Acute central nervous system inflammation following COVID-19 vaccination: An observational cohort study.

BACKGROUND: Reports suggest a potential association between coronavirus disease 2019 (COVID-19) vaccines and acute central nervous system (CNS) inflammation. OBJECTIVE: The main objective of this study is to describe features of acute CNS inflammation following COVID-19 vaccination. METHODS: A retrospective observational cohort study was performed at the BARLO MS Centre in Toronto, Canada. Clinicians reported acute CNS inflammatory events within 60 days after a COVID-19 vaccine from March 2021 to August 2022. Clinical characteristics were evaluated. RESULTS: Thirty-eight patients (median age 39 (range: 20-82) years; 60.5% female) presented within 0-55 (median 15) days of a receiving a COVID-19 vaccine and were diagnosed with relapsing remitting multiple sclerosis (MS) (n = 16), post-vaccine transverse myelitis (n = 7), clinically isolated syndrome (n = 5), MS relapse (n = 4), tumefactive demyelination (n = 2), myelin oligodendrocyte glycoprotein antibody disease (n = 1), neuromyelitis optica spectrum disorder (n = 1), chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (n = 1) and primary autoimmune cerebellar ataxia (n = 1). Twenty-two received acute treatment and 21 started disease-modifying therapy. Sixteen received subsequent COVID-19 vaccination, of which 87.5% had no new or worsening neurological symptoms. CONCLUSION: To our knowledge, this is the largest study describing acute CNS inflammation after COVID-19 vaccination. We could not determine whether the number of inflammatory events was higher than expected.

Complement Inhibition in Myasthenia Gravis and Neuromyelitis Optica Spectrum Disorder.

The complement system is a tightly controlled signaling network that plays a role in innate immune surveillance. However, abnormal signaling through this pathway contributes to tissue damage in several inflammatory, autoimmune, and degenerative diseases. Myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) have complement dysfunction at the core of pathogenesis, providing a strong rationale for therapeutic targeting of complement components. The purpose of this paper is to briefly review the role of complement activation in the pathogenesis of MG and NMOSD, to discuss the rationale and evidence for complement inhibition as a method to manage these diseases, and to provide a Canadian perspective on the use of complement inhibition therapy through real-world cases of MG and NMOSD.

Clinical and MRI characteristics of multiple sclerosis in patients of Middle Eastern and North African ancestry residing in Ontario, Canada.

BACKGROUND: Multiple sclerosis (MS) incidence is rising in traditionally low-burden regions, including the Middle East and North Africa (MENA). OBJECTIVES: Our objective was to evaluate disease characteristics in MS patients of MENA descent (MENA-MS). METHODS: MENA-MS patients and age- and sex-matched MS patients of European descent (EUR-MS) were identified through the MS Clinic Registry of St. Michael's Hospital in Toronto, Canada. Disease activity and severity were evaluated by the annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, change in the Expanded Disability Status Scale (EDSS), progression index (PI), and MS Severity Score (MSSS). RESULTS: All MS patients within the registry identified to be of MENA origin (n = 192), and age- and sex-matched EUR-MS patients were included. Mean age was 42.9 years, 67% female. A total of 25% and 24% of EUR-MS and MENA-MS had progressive disease, with similar mean disease durations (11.5 and 11.4 years, respectively). Clinical and radiological disease activity (ARR, proportion with new/enlarging MRI lesions) was similar. MENA-MS showed greater disability progression over time (EDSS change = 0.24 vs. 0.06, p = 0.01), a higher MSSS (3.12 vs. 2.67, p = 0.04), and higher PI (0.34 vs. 0.27, p = 0.07). CONCLUSION: MENA-MS patients demonstrate higher disease severity compared to EUR-MS patients, despite having similar inflammatory measures of disease activity, with disability progression in the absence of relapses. These observations illustrate the importance of the intersections of environmental, socioeconomic, and genetic determinants in optimizing individualized MS care.

Cognitive impairment, the central vein sign, and paramagnetic rim lesions in RIS.

