Background: The modified Rankin Scale (mRS) aligns with the World Health Organization’s disability definition by having scores determined by: 1) impairments (neurologic deficits), 2) functional limitations (difficulties in performing activities), and 3) social role restrictions (reduced work, family/relationship, recreational/leisure responsibilities). Social role restrictions are particularly important in assigning patients between mRS 1 (“able to perform all work, family, and social roles”) vs mRS 2 (“unable to perform all work, family, and social roles, but able to live independently”). Since social role disparities exist in modern societies, mRS scores could vary between age groups and between sexes for cultural rather than clinical reasons. Methods: We studied patients with a final diagnosis of acute ischemic or hemorrhagic stroke in the NIH FAST-MAG phase 3 trial, a multicenter, placebo-controlled, randomized trial of prehospital- initiated magnesium sulfate in stroke patients within 2h of onset. Patients were stratified by sex and 4 age groups to distinguish working- and retirement-age populations: 1) <60y; 2) <65y; 3) ≥65y; and 4) >70y. We calculated the 3m mRS 1 vs 2 distributions for each age group and for men and women. Results: Among 1622 final diagnosis stroke patients, 57.8% were men, 42.2% women. At 3 months, 615 (31.8%) of patients had an mRS score of 1 or 2. Age was strongly associated with greater likelihood of an mRS 2 than mRS 1 score. Among patients <65 years, the rate of mRS 2 outcomes among all patients with an mRS 2 or mRS 1 score was 65.8%; among patients age ≥65, the rate of mRS 2 outcomes among all patients with mRS 2 or mRS 1 was 33.3%. A sex-age interaction was also noted (Figures 1, 2). Below age 60, men were more likely than women to receive an mRS score of 2 rather than 1. But as age increased, women were increasingly more likely than men to receive an mRS score of 2 rather than 1. Conclusions: Global disability scores on the modified Rankin Scale exhibit age-based and sex-based disparities. Individuals of retirement age are more likely to be scored as nondisabled compared with working age persons. Further, in the retirement age group but not earlier, men are more likely to be scored as nondisabled compared with women. This influence of culturally determined life roles upon scale scores should be incorporated into interpretation of clinical trial mRS outcome distributions.

Background: A prehospital, paramedic-administered scale to distinguish intracerebral hemorrhage (ICH) from acute cerebral ischemia (ACI) could improve routing to appropriate centers, enrich field randomized trials with targeted subtype patients, and potentially guide prehospital clinical treatment such as hyperacute blood pressure (BP) lowering. We aimed to create a quickly administered prehospital scale from prospectively performed field assessments. Methods: Two scales were created from NIH Field Administration of Stroke Therapy Magnesium (FAST-MAG) trial data, using logistic regression model with backward stepwise variable selection and retention criterion of p<0.1. Scale one—CASPR-DB (Data-Based)—assessed 26 candidate variables available in routine prehospital care in 1675 patients (77.3% ACI, 22.7% ICH), who were randomly assigned to training (n=1114) or validation (n=561) sets. Scale two—CASPR-CS (Clinical Symptoms)—came from a subset of patients (n=467) in whom three additional clinical symptoms elicited in the field were also candidate items—headache, nausea, and progressing deficit. Results: For the CASPR-DB scale, the logistic regression model selected 10 of the 26 candidate variables in the training population. Factors associated with ICH were higher Los Angeles Motor Scale (LAMS) score, higher Glasgow Coma Score (GCS), higher systolic BP, Hispanic and Caucasian race-ethnicity, male sex, use of anti-platelet agents, decreased age, and absence of diabetes, atrial fibrillation, or valvular heart disease. Each was given a point value between 1-3, yielding a 19-point scale (Table 1). For the CASPR-CS scale, the logistic regression model selected 10 of the 29 candidate variables. All three symptom items—headache, nausea, and progressing deficit—were associated with ICH, along with 7 data-based variables. Each was given a point value between 1-3, yielding a 20-point scale (Table 2). CASPR-DB performance in training was sensitivity 64.4%, specificity 78.6%, accuracy 71.5%, c=0.774 and in validation was sensitivity 69.3%, specificity 61.7%, accuracy 71.5%, c=0.710. CASPR-CS performance was sensitivity 71.8%, specificity 77.8%, accuracy 74.8%, c=0.830. Figure 1 shows the proportions of ICH patients at each CASPR-CS score level. Conclusions: The CASPR-DB scale shows good and CASPR-CS scale very good performance in distinguishing ICH vs ACI in prehospital setting. These readily performable scales could improve prehospital routing and treatment of ICH patients.

