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Background: Stroke is a leading cause of long-term disability. Greater rehabilitation therapy after stroke is known to improve functional outcomes. This study examined therapy doses during the first year of stroke recovery and identified factors that predict rehabilitation therapy dose. Methods: Adults with new radiologically confirmed stroke were enrolled 2 to 10 days after stroke onset at 28 acute care hospitals across the United States. Following an initial assessment during acute hospitalization, the number of physical therapy, occupational therapy, and speech therapy sessions were determined at visits occurring 3, 6, and 12 months following stroke. Negative binomial regression examined whether clinical and demographic factors were associated with therapy counts. False discovery rate was used to correct for multiple comparisons. Results: Of 763 patients enrolled during acute stroke admission, 510 were available for follow-up. Therapy counts were low overall, with most therapy delivered within the first 3 months; 35.0% of patients received no physical therapy; 48.8%, no occupational therapy, and 61.7%, no speech therapy. Discharge destination was significantly related to cumulative therapy; the percentage of patients discharged to an inpatient rehabilitation facility varied across sites, from 0% to 71%. Most demographic factors did not predict therapy dose, although Hispanic patients received a lower cumulative amount of physical therapy and occupational therapy. Acutely, the severity of clinical factors (grip strength and National Institutes of Health Stroke Scale score, as well as National Institutes of Health Stroke Scale subscores for aphasia and neglect) predicted higher subsequent therapy doses. Measures of impairment and function (Fugl-Meyer, modified Rankin Scale, and Stroke Impact Scale Activities of Daily Living) assessed 3 months after stroke also predicted subsequent cumulative therapy doses. Conclusions: Rehabilitative therapy doses during the first year poststroke are low in the United States. This is the first US-wide study to demonstrate that behavioral deficits predict therapy dose, with patients having more severe deficits receiving higher doses. Findings suggest directions for identifying groups at risk of receiving disproportionately low rehabilitation doses.

Background: Nonstenotic carotid plaque and undetected atrial fibrillation are potential mechanisms of embolic stroke of undetermined source (ESUS), but it is unclear which is more likely to be the contributing stroke mechanism. We explored the relationship between left atrial enlargement (LAE) and nonstenotic carotid plaque across age ranges in an ESUS population. Methods: A retrospective multicenter cohort of consecutive patients with unilateral, anterior circulation ESUS was queried (2015 to 2021). LAE and plaque thickness were determined by transthoracic echocardiography and computed tomography angiography, respectively. Descriptive statistics were used to compare plaque features in relation to age and left atrial dimensions. Results: Among the 4155 patients screened, 273 (7%) met the inclusion criteria. The median age was 65 years (interquartile range [IQR] 54–74), 133 (48.7%) were female, and the median left atrial diameter was 3.5 cm (IQR 3.1–4.1). Patients with any LAE more frequently had hypertension (85.9% versus 67.2%, P P =0.01), dyslipidemia (56.4% versus 40.0%, P =0.01), and coronary artery disease (22.8% versus 11.3%, P =0.02). Carotid plaque thickness was greater ipsilateral versus contralateral to the stroke hemisphere in the overall cohort (median 1.9 mm [IQR 0–3] versus 1.5 mm [IQR 0–2.6], P P P =0.047) and less moderate-to-severe LAE (6.3% versus 15.3%, P =0.02). Conclusions: Younger patients with ESUS had greater prevalence of ipsilateral nonstenotic plaque, while the elderly had more LAE. The differential effect of age on the probability of specific mechanisms underlying ESUS should be considered in future studies.