OBJECTIVE: The central vein sign (CVS) and "paramagnetic rim lesions" (PRL) are emerging imaging biomarkers in multiple sclerosis (MS) reflecting perivenular demyelination and chronic, smoldering inflammation. The objective of this study was to assess relationships between cognitive impairment (CI) and the CVS and PRL in radiologically isolated syndrome (RIS). METHODS: Twenty-seven adults with RIS underwent 3.0 T MRI of the brain and cervical spinal cord (SC) and cognitive assessment using the minimal assessment of cognitive function in MS battery. The CVS and PRL were assessed in white-matter lesions (WMLs) on T2*-weighted segmented echo-planar magnitude and phase images. Multivariable linear regression evaluated relationships between CI and MRI measures. RESULTS: Global CI was present in 9 (33%) participants with processing speed and visual memory most frequently affected. Most participants (93%) had ⩾ 40% CVS + WML (a threshold distinguishing MS from other WM disorders); 63% demonstrated PRL. Linear regression revealed that CVS + WML predicted performance on verbal memory(ß =-0.024, p = 0.03) while PRL predicted performance on verbal memory (ß = -0.040, p = 0.04) and processing speed (ß = -0.039, p = 0.03). CONCLUSIONS: CI is common in RIS and is associated with markers of perivenular demyelination and chronic inflammation in WML, such as CVS + WML and PRL. A prospective follow-up of this cohort will ascertain the importance of CI, CVS, and PRL as risk factors for conversion from RIS to MS.

Managing Multiple Sclerosis: Treatment Initiation, Modification, and Sequencing.

Recent therapeutic advances in the management of multiple sclerosis (MS) have raised questions about the selection of appropriate patient candidates for various treatments and, if the plan is to move from one treatment to another, the appropriate sequencing of these therapies. The selected approach should provide optimal disease management without limiting future therapeutic options based on safety concerns, and recognize potential future treatments and the possibility of combination therapies. Additional challenges include incorporation of patient needs and preferences into the overall therapeutic approach, in order to ensure optimal outcomes in the short and long term. The objective of this manuscript is to provide an overview of what is currently known regarding the impact of various therapies for MS on future therapeutic choices (sequencing). In this context, we reviewed the available evidence in support of various treatments and, based on the presence of disease activity, suggested a scheme for switching or escalating therapy with the main focus on sequencing of therapeutic approaches.

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events.

BACKGROUND AND PURPOSE: Previous studies reported Fabry disease in 0% to 4% of young patients with cryptogenic ischemic stroke (IS). We sought to determine the prevalence of Fabry and outcomes among young Canadians with cryptogenic IS or transient ischemic attack (TIA). METHODS: We prospectively enrolled individuals aged 18 to 55 with IS or speech or motor TIA, and no cause identified despite predetermined investigation. α-galactosidase-A gene was sequenced for Fabry diagnosis. National Institutes of Health Stroke Scale score was measured at presentation to quantify stroke severity. Modified Rankin Scale determined functional outcomes ≤7 days after presentation and 6 months later. RESULTS: We enrolled 365 patients with IS and 32 with TIA. α-galactosidase-A sequencing identified a single carrier of a genetic variant of unknown significance (p.R118C) and no well-recognized pathogenic variants. Mean National Institutes of Health Stroke Scale score was 3.1. Proportion of patients with modified Rankin Scale of 0 to 2 was 70.7% at ≤7 days and 87.4% at 6 months. National Institutes of Health Stroke Scale score at presentation and diabetes mellitus predicted 6-month modified Rankin Scale. Thirteen patients experienced 5 recurrent IS and 9 TIA during follow-up. No patient died. Most patients (98.7%) returned home. Among previous workers, 43% had residual working limitations. CONCLUSIONS: In this Canadian cohort of patients with cryptogenic IS or TIA, the prevalence of Fabry was 0.3% if p.R118C variant is considered as pathogenic. This suggests that more cost-effective methods should be applied for diagnosis of Fabry rather than systematic genetic screening in this population. Overall, cryptogenic IS in young adults is associated with favorable outcomes.

