Approach to Managing the Initial Presentation of Multiple Sclerosis: A Worldwide Practice Survey.

Background and Objectives: Available disease-modifying therapies (DMTs) for multiple sclerosis (MS) are rapidly expanding; although escalation approaches aim to balance safety and efficacy, emerging evidence suggests superior outcomes for people with MS who are exposed to early high-efficacy therapies. We aimed to explore practice differences in prevailing management strategies for relapsing-remitting MS. Methods: We used a worldwide electronic survey launched by the Practice Current section of Neurology® Clinical Practice. Questions pertained to a case of a 37-year-old woman presenting with optic neuritis. Respondents were asked to indicate their initial investigations, relapse management strategy, choice of disease-modifying therapy, and plan for follow-up imaging (contrast/noncontrast). Survey responses were stratified by key demographic variables along with 95% confidence intervals (95% CIs). Results: We received 153 responses from 42 countries; 32.3% responders identified as MS specialists. There was a strong preference for intravenous delivery of high-dose corticosteroids (87.7%, 95% CI 80.7-92.5), and most of the responders (61.3%, 95% CI 52.6-69.4) indicated they would treat a nondisabling (mild sensory) MS relapse. When asked to select a single initial DMT, 56.6% (95% CI 47.6-65.1) selected a high-efficacy therapy (67.5% MS specialists vs 53.7% non-MS specialists). The most selected agents overall were fingolimod (14.7%), natalizumab (15.5%), and dimethyl fumarate (20.9%). Two-thirds of respondents indicated they would request contrast-enhanced surveillance MRI. Discussion: Although there is a slight preference for initiating high-efficacy DMT at the time of initial MS diagnosis, opinions regarding the most appropriate treatment paradigm remain divided.

Mechanical Thrombectomy Access Score: A Systematic Review and Modified Delphi of Global Barriers to Endovascular Therapy.

BACKGROUND: The availability of mechanical thrombectomy (MT) for acute ischemic stroke is limited, and vast disparities exist between countries. We aim to create a MT access score to measure the drivers of access to help quantify and accelerate treatment worldwide. METHODS: We used a systematic review complemented by a modified Delphi method. In the first of 3 rounds, 4 independent investigators performed a systematic literature review using key search terms that drive MT access, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In the second round, a panel of 6 anonymous international experts selected key attributes needed for scoring. In the final round, a total of 12 attributes were selected on consensus, each given a score on a 0 to 3 scale. An ultimate MT access score (range, 0-36) was proposed as a new tool to use in identifying barriers to MT access and assist in providing an initial framework for public health interventions. RESULTS: Of 2864 abstracts screened, 121 studies were included in the final systematic review. A total of 34 attributes that potentially drive MT access were initially identified. In the final round, 12 attributes were selected by the expert panel: public awareness, emergency medical services transportation, prehospital large vessel occlusion screening, interhospital transfer policy, emergency department protocols, stroke imaging protocols, emergency department stroke expertise or telestroke availability, interventionalists, MT-capable centers, device availability, and insurance coverage. These attributes were weighted as part of the final score of 0 to 36. CONCLUSIONS: The MT access score represents the first tool to quantify barriers to global MT access. Its implementation stands not just as an academic achievement but as a beacon of hope for improving stroke care and outcomes worldwide, bringing us a step closer to bridging the gap in stroke treatment disparities.

Factors Influencing the Association of 24-hour National Institutes of Health Stroke Scale & 90-day Modified Rankin Score.

