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The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. "Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.

BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P = 0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders. [ABSTRACT FROM AUTHOR]

Background: While standard clinical assessments provide great value for people with multiple sclerosis (PwMS), they are limited in their ability to characterize patient perspectives and individual-level symptom heterogeneity., Objectives: To identify PwMS subgroups based on patient-reported outcomes (PROs) of physical, cognitive, and emotional symptoms. We also sought to connect PRO-based subgroups with demographic variables, functional impairment, hypertension and smoking status, traditional qualitative multiple sclerosis (MS) symptom groupings, and neuroperformance measurements., Methods: Using a cross-sectional design, we applied latent profile analysis (LPA) to a large database of PROs; analytic sample N = 6619)., Results: We identified nine distinct MS subtypes based on PRO patterns. The subtypes were primarily categorized into low, moderate, and high mobility impairment clusters. Approximately 70% of participants were classified in a low mobility impairment group, 10% in a moderate mobility impairment group, and 20% in a high mobility impairment group. Within these subgroups, several unexpected patterns were observed, such as high mobility impairment clusters reporting low non-mobility impairment., Conclusions: The present study highlights an opportunity to advance precision medicine approaches in MS. Combining PROs with data-driven methodology allows for a cost-effective and personalized characterization of symptom presentations. that can inform clinical practice and future research designs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: Paramagnetic rim lesions (PRLs) are an MRI biomarker of chronic inflammation in people with multiple sclerosis (MS). PRLs may aid in the diagnosis and prognosis of MS. However, manual identification of PRLs is time-consuming and prone to poor interrater reliability. To address these challenges, the Automated Paramagnetic Rim Lesion (APRL) algorithm was developed to automate PRL detection. The primary objective of this study is to evaluate the accuracy of APRL for detecting PRLs in a multicenter setting., Methods: We applied APRL to a multicenter dataset, which included 3-Tesla MRI acquired in 92 participants (43 with MS, 14 with clinically isolated syndrome [CIS]/radiologically isolated syndrome [RIS], 35 without RIS/CIS/MS). Subsequently, we assessed APRL's performance by comparing its results with manual PRL assessments carried out by a team of trained raters., Results: Among the 92 participants, expert raters identified 5637 white matter lesions and 148 PRLs. The automated segmentation method successfully captured 115 (78%) of the manually identified PRLs. Within these 115 identified lesions, APRL differentiated between manually identified PRLs and non-PRLs with an area under the curve (AUC) of .73 (95% confidence interval [CI]: [.68, .78]). At the subject level, the count of APRL-identified PRLs predicted MS diagnosis with an AUC of .69 (95% CI: [.57, .81])., Conclusion: Our study demonstrated APRL's capability to differentiate between PRLs and lesions without paramagnetic rims in a multicenter study. Automated identification of PRLs offers greater efficiency over manual identification and could facilitate large-scale assessments of PRLs in clinical trials., (© 2024 American Society of Neuroimaging.)

Background: Effective communication between providers and people with multiple sclerosis (pwMS) is essential., Objectives: To determine the level of concordance between provider- and pwMS-reported disease course., Methods: Patient encounters from December 2015 through April 2020 were retrospectively reviewed for MS disease course self-reported by the patient and separately documented by the provider at each visit. The proportion of agreement was compared across disease course Cohen's kappa, and subsequently stratified by sex, race, and level education., Results: Across 1335 encounters, the proportion of disease course agreement varied. Compared with RRMS, there was statistically significant difference across all other disease courses. Overall concordance between providers and pwMS was 64 % with a Cohen's kappa of 0.312. Concordance was higher amongst female patients, black patients, and patients with a higher level of education (>14 years)., Conclusion: Overall agreement on MS disease course amongst patients and providers was suboptimal. A concerted effort to understand these discrepancies is needed., Competing Interests: Declaration of competing interest Dr. Aboseif has no disclosures. Dr. Amin received a Novartis fellowship award (NGC44741). Dr. Macaron has served on advisory boards for Biologix, Genentech-Roche, Merck, and Novartis; received speaker fees from Biologix, Merck, and Novartis; and participated in educational activities for Neurology Live and John Hopkins's e-Literature Review. Dr. Ontaneda receives research support from Genentech, Genzyme, National Institutes of Health, National Multiple Sclerosis Society, Novartis Patient Centered Outcomes Research Institute, and Race to Erase MS Foundation. He has received consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Janssen, Merck, and Novartis., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The use of ultra-high-field 7-Tesla (7T) MRI in multiple sclerosis (MS) research has grown significantly over the past two decades. With recent regulatory approvals of 7T scanners for clinical use in 2017 and 2020, the use of this technology for routine care is poised to continue to increase in the coming years. In this context, the North American Imaging in MS Cooperative (NAIMS) convened a workshop in February 2023 to review the previous and current use of 7T technology for MS research and potential future research and clinical applications. In this workshop, experts were tasked with reviewing the current literature and proposing a series of consensus statements, which were reviewed and approved by the NAIMS. In this review and consensus paper, we provide background on the use of 7T MRI in MS research, highlighting this technology's promise for identification and quantification of aspects of MS pathology that are more difficult to visualize with lower-field MRI, such as grey matter lesions, paramagnetic rim lesions, leptomeningeal enhancement and the central vein sign. We also review the promise of 7T MRI to study metabolic and functional changes to the brain in MS. The NAIMS provides a series of consensus statements regarding what is currently known about the use of 7T MRI in MS, and additional statements intended to provide guidance as to what work is necessary going forward to accelerate 7T MRI research in MS and translate this technology for use in clinical practice and clinical trials. This includes guidance on technical development, proposals for a universal acquisition protocol and suggestions for research geared towards assessing the utility of 7T MRI to improve MS diagnostics, prognostics and therapeutic efficacy monitoring. The NAIMS expects that this article will provide a roadmap for future use of 7T MRI in MS., Competing Interests: D.M.H. has received research funding from EMD-Serono and Roche-Genentech, consulting fees from Horizon Therapeutics, TG Therapeutics and EMD-Serono and royalties from Up To Date, Inc. F.B. has received speaker honoraria from EMD-Serono, Sanofi and Novartis and serves/ed as site PI of multi-centre studies sponsored by EMD-Serono and Novartis and on advisory boards for Sanofi, EMD-Serono and Biogen. S.N. has received research funding from Roche-Genentech and Immunotec, consulting fees from Sana Biotechnology and personal compensation from NeuroRx Research. S.G. has received research funding from Roche-Genentech. E.S.B. has received consulting fees from EMD-Serono. .J.Z. has received research support from Novartis, I-Mab Biopharma and the Race to Erase MS Foundation. R.B. has received speaking honoraria from EMD-Serono and research support from Bristol-Myers Squibb, EMD-Serono and Novartis. A.C. was supported by the ECTRIMS post-doctoral training fellowship (2022). A.C. has received speaker honoraria from Novartis. S.Y.H. has received research funding and consulting fees from Siemens Healthineers. The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; and (iii) research support from Siemens, GeNeuro and Roche. E.C.K. has received research funding from Abbvie, Biogen and Genentech and consulting fees from EMD-Serono, Genentech, INmune Bio, Myrobalan Therapeutics, OM1, Inc. and TG Therapeutics. C.M. has received research funding from Genentech-Roche. C.L., J.D., M.D., D.A.R. and P.B. have no disclosures to report., (Published by Oxford University Press on behalf of the Guarantors of Brain 2024.)