Introduction: In patients with cryptogenic stroke (CS), complex aortic plaque may be a potential underlying etiology. We performed a systematic review to determine the prevalence of complex aortic plaque in CS patients. Methods: A systematic review and meta-analysis were performed according to PRISMA guidelines (PROSPERO: CRD42022300865). PubMed and EMBASE databases were searched from Jan 1980 to Nov 2021 for studies assessing aortic (ascending, arch, descending) plaque by transesophageal echocardiogram (TEE), CT/CTA, or MRI in at least 10 CS patients. Prevalence rates were pooled using a random-effects model. I 2 statistics assessed heterogeneity. An Egger’s test assessed publication bias. Results: From 2712 articles, 31 met inclusion criteria. Ascending, arch, and descending aorta were assessed in 65%, 100%, 55% of studies, respectively. Studies investigated aortic plaque by TEE (84%), CT/CTA (19%) and MRI (16%). The prevalence of complex aortic plaque in 4666 CS patients was heterogeneous across studies and yielded a summary prevalence of 30% (95% CI 23-38%, I 2 = 96%; Figure 1) contrasting with 11% (95% CI 5-20%, I 2 =83%) in 677 patients without stroke. Prevalence rates in women and men were 26% (95% CI 14%-43%, I 2 = 94%) and 35% (95% CI 21-52%, I 2 = 97%), respectively. To investigate geographic differences, 14 studies from Europe were pooled (32%, 95% CI 23-43%, I 2 =93%), 3 from the Middle East (34%, 95% CI 11-67%, I 2 =94%) and 3 from the US (28%, 95% CI 13-51%, I 2 =90%). No publication bias was detected (p=0.66). Sources of heterogeneity included patient selection, imaging technology (e.g, transducer frequency) and plaque measurement criteria. Conclusions: Studies suggest a prevalence rate of complex aortic plaque in approximately 30% of CS patients. However, significant heterogeneity in the results indicate a need for less variability in CS patient selection and more reproducible imaging methods/criteria for detecting complex aortic plaque.

Introduction: Hematoma volume predicts poor outcome after intracerebral hemorrhage (ICH), while outcome associations with perihematomal edema (PHE) remain controversial. Prior studies using non-standardized timing of serial CT imaging reported larger ICH and PHE volumes in men than women, but worse outcome in women. Leveraging data from a cohort with early admission and time-locked follow-up imaging, we investigated the role of sex on PHE and outcomes. Methods: We conducted a post hoc analysis of the randomized FAST (Factor VII for Acute-Hemorrhagic Stroke Treatment) trial. Participants underwent CT imaging within 3 hours of symptom onset, and at 24 and 72 hours. Lesion volumes were calculated using computerized planimetric techniques (AnalyzeDirect). Outcomes (modified Rankin Scale, mRS) were assessed at 90 days. Two-way repeated measures ANOVA tested whether changes in lesion volumes were driven by an interaction between sex and time. Multivariable logistic regression tested for associations between PHE and poor outcome (mRS 4-6). Results: Of 842 subjects, 781 with supratentorial ICH (mean age 65 years, 38% women) were included. Men (n=485) compared to women (n=296) had similar mean ICH and PHE volumes at baseline (p=0.063 and p=0.98) but larger ICH and PHE at 24 hours (p=0.002 and p=0.017) and 72 hours (p=0.002 and p=0.003). All volumes varied over CT time points according to sex (Figure 1 A-C, all three ANOVA: p Conclusions: Men had greater early lesion expansion than women. In both sexes, PHE expanded beyond 24 hours and was associated with poor outcome. While mechanisms explaining sex differences need further investigation, future ICH studies should be carefully adjusted for sex.

Introduction: We examined qualitative features of calcified plaque in patients with embolic stroke of undetermined source (ESUS). Methods: A retrospective cohort of anterior circulation acute ischemic stroke patients with CTA neck and meeting criteria for ESUS was identified. A segmentation software measured carotid bifurcation calcified plaque volumes. A neuroradiologist manually measured maximum carotid wall and calcified wall thickness (WT), maximum craniocaudal calcified plaque length, degree of circumferential involvement (none, punctate, 90°, 180°, 270°, 360°) and assessed for intimal, transmural, and adventitial calcifications. Descriptive statistics included medians and interquartile ranges. Differences between ipsilateral (carotid ipsi ) and contralateral (carotid contra ) carotid arteries to stroke side were tested using Wilcoxon Signed-Rank, McNemar, and marginal homogeneity tests. Results: Ninety-four subjects met criteria for ESUS. Mean age was 65 years and 55% were women. Carotid ipsi had a significantly higher volume of calcified plaque [Vol ipsi =39.1 (12.4, 86.7) vs Vol contra =25.9 (4.9, 71.7), p=0.05] and maximum calcified WT [CalcWT ipsi= 1.4 (0, 2.6) vs CalcWT contra =0 (0, 2.1), p=0.03] than carotid contra . There were no significant differences in the maximum craniocaudal calcified plaque length (p=0.09) or degree of circumferential calcified plaque involvement (p=0.35) between carotid ipsi and carotid contra . Intimal (p=0.03) but not transmural (p=0.14) or adventitial (p=0.12) calcifications were significantly more frequent in carotid ipsi than carotid contra . A subgroup analysis (n=48) including either carotid artery measuring ≥3mm in maximum WT showed intimal calcifications remained significantly associated with stroke side (p=0.02; Figure). Conclusion: Higher calcified plaque volumes, calcified wall thickness and intimal calcifications may be associated with ischemic stroke in patients with ESUS.