PURPOSE: The modified Rankin Scale (mRS) at 90 days is the primary outcome in most acute stroke studies, but the long follow-up period has disadvantages. The National Institutes of Health Stroke Scale (NIHSS) at 24 h shows a strong, but imperfect, association with 90-day mRS. This study examines the association between 24-hour NIHSS and 90-day mRS and reasons for discrepancies. METHODS: Data are from the ESCAPE-NA1 thrombectomy patients. To address the non-normality distribution of the NIHSS and include deceased patients, a 7-point ordinal score was generated by grouping 24-hour NIHSS. The association of ordinal 24-hour NIHSS and 90-day mRS was assessed with adjusted ordinal logistic regression. Differences in baseline and treatment/post-treatment variables were compared between patients with discordant and concordant outcomes. RESULTS: One-thousand-seventy-six patients with available 24-hour NIHSS and 90-day mRS were included (median 24-hour NIHSS 6[IQR: 2-14], median 90-day mRS 2[IQR: 1-4]). Ordinal 24-hour NIHSS was associated with 90-day mRS (adjusted cOR 2.53 [95%CI 2.33-2.74]). Forty-eight (4.5%) patients had discordant outcomes. Of those, 19(1.8%) had 24-hour NIHSS < 6 and 90-day mRS5-6; all of which had ≥ 1 severe adverse event, most commonly pneumonia (6[31.6%]) or recurrent stroke (4[21.1%]). Twenty-nine patients (2.7%) had 24-hour NIHSS > 14 and 90-day mRS 0-2. In these patients, baseline NIHSS and ASPECTS was lower, and collateral status was worse. CONCLUSION: An ordinal NIHSS score that includes death at 24 h shows a strong association with 90-day mRS, suggesting that it could be used as an alternative outcome. Patients with discrepant outcomes differed from the remaining patients regarding their baseline NIHSS, ASPECTS, collateral status, and post-stroke complications.

An Introduction to Bayesian Approaches to Trial Design and Statistics for Stroke Researchers.

While the majority of stroke researchers use frequentist statistics to analyze and present their data, Bayesian statistics are becoming more and more prevalent in stroke research. As opposed to frequentist approaches, which are based on the probability that data equal specific values given underlying unknown parameters, Bayesian approaches are based on the probability that parameters equal specific values given observed data and prior beliefs. The Bayesian paradigm allows researchers to update their beliefs with observed data to provide probabilistic interpretations of key parameters, for example, the probability that a treatment is effective. In this review, we outline the basic concepts of Bayesian statistics as they apply to stroke trials, compare them to the frequentist approach using exemplary data from a randomized trial, and explain how a Bayesian analysis is conducted and interpreted.

Comparison of SIMOA and VEUS technologies for serum neurofilament light chain measurement in multiple sclerosis.

INTRODUCTION: The gold standard for serum neurofilament light chain (sNfL) determination is the single molecule array (SIMOA), the use of which is limited by availability and cost. The VEUS method is a fully automated, user-friendly diagnostic system requiring no sample preparation, with high reported sensitivity, multiplexing capability, and rapid diagnostics. The aim of this study was to compare the SIMOA and VEUS methods for determining sNfL levels in patients with multiple sclerosis (MS). METHODOLOGY: A single-centre cross-sectional study was conducted at the MS Centre of University Hospital Ostrava. Patients were enrolled in the study from January 18 to January 31, 2024. Inclusion criteria were: 1) diagnosis of MS according to the revised 2017 McDonald criteria, 2) age ≥18 years, and 3) signed informed consent. The NF-light V2 diagnostic kit (SIMOA, Quanterix) and the Singleplex Neurology assay kit (VEUDx, EZDiatech) were used to determine sNfL concentrations. The two methods were compared by use of Spearman correlation, Passing-Bablok regression, and Bland-Altman analysis. RESULTS: A total of 49 patients were included in the study, of whom 39 (79.6 %) were female. The median sNfL concentration was 7.73 (IQR 5.80-9.93) ng/L determined by SIMOA and 1.31 (IQR 1.18-1.65) ng/L by VEUS. We did not find a correlation between SIMOA and VEUS (rs = 0.025, p = 0.866). Passing-Bablok regression demonstrated a systematic and proportional difference between the two methods. A significant disagreement between them was also confirmed by the Bland-Altman plots. On average, sNfL values measured by SIMOA were 3.56 ng/L (95 % CI 0.78 to 6.34) higher than those measured by VEUS. CONCLUSION: Our investigation uncovered noteworthy disparities between the SIMOA and VEUS techniques in determining sNfL levels. Specifically, the VEUS technique systematically produces lower estimates of sNFL levels. This substantial variance emphasizes the importance of carefully evaluating assay methods when quantifying sNfL.