Background: Recent studies have demonstrated time of day variations in ischemic stroke presentation and outcomes with findings that events occurring in the evening hours tend to be more severe, progress faster, and have poorer outcomes. Much less is known about circadian/diurnal influences on intracerebral hemorrhage. Methods: We analyzed patient records with a final diagnosis of intracerebral hemorrhage (ICH) from the Field Administration of Stroke Therapy - Magnesium (FAST-MAG) randomized trial database. Patients were grouped into six discrete 4-hour time windows by symptom onset time. Patient demographics, clinical features, medical history, stroke severity, and were examined for association with time of day. Results: Among 380 patients with ICH, 90% had last known well times during the day between 07:00 – 22:59. Thirty-two baseline patient features were generally similar across the six time-of-day intervals, except initial field systolic blood pressure was highest between 19:00 – 22:59 (mean 181 mmHg vs 165 – 176 mmHg) and last known well to paramedic evaluation longest between 03:00 – 10:59 (median 27 min vs 16 – 23 min). Among outcomes, early neurologic deterioration showed diurnal variation, with peaks of 47% between 15:00 – 18:59 and 49% between 19:00 – 22:59 vs 21% – 41% in other intervals (Figure 1). A higher proportion of patients were severely disabled (mRS 5) or dead (mRS 6) at 90 days in the 19:00 – 22:59 (54%) and 23:00 – 02:59 (64%) than in other time intervals. Conclusions: Hemorrhagic strokes with late afternoon to evening onset times are associated with increased frequency of hyperacute neurological deterioration and poorer 90-day outcomes. This finding suggests that circadian influences upon stroke course have commonalities across ischemic and hemorrhagic stroke subtypes.

Background: Patients with stroke frequently suffer from post-stroke mood disturbances (PSMD) which decrease their quality of life. It remains unclear whether the prevalence of PSMD differs according to stroke subtype. The aim of our study was to investigate PSMD incidence among stroke subtypes in the large, prospective Field Administration of Stroke Therapy - Magnesium (FAST-MAG) Trial. Methods: In the publicly-available FAST-MAG database, we identified all patients with imaging-confirmed diagnoses of ischemic stroke (IS), transient ischemic attack (TIA), and intracerebral hemorrhage (ICH). Data on age, sex, NIHSS at presentation, stroke subtypes, and Stroke Impact Scale (SIS) 64 v3.0 at 90 days were collected. Differences in SIS Emotion Domain scores between IS, TIA, and ICH were assessed using the Mann-Witney U Test. Results: SIS Emotion Domain scores were available in 1239/1370 (90.4%) of patients. Mean age was 68.7 years (SD 13.4), and 41% were female. Median NIHSS was 7.0 (IQR 3-14). 65.3% had IS, 14.3% TIA, and 20.3% ICH. The preponderance of SIS-64 scores were patient-reported (86%) with the remainder completed by a patient proxy (14%). Emotion domain scores at 3 months were: lowest (most abnormal) in ICH patients (median 77.8, IQR 58.3-88.9); intermediate in IS patients (median 83.3, IQR 66.7-94.4); and highest in TIA patients (median 88.9, IQR 72.2-97.2), p<.01) (Figure). Neither age nor sex were strongly associated, but more abnormal mood scores were associated with greater presenting deficit severity (NIHSS 0-4: median SIS-64 mood score 88.9; NIHSS 5-14: 81.3; NIHSS ≥15: 75.0; Spearman’s rho: -0.30, p<.01). Conclusions: In this prospective study of a large population with broad enrollment criteria, mood disturbances at 90 days were most common among ICH patients and least common among TIA patients. Further work should investigate the driving factors of greater PSMD in patients with ICH compared to other patients with acute cerebrovascular disease.

Background:Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. Methods:This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 hours of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 hours will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient reported quality of life measures. Discussion:In-vitro and in-vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. Trial registration:ClinicalTrials.gov (NCT04217551, 2019-12-30).