Background: Sex differences in patients with embolic stroke of undetermined source (ESUS) and non-stenotic internal carotid artery (ICA) plaque have not been reported. Non-stenotic ICA plaque has been identified in patients with ESUS, is inversely proportional to cardioembolic stroke risk in our cohort, and could represent a stroke mechanism in these patients. Sex differences have been observed in patients with stroke and stenotic ICA plaque. Thus, we examined whether sex differences were present in a cohort of patients with ESUS and non-stenotic plaque. Methods: A retrospective multicenter cohort of consecutive patients with ESUS was queried (2015-2021). Patients with unilateral, anterior circulation ESUS who had a CTA neck scan and a transthoracic echocardiogram (TTE) were included. Multiple linear regression was used to model independent contributors to thicker ipsilateral plaque. Results: Of the 273 included patients with unilateral anterior ESUS and adequate TTE or TEE, 133 (49%) were women. While vascular profiles were largely similar, women were older but had less significant ipsilateral plaque compared to men (Table). After adjustment for independent predictors of greater ipsilateral plaque, female sex remained strongly and independently protective against plaque thickness (β -0.46, 95%CI -0.83- -0.09), while older age (β 0.03/yr, 95%CI 0.01-0.04), tobacco use (β 0.38, 95%CI 0.002-0.76), and coronary artery disease (β 0.46, 95%CI -0.05 - 0.97) were associated with thicker ICA plaque. Conclusion: Non-stenotic ICA plaque may contribute to ESUS, but it is less common in women than men. Further investigation of factors that might account for this difference, such as hormonal factors, is warranted. Table.

Background: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of all strokes. Potential contributors to ESUS include patent foramen ovale (PFO) and non-stenotic plaque ( Methods: A retrospective multicenter cohort of consecutive patients with ESUS was queried (2015-2021). Patients with unilateral, anterior circulation ESUS who had a CTA neck scan and a transthoracic echocardiogram (TTE) and/or transesophageal echocardiogram (TEE) with adequate visualization of a PFO were included. Patients with prior carotid stent, endarterectomy or alternative etiologies were excluded from the study. Descriptive statistics were used to characterize patients with and without PFO, with multivariable logistic regression used to predict the presence of a PFO based on clinicoradiographic factors as well as degree of luminal stenosis and ipsilateral plaque thickness >3mm, based on previously published thresholds of clinical relevance. Results: Of the 234 included patients with unilateral anterior ESUS and adequate TTE or TEE, 17 (7.3%) had a PFO and 64 (27.4%) had ≥3mm of ipsilateral ICA plaque. Patients with PFO had significantly less NSP and less ipsilateral cervical ICA stenosis (0% [IQR 0-0%] vs. 0% [IQR 0-50%], p=0.03; Table). After adjustment for all predictors of PFO in multivariable regression (p Conclusion: Ipsilateral NSP is more common in ESUS patients without a PFO. While this study is limited by the small PFO event rate, it supports the notion that NSP and PFO may be independent contributors to ESUS.

Background: Nonstenotic internal carotid artery (ICA) plaque as a mechanism of embolic stroke of undetermined source (ESUS) is controversial. Studies show an inverse relationship between cardioembolic stroke risk and nonstenotic plaque in ESUS patients. We explored this relationship using left atrial enlargement (LAE) as a marker of cardioembolic stroke predisposition. Methods: A retrospective multicenter cohort of consecutive patients with unilateral, anterior circulation ESUS was queried. ESUS diagnosis was based on an embolic stroke pattern without an identifiable source on imaging and ≥24hrs of telemetry. Descriptive statistics were used to differentiate clinical, laboratory, and imaging predictors of sex adjusted LAE. Results: Of the 4155 patients screened, 273 (7%) met the inclusion criteria. Compared to patients without LAE, those with LAE were older (68y vs 62y, p Discussion: Clinically relevant ipsilateral ICA plaque was more frequent in this ESUS cohort, regardless of LAE. When stratified by age, younger patients had greater ipsilateral ICA plaque burden and less LAE. While nonstenotic plaque and LAE frequently co-exist, younger ESUS patients were at greater risk of nonstenotic plaque than the elderly, who were at greater risk of LAE.