The treatment effect across ASPECTS in acute ischemic stroke: Analysis from the AcT trial.

BACKGROUND: Early ischemic changes on baseline imaging are commonly evaluated for acute stroke decision-making and prognostication. AIMS: We assess the association of early ischemic changes on clinical outcomes and whether it differs between intravenous tenecteplase and Alteplase. METHODS: Data are from the phase 3, Alteplase compared to Tenecteplase (AcT) trial. Subjects with anterior circulation stroke were included. Early ischemic changes were assessed using the Alberta Stroke Program Early CT score (ASPECTS). Efficacy outcomes included modified Rankin scale (mRS) 0-1, mRS 0-2, and ordinal mRS at 90 days. Safety outcomes included 24-h symptomatic intracerebral hemorrhage (sICH), any hemorrhage on follow-up scan, and 90-day mortality rate. Mixed-effects logistic regression was used to assess the association of ASPECTS (continuous and categorical (0-4 vs 5-7 vs 8-10)) with outcomes and if these associations were modified by thrombolytic type after adjusting for age, sex, and baseline stroke severity. RESULTS: Of the 1577 patients in the trial, 901 patients (56.3%; median age 75 years (IQR 65-84), 50.8% females, median National Institute of Health Stroke Scale (NIHSS) 14 (IQR 17-19)) with anterior circulation stroke were included. mRS 0-1 at 90 days was achieved in 1/14 (0.3%), 43/160 (14.7%), and 252/726 (85.1%) in the ASPECTS 0-4, 5-7, and 8-10 groups respectively. Every one-point decrease in ASPECTS was associated with 2.7% and 1.9% decrease in chances of mRS 0-1 and mRS 0-2 at 90 days, respectively, and 1.9% chances of increase in mortality at 90 days. Subgroup analysis in endovascular thrombectomy (EVT)-treated population showed similar results. Thrombolytic type did not modify this association between ASPECTS and 90-day mRS 0-1 (P-interaction 0.75). There was no significant interaction by thrombolytic type with any other outcomes. CONCLUSION: Similar to prior studies, we found that every one-point decrease in ASPECTS was associated with poorer clinical and safety outcomes. This effect did not differ between alteplase and tenecteplase. DATA ACCESS STATEMENT: Data shall made available on reasonable request from the PI (BMM).

Utilization, Workflow, and Outcomes of Endovascular Thrombectomy in Patients With vs Without Premorbid Disability in a National Registry.

