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Background and Purpose Accurate classification of ischemic stroke subtype is important for effective secondary prevention of stroke. We used diffusion-weighted image (DWI) and atrial fibrillation (AF) data to train a deep learning algorithm to classify stroke subtype. Methods Model development was done in 2,988 patients with ischemic stroke from three centers by using U-net for infarct segmentation and EfficientNetV2 for subtype classification. Experienced neurologists (n=5) determined subtypes for external test datasets, while establishing a consensus for clinical trial datasets. Automatically segmented infarcts were fed into the model (DWI-only algorithm). Subsequently, another model was trained, with AF included as a categorical variable (DWI+AF algorithm). These models were tested: (1) internally against the opinion of the labeling experts, (2) against fresh external DWI data, and (3) against clinical trial dataset. Results In the training-and-validation datasets, the mean (±standard deviation) age was 68.0±12.5 (61.1% male). In internal testing, compared with the experts, the DWI-only and the DWI+AF algorithms respectively achieved moderate (65.3%) and near-strong (79.1%) agreement. In external testing, both algorithms again showed good agreements (59.3%–60.7% and 73.7%–74.0%, respectively). In the clinical trial dataset, compared with the expert consensus, percentage agreements and Cohen’s kappa were respectively 58.1% and 0.34 for the DWI-only vs. 72.9% and 0.57 for the DWI+AF algorithms. The corresponding values between experts were comparable (76.0% and 0.61) to the DWI+AF algorithm. Conclusion Our model trained on a large dataset of DWI (both with or without AF information) was able to classify ischemic stroke subtypes comparable to a consensus of stroke experts.

Abstract The effect of arterial tortuosity on intracranial atherosclerosis (ICAS) is not well understood. This study aimed to evaluate the effect of global intracranial arterial tortuosity on intracranial atherosclerotic burden in patients with ischemic stroke. We included patients with acute ischemic stroke who underwent magnetic resonance angiography (MRA) and classified them into three groups according to the ICAS burden. Global tortuosity index (GTI) was defined as the standardized mean curvature of the entire intracranial arteries, measured by in-house vessel analysis software. Of the 516 patients included, 274 patients had no ICAS, 140 patients had a low ICAS burden, and 102 patients had a high ICAS burden. GTI increased with higher ICAS burden. After adjustment for age, sex, vascular risk factors, and standardized mean arterial area, GTI was independently associated with ICAS burden (adjusted odds ratio [adjusted OR] 1.33; 95% confidence interval [CI] 1.09–1.62). The degree of association increased when the arterial tortuosity was analyzed limited to the basal arteries (adjusted OR 1.48; 95% CI 1.22–1.81). We demonstrated that GTI is associated with ICAS burden in patients with ischemic stroke, suggesting a role for global arterial tortuosity in ICAS.

Aging manifests as many phenotypes, among which age-related changes in brain vessels are important, but underexplored. Thus, in the present study, we constructed a model to predict age using cerebrovascular morphological features, further assessing their clinical relevance using a novel pipeline.Age prediction models were first developed using data from a normal cohort (n = 1181), after which their relevance was tested in two stroke cohorts (n = 564 and n = 455). Our novel pipeline adapted an existing framework to compute generic vessel features for brain vessels, resulting in 126 morphological features. We further built various machine learning models to predict age using only clinical factors, only brain vessel features, and a combination of both. We further assessed deviation from healthy aging using the age gap and explored its clinical relevance by correlating the predicted age and age gap with various risk factors.The models constructed using only brain vessel features and those combining clinical factors with vessel features were better predictors of age than the clinical factor-only model (r = 0.37, 0.48, and 0.26, respectively). Predicted age was associated with many known clinical factors, and the associations were stronger for the age gap in the normal cohort. The age gap was also associated with important factors in the pooled cohort atherosclerotic cardiovascular disease risk score and white matter hyperintensity measurements.Cerebrovascular age, computed using the morphological features of brain vessels, could serve as a potential individualized marker for the early detection of various cerebrovascular diseases.

Ischemic stroke is a major cause of mortality worldwide. Proper etiological subtyping of ischemic stroke is crucial for tailoring treatment strategies. This study explored the utility of circulating microRNAs encapsulated in extracellular vesicles (EV-miRNAs) to distinguish the following ischemic stroke subtypes: large artery atherosclerosis (LAA), cardioembolic stroke (CES), and small artery occlusion (SAO). Using next-generation sequencing (NGS) and machine-learning techniques, we identified differentially expressed miRNAs (DEMs) associated with each subtype. Through patient selection and diagnostic evaluation, a cohort of 70 patients with acute ischemic stroke was classified: 24 in the LAA group, 24 in the SAO group, and 22 in the CES group. Our findings revealed distinct EV-miRNA profiles among the groups, suggesting their potential as diagnostic markers. Machine-learning models, particularly logistic regression models, exhibited a high diagnostic accuracy of 92% for subtype discrimination. The collective influence of multiple miRNAs was more crucial than that of individual miRNAs. Additionally, bioinformatics analyses have elucidated the functional implications of DEMs in stroke pathophysiology, offering insights into the underlying mechanisms. Despite limitations like sample size constraints and retrospective design, our study underscores the promise of EV-miRNAs coupled with machine learning for ischemic stroke subtype classification. Further investigations are warranted to validate the clinical utility of the identified EV-miRNA biomarkers in stroke patients.