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs., (© 2024. Springer Nature Limited.)

The differential diagnosis of suspected multiple sclerosis has been developed using data from North America, northern Europe, and Australasia, with a focus on White populations. People from minority ethnic and racial backgrounds in regions where prevalence of multiple sclerosis is high are more often negatively affected by social determinants of health, compared with White people in these regions. A better understanding of changing demographics, the clinical characteristics of people from minority ethnic or racial backgrounds, and the social challenges they face might facilitate equitable clinical approaches when considering a diagnosis of multiple sclerosis. Neuromyelitis optica, systemic lupus erythematous, neurosarcoidosis, infections, and cerebrovascular conditions (eg, hypertension) should be considered in the differential diagnosis of multiple sclerosis for people from minority ethnic and racial backgrounds in North America, northern Europe, and Australasia. The diagnosis of multiple sclerosis in people from a minority ethnic or racial background in these regions requires a comprehensive approach that considers the complex interplay of immigration, diagnostic inequity, and social determinants of health., Competing Interests: Declaration of interests LA has received research support from the National Multiple Sclerosis Society, National Institutes of Health National Institute of Neurological Disorders and Stroke, Bristol Myers Squibb Foundation, Race to Erase MS Foundation, and Biogen Idec; is a local Principal Investigator for commercial trials funded by Genentech, Sanofi, and Genzyme; and declares consulting fees from Biogen Idec, Novartis, Genentech, and EMD Serono. DR has received research support from MS Canada, the National Multiple Sclerosis Society, Consortium of Multiple Sclerosis Centers, University of Toronto Division of Neurology, and Roche Canada; and has received speaker or consultant fees from Alexion, Biogen, EMD Serono, Horizon Therapeutics, Novartis, Roche, and Sanofi Aventis. OC is a member of the data and safety monitoring board for Novartis, has served on one advisory board for Biogen, and has received a speaker honorarium from Merck. DO has received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis; and has received consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Genzyme, Janssen, Novartis, and Merck. MM has served on scientific advisory boards for Sanofi, Novartis, and Merck; and received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, and Bristol Myers Squibb. VR has received honoraria from the Autonomous University of Barcelona, Roche, Corne Neurosciences, and the Multiple Sclerosis Association of America; and is a consultant (Expert Opinion Program) for Teladoc Health International. DK has served as a consultant for CVS Health. RD has received research support from the UK MS Society, National Multiple Sclerosis Society, BMA Foundation, Horne Family Charitable Foundation, Biogen, and Merck; and has received honoraria for advisory boards and educational activities from Biogen, Novartis, Sandoz, Roche, Janssen, and Merck. MW is a co-investigator for a study funded by Genentech; has received honoraria and consulting fees from Alexion, Biogen Idec, Novartis, Genentech, Horizon Therapeutics, EMD Serono, Octave Biosciences, TG Therapeutics, and Sanofi/Genzyme; and has participated in speakers bureau for Biogen Idec, Genentech, EMD Serono, and TG Therapeutics. RAM is a co-investigator on a study funded in part by Biogen and Roche (no funds to her or her institution). JAC has received personal compensation for consulting for Biogen, Convelo, EMD Serono, Gossamer Bio, Mylan, and PSI; and serves as an Editor for Multiple Sclerosis. BB served as a consultant for Novartis, Roche, and UCB; and is funded by the National Multiple Sclerosis Society and National Institutes of Health for work unrelated to this paper. BH served on scientific advisory boards for Novartis; and has served as a data and safety monitoring board member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; and his institution has received institutional research grants from Roche. BH has received honoraria for counselling for the Gerson Lehrmann Group; and holds part of two patents: (1) the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis, and (2) genetic determinants of neutralising antibodies to interferon. SDN reports grants or contracts from Biogen, Roche, Genentech, National Multiple Sclerosis Society, Department of Defense, and Patient Centered Outcomes Research Institute; reports personal compensation for consulting for Biogen, Roche, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Novartis, Horizon Therapeutics, and TG Therapeutics; and participates on a data safety monitoring board and advisory board for MedDay Pharmaceuticals; and reports support from the Stiff Person Syndrome Research Foundation. AJS reports grant funding from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, and Bristol Myers Squibb; is contracted for research with Sanofi, Biogen, Novartis, Actelion, and Genentec; has received personal compensation for consulting from EMD Serono and Octave Bioscience; has received payment or honoraria for lectures for EMD Serono; has been called for expert testimony by The Jacob D Fuchsberg Law Firm and Koskoff Koskoff & Bieder; participates on a data safety monitoring board for Patient Centered Outcomes Research Institute and Yale University; participates on an advisory board for Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics, and Horizon Therapeutics; and is content Chair for the American Academy of Neurology Institute Multiple Sclerosis Quality Measure Development Work Group and Section Editor for Multiple Sclerosis and Related Disorders. WR3rd has research grant support from the National Institutes of Health and the Veterans Administration; reports honoraria, consulting fees, and support for advisory activities for the Consortium of Multiple Sclerosis Centers, the University of Maryland, the University of Calgary, Temple University, Thomas Jefferson University, the Chan Zuckerberg Initiative, the American Association for Cancer Research, and the Alzheimer's Association of Georgia; and receives compensation for serving as Director of specialty programming for Mediflix. AS and BT declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Loss of mobility is common in persons with multiple sclerosis (PwMS), but little is known about this impairment from the patient's perspective., Objective: The aim is to model longitudinal variation in a mobility patient-reported outcome (PRO) and compare trajectories to those observed for Timed 25-Foot Walk (T25FW) in a retrospective cohort., Methods: Latent-class growth analysis was applied to 47,508 measures of Performance Scales© Mobility PRO (PS-Mobility) over ~4 years for 8524 PwMS. For 7347 PwMS, there were 41,988 T25FW measures during this period. Repeated measures correlation and concordance of trajectory assignment were evaluated., Results: At the group level, PS-Mobility and T25FW linearly worsened and repeated-measures correlation was moderate. Eight latent classes with varying shapes that worsened described PS-Mobility variation, compared to six latent classes for T25FW that differed by intercept. The agreement between PS-Mobility and T25FW cluster assignment was modest. A higher proportion of individuals who were Black/African American, older, Medicaid beneficiaries, living in deprived neighborhoods, had longer disease duration, had progressive disease, and ever smokers were assigned to more impaired clusters., Discussion: Cross-sectionally, PS-Mobility and T25FW were highly correlated, but longitudinally correlation was modest to moderate, underscoring the importance of considering both objective and subjective perspectives in evaluating mobility changes in PwMS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: The central vein sign (CVS) is a proposed diagnostic imaging biomarker for multiple sclerosis (MS). The proportion of white matter lesions exhibiting the CVS (CVS+) is higher in patients with MS compared to its radiological mimics. Evaluation for CVS+ lesions in prior studies have been performed by manual rating, an approach that is time-consuming and has variable inter-rater reliability. Accurate automated methods would facilitate efficient assessment for CVS. The objective of this study was to compare the performance of an automated CVS detection method with manual rating for the diagnosis of MS., Materials and Methods: 3T MRI was acquired in 86 participants undergoing evaluation for MS in a 9-site multicenter study. Participants presented with either typical or atypical clinical syndromes for MS. An automated CVS detection method was employed and compared to manual rating, including total CVS+ proportion and a simplified counting method in which experts visually identified up to 6 CVS+ lesions using FLAIR* contrast (a voxel-wise product of T 2 FLAIR and post-contrast T 2 *-EPI images)., Results: Automated CVS processing was completed in 79 of 86 participants (91%), of whom 28 (35%) fulfilled the 2017 McDonald criteria at the time of imaging. The area under the receiver-operator characteristic curve (AUC) for discrimination between participants with and without MS for the automated CVS approach was 0.78 (95% confidence interval: [0.67,0.88]). This was not significantly different from simplified manual counting methods (select6*) (0.80 [0.69,0.91]) or manual assessment of total CVS+ proportion (0.89 [0.82,0.96]). In a sensitivity analysis excluding 11 participants whose MRI exhibited motion artifact, the AUC for the automated method was 0.81 [0.70,0.91], which was not statistically different from that for select6* (0.79 [0.68,0.92]) or manual assessment of total CVS+ proportion (0.89 [0.81,0.97])., Conclusions: Automated CVS assessment was comparable to manual CVS scoring for differentiating patients with MS from those with other diagnoses. Large, prospective, multicenter studies utilizing automated methods and enrolling the breadth of disorders referred for suspicion of MS are needed to determine optimal approaches for clinical implementation of an automated CVS detection method., Abbreviations: CVS= central vein sign; CVS+ = white matter lesions exhibiting the CVS; MRI = magnetic resonance imaging; MS = multiple sclerosis; T 2 FLAIR = T 2 fluid-attenuated inversion recovery; T 2 *-EPI = T 2 *-weighted 3D echo planar imaging; FLAIR* = a voxel-wise product of T 2 FLAIR and post-contrast T 2 *-EPI images; select6* = simplified counting method in which experts visually identified up to 6 CVS+ lesions on FLAIR* imaging., Competing Interests: Disclosures: D.S. Reich’s lab has received research support from Abata Therapeutics and Sanofi-Genzyme. A.J. Solomon reports consulting or advisory board compensation for Octave Bioscience, TG Therapeutics, Kiniksa Pharmaceuticals, Genentech, and Horizon Therapeutics, non-promotional speaking for EMD Serono, contracted research for Sanofi, Actelion, Genentech/Roche, Novartis, and research funding from Bristol Meyers Squibb., (© 2024 by American Journal of Neuroradiology.)

