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Background: We aimed to evaluate covert brain infarction (CBI), frequently encountered during the diagnostic work-up of acute ischemic stroke, as a risk factor for stroke recurrence in patients with atrial fibrillation (AF). Methods: For this prospective cohort study, from patients with acute ischemic stroke hospitalized at 14 centers between 2017 and 2019, we enrolled AF patients without history of stroke or transient ischemic attack and divided them into the CBI (+) and CBI (−) groups. The 2 groups were compared regarding the 1-year cumulative incidence of recurrent ischemic stroke and all-cause mortality using the Fine and Gray subdistribution hazard model with nonstroke death as a competing risk and the Cox frailty model, respectively. Each CBI lesion was also categorized into either embolic-appearing (EA) or non-EA pattern CBI. Adjusted hazard ratios and 95% CIs of any CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were estimated. Results: Among 1383 first-ever stroke patients with AF, 578 patients (41.8%) had CBI. Of these 578 with CBI, EA pattern CBI only, non-EA pattern CBI only, and both CBIs were 61.8% (n=357), 21.8% (n=126), and 16.4% (n=95), respectively. The estimated 1-year cumulative incidence of recurrent ischemic stroke was 5.2% and 1.9% in the CBI (+) and CBI (−) groups, respectively ( P =0.001 by Gray test). CBI increased the risk of recurrent ischemic stroke (adjusted hazard ratio [95% CI], 2.91 [1.44–5.88]) but did not the risk of all-cause mortality (1.32 [0.97–1.80]). The EA pattern CBI only and both CBIs elevated the risk of recurrent ischemic stroke (2.76 [1.32–5.77] and 5.39 [2.25–12.91], respectively), while the non-EA pattern only did not (1.44 [0.40–5.16]). Conclusions: Our study suggests that AF patients with CBI might have increased risk of recurrent stroke. CBI could be considered when estimating the stroke risk in patients with AF.

The expected growth of stroke burden in Korea in early 2000s led to the initiation of a government-funded clinical research project with the goal of development and implementation of national stroke guidelines. The CRCS-K (Clinical Research Collaboration for Stroke in Korea) began as a part of this project. For stroke epidemiology and quality of care research, the CRCS-K developed a multicenter, prospective, stroke registry and began collection of data in 2008. Now, about 100 000 cases have been registered at 17 university hospitals or regional stroke centers and about 200 articles have been published based on the registry experience. The analysis of the 10-year secular trends showed overall improvement of stroke care and outcomes and areas for improvement. This large-scale, high-quality dataset provides opportunities to explore and compare treatment disparities using the comparative effectiveness research methods, design and conduct a registry-based randomized clinical trial, connect the registry data with other data sources including the national claims data and neuroimaging or genetic data, and collaborate with other international researchers. An international stroke registry consortium may be a viable future direction.

Background: Stroke of other determined etiology (OE) includes patients with an uncommon cause of stroke. We described the general characteristics, management, and outcomes of stroke in OE and its subgroups. Methods: This study is a retrospective analysis of a prospective, multicenter, nationwide registry, the Clinical Research Center for Stroke-Korea-National Institutes of Health registry. We classified OE strokes into 10 subgroups according to the literature and their properties. Each OE subgroup was compared according to clinical characteristics, sex, age strata, lesion locations, and management. Moreover, 1-year composites of stroke and all-cause mortality were investigated according to the OE subgroups. Results: In total, 2119 patients with ischemic stroke with OE types (mean age, 55.6±16.2 years; male, 58%) were analyzed. In the Clinical Research Center for Stroke-Korea-National Institutes of Health registry, patients with OE accounted for 2.8% of all patients with stroke. The most common subtypes were arterial dissection (39.1%), cancer-related coagulopathy (17.3%), and intrinsic diseases of the arterial wall (16.7%). Overall, strokes of OE were more common in men than in women (58% versus 42%). Arterial dissection, intrinsic diseases of the arterial wall and stroke associated with migraine and drugs were more likely to occur at a young age, while disorders of platelets and the hemostatic system, cancer-related coagulopathy, infectious diseases, and hypoperfusion syndromes were more frequent at an old age. The composite of stroke and all-cause mortality within 1 year most frequently occurred in cancer-related coagulopathy, with an event rate of 71.8%, but least frequently occurred in stroke associated with migraine and drugs and arterial dissection, with event rates of 0% and 7.2%, respectively. Conclusions: This study presents the different characteristics, demographic findings, lesion locations, and outcomes of OE and its subtypes. It is characterized by a high proportion of arterial dissection, high mortality risk in cancer-related coagulopathy and an increasing annual frequency of cancer-related coagulopathy in patients with stroke of OE.

Background and Purpose— There is a paucity of information about the role of resting heart rate in the prediction of outcome events in patients with ischemic stroke with atrial fibrillation. We aimed to investigate the relationships between the level and variability of heart rate in the acute stroke period and stroke recurrence and mortality after acute ischemic stroke in patients with atrial fibrillation. Methods— Acute patients with ischemic stroke who had atrial fibrillation and were hospitalized within 48 hours of stroke onset were identified from a multicenter prospective stroke registry database. The acute stroke period was divided into early (within 24 hours of hospitalization) and late (72 hours to 7 days from onset) stages, and data on heart rate in both stages were collected. Moreover, the level and variability of heart rate were assessed using mean values and coefficients of variation. Outcome events were prospectively monitored up to 1 year after the index stroke. Results— Among 2046 patients eligible for the early acute stage analysis, 102 (5.0%) had a stroke recurrence, and 440 (21.5%) died during the first year after stroke. A statistically significant nonlinear J-shaped association was observed between mean heart rate and mortality ( P P >0.1 for quadratic and overall effect). The nonlinear and overall effects of the coefficients of variation of heart rate were not significant for all outcome variables. The same results were observed in the late acute stage analysis (n=1576). Conclusions— In patients with atrial fibrillation hospitalized for acute ischemic stroke, the mean heart rate during the acute stroke period was not associated with stroke recurrence but was associated with mortality (nonlinear, J-shaped association). The relationships between heart rate and outcomes were not observed with respect to heart rate variability.

Introduction: Although the heritability of stroke might be higher in young-age stroke population, it is even uncertain how many of them has monogenic causes of stroke. We aimed to estimate the prevalence and clinical characteristics of 15 monogenic disorders associated with stroke in a large, unselected young-age stroke population Methods: From a prospective, nationwide, multicenter, acute stroke registry of consecutive patients admitted to 15 academic or regional stroke centers in Korea, we enrolled all patients aged 55 years or younger except those who refuse to participate in this study. We performed genetic analysis using a customized targeted next-generation sequencing panel ( GLA, NOTCH3, HTRA1, RNF213, ACVRL1, ENG, CBS, TREX1, ABCC6, COL4A1, FBN1, NF1, COL3A1, MT-TL1, and APP ) to find clinically relevant genetic variants, and reviewed clinical information of the patients. Results: Genetic analysis was performed in 1,033 patients (male 70.7%, mean age 45.8±7.9). Twenty-eight clinically relevant genetic variants were identified in 131 (12.7%) patients, and were found most frequently in RNF213 (59, 5.7%) followed by ABCC6 (53, 5.1%) and NOTCH3 (15, 1.5%). Genetic variants were more commonly observed in younger group than older group (17.1% vs. 9.3%, p=0.021), but were not different according to vascular risk factor burden. Patients with premature ( Conclusion: Clinically relevant genetic variants were not uncommon than expected. We might have opportunities to improve our daily practice by genetic counseling patients and their families to reduce the future stroke.

Background: Incidence of gastrointestinal (GI) bleeding after acute ischemic stroke (AIS) was reported as 1.5% during hospitalization, one-thirds of which required blood transfusion. However, it is not known about the long-term incidence and the incidence rates by period after AIS. Methods: AIS patients who were admitted to the 14 participating hospitals between 2011 and 2013 were identified using a nationwide multicenter prospective stroke registry database. GI bleeding was captured with related diagnosis codes by International Classification of Diseases-10th Revision through the linkage between the registry database and the claims data. Bleeding requiring at least 2 packs of blood transfusion was defined as major GI bleeding. Incidence rates were calculated for each period as follow; 0-30 days, 31-90 days, 91-180 days, 181-365 days, 1-2 years, 2-3years, after 3 years. Results: Of 10,818 AIS patients, 59.0% were male and mean age was 67.5 ± 12.9 years. The median follow-up duration was 3.1 (interquartile range 2.3 to 4.0) years. During 31,208 person-years, 947 patients (8.8%) had 1,224 episodes of major GI bleeding. Annual incidence rate was 3.92 per 100 person-years. The incidence rates by periods were the highest at 19.21 per 100 person-years in the first month of AIS, gradually decreased to 9.02 in one to three months, 6.18 in three to six months, and 3.48 in six to twelve months. After three years, it remained at about 2.62 events per 100 person-years. During the observation period, only one major GI bleeding occurred without recurrence in about 80% of patients, about 13% recurred twice, and about 6% of patients had three or more recurrences. In the multivariable recurrent event analysis, anemia at admission, lower eGFR below 60, and mRS at 3 months ≥4 were independently associated with higher risk of major GI bleeding during the most of the observation period above 3 years. Conclusions: Major GI bleeding, requiring transfusion, seems to occur frequently after AIS, and the risk was gradually decreased after stroke. The efforts are needed to prevent it, especially in stroke patients with anemia and decreased renal function.