Introduction: This trial, conducted according to the request of the Korean Ministry of Food and Drug Safety, investigated the potential of oxiracetam in mitigating post-stroke cognitive decline, and whether physical activity could augment its efficacy. The mechanisms behind these effects were explored using functional neuroimaging. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, we enrolled patients reporting subjective cognitive decline more than three months post-stroke and at a high risk of dementia. Participants were randomly assigned to a 36-week regimen of either 800 mg oxiracetam or a placebo, administered twice daily, in conjunction with recommended physical activity. Physical activity levels were monitored using wrist actigraphy. Cognitive function was assessed using a mini-mental state examination (MMSE) and clinical dementia rating sum of boxes (CDR-SB) at baseline and 36 weeks. Other assessments included the 60-minute protocol of Vascular Cognitive Impairment Harmonization Standards, Euro QoL, patient's global assessment, and resting-state functional MRI-derived neural network attributes. Results: Of the 500 participants (mean age 68.9 years, male 76.1%, median interval between stroke and randomization 32 months), 457 were analyzed. Both groups have equally adhered to the exercise guidelines (moderate-to-vigorous physical activity per day; 23.7±26.1 vs. 24.1±28.7 minutes; p=0.75). No significant difference was observed in changes to MMSE and CDR-SB scores between the two groups (MMSE, 0.13±2.27 vs. 0.27±2.09, p=0.49; CDR-SB -0.14±0.70 vs. -0.08±0.80, p=0.38). Although increased baseline exercise time correlated with better MMSE scores, the correlation was weak (R= 0.11, p=0.02). Verbal memory, phonemic fluency, language, NPI-Q, and geriatric depression scale also improved significantly within each group. However, only the intervention group showed significant improvements in CDR-SB and EuroQoL scores. A predetermined multivariate analysis showed a significant change in the normalized clustering coefficient for the secondary efficacy endpoint (r=0.09, SE=0.04, p=0.03). Discussion: This study failed to confirm the efficacy of oxiracetam in preventing post-stroke cognitive decline. Nonetheless, adherence to the exercise guidelines appeared to help participants maintain their cognitive functions, despite being a chronic stage post-stroke and having a high dementia risk.

Background and Purpose This study aimed to evaluate whether extracellular-vesicle-incorporated microRNAs (miRNAs) are potential biomarkers for cancer-related stroke. Methods This cohort study compared patients with active cancer who had embolic stroke of unknown sources (cancer-stroke group) with patients with only cancer, patients with only stroke, and healthy individuals (control groups). The expression profiles of miRNAs encapsulated in plasma exosomes and microvesicles were evaluated using microarray and validated using quantitative real-time polymerase chain reaction. The XENO-QTM miRNA assay technology was used to determine the absolute copy numbers of individual miRNAs in an external validation cohort. Results This study recruited 220 patients, of which 45 had cancer-stroke, 76 were healthy controls, 39 were cancer controls, and 60 were stroke controls. Three miRNAs (miR-205-5p, miR-645, and miR-646) were specifically incorporated into microvesicles in patients with cancer-related stroke, cancer controls, and stroke controls. The area under the receiver operating characteristic curves of these three miRNAs were 0.7692–0.8510 for the differentiation of patients with cancer-stroke from cancer-controls and 0.8077–0.8846 for the differentiation of patients with cancer-stroke from stroke controls. The levels of several miRNAs were elevated in the plasma exosomes of patients with cancer, but were lower than those in plasma microvesicles. An in vivo study showed that systemic injection of miR-205-5p promoted the development of arterial thrombosis and elevation of D-dimer levels Conclusion Stroke due to cancer-related coagulopathy was associated with deregulated expression of miRNAs, particularly microvesicle-incorporated miR-205-5p, miR-645, and miR-646. Further prospective studies of extracellular-vesicle-incorporated miRNAs are required to confirm the diagnostic role of miRNAs in patients with stroke and to screen the roles of miRNAs in patients with cancer.

