OCTA. Our study aimed to develop criteria for OCTA quality assessment. METHODS: To establish criteria through (1) extensive literature review on OCTA artifacts and image quality to generate standardized and easy-to-apply OCTA QC criteria, (2) application of OCTA QC criteria to evaluate interrater agreement, (3) identification of reasons for interrater disagreement, revision of OCTA QC criteria, development of OCTA QC scoring guide and training set, and (4) validation of QC criteria in an international, interdisciplinary multicenter study. RESULTS: We identified 7 major aspects that affect OCTA quality: (O) obvious problems, (S) signal strength, (C) centration, (A) algorithm failure, (R) retinal pathology, (M) motion artifacts, and (P) projection artifacts. Seven independent raters applied the OSCAR-MP criteria to a set of 40 OCTA scans from people with MS, Sjogren syndrome, and uveitis and healthy individuals. The interrater kappa was substantial (κ 0.67). Projection artifacts were the main reason for interrater disagreement. Because artifacts can affect only parts of OCTA images, we agreed that prior definition of a specific region of interest (ROI) is crucial for subsequent OCTA quality assessment. To enhance artifact recognition and interrater agreement on reduced image quality, we designed a scoring guide and OCTA training set. Using these educational tools, 23 raters from 14 different centers reached an almost perfect agreement (κ 0.92) for the rejection of poor-quality OCTA images using the OSCAR-MP criteria. DISCUSSION: We propose a 3-step approach for standardized quality control: (1) To define a specific ROI, (2) to assess the occurrence of OCTA artifacts according to the OSCAR-MP criteria, and (3) to evaluate OCTA quality based on the occurrence of different artifacts within the ROI. OSCAR-MP OCTA QC criteria achieved high interrater agreement in an international multicenter study and is a promising QC protocol for application in the context of future clinical trials and studies.

Global and Regional Deep Learning Models for Multiple Sclerosis Stratification From MRI.

BACKGROUND: The combination of anatomical MRI and deep learning-based methods such as convolutional neural networks (CNNs) is a promising strategy to build predictive models of multiple sclerosis (MS) prognosis. However, studies assessing the effect of different input strategies on model's performance are lacking. PURPOSE: To compare whole-brain input sampling strategies and regional/specific-tissue strategies, which focus on a priori known relevant areas for disability accrual, to stratify MS patients based on their disability level. STUDY TYPE: Retrospective. SUBJECTS: Three hundred nineteen MS patients (382 brain MRI scans) with clinical assessment of disability level performed within the following 6 months (~70% training/~15% validation/~15% inference in-house dataset) and 440 MS patients from multiple centers (independent external validation cohort). FIELD STRENGTH/SEQUENCE: Single vendor 1.5 T or 3.0 T. Magnetization-Prepared Rapid Gradient-Echo and Fluid-Attenuated Inversion Recovery sequences. ASSESSMENT: A 7-fold patient cross validation strategy was used to train a 3D-CNN to classify patients into two groups, Expanded Disability Status Scale score (EDSS) ≥ 3.0 or EDSS < 3.0. Two strategies were investigated: 1) a global approach, taking the whole brain volume as input and 2) regional approaches using five different regions-of-interest: white matter, gray matter, subcortical gray matter, ventricles, and brainstem structures. The performance of the models was assessed in the in-house and the independent external cohorts. STATISTICAL TESTS: Balanced accuracy, sensitivity, specificity, area under receiver operating characteristic (ROC) curve (AUC). RESULTS: With the in-house dataset, the gray matter regional model showed the highest stratification accuracy (81%), followed by the global approach (79%). In the external dataset, without any further retraining, an accuracy of 72% was achieved for the white matter model and 71% for the global approach. DATA CONCLUSION: The global approach offered the best trade-off between internal performance and external validation to stratify MS patients based on accumulated disability. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Myelin Oligodendrocyte Glycoprotein Antibodies in Adults with a First Demyelinating Event Suggestive of Multiple Sclerosis.