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this consensus statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. Elements of this work were written by employees of the US Government.)

Background: The impact of teleneurology on healthcare utilization (HCU) in MS is unknown., Objective: Evaluate the association between teleneurology and HCU., Methods: A retrospective longitudinal analysis of HCU among adult MS and clinically isolated syndrome (CIS) patients residing in the Cleveland/Akron area from July 2020 to July 2022. Negative binomial regression models evaluated the association between number of laboratory and MRI orders per visit and number of emergency visits per patient across patient groups with variable proportions of teleneurology visits., Results: A total of 3208 patients completed 15,795 visits. Patients using teleneurology had more visits (rate ratio (RR) 1.707-1.719, p < 0.001). Teleneurology visits had fewer laboratory (RR 0.571) and MRI orders (RR 0.693, p < 0.001). There was no difference in emergency care utilization for teleneurology patients ( p ⩾ 0.05). More emergency visits were observed in Black (RR 1.414) and Medicaid (RR 1.893) patients, regardless of visit type ( p < 0.001)., Conclusion: Teleneurology visits were associated with fewer orders, suggesting teleneurology may be incorporated into healthcare models without increasing utilization related to the visit. Teleneurology was also associated with increased visit volumes but no difference in emergency HCU. More studies are needed to clarify the ultimate impact of teleneurology on overall HCU. More emergency visits, regardless of visit type, were observed among at-risk populations, warranting further investigation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.N.P. declares that there is no conflict of interest. D.O. receives research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme and Novartis, and consulting fees from Biogen Idec, BMS, Genentech/Roche, Genzyme, Janssen, Novartis and Merck. T.H. declares that there is no conflict of interest. A.M.P., N.W., B.R.C., S.R., and E.S.M. are employees and stockholders of F. Hoffmann-La Roche Ltd. M.P.M. has received research support from the National Institutes of Health, Agency for Healthcare Research and Quality, Genentech, Novartis, and Biogen and consulting fees from Genentech and EMD Serono.

Background: Cerebrospinal fluid (CSF) oligoclonal bands (OCB) are a diagnostic biomarker in multiple sclerosis (MS). The central vein sign (CVS) is an imaging biomarker for MS that may improve diagnostic accuracy., Objectives: The objective of the study is to examine the diagnostic performance of simplified CVS methods in comparison to OCB in participants with clinical or radiological suspicion for MS., Methods: Participants from the CentrAl Vein Sign in MS (CAVS-MS) pilot study with CSF testing were included. Select-3 and Select-6 (counting up to three or six CVS+ lesions per scan) were rated on post-gadolinium FLAIR* images. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value for Select-3, Select-6, OCB, and combinations thereof were calculated for MS diagnosis at baseline and at 12 months., Results: Of 53 participants, 25 were OCB+. At baseline, sensitivity for MS diagnosis was 0.75 for OCB, 0.83 for Select-3, and 0.71 for Select-6. Specificity for MS diagnosis was 0.76 for OCB, 0.48 for Select-3, and 0.86 for Select-6. At 12 months, PPV for MS diagnosis was 0.95 for Select-6 and 1.00 for Select-6 with OCB+ status., Discussion: Results suggest similar diagnostic performance of simplified CVS methods and OCB. Ongoing studies will refine whether CVS could be used in replacement or in conjunction with OCB., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article:Karlo Toljan: Training grant: National MS Society (FP-2207-39855).Lynn Daboul: Research support: NIH Medical Research Scholars Program.Praneeta Raza: Nothing to disclose.Melissa L. Martin: Nothing to disclose.Quy Cao: Nothing to disclose.Carly M. O’Donnell: Nothing to disclose.Paulo Rodrigues: Employed by and holds options of QMENTA.John Derbyshire: Nothing to disclose.Christina J. Azevedo: Research support: National Multiple Sclerosis Society, National Institutes of Health. Consulting: Genentech, EMD Serono, Alexion Pharmaceuticals, Sanofi Genzyme, Horizon Therapeutics.Amit Bar-Or: Consulting: Accure, Atara Biotherapeutics, Biogen, Bristol Myers Squibb, GlaxoSmithKline, Gossamer, Janssen, AstraZeneca, EMD Serono, Novartis, Genentech, Sanofi. Research support: Biogen, Genentech, EMD Serono, Novartis.Eduardo Caverzasi: Nothing to disclose.Peter A Calabresi: Research support: Genentech. Advisory board: Lilly, Novartis, Idorsia, and Project Efflux.Bruce A. C. Cree: Consulting: Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Immunic AG, Kyverna, Neuron23, Novartis, Sanofi, and TG Therapeutics; research support from Genentech.Leorah Freeman: Advisory board: Genentech, Novartis, Celgene. Consulting: EMD Serono, Celgene, Biogen. Program sponsorship: Biogen, EMD Serono.Roland G. Henry: Consulting: Neurona, Roche, Novartis, Sanofi, QIA, Celgene/BMS, Atara, Medday, Boston Pharma. Research support: Roche, Atara.Erin E Longbrake: Consulting: Genentech, Sanofi, Alexion, Biogen, EMD Serono, Bristol Myers Squibb.Jiwon Oh: Research support: Biogen, Roche, EMD Serono. Consulting: EMD Serono, Sanofi, Biogen, Roche, Celgene, Novartis.Nico Papinutto: Research support: Race to Erase MS Foundation.Daniel Pelletier: Consulting: Sanofi, Roche, Novartis.Rohini D. Samudralwar: Advisory board: Biogen, EMD Serono, Sanofi. Consulting: EMD Serono, Biogen.Matthew K. Schindler: Nothing to disclose.Elias S. Sotirchos: Consulting for Alexion, Viela Bio, Horizon Therapeutics, Genentech, Ad Scientiam. Honoraria: Alexion, Viela Bio, Biogen.Nancy L. Sicotte: Research support: NIH, National MS Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Biogen.Andrew J. Solomon: Advisory board: Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics. Consulting: Octave Bioscience. Non-promotional speaking: EMD Serono. Research support: Bristol Myers Squibb, Sanofi, Biogen, Novartis, Janssen, Genentech. Trainee funding: Biogen.Russell T. Shinohara: Consulting: Octave Bioscience. Research support: NIH, National MS Society.Daniel S. Reich: Supported by Intramural Research Program of NINDS. Research support: Abata, Sanofi.Pascal Sati: Research support: NIH, National MS Society, Erwin Rautenberg Foundation.Daniel Ontaneda: Research support: NIH, National MS Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Bristol Myers Squibb, Genentech, Sanofi, Novartis. Consulting: Biogen, Bristol Myers Squibb, Genentech, Sanofi, Janssen, Novartis, Pipeline Therapeutics, and Merck.

