Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels Reflect Different Mechanisms of Disease Progression under B-Cell Depleting Treatment in Multiple Sclerosis.

OBJECTIVE: To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events. METHODS: A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores. RESULTS: Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high. INTERPRETATION: Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024.

A Multicenter Longitudinal MRI Study Assessing LeMan-PV Software Accuracy in the Detection of White Matter Lesions in Multiple Sclerosis Patients.

BACKGROUND: Detecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan-PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow-up of MS patients; however, multicenter validation studies are lacking. PURPOSE: To assess the accuracy of LeMan-PV for the longitudinal detection NEL white-matter MS lesions in a multicenter clinical setting. STUDY TYPE: Retrospective, longitudinal. SUBJECTS: A total of 206 patients with a definitive MS diagnosis and at least two follow-up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow-up = 45.2 years (range: 36.9-52.8 years); 70 males. FIELD STRENGTH/SEQUENCE: Fluid attenuated inversion recovery (FLAIR) and T1-weighted magnetization prepared rapid gradient echo (T1-MPRAGE) sequences at 1.5 T and 3 T. ASSESSMENT: The study included 313 MRI pairs of datasets. Data were analyzed with LeMan-PV and compared with a manual "reference standard" provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating-accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1-score, lesion-wise False-Positive-Rate (aFPR), and other measures were used to assess LeMan-PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T. STATISTICAL TESTS: Intraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers. RESULTS: The interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue < 10-20 , CK = 0.82, P value = 0) and good (ICC = 0.75, P value < 10-12 , CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan-PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1-score = 0.44, aFPR = 1.31. When both follow-ups were acquired at 3 T, LeMan-PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1-score = 0.28, aFPR = 3.03). DATA CONCLUSION: In this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan-PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan-PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological-routine flow. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

OBJECTIVE: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. METHODS: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgGIF and IgMIF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. RESULTS: By categorical analysis, in patients with IgMIF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgMIF < median. Dose-dependent associations were also found for IgMIF but not for IgGIF with magnetic resonance imaging-defined disease activity and sNfL. INTERPRETATION: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.

An overview of pivotal trials and real-world evidence for CD20-depleting therapy in multiple sclerosis : Immunotherapy with rituximab, ocrelizumab, and ofatumumab.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system leading to demyelination and neurodegeneration of brain tissue. For a long time, research focused on T cells as the primary mechanism of disease. Driven by reports on the clinical results of B cell-depleting therapies, this therapeutic approach has come into focus in the last decade, and new highly effective treatments have been developed and are now complementing the therapeutic landscape. This review provides an overview of the development of B cell-depleting therapies and shows the advantages and disadvantages of current developments. In addition, we discuss basic considerations for CD20-depleted MS patients in the face of the COVID-19 pandemic.

Percutaneous closure of patent foramen ovale in migraine with aura, a randomized controlled trial.

AIMS: Migraine with aura and patent foramen ovale (PFO) are associated. The Percutaneous Closure of PFO in Migraine with Aura (PRIMA) trial is a multicentre, randomized trial to investigate the effect of percutaneous PFO closure in patients refractory to medical treatment. METHODS: Migraine with aura patients and PFO who were unresponsive to preventive medications were randomized to PFO closure or medical treatment. Both groups were given acetylsalicylic acid 75-100 mg/day for 6 months and clopidogrel 75 mg/day for 3 months. The primary endpoint was reduction in monthly migraine days during months 9-12 after randomization compared with a 3-month baseline phase before randomization. The committee reviewing the headache diaries were blinded to treatment assignment. RESULTS: One hundred and seven patients were randomly allocated to treatment with an Amplatzer PFO Occluder (N = 53) or control with medical management (N = 54). The trial was terminated prematurely because of slow enrolment. Eighty-three patients (40 occluder, 43 control) completed 12-month follow-up. Mean migraine days at baseline were 8 (±4.7 SD) in the closure group and 8.3 (±2.4) in controls. The primary endpoint was negative with -2.9 days after PFO closure vs. -1.7 days in control group (P = 0.17). Patent foramen ovale closure caused five adverse events without permanent sequelae. CONCLUSION: In patients with refractory migraine with aura and PFO, PFO closure did not reduce overall monthly migraine days.