Background and Purpose— This study aimed to compare the effectiveness of dual antiplatelet therapy with clopidogrel plus aspirin (DAPT) with that of aspirin monotherapy (AM) in patients with acute, nonminor, and noncardioembolic stroke. Methods— Using a prospective, nationwide, multicenter stroke registry database, acute (within 24 hours of onset), nonminor (baseline National Institutes of Health Stroke Scale score, 4–15), and noncardioembolic stroke patients were identified. Propensity scores using inverse probability of treatment weighting were used to adjust baseline imbalances between the DAPT and AM groups. A primary outcome measure was a composite of all types of stroke (ischemic and hemorrhagic), myocardial infarction, and all-cause mortality within 3 months of stroke onset. Results— Among the 4461 patients meeting the eligibility criteria (age, 69±13 years; men, 57.7%), 52.5% (n=2340) received AM, and 47.5% (n=2121) received DAPT. The primary outcome event was not significantly different between the DAPT group and the AM group (20.9% versus 22.6%, P =0.13). The event rates of all types of stroke were also not different between the 2 groups (19.3% versus 20.1%, P =0.35), while all-cause mortality was significantly lower in the DAPT group than in the AM group (3.4% versus 4.9%, P =0.02). In the propensity-weighted Cox proportional hazards models with robust estimation, DAPT did not reduce the risk of the primary outcome event (hazards ratio, 0.91; 95% CI, 0.79–1.04) but did reduce the risk of all-cause mortality (0.69; 0.49–0.97). There was no treatment heterogeneity among the predefined subgroups, although the potential benefits of DAPT were suggested in subpopulations of moderate-to-severe relevant arterial stenosis and relatively severe deficits (National Institutes of Health Stroke Scale score, 12–15). Conclusions— Compared to AM, clopidogrel plus aspirin did not reduce the risk of the primary outcome event during the first 3 months after a nonminor, noncardioembolic, ischemic stroke.

Background and Purpose— Two large-scale randomized controlled trials of recurrent stroke prevention suggest that dual antiplatelet therapy with clopidogrel plus aspirin is beneficial for prevention of subsequent ischemic events. There is a paucity of data, however, on the efficacy or effectiveness of such an approach in the treatment of stroke patients with symptomatic large artery atherosclerotic occlusive disease. Methods— We used a multicenter stroke registry database (Clinical Research Collaboration for Stroke in Korea) to analyze acute ischemic stroke patients due to large artery atherosclerotic occlusive disease who were treated with aspirin alone or combination of clopidogrel and aspirin from May 2008 to May 2015. The results were analyzed by intention-to-treat, per-protocol, and as-treated methodologies. The primary end point was the 1-year composite outcome of stroke recurrence, myocardial infarction, and all-cause death. To balance the differences between groups, a frailty model using propensity scores and inverse probability of treatment weighting was used. Results— A total of 5934 patients with symptomatic large artery atherosclerotic occlusive disease were treated either with clopidogrel plus aspirin (n=2903, 49%) or aspirin (n=3031, 51%). The frequency of the primary outcome was 12% (n=353) in the clopidogrel-aspirin group and 14% (n=410) in the aspirin group. The hazards of the primary outcome with combination over aspirin only were significantly reduced in the per-protocol and as-treated analyses (hazard ratio, 0.71; 95% CI, 0.57–0.88; P =0.002 and hazard ratio, 0.81; 95% CI, 0.69–0.96; P =0.02, respectively), but there was borderline significance in the intention-to-treat analysis (hazard ratio, 0.86; 95% CI, 0.74–1.01; P =0.06). Combination therapy was beneficial for all-cause death in all analyses but did not reduce recurrent stroke. Conclusions— Compared with patients receiving aspirin monotherapy, the primary outcome seemed to occur less frequently in patients receiving dual antiplatelet therapy, which is explained mainly by the decrease of all-cause death. Since this is a nonrandomized, retrospective, observational study, our study should be cautiously interpreted.

Background and Purpose— This study aimed to compare the effectiveness of dual antiplatelet therapy with clopidogrel-aspirin to that of aspirin monotherapy in patients with acute minor cerebral ischemia using a prospective, nationwide, multicenter, stroke registry database in South Korea. Methods— CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events)-like patients who met eligibility criteria modeled on the CHANCE trial eligibility criteria, including (1) acute minor ischemic stroke defined as National Institutes of Health Stroke Scale score ≤3 or lesion positive transient ischemic attack within 24 hours of onset and (2) noncardioembolic stroke mechanism. Propensity scores using the inverse probability of treatment weighting was used to adjust for baseline imbalances. The primary outcome was the composite of all stroke (ischemic and hemorrhagic), myocardial infarction, and vascular death by 3 months. Results— Among 5590 patients meeting the eligibility criteria, age was 64±13 year and 62.6% were male. Aspirin and combination of clopidogrel-aspirin were administered in 66.1% and 33.9% of patients, respectively. In unadjusted analysis, rates of the 3-month primary vascular event outcome were lower with clopidogrel-aspirin versus aspirin, 9.9% versus 12.2% (hazard ratio, 0.79 [0.67–0.95]). In propensity-weighted Cox proportional hazards regression with robust estimation, clopidogrel-aspirin was associated with a lower risk of the primary vascular event outcome (hazard ratio, 0.76 [0.63–0.92]) and all stroke events (hazard ratio, 0.74 [0.61–0.90]). Among 6 predefined subgroup analyses, 3 showed potential modification of treatment effect, with lesser benefit associated with the absence of prior antiplatelet use ( P interaction =0.01) and younger age (P interaction =0.07), and absence of benefit associated with small vessel occlusion subtype ( P interaction =0.08). Conclusions— Dual antiplatelet therapy with aspirin and clopidogrel was associated with reduced stroke, myocardial infarction, and vascular death in the 3 months following a presenting minor, noncardioembolic ischemic stroke. Benefits may be particularly magnified in patients with a history of prior antiplatelet therapy, older age, and nonsmall vessel disease stroke mechanism.

Background: The significance of silent brain infarction (SBI) for stroke recurrence in acute ischemic stroke (AIS) patients with atrial fibrillation (AF) has yet to be elucidated. This study aims to evaluate SBI as an independent predictor and which characteristics of SBI are associated with stroke recurrence in AIS patients with AF. Methods: A multicenter prospective cohort recruited AIS patients with non-valvular AF from 14 centers from Oct 2017 to Dec 2018, and followed for ischemic stroke recurrence, all types of stroke and TIA, and all-cause mortality. Three patient groups; stroke patients with prior stroke history (PS), first-ever stroke with SBI [F-SBI(+)] and first-ever stroke without SBI [F-SBI(-)] were compared with Cox frailty model according to predetermined covariates. SBI subtypes; embolic-appearing pattern (EAP) and non-EAP, and SBI characteristics; size, numbers, and vascular territory involvements were assessed. Results: A total of 978 AF-AIS patients [27.5% PS, 29.1% F-SBI(+), 43.4% F-SBI(-)] were followed for 365 [348-374] days (median). Incidence of ischemic stroke recurrence in F-SBI(+) was higher than F-SBI(-), however, there was no significant difference compared to PS (p=0.860). Adjusted hazards for ischemic stroke recurrence and all kinds of stroke and TIA in F-SBI(+) were shown to be elevated [HR 3.87 (95% CI 1.53-9.16) and 2.60 (1.21-5.56)], and similar to PS [4.20 (1.73-10.24) and 2.90 (1.36-6.18)] when compared to F-SBI(-), respectively. Despite irrelevance in non-EAP SBI, a 4-fold increase of hazards in EAP SBI was observed [4.07 (1.63-10.13)]. Other SBI characteristics were not associated with outcomes. SBI and SBI features did not increase all-cause mortality. Conclusions: SBI and specifically, EAP SBI elevated stroke recurrence in AF-AIS patients as much prior stroke has increased the risk. Considering SBI to predict recurrence is suggested likewise prior stroke history is scored in AF thromboembolic risk estimation tools.

Background and Purpose— We evaluated whether hemoglobin concentration at admission was associated with stroke recurrence and composite vascular events (stroke, myocardial infarction, and vascular death) in acute ischemic stroke. Methods— We collected data from patients with acute ischemic stroke or transient ischemic attack from a multicenter stroke registry database in Korea. The association of hemoglobin concentration with 1-year stroke recurrence and composite vascular events was evaluated with respect to age, presence of cerebral artery stenosis, stroke severity, and stroke subtype. Results— Hemoglobin levels were inversely associated with stroke recurrence and composite vascular events. One-year rates of stroke recurrence and composite vascular events were significantly higher in patients with anemia or moderate anemia. In multivariable analyses, moderate anemia remained an independent predictor of stroke recurrence (adjusted hazard ratio, 1.43 [95% CI, 1.16–1.75]) and composite vascular events (adjusted hazard ratio, 1.26 [95% CI, 1.07–1.48]). Moderate anemia increased the risk of composite vascular events in patients with mild-to-moderate stroke severity (National Institutes of Health Stroke Scale score P =0.01 for interaction). Conclusions— Hemoglobin concentration could be an independent predictor of stroke recurrence and composite vascular events.

Introduction: Although the effect of blood pressure in post-stroke outcome is well recognized, the long-term time course of BP following acute ischemic stroke and it’s influence to outcomes have not been well elucidated. Method: From a multicenter prospective registry of acute ischemic stroke patients, a total of 5,514 patients with measurement of systolic blood pressure (SBP) in more than 2 of 7 prespecified time points up to 1 year after symptom onset were analyzed. The patients were grouped according to longitudinal SBPs of each patient using a group-based trajectory model, and number of groups were determined by the optimal delta-Bayesian Information Criterion. Outcome measures, which were stroke recurrence, mortality and composite of each events along with myocardial infarction were prospectively collected up to 1 year after symptom onset. Results: Patients were categorized into four groups according to their SBP trajectories: low (27.0%), moderate (59.5%), persistently high (1.2%), and slowly dropping (12.4%). After adjustment for pre-determined covariates, there were higher risk of stroke recurrence in persistently high SBP group (hazard ratio (HR), 2.28 [95% confidence interval (CI), 1.01-5.12]). Mortality was higher only in the slowly dropping SBP group (HR, 1.50 [95% CI, 1.09-2.05]). Composite events were higher in both persistently high (HR, 1.96 [95% CI, 1.02-3.75]) and slowing dropping (HR, 1.54 [95% CI, 1.18-2.00]) SBP groups. Conclusion: There were a group of patterns in long-term longitudinal SBP changes after acute ischemic stroke. Especially, slow BP droppers might have a distinct nature with higher mortality and would be a target for future investigations.