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS., (© 2024. The Author(s).)

Background and Objectives: Up to 65% of people with multiple sclerosis (MS) experience disease-related cognitive impairment, but even after decades of research, still very little is known about the cognitive issues among older adults with MS (EwMS; individuals aged 60+). To date, few studies have attempted to characterize cognitive impairment in this group or compare EwMS with those with other neurodegenerative diseases. Our goal was to address this knowledge gap by comparing EwMS with individuals experiencing cognitive impairment due to probable Alzheimer disease (AD) with biomarker confirmation., Methods: We conducted an observational study of individuals seen for routine clinical care at the Cleveland Clinic. After excluding for potential confounding factors, 6 groups were assembled based on the results of their clinical workup and neuropsychological examination: cognitively normal, cognitively normal with MS, mild neurocognitive disorder (due to MS or AD), and major neurocognitive disorder (due to MS or AD). These groups were compared in terms of cognitive test performance, percentage of the group impaired on specific cognitive skills, and rates of cognitive impairment., Results: The sample comprised 140 individuals (64 EwMS and 76 demographically matched individuals from a memory clinic). Among those with mild neurocognitive disorder, differences between MS and AD were marked. However, in those with major neurocognitive disorder, these differences largely disappeared, except persistent performance differences on a measure of rote verbal memory. EwMS outperformed those with AD on memory tests at each level of cognitive impairment. EwMS also exhibited both subcortical and cortical deficits, rather than solely subcortical deficits., Discussion: The overall characterization of the cognitive profile of MS may be different than once described, involving both classically cortical and subcortical functions. Clinically, our results suggest that distinguishing between the cognitive effects of MS and AD at more severe levels of cognitive impairment may be less reliable than once thought. Future work to replicate these findings in other samples and deepen the understanding of cognition in older individuals with MS is needed., Competing Interests: L.M. Hancock has received research support from Bristol Myers Squibb, NIH, and Clinical Translational Science Institute and Advancing a Healthier Wisconsin Research and Education Program; R. Galioto has received research support from NIH, the National Academy of Neuropsychology, and the American Psychological Association; D. Ontaneda has received research support from the NIH, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis. Consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche and Novartis. K. Nakamura has received personal licensing fee from Biogen and fee from INmune Bio and has received research support from Department of Defense, NIH, Patient-Centered Outcomes Research Institute, and Biogen; J.B. Miller acknowledges the following funding/supports: Nevada Exploratory Alzheimer's Disease Research Center (National Institute on Aging P20 AG068053), the Center for Neurodegeneration and Translational Neuroscience (National Institute of Graduate Medical Studies P20 GM109025), and the Keep Memory Alive foundation; L.H. Hua has received personal fees for speaking, consulting, and advisory board activities from Alexion, EMD Serono, Genentech, Horizon, and Novartis, and TG therapeutics; and has received research support paid to her institution from Biogen. T. Rhoads and K. Krishnan have nothing to disclose. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

In this paper, we analyse the different advances in artificial intelligence (AI) approaches in multiple sclerosis (MS). AI applications in MS range across investigation of disease pathogenesis, diagnosis, treatment, and prognosis. A subset of AI, Machine learning (ML) models analyse various data sources, including magnetic resonance imaging (MRI), genetic, and clinical data, to distinguish MS from other conditions, predict disease progression, and personalize treatment strategies. Additionally, AI models have been extensively applied to lesion segmentation, identification of biomarkers, and prediction of outcomes, disease monitoring, and management. Despite the big promises of AI solutions, model interpretability and transparency remain critical for gaining clinician and patient trust in these methods. The future of AI in MS holds potential for open data initiatives that could feed ML models and increasing generalizability, the implementation of federated learning solutions for training the models addressing data sharing issues, and generative AI approaches to address challenges in model interpretability, and transparency. In conclusion, AI presents an opportunity to advance our understanding and management of MS. AI promises to aid clinicians in MS diagnosis and prognosis improving patient outcomes and quality of life, however ensuring the interpretability and transparency of AI-generated results is going to be key for facilitating the integration of AI into clinical practice., (© 2024. The Author(s).)

Background and Purpose: Slowly expanding lesions (SELs) are thought to represent a subset of chronic active lesions and have been associated with clinical disability, severity, and disease progression. The purpose of this study was to characterize SELs using advanced magnetic resonance imaging (MRI) measures related to myelin and neurite density on 7 Tesla (T) MRI., Methods: The study design was retrospective, longitudinal, observational cohort with multiple sclerosis (n = 15). Magnetom 7T scanner was used to acquire magnetization-prepared 2 rapid acquisition gradient echo and advanced MRI including visualization of short transverse relaxation time component (ViSTa) for myelin, quantitative magnetization transfer (qMT) for myelin, and neurite orientation dispersion density imaging (NODDI). SELs were defined as lesions showing ≥12% of growth over 12 months on serial MRI. Comparisons of quantitative measures in SELs and non-SELs were performed at baseline and over time. Statistical analyses included two-sample t-test, analysis of variance, and mixed-effects linear model for MRI metrics between lesion types., Results: A total of 1075 lesions were evaluated. Two hundred twenty-four lesions (21%) were SELs, and 216 (96%) of the SELs were black holes. At baseline, compared to non-SELs, SELs showed significantly lower ViSTa (1.38 vs. 1.53, p < .001) and qMT (2.47 vs. 2.97, p < .001) but not in NODDI measures (p > .27). Longitudinally, only ViSTa showed a greater loss when comparing SEL and non-SEL (p = .03)., Conclusions: SELs have a lower myelin content relative to non-SELs without a difference in neurite measures. SELs showed a longitudinal decrease in apparent myelin water fraction reflecting greater tissue injury., (© 2024 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