Background and Objectives: Given the paucity of high-quality safety/efficacy data on acute stroke therapies in patients with premorbid disability, they risk being routinely excluded from such therapies. We examined utilization of endovascular thrombectomy (EVT), associated workflow, and poststroke outcomes among patients with vs without premorbid disability. Methods: We used national registry data on thrombolysis/EVT for the Czech Republic from 1 January 2016 to 31 December 2020. Premorbid disability was defined as prestroke modified Rankin Scale score (mRS) ≥3. We compared proportions of patients with vs without premorbid disability who received EVT and examined workflow times. We compared ΔmRS-change in mRS from prestroke to 3 months-in patients with vs without premorbid disability, in addition to intracerebral hemorrhage (ICH), mortality, and discharge NIHSS (National Institutes of Health Stroke Scale score), adjusting for age, sex, baseline NIHSS, and comorbidities, and verified using propensity score weighting (PSW) and matching for differences in treatment assignment. We stratified by age group (<65, 65-74, 75-84, ≥85 years) to explore outcome heterogeneity with vs without premorbid disability. Results: Among 22,405 patients with ischemic stroke who received thrombolysis/EVT/both, 1,712 (7.6%) had prestroke mRS ≥ 3. Patients with prestroke disability were less likely to receive EVT vs those without (10.1% vs 20.7%, aOR: 0.30, 95% CI 0.24-0.36). When treated, they had longer door-to-arterial puncture times (median: 75 minutes, IQR: 58-100 vs 54, IQR: 27-77, adjusted difference: 12.5, 95% CI 2.68-22.3). Patients with prestroke disability receiving thrombolysis/EVT/both had worse ΔmRS (adjusted rate ratio, aIRR on PSW: 1.57, 95% CI 1.43-1.72), rates of 3-month mRS 5-6, discharge NIHSS, and mortality (aOR-PSW [mortality]: 2.54, 95% CI 1.92-3.34), while ICH did not significantly differ. 32.1% of patients with prestroke disability receiving thrombolysis/EVT/both successfully returned to prestroke state, but this proportion ranged from 19.6% for those older than 85 years to 66.0% for those younger than 65 years. Regardless of premorbid disability, EVT was associated with better outcomes including lower ΔmRS (aIRR-PSW: 0.87, 95% CI 0.83-0.91) and mortality, with no interaction of treatment effect by premorbid disability status (e.g., mortality pinteraction = 0.73). EVT recipients with premorbid disability did not differ significantly for several outcomes including ΔmRS (aIRR: 0.99, 95% CI 0.84-1.17) but were more likely to have 3-month mRS 5-6 (70.1% vs 39.5% without premorbid disability, aOR: 1.85, 95% CI 1.12-3.04). Discussion: Patients with premorbid disability were less likely to receive EVT, had slower treatment times, and had worse outcomes compared with patients without premorbid disability. However, regardless of premorbid disability, patients fared better with EVT vs medical management and one-third with prestroke disability returned to their prestroke status.

Challenges to Widespread Implementation of Stroke Thrombectomy.

Endovascular treatment (EVT) for acute ischemic stroke is one of the most efficacious and effective treatments in medicine, yet globally, its implementation remains limited. Patterns of EVT underutilization exist in virtually any health care system and range from a complete lack of access to selective undertreatment of certain patient subgroups. In this review, we outline different patterns of EVT underutilization and possible causes. We discuss common challenges and bottlenecks that are encountered by physicians, patients, and other stakeholders when trying to establish and expand EVT services in different scenarios and possible pathways to overcome these challenges. Lastly, we discuss the importance of implementation research studies, strategic partnerships, and advocacy efforts to mitigate EVT underutilization.

Cytoprotective agents in stroke: Still uncertainty in the next frontier.

INTRODUCTION: Despite substantial improvement of acute ischemic stroke (AIS) care with the advent of extended time windows for intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), a substantial portion of patients still suffer poor outcomes. Additional adjuvant therapies are needed but pharmacologic interactions among therapies may dictate how they could be used. We conducted a survey to determine physician decision-making regarding the use of cytoprotective agents in patients presenting with AIS. METHODS: The survey was structured, web-based, anonymous, and invite-only among physicians across the world treating patients presenting with AIS. Respondents were asked about the use of a hypothetical cytoprotective agent (that provided an added 10% benefit) in the context of a treatment interaction with IVT or its timing in relation to IVT. RESULTS: A total of 282 stroke physicians (74.9% males, mean age 46 years) participated in the survey. When the respondent could give both the cytoprotective agent and IVT with no treatment interaction, 177 (78.0%) chose to administer both. In the presence of treatment interaction, 88 (38.3%) would withhold IVT, 83 (36.1%) would withhold the cytoprotective agent and 56 (24.4%) were uncertain. Lastly, 111 (48.9%) were willing to administer the cytoprotective agent if it meant a necessary 10-minute delay in IVT administration. CONCLUSIONS: Pharmacologic interactions result in major uncertainty about cytoprotective treatment choices.

Endovascular treatment to improve outcomes for medium vessel occlusions: The ESCAPE-MeVO trial.