PurposeLenticulostriate infarction requires further research of arterial hemodynamic factors, as the disease is diagnosed in the absence of major arterial stenosis or cardioembolism.MethodsIn this multicenter retrospective cohort study, we included patients who were hospitalized for lenticulostriate infarction from January 2015 to March 2021 at three stroke centers in South Korea. We obtained hemodynamic information on cerebral arteries using signal intensity gradient (SIG), an in-vivo approximated wall shear stress (WSS) derived from Time-of-Flight Magnetic Resonance Angiography (TOF-MRA). A favorable outcome was defined as a modified Rankin Scale of 0 to 2 at hospital discharge.ResultsA total of 294 patients were included, of whom 146 (49.7%) had an unfavorable outcome. The unfavorable outcome group showed significantly lower SIG in both middle cerebral arteries (MCAs) than the favorable group (5.2 ± 1.2 SI/mm vs. 5.9 ± 1.2, p

BackgroundConstipation symptoms are highly prevalent in acute ischemic stroke, but the clinical and neuroimaging predictors are unknown. This study aimed to identify lesions and clinical features associated with acute constipation.MethodsData from patients with acute ischemic stroke registered in a hospital-based stroke registry between January 2018 and December 2019 were analyzed. Clinical, laboratory, and imaging features were examined for associations with acute constipation. Using the topographic lesion on diffusion-weighted images, multivariate support vector regression-based lesion-symptom mapping (SVR-LSM) was conducted and compared between the non-constipation and acute constipation groups.ResultsA total of 256 patients (mean age 67 years, men: 64%) were included. Acute constipation was noted in 81 patients (32%). Initial stroke severity, represented by initial National Institutes of Health and Stroke Scale (NIHSS) scores, was associated with acute constipation. Laboratory parameters, including fibrin degradation products (FDP), fibrinogen, D-dimer, lipoprotein (a), and free fatty acid levels, also showed statistically significant differences between the non-constipation and constipation groups. FDP, D-dimer, and free fatty acid levels were independently associated with acute constipation in the logistic regression model after adjusting for initial NIHSS scores and potassium levels. SVR-LSM revealed that bilateral lesions in the precentral gyrus, insula, opercular part of the inferior frontal gyrus, the inferior parietal lobule, and lesions in the right middle frontal gyrus were significantly associated with acute constipation. The results were consistent after controlling for the initial NIHSS scores and poststroke potassium levels. When cardioembolic stroke subjects were excluded, the right insular and prefrontal cortex lesions lost their association with acute constipation.ConclusionAcute constipation symptoms after acute ischemic stroke are mainly related to bilateral lesions in the insula, precentral gyrus, postcentral gyrus, and inferior parietal lobule. Clinically important predictors of acute constipation include initial neurological severity and thromboembolic markers of stroke.

Abstract Identifying the cerebral arterial branches is essential for undertaking a computational approach to cerebrovascular imaging. However, the complexity and inter-individual differences involved in this process have not been thoroughly studied. We used machine learning to examine the anatomical profile of the cerebral arterial tree. The method is less sensitive to inter-subject and cohort-wise anatomical variations and exhibits robust performance with an unprecedented in-depth vessel range. We applied machine learning algorithms to disease-free healthy control subjects (n = 42), patients with stroke with intracranial atherosclerosis (ICAS) (n = 46), and patients with stroke mixed with the existing controls (n = 69). We trained and tested 70% and 30% of each study cohort, respectively, incorporating spatial coordinates and geometric vessel feature vectors. Cerebral arterial images were analyzed based on the ‘segmentation-stacking’ method using magnetic resonance angiography. We precisely classified the cerebral arteries across the exhaustive scope of vessel components using advanced geometric characterization, redefinition of vessel unit conception, and post-processing algorithms. We verified that the neural network ensemble, with multiple joint models as the combined predictor, classified all vessel component types independent of inter-subject variations in cerebral arterial anatomy. The validity of the categorization performance of the model was tested, considering the control, ICAS, and control-blended stroke cohorts, using the area under the receiver operating characteristic (ROC) curve and precision-recall curve. The classification accuracy rarely fell outside each image’s 90–99% scope, independent of cohort-dependent cerebrovascular structural variations. The classification ensemble was calibrated with high overall area rates under the ROC curve of 0.99–1.00 [0.97–1.00] in the test set across various study cohorts. Identifying an all-inclusive range of vessel components across controls, ICAS, and stroke patients, the accuracy rates of the prediction were: internal carotid arteries, 91–100%; middle cerebral arteries, 82–98%; anterior cerebral arteries, 88–100%; posterior cerebral arteries, 87–100%; and collections of superior, anterior inferior, and posterior inferior cerebellar arteries, 90–99% in the chunk-level classification. Using a voting algorithm on the queued classified vessel factors and anatomically post-processing the automatically classified results intensified quantitative prediction performance. We employed stochastic clustering and deep neural network ensembles. Ma-chine intelligence-assisted prediction of vessel structure allowed us to personalize quantitative predictions of various types of cerebral arterial structures, contributing to precise and efficient decisions regarding the cerebrovascular disease.