This study aimed to determine whether choroid plexus volume (CPV) could differentiate multiple sclerosis (MS) from its mimics. A secondary analysis of two previously enrolled studies, 50 participants with MS and 64 with alternative diagnoses were included. CPV was automatically segmented from 3T magnetic resonance imaging (MRI), followed by manual review to remove misclassified tissue. Mean normalized choroid plexus volume (nCPV) to intracranial volume demonstrated relatively high specificity for MS participants in each cohort (0.80 and 0.76) with an area under the receiver-operator characteristic curve of 0.71 (95% confidence interval (CI) = 0.55-0.87) and 0.65 (95% CI = 0.52-0.77). In this preliminary study, nCPV differentiated MS from its mimics., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: E.L. has no relevant disclosures. Z.R. has relevant disclosures. V.G. has no relevant disclosures. In the last 3 years, Dr C.J.A. has received consulting fees from Horizon Therapeutics, Genentech, Sanofi Genzyme, TG Therapeutics, and EMD Serono. She has received grant support from the National Institutes of Health and the National Multiple Sclerosis Society. P.A.C. is PI on grants to JHU from the Myelin Repair Foundation and Genentech. He has received consulting fees from Lilly, Idorsia, and Novartis. B.A.C.C. has no relevant disclosures. L.F. has received fees for consultancy and/or advisory board participation from Genentech, Novartis, Bristol Myers Squibb, EMD Serono, Sanofi, Horizon Therapeutics, and TG Therapeutics; has received honorarium for participation in educational programs from Medscape, Inc., the MS Association of America and Impact Education; has received program sponsorship from EMD Serono; and grant support from NIH/NINDS, PCORI, Genentech, and EMD Serono through her institution. E.E.L. has received honoraria for consulting from Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, TG Therapeutics, Janssen, and NGM Bio. She has received research from Biogen and Genentech. J.O. is none relevant to this manuscript. M.K.S. has no relevant disclosures. N.L.S. received grant funding from NIH, PCORI, and NMSS. D.S.R. received research funding from Abata and Sanofi. D.O. received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, Bristol Myers Squibb, and Novartis, and also received consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Novartis, Pipeline Therapeutics, and Merck. P.S. received support from the National Institutes of Health, Department of Defense, National Multiple Sclerosis Society and the Erwin Rautenberg Foundation. Q.C. has no relevant disclosures. R.T.S. received consulting income from Octave Bioscience and compensation for scientific reviewing from the American Medical Association. A.J.S. as consulting or advisory board: Genentech, Octave Bioscience, Horizon Therapeutics, Kiniksa Pharmaceuticals, and TG Therapeutics; non-promotional speaking: EMD Serono; research funding: Bristol Meyers Squibb; and contract research: Sanofi, Actelion, Genentech, and Novartis.

Background: Cognitive dysfunction is a known symptom of multiple sclerosis (MS), with memory recognized as a frequently impacted domain. Here, we used high-resolution MRI at 7 tesla to build on cross-sectional work by evaluating the longitudinal relationship of diffusion tensor imaging (DTI) measures of the fornix to episodic memory performance., Methods: A sample of 80 people with multiple sclerosis (mean age 51.9 ± 8.1 years; 24% male) underwent baseline clinical evaluation, neuropsychological assessment, and MRI. Sixty-four participants had follow-up neuropsychological testing after 1-2 years. Linear regression was used to assess the relationship of baseline imaging measures to follow-up episodic memory performance, measured using the Selective Reminding Test and Brief Visuospatial Memory Test. A reduced prediction model included cognitive function at baseline, age, sex, and disease course., Results: Radial (β = -0.222, p  < 0.026; likelihood ratio test (LRT) p  < 0.018), axial (β = -0.270, p  < 0.005; LRT p  < 0.003), and mean (β = -0.242, p  < 0.0139; LRT p  < 0.009) diffusivity of the fornix significantly added to the model, with follow-up analysis indicating that a longer prediction interval may increase accuracy., Conclusion: These results suggest that fornix DTI has predictive value specific to memory function in MS and warrants additional investigation in the drive to develop predictors of disease progression., Competing Interests: K.S. has received salary support from Genzyme and from Novartis. K.R.M. is funded by NIH NINDS and has received consultation fees from Bristol-Myers Squibb and Genentech. K.N. has received licensing fees from Biogen and fees from INmune Bio., (© The Author(s), 2024.)

Background: Cognitive impairment (CI) is common in multiple sclerosis (MS). Processing speed (PS) is often affected, making it an ideal target for monitoring CI. This study aims to evaluate the association between disease-modifying therapy (DMT) use and intensity and longitudinal changes in Processing Speed Test (PST) scores for individuals with MS., Methods: A retrospective analysis of individual PST scores at a single MS center was conducted. Individuals with 2 or more PST assessments were included. Scores on the PST were compared longitudinally between those who had been on a DMT for 2 or more years and those who had been off a DMT for 2 or more years and between those on high-efficacy DMTs and those on low-/moderate-efficacy DMTs. A linear regression model was approximated to evaluate the rate of cognitive change over time. A propensity score adjustment was conducted using a multivariable logistic regression., Results: The cohort was 642 individuals, 539 on DMT and 103 off DMT. Median age and disease duration was 49.7 (IQR 42.4-57.9) and 16.6 years (IQR 9.3-23.0) in the DMT group, and 58.9 (IQR 52.2-65.3) and 20.0 years (IQR 14.1-31.4) in the non-DMT group. Both cohorts were predominantly female (75% DMT, 79.6% non-DMT), with a mean of 4 assessments (IQR 3-5), and an average monitoring duration of 1.9 years (1.2-2.4) in the DMT group, and 1.8 years (1.4-2.4) in the non-DMT group. After adjusting for multiple factors, DMT status and intensity were not found to be significant predictors of longitudinal PST change., Conclusions: Neither DMT status nor intensity was a significant predictor of cognitive processing speed over a period of approximately 2 years. Future prospective studies are needed to further support these findings., Competing Interests: FINANCIAL DISCLOSURES: Dr Amin received a Novartis fellowship award (NGC44741). Dr Macaron has served on advisory boards for Biologix, Genentech-Roche, Merck, and Novartis; received speaker fees from Biologix, Merck, and Novartis; and participated in educational activities for NeurologyLive® and John Hopkins's e-Literature Review. Dr Ontaneda receives research support from Genentech, Genzyme, National Institutes of Health, National Multiple Sclerosis Society, Novartis Patient Centered Outcomes Research Institute, and Race to Erase MS Foundation. He has received consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Janssen, Merck, and Novartis. The other authors have no conflicts of interest., (© 2024 Consortium of Multiple Sclerosis Centers.)