Introduction: Non-stenotic carotid plaque may be the cause of ischemic stroke in some patients with embolic stroke of undetermined source (ESUS). We examined sex-differences in carotid plaque composition in patients with ESUS. Methods: A retrospective cohort of anterior circulation acute ischemic stroke patients with CTA head/neck and meeting criteria for ESUS was identified. Carotid artery bifurcations (4cm segment) ipsilateral to the stroke were evaluated using a semi-automated segmentation software to measure total plaque volume and plaque subcomponents (calcium, intraplaque hemorrhage [IPH], and lipid rich necrotic core [LRNC]). Sex-differences in baseline vascular risk factors and plaque subcomponent volumes were tested by Mann-Whitney U tests or students t-tests for continuous variables and Fisher’s exact test for categorical variables. Associations of each plaque subcomponent were tested by multivariate linear regressions. Results: Of 94 patients, 55% were women. Mean age of the cohort was 65 years. Women had higher body mass indices than men (29.2 vs 26.3; p=0.02). There were no other significant differences in age or vascular risk factors between men and women. Overall plaque volume (p=0.001) was significantly greater in men as was the volume of calcification (p Conclusions: Sex-differences in carotid plaque composition in ESUS suggest the possibility of a differential contribution of non-stenotic carotid plaque to stroke mechanism in men versus women.

Background and Purpose: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals. Methods: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS ( Results: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P =0.78), death (4.9% versus 8.5%, P =0.68), fatal strokes (2.4% versus 8.5%, P =0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P =0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm. Conclusions: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials. Registration: URL: https://www.clinicaltrials.gov/ ; Unique identifier: NCT02283294.

Background and Purpose: Initial reports suggest a significant risk of thrombotic events, including stroke, in patients hospitalized with coronavirus disease 2019 (COVID-19). However, there is little systematic data on stroke incidence and mechanisms, particularly in racially diverse populations in the United States. Methods: We performed a retrospective, observational study of stroke incidence and mechanisms in all patients with COVID-19 hospitalized from March 15 to May 3, 2020, at 3 Philadelphia hospitals. Results: We identified 844 hospitalized patients with COVID-19 (mean age 59 years, 52% female, 68% Black); 20 (2.4%) had confirmed ischemic stroke; and 8 (0.9%) had intracranial hemorrhage. Of the ischemic stroke patients, mean age was 64 years, with only one patient (5%) under age 50, and 80% were Black. Conventional vascular risk factors were common, with 95% of patients having a history of hypertension and 60% a history of diabetes mellitus. Median time from onset of COVID symptoms to stroke diagnosis was 21 days. Stroke mechanism was cardioembolism in 40%, small vessel disease in 5%, other determined mechanism in 20%, and cryptogenic in 35%. Of the 11 patients with complete vascular imaging, 3 (27%) had large vessel occlusion. Newly positive antiphospholipid antibodies were present in >75% of tested patients. Of the patients with intracranial hemorrhage, 5/8 (63%) were lobar intraparenchymal hemorrhages, and 3/8 (38%) were subarachnoid hemorrhage; 4/8 (50%) were on extracorporeal membrane oxygenation. Conclusions: We found a low risk of acute cerebrovascular events in patients hospitalized with COVID-19. Most patients with ischemic stroke had conventional vascular risk factors, and traditional stroke mechanisms were common.

Background and Purpose— The Graeb score is a visual rating scale of intraventricular hemorrhage (IVH) on noncontrast head CT. Little data exist in the hyperacute ( Methods— A retrospective analysis of multicenter prospective intracranial hemorrhage study was performed. oGS and mGS inter-observer agreement and IVH volume correlation on the baseline noncontrast head CT were calculated by intraclass correlation coefficient and Pearson coefficient respectively. Predictors of poor outcome (modified Rankin Scale scores ≥4) at 3 months were identified using a backward stepwise selection multivariable analysis. oGS and mGS performance for modified Rankin Scale scores ≥4 was determined by receiver operating characteristic analysis. Results— One hundred forty-one patients (65±12 years) with median (interquartile range) time to CT of 82.5 (70.3–157.5) minutes were included. IVH was observed in 43 (30%) patients. Inter-observer agreement was excellent for both oGS (intraclass correlation coefficient, 0.90 [95% CI, 0.80–0.95]) and mGS (intraclass correlation coefficient, 0.97 [95% CI, 0.84–0.99]). mGS (R=0.79; P P P =0.02). Models of thresholded oGS and mGS were not different from a model of planimetric baseline intracranial hemorrhage and IVH volume for poor outcome prediction. Area under the curves were 0.70, 0.73, and 0.72, respectively. Conclusions— Excellent correlation for oGS and mGS with IVH volume was seen. Thresholded oGS and mGS are reasonable surrogates for planimetric IVH volume for hyperacute intracranial hemorrhage studies.