Background Although it is well known that the disordered brain provokes cardiac autonomic dysfunction, the detailed location of brain lesions related to cardiac function warrants further investigation. We aimed to elucidate the brain lesions topographically associated with left ventricular (LV) systolic function measured by myocardial strain in patients with acute ischemic stroke without preexisting primary cardiac dysfunction by using support vector regression lesion‐symptom mapping. Methods and Results Subjects were those with LV ejection fraction of 50% or more among patients with acute ischemic stroke registered in the Samsung Medical Center stroke registry between 2016 and 2017. To evaluate LV systolic performance and contractility, we measured LV ejection fraction and LV global and regional longitudinal strain using 2‐dimensional speckle‐tracking echocardiography. The association between stroke lesion location and cardiac strain was assessed using support vector regression lesion‐symptom mapping. Of a total of 776 patients, 286 subjects (mean age of 67.0 years, 65.4% men) were finally enrolled in this study. The mean global longitudinal strain was −17.0±3.4%, and the mean LV ejection fraction was 64.7±5.7%. The support vector regression lesion‐symptom mapping analysis revealed that the right insula and peri‐insular regions and left parietal cortex were associated with impaired LV global longitudinal strain in patients with acute ischemic stroke. In addition, impaired regional longitudinal strain showed topographical associations with these regions. Conclusions This study suggests that brain lesions in the right insula and peri‐insular regions and left parietal cortex are topographically associated with impaired LV strain in patients with acute ischemic stroke without preexisting cardiac dysfunction.

Background d‐Dimer level is a marker of hypercoagulability, which is associated with thrombus formation and resolution. We investigated the value of d‐dimer levels in predicting outcomes of acute ischemic stroke in patients who underwent endovascular treatment (EVT). Methods We analyzed data of patients who underwent only EVT from the SECRET (Selection Criteria in Endovascular Thrombectomy and Thrombolytic Therapy) registry. d‐Dimer levels were routinely measured in 10 of 15 participating hospitals. Patients were grouped into tertiles (tertile 1, tertile 2, and tertile 3) according to d‐dimer levels (lowest, moderate, and highest, respectively). We compared serial scores on the National Institutes of Health Stroke Scale at baseline, on day 1 of hospitalization, and at discharge; functional outcome 3 months after EVT; and rate of mortality within 6 months after EVT. Results In the 170 patients, the median d‐dimer level was 477 ng/mL (interquartile range, 249–988 ng/mL). In tertile 3, the National Institutes of Health Stroke Scale score was higher at discharge than on day 1 of hospitalization. Poor outcome 3 months after EVT (modified Rankin Scale score, ≥3) was more common with high d‐dimer levels (26.3% of tertile 1, 57.1% of tertile 2, and 76.4% of tertile 3; P

Background and aimsPleiotropic effects of statins result in the stabilization of symptomatic intracranial arterial plaque. However, little is known about the effect of statins in non-symptomatic cerebral arteries. We hypothesized that intensive statin therapy could produce a change in the non-symptomatic cerebral arteries.MethodsThis is a sub-study of a prospective observational study under the title of “Intensive Statin Treatment in Acute Ischemic Stroke Patients with Intracranial Atherosclerosis: a High-Resolution Magnetic Resonance Imaging (HR-MRI) study.” Patients with statin-naive acute ischemic stroke who had symptomatic intracranial artery stenosis (above 50%) were recruited for this study. HR-MRI was performed to assess the patients’ cerebral arterial status before and 6 months after the statin therapy. To demonstrate the effect of statins in the non-symptomatic segment of intracranial cerebral arteries, we excluded symptomatic segments from the data to be analyzed. We compared the morphological changes using cerebrovascular morphometry.ResultsA total of 54 patients (mean age: 62.9 ± 14.4 years, 59.3% women) were included in this study. Intensive statin therapy produced significant morphological changes of overall cerebral arteries. Among the morphological features, the arterial luminal area showed the highest number of significant changes with a range from 5.7 and 6.7%. Systolic blood pressure (SBP) was an independent factor associated with relative changes in posterior circulation bed maximal diameter percentage change (beta −0.21, 95% confidence interval −0.36 to −0.07, p = 0.005).ConclusionIntensive statin therapy produced a favorable morphological change in cerebral arteries of not only the target arterial segment but also non-symptomatic arterial segments. The change in cerebral arterial luminal diameter was influenced by the baseline SBP and was dependent on the topographic distribution of the cerebral arteries.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT02458755.

Abstract We aimed to develop a novel prediction model for early neurological deterioration (END) based on an interpretable machine learning (ML) algorithm for atrial fibrillation (AF)-related stroke and to evaluate the prediction accuracy and feature importance of ML models. Data from multicenter prospective stroke registries in South Korea were collected. After stepwise data preprocessing, we utilized logistic regression, support vector machine, extreme gradient boosting, light gradient boosting machine (LightGBM), and multilayer perceptron models. We used the Shapley additive explanation (SHAP) method to evaluate feature importance. Of the 3,213 stroke patients, the 2,363 who had arrived at the hospital within 24 h of symptom onset and had available information regarding END were included. Of these, 318 (13.5%) had END. The LightGBM model showed the highest area under the receiver operating characteristic curve (0.772; 95% confidence interval, 0.715–0.829). The feature importance analysis revealed that fasting glucose level and the National Institute of Health Stroke Scale score were the most influential factors. Among ML algorithms, the LightGBM model was particularly useful for predicting END, as it revealed new and diverse predictors. Additionally, the effects of the features on the predictive power of the model were individualized using the SHAP method.