Occlusion Location of Middle Cerebral Artery Stroke and Outcome after Endovascular Treatment.

BACKGROUND: The aim of this study was to analyze the influence of the location of middle cerebral artery (MCA) occlusion on recanalization, complications and outcome after endovascular therapy. METHODS: Four-hundred sixty-four patients with acute MCA occlusions were treated with endovascular therapy. RESULTS: Two-hundred ninety-three patients had M1 occlusions, 116 had M2, and 55 had M3/4 occlusions. Partial or complete recanalization was more frequently achieved in M1 (76.8%) than in M2 (59.1%) or M3/4 (47.3%, p < 0.001) occlusions, but favorable outcome (modified Rankin Scale 0-2) was less frequent in M1 (50.9%) than M2 (63.7%) or M3/4 (72.7%, p = 0.018) occlusions. Symptomatic intracerebral hemorrhage (ICH) did not differ between occlusion sites, but asymptomatic ICH was more common in M1 (22.6%) than in M2 occlusions (8.6%, p = 0.003). Recanalization was associated with favorable outcome in M1 (p < 0.001) and proximal M2 (p = 0.003) but not in distal M2 or M3/4 occlusions. CONCLUSIONS: Recanalization with endovascular therapy was more frequently achieved in patients with proximal than distal MCA occlusions, but recanalization was associated with favorable outcome only in M1 and proximal M2 occlusions. Outcome was better with distal than proximal occlusions. This study shows that recanalization can be used as a surrogate marker for clinical outcome only in patients with proximal occlusions.

Antimyelin antibodies as predictors of disability after clinically isolated syndrome.

There is controversy whether determination of antibodies against myelin, myelin oligodendrocyte glycoprotein, and myelin basic protein in serum from patients with a first episode suggestive of multiple sclerosis is of prognostic value. We evaluated whether detection of antimyelin antibodies in serum indicates a worse course with earlier time to a second relapse and increased progression of disability. We conducted a prospective study at the Department of Neurology, Inselspital Bern, Switzerland from 2004 to 2008 in patients presenting with a clinically isolated syndrome (CIS) and a follow-up of at least 4 months. Antimyelin antibodies were assessed by Western blot. Results were correlated with clinical course and sex. Among 93 consecutive patients with a CIS, 74 (80%) were positive for either one or both antimyelin antibodies. A relapse occurred in 49 (53%) and the median EDSS was 2 (range 1-3.5) after a mean observation period of 20 months. Presence of antimyelin antibodies at CIS neither increased the risk for a second relapse nor for progression of disability. Stratification for gender did not reveal differences for any of the clinical surrogates. The sole determination of antimyelin antibodies in serum is of limited prognostic value for the identification of patients with different short-term course.

MultiSCRIPT-Cycle 1-a pragmatic trial embedded within the Swiss Multiple Sclerosis Cohort (SMSC) on neurofilament light chain monitoring to inform personalized treatment decisions in multiple sclerosis: a study protocol for a randomized clinical trial.