OBJECTIVE: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) distinguish multiple sclerosis (MS) from MOG-associated disease in most cases. However, studies analyzing MOG-Ab at the time of a first demyelinating event suggestive of MS in adults are lacking. We aimed to (1) evaluate the prevalence of MOG-Ab in a first demyelinating event suggestive of MS and (2) compare clinical and paraclinical features between seropositive (MOG-Ab+) and seronegative (MOG-Ab-) patients. METHODS: Six hundred thirty adult patients with available serum samples obtained within 6 months from the first event were included. MOG-Ab were analyzed using a live cell-based assay. Statistical analyses included parametric and nonparametric tests, logistic regression, and survival models. RESULTS: MOG-Ab were positive in 17 of 630 (2.7%). Fourteen out of 17 (82.4%) MOG-Ab+ patients presented with optic neuritis (ON) compared to 227of 613 (37.0%) MOG-Ab- patients (p = 0.009). Cerebrospinal fluid-restricted oligoclonal bands (CSF-OBs) were found in 2 of 16 (12.5%) MOG-Ab+ versus 371 of 601 (61.7%) MOG-Ab- subjects (p < 0.001). Baseline brain magnetic resonance imaging (MRI) was normal in 9 of 17 (52.9%) MOG-Ab+ versus 153 of 585 (26.2%) MOG-Ab- patients (p = 0.029). Absence of CSF-OBs and ON at onset were independently associated with MOG-Ab positivity (odds ratio [OR] = 9.03, 95% confidence interval [CI] = 2.04-53.6, p = 0.009; and OR = 4.17, 95% CI = 1.15-19.8, p = 0.042, respectively). Of MOG-Ab+ patients, 22.9% (95% CI = 0.0-42.7) compared to 67.6% (95% CI = 63.3-71.3) of MOG-Ab- patients fulfilled McDonald 2017 criteria at 5 years (log-rank p = 0.003). INTERPRETATION: MOG-Ab are infrequent in adults with a first demyelinating event suggestive of MS. However, based on our results, we suggest to determine these antibodies in those patients with ON and absence of CSF-OBs, as long as the brain MRI is not suggestive of MS. ANN NEUROL 2023.

A single-dose strategy for immunization with live attenuated vaccines is an effective option before treatment initiation in multiple sclerosis patients.

BACKGROUND: Mumps-Measles-Rubella (MMR) and Varicella zoster vaccines (VAR) are live attenuated vaccines, usually administered in a two-dose scheme at least 4 weeks apart. However, single-dose immunization schemes may also be effective and can reduce delays in immunosuppressive treatment initiation in patients with multiple sclerosis (pwMS) who need to be immunized. OBJECTIVES: To evaluate the immunogenicity of a single-dose attempt (SDA) versus the standard immunization scheme (SIS) with VAR and/or MMR in pwMS. METHODS: Retrospective observational study in pwMS vaccinated against VAR and/or MMR. We compared seroprotection rates and antibody geometric mean titers (GMTs) between the two strategies. RESULTS: Ninety-six patients were included. Thirty-one patients received VAR and 67 MMR. In the SDA group, the seroprotection rate was 66.7% (95% confidence interval (CI): 53.3-78.3) versus 97.2% (95% CI: 85.5-99.9) in the SIS (p < 0.001). For the seroprotected patients, GMTs were similar for both schemes. CONCLUSION: An SDA of VAR and/or MMR vaccines could be sufficient to protect almost two-thirds of patients. Testing immunogenicity after a single dose of VZ and/or MMR could be included in routine clinical practice to achieve rapid immunization.

Association of Very Early Treatment Initiation With the Risk of Long-term Disability in Patients With a First Demyelinating Event.