Background: Women, compared with men, tend to have worse functional outcome after stroke. The gender effect is not fully explained by age, pre-stroke dependency, and stroke severity. We hypothesized that it might be due to different prognostic impacts of stroke-related brain lesions in women vs. men. Objective: To investigate if the effects of acute infarct volume and white matter hyperintensity (WMH) volume on initial stroke severity and 3-month functional outcome are modified by gender. Methods: This prospective study included 6748 patients with acute ischemic stroke ( Results: Women, compared with men, were older (mean 72 vs. 65, p2: adjusted OR [95%], 1.36 [1.09-1.69]). The association of WMH volume with 3-month mRS score was significantly modified by gender (p-for-interaction=0.049), with the WMH effect being greater in women (adjusted ORs of the highest vs. lowest quartile for the worse outcome: 2.47 in women vs. 1.51 in men). Conclusion: Women, compared with men, are probably more susceptible to the adverse effects of infarct volume and WMH volume on stroke severity and functional outcome.

Background and Purpose— Quantitative imaging for the noninvasive assessment of thrombolysis is needed to advance basic and clinical thrombosis-related research and tailor tissue-type plasminogen activator (tPA) treatment for stroke patients. We quantified the evolution of cerebral thromboemboli using fibrin-targeted glycol chitosan–coated gold nanoparticles and microcomputed tomography, with/without tPA therapy. Methods— We injected thrombi into the distal internal carotid artery in mice (n=50). Fifty-five minutes later, we injected fibrin-targeted glycol chitosan–coated gold nanoparticles, and 5 minutes after that, we treated animals with tPA or not (25 mg/kg). We acquired serial microcomputed tomography images for 24 hours posttreatment. Results— Thrombus burden at baseline was 784×10 3 ±59×10 3 μm 2 for the tPA group (n=42) and 655×10 3 ±103×10 3 μm 2 for the saline group (n=8; P =0.37). Thrombus shrinkage began at 0.5 to 1 hour after tPA therapy, with a maximum initial rate of change at 4603±957 μm 2 /min. The rate of change lowered to ≈61% level of the initial in hours 1 to 2, followed by ≈29% and ≈1% in hours 2 to 3 and 3 to 24, respectively. Thus, 85% of total thrombolysis over 24 hours (≈500 μm 2 , equivalent to 64% of the baseline thrombus burden) occurred within the first 3 hours of treatment. Thrombus burden at 24 hours could be predicted at around 1.5 to 2 hours. Saline treatment was not associated with significant changes in the thrombus burden. Infarct size was smaller in the tPA group versus saline group (18.1±2.3 versus 45.8±3.3 mm 2 ; P r =0.71; P Conclusions— Thromboembolic burden and the efficacy of tPA therapy can be assessed serially, noninvasively, and quantitatively using high-resolution microcomputed tomography and a fibrin-binding nanoparticle imaging agent.

Background and Purpose— We compared baseline characteristics and outcomes at 3 months between patients with minor anterior circulation infarction (ACI) versus minor posterior circulation infarction (PCI), including the influence of large vessel disease on outcomes. Methods— This study is an analysis of a prospective multicenter registry database in South Korea. Eligibility criteria were patients with ischemic stroke admitted within 7 days of stroke onset, lesions in either anterior or posterior circulation, and National Institutes of Health Stroke Scale score of ≤4 at baseline. Patients were divided into 4 groups for further analysis: minor ACI with and without internal carotid artery/middle cerebral artery large vessel disease and minor PCI with and without vertebrobasilar large vessel disease. Results— A total of 7178 patients (65.2±12.6 years) were analyzed in this study, and 2233 patients (31.1%) had disability (modified Rankin Scale score 2–6) at 3 months. Disability was 32.3% in minor PCI and 30.3% in minor ACI ( P =0.07), and death was 1.3% and 1.5%, respectively ( P =0.82). In a multivariable logistic regression analysis, minor PCI was significantly associated with disability at 3 months when compared with minor ACI (odds ratio, 1.23; 95% confidence interval, 1.09–1.37; P Conclusions— Our study showed that minor PCI exhibited more frequent disability at 3 months than minor ACI. Especially, the presence of vertebrobasilar large vessel disease in minor PCI had a substantially higher risk of disability. Our results suggest that minor PCI with vertebrobasilar large vessel disease could require more meticulous care and are important targets for further study.

Background and Purpose- Two large-scale randomized controlled trials of recurrent stroke prevention suggest that dual antiplatelet therapy with clopidogrel plus aspirin is beneficial for prevention of subsequent ischemic events. There is a paucity of data, however, on the efficacy or effectiveness of such an approach in the treatment of stroke patients with symptomatic large artery atherosclerotic occlusive disease. Methods- We used a multicenter stroke registry database (Clinical Research Collaboration for Stroke in Korea) to analyze acute ischemic stroke patients due to large artery atherosclerotic occlusive disease who were treated with aspirin alone or combination of clopidogrel and aspirin from May 2008 to May 2015. The results were analyzed by intention-to-treat, per-protocol, and as-treated methodologies. The primary end point was the 1-year composite outcome of stroke recurrence, myocardial infarction, and all-cause death. To balance the differences between groups, a frailty model using propensity scores and inverse probability of treatment weighting was used. Results- A total of 5934 patients with symptomatic large artery atherosclerotic occlusive disease were treated either with clopidogrel plus aspirin (n=2903, 49%) or aspirin (n=3031, 51%). The frequency of the primary outcome was 12% (n=353) in the clopidogrel-aspirin group and 14% (n=410) in the aspirin group. The hazards of the primary outcome with combination over aspirin only were significantly reduced in the per-protocol and as-treated analyses (hazard ratio, 0.71; 95% CI, 0.57-0.88; P=0.002 and hazard ratio, 0.81; 95% CI, 0.69-0.96; P=0.02, respectively), but there was borderline significance in the intention-to-treat analysis (hazard ratio, 0.86; 95% CI, 0.74-1.01; P=0.06). Combination therapy was beneficial for all-cause death in all analyses but did not reduce recurrent stroke. Conclusions- Compared with patients receiving aspirin monotherapy, the primary outcome seemed to occur less frequently in patients receiving dual antiplatelet therapy, which is explained mainly by the decrease of all-cause death. Since this is a nonrandomized, retrospective, observational study, our study should be cautiously interpreted.

Background and Purpose: Stroke is one of the most devastating and costly health problems of today. However, there is lack of knowledge about how costly it is in a long-term perspective and how much the long-term cost differs according to 3-month functional outcome, a major primary outcome variable of acute stroke intervention trials. Methods: Acute ischemic stroke patients who were registered into the multi-center stroke registry (Clinical Research Collaboration for Stroke in Korea, CRCS-K) in South Korea between 2011 and 2013 were matched to the National Health Insurance Service claim database. All the healthcare expenditure was extracted from the claim database and converted into daily cost of each individual. Yearly expenditures and cumulative expenditure up to 5 yeas were obtained and expressed in US dollars and were compared according to 3-month functional outcome (modified Rankin disability scale, mRS).Results: A total of 11,136 acute ischemic stroke patients (mean age, 68 years; men 58%) were analyzed. The median follow-up period was 1,418 days. The mean cumulative healthcare expenditure over 5 years was $74,295 (SD, $91,049) and showed a dramatic increment during the first month followed by a constant increase without a considerable change. The mean 5-year cumulative expenditure differed significantly according to 3-month functional outcome; $32,261 in those with 3-month mRS 0 and $163,244 in those with 3-month mRS 5. After adjusting for the selected potential confounders, the yearly expenditures and the cumulative one at each time point differed significantly according to 3-month mRS scores. Figure given below is showing the median 5-year cumulative daily expenditure by 3-month mRS. Conclusions: This study shows that the impact of 3-month functional outcome on the long-term healthcare expenditure following acute ischemic stroke may be more than expected. The efforts for improving functional outcomes are urgent.

Background: Strict blood pressure (BP) control among acute ischemic stroke (AIS) survivors would improve prognosis and decrease recurrent vascular events, which, however, has not been investigated in detail. Methods: AIS survivors at discharge who was admitted between 2010 and 2011 were included in the analysis dataset. Baseline characteristics were gathered through a multicenter prospective stroke registry (CRCS-K). BP measurements, clinic visit and prescription of BP-lowering medications after discharge were collected through medical records until 1 year (± 2 months of grace period). Recurrent vascular events until 1 year after stroke including stroke, myocardial infarction and death were gathered through a structured telephone interview by trained research registrars or medical records review. Individual treatment intensification (TI) scores were calculated by the following equation; (observed medication change - predicted medication change by a standard guideline) / number of clinic visit. TI scores were categorized into quintile groups and their associations with recurrent events were assessed by Cox proportional hazard models. Results: Of the 3482 AIS survivors, 2675 (77%) were diagnosed of hypertension and 1977 (57%) had BP-lowering medication prescription at discharge. Median NIHSS score at admission was 3 [1 - 6] points and 1573 (45.3%) had mRS score 0f 0 - 1 at discharge. TI score over 1-year after discharge was mean - 0.24 ± 0.30 and median - 0.15 [- 0.42, 0]. Compared to Q3 (third quintile; group TI score, - 0.15 ± 0.05), Q5 (group TI score, 0.04 ± 0.08) had higher proportion of cardioembolic stroke (32% vs 20%) and higher median NIHSS score (4 vs 3). Extreme groups of TI scores, Q1 or Q5, showed increased hazard for having mortality or composite events (see Table). Conclusions: Physicians’ attitudes toward elevated BP, represented by the TI score, was significantly associated with long-term vascular outcomes.