Importance: Early treatment initiation in multiple sclerosis (MS) is crucial in preventing irreversible neurological damage and disability progression. The current assessment of disease activity relies on relapse rates and magnetic resonance imaging (MRI) lesion activity, but inclusion of other early, often "hidden," indicators of disease activity may describe a more comprehensive picture of MS., Observations: Early indicators of MS disease activity other than relapses and MRI activity, such as cognitive impairment, brain atrophy, and fatigue, are not typically captured by routine disease monitoring. Furthermore, silent progression (neurological decline not clearly captured by standard methods) may occur undetected by relapse and MRI lesion activity monitoring. Consequently, patients considered to have no disease activity actually may have worsening disease, suggesting a need to revise MS management strategies with respect to timely initiation and escalation of disease-modifying therapy (DMT). Traditionally, first-line MS treatment starts with low- or moderate-efficacy therapies, before escalating to high-efficacy therapies (HETs) after evidence of breakthrough disease activity. However, multiple observational studies have shown that early initiation of HETs can prevent or reduce disability progression. Ongoing randomized clinical trials are comparing escalation and early HET approaches., Conclusions and Relevance: There is an urgent need to reassess how MS disease activity and worsening are measured. A greater awareness of "hidden" indicators, potentially combined with biomarkers to reveal silent disease activity and neurodegeneration underlying MS, would provide a more complete picture of MS and allow for timely therapeutic intervention with HET or switching DMTs to address suboptimal treatment responses., (© 2023. The Author(s).)

Despite the success of disease-modifying treatments in relapsing multiple sclerosis, for many individuals living with multiple sclerosis, progressive disability continues to accrue. How to interrupt the complex pathological processes underlying progression remains a daunting and ongoing challenge. Since 2014, several immunomodulatory approaches that have modest but clinically meaningful effects have been approved for the management of progressive multiple sclerosis, primarily for people who have active inflammatory disease. The approval of these drugs required large phase 3 trials that were sufficiently powered to detect meaningful effects on disability. New classes of drug, such as Bruton tyrosine-kinase inhibitors, are coming to the end of their trial stages, several candidate neuroprotective compounds have been successful in phase 2 trials, and innovative approaches to remyelination are now also being explored in clinical trials. Work continues to define intermediate outcomes that can provide results in phase 2 trials more quickly than disability measures, and more efficient trial designs, such as multi-arm multi-stage and futility approaches, are increasingly being used. Collaborations between patient organisations, pharmaceutical companies, and academic researchers will be crucial to ensure that future trials maintain this momentum and generate results that are relevant for people living with progressive multiple sclerosis., Competing Interests: Declaration of interests JC reports grants from the National Institute for Health Research Health Technology Assessment Programme, the UK Multiple Sclerosis Society, the US National Multiple Sclerosis Society, the Rosetrees Trust, and in part from the National Institute for Health Research University College London Hospitals Biomedical Research Centre; being a local principal investigator for an academic trial in multiple sclerosis funded by the Multiple Sclerosis Society of Canada and for commercial trials funded by Ionis and Roche; and advisory board participation or consultancy for Biogen, Janssen, Lucid, Merck, NervGen, Novartis, and Roche. TW reports research funding from the MS-STAT2 trial grant; and honoraria for educational talks from Novartis and Merck. VL reports research funding from the National Health and Medical Research Council, Multiple Sclerosis Research Australia, Australian and New Zealand Association of Neurologists Education and Research Foundation, Trish Multiple Sclerosis Research Foundation, Brain Foundation, and Australian Rotary Health; and honoraria for educational talks from Roche. RAM reports research funding from the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada, Crohn's and Colitis Canada, the National Multiple Sclerosis Society, the Consortium of Multiple Sclerosis Centers, the Arthritis Society, and the US Department of Defense; support by the Waugh Family Chair in Multiple Sclerosis; and being a co-investigator on a study funded in part by Biogen Idec and Roche (no funds to RAM or her institution). DO reports research support from the National Institutes of Health, the National Multiple Sclerosis Society, the Patient Centered Outcomes Research Institute, the Race to Erase MS Foundation, Bristol Myers Squibb, Genentech, Genzyme, and Novartis; and consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Genzyme, Janssen, Novartis, Merck, and Pipeline Therapeutics. RJF reports personal consulting fees from AB Science, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, Immunic, INmune Bio, Janssen, Lily, Novartis, Sanofi, Siemens, and TG Therapeutics; and clinical trial contracts and research grant funding from Biogen, Novartis, and Sanofi., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: We aimed to investigate the prognostic factors associated with clinical outcomes in CV2/Collapsin response-mediator protein 5 (CRMP5)-IgG paraneoplastic neurologic disorders (PND)., Methods: This is a retrospective study of patients with CV2/CRMP5-IgG PND evaluated between 2002-2022. We examined the association of clinical variables (including age, clinical phenotype [autoimmune encephalopathy, myelopathy, polyneuropathy/radiculopathy, MG, cerebellar ataxia, chorea, optic neuropathy], cancer) with three clinical outcomes (wheelchair dependence, modified Rankin Scale [mRS], mortality) using univariate logistic regression and Cox proportional hazards modeling. Kaplan-Meier estimates were used to determine the probability of survival., Results: Twenty-seven patients (56% female) with CV2/CRMP5-IgG PND were identified with a median follow-up of 54 months (IQR = 11-102). An underlying tumor was identified in 15 patients (56%) including small cell lung cancer (SCLC) (8, [53%]), thymoma (4, [27%]), and other histologies (3, [20%]). At last follow-up, 10 patients (37%) needed a wheelchair for mobility and this outcome was associated with myelopathy (HR = 7.57, 95% CI = 1.87-30.64, P = 0.005). Moderate-severe mRS = 3-5 was associated with CNS involvement (encephalopathy, myelopathy, or cerebellar ataxia) (OR = 7.00, 95% CI = 1.18-41.36, P = 0.032). The probability of survival 4 years after symptom onset was 66%. Among cancer subtypes, SCLC (HR = 18.18, 95% CI = 3.55-93.04, P < 0.001) was significantly associated with mortality, while thymoma was not., Interpretation: In this retrospective longitudinal study of CV2/CRMP5-IgG PND, patients with CNS involvement, particularly myelopathy, had higher probability of disability. SCLC was the main determinant of survival in this population., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Ibudilast has shown beneficial effects on several imaging outcomes in progressive multiple sclerosis (MS). Slowly enlarging lesions are a proposed imaging biomarker of compartmentalized inflammation within chronic active lesions., Objective: To assess the treatment effect of ibudilast on slowly enlarging lesion volumes over 96 weeks from a phase II clinical trial of ibudilast (Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS])., Methods: In total, 255 participants with progressive MS from 28 sites were randomized to oral ibudilast or placebo. Participants with at least four analyzable magnetic resonance imaging (MRI) were included. Slowly enlarging lesions were quantified using Jacobian determinant maps. A linear model was used to assess the effect of ibudilast. Magnetization transfer ratio within slowly enlarging lesions was assessed to determine the effect of ibudilast on tissue integrity., Results: In total, 195 participants were included in this analysis. Ibudilast significantly decreased slowly enlarging lesion volume (23%, p = 0.003). Ibudilast also reduced magnetization transfer ratio change in slowly enlarging lesions: 0.22%/year, p = 0.04., Conclusion: Ibudilast showed a significant effect on baseline volume of lesions that were slowly enlarging and magnetization transfer ratio in slowly enlarging lesions. The results support the use of slowly enlarging lesions for assessment of compartmentalized inflammation represented by chronic active lesions and provide further support for the neuroprotective effects of ibudilast in progressive MS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K.N.: personal licensing fee from Biogen and fee for scientific advisory meeting from INmune Bio, received research support from Department of Defense, National Institutes of Health, and Patient Centered Outcomes Research Institute. B.T.: nothing to disclose. J.B.: nothing to disclose. J.A.C.: personal compensation for consulting for Astoria, Bristol Myers Squibb, Convelo, EMD Serono, FiND Therapeutics, INMune, and Sandoz; and serving as an Editor of Multiple Sclerosis Journal. R.J.F.: personal consulting fees from AB Science, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Greenwich Biosciences, Immunic, INmune Bio, Janssen, Lily, Novartis, Sanofi, Siemens, and TG Therapeutics; Advisory committees for AB Science, Biogen, Immunic, Janssen, Novartis, and Sanofi; Clinical trial contract and research grant funding from Biogen, Novartis, and Sanofi. D.O.: research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis. Consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Genzyme, Janssen, Novartis, Merck, and Pipeline Therapeutics.