Background: Long-term disability after stroke is standardly assessed 3 months post-onset, using the modified Rankin Scale (mRS). The value of an early, day 4 mRS assessment for projecting the 3-month disability outcome has not been formally investigated. Methods: In this cohort of patients with acute cerebral ischemia and intracranial hemorrhage, we analyzed day 4 and day 90 mRS assessments in the NIH Field Administration of Stroke Therapy- Magnesium (FAST-MAG) Phase 3 trial. The performance of day 4 mRS, alone and as part of multivariate models, in predicting day 90 mRS was assessed using correlation coefficients, percent agreement, and the kappa statistics. Results: Among the 1573 acute cerebrovascular disease (ACVD) patients, 1206 (76.7%) had acute cerebral ischemia (ACI), while 367 (23.3%) had intracranial hemorrhage. Among all 1573 ACVD patients, day 4 mRS and day 90 mRS correlated strongly, Spearman's rho=0.79, in unadjusted analysis with weighted kappa of 0.59. For dichotomized outcomes, simple carry-forward of the day 4 mRS performed fairly well in agreeing with day 90 mRS: mRS 0-1 (kappa=0.67), 85.4%; mRS 0-2 (k=0.59), 79.5%; fatal outcome, 88% (k=0.33). Correlations of 4d and 90d mRS were stronger for ACI than ICH patients, 0.76 vs 0.71. Conclusions: In this acute cerebrovascular disease patient cohort, assessment of global disability performed on day 4 is highly informative regarding long-term, 3-month mRS disability outcome, alone, and even more strongly in combination with baseline prognostic variables. The day 4 mRS is a useful measure for imputing the final patient disability outcome in clinical trials and quality improvement programs.

Background: In acute stroke trials, the three most commonly used outcome scales are the modified Rankin Scale (mRS) to assess global disability, the Barthel Index (BI) to assess instrumental activities of daily living, and the National Institutes of Health Stroke Scale (NIHSS) to assess neurologic deficit severity. The value of early scale assessments to forecast 3-month disability outcomes has not been formally investigated. Methods: In this cohort study of patients with acute ischemic stroke (AIS) in the NIH Field Administration of Stroke Therapy- Magnesium (FAST-MAG) Phase 3 trial, we assessed the performance of day 2, 4, and 30, BI, and NIHSS to forecast their day 90 counterparts using correlation coefficients and absolute differences. Results: Among 1041 with AIS, mRS on d2 (r=0.67) and d4 (r=0.72) showed strong correlation and mRS on d30 (r=0.89) very strong correlation with d90 mRS. However, value shifts were common. For example, d4 mRS exactly matched d90 mRS in only 35.8%, while 40.2 % had better and 24 % had worse outcomes. D4 BI exactly matched d90 BI in only 41.2%, while 48.5% had better and 11.2% had worse outcomes. For NIHSS, d4 exactly matched d90 value in only 20.5%, while 57.9% had better and 22.6% had worse outcomes. (Figure) Conclusions: mRS, BI, and NIHSS outcomes as early as days 2 and 4 post-stroke correlate strongly with their longterm, 3m outcome rank ordering but only moderately with their absolute values. Delineation of this outcome trajectory provides a foundation for imputing final patient disability, ADL, and deficit outcomes in clinical trials and quality improvement programs.

BackgroundValidating the National Institutes of Health NIH Stroke Scale (NIHSS) as a tool to assess deficit severity and prognosis in patients with acute intracerebral hemorrhage would harmonize the assessment of intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) patients, enable clinical use of a readily implementable and non-imaging dependent prognostic tool, and improve monitoring of ICH care quality in administrative datasets.MethodsAmong randomized trial ICH patients, the relation between NIHSS scores early after Emergency Department arrival and 3-month outcomes of dependency or death (modified Rankin Scale, mRS 3–6) and case fatality was examined. NIHSS predictive performance was compared to a current standard prognostic scale, the intracerebral hemorrhage score (ICH score).ResultsAmong the 384 patients, the mean age was 65 (±13), with 66% being male. The median NIHSS score was 16 (interquartile range (IQR) 9–25), the mean initial hematoma volume was 29 mL (±38), and the ICH score median was 1 (IQR 0–2). At 3 months, the mRS had a median of 4 (IQR 2–6), with dependency or death occurring in 70% and case fatality in 26%. The NIHSS and ICH scores were strongly correlated (r = 0.73), and each was strongly correlated with the 90-day mRS (NIHSS, r = 0.61; ICH score, r = 0.62). The NIHSS performed comparably to the ICH score in predicting both dependency or death (c = 0.80 vs. 0.80, p = 0.83) and case fatality (c = 0.78 vs. 0.80, p = 0.29). At threshold values, the NIHSS predicted dependency or death with 74.1% accuracy (NIHSS 17.5) and case fatality with 75.0% accuracy (NIHSS 18.5).ConclusionThe NIHSS forecasts 3-month functional and case fatality outcomes with accuracy comparable to the ICH Score. Widely documented in routine clinical care and administrative data, the NIHSS can serve as a valuable measure for clinical prognostication, therapy development, and case-mix risk adjustment in ICH patients.Clinical trial registrationClinicaltrials.gov, NCT00059332.