Background: Current territorial maps are difficult to interpret because of highly variable territorial boundaries noted, thus complicating the assessment of stroke mechanism . Objective: To offer further knowledge on the variable anatomy of cerebral artery territory by providing terriorial maps of the anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA, respectively). Methods and Results: Digital maps of supratentorial infarcts were generated using diffusion-weighted MRIs of 1160 acute ( Conclusion: The new topographic brain atlas can be used in clinical care and research to objectively define the supratentorial arterial territories and their borders.

Background and Objectives: The aim of this study was to evaluate the clinical characteristics and outcomes of acute ischemic stroke according to the patients’ arrival time at hospital. Methods: In this prospective stroke registry, all consecutive patients, who admitted via emergency room of 12 participating centers nationwide from 2009/12 to 2017/11, were identified. All patients were presented with first-ever stroke within 7 days from symptom onset, and had relevant ischemic lesions on brain imaging. We categorized hospital arrival time into 4 groups, such as early morning (EM, 0 to 6), late morning (LM, 6 to 12), afternoon (AF, 12 to 18), and evening (EV, 18 to 24 o’clock). Results: Total of 31992 patients were included. In patients arriving in EM, the number was 2034 (6.4%) [vs. 9400 (29.4%), 13277 (41.5%), 7281 (22.8%)], age (mean) was 64.9 years (vs. 68.2, 67.4, and 67.0, p Conclusion: Though the number of patients arriving at hospital in EM was lowest, that group required highest rate of thrombolysis, showed younger age, higher cardioembolism, higher stroke severity, and poor functional outcome at 3 months. Adequate management needs to be considered for the patients arriving in EM.

Background and Purpose— Randomized trials comparing the use of multimodal magnetic resonance imaging (MRI) to multimodal computed tomography (CT)/ CT angiography (CTA) for selecting candidates for endovascular therapy (EVT) have not been reported. This study aimed to elucidate whether MRI-based selection for EVT is safe and effective within and after a 6-hour time window compared with conventional CTA-based selection. Methods— Data from a prospective, nationwide, multicenter stroke registry were analyzed. Workflow timelines were compared between patients selected for EVT based on MRI (the MRI group) and CTA (the CTA group). Multivariable ordinal and binary logistic regression analyses were performed to explore the relationships between decision imaging for EVT and clinical outcomes, including good and excellent outcomes (modified Rankin Scale scores of 0–2 and 0–1, respectively) at 3-month, modified Rankin Scale score distributions and safety outcomes (symptomatic intracranial hemorrhage [SICH] and mortality). Results— Ultimately, 1265 patients (age, 69±12 yrs; men, 55%) were enrolled in this study. The median National Institutes of Health Stroke Scale score was 15 (11–19). All workflow time metrics were significantly delayed in the MRI group compared with the CTA group. There was no difference in good 3-month outcomes in patients arriving within 6 hours of onset between the MRI and CTA groups (38.1% versus 38.5%), but SICH and mortality rates were lower in the MRI group than the CTA group (3.8% versus 7.7%, P =0.01 for SICH; 15.4% versus 20.9%, P =0.04 for mortality). In the multivariable analysis, decision imaging was not significantly associated with 3-month functional outcomes (all P >0.1) or mortality ( P =0.051); however, the MRI group was less likely to develop SICH than the CTA group ( P =0.01; odds ratio, 0.34 [95% CI, 0.17–0.77]). Conclusions— Our study found MRI-based selection for EVT was not associated with improving functional outcome compared with CT-based selection, but may be better at reducing the risk of SICH, despite the delays in all workflow time metrics.

Background and Purpose— Since its introduction, controversy has existed about the administration of intravenous heparin for the treatment of acute ischemic stroke. We studied trends in the intravenous heparin use during a 6-year time period and the potential influence of clinical guidelines in national language on intravenous heparin administration in Korea. Methods— On the basis of a prospective nationwide multicenter stroke registry, we collected data on patients with acute ischemic stroke who arrived within 7 days of symptom onset during the time period 2008 to 2013. We studied patient demographics, prestroke medical history, stroke characteristics, and stroke treatment. Data from a total of 23 425 patients from 12 university hospitals or regional stroke centers were analyzed. Results— The administration of intravenous heparin steadily decreased throughout the study period: 9.7% in 2008, 10.9% in 2009, 9.4% in 2010, 6.0% in 2011, 4.7% in 2012, and 4.3% in 2013 ( P for trend P P Conclusions— Use of intravenous heparin for acute ischemic stroke treatment has decreased in Korea, and this change may be attributable to the spread and successful implementation of regional clinical practice guidelines.

Background and Purpose— Blood pressure dynamics in patients with acute ischemic stroke may serve as an important modifiable and prognostic factor. Methods— A total of 8376 patients with acute ischemic stroke were studied from a prospective multicenter registry. Patients were eligible if they had been admitted within 24 hours of symptom onset and had ≥5 systolic blood pressure (SBP) measurements during the first 24 hours of hospitalization. SBP trajectory groups in the first 24 hours were identified using the TRAJ procedure in SAS software with delta-Bayesian Information Criterion and prespecified modeling parameters. Vascular events, including recurrent stroke, myocardial infarction, and death, were prospectively collected. The risk of having vascular events was calculated using the frailty model to adjust for clustering by hospital. Results— The group-based trajectory model classified patients with acute ischemic stroke into 5 SBP trajectory groups: low (22.3%), moderate (40.8%), rapidly stabilized (11.9%), acutely elevated (18.5%), and persistently high (6.4%) SBP. The risk of having vascular events was increased in the acutely elevated (hazard ratio, 1.28 [95% confidence interval, 1.12–1.47]) and the persistently high SBP groups (hazard ratio, 1.67 [95% confidence interval, 1.37–2.04]) but not in the rapidly stabilized group (hazard ratio, 1.13 [95% confidence interval, 0.95–1.34]), when compared with the moderate SBP group. Conclusions— SBP during the first 24 hours after acute ischemic stroke may be categorized into distinct trajectory groups, which differ in relation to stroke characteristics and frequency of subsequent recurrent vascular event risks. The findings may help to recognize potential candidates for future blood pressure control trials.

Backgrounds: Previous studies demonstrated the association of resting heart rate with cardiovascular outcomes while there were only few evidence for patients who experienced ischemic stroke. As atrial fibrillation (AF) is characterized by rapidity and irregularity of heart rate, heart rate characteristics might be a predictor for future vascular event in patients with AF acute ischemic stroke. Methods: From a multicenter prospective registry of stroke patients, acute ischemic stroke patients with AF who admitted within 48 hours after stroke onset were included. Heart rate data during the first 24 hours after admission were collected and level and variability of heart rate were assessed by mean and coefficient of variation (CV). Primary outcome was a composite of stroke recurrence, myocardial infarction and all-cause death, which was prospectively captured until 1 year after stroke onset. Results: A total of 2,046 patients were included for the final analysis. There were 102 (5.0%) stroke recurrence, 9 (0.4%) myocardial infarction and 440 (21.5%) death events within 1 year after stroke onset. Proportional hazards regression models were constructed and the non-linearity of effects of heart rate parameters were examined for outcome events. Among all the associations, effects of mean heart rate on primary outcome and all-cause mortality were non-linear ( p’s for quadratic effect = 0.017 and 0.032, respectively). The overall effects were significant only for effects of mean heart rate on primary outcome and all-cause mortality (P =0.013 and P=0.006, respectively). Effects of CV on outcome variables were not significant. Conclusion: This study suggests that mean heart rate during the first day of hospitalization was a predictor of future vascular events in AF patients presenting with acute ischemic stroke and the association seems to be non-linear ‘J shaped’. However, heart rate variability did not affect.

Backgrounds: Small vessel occlusion (SVO) accounts for 15-20% of acute ischemic stroke (AIS). Given the mechanism of vessel occlusion, sharing pathophysiology with intracerebral hemorrhage (ICH), and minor symptom presentation, the efficacy and safety of intravenous tissue plasminogen activator (IV-TPA) in patients with AIS due to SVO remain unclear, particularly in Asian patients who are at a higher ICH risk than other populations. Methods: Using a multicenter stroke registry of 15 centers in South Korea, we identified patients with AIS due to SVO admitted within 24 h from onset. The other inclusion criteria were prestroke mRS score 0-1, initial NIHSS Results: Between FEB 1, 2011 and JAN 31, 2016, we identified 202 patients in the IV-TPA group and 2381 patients in the control group. The IV-TPA group versus the control group had higher median (IQR) NIHSS score (5 [4-6] vs 2 [1-4]) and shorter onset-to-arrival time (1 [1-2] vs 10 [4-16], h). In addition, the TPA group compared to the control group had more prestroke mRS 0, less prior stroke, more males, higher initial SBP, less prestroke antiplatelet, less prestroke statin, and less aspirin/clopidogrel dual therapy after admission. At 3 months, 116 (57.4%) in the IV-TPA group and 1589 (66.7%) in the control group had mRS 0-1. No patients in the IV-TPA group and 19 (0.8%) in the control group died. On multivariable analyses adjusting for covariates, adjusted OR (95% CI) with IV-TPA was 1.55 (1.06-2.27) (P=0.022) for 3-month mRS 0-1 outcome, 1.38 (1.02-1.86) (P=0.039) for 3-month mRS favorable shift, and 0.15 (0.01-2.18) (P=0.166) for 3-month mortality. Three (1.5%) in the IV-TPA group and one (0.04%) in the control group had symptomatic ICH. Conclusion: This observational study suggests that IV-TPA improves outcome in patients with AIS due to SVO with an acceptable risk of symptomatic ICH.