Background and Objectives: Longitudinal outcomes in anti-NMDA receptor encephalitis (anti-NMDARe) are still not fully understood and may not be adequately captured with the modified Rankin Scale (mRS), often the sole reported outcome. We aim to characterize longitudinal outcomes in anti-NMDARe using multiple outcome measures., Methods: This single-center, retrospective, observational study examined outcome measures (mRS and Clinical Assessment Scale in Autoimmune Encephalitis [CASE]) in adults with NMDA receptor-IgG in CSF at short- and long-term follow-ups using linear and logistic regression modeling. Patients with evaluations for cognitive impairment (Montreal Cognitive Assessment/Mini-Mental State Examination), depression (Patient Health Questionnaire-9), and anxiety (General Anxiety Disorder-7) >6 months from symptom onset were correlated with final CASE scores., Results: Thirty-eight patients (76% female, median disease onset age = 28 years, range = 1-75 years) were included. The majority received first-line immunosuppressants (97%) at a median of 3.9 weeks (interquartile range [IQR] = 2.1-9.7) from symptom onset and 68% received second-line therapies. At baseline, median/mean mRS and CASE were 4 (IQR = 3-5) and 12.9 (SD = 7.2), respectively. At short-term follow-up (median = 10 weeks, IQR = 6-17), factors associated with higher CASE and mRS included dysautonomia, coma/lethargy, seizures/status epilepticus, and intensive care unit admission ( p < 0.05). At long-term follow-up (median = 70 weeks, IQR = 51-174), median/mean mRS and CASE were 2 (IQR = 1-3) and 4.4 (SD = 4.2), respectively. Only weakness at symptom onset predicted higher mRS scores (odds ratio = 5.6, 95% confidence interval 1.02-30.9, p = 0.047). Despite both mRS and CASE improving from baseline ( p < 0.001), only 9 patients (31%) returned to their premorbid function. Among patients with cognitive and mood evaluations >6 months from onset, moderate-severe cognitive impairment (42%), depression (28%), and anxiety (30%) were frequent. Cognitive and depression measures were associated with final CASE subscores (including memory, language, weakness, and psychiatric)., Discussion: Multiple clinical factors influenced short-term outcomes, but only onset weakness influenced long-term mRS, highlighting that mRS is predominantly affected by global motor function. Although mRS and CASE improved over time for most patients, these outcome measures did not capture the full extent of long-term functional impairment in terms of mood, cognition, and the ability to return to premorbid function. This emphasizes the need for increased utilization of more nuanced cognitive and mood outcome measures.

Objective: Multiple sclerosis (MS) is a debilitating inflammatory and neurodegenerative disease which commonly involves cognitive dysfunction. Magnetic resonance imaging (MRI) studies have shown that patients with MS (pwMS) have diffuse patterns of brain atrophy, however, the relationship between the presentation of cognitive dysfunction and brain tissue loss remains understudied. Given the integral function of thalamus as a central nervous system relay center and its involvement in various brain circuits, thalamic atrophy may play a key role in the development and progression of cognitive dysfunction. The purpose of this study is to examine the relationship between cognitive impairment in pwMS and thalamic atrophy., Methods: A total of 121 pwMS who had neuropsychological testing and quantitative MRI within 1 year of each were retrospectively identified. Grouped LASSO linear regression with 10-fold cross validation was used to estimate each neuropsychological test score with thalamic volume as the focal predictor and all other demographic and MRI metrics as covariates., Results: Rates of impairment ranged from 19% to 44%. Results showed notable associations between thalamic volume and Symbol Digit Modalities Test (β = 0.11), Brief Visuospatial Memory Test, delayed (β = 0.12), California Verbal Learning Test, delayed and total (β = 0.24 and β = 0.15 respectively), and Trail Making Test Part A (β = -0.01), after adjusting for covariates., Conclusions: These findings demonstrate an independent association between thalamic volumes and processing speed and memory performance, after accounting for demographic, clinical, and other MRI variables, among pwMS., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: The diagnosis of multiple sclerosis (MS) relies heavily on neuroimaging with magnetic resonance imaging (MRI) and exclusion of mimics. This can be a challenging task due to radiological overlap in several disorders and may require ancillary testing or longitudinal follow up. One of the most common radiological MS mimickers is non-specific white matter disease (NSWMD). We aimed to develop and evaluate models leveraging machine learning algorithms to help distinguish MS and NSWMD., Methods: All adult patients who underwent MRI brain using a demyelinating protocol with available electronic medical records between 2015 and 2019 at Cleveland Clinic affiliated facilities were included. Diagnosis of MS and NSWMD were assessed from clinical documentation. Those with a diagnosis of MS and NSWMD were matched using total T2 lesion volume (T2LV) and used to train models with logistic regression and convolutional neural networks (CNN). Performance metrices were reported for each model., Results: A total of 250 NSWMD MRI scans were identified, and 250 unique MS MRI scans were matched on T2LV. Cross validated logistic regression model was able to use 20 variables (including spinal cord area, regional volumes, and fractions) to predict MS compared to NSWMD with 68.0% accuracy while the CNN model was able to classify MS compared to NSWMD in two independent validation and testing cohorts with 77% and 78% accuracy on average., Conclusion: Automated methods can be used to differentiate MS compared to NSWMD. These methods can be used to supplement currently available diagnostic tools for patients being evaluated for MS., Competing Interests: Declaration of competing interest Dr. Moein Amin: Novartis and Biogen fellowship awards. Dr. Kunio Nakamura: Received licensing fee from Biogen; received Research Support from Department of Defense, National Institutes of Health, Patient Centered Outcomes Research Institute, and Biogen. Dr. Daniel Ontaneda: Research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis. Consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Novartis, and Merck.), (Copyright © 2023. Published by Elsevier B.V.)