Background We investigated the impact of the ring finger protein 213 p.R4810K variant, a founder variant for moyamoya disease in East Asians, on endovascular therapy outcomes in patients with acute anterior‐circulation large‐vessel occlusion stroke in comparison with noncarriers. Methods Of the consecutive patients with ischemic stroke admitted to our institute from 2011 to 2021, patients who underwent endovascular therapy for acute occlusion of the intracranial internal carotid artery or M1 segment of the middle cerebral artery were included. Outcomes were instant reocclusion, final modified Thrombolysis in Cerebral Infarction reperfusion ≥2b, and early reocclusion. Instant reocclusion was defined as the occurrence of reocclusion during the procedure, and early reocclusion was defined as reocclusion detected on magnetic resonance angiography within 2 weeks after the confirmation of successful reperfusion. Results Of the 277 patients analyzed (128 women; median age, 76 years), 10 patients (3.6%) carried the ring finger protein 213 p.R4810K variant. Variant carriers were younger (P=0.01) and more frequently had intracranial atherosclerotic disease‐related large‐vessel occlusion as a cause of acute large‐vessel occlusion (P

Background and Purpose We aimed to develop a model predicting early recanalization after intravenous tissue plasminogen activator (t-PA) treatment in large-vessel occlusion. Methods Using data from two different multicenter prospective cohorts, we determined the factors associated with early recanalization immediately after t-PA in stroke patients with large-vessel occlusion, and developed and validated a prediction model for early recanalization. Clot volume was semiautomatically measured on thin-section computed tomography using software, and the degree of collaterals was determined using the Tan score. Follow-up angiographic studies were performed immediately after t-PA treatment to assess early recanalization. Results Early recanalization, assessed 61.0±44.7 minutes after t-PA bolus, was achieved in 15.5% (15/97) in the derivation cohort and in 10.5% (8/76) in the validation cohort. Clot volume (odds ratio [OR], 0.979; 95% confidence interval [CI], 0.961 to 0.997; P=0.020) and good collaterals (OR, 6.129; 95% CI, 1.592 to 23.594; P=0.008) were significant factors associated with early recanalization. The area under the curve (AUC) of the model including clot volume was 0.819 (95% CI, 0.720 to 0.917) and 0.842 (95% CI, 0.746 to 0.938) in the derivation and validation cohorts, respectively. The AUC improved when good collaterals were added (derivation cohort: AUC, 0.876; 95% CI, 0.802 to 0.950; P=0.164; validation cohort: AUC, 0.949; 95% CI, 0.886 to 1.000; P=0.036). The integrated discrimination improvement also showed significantly improved prediction (0.097; 95% CI, 0.009 to 0.185; P=0.032). Conclusions The model using clot volume and collaterals predicted early recanalization after intravenous t-PA and had a high performance. This model may aid in determining the recanalization treatment strategy in stroke patients with large-vessel occlusion.

Background and Purpose Previous studies have assessed the relationship between cerebral vessel tortuosity and intracranial aneurysm (IA) based on two-dimensional brain image analysis. We evaluated the relationship between cerebral vessel tortuosity and IA according to the hemodynamic location using three-dimensional (3D) analysis and studied the effect of tortuosity on the recurrence of treated IA. Methods We collected clinical and imaging data from patients with IA and disease-free controls. IAs were categorized into outer curvature and bifurcation types. Computerized analysis of the images provided information on the length of the arterial segment and tortuosity of the cerebral arteries in 3D space. Results Data from 95 patients with IA and 95 controls were analyzed. Regarding parent vessel tortuosity index (TI; P

Abstract The eligibility of reperfusion therapy has been expanded to increase the number of patients. However, it remains unclear the reperfusion therapy will be beneficial in stroke patients with various comorbidities. We developed a reperfusion comorbidity index for predicting 6-month mortality in patients with acute stroke receiving reperfusion therapy. The 19 comorbidities included in the Charlson comorbidity index were adopted and modified. We developed a statistical model and it was validated using data from a prospective cohort. Among 1026 patients in the retrospective nationwide reperfusion therapy registry, 845 (82.3%) had at least one comorbidity. As the number of comorbidities increased, the likelihood of mortality within 6 months also increased (p