Objective: Neurologic Deterioration (ND) is known to be related to disability and poor outcomes. However, no large epidemiologic study on ND has been reported. Methods: Patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) admitted within 7 days of symptom onset were identified. Under a component of a quality assurance program of stroke care, we have captured ND during hospitalization prospectively with regular monitoring and systemic audits. ND was defined as any new neurological symptoms/signs or neurological worsening within 3 weeks of onset, satisfying one or more of the followings: increase of total NIHSS score ≥ 2, subscore 1a, 1b, or 1c (level of consciousness) ≥ 1, or subscore 5a, 5b, 6a, or 6b (motor)≥1, or any new neurological deficit (even unmeasurable by NIHSS scores). We investigated the incidence, timing, causes and outcomes of ND. Results: From December 2010 to September 2015, 29446 patients with AIS or TIA were admitted to 15 participating centers. Seventy-one percent of the patients were hospitalized within 24hours of onset. Deterioration occurred in 18.2% during median 10.1 days of hospitalization, its cumulative incidence was 5.6% at 1 day, 9.1% at 2 days, 10.9% at 3 days, 14.2% at one week. As causes of ND, progression was most common (73%), followed by recurrence (8.5%). Compared to those without ND, patients with ND were more likely to be older, be females, be hospitalized earlier, have stroke subtypes of large arterial disease or cardioembolism, have relevant steno-occlusion of major cerebral arteries, and have severer neurologic deficits. ND was independently associated with poorer functional outcome (modified Rankin scale 3 or more) at 3 months (adjusted odds ratio, 5.58; 95% confidence intervals (CI), 5.10-6.11) and one year (4.85; 4.43-5.32), and incidence of major vascular events (stroke, myocardial infarction, all-cause death) up to one year (adjusted hazards ratio, 1.64; 95% CI, 1.50-1.79). Conclusions: Our study reveals that about one fifths of AIS or TIA patients deteriorate neurologically during hospitalization and this deterioration is associated with poor functional outcome and subsequent major vascular events. Further researches for its prediction, detection and treatment are warranted.

Background: Although dual antiplatelet treatment with aspirin and clopidogrel is widely used in stroke patients due to large artery atherosclerosis (LAA), there are limited data to justify this. Methods: We used a multicenter, prospective stroke registry database (CRCS-K) to analyze acute ischemic stroke patients due to LAA who were treated with aspirin alone or combination of aspirin and clopidogrel from May, 2008 to May 2015. Results were analyzed by intention-to-treat (ITT), as-treated (AT), and per-protocol (PP) method. Primary endpoint was the 1-year composite outcome of stroke recurrence, myocardial infarction (MI), and all-cause death. To balance the differences between groups, a frailty model with inverse probability of treatment weighting was used. Results: A total of 5,934 patients due to LAA were treated either aspirin alone (n=3,031, 51%) or combination of aspirin and clopidogrel (n=2,903, 49%). Primary outcome was 14% (n=410) in aspirin alone group and 12% (n=353) in aspirin plus clopidogrel group. In ITT analysis, compared to aspirin alone, aspirin plus clopidogrel did not decrease the hazards of primary outcome (adjusted hazards ratio, 0.86; 95% confidence intervals, 0.74-1.01; p=0.06), but decreased all-cause mortality significantly (0.80; 0.66-0.98; p=0.03). Stroke recurrence and a composite of stroke recurrence, MI, and vascular death were not reduced by aspirin plus clopidogrel. Results of AT and PP analyses are shown in the table below. Conclusion: Addition of clopidogrel to aspirin may decrease all-cause death and perhaps the composite of stroke recurrence, MI and all-cause death in patients with large artery atherosclerotic stroke.

Background and Purpose— Patients with minor ischemic stroke or transient ischemic attack are at high risk of recurrent stroke and vascular events, which are potentially disabling or fatal. This study aimed to evaluate contemporary subsequent vascular event risk after minor ischemic stroke or transient ischemic attack in Korea. Methods— Patients with minor ischemic stroke or high-risk transient ischemic attack admitted within 7 days of symptom onset were identified from a Korean multicenter stroke registry database. We estimated 3-month and 1-year event rates of the primary outcome (composite of stroke recurrence, myocardial infarction, or all-cause death), stroke recurrence, a major vascular event (composite of stroke recurrence, myocardial infarction, or vascular death), and all-cause death and explored differences in clinical characteristics and event rates according to antithrombotic strategies at discharge. Results— Of 9506 patients enrolled in this study, 93.8% underwent angiographic assessment and 72.7% underwent cardiac evaluations; 25.1% had symptomatic stenosis or occlusion of intracranial arteries. At discharge, 95.2% of patients received antithrombotics (antiplatelet polytherapy, 37.1%; anticoagulation, 15.3%) and 86.2% received statins. The 3-month cumulative event rate was 5.9% for the primary outcome, 4.3% for stroke recurrence, 4.6% for a major vascular event, and 2.0% for all-cause death. Corresponding values at 1 year were 9.3%, 6.1%, 6.7%, and 4.1%, respectively. Patients receiving nonaspirin antithrombotic strategies or no antithrombotic agent had higher baseline risk profiles and at least 1.5× higher event rates for clinical event outcomes than those with aspirin monotherapy. Conclusions— Contemporary secondary stroke prevention strategies based on thorough diagnostic evaluation may contribute to the low subsequent vascular event rates observed in real-world clinical practice in Korea.

Background: We have evaluated whether anemia at admission is associated with ischemic stroke recurrence and composite outcome events (stroke, myocardial infarction, and vascular death) according to the age, presence of cerebral artery stenosis, stroke subtype, and initial severity of stroke. Methods: All 27145 patients with transient ischemia attack or acute ischemic stroke admitted between April 2008 and November 2014 from the stroke registry of the fifth section of the Clinical Research Center for Stroke (CRCS-5) were selected. The association between anemia and 1-year stroke recurrence, composite outcome events according to age, presence of cerebral artery stenosis, stroke mechanism, and initial severity of stroke were evaluated. Results: The cumulative 1-year stroke recurrence rate, composite outcome events were significantly higher in patients with anemia than without anemia ( 7.2% vs. 4.8%, p Conclusion: Anemia is an independent predictor of 1-year ischemic stroke recurrence, composite outcome events of stroke, myocardial infarction, and vascular death. Our data suggests that more attention should be paid to the anemic patients with mild to moderate neurological deficit, small vessel occlusion subtype, and stroke of other determined etiology.

Background: There is no specific recommendation on statin therapy for cardioembolic stroke (CES) patients in current stroke guidelines. We evaluated the effect of statin on major vascular events following acute ischemic stroke in patients with CES and no other indications for statin. Methods: Using a prospective multicenter stroke registry database, we identified acute ischemic stroke patients who were hospitalized between 2008 and 2015 and were categorized into CES according to the Trial of Org 10172 in Acute Stroke Treatment classification. Patients who had established indications for statin in accordance with the recent stroke guidelines were excluded. Primary outcome measure was a major vascular event, a composite of stroke recurrence, myocardial infarction and vascular death; and secondary outcome measures were stroke recurrence and all-cause death. We performed frailty model analysis to estimate hazard ratios (HRs) of statin therapy on outcomes accounting for variation in quality of care among centers. Stabilized inverse probability of treatment weighting method with propensity scores was used to remove baseline imbalances between statin users and non-users. Results: Of the 6124 CES patients, 2987 patients (male, 52%; mean age, 73±12 years) met the eligibility criteria; and 2125 (71%) of 2987 patients were on statin at discharge. Compared to the non-users, the statin users were more likely to arrive at hospitals later, have milder neurologic deficits at presentation, be on stain prior to index stroke and have hyperlipidemia and were less likely to have atrial fibrillation and occlusion of relevant cerebral arteries. During the median follow-up of 364 days, major vascular events were observed in 118 patients (5.6%) among the statin users and 177 patients (20.5%) among the non-users, respectively (p Conclusion: This study suggests that statin therapy may reduce major vascular events and all-cause death in cardioembolic stroke patients without definite indications for statin.

Background: The purpose of the study is to evaluate whether prestroke glycemic control is associated with functional outcome in patients with acute ischemic stroke after endovascular treatment. Methods: We reviewed the acute ischemic stroke patients who underwent endovascular recanalization in the participating centers between April 2008 and March 2015 from the Clinical Research Center for Stroke-5th division (CRCS-5) registry. The relationship between the level of HbA1c on admission and functional outcome at 3 month, stroke recurrence and composite outcome (stroke, myocardial infarction, or vascular death) occurrence were assessed. Results: All 829 study subjects were classified as 4 groups according to quartiles of HbA1c on admission: 1 st quartile (HbA1c ≤5.6%), 2 nd quartile (5.6% < HbA1c ≤5.9%), 3 rd quartile (5.9% < HbA1c ≤6.5%), 4 th quartile (HbA1c >6.5%). END occurred more frequently in the highest quartile of HbA1c (P=0.02). Among the components of END, the frequency of symptomatic hemorrhagic transformation occurred more often in the group with higher quartiles (P=0.03), while stroke recurrence or recurrence was not significantly different according to the quartiles of HbA1c (P=0.27). After adjusting for significant variables (age, sex, initial NIHSS, diabetes, complete recanalization, procedure time, occurrence of END, P6.5% was still inversely associated with favorable functional outcome at 3 month (adjusted OR 0.48, 95% CI 0.25-0.93 as quartiles, adjusted OR 0.40, 95% CI 0.22-0.73 as a dichotomized variable). No significant heterogeneities were observed according to the age, diagnosis of diabetes on admission, stroke subtype, recanalization degree, and reperfusion time. The cumulative risk of both stroke recurrence and composite even rates were not significantly different according to the quartiles of HbA1c on admission (P=0.64, P=0.19, respectively). Conclusion: Prestroke glycemic control is associated with occurrence of symptomatic hemorrhagic ransformaion and functional outcome in patients with acute ischemic stroke after endovascular treatment. More stringent glycemic control of HbA1c below or equal to 6.5 % may have beneficial effect on neurological recovery after stroke.