In-Patient Code Stroke: A Quality Improvement Strategy to Overcome Knowledge-to-Action Gaps in Response Time.

BACKGROUND AND PURPOSE: Stroke is a relatively common and challenging condition in hospitalized patients. Previous studies have shown delays in recognition and assessment of inpatient strokes leading to poor outcomes. The goal of this quality improvement initiative was to evaluate an in-hospital code stroke algorithm and educational program aimed at reducing the response times for inpatient stroke. METHODS: An inpatient code stroke algorithm was developed, and an educational intervention was implemented over 5 months. Data were recorded and compared between the 36-month period before and the 15-month period after the intervention was implemented. Outcome measures included time from last seen normal to initial assessment and from last seen normal to brain imaging. RESULTS: During the study period, there were 218 inpatient strokes (131 before the intervention and 87 after the intervention). Inpatient strokes were more common on cardiovascular wards (45% of cases) and occurred mainly during the perioperative period (60% of cases). After implementation of an inpatient code stroke intervention and educational initiative, there were consistent reductions in all timed outcome measures (median time to initial assessment fell from 600 [109-1460] to 160 [35-630] minutes and time to computed tomographic scan fell from 925 [213-1965] to 348.5 [128-1587] minutes). CONCLUSIONS: Our study reveals the efficacy of an inpatient code stroke algorithm and educational intervention directed at nurses and allied health personnel to optimize the prompt management of inpatient strokes. Prompt assessment may lead to faster stroke interventions, which are associated with better outcomes.

Atrial fibrillation in patients with cryptogenic stroke.

BACKGROUND: Atrial fibrillation is a leading preventable cause of recurrent stroke for which early detection and treatment are critical. However, paroxysmal atrial fibrillation is often asymptomatic and likely to go undetected and untreated in the routine care of patients with ischemic stroke or transient ischemic attack (TIA). METHODS: We randomly assigned 572 patients 55 years of age or older, without known atrial fibrillation, who had had a cryptogenic ischemic stroke or TIA within the previous 6 months (cause undetermined after standard tests, including 24-hour electrocardiography [ECG]), to undergo additional noninvasive ambulatory ECG monitoring with either a 30-day event-triggered recorder (intervention group) or a conventional 24-hour monitor (control group). The primary outcome was newly detected atrial fibrillation lasting 30 seconds or longer within 90 days after randomization. Secondary outcomes included episodes of atrial fibrillation lasting 2.5 minutes or longer and anticoagulation status at 90 days. RESULTS: Atrial fibrillation lasting 30 seconds or longer was detected in 45 of 280 patients (16.1%) in the intervention group, as compared with 9 of 277 (3.2%) in the control group (absolute difference, 12.9 percentage points; 95% confidence interval [CI], 8.0 to 17.6; P<0.001; number needed to screen, 8). Atrial fibrillation lasting 2.5 minutes or longer was present in 28 of 284 patients (9.9%) in the intervention group, as compared with 7 of 277 (2.5%) in the control group (absolute difference, 7.4 percentage points; 95% CI, 3.4 to 11.3; P<0.001). By 90 days, oral anticoagulant therapy had been prescribed for more patients in the intervention group than in the control group (52 of 280 patients [18.6%] vs. 31 of 279 [11.1%]; absolute difference, 7.5 percentage points; 95% CI, 1.6 to 13.3; P=0.01). CONCLUSIONS: Among patients with a recent cryptogenic stroke or TIA who were 55 years of age or older, paroxysmal atrial fibrillation was common. Noninvasive ambulatory ECG monitoring for a target of 30 days significantly improved the detection of atrial fibrillation by a factor of more than five and nearly doubled the rate of anticoagulant treatment, as compared with the standard practice of short-duration ECG monitoring. (Funded by the Canadian Stroke Network and others; EMBRACE ClinicalTrials.gov number, NCT00846924.).

Decision making under uncertainty, therapeutic inertia, and physicians' risk preferences in the management of multiple sclerosis (DIScUTIR MS).