Background and Purpose— While combination aspirin and clopidogrel reduces recurrent stroke compared with aspirin alone in patients with transient ischemic attack (TIA) or minor stroke, the effect on disability is uncertain. Methods— The POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) randomized patients with TIA or minor stroke (National Institutes of Health Stroke Scale score ≤3) within 12 hours of onset to dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel versus aspirin alone. The primary outcome measure was a composite of stroke, myocardial infarction, or vascular death. We performed a post hoc exploratory analysis to examine the effect of treatment on overall disability (defined as modified Rankin Scale score >1) at 90 days, as well as disability ascribed by the local investigator to index or recurrent stroke. We also evaluated predictors of disability. Results— At 90 days, 188 of 1964 (9.6%) of patients enrolled with TIA and 471 of 2586 (18.2%) of those enrolled with stroke were disabled. Overall disability was similar between patients assigned DAPT versus aspirin alone (14.7% versus 14.3%; odds ratio, 0.97 [95% CI, 0.82–1.14]; P =0.69). However, there were numerically fewer patients with disability in conjunction with a primary outcome event in the DAPT arm (3.0% versus 4.0%; odds ratio, 0.73 [95% CI, 0.53–1.01]; P =0.06) and significantly fewer patients in the DAPT arm with disability attributed by the investigators to either the index event or recurrent stroke (5.9% versus 7.4%; odds ratio, 0.78 [95% CI, 0.62–0.99]; P =0.04). Notably, disability attributed to the index event accounted for the majority of this difference (4.5% versus 6.0%; odds ratio, 0.74 [95% CI, 0.57–0.96]; P =0.02). In multivariate analysis, age, subsequent ischemic stroke, serious adverse events, and major bleeding were significantly associated with disability in TIA; for those with stroke, female sex, hypertension, or diabetes mellitus, National Institutes of Health Stroke Scale score, recurrent ischemic stroke, subsequent myocardial infarction, and serious adverse events were associated with disability. Conclusions— In addition to reducing recurrent stroke in patients with acute minor stroke and TIA, DAPT might reduce stroke-related disability. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00991029.

Background and Purpose: To assess the effect of combination antiplatelet therapy with aspirin and clopidogrel versus aspirin alone on disability following TIA or minor stroke and to identify factors associated with disability. Methods: The POINT trial randomized patients with TIA or minor stroke (NIHSS≤3) within 12 hours of onset to dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel versus aspirin alone. The primary outcome measure was a composite of stroke, MI, or vascular death. We performed a post-hoc exploratory analysis to examine the effect of treatment on overall disability (defined as mRS>1) at 90 days as well as disability ascribed by the local investigator to index or recurrent stroke. We also evaluated predictors of disability. Results: At 90 days, 188/1964 (9.6%) of patients enrolled with TIA and 471/2586 (18.2%) of those enrolled with stroke were disabled. Overall disability was similar between patients assigned DAPT versus aspirin alone (14.7% vs. 14.3%, OR 0.97, 95%CI 0.82-1.14, p=0.69). However, there were numerically fewer patients with disability in conjunction with a primary outcome event in the DAPT arm (3.0% vs. 4.0%, OR 0.73, 95%CI 0.53-1.01, p=0.06), and significantly fewer patients in the DAPT arm with disability attributed by the investigators to either the index event or recurrent stroke (5.9% vs. 7.4%, OR 0.78, 95% CI 0.62-0.99, p=0.04). Notably, disability attributed to the index event accounted for the majority of this difference (4.5% vs. 6.0%, OR 0.74 95% CI 0.57-0.96, p=0.02). In multivariate analysis of patients enrolled with TIA, disability was significantly associated with age, subsequent ischemic stroke, serious adverse events, and major bleeding. In patients enrolled with stroke, disability was associated with female sex, hypertension, diabetes, NIHSS score, recurrent ischemic stroke, subsequent myocardial infarction, and serious adverse events. Conclusions: In addition to reducing recurrent stroke in patients with acute minor stroke and TIA, dual antiplatelet therapy might reduce stroke-related disability.