RATIONALE: Clinical outcomes in acute ischemic stroke due to medium vessel occlusion (MeVO) are often poor when treated with best medical management. Data from non-randomized studies suggest that endovascular treatment (EVT) may improve outcomes in MeVO stroke, but randomized data on potential benefits and risks are hitherto lacking. Thus, there is insufficient evidence to guide EVT decision-making in MeVO stroke. AIMS: The primary aim of the ESCAPE-MeVO trial is to demonstrate that acute, rapid EVT in patients with acute ischemic stroke due to MeVO results in better clinical outcomes compared to best medical management. Secondary outcomes are to demonstrate the safety of EVT, its impact on self-reported health-related quality of life, and cost-effectiveness. SAMPLE SIZE ESTIMATES: Based on previously published data, we estimate a sample size of 500 subjects to achieve a power of 85% with a two-sided alpha of 0.05. To account for potential loss to follow-up, 530 subjects will be recruited. METHODS AND DESIGN: ESCAPE-MeVO is a multicenter, prospective, randomized, open-label study with blinded endpoint evaluation (PROBE design), clinicaltrials.gov: NCT05151172. Subjects with acute ischemic stroke due to MeVO meeting the trial eligibility criteria will be allocated in a 1:1 ratio to best medical care plus EVT versus best medical care only. Patients will be screened only at comprehensive stroke centers to determine if they are eligible for the trial, regardless of whether they were previously treated at a primary care center. Key eligibility criteria are (1) acute ischemic stroke due to MeVO that is clinically and technically eligible for EVT, (2) last-known well within the last 12 h, (3) National Institutes of Health Stroke Scale > 5 or 3-5 with disabling deficit, (4) high likelihood of salvageable tissue on non-invasive neuroimaging. STUDY OUTCOMES: The primary outcome is the modified Rankin scale 90 days after randomization (shift analysis), whereby modified Rankin Score 5 and 6 will be collapsed into one category. Secondary outcomes include dichotomizations of the modified Rankin Score at 90 days, 24 h National Institutes of Health Stroke Score, difference between 24 h and baseline National Institutes of Health Stroke Score, mortality at 90 days, health-related quality of life (EQ-5D-5 L), Lawton scale of instrumental activities of daily living score, reperfusion quality (MeVO expanded Thrombolysis in Cerebral Infarction Score) and infarct volume at 24 h, and cost-effectiveness of endovascular recanalization. Safety outcomes include symptomatic and asymptomatic intracranial hemorrhage and procedural complications. DISCUSSION: The ESCAPE-MeVO trial will demonstrate the effect of endovascular thrombectomy in addition to best medical management vis-à-vis best medical management in patients with acute ischemic stroke due to MeVO and provide data for evidence-based treatment decision-making in acute MeVO stroke. DATA ACCESS STATEMENT: The raw data discussed in this mansucript will be made available by the corresponding author upon reasonable request.

Time From Hospital Arrival Until Endovascular Thrombectomy and Patient-Reported Outcomes in Acute Ischemic Stroke.