Background Unlike patients with stroke caused by other mechanisms, the effect of elevated plasma total homocysteine (tHcy) on the prognosis of patients with both ischemic stroke and atrial fibrillation (AF) is unknown. This study aimed to evaluate the association between tHcy level and the functional outcome of patients with AF‐related stroke. Methods and Results We included consecutive patients with AF‐related stroke between 2013 and 2015 from the registry of a real‐world prospective cohort from 11 large centers in South Korea. A 3‐month modified Rankin Scale score ≥3 was considered an unfavorable outcome. Since tHcy is strongly affected by renal function, we performed a subgroup analysis according to the presence of renal dysfunction. A total of 910 patients with AF‐related stroke were evaluated (mean age, 73 years; male sex, 56.0%). The mean tHcy level was 11.98±8.81 μmol/L. In multivariable analysis, the tHcy level (adjusted odds ratio, 1.04; 95% CI, 1.01–1.07, per 1 μmol/L) remained significantly associated with unfavorable outcomes. In the subgroup analysis based on renal function, tHcy values above the cutoff point (≥14.60 μmol/L) showed a close association with the unfavorable outcome only in the normal renal function group (adjusted odds ratio, 3.10; 95% CI, 1.60–6.01). In patients with renal dysfunction, tHcy was not significantly associated with the prognosis of AF‐related stroke. Conclusions A higher plasma tHcy level was associated with unfavorable outcomes in patients with AF‐related stroke. This positive association may vary according to renal function but needs to be verified in further studies.

Background and PurposeCollateral flow in acute ischemic stroke is known as a predictor of treatment outcome and long-term prognosis. However, factors determining the initial collateral flow remain unclear. We investigated factors related to collateral flow in patients with acute ischemic stroke caused by large vessel occlusion (AIS-LVO) and further analyzed the results according to stroke etiology.MethodsThis was a retrospective study using prospective stroke registry data from a single university hospital from October 2014 to May 2021. AIS-LVO with middle cerebral artery M1 occlusion identified by pre-treatment multiphasic computed tomography angiography was included. Collateral flow score was graded on a 6-point ordinal scale according to pial arterial filling.ResultsA total of 74 patients [cardioembolism (CE): 57; large artery atherosclerosis (LAA): 17] was included. The mean age of all patients was 72.2 ± 11.7 years, and 37.8 % (n = 28) were men. Multivariate regression analysis showed that initial SBP [odds ratio (OR): 0.994; 95% confidence interval (CI): 0.990–0.998; p = 0.002] and stroke etiology (OR: 0.718; 95% CI: 0.548–0.940; p = 0.019) were independent factors of the collateral flow grade. Collateral flow grade was independently associated with initial SBP in the CE group (OR: 0.993; 95% CI: 0.989–0.998; p = 0.004) but not in the LAA group (OR: 0.992; 95% CI: 0.980–1.004; p = 0.218). Initial SBP was significantly correlated with NIHSS score in the CE group but not in the LAA group (r2= 0.091, p = 0.023; r2 = 0.043, p = 0.426, respectively).ConclusionsElevated initial SBP was associated with poor cerebral collateral flow and more severe symptoms in the CE group, but not in the LAA group in patients with AIS-LVO. These findings suggest differential effects of initial SBP elevation on collateral flow by stroke subtypes.

BackgroundThis study aimed to investigate clinical outcome predictors of acute stroke patients with large vessel occlusion and active cancer and validate the significance of D-dimer levels for endovascular thrombectomy decisions.MethodsWe analyzed a prospectively collected hospital-based stroke registry to determine clinical EVT outcomes of acute stroke patients within 24 h with following criteria: age ≥18 years, NIHSS ≥6, and internal carotid artery or middle cerebral artery lesion. All patients were classified into EVT and non-EVT groups. Patients were divided into two groups by initial D-dimer level. We explored variables potentially associated with successful recanalization as well as 3-month functional outcomes and mortality rates.ResultsAmong 68 patients, 36 were treated with EVT, with successful recanalization in 55.6%. The low D-dimer group showed a higher rate of successful recanalization and favorable outcome than the high D-dimer group. The mortality rate was higher in the high D-dimer group. No EVT and high D-dimer level were independent predictors of mortality, whereas lesion volume and low D-dimer level were independently associated with favorable outcomes.ConclusionsD-dimer level is a prognostic factor in acute LVO stroke patients with active cancer, and its high value for EVT decisions provisionally supports its testing in this patient population.

Systemic cancer and ischemic stroke are common conditions and two of the most frequent causes of death among the elderly. The association between cancer and stroke has been reported worldwide. Stroke causes severe disability for cancer patients, while cancer increases the risk of stroke. Moreover, cancer-related stroke is expected to increase due to advances in cancer treatment and an aging population worldwide. Because cancer and stroke share risk factors (such as smoking and obesity) and treatment of cancer can increase the risk of stroke (e.g., accelerated atherosclerosis after radiation therapy), cancer may accelerate conventional stroke mechanisms (i.e., atherosclerosis, small vessel disease, and cardiac thrombus). In addition, active cancer and chemotherapy may enhance thrombin generation causing stroke related to coagulopathy. Patients with stroke due to cancer-related coagulopathy showed the characteristics findings of etiologic work ups, D-dimer levels, and infarct patterns. In this review, we summarized the frequency of cancer-related stroke among patients with ischemic stroke, mechanisms of stroke with in cancer patients, and evaluation and treatment of cancer-related stroke. We discussed the possibility of cancer-related stroke as a stroke subtype, and presented the most recent discoveries in the pathomechanisms and treatment of stroke due to cancer-related coagulopathy.