BACKGROUND: Treatment decisions for persons with relapsing-remitting multiple sclerosis (RRMS) rely on clinical and radiological disease activity, the benefit-harm profile of drug therapy, and preferences of patients and physicians. However, there is limited evidence to support evidence-based personalized decision-making on how to adapt disease-modifying therapy treatments targeting no evidence of disease activity, while achieving better patient-relevant outcomes, fewer adverse events, and improved care. Serum neurofilament light chain (sNfL) is a sensitive measure of disease activity that captures and prognosticates disease worsening in RRMS. sNfL might therefore be instrumental for a patient-tailored treatment adaptation. We aim to assess whether 6-monthly sNfL monitoring in addition to usual care improves patient-relevant outcomes compared to usual care alone. METHODS: Pragmatic multicenter, 1:1 randomized, platform trial embedded in the Swiss Multiple Sclerosis Cohort (SMSC). All patients with RRMS in the SMSC for ≥ 1 year are eligible. We plan to include 915 patients with RRMS, randomly allocated to two groups with different care strategies, one of them new (group A) and one of them usual care (group B). In group A, 6-monthly monitoring of sNfL will together with information on relapses, disability, and magnetic resonance imaging (MRI) inform personalized treatment decisions (e.g., escalation or de-escalation) supported by pre-specified algorithms. In group B, patients will receive usual care with their usual 6- or 12-monthly visits. Two primary outcomes will be used: (1) evidence of disease activity (EDA3: occurrence of relapses, disability worsening, or MRI activity) and (2) quality of life (MQoL-54) using 24-month follow-up. The new treatment strategy with sNfL will be considered superior to usual care if either more patients have no EDA3, or their health-related quality of life increases. Data collection will be embedded within the SMSC using established trial-level quality procedures. DISCUSSION: MultiSCRIPT aims to be a platform where research and care are optimally combined to generate evidence to inform personalized decision-making in usual care. This approach aims to foster better personalized treatment and care strategies, at low cost and with rapid translation to clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT06095271. Registered on October 23, 2023.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. METHODS: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. RESULTS: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). DISCUSSION: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Contrast-Enhancing Lesion Segmentation in Multiple Sclerosis: A Deep Learning Approach Validated in a Multicentric Cohort.

The detection of contrast-enhancing lesions (CELs) is fundamental for the diagnosis and monitoring of patients with multiple sclerosis (MS). This task is time-consuming and suffers from high intra- and inter-rater variability in clinical practice. However, only a few studies proposed automatic approaches for CEL detection. This study aimed to develop a deep learning model that automatically detects and segments CELs in clinical Magnetic Resonance Imaging (MRI) scans. A 3D UNet-based network was trained with clinical MRI from the Swiss Multiple Sclerosis Cohort. The dataset comprised 372 scans from 280 MS patients: 162 showed at least one CEL, while 118 showed no CELs. The input dataset consisted of T1-weighted before and after gadolinium injection, and FLuid Attenuated Inversion Recovery images. The sampling strategy was based on a white matter lesion mask to confirm the existence of real contrast-enhancing lesions. To overcome the dataset imbalance, a weighted loss function was implemented. The Dice Score Coefficient and True Positive and False Positive Rates were 0.76, 0.93, and 0.02, respectively. Based on these results, the model developed in this study might well be considered for clinical decision support.

Correlation of disability with quality of life in patients with multiple sclerosis treated with natalizumab: primary results and post hoc analysis of the TYSabri ImPROvement study (PROTYS).

Background: In patients with multiple sclerosis (MS), relapses and disability progression have been associated with decreased health-related quality of life (HRQoL). Methods: PROTYS, a prospective, multicentre, single-arm, observational study in seven Swiss MS centres, evaluated correlations between change in disability status (measured through the Expanded Disability Status Scale (EDSS)) and HRQoL changes (measured through the global Multiple Sclerosis International Quality of Life (MusiQoL) index questionnaire) in 35 patients with relapsing remitting MS on natalizumab for 1 year. In addition, several other scales were also used, such as: Multiple Sclerosis Intimacy and Sexuality Questionnaire-19, EuroQoL-5 Dimension, and Fatigue Scale of Motor and Cognitive Function. A post hoc analysis further assessed the association between HRQoL changes after 1 year and the MusiQoL subscores and other patient-reported outcome (PRO) measures. Results: At 1 year, patients were categorised into 'EDSS improved' (6/35), 'EDSS stable' (28/35) and 'EDSS worsened' (1/35). Mean disability scores decreased for 'EDSS improved' and 'EDSS stable' but increased for 'EDSS worsened'. Mean MusiQoL index score for 'EDSS improved' increased from 61.2 at baseline to 66.3 at 1 year, while the 'EDSS stable' group increased from 67.9 to 70.8. No meaningful statistical relationship was observed between EDSS group and changes in MusiQoL score. For the post hoc analysis, patients were categorised in 'MusiQoL improved' (n=21) and 'MusiQoL worsened' (n=14) groups. MusiQoL subscores for 'symptoms,' 'psychological well-being' and 'activities of daily living', as well as scores for several related PRO measures, correlated with improvement of the MusiQoL global index. There was no correlation between the changes in MusiQoL global index and EDSS score. Conclusions: Natalizumab treatment for 1 year resulted in either improved or stable EDSS status in most patients, and although no significant relationship was observed between global HRQoL change and EDSS change, several domains of HRQoL seemed to improve with natalizumab treatment. Trial registration number: NCT02386566.