Importance: The time-benefit association of endovascular thrombectomy (EVT) in ischemic stroke with patient-reported outcomes is unknown. Objective: To assess the time-dependent association of EVT with self-reported quality of life in patients with acute ischemic stroke. Design, Setting, and Participants: Data were used from the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, which tested the effect of nerinetide on functional outcomes in patients with large vessel occlusion undergoing EVT and enrolled patients from March 1, 2017, to August 12, 2019. The ESCAPE-NA1 trial was an international randomized clinical trial that recruited patients from 7 countries. Patients with EuroQol 5-dimension 5-level (EQ-5D-5L) index values at 90 days and survivors with complete domain scores were included in the current study. Data were analyzed from July to September 2023. Exposure: Hospital arrival to arterial puncture time and other time metrics. Main Outcomes and Measures: EQ-5D-5L index scores were calculated at 90 days using country-specific value sets. The association between time from hospital arrival to EVT arterial-access (door-to-puncture) and EQ-5D-5L index score, quality-adjusted life years, and visual analog scale (EQ-VAS) were evaluated using quantile regression, adjusting for age, sex, stroke severity, stroke imaging, wake-up stroke, alteplase, and nerinetide treatment and accounting for clustering by site. Using logistic regression, the association between door-to-puncture time and reporting no or slight symptoms (compared with moderate, severe, or extreme problems) was determined in each domain (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression) or across all domains. Time from stroke onset was also evaluated, and missing data were imputed in sensitivity analyses. Results: Among 1105 patients in the ESCAPE-NA1 trial, there were 1043 patients with EQ-5D-5L index values at 90 days, among whom 147 had died and were given a score of 0, and 1039 patients (mean [SD] age, 69.0 [13.7] years; 527 male [50.7%]) in the final analysis as 4 did not receive EVT. There were 896 survivors with complete domain scores at 90 days. There was a strong association between door-to-puncture time and EQ-5D-5L index score (increase of 0.03; 95% CI, 0.02-0.04 per 15 minutes of earlier treatment), quality-adjusted life years (increase of 0.29; 95% CI, 0.08-0.49 per 15 minutes of earlier treatment), and EQ-VAS (increase of 1.65; 95% CI, 0.56-2.72 per 15 minutes of earlier treatment). Each 15 minutes of faster door-to-puncture time was associated with higher probability of no or slight problems in each of 5 domains and all domains concurrently (range from 1.86%; 95% CI, 1.14-2.58 for pain or discomfort to 3.55%; 95% CI, 2.06-5.04 for all domains concurrently). Door-to-puncture time less than 60 minutes was associated higher odds of no or slight problems in each domain, ranging from odds ratios of 1.49 (95% CI, 1.13-1.95) for pain or discomfort to 2.59 (95% CI, 1.83-3.68) for mobility, with numbers needed to treat ranging from 7 to 17. Results were similar after multiple imputation of missing data and attenuated when evaluating time from stroke onset. Conclusions and Relevance: Results suggest that faster door-to-puncture EVT time was strongly associated with better health-related quality of life across all domains. These results support the beneficial impact of door-to-treatment speed on patient-reported outcomes and should encourage efforts to improve patient-centered care in acute stroke by optimizing in-hospital processes and workflows.

Worldwide Survey on Approach to Thrombolysis in Acute Ischemic Stroke With Large Vessel Occlusion.

Background and Objectives: With recent trials suggesting that endovascular thrombectomy (EVT) alone may be noninferior to combined intravenous thrombolysis (IVT) with alteplase and EVT and that tenecteplase is non-inferior to alteplase in treating acute ischemic stroke, we sought to understand current practices around the world for treating acute ischemic stroke with large vessel occlusion (LVO) depending on the center of practice (IVT-capable vs IVT and EVT-capable stroke center). Methods: The electronic survey launched by the Practice Current section of Neurology: Clinical Practice included 6 clinical and 8 demographic questions. A single-case scenario was presented of a 65-year-old man presenting with right hemiplegia with aphasia with a duration of 1 hour. Imaging showed left M1-MCA occlusion with no early ischemic changes. The respondents were asked about their treatment approach in 2 settings: the patient presented to (1) the IVT-only capable center and (2) the IVT and EVT-capable center. They were also asked about the thrombolytic agent of choice in current and ideal circumstances for these settings. Results: A total of 203 physicians (42.9% vascular neurologists) from 44 countries completed the survey. Most participants (55.2%) spent ≥50% of their time delivering stroke care. The survey results showed that in current practice, more than 90% of respondents would offer IVT + EVT to patients with LVO stroke presenting to either an EVT-capable (91.1%) or IVT-only-capable center (93.6%). Although nearly 80% currently use alteplase for thrombolysis, around 60% would ideally like to switch to tenecteplase independent of the practice setting. These results were similar between stroke and non-stroke neurologists. Discussion: Most physicians prefer IVT before EVT in patients with acute ischemic stroke attributable to large vessel occlusion independent of the practice setting.