BACKGROUND: The management of multiple sclerosis (MS) is rapidly changing by the introduction of new and more effective disease-modifying agents. The importance of risk stratification was confirmed by results on disease progression predicted by different risk score systems. Despite these advances, we know very little about medical decisions under uncertainty in the management of MS. The goal of this study is to i) identify whether overconfidence, tolerance to risk/uncertainty, herding influence medical decisions, and ii) to evaluate the frequency of therapeutic inertia (defined as lack of treatment initiation or intensification in patients not at goals of care) and its predisposing factors in the management of MS. METHODS/DESIGN: This is a prospective study comprising a combination of case-vignettes and surveys and experiments from Neuroeconomics/behavioral economics to identify cognitive distortions associated with medical decisions and therapeutic inertia. Participants include MS fellows and MS experts from across Spain. Each participant will receive an individual link using Qualtrics platform(©) that includes 20 case-vignettes, 3 surveys, and 4 behavioral experiments. The total time for completing the study is approximately 30-35 min. Case vignettes were selected to be representative of common clinical encounters in MS practice. Surveys and experiments include standardized test to measure overconfidence, aversion to risk and ambiguity, herding (following colleague's suggestions even when not supported by the evidence), physicians' reactions to uncertainty, and questions from the Socio-Economic Panel Study (SOEP) related to risk preferences in different domains. By applying three different MS score criteria (modified Rio, EMA, Prosperini's scheme) we take into account physicians' differences in escalating therapy when evaluating medical decisions across case-vignettes. CONCLUSIONS: The present study applies an innovative approach by combining tools to assess medical decisions with experiments from Neuroeconomics that applies to common scenarios in MS care. Our results will help advance the field by providing a better understanding on the influence of cognitive factors (e.g., overconfidence, aversion to risk and uncertainty, herding) on medical decisions and therapeutic inertia in the management of MS which could lead to better outcomes.

Anti-JC Virus Antibody Prevalence in Canadian MS Patients.

BACKGROUND: Anti-John Cunningham (JCV) antibodies have been detected in approximately 50% to 60% of multiple sclerosis (MS) patients. Age, sex, and geographic location have been associated with seroprevalence differences. We describe anti-JCV antibody prevalence in the Canadian cohort of patients enrolled in the JCV Epidemiology in MS study. METHODS: This cross-sectional multicenter study evaluated the effects of demographic and disease characteristics on anti-JCV antibody seroprevalence in MS patients irrespective of disease type and treatment. A single blood sample was collected for analysis of anti-JCV antibodies using a two-step enzyme-linked immunosorbent assay (ELISA). Chi-square and logistic regression tests were used to determine significance. RESULTS: A total of 4198 Canadian MS patients participated in the study; the overall anti-JCV antibody prevalence was 56.3% (95% confidence interval: 54.8% to 57.8%). Seroprevalence was significantly associated with age (increasing from 45% in young to 61% in those >60 years), sex, and region (p<0.0001 for age and sex; p=0.005 for region). No significant differences in anti-JCV antibody prevalence were associated with race, MS disease type and duration, or number and duration of treatments. Immunosuppressant use was associated with a higher seroprevalence rate (63.4%) compared with no immunosuppressant use (55.9%; p=0.040). CONCLUSIONS: Canadian MS patients had an overall anti-JCV antibody seroprevalence that was consistent with previous studies using the two-step ELISA. Significant associations of anti-JCV antibody positivity were found with age, sex, region, and immunosuppressant therapy, whereas seroprevalence was not associated with race, MS type, MS duration, or number or duration of MS treatments.

Low-Field (64mT) Portable MRI for Rapid Point-of-Care Diagnosis of DIS in Patients Presenting with Optic Neuritis.