The Clinical Trials Methodology Course (CTMC), given from 2014 to 2023, was conducted to educate early-career clinical investigators from various backgrounds in neurosciences in the design of clinical trials and to provide mentorship to enhance academic careers and retention plus improve research productivity and the likelihood of successful grant applications. This summary describes the rationale, history, structure, and trainee outcomes of the CTMC. The course used small groups, consisting of 1-2 clinical faculty advisor(s), 1 faculty biostatistician, and 2-4 trainees who met remotely approximately weekly over 12 weeks. Faculty and trainees then met for a 4-day in-person residential course. Follow-up activities included 2-3 follow-up remote meetings and a mock study section review of draft grant applications. The CTMC enrolled 243 trainees from 2014 to 2023 (excluding 2020) into Foundation (173) or other (70) tracks. Ninety-six percent of trainees remained in academic positions. Trainees published 7,666 peer-reviewed articles from their enrollment year to 2023 (mean 31.5 articles per trainee, or mean ± SD of 5.0 ± 5.1 articles per year per trainee). There were 7,120 unique articles; trainees were coauthors in 546. Of 173 Foundation Track trainees, 109 (63%) submitted an NIH grant as principal investigator or co-principal investigator, and 68 (62% of 109 submitters) were funded within a median of 3 years after course completion. Of the 243 total trainees, 91 (38%) were principal investigators for at least 1 NIH grant since their course participation to 2023. Trainees have participated as medical monitors, members of data and safety monitoring boards, investigators for NIH research networks, and faculty in the CTMC itself. CTMC has provided a robust foundation in clinical trial methodology in neuroscience research to a generation of clinical investigators.

BackgroundThe modified Rankin Scale (mRS) assessment of global disability is the most common primary endpoint in acute stroke trials but lacks granularity (7 broad levels) and is ordinal (scale levels unknown distances apart), which constrains study power. Disability scales that are linear and continuous may better discriminate outcomes, but computerized administration in stroke patients is challenging. We, therefore, undertook to develop a staged use of an ordinal followed by a linear scale practical to use in multicenter trials.MethodsConsecutive patients undergoing 3-month final visits in the NIH FAST-MAG phase 3 trial were assessed with the mRS followed by 15 mRS level-specific yes–no items of the Academic Medical Center Linear Disability Score (ALDS), a linear disability scale derived using item response theory.ResultsAmong 55 patients, aged 71.2 (SD ± 14.2), 67% were men and the entry NIHSS was 10.7 (SD ± 9.5). At 90 days, the median mRS score was 3 (IQR, 1–4), and the median ALDS score was 78.8 (IQR, 3.3–100). ALDS scores correlated strongly with 90 days outcome measures, including the Barthel Index (r = 0.92), NIHSS (r = 0.87), and mRS (r = 0.94). ALDS scores also correlated modestly with entry NIHSS (r = 0.38). At 90 days, the ALDS showed greater scale granularity than the mRS, with fewer patients with identical values, 1.9 (SD ± 3.2) vs. 8.0 (SD ± 3.6), p < 0.001. When treatment effect magnitudes were small to moderate, projected trial sample size requirements were 2–12-fold lower when the ALDS rather than the mRS was used as the primary trial endpoint.ConclusionAmong patients enrolled in an acute neuroprotective stroke trial, the ALDS showed strong convergent validity and superior discrimination characteristics compared with the modified Rankin Scale and increased projected trial power to detect clinically meaningful treatment benefits.