Background and Purpose— Micro–computed tomography (mCT) offers high-resolution images, but it suffers from low contrast sensitivity and poor soft tissue contrast. We introduce a new mCT imaging technique with improved sensitivity for the dynamic spatial and temporal characterization of poststroke blood–brain barrier (BBB) dysfunction in small animals in vivo. Methods— Transient middle cerebral artery occlusion was induced for 1 hour in 10- to 12-week-old C57BL/6 mice (n=35). At 4, 24, and 48 hours after ischemic stroke, serial in vivo mCT imaging was performed 5 minutes after intravenous infusion (n=3) or intracarotid infusion of iopromide (240 μL) for 5 minutes (n=32). After intravenous injection of 2% Evans blue, we performed ex vivo near-infrared fluorescent imaging of parenchymal Evans blue leakage, visual assessment of poststroke parenchymal hematoma, triphenyltetrazolium chloride staining of the brain tissue, and quantitative mapping of stroke-related brain lesions. Results— Infarct-related BBB dysfunction could be demonstrated with intra-arterial but not with intravenous infusion of iopromide. Iopromide leakage across the dysfunctional BBB showed a monophasic (not biphasic) course for 48 hours after ischemic insult in both the parenchymal hematoma (n=5) and the non–parenchymal hematoma (n=24) groups, with relatively severe leakiness and greater hemispheric midline shift in animals with hemorrhage. Parenchymal staining on in vivo mCT overlapped with ex vivo fluorescent staining because of Evans blue. Multivariable analyses showed that midline shift and the amount of iopromide leakage at each of the 3 time points predicted the final infarct size at 48 hours. Conclusions— The new mCT BBB imaging technique, based on the intra-arterial infusion of clinically available iopromide, allows serial quantitative visualization of poststroke BBB dysfunction in mice, with high resolution and in a sensitive manner.

Background and Purpose— A role of neural networks in the development of poststroke dementia has not been clearly established. We hypothesized that stroke-mediated disruption of subcortical cholinergic pathway or large-scale neural networks contributes to poststroke dementia. Methods— A matched case–control study was conducted in a predetermined cohort with acute ischemic stroke. Cases were defined as newly developed dementia diagnosed >3 months after stroke using the Korean Vascular Cognitive Impairment Harmonization Standards. Each case was matched to 2 controls for age, education, and initial stroke severity. The Cholinergic Pathways HyperIntensities Scale was applied with some modifications to characterize disruption of cholinergic pathways by acute stroke lesions. Involvement of major cortical hub locations of the default mode network, central executive network, and salience network was also investigated. Results— After matching, 38 cases and 66 matched controls were included. Cholinergic Pathways HyperIntensities Scale scores were significantly higher in cases than in controls (2.2±2.9 versus 0.9±1.4). Acute ischemic lesions affecting the default mode and central executive networks were more frequently observed in cases compared with controls (36.8% versus 7.6% and 26.3% versus 6.1%, respectively). These findings remained significant in the multiple logistic regression models adjusted for various sets of potential confounders. Lesion location analysis revealed that cases were more likely to have acute lesions in the left corona radiata, hippocampal formation, and posterior parietal cortex. Conclusions— Disruption of cholinergic pathways and major hubs of large-scale neural networks might contribute to newly developed dementia after acute ischemic stroke.

Background: The widespread use of drip-and-ship strategy in acute ischemic stroke (AIS) is confined by the safety concerns during transfer. However, recent development of endovascular therapy (EVT) might add the advantage of higher recanalization rate to this strategy. We evaluated the effectiveness and safety of drip-and-ship versus conventional (front-door) strategy of preceding intravenous thrombolysis (IVT) in large artery occlusion stroke patients receiving EVT. Method: From a prospective multicenter stroke registry (CRCS-5) database, we identified AIS patients treated with IVT and EVT within 8 h of onset and admitted to the 14 participating centers between 2008 and 2013. Safety outcomes were symptomatic intracranial hemorrhage (sICH), and 3-month mortality. Effectiveness outcome was a 3-month modified Rankin Scale (mRS) score. We performed multivariable logistic regression analysis using generalized estimating equation to estimate adjusted odds ratio (OR) and 95% confidence interval (CI) of the drip-and-ship versus the front-door. Results: Of 16929 AIS patients registered during 64 months, 480 were treated with IVT and EVT within 8 h, and 61 (13%) were categorized into drip-and-ship group. Mean onset to IVT and IVT to EVT times were 117±51 and 187±69 minutes in drip-and-ship strategy and 127±59 and 75±38 minutes in front-door strategy, respectively. Forty-eight drip-and-ship cases were matched to 146 front-door cases by age and initial NIH stroke scale (NIHSS). Compared to the front-door cases, the drip-and-ship cases were more likely to be a habitual smoker, and treated with standard dose alteplase. sICH developed in 5.5% of the front-door strategy and 10.4% of the drip-and-ship strategy (p=0.146). After adjustment for age, initial NIHSS, pre-stroke mRS score, and variables with p Conclusion: The drip-and-ship strategy did not improve functional recovery at 3 months, and the safety issues might still exist in patients receiving EVT. However, there is a possible underestimation of initial stroke severity in drip and ship patients.

Objective: To measure the impact of cerebral white matter hyperintensity (WMH) burden on the outcomes of stroke in general, and stroke subtype specifically. Methods: A total of 3814 acute ischemic stroke patients were prospectively enrolled from 11 stroke centers. WMH volume on MRI were quantified and categorized into quintiles. First, the impact of WMH on 3-month modified Rankin scale (mRS) in the entire patient population was studied, and in each stroke type that was determined by the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Then, we analyzed inter-group differences by: initial NIH stroke scale at admission, early neurological deterioration during the first 3 weeks after stroke onset, and functional recovery as well as stroke recurrence during the 3-month period following the initial infarct. Results: Mean age was 67.1 ± 12.9, and 58.7% were men. In large artery atherosclerosis (LAA) stroke, top two WMH quintiles were independently associated with mRS at 3months. However, only the highest quintile was associated with mRS at 3 months in small vessel occlusion (SVO) and cardioembolism (CE). WMHs were independently associated with initial neurological severity in SVO stroke, but not in other subtypes. WMHs were related with early neurological deterioration only in LAA stroke. Regardless of stroke subtypes, WMHs were not associated with stroke recurrence. Higher WMH volume was independently associated with poor functional recovery in LAA stroke but not in CE subtype. Conclusion: To our knowledge, this is the first study to demonstrate that WMH volume is an independent predictor of outcomes for certain types of stroke subtypes.

Background and hypothesis: Post-stroke emotional symptoms are common and adversely influence the patients’ outcome. We aim to evaluate the efficacy of escitalopram in patients with acute stroke for the prevention of various emotional disorders, and for improvement of neurologic, cognitive function and patient quality of life. Method: In this multicenter, placebo-controlled, double-blind trial, 405 stroke patients (within 21 days after onset) were randomized either to the escitalopram (n = 217) (5 mg -10mg) or placebo (n = 188) for 3 months. Depressive symptoms (Montgomery-Asberg Depression Rating Scale [MADRS] and mini-international neuropsychiatric interview [MINI]), emotional incontinence (Kim’s criteria), anger proneness (Modified Spielberger trait), cognition (MOCA test), Modified Rankin scale (MRS), and quality of life (Stroke Specific QOL) were assessed initially, and at 3 and 6-months. Results: Baseline characteristics were similar between the groups. Proportions of patients with MADRS≥16, the primary outcome, were not different at 3-month (placebo vs. escitalopram group, 13.8% vs. 12.0%, p=0.579). However, new development of depression determined by MINI was lower in the escitalopram group (0 vs. 4 patients, P = 0.046). For the secondary outcomes, anger proneness score was lower in the escitalopram group (21.5 vs 20.1 at 3-month, P = 0.011). There were no significant differences in other items at 3-months: emotional incontinence (% of patients, 8.5% vs. 10.2%, p=0.565), MOCA score (21.1±6.8 vs. 20.9±7.2, p=0.704), MRS (3.1±1.2 vs. 3.0±1.3, p=0.822), and patient quality of life (165.0±38.8 vs. 166.7±39.1, p=0.667). When chronological changes of MADRS were analyzed after categorizing patients into normal (0-6), mild (7-15), and moderate/severe (≥16) depression groups, escitalopram significantly improved MADRS of patients with mild depression (10.30 to 7.23 vs. 10.91 to 5.06, p = 0.036). Conclusion: Escitalopram was not effective in the prevention of post-stroke depressive symptoms, and did not improve cognitive function, neurologic severity, and patient quality of life. However, it prevented development of depression defined by MINI, anger-proneness and seems to improve depressive symptoms in patients with mild depression.