BACKGROUND AND PURPOSE: Low-field 64mT portable brain MRI (pMRI) has recently shown diagnostic promise for MS. This study aimed to evaluate the utility of pMRI in assessing dissemination in space (DIS) in patients presenting with optic neuritis and determine whether deploying pMRI in the MS clinic can shorten the time from symptom onset to MRI. MATERIALS AND METHODS: Newly diagnosed optic neuritis patients referred to a tertiary academic MS center from July 2022 to January 2024 underwent both point-of-care pMRI and subsequent conventional 3T MRI (cMRI). Images were evaluated for periventricular (PV), juxtacortical (JC) and infratentorial (IT) lesions. DIS was determined on brain MRI per 2017 McDonald criteria. Test characteristics were computed using cMRI as the reference. Interrater and intermodality agreement between pMRI and cMRI were evaluated using Cohen's kappa. Time from symptom onset to pMRI and cMRI during the study period was compared to the preceding 1.5 years before pMRI implementation using Kruskal-Wallis with post-hoc Dunn's tests. RESULTS: Twenty patients (median age: 32.5 [IQR, 28-40]; 80% females) were included, of whom 9 (45%) and 5 (25%) had DIS on cMRI and pMRI, respectively. Median time interval between pMRI and cMRI was 7 days (IQR, 3.5-12.5). Interrater agreement was very good for PV (95%, κ=0.89), and good for JC and IT lesions (90%, κ=0.69 for both). Intermodality agreement was good for PV (90%, κ=0.80) and JC (85%, κ=0.63), and moderate for IT lesions (75%, κ=0.42) and DIS (80%, κ=0.58). pMRI had a sensitivity of 56% and specificity of 100% for DIS.The median time from symptom onset to pMRI was significantly shorter (8.5 days [IQR 7-12]) compared to the interval to cMRI before pMRI deployment (21 days [IQR 8-49], n=50) and after pMRI deployment (15 days [IQR 12-29], n=30) (both p<0.01). Time from symptom onset to cMRI in those periods was not significantly different (p=0.29). CONCLUSIONS: In optic neuritis patients, pMRI exhibited moderate concordance, moderate sensitivity and high specificity for DIS compared to cMRI. Its integration into the MS clinic reduced the time from symptom onset to MRI. Further studies are warranted to evaluate the role of pMRI in expediting early MS diagnosis and as an imaging tool in resource-limited settings. ABBREVIATIONS: pMRI = portable MRI; cMRI = conventional MRI; pwMS = patients with MS; PV = periventricular; JC= juxtacortical; IT = infratentorial; DIS = dissemination in space.

Treatment optimization in MS: Canadian MS Working Group updated recommendations.

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

Utility of the Canadian Treatment Optimization Recommendations (TOR) in MS care.

OBJECTIVES: Criteria for Treatment Optimization Recommendations (TOR) for patients with multiple sclerosis (MS) identify suboptimal response to disease-modifying treatment (DMT). The Canadian TOR (CanTOR) were used to indicate recommendations for treatment switches or treatment maintenance based on relapse, disease progression and magnetic resonance imaging (MRI) criteria in patients. We assessed concordance between the TOR and clinicians' decisions regarding treatment response and identified prevalence of patients with MS receiving DMT meeting medium/high levels of concern according to TOR. METHODS: Prospective baseline and end-of-study assessments of patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome were conducted in this open-label, 12-month, Phase IV, observational Canadian study. RESULTS: Data were reported for 184 patients (female 72%, mean age 39 years) of which 96% had RRMS. The TOR criteria identified 19 (10.3%) patients with suboptimal response to treatment. Twelve patients had ≥1 high level of concern. Two patients had ≥2 medium levels of concern. Concordance between TOR and clinician decision in maintaining treatment was 95.3%. Where treatment change was recommended by the TOR, concordance was 29.4%. Clinicians identified the TOR as the principal reason for changing treatment in 50.0% of cases where the TOR identified suboptimal response. The TOR were considered useful by 70.6% of clinicians when treatment optimization was recommended and by 55.3% when maintaining treatment was recommended. CONCLUSIONS: The TOR criteria can identify suboptimal response in this patient cohort. Concordance between TOR and clinician decision was high when maintaining treatment was recommended. Usefulness of the TOR was most apparent when treatment optimization was recommended.

Bilateral medial medullary infarction: a systematic review.