BACKGROUND: Observational studies suggest that magnesium may have hemostatic effects. FAST-MAG (Field Administration of Stroke Therapy-Magnesium) was a pragmatic clinical trial of magnesium sulfate administered prehospital for acute clinical stroke syndromes and included patients with intracerebral hemorrhage. Exploratory secondary analysis by the treatment group found no reduction in hematoma expansion (HE) associated with magnesium treatment in intracerebral hemorrhage but did not consider serum magnesium levels achieved. We analyzed FAST-MAG intracerebral hemorrhage data for associations between serum magnesium level, HE, and early neurological deterioration, accounting for groupwise biases. METHODS: HE was defined as hematoma volume increase ≥3 mL within 24 hours and early neurological deterioration as ≥1-point Glasgow Coma Scale decline from arrival to hospital day 4. Comparing treatment and placebo groups confirmed biased availability of neuroimaging data. Therefore, HE and neurological deterioration were analyzed and stratified by treatment and placebo groups using univariate tests and adjusted logistic regression. RESULTS: Spontaneous intracerebral hemorrhage was present in 381 patients. Placebo patients had fewer serial neuroimaging studies available (123 [65.4%] versus 145 [75.1%]; P =0.038). Necessary data were available in 104 magnesium- and 85 placebo-treated patients (age, 64.9 [13.0] years; 67.7% male). In the magnesium group, higher magnesium level was associated with less HE (adjusted odds ratio, 0.64 per mg/dL [95% CI, 0.42–0.93]) and less neurological deterioration (adjusted odds ratio, 0.54 per mg/dL [95% CI, 0.33–0.82]). In the placebo group, magnesium level was not associated with either HE or neurological deterioration. CONCLUSIONS: Magnesium may exhibit a hemostatic effect that was only observable in the FAST-MAG magnesium treatment group. Equipoise should be maintained, and specific trials are needed. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00059332.

Background and ObjectivesInvestigations of rapid neurologic improvement (RNI) in patients with acute cerebral ischemia (ACI) have focused on RNI occurring after hospital arrival. However, with stroke routing decisions and interventions increasingly migrating to the prehospital setting, there is a need to delineate the frequency, magnitude, predictors, and clinical outcomes of patients with ACI with ultra-early RNI (U-RNI) in the prehospital and early postarrival period.MethodsWe analyzed prospectively collected data of the prehospital Field Administration of Stroke Therapy-Magnesium (FAST-MAG) randomized clinical trial. Any U-RNI was defined as improvement by 2 or more points on the Los Angeles Motor Scale (LAMS) score between the prehospital and early post-emergency department (ED) arrival examinations and classified as moderate (2-3 point) or dramatic (4-5 point) improvement. Outcome measures included excellent recovery (modified Rankin Scale [mRS] score 0-1) and death by 90 days.ResultsAmong the 1,245 patients with ACI, the mean age was 70.9 years (SD 13.2); 45% were women; the median prehospital LAMS was 4 (interquartile range [IQR] 3-5); the median last known well to ED-LAMS time was 59 minutes (IQR 46-80 minutes), and the median prehospital LAMS to ED-LAMS time was 33 minutes (IQR 28-39 minutes). Overall, any U-RNI occurred in 31%, moderate U-RNI in 23%, and dramatic U-RNI in 8%. Any U-RNI was associated with improved outcomes, including excellent recovery (mRS score 0-1) at 90 days 65.1% (246/378) vs 35.4% (302/852), p < 0.0001; decreased mortality by 90 days 3.7% (14/378) vs 16.4% (140/852), p < 0.0001; decreased symptomatic intracranial hemorrhage 1.6% (6/384) vs 4.6% (40/861), p = 0.0112; and increased likelihood of being discharged home 56.8% (218/384) vs 30.2% (260/861), p < 0.0001.DiscussionU-RNI occurs in nearly 1 in 3 ambulance-transported patients with ACI and is associated with excellent recovery and decreased mortality at 90 days. Accounting for U-RNI may be useful for routing decisions and future prehospital interventions.