Treatment options for patients newly diagnosed with multiple sclerosis (MS) are expanding with the continuous development and approval of new disease-modifying therapies (DMTs). The optimal initial treatment strategy, however, remains unclear. The 2 main treatment paradigms currently employed are the escalation (ESC) approach and the early highly effective treatment (EHT) approach. The ESC approach consists of starting a lower- or moderate-efficacy DMT, which offers a potentially safer approach, while the EHT approach favors higher-efficacy treatment early in the disease course, despite a potential increase in risk. Randomized clinical trials aiming to directly compare these approaches in newly diagnosed MS patients are currently underway., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: A shortage of neurology clinicians and healthcare disparities may hinder access to neurologic care. This study examined disparities in geographic access to neurologists and subspecialty multiple sclerosis (MS) care among various demographic segments of the United States., Methods: Neurologist practice locations from 2022 CMS Care Compare physician data and MS Center locations as defined by the Consortium of Multiple Sclerosis Centers were used to compute spatial access for all U.S. census tracts. Census tract-level community characteristics (sex, age, race, ethnicity, education, income, insurance, % with computer, % without a vehicle, % with limited English, and % with hearing, vision, cognitive, and ambulatory difficulty) were obtained from 2020 American Community Survey 5-year estimates. Rural-urban status was obtained from 2010 rural-urban commuting area codes. Logistic and linear regression models were used to examine access to a neurologist or MS Center within 60 miles and 60-mile spatial access ratios., Results: Of 70,858 census tracts, 388 had no neurologists within 60 miles and 17,837 had no MS centers within 60 miles. Geographic access to neurologists (spatial access ratio [99% CI]) was lower for rural (-80.49%; CI [-81.65 to -79.30]) and micropolitan (-60.50%; CI [-62.40 to -58.51]) areas compared with metropolitan areas. Tracts with 10% greater percentage of Hispanic individuals (-4.53%; CI [-5.23 to -3.83]), men (-6.76%; CI [-8.96 to -4.5]), uninsured (-7.99%; CI [-9.72 to -6.21]), individuals with hearing difficulty (-40.72%; CI [-44.62 to -36.54]), vision difficulty (-13.0%; [-18.72 to -6.89]), and ambulatory difficulty (-15.68%; CI [-19.25 to -11.95]) had lower access to neurologists. Census tracts with 10% greater Black individuals (3.50%; CI [2.93-10.71]), college degree holders (-7.49%; CI [6.67-8.32]), individuals with computers (16.57%, CI [13.82-19.40]), individuals without a vehicle (9.57%; CI [8.69-10.47]), individuals with cognitive difficulty (25.63%; CI [19.77-31.78]), and individuals with limited English (18.5%; CI [16.30-20.73]), and 10-year older individuals (8.85%; CI [7.03-10.71]) had higher spatial access to neurologists. Covariates for access followed similar patterns for MS centers., Discussion: Geographic access to neurologists is decreased in rural areas, in areas with higher proportions of Hispanics, populations with disabilities, and those uninsured. Access is further limited for MS subspecialty care. This study highlights disparities in geographic access to neurologic care.

Background: The worldwide incidence of multiple sclerosis (MS) is estimated at 0.5-10 cases per 100,000 person-years and is probably increasing. In 2014, a previous study estimated the incidence of multiple sclerosis in Uruguay at 1.2 cases per 100,000 person-years., Objectives: We conducted an observational, prospective, population-based study to determine MS incidence from diagnosis in Uruguay., Methods: The population studied included people older than 18 years of age who were living in Uruguay between July 1, 2019, and June 30, 2021. The diagnosis was based on 2017 McDonald criteria. Multiple data sources were employed including neurologists, magnetic resonance imaging centers, laboratories performing oligoclonal band testing, neurophysiology laboratories, neurorehabilitation centers, the institution Fondo Nacional de Recursos, and the MS Patients' Association of Uruguay (EMUR). The capture-recapture method was used to estimate incidence., Results: 155 new MS cases were confirmed after review. The median age was 35 (range 18-62). Thirteen patients (8.38%) were diagnosed with late-onset MS. The crude incidence rate was 2.89 cases per 100,000 person-years, 3.95 among females, and 1.72 among male patients. The incidence rate estimated using the capture-recapture method was 3.18 (95% CI: 3.02-3.34)., Conclusions: According to the Atlas of MS, Uruguay has a low incidence rate (2.0-3.99), even though it is one of the highest in Latin America. Our country aligns with the global trend of increasing incidence. Age and sex distribution were similar to other studies, with a high incidence of patients with late-onset multiple sclerosis. The capture-recapture method confirms the exhaustivity of our investigation., (© 2024 S. Karger AG, Basel.)

Background: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established., Objective: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS., Methods: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed., Results: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female ( n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*., Conclusion: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.D., C.M.O.D, M.A., J.D., E.C., P.Ra., and M.K.S. have declared no conflicts of interest. P.Ro. employed by and holds stocks in QMENTA. C.A. received consulting fees for scientific advisory boards for Genentech, EMD Serono, Alexion Pharmaceuticals, and Sanofi Genzyme. A.B.O. has received personal fees for advisory board participation and consulting from Abata, Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Horizon Therapeutics, Immunic, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sangamo, Sanofi Genzyme, Viracta; and grant support to the University of Pennsylvania from Biogen Idec, Roche/Genentech, Merck/EMD Serono, and Novartis. P.A.C. is a PI on grants to JHU from Biogen and Annexon and served on scientific advisory boards for Disarm Therapeutics and Biogen. B.A.C.C. received compensation for consulting from Alexion, Atara, Biogen, EMD Serono, Novartis, Sanofi, and TG Therapeutics. L.F. received fees for consultancy and advisory board participation from Genentech, Novartis, Celgene/Bristol Myers Squibb, EMD Serono, and TG Therapeutics; received fees for educational activities from Medscape, LLC, and the MS Association of America; program sponsorship to UT from EMD Serono; and grant support to UT from NIH/NINDS, PCORI, Genentech, and EMD Serono. R.G.H. received research support from Roche, Genentech, Atara, and MedDay and consulting for Novartis, Sanofi/Genzyme, Roche/Genentech, QIA, and Neurona. E.E.L. received research support from Genentech, Biogen and consulting for Genentech, Janssen, TG Therapeutics, NGM Bio, Bristol Myers Squibb, and EMD Serono. J.O. received research support from Biogen Idec, Roche, and EMD Serono; consulting compensation from EMD Serono, Sanofi/Genzyme, Biogen Idec, Roche, Celgene, and Novartis. N.P. received research support from the Race to Erase MS Foundation. D.P. received consulting compensation from EMD Serono, Sanofi Genzyme, Roche, and Novartis. V.P. employed by and holds stocks in QMENTA. M.R. employed by and holds stock options in QMENTA. R.D.S. received fees for advisory board participation (Biogen, EMD Serono, Sanofi Genzyme) and consulting (EMD Serono, Biogen). E.S. received fees for scientific advisory boards and consulting for Alexion, Viela Bio, Horizon Therapeutics, Genentech, and Ad Scientiam; speaking honoraria from Alexion, Viela Bio, and Biogen. N.L.S. received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Race to Erase MS Foundation, and Biogen Idec. A.J.S. received fees for consulting: Greenwich Biosciences, Horizon Therapeutics, Kiniksa Pharmaceuticals, Octave Bioscience, TG Therapeutics; non-promotional speaking: EMD Serono; research funding: Bristol Myers Squibb; contracted research: Sanofi, Novartis, Actelion, Genentech/Roche. R.T.S. supported NIH R01NS112274, R01MH112847, and R01MH123550 and received consulting income from Octave Bioscience. D.S.R. supported by the Intramural Research Program of NINDS; received additional research support from Vertex Pharmaceuticals, Sanofi Genzyme, and Abata Therapeutics. P.S. received research support from the National Institutes of Health and the National Multiple Sclerosis Society. D.O. received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis; consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Novartis, and Merck.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: D.O. received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis and consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Novartis, and Merck. L.A. has research support from the National Institutes of Health, Bristol Myer Squibb Foundation, and Race to Erase MS Foundation. She is a local PI for commercial trials funded by Genentech and Sanofi, Genzyme, and consulting fees from Biogen Idec, Novartis, Genentech, and EMD Serono.