Bilateral infarction of the medial medulla (MMI) is rare. Limited information is available on clinical characteristics, etiology, and prognosis. High-resolution neuroimaging has a major role in elucidating the underlying stroke mechanism. The aim of this systematic review was to analyze the clinical presentations, stroke mechanisms, and outcomes in patients with bilateral MMI. We performed a systematic review of the literature from 1992-2011 that reported on clinical presentations, stroke mechanism, and/or outcomes in patients with magnetic resonance imaging-proven bilateral MMI. Medline, EMBASE, and Web of Science Scholars Portal were searched without language restriction. Two reviewers independently assessed identified studies to determine eligibility, validity, and quality. The primary outcome was inpatient mortality; a secondary outcome was case fatality at 12 months. We identified 138 articles from Medline, EMBASE, and Scholars Portal including the MeSH terms "brainstem infarction," "medulla," and "bilateral." Twenty-nine articles met our inclusion criteria, including a total of 38 cases with bilateral MMI, and included in our study. These 38 patients had a mean age of 62.2 years and were predominately male (74.2%). The most common clinical presentations were motor weakness in 78.4%, dysarthria in 48.6%, and hypoglossal palsy in 40.5%. The most common vascular pathology was vertebral artery atherosclerosis, in 38.5%. The clinical outcome was poor (mortality, 23.8%; dependency, 61.9%). Bilateral medial medullary infarction is a rare stroke syndrome. Clinical presentations were mostly rostral medullary lesions. Large-artery atherosclerosis and branch disease were the most common stroke mechanisms. The clinical outcome was usually poor.

Prevalence of Fabry disease in young patients with cryptogenic ischemic stroke.

BACKGROUND: A German study diagnosed 4% of young cryptogenic ischemic stroke patients with Fabry disease, an X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A (α-GAL-A) gene resulting in an accumulation of glycosphingolipids. A lower prevalence was found in other geographic regions. AIM: To determine the prevalence of Fabry disease in a Canadian population of young cryptogenic ischemic stroke patients. MATERIALS AND METHODS: Patients with cryptogenic ischemic stroke at age 16-55 were retrospectively identified in our institutional stroke database and underwent a focused clinical evaluation. We sequenced the α-GAL-A gene and measured the levels of blood globotriaosylsphingosine in subjects with mutations of undetermined pathogenicity. Fabry disease was diagnosed in patients with pathogenic mutations or increased levels of blood globotriaosylsphingosine. RESULTS: Ninety-three of 100 study subjects had normal α-GAL-A gene polymorphisms. Seven had mutations of undetermined pathogenicity, including one with increased globotriaosylsphingosine (prevalence, 1%; 95% confidence interval, <.01%-6%). No subjects had angiokeratomas or other clinical manifestations of Fabry disease. Investigation results suggestive of Fabry disease (idiopathic hypertrophic cardiomyopathy, proteinuria, vertebrobasilar dolichoectasia, and the pulvinar sign) were found only in subjects with normal α-GAL-A genes. Apart from the 100 study subjects, our database included another patient with a family history of Fabry disease and a pathogenic mutation identified before her ischemic stroke presentation as the first clinical manifestation of Fabry disease. Both Fabry patients experienced recurrent ischemic stroke. CONCLUSIONS: Fabry disease accounts for a small proportion of young Canadians with cryptogenic ischemic stroke. Identification of Fabry biomarkers remains a research priority to delineate stroke patients disserving routine screening.

Expert opinion on the long-term use of cladribine tablets for multiple sclerosis: Systematic literature review of real-world evidence.

BACKGROUND: Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT. METHODS: Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2-3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question. RESULTS: A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1-21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to 18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided. CONCLUSIONS: RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated.

Expert opinion on COVID-19 vaccines and cladribine tablets in MS: A plain language summary.