OBJECTIVES:To delineate diurnal variation onset distinguishing ischemic from hemorrhagic stroke, wake from sleep onset, and weekdays from weekends/holidays. MATERIALS AND METHODS:We analyzed patients enrolled in the FAST-MAG trial of field-initiated neuroprotective agent in patients with hyperacute stroke within 2h of symptoms onset. Stroke onset times were analyzed in 1h, 4h, and 12h time blocks throughout the 24h day-night cycle. Patient demographic, clinical features, stroke severity, and prehospital workflow were evaluated for association with onset times. RESULTS:Among 1615 acute cerebrovascular disease patients, final diagnoses were acute cerebral ischemia in 76.5% and Intracerebral hemorrhage in 23.5%. Considering all acute cerebrovascular disease patients, frequency of wake onset times showed a bimodal pattern, with peaks on onsets at 09:00-13:59 and 17:00-18:59 and early morning (00:00-05:59) onset in only 3.8%. Circadian rhythmicity differed among stroke subtypes: in acute cerebral ischemia, a single broad plateau of elevated incidences was seen from 10:00-21:59; in Intracerebral hemorrhage, bimodal peaks occurred at 09:00 and 19:00. The ratio of Intracerebral hemorrhage to acute cerebral ischemia occurrence was highest in early morning, 02:00-06:59. Marked weekday vs weekends pattern variation was noted for acute cerebral ischemia, with a broad plateau between 09:00 and 21:59 on weekdays but a unimodal peak at 14:00-15:59 on weekends. CONCLUSIONS:Wake onset of acute cerebrovascular disease showed a marked circadian variation, with distinctive patterns of a broad elevated plateau among acute cerebral ischemia patients; a bimodal peak among intracerebral hemorrhage patients; and a weekend change in acute cerebral ischemia pattern to a unimodal peak.

Background Many stroke recovery interventions are most beneficial when started 2-14d post-stroke, a time when patients become eligible for inpatient rehabilitation facilities (IRF) and neuroplasticity is often at its peak. Clinical trials focused on recovery need to expand the time from this plasticity to later outcome timepoints. Methods The disability course of patients with acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) enrolled in Field Administration of Stroke Therapy Magnesium (FAST-MAG) Trial with moderate-severe disability (modified Rankin Scale [mRS] 3–5) on post-stroke day4 who were discharged to IRF 2-14d post-stroke were analyzed. Results Among 1422 patients, 446 (31.4%) were discharged to IRFs, including 23.6% within 2-14d and 7.8% beyond 14d. Patients with mRS 3–5 on day4 discharged to IRFs between 2-14d accounted for 21.7% (226/1041) of AIS patients and 28.9% (110/381) of ICH patients, ( p < 0.001). Among these AIS patients, age was 69.8 (± 12.7), initial NIHSS median 8 (IQR 4–12), and day4 mRS = 3 in 16.4%, mRS = 4 in 50.0%, and mRS = 5 in 33.6%. Among these ICH patients, age was 62.4 (± 11.7), initial NIHSS median 9 (IQR 5–13), day 4 mRS = 3 in 9.4%, mRS = 4 in 45.3%, and mRS = 5 in 45.3% ( p < 0.01 for AIS vs ICH). Between day4 to day90, mRS improved ≥ 1 levels in 72.6% of AIS patients vs 77.3% of ICH patients, p = 0.3. For AIS, mRS improved from mean 4.17 (± 0.7) to 2.84 (± 1.5); for ICH, mRS improved from mean 4.35 (± 0.7) to 2.75 (± 1.3). Patients discharged to IRF beyond day14 had less improvement on day90 mRS compared with patients discharged between 2-14d. Conclusions In this acute stroke cohort, nearly 1 in 4 patients with moderate-severe disability on post-stroke day4 were transferred to IRF within 2-14d post-stroke. ICH patients had nominally greater mean improvement on mRS day90 than AIS patients. This course delineation provides a roadmap for future rehabilitation intervention studies.