Prevalence and Burden of Migraine in Switzerland: Cross-Sectional Study in ten Specialised Headache Centres from the BECOME Study.

INTRODUCTION: There is limited real-world evidence on the burden of migraine among patients with prior preventive treatment failure (PPTF). In the BECOME Swiss subanalysis, we aimed to assess current prevalence of PPTF in patients with migraine seen at specialised headache centres in Switzerland and burden of migraine in these patients. Furthermore, we assessed this burden in subgroups stratified by monthly migraine days (MMDs) and number of PPTFs. METHODS: BECOME was a prospective, multicentre, non-interventional two-part study conducted in 17 countries across Europe and Israel. This subanalysis includes patients visiting ten headache specialist centres in Switzerland. In part 1, patients visiting the centres over 3 months were screened by physicians for frequency of PPTF, MMD and other migraine characteristics. Patients with ≥ 1 PPTF and ≥ 4 MMDs were invited to take part in part 2. The primary endpoint was the proportion of patients with ≥ 1 PPTF (part 1). Other endpoints included proportion of patients specified by number of PPTF and MMD (part 1, part 2), and impact of migraine on patient-reported outcomes (PROs; part 2). RESULTS: Patients (1677) from ten Swiss centres were included in part 1, of which 855 (51.0%) reported ≥ 1 PPTF. One hundred fifty-five patients were included in part 2: 6.5% reported ≥ 4 PPTFs and 43.2% reported ≥ 15 MMDs. Mean EuroQoL 5 and EuroQoL visual analogue scale (EQ-VAS) were 0.8 ± 0.2 and 69.6 ± 20.2, respectively, suggesting a mild level of impairment in the daily functioning and self-reported health of the patients. Mean six-item Headache Impact Test (HIT-6) and modified Migraine Disability Assessment (mMIDAS) scores were 63.3 ± 6.5 and 22.7 ± 21.8, respectively, corresponding to severe migraine burden. Patients also reported impairment in work-related productivity and general activities (48.6 ± 22.8) but no associations of anxiety (7.2 ± 4.4) or depression (6.0 ± 4.4) with migraine were noted. Burden of migraine increased with increasing frequency of PPTF and MMD. CONCLUSIONS: Migraine-related quality of life, as well as work productivity are significantly affected in Swiss patients with migraine. Increasing migraine burden is associated with increasing migraine frequency and prior treatment failures.

Endovascular therapy of 623 patients with anterior circulation stroke.

BACKGROUND AND PURPOSE: Endovascular therapy of acute ischemic stroke has been shown to be beneficial for selected patients. The purpose of this study is to determine predictors of outcome in a large cohort of patients treated with intra-arterial thrombolysis, mechanical revascularization techniques, or both. METHODS: We prospectively acquired data for 623 patients with acute cerebral infarcts in the carotid artery territory who received endovascular treatment at a single center. Logistic regression analysis was performed to determine predictors of outcome. RESULTS: Median National Institutes of Health Stroke Scale (NIHSS) at admission was 15. Partial or complete recanalization was achieved in 70.3% of patients; it was independently associated with hypercholesterolemia (P=0.02), absence of coronary artery disease (P=0.023), and more proximal occlusion site (P<0.0001). After 3 months, 80.5% of patients had survived, and 48.9% of patients reached favorable outcome (modified Rankin scale score 0-2). Good collaterals (P<0.0001), recanalization (P=0.023), hypercholesterolemia (P=0.03), lower NIHSS at admission (P=0.001), and younger age (P<0.0001) were independent predictors for survival. More peripheral occlusion site (P<0.0001), recanalization (P<0.0001), hypercholesterolemia (P=0.002), good collaterals (P=0.002), lower NIHSS (P<0.0001), younger age (P<0.0001), absence of diabetes (P=0.002), and no previous antithrombotic therapy (P=0.036) predicted favorable outcome. Time to treatment was only a predictor of outcome, when collaterals were excluded from the model. Symptomatic intracerebral hemorrhage occurred in 5.5% and was independently predicted by poor collaterals (P=0.004). CONCLUSIONS: Several independent predictors for outcome and complications were identified. Unlike in intravenous thrombolysis trials, time to treatment was a predictor of outcome only when collaterals were excluded from the model, indicating the important role of collaterals for the time window.