BACKGROUND AND OBJECTIVES: Early treatment is associated with better long-term outcomes in patients with a first demyelinating event and early multiple sclerosis (MS). However, magnetic resonance (MR) findings are not usually integrated to construct propensity scores (PSs) when evaluating outcomes. We assessed the association of receiving very early treatment with the risk of long-term disability including an MR score (MRS) in patients with a first demyelinating event. METHODS: We included 580 patients with a first demyelinating event prospectively collected between 1994 and 2021, who received at least 1 disease-modifying drug (DMD). Patients were classified into tertiles according to the cohort's distribution of the time from the first demyelinating event to the first DMD: first tertile (FT) or very early treatment (6 months; n = 194), second tertile (6.1-16 months, n = 192), and third tertile (TT) (16.1 months, n = 194). A 5-point MRS was built according to the sum of the following indicators: ≥9 brain lesions (1 point); ≥1 infratentorial lesion (1 point); ≥1 spinal cord (SC) lesion (1 point); ≥1 contrast-enhancing (CE) brain lesion (1 point); and ≥1 CE SC lesion (1 point). PS based on covariates and the MRS was computed for each of the outcomes. Inverse PS-weighted Cox and linear regression models assessed the risk of different outcomes between tertile groups. Finally, to confirm the role of MR in treatment decision, we studied the time elapsed from the first demyelinating event to treatment initiation according to the MRS in all patients with radiologic available information, renamed as raw-MRS. RESULTS: Very early treatment decreased the risk of reaching Expanded Disability Status Scale 3.0 (hazard ratio [HR] 0.55, 95% CI 0.32-0.97), secondary progressive MS (HR 0.40, 95% CI 0.19-0.85), and sustained disease progression at 12 months after treatment initiation (HR 0.50, 95% CI 0.29-0.84), when compared with patients from the TT group. Patients from the FT group had a lower disability progression rate (ß estimate -0.009, 95% CI -0.016 to -0.002) and a lower severe disability measured by the Patient-Determined Disease Step (ß estimate -0.52, 95% CI -0.91 to -0.13) than the TT group. Finally, there was a 62.4% reduction in the median time between the first demyelinating event and the first-ever treatment initiation from patients displaying a raw-MRS 1 to patients with a raw-MRS 5. DISCUSSION: Using PS models with and without MRS, we showed that treatment initiation at very early stages is associated with a reduction in the risk of long-term disability accrual in patients with a first demyelinating event. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that earlier treatment of patients with MS presenting with a first demyelinating event is associated with improved clinical outcomes.

Longitudinal stability of inter-eye differences in optical coherence tomography measures for identifying unilateral optic nerve lesions in multiple sclerosis.

INTRODUCTION: Optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell+inner plexiform layer (GCIPL) thickness inter-eye differences (IEDs) are robust measurements for identifying clinical history acute ON in people with MS (PwMS). This study investigated the utility and durability of these measures as longitudinal markers to identify optic nerve lesions. METHODS: Prospective, multi-center international study of PwMS (with/without clinical history of ON) and healthy controls. Data from two sites in the International MS Visual System Consortium (IMSVISUAL) were analyzed. Mixed-effects models were used to compare inter-eye differences based on MS and acute ON history. RESULTS: Average age of those with MS (n = 210) was 39.1 ± 10.8 and 190 (91%) were relapsing-remitting. Fifty-nine (28.1%) had a history of acute unilateral ON, while 9/210 (4.3%) had >1 IB episode. Median follow-up between OCT scans was 9 months. By mixed-effects modeling, IEDs were stable between first and last visits within groups for GCIPL for controls (p = 0.18), all PwMS (p = 0.74), PwMs without ON (p = 0.22), and PwMS with ON (p = 0.48). For pRNFL, IEDs were within controls (p = 0.10), all PwMS (p = 0.53), PwMS without ON history (p = 0.98), and PwMS with history of ON (p = 0.81). CONCLUSION: We demonstrated longitudinal stability of pRNFL and GCIPL IEDs as markers for optic nerve lesions in PwMS, thus reinforcing the role for OCT in demonstrating optic nerve lesions.

Validation of the Spanish version of DYsphagia in MUltiple Sclerosis questionnaire (DYMUS).

BACKGROUND: Dysphagia is a common symptom in multiple sclerosis that can occur even early in the disease course and can lead to serious complications. Early recognition and treatment can promote comfort, safety and optimal nutritional status. Few dysphagia rating scales are available in Spanish. The aim of this study was to translate the Dysphagia in Multiple Sclerosis Questionnaire (DYMUS) into Spanish and to validate it. METHODS: Forward and backward translation method was used to translate the original English version of DYMUS into Spanish. A pilot-study with 10 PwMS was carried on in order to improve the intelligibility of the instrument, comprehensibility and content validity of the questionnaire. The questionnaire was filled out by 100 PwMS who were asked a dichotomous question on their swallowing ("Do you have swallowing troubles?"). Descriptive data are presented as median and quartiles for continuous variables and frequency and percentage for categorical ones. Internal consistency reliability was estimated by Cronbach's alfa. Test-retest reliability was estimated by intraclass correlation coefficient. Concurrent validity with a speech and language therapy assessment (SLT-A) was measured with the weighted kappa statistic for the concordance for both dysphagia type and degree categories. Confirmatory factor analysis by means of structural equation models was used to verify the two-factor (solids and liquids) structure of the DYMUS questionnaire. As the goodness of fit evaluation was poor, an additional exploratory factor analysis was carried out. RESULTS: Internal consistency was high. The globus sensation question and the weight loss questions (item 3 and 10) are the least specific with dysphagia symptomatology so they are worst correlated with the sum of the others (item-rest correlation, 0.243 and 0.248, respectively). The test-retest reliability of the DYMUS among 40 patients using ICC was 0.75 (95% CI 0.57 - 0.86). Concurrent validity with SLT-A was poor (weighted kappa 0.37 for dysphagia type and 0.38 for dysphagia degree). The DYMUS questionnaire detected three times more dysphagia (53% versus 17%) than the dichotomous question. Confirmatory factors analysis failed to confirm the bidimensional structure (solid and liquid items) often reported in other validation studies. The subsequent exploratory factor analysis also identified two factors, but with poor interpretability. CONCLUSION: DYMUS-SP scale is not a sufficiently useful scale to detect dysphagia in PwMS due to the poor concurrent validity and the probable overdiagnosis of the condition; however, it can be helpful as a screening tool when combined with other measures.