WHAT IS THIS SUMMARY ABOUT?: People with multiple sclerosis (shortened to MS) who are taking cladribine tablets may have concerns about whether they can be vaccinated against COVID-19. This summary details the findings from a previously published article, in which an international committee of 10 MS experts developed recommendations to answer some important questions about COVID-19 vaccines in people with MS (including relapsing-remitting or active secondary progressive disease) taking cladribine tablets. WHAT WERE THE RESULTS?: The committee identified 13 recommendations, which were all agreed upon by at least three-quarters (75%) of the 38 voting MS experts. Generally, they recommended that people with MS taking cladribine tablets should be vaccinated for COVID-19 as soon as possible, because the vaccine is thought to be both safe and effective, and vaccine responses were not likely to be affected by cladribine tablets. WHAT DO THE RESULTS MEAN?: Overall, people with MS taking cladribine tablets should receive the COVID-19 vaccine to protect themselves, unless advised differently by their healthcare provider.

Language discordance as a marker of disparities in cerebrovascular risk and stroke outcomes: A multi-center Canadian study.

Background: Differences in ischemic stroke outcomes occur in those with limited English proficiency. These health disparities might arise when a patient's spoken language is discordant from the primary language utilized by the health system. Language concordance is an understudied concept. We examined whether language concordance is associated with differences in vascular risk or post-stroke functional outcomes, depression, obstructive sleep apnea and cognitive impairment. Methods: This was a multi-center observational cross-sectional cohort study. Patients with ischemic stroke/transient ischemic attack (TIA) were consecutively recruited across eight regional stroke centers in Ontario, Canada (2012 - 2018). Participants were language concordant (LC) if they spoke English as their native language, ESL if they used English as a second language, or language discordant (LD) if non-English speaking and requiring translation. Results: 8156 screened patients. 6,556 met inclusion criteria: 5067 LC, 1207 ESL and 282 LD. Compared to LC patients: (i) ESL had increased odds of diabetes (OR = 1.28, p = 0.002), dyslipidemia (OR = 1.20, p = 0.007), and hypertension (OR = 1.37, p<0.001) (ii) LD speaking patients had an increased odds of having dyslipidemia (OR = 1.35, p = 0.034), hypertension (OR = 1.37, p<0.001), and worse functional outcome (OR = 1.66, p<0.0001). ESL (OR = 1.88, p<0.0001) and LD (OR = 1.71, p<0.0001) patients were more likely to have lower cognitive scores. No associations were noted with obstructive sleep apnea (OSA) or depression. Conclusions: Measuring language concordance in stroke/TIA reveals differences in neurovascular risk and functional outcome among patients with limited proficiency in the primary language of their health system. Lower cognitive scores must be interpreted with caution as they may be influenced by translation and/or greater vascular risk. Language concordance is a simple, readily available marker to identify those at risk of worse functional outcome. Stroke systems and practitioners must now study why these differences exist and devise adaptive care models, treatments and education strategies to mitigate barriers influenced by language discordance.

Delirium in acute stroke: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Delirium is common in the early stage after hospitalization for an acute stroke. We conducted a systematic review and meta-analysis to evaluate the outcomes of acute stroke patients with delirium. METHODS: We searched MEDLINE, EMBASE, CINAHL, Cochrane Library databases, and PsychInfo for relevant articles published in English up to September 2011. We included observational studies for review. Two reviewers independently assessed studies to determine eligibility, validity, and quality. The primary outcome was inpatient mortality and secondary outcomes were mortality at 12 months, institutionalization, and length of hospital stay. RESULTS: Among 78 eligible studies, 10 studies (n=2004 patients) met the inclusion criteria. Stroke patients with delirium had higher inpatient mortality (OR, 4.71; 95% CI, 1.85-11.96) and mortality at 12 months (OR, 4.91; 95% CI, 3.18-7.6) compared to nondelirious patients. Patients with delirium also tended to stay longer in hospital compared to those who did not have delirium (mean difference, 9.39 days; 95% CI, 6.67-12.11) and were more likely to be discharged to a nursing homes or other institutions (OR, 3.39; 95% CI, 2.21-5.21). CONCLUSIONS: Stroke patients with development of delirium have unfavorable outcomes, particularly higher mortality, longer hospitalizations, and a greater degree of dependence after discharge. Early recognition and prevention of delirium may improve outcomes in stroke patients.