Adverse effect of early epileptic seizures in patients receiving endovascular therapy for acute stroke.

BACKGROUND AND PURPOSE: The aim of this study was to analyze epileptic seizures and their impact on outcome in patients with stroke treated with endovascular therapy. METHODS: From December 1992 to December 2010 we managed 805 patients with stroke with endovascular therapy. Epileptic seizures, bleeding complications, and 3-month outcomes were recorded prospectively. Outcomes of patients with early seizures (within 24 hours of stroke onset) and patients with late seizures (>24 hours after stroke) were compared with outcomes of seizure-free patients using uni- and multivariable statistics. RESULTS: Forty-four of 805 patients (5.5%) had seizures between stroke onset and 3-month follow-up, 26 patients early and 18 late. Outcome of patients with late seizures and seizure-free patients was similar (P=0.144 and 0.807). Patients with early seizures had higher baseline National Institutes of Health Stroke Scale (P=0.023) and were younger (P=0.021) than seizure-free patients. Their mortality rate was 50% compared with 22.3% of the seizure free-patients (P=0.003), and less patients reached a favorable outcome (modified Rankin Scale 0-2): 15.4% and 46.8%, respectively (P=0.001). Early seizures independently predicted an unfavorable outcome (P=0.014; OR, 4.749; 95% CI, 0.376-3.914) and increased mortality (P=0.001; OR, 5.861; 95% CI, 0.770-2.947) in multiregression analysis. Patients with early seizures had a 1.6-fold higher risk for unfavorable outcome and a 2.2-fold higher risk for death compared with seizure-free patients. CONCLUSIONS: Seizures within 24 hours of stroke onset were associated with worse outcome in patients with stroke undergoing endovascular therapy. Our findings confirm a need for trials for prophylactic anticonvulsive treatment in patients receiving endovascular therapy for acute stroke.

Impact of thrombolysis on stroke outcome at 12 months in a population: the Bern stroke project.

BACKGROUND AND PURPOSE: Thrombolysis improves outcome of patients with acute ischemic stroke, but it is unknown whether thrombolysis has a measurable effect on long-term outcome in a defined population. METHODS: We prospectively assessed demographic data, management, and outcome of acute ischemic stroke patients admitted within 48 hours to 18 primary care hospitals of the canton of Bern (969 299 inhabitants) during 12 months. Blinded follow-up was obtained at 3 and 12 months. Predictors of mortality and favorable outcome (modified Rankin Scale score ≤2) at 3 and 12 months using logistic regression were analyzed. RESULTS: From December 2007 to December 2008, 807 patients (mean age, 72 years) were included. Median National Institutes of Health Stroke Scale score on admission was 5; 107 patients (13%) received intravenous, intra-arterial, or mechanical thrombolysis. Estimated cumulative mortality at 3 months was 20.6% and at 12 months 27.4%. Age 75 years or older, higher National Institutes of Health Stroke Scale scores, and higher Charlson comorbidity index were independent predictors of mortality at 3 and 12 months. Estimated favorable outcome at 3 months was 48.2% and at 12 months was 44.6%. Thrombolysis was the only modifiable independent predictor of favorable outcome at 3 (relative risk, 1.49; 95% CI, 1.18-1.89) and 12 months (relative risk, 1.59; 95% CI, 1.24-2.04), whereas age younger than 75 years, male gender, National Institutes of Health Stroke Scale score <4, and lower Charlson comorbidity index were nonmodifiable predictors. CONCLUSIONS: Thirteen percent of acute ischemic stroke patients admitted within 48 hours to Bernese hospitals underwent thrombolysis, which exerted a measurable effect on 3-month outcome in this population. This effect was sustained at 12 months. Age, stroke severity, Charlson comorbidity index, and male gender were independent nonmodifiable predictors of outcome.