Deciphering multiple sclerosis disability with deep learning attention maps on clinical MRI.

The application of convolutional neural networks (CNNs) to MRI data has emerged as a promising approach to achieving unprecedented levels of accuracy when predicting the course of neurological conditions, including multiple sclerosis, by means of extracting image features not detectable through conventional methods. Additionally, the study of CNN-derived attention maps, which indicate the most relevant anatomical features for CNN-based decisions, has the potential to uncover key disease mechanisms leading to disability accumulation. From a cohort of patients prospectively followed up after a first demyelinating attack, we selected those with T1-weighted and T2-FLAIR brain MRI sequences available for image analysis and a clinical assessment performed within the following six months (N = 319). Patients were divided into two groups according to expanded disability status scale (EDSS) score: ≥3.0 and < 3.0. A 3D-CNN model predicted the class using whole-brain MRI scans as input. A comparison with a logistic regression (LR) model using volumetric measurements as explanatory variables and a validation of the CNN model on an independent dataset with similar characteristics (N = 440) were also performed. The layer-wise relevance propagation method was used to obtain individual attention maps. The CNN model achieved a mean accuracy of 79% and proved to be superior to the equivalent LR-model (77%). Additionally, the model was successfully validated in the independent external cohort without any re-training (accuracy = 71%). Attention-map analyses revealed the predominant role of frontotemporal cortex and cerebellum for CNN decisions, suggesting that the mechanisms leading to disability accrual exceed the mere presence of brain lesions or atrophy and probably involve how damage is distributed in the central nervous system.

Using The Virtual Brain to study the relationship between structural and functional connectivity in patients with multiple sclerosis: a multicenter study.

The relationship between structural connectivity (SC) and functional connectivity (FC) captured from magnetic resonance imaging, as well as its interaction with disability and cognitive impairment, is not well understood in people with multiple sclerosis (pwMS). The Virtual Brain (TVB) is an open-source brain simulator for creating personalized brain models using SC and FC. The aim of this study was to explore SC-FC relationship in MS using TVB. Two different model regimes have been studied: stable and oscillatory, with the latter including conduction delays in the brain. The models were applied to 513 pwMS and 208 healthy controls (HC) from 7 different centers. Models were analyzed using structural damage, global diffusion properties, clinical disability, cognitive scores, and graph-derived metrics from both simulated and empirical FC. For the stable model, higher SC-FC coupling was associated with pwMS with low Single Digit Modalities Test (SDMT) score (F=3.48, P$\lt$0.05), suggesting that cognitive impairment in pwMS is associated with a higher SC-FC coupling. Differences in entropy of the simulated FC between HC, high and low SDMT groups (F=31.57, P$\lt$1e-5), show that the model captures subtle differences not detected in the empirical FC, suggesting the existence of compensatory and maladaptive mechanisms between SC and FC in MS.

Spinal cord reserve in multiple sclerosis.

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 mm2 vs 65.02 mm2, p<0.001) was lower in people with MS compared with HC; no differences in SCaA were observed (213.24 mm2 vs 212.61 mm2, 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.

Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis.

Importance: Progression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS). Objective: To investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA. Design, Setting, and Participants: This cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments. Exposures: Exposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA). Main Outcomes and Measures: Expanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0. Results: Of the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P < .001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009). Conclusions and Relevance: Results of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course.