Background and Purpose: Successful reperfusion therapy is supposed to be comprehensive and validated beyond the grade of recanalization. This study aimed to develop a novel scoring system for defining the successful recanalization after endovascular thrombectomy.Methods: We analyzed the data of consecutive acute stroke patients who were eligible to undergo reperfusion therapy within 24 h of onset and who underwent mechanical thrombectomy using a nationwide multicenter stroke registry. A new score was produced using the predictors which were directly linked to the procedure to evaluate the performance of the thrombectomy procedure.Results: In total, 446 patients in the training population and 222 patients in the validation population were analyzed. From the potential components of the score, four items were selected: Emergency Room-to-puncture time (T), adjuvant devices used (A), procedural intracranial bleeding (B), and post-thrombectomy reperfusion status [Thrombolysis in Cerebral Infarction (TICI)]. Using these items, the TAB-TICI score was developed, which showed good performance in terms of discriminating early neurological aggravation [AUC 0.73, 95% confidence interval (CI) 0.67–0.78, P < 0.01] and favorable outcomes (AUC 0.69, 95% CI 0.64–0.75, P < 0.01) in the training population. The stability of the TAB-TICI score was confirmed by external validation and sensitivity analyses. The TAB-TICI score and its derived grade of successful recanalization were significantly associated with the volume of thrombectomy cases at each site and in each admission year.Conclusion: The TAB-TICI score is a valid and easy-to-use tool to more comprehensively define successful recanalization after endovascular thrombectomy in acute stroke patients with large vessel occlusion.

Background: Ischemic stroke with atrial fibrillation (AF) may recur despite appropriate treatment. It may be AF-related or AF-unrelated. We compared the factors associated with AF-related and AF-unrelated recurrences among ischemic stroke patients with AF.Methods: Patients with ischemic stroke and AF were enrolled from 11 centers in Korea. Ischemic stroke recurrence was classified as AF-related if the lesion pattern was compatible with cardioembolism without significant stenosis or as AF-unrelated if the lesion was more likely due to small vessel disease or arterial stenosis. Factors associated with stroke recurrence (AF-related and AF-unrelated) were investigated.Results: Among the 2,239 patients, 115 (5.1%) experienced recurrence (75 AF-related and 40 AF-unrelated). Factors independently associated with any stroke recurrence included AF diagnosed before stroke, small subcortical infarctions, and small scattered lesions in a single vascular territory. Type of AF was associated with the type of stroke recurrence, with persistent AF being associated with AF-related stroke [hazard ratio (HR) = 2.94, 95% confidence interval (CI) 1.69–5.26; p < 0.001]. By contrast, paroxysmal AF (HR = 3.76, 95% CI 1.56–9.04; p = 0.003), AF diagnosed before stroke (HR = 2.38, 95% CI 1.19–4.55; p = 0.014), small scattered lesions in a single vascular territory (reference: corticosubcortical lesion, HR = 3.19, 95% CI 1.18–8.63; p = 0.022), and the use of antiplatelet agents (HR = 2.11, 95% CI 1.11–4.03; p = 0.024) were independently associated with AF-unrelated stroke.Conclusion: Persistent AF was more associated with AF-related stroke recurrence, whereas paroxysmal AF was more associated with AF-unrelated stroke recurrence. A scattered lesion in a single vascular territory may predict AF-unrelated stroke recurrence.

Background and Purpose To investigate the number and characteristics of patients eligible for endovascular treatment (EVT) determined using three different selection methods: clinical-core mismatch, target mismatch, and collateral status. Methods Using the data of consecutive patients from two prospectively maintained registries of university medical centers, the number and characteristics of patients according to the three selection methods were investigated and their correlation was analyzed. Patients with anterior circulation stroke due to occlusion of the middle cerebral and/or internal carotid artery and a National Institute of Health Stroke Scale (NIHSS) score of ≥6 points, who arrived within 8 hours or between 6 and 12 hours of symptom onset and underwent magnetic resonance imaging prior to EVT, were included. Collateral status was assessed using magnetic resonance perfusion-derived collateral flow maps. Results Three hundred thirty-five patients were investigated; the proportions of patients who were eligible and ineligible for EVT in all three selection methods were both small (n=85, 25.4%; n=54, 16.1%, respectively). The intercorrelation among the three selection methods was low (κ=0.235). The baseline NIHSS score and onset-to-selection time interval were associated with the presence of clinical-core mismatch, while the penumbra/core volume ratio and onset-to-selection time interval were related to target mismatch; none of these variables were associated with collateral status. The infarct core volume was associated with favorable profiles in all three selection methods. Conclusions Although the application of individual selection methods resulted in favorable outcomes after EVT in clinical trials, there is a significant discrepancy in EVT eligibility depending on the selection method used.