Plaque characteristics of asymptomatic carotid stenosis and risk of stroke.

BACKGROUND: The optimal treatment of asymptomatic carotid stenosis (ACS) is controversial. To optimize the risk-benefit ratio of carotid artery revascularization, it is crucial to identify ACS patients who are at increased stroke risk. Recent data suggest that plaque vulnerability depends on its composition. Therefore, we assessed plaque composition in ACS to determine predictors for ipsilateral cerebrovascular events. METHODS: 62 patients with 65 ACS ≥50% underwent 3-T MRI of the carotid bifurcation (TOF, special dark-blood weighted noncontrast and contrast-enhanced T(1) and T(2) images) and of the brain. The different plaque components (lipid core, intraplaque hemorrhage, calcification and the status of the fibrous cap) were assessed. Furthermore, the plaque volume and the volume of clinically silent cortical and subcortical infarcts in the territory of the stenosed carotid artery as seen on FLAIR images were determined by using a semi-automated software. Carotid stenosis was considered asymptomatic if there had not been any clinically apparent ischemic events in the corresponding vascular territory within the previous 6 months. During follow-up, information on the occurrence of cerebrovascular events, medical treatment and sonographic changes of the stenosis was collected. RESULTS: At baseline, 24 ACS (37%) were classified as high grade. A lipid-rich necrotic core was the dominant plaque component in 16 ACS (25%). The plaque volume was higher in ACS with a lipid-rich necrotic core as dominant plaque component (p = 0.002) and in patients with prior stroke/TIA (p = 0.010). After a median follow-up of 18.9 months (interquartile range 3.5-30.1) there were 2 ipsilateral strokes and 3 ipsilateral TIAs. The average annual event rate was 7.7%. A lipid-rich necrotic core (HR 7.21; 95% CI 1.12-46.28; p = 0.037), sonographic progression of the stenosis (HR 7.00; 95% CI 1.13-41.34; p = 0.036), history of stroke (HR 11.03; 95% CI 1.23-99.36; p = 0.032), and the volume of clinically asymptomatic ischemic brain lesions (HR 1.14/cm(3); 95% CI 1.03-1.25; p = 0.008) predicted cerebrovascular events. Patients on statin therapy at follow-up were at lower risk of events (HR 0.17; 95% CI 0.03-1.00; p = 0.05). CONCLUSIONS: In addition to medical history and sonographic findings, a lipid-rich necrotic core within the plaque turned out as a predictor of cerebrovascular events. Therefore, MR imaging of carotid plaques deserves further attention and might be helpful to improve risk stratification of asymptomatic carotid disease. The identified predictors could be combined in a risk model and tested in larger prospective studies.

Oral disease modifying therapies - A game changer for treatment decision in untreated patients with RRMS and CIS? - A swiss single center cross-sectional study.

