Diagnostic performance of central vein sign versus oligoclonal bands for multiple sclerosis.

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.

Trends in direct healthcare utilization observed for persons with MS among teleneurology users and diverse populations.

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.

Differential diagnosis of suspected multiple sclerosis: considerations in people from minority ethnic and racial backgrounds in North America, northern Europe, and Australasia.

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.

Mobility trajectories in multiple sclerosis: A comparative study of timed 25-foot walk and a patient-reported outcome measure.

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.

Discordance of reported multiple sclerosis clinical course amongst patients and providers.

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.

Disability independent of cerebral white matter demyelination in progressive multiple sclerosis.

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.

Artificial Intelligence and Multiple Sclerosis.

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.

Comparing Cognitive Profiles in Older Adults With Multiple Sclerosis and Alzheimer Disease: More Similarities Than Differences.

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.

Longitudinal myelin content measures of slowly expanding lesions using 7T MRI in multiple sclerosis.

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.

Association Between Disease-Modifying Therapy and Information Processing Speed in Multiple Sclerosis.

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.

High-resolution diffusion tensor imaging of the fornix predicts memory function in multiple sclerosis.

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 (ß = -0.222, p < 0.026; likelihood ratio test (LRT) p < 0.018), axial (ß = -0.270, p < 0.005; LRT p < 0.003), and mean (ß = -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.

Choroid plexus volume differentiates MS from its mimics.

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.

INCIDENCE OF MULTIPLE SCLEROSIS IN URUGUAY. A PROSPECTIVE POPULATION-BASED STUDY.

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 female 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.

Clinical trials for progressive multiple sclerosis: progress, new lessons learned, and remaining challenges.

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.

Geographic Disparities in Access to Neurologists and Multiple Sclerosis Care in the United States.

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.

Imaging chronic active lesions in multiple sclerosis: a consensus statement.

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.

Ibudilast reduces slowly enlarging lesions in progressive multiple sclerosis.

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.

Longitudinal Disability, Cognitive Impairment, and Mood Symptoms in Patients With Anti-NMDA Receptor Encephalitis.

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.

Differentiating multiple sclerosis from non-specific white matter changes using a convolutional neural network image classification model.

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.

Predicting disability and mortality in CV2/CRMP5-IgG associated paraneoplastic neurologic disorders.

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.