Importance:Cryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase neuropathy risk. Diet and exercise have shown promise but are limited by poor adherence. Objective:To determine whether topiramate can slow decline in intraepidermal nerve fiber density (IENFD) and/or neuropathy-specific quality of life measured using the Norfolk Quality of Life-Diabetic Neuropathy (NQOL-DN) scale. Design, Setting, and Participants:Topiramate as a Disease-Modifying Therapy for CSPN (TopCSPN) was a double-blind, placebo-controlled, randomized clinical trial conducted between February 2018 and October 2021. TopCSPN was performed at 20 sites in the National Institutes of Health-funded Network for Excellence in Neurosciences Clinical Trials (NeuroNEXT). Individuals with CSPN and metabolic syndrome aged 18 to 80 years were screened and randomly assigned by body mass index (<30 vs ≥30), which is calculated as weight in kilograms divided by height in meters squared. Patients were excluded if they had poorly controlled diabetes, prior topiramate treatment, recurrent nephrolithiasis, type 1 diabetes, use of insulin within 3 months before screening, history of foot ulceration, planned bariatric surgery, history of alcohol or drug overuse in the 2 years before screening, family history of a hereditary neuropathy, or an alternative neuropathy cause. Interventions:Participants received topiramate or matched placebo titrated to a maximum-tolerated dose of 100 mg per day. Main Outcomes and Measures:IENFD and NQOL-DN score were co-primary outcome measures. A positive study was defined as efficacy in both or efficacy in one and noninferiority in the other. Results:A total of 211 individuals were screened, and 132 were randomly assigned to treatment groups: 66 in the topiramate group and 66 in the placebo group. Age and sex were similar between groups (topiramate: mean [SD] age, 61 (10) years; 38 male [58%]; placebo: mean [SD] age, 62 (11) years; 44 male [67%]). The difference in change in IENFD and NQOL-DN score was noninferior but not superior in the intention-to-treat (ITT) analysis (IENFD, 0.21 fibers/mm per year; 95% CI, -0.43 to ∞ fibers/mm per year and NQOL-DN score, -1.52 points per year; 95% CI, -∞ to 1.19 points per year). A per-protocol analysis excluding noncompliant participants based on serum topiramate levels and those with major protocol deviations demonstrated superiority in NQOL-DN score (-3.69 points per year; 95% CI, -∞ to -0.73 points per year). Patients treated with topiramate had a mean (SD) annual change in IENFD of 0.56 fibers/mm per year relative to placebo (95% CI, -0.21 to ∞ fibers/mm per year). Although IENFD was stable in the topiramate group compared with a decline consistent with expected natural history, this difference did not demonstrate superiority. Conclusion and Relevance:Topiramate did not slow IENFD decline or affect NQOL-DN score in the primary ITT analysis. Some participants were intolerant of topiramate. NQOL-DN score was superior among those compliant based on serum levels and without major protocol deviations. Trial Registration:ClinicalTrials.gov Identifier: NCT02878798.

Background: Long-term disability after stroke is standardly assessed 3m post-onset, using the modified Rankin Scale (mRS), but clinical trial patients lost to follow-up require imputation of likely outcome. An early post-onset, e.g. day 4, mRS is often available but its utility to forecast outcome in ischemic and in hemorrhagic stroke patients has not been delineated. Methods: We analyzed all patients with acute cerebral ischemia (ACI) and with intracranial hemorrhage (ICH) enrolled in the NIH Field Administration of Stroke Therapy- Magnesium (FAST-MAG) Phase 3 trial. The performance of ordinal day 4 mRS, alone and as part of multivariate models, in predicting ordinal day 90 mRS was assessed using Spearman correlation coefficients (r s ) and kappa (chance corrected agreement) statistics. Results: Among the 1206 acute cerebral ischemic patients, age was 70.9, 45.5 % were female, and initial NIHSS was 9.28 ± 8.28. In univariate analysis, day 4 mRS and day 90 mRS correlated strongly, r s = 0.76, weighted kappa = 0.71 increasing in multivariate analysis to r s = 0.78 and weighted kappa = 0.76 (Figure 1A). Among the 367 intracranial hemorrhage patients, age was 65.4, 32.7% were female, and initial NIHSS was 18.3 ± 11. In univariate analysis, day 4 mRS and day 90 mRS also correlated moderately r s = 0.64, weighted kappa = 0.63, increasing in multivariate analysis to r s = 0.81 and weighted kappa = 0.78 (Figure 1B). In the multivariate predictive models, day 4 mRS was the most determinative variable along with age and initial NIHSS for both ICH and ACI. Conclusion: For both acute cerebral ischemia and intracranial hemorrhage patients, long-term, 3m mRS disability outcomes can be predicted well using mRS assessment on day 4, alone and even more accurately in combination with baseline prognostic variables. Age and baseline NIHSS exert more additional influence on 3m mRS outcome in ICH than ACI, likely reflecting the better functional recovery among ICH than ACI stroke survivors.