INTRODUCTION: Several disease-modifying therapies (DMTs) show efficacy in relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS). However, there is still a relevant proportion of patients who remain untreated. We provide real-world data on untreated and treated patients and we report whether and how the introduction of oral DMTs changed the treatment decision. Furthermore, we discuss possible reasons for not receiving DMTs. METHODS: We conducted a retrospective cross-sectional study and analysed demographic and clinical data of patients with RRMS and CIS at our MS center. Comparison was made between untreated and treated patients in 2010 (before the introduction of oral DMTs) and in 2014 (after the introduction of oral DMTs). Furthermore, we analysed reasons for the decision against DMTs in patients who never received DMTs and patients who discontinued DMTs. RESULTS: We analysed datasets of 344 MS patients in 2010 and 253 in 2014. There were more untreated patients in CIS than in RRMS. In RRMS, the proportion of untreated patients decreased significantly between 2010 and 2014 from 23.6% to 11.1%, while the use of oral medications increased significantly from <1% to more than 50% in 2014. In CIS, there was no significant change in untreated patients between 2010 and 2014 (61.1% in 2010 to 52.6% in 2014). Untreated patients with RRMS were significantly older and had lower ARR than treated patients. Patients who never received DMT had lower EDSS compared to patients that had been treated before. The main reasons for the decision against DMT were "belief in a benign course" and "fear of adverse effects". Treatment discontinuation was caused mainly by the adverse effects. DISCUSSION: In our data a relevant proportion of patients with RRMS and CIS did not receive any DMT. We hypothesize that in patients with RRMS the introduction of oral DMTs translated to a higher rate of treatment, whereas in CIS there no change was observed. This could be due to limited therapeutic options in CIS. There is more information needed regarding the treatment recommendation for older patients and patients with mild course of the disease.

SARS-CoV-2 mRNA Vaccination in People with Multiple Sclerosis Treated with Fingolimod: Protective Humoral Immune Responses May Develop after the Preferred Third Shot.

Evidence suggests limited development of protective IgG responses to mRNA-based vaccines in sphingosine-1-phosphate receptor (S1PR)-modulator treated individuals with multiple sclerosis (MS). We studied the extent of the humoral immune response after the preferred third mRNA SARS-CoV-2 vaccine in S1PR-modulator treated people with MS (pwMS) and insufficient IgG responses after the standard immunization scheme. Eight pwMS that were treated with fingolimod received a third homologous SARS-CoV-2 mRNA vaccine dose, either the Moderna's mRNA-1273 or Pfizer-BioNTech's BNT162b2 vaccine. We quantified the serum levels of IgG antibodies against the receptor-binding domain of SARS-CoV-2 four weeks later. An antibody titer of 100 AU/mL or more was considered protective. After the third vaccination, we found clinically relevant IgG titers in four out of eight individuals (50%). We conclude that the humoral immune response may reach protective levels after the third preferred dose of the homologous SARS-CoV-2 mRNA vaccine. Vaccine shots in S1PR-modulator treated pwMS ahead of schedule may be a strategy to overcome insufficient humoral immune responses following the standard vaccination scheme.

Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis.

Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Patent foramen ovale may be causal for the first stroke but unrelated to subsequent ischemic events.

BACKGROUND AND PURPOSE: Studies with very long follow-up are scarce in patients with cryptogenic stroke and patent foramen ovale (PFO). Little is known about the etiology of recurrent cerebrovascular events (CVE) in PFO patients. METHODS: We collected information on recurrent CVE in 308 patients with cryptogenic stroke and PFO and sought to determine concurrent stroke causes that had emerged or been newly detected since the index event. One hundred fifty-eight patients received aspirin (48%), clopidogrel (2%), or oral anticoagulants (50%; medical group). One hundred fifty patients underwent percutaneous PFO closure (closure group). RESULTS: Mean age at index event was 50 years (SD 13). In 33% of patients, the index stroke or transient ischemic attack was preceded by at least 1 CVE. Mean follow-up was 8.7±4.0 years. During follow-up, 32 recurrent CVE (13 strokes and 19 transient ischemic attacks) occurred in the medical and 16 recurrent CVE (8 strokes and 8 transient ischemic attacks) in the closure group. Concurrent etiologies were identified for 12 recurrent CVE in the medical group (38%): large artery disease (9%), small artery disease (6%), cardioembolism (13%), cerebral vasculitis (3%), and antiphospholipid-antibody-syndrome (6%). In the closure group, 7 recurrent CVE had a concurrent etiology (44%): large artery disease (6%), small artery disease (19%), cardioembolism (13%), and thrombophilic disorder (6%). The frequency of concurrent etiologies did not differ between patients with recurrent CVE under medical treatment and those undergoing PFO closure (P=0.68). CONCLUSIONS: Concurrent etiologies are identified for more than one third of recurrent ischemic events in patients with cryptogenic stroke, casting doubt on the sole causal role of PFO.