Introduction: Predicting outcomes of acute stroke patients initially presenting with mild neurologic deficits is important in making decision for thrombolytic therapy. Previous researches with a small sample size have failed to find specific items of NIH Stroke Scale or clinical syndromes to be predictive of functional outcome. Hypothesis: We hypothesized that certain items of the NIH Stroke Scale or their combinations would be independently associated with unfavorable functional outcome after mild stroke Methods: Using a multicenter stroke registry database, we identified patients with acute ischemic stroke who presented within 4.5 hours of symptom onset and had initial NIH Stroke Scale scores ≤ 5. Functional outcomes at three months after the stroke were classified as favorable (modified Rankin Scale score [mRS] 0 to 1) or unfavorable (mRS 2-6). The individual NIH Stroke Scale items were dichotomized as absent (0) or present (≥1) for the analysis. The NIH Stroke Scale items and the total score were tested for predicting the outcomes in multivariable models adjusting for demographics and clinical characteristics. Area under the ROC curve (AUC) was used to assess the performance of multivariable models. Results: Among 2,209 patients who met the eligible criteria, 588 patients (26.6%) exhibited unfavorable functional outcome (mRS 2-6) at three months. The most frequently present items were item 10 (dysarthria, 37.5%), item 4 (facial palsy, 21.1%), item 8 (sensory, 15.0%), and items indicating limb paralysis. Among 15 items of NIH Stroke Scale, all items except for item 8 (sensory) and item 11 (extinction) were significantly associated with unfavorable functional outcomes in bivariate analysis (P Conclusions: Simply using the total score was as effective as using all NIH Stroke Scale items in predicting outcomes of patients presented with mild stroke symptom.

Introduction: The utilization of drip-and-ship thrombolysis paradigm, clinical characteristics and outcomes of patients treated with the paradigm could vary with regional stroke care system. Hypothesis: We hypothesized that clinical characteristics and functional outcomes of patients treated with drip-and-ship paradigm would be different from those of patients treated via direct visit. Methods: From a multicenter stroke registry, we identified acute ischemic stroke patients treated with tPA who arrived hospital within 6 hours from the symptom onset. Functional outcomes at three months after the stroke were classified as favorable (modified Rankin Scale score [mRS] 0 to 1) or unfavorable (mRS 2-6). Using multivariable analysis, we compared the modified Rankin scale (mRS) score at 3 months and symptomatic intracranial hemorrhages (SICH) between patients treated with drip-and-ship paradigm and those treated via direct visit. Results: Among 1,843 patients who met the eligible criteria, 244 patients (13.2%; 95% CI, 11.7-14.9) were treated using drip-and-ship paradigm. Patients treated with drip-and-ship paradigm had shorter onset to needle time compared with patients treated via direct visit (median[IQR], 110 minutes[79-150] vs 126 minutes[90-173], p Conclusions: Drip-and-ship thrombolysis paradigm was used in less than 15% of patients treated with tPA, and use of the paradigm caused a significant delay in onset to groin puncture time for endovascular therapy.

Background and Purpose— In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence. Methods— In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding. Results— Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77–1.35; P =0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P =0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group. Conclusions— Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00814268.

Background and Purpose— High experimental variability in mouse embolic stroke models could mask the effects of experimental treatments. We hypothesized that imaging thrombus directly would allow this variability to be controlled. Methods— We optically labeled thrombi with a near-infrared fluorescent (NIRF) probe C15 that is covalently linked to fibrin by factor-XIIIa. Labeled thrombus was injected into the left distal internal carotid artery (ICA) of C57/BL6 mice (n=47), near its bifurcation, and laser-Doppler cerebral-blood-flow (CBF) was assessed for 30 minutes. NIRF thrombus imaging was done ex vivo at 24 hours. Results— CBF variably decreased to 43.9±17.3% at 5 minutes (rCBF; 11.2∼80.4%). NIRF thrombus imaging at 24 hours showed variability in distribution (ICA bifurcation, adjacent and/or remote areas) and burden (2279±1270 pixels; 0∼5940 pixels). Final infarct size was also variable (21.0±10.3%; 4.7∼60.3% of the bihemispheric volume). Despite this heterogeneity, a strong thrombus-infarct correlation was maintained. The left hemispheric target infarct size (% of the hemisphere) correlated with thrombus burden, as a stronger predictor of infarct volume ( P P =0.02, r=−0.34). The infarct size was best predicted by a combination of thrombus imaging and CBF: left-hemispheric big-thrombi (>1865 pixels)/low-rCBF (≤42%) had an infarct volume of 56.9±10.4% (n=12), big-thrombi/high-rCBF had 45.9±23.5% (n=11), small-thrombi/low-rCBF 35.7±17.3% (n=11) and small-thrombi/ high-rCBF 27.3±16.4% (n=12). Conclusions— This is the first study to demonstrate that the highly heterogeneous nature of the mouse embolic stroke model can be characterized and managed by using near-infrared fluorescent thrombus imaging combined with CBF monitoring to stratify animals into useful subgroups.

Background and Purpose— An optimal strategy for management of symptomatic intracranial atherosclerotic stenosis (ICAS) has not yet been established. We compared the efficacy of 2 combinations of antiplatelets, aspirin plus cilostazol (cilostazol group) verus aspirin plus clopidogrel (clopidogrel group), on the progression of ICAS, which is known to be associated with clinical stroke recurrence. Methods— In this investigator-initiated double-blind trial, 457 patients with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or the basilar artery were randomly allocated into either a cilostazol group or a clopidogrel group. After 7 months of treatment, follow-up MR angiogram and MRI were performed. The primary end point was the progression of ICAS in comparison with stenosis on the baseline MR angiogram. Secondary end points included the occurrence of new ischemic lesions on MRI, composite of cardiovascular events, and major bleeding complications. Results— Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the clopidogrel group ( P =0.312). Cilostazol did not reduce the progression of symptomatic ICAS (20 of 202) compared to clopidogrel (32 of 207) (odds ratio, 0.61; P =0.092), although favorable changes in serum lipoproteins were observed in the cilostazol group. There were no significant differences between the 2 groups with respect to new ischemic lesions (18.7% versus 12.0%; P =0.078) and major hemorrhagic complications (0.9% versus 2.6%; P =0.163). Conclusions— This trial failed to show significant difference in preventing progression of ICAS and new ischemic lesions between the 2 combination antiplatelet therapies in the patients with symptomatic ICAS. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00130039.

Background and Purpose— Selecting among different antiplatelet strategies when patients experience a new ischemic stroke while taking aspirin is a common clinical challenge, currently addressed by a paucity of data. Methods— This study is an analysis of a prospective multicenter stroke registry database from 14 hospitals in South Korea. Patients with acute noncardioembolic stroke, who were taking aspirin for prevention of ischemic events at the time of onset of stroke, were enrolled. Study subjects were divided into 3 groups according to the subsequent antiplatelet therapy strategy pursued; maintaining aspirin monotherapy (MA group), switching aspirin to nonaspirin antiplatelet agents (SA group), and adding another antiplatelet agent to aspirin (AA group). The primary study end point was the composite of stroke (ischemic and hemorrhagic), myocardial infarction, and vascular death up to 1 year after stroke onset. Results— A total of 1172 patients were analyzed for this study. Antiplatelet strategies pursued in study patients were MA group in 212 (18.1%), SA group in 246 (21.0%), and AA group in 714 (60.9%). The Cox proportional hazards regression analysis showed that, compared with the MA group, there was a reduction in the composite vascular event primary end point in the SA group (hazard ratio, 0.50; 95% confidence interval, 0.27–0.92; P =0.03) and in the AA group (hazard ratio, 0.40; 95% confidence interval, 0.24–0.66; P Conclusions— This study showed that, compared with maintaining aspirin, switching to or adding alternative antiplatelet agents may be better in preventing subsequent vascular events in patients who experienced a new ischemic stroke while taking aspirin.

Background and Purpose— The low-dose (0.6 mg/kg) alteplase strategy to treat acute ischemic stroke patients became widespread in East Asian countries, without rigorous testing against standard-dose (0.9 mg/kg) alteplase treatment. Our aim was to investigate the comparative effectiveness and safety of the low-dose versus standard-dose intravenous alteplase strategy. Methods— A total of 1526 acute ischemic stroke patients who qualified for intravenous alteplase and treated within 4.5 hours were identified from a prospective, multicenter, and nationwide stroke registry database. Primary outcomes were a modified Rankin scale score of 0 to 1 at 3 months after stroke and occurrence of symptomatic hemorrhagic transformation. Inverse probability of low-dose alteplase weighting by propensity scores was used to remove baseline imbalances between the 2 groups, and variation among centers were also accounted using generalized linear mixed models with a random intercept. Results— Low-dose intravenous alteplase was given to 450 patients (29.5%) and standard-dose intravenous alteplase to 1076 patients (70.5%). Low-dose alteplase treatment was comparable to standard-dose therapy according to the following adjusted outcomes and odds ratios (95% confidence intervals): modified Rankin scale score 0 to 1 at 3 months and 0.95 (0.68–1.32); modified Rankin scale 0 to 2 at 3 months and 0.84 (0.62–1.15); symptomatic hemorrhagic transformation and 1.05 (0.65–1.70); and 3-month mortality and 0.54 (0.35–0.83). The associations were unchanged when the analysis was limited to those without endovascular recanalization. Conclusions— The low-dose alteplase strategy was comparable to the standard-dose treatment in terms of the effectiveness and safety.

Background: The low-dose (0.6 mg/Kg) alteplase strategy to treat acute ischemic stroke patients became widespread in East Asian countries, without rigorous testing against the concurrent standard-dose (0.9 mg/Kg) regimen. The aim of the current study was to investigate the comparative effectiveness and safety of low-dose alteplase treatment against standard dose regimen. Methods: A total of 1572 acute ischemic stroke patients who arrived within 4.5 hours from their last seen normal and treated with alteplase between November 2009 and March 2013 were identified from a prospective, multicenter and nationwide stroke registry database containing 15814 case records. Acute stroke management including the decision on the dose of alteplase was performed according to the current guideline and the attending physicians’ discretion. Inverse probability of low-dose strategy weighting (IPTW) by the propensity score was primarily utilized to remove baseline imbalance between the two doses. Results: From a total of 1572 cases who met the eligibility criteria, low-dose alteplase was infused in 464 (29.5%) subjects and standard-dose in 1108 (70.5%) cases. Low-dose group showed shorter onset-to-arrival delay, higher NIHSS score at arrival, and more frequent endovascular treatment. The balance between alteplase doses were adequately balanced using IPTW technique, and the low-dose alteplase treatment was not associated with a mRS score of 0 - 1 at 3 months and with symptomatic HT or 3-month mortality (see Figure A). When the analyses were limited to the subgroup without endovascular treatment, the neutral associations with mRS score 0 - 1 and symptomatic HT were retained but the odds for 3-month mortality was significantly lower in the low-dose alteplase group (see Figure B). Conclusion: The low-dose alteplase strategy was as comparable as the standard-dose treatment in terms of the effectiveness and safety, also with possibly decreasing 3-month mortality.

Objective: This study aimed to describe clinical outcomes in patients treated with intravenous (IV) tPA according to evidence of previous Intracranial hemorrhage (ICH) and investigate the associations between previous ICH and clinical outcomes. Methods: Using a prospective multicenter stroke registry database, we identified acute ischemic stroke patients who were hospitalized to the 14 participating centers between January 2011 and July 2013 and were treated with IV tPA within 4.5 h of onset. Presence of previous ICH was screened using the formal radiologic reports or the clinical history of ICH from the registry database. If suspected, previous ICH was confirmed through direct review of brain MRI. As clinical outcomes, modified Rankin scale (mRS) 0-1 at discharge, mortality during hospitalization and symptomatic hemorrhagic transformation (sHT) were collected. sHT was defined according to the definition of SITS-MOST trial. Results: Among 1495 patients who were treated with IV tPA, 70 (4.7%) had evidence of previous ICH. sHT developed in 69 (4.6%) of all subjects; 7.1% (n=5) of 70 patients with previous ICH and 4.5% (n=64) of 1425 without previous ICH (p=0.25 on Fisher’s exact test). Hospital Mortality and mRS 0-1 at discharge was observed in 5.6% and 26.6% of all subjects and in 8.6% and 22.9% of those with previous ICH and 5.4% and 26.7% in those without it (p=0.28 on Fisher’s exact test and p=0.47 on Pearson’s chi-squared test, respectively). Multivariable logistic regression analysis with adjustment for age, initial National Institute of Health Stroke Scale, initial glucose and tPA dose showed that previous ICH was not associated with sHT, mortality during hospitalization and having discharge mRS 0-1 (p’s >0.4). Review of MRI on 5 patients who had previous ICH and developed sHT after IV tPA demonstrated that, in 4 cases, location of sHT was different from where previous ICH had developed, but in 1 case sHT occurred exactly where previous ICH had developed. Conclusions: This study shows that previous ICH may not increase the risk of sHT and death and aggravate functional outcome at discharge. However, it should be noted that the retrospective nature and small sample size of this study limit the generalization of its results.

Background: Since the introduction of intravenous (IV) heparin for the treatment of acute ischemic stroke in 1941, its use has been an area of great controversy among neurologists. Current American Heart Association guideline does not recommend IV heparin for the treatment of acute ischemic stroke. We sought to obtain updated information regarding the practices of Korean neurologists with regard to acute heparin use. Methods: Based on a prospective multicenter stroke registry database (CRCS-5), we collected patients with acute ischemic stroke, arrived within 7 days of symptom onset, from 2008 to 2013. Patient’s demographics, medical history and stroke characteristics were compared between IV heparin user and non-user. Results: Total of 23,425 patients from 12 regional stroke centers or university hospitals across the nation was analyzed. The mean age was 67.8 years and 58.1% was male. Median initial NIHSS score was 4 (interquartile range, 2 - 9). Large artery atherosclerosis was the most common cause of acute ischemic stroke (37.1%), followed by cardioembolism (21.9%), and small-vessel occlusion (18.9%). During the study period, use of IV heparin decreased; 9.7% in 2008; 10.9% in 2009; 9.4% in 2010; 6.0% in 2011; 4.7% in 2012; 4.3% in 2013 (p for trend < 0.001). The most prominent reduction was observed between 2010 and 2011, just after the first release of the Korean Stroke Guidelines in October, 2009. Cardioembolism (17.1%) and stroke of two or more causes (15.3%) were associated with IV heparin, and the decrease of IV heparin use in these stroke subtypes was a major contributor of the decrease in general. Age (age ≥ 75, 7.5%; age

Background and Purpose: A recent study showed that cardiogenic emboli might flow more frequently into the right hemisphere, whereas atheromatous aortic arch emboli might flow more frequently into the left hemisphere. We tried to 1) see if cardioembolic (CE) infarct volume would be larger in the right hemisphere than in the left hemisphere, and 2) depict anatomical regions showing CE vs. large artery atherosclerotic (LAA) infarction-related right-left propensity. Methods: In this study on carotid artery territory CE (n = 694) vs. LAA (n = 1162) acute ischemic stroke patients who were enrolled consecutively from 11 nationwide stroke centers, we quantitatively registered diffusion magnetic resonance imaging lesions onto the Montreal Neurologic Institute brain template. Results: In patients with bilateral CE stroke (n = 163), right hemispheric infarct size was about two times bigger than the contralateral left hemispheric infarct size (p = 0.002). However, in patients with either unilateral (n = 925) or bilateral (n = 184) LAA stroke, there was no significant difference in the right vs. left hemispheric infarct size between the right vs. left unilateral infarct groups or within the bilateral infarct group (all p > 0.05). In patients with unilateral CE stroke (n = 510), there was no significant difference in the infarct size between the groups with right vs. left hemispheric lesions. Age and infarct volume-adjusted p-value maps of the CE vs. LAA stroke patients, which were corrected for multiple comparisons, revealed the brain regions with a significantly higher infarct frequency in CE stroke than in LAA stroke. The significant clusters were observed only in the right hemisphere, encompassing both the superior and inferior division middle cerebral artery territories, particularly in the pial and corticosubcortical regions including the claustrum and insula. Conclusion: The present multi-center quantitative magnetic resonance imaging study confirms the ‘right > left’ propensity of CE (vs. LAA) stroke.

Background and Purpose— Neural progenitor cells (NPC) have been reported to aid in the functional recovery from stroke and hold promise as a novel treatment for a variety of neurological diseases. There is a need for imaging tools to study the in vivo migratory behavior of these cells. Methods— C17.2 NPC, stably transfected with firefly luciferase, were serially imaged through intact skull and skin by bioluminescence imaging over 2 to 3 weeks in nu/nu mice with closed-vessel middle cerebral artery infarcts, followed by contralateral intraparenchymal or intraventricular injections of NPC. Results— NPC migrated to the site of infarct from the contraleral parenchyma, crossing the midline at 7 days. In control animals without infarcts, NPC remained at the site of administration. Intraventricular cell administration resulted in a wide distribution of cells, including the site of infarct. Within the infarct area, NPC colabeled with the neuronal marker NeuN and with astroglial marker glial fibrillary acidic protein. The time course and magnitude of NPC recruitment were longitudinally compared between the treatment groups. Conclusions— NPC recruitment to infarct can be assessed noninvasively by serial in vivo imaging. Images correlate well with histological cell distributions. NPC are recruited to infarcts with both parenchymal and cerebrospinal fluid administration, but higher initial photon counts suggest that cerebrospinal fluid administration is more efficient at early infarct seeding.

Background and Purpose— We aimed to generate rigorous graphical and statistical reference data based on volumetric measurements for assessing the relative severity of white matter hyperintensities (WMHs) in patients with stroke. Methods— We prospectively mapped WMHs from 2699 patients with first-ever ischemic stroke (mean age=66.8±13.0 years) enrolled consecutively from 11 nationwide stroke centers, from patient (fluid-attenuated-inversion-recovery) MRIs onto a standard brain template set. Using multivariable analyses, we assessed the impact of major (age/hypertension) and minor risk factors on WMH variability. Results— We have produced a large reference data library showing the location and quantity of WMHs as topographical frequency-volume maps. This easy-to-use graphical reference data set allows the quantitative estimation of the severity of WMH as a percentile rank score. For all patients (median age=69 years), multivariable analysis showed that age, hypertension, atrial fibrillation, and left ventricular hypertrophy were independently associated with increasing WMH (0–9.4%, median=0.6%, of the measured brain volume). For younger (≤69) hypertensives (n=819), age and left ventricular hypertrophy were positively associated with WMH. For older (≥70) hypertensives (n=944), age and cholesterol had positive relationships with WMH, whereas diabetes mellitus, hyperlipidemia, and atrial fibrillation had negative relationships with WMH. For younger nonhypertensives (n=578), age and diabetes mellitus were positively related to WMH. For older nonhypertensives (n=328), only age was positively associated with WMH. Conclusions— We have generated a novel graphical WMH grading (Kim statistical WMH scoring) system, correlated to risk factors and adjusted for age/hypertension. Further studies are required to confirm whether the combined data set allows grading of WMH burden in individual patients and a tailored patient-specific interpretation in ischemic stroke-related clinical practice.