Despite the great socioeconomic burden of stroke, there have been few reports of stroke statistics in Korea. In this scenario, the Epidemiologic Research Council of the Korean Stroke Society launched the “Stroke Statistics in Korea” project, aimed at writing a contemporary, comprehensive, and representative report on stroke epidemiology in Korea. This report contains general statistics of stroke, prevalence of behavioral and vascular risk factors, stroke characteristics, pre-hospital system of care, hospital management, quality of stroke care, and outcomes. In this report, we analyzed the most up-to-date and nationally representative databases, rather than performing a systematic review of existing evidence. In summary, one in 40 adults are patients with stroke and 232 subjects per 100,000 experience a stroke event every year. Among the 100 patients with stroke in 2014, 76 had ischemic stroke, 15 had intracerebral hemorrhage, and nine had subarachnoid hemorrhage. Stroke mortality is gradually declining, but it remains as high as 30 deaths per 100,000 individuals, with regional disparities. As for stroke risk factors, the prevalence of smoking is decreasing in men but not in women, and the prevalence of alcohol drinking is increasing in women but not in men. Population-attributable risk factors vary with age. Smoking plays a role in young-aged individuals, hypertension and diabetes in middle-aged individuals, and atrial fibrillation in the elderly. About four out of 10 hospitalized patients with stroke are visiting an emergency room within 3 hours of symptom onset, and only half use an ambulance. Regarding acute management, the proportion of patients with ischemic stroke receiving intravenous thrombolysis and endovascular treatment was 10.7% and 3.6%, respectively. Decompressive surgery was performed in 1.4% of patients with ischemic stroke and in 28.1% of those with intracerebral hemorrhage. The cumulative incidence of bleeding and fracture at 1 year after stroke was 8.9% and 4.7%, respectively. The direct costs of stroke were about ₩1.68 trillion (KRW), of which ₩1.11 trillion were for ischemic stroke and ₩540 billion for hemorrhagic stroke. The great burden of stroke in Korea can be reduced through more concentrated efforts to control major attributable risk factors for age and sex, reorganize emergency medical service systems to give patients with stroke more opportunities for reperfusion therapy, disseminate stroke unit care, and reduce regional disparities. We hope that this report can contribute to achieving these tasks.

Background Although antiplatelet agents are frequently prescribed in moyamoya disease in routine clinical practice, there are no large‐scale epidemiologic trials or randomized trial evidence to support their use in patients with moyamoya disease. Methods and Results Using the Korean National Health Insurance Service database, patients diagnosed with moyamoya disease between 2002 and 2016 were followed up for up to 14 years to assess, using time‐dependent Cox regression in all patients and in a propensity score–matched cohort, the association of antiplatelet therapy and individual antiplatelet agents with survival. Among 25 978 patients with newly diagnosed moyamoya disease, mean age was 37.6±19.9 years, 61.6% were women, and total follow‐up was 163 347 person‐years. Among 9154 patients who were prescribed antiplatelet agents at least once during the follow‐up period, the proportion prescribed cilostazol gradually increased from 5.5% in 2002 to 56.0% in 2016. Any antiplatelet use was associated with reduced risk of death (hazard ratio, 0.77; 95% CI, 0.70–0.84) in a multivariate model. Among individual antiplatelet agents, cilostazol was associated with greater reduction in mortality than the 5 other antiplatelet regimens. Subgroup analysis, according to the age group and history of ischemic stroke, and sensitivity analysis, using propensity score–matched analysis, revealed consistent results. Conclusions Antiplatelet therapy is associated with substantial improvement in survival in patients with moyamoya disease, and cilostazol is associated with greater survival benefit compared with other antiplatelet regimens. These results provisionally support the use of antiplatelet therapy in patients with moyamoya disease and the conduct of confirmatory randomized controlled trials.

In animal models of stroke, behavioral assessments could be complemented by a variety of neuroimaging studies to correlate them with recovery and better understand mechanisms of improvement after stem cell therapy. We evaluated morphological and connectivity changes after treatment with human mesenchymal stem cells (hMSCs) in a rat stroke model, through quantitative measurement of T2-weighted images and diffusion tensor imaging (DTI). Transient middle cerebral artery occlusion rats randomly received PBS (PBS-only), FBS cultured hMSCs (FBS-hMSCs), or stroke patients' serum cultured hMSCs (SS-hMSCs). Functional improvement was assessed using a modified neurological severity score (mNSS). Quantitative analyses of T2-weighted ischemic lesion and ventricular volume changes were performed. Brain microstructure/connectivity changes were evaluated in the ischemic recovery area by DTI-derived microstructural indices such as relative fractional anisotropy (rFA), relative axial diffusivity (rAD), and relative radial diffusivity (rRD), and relative fiber density (rFD) analyses. According to mNSS results, the SS-hMSCs group showed the most prominent functional improvement. Infarct lesion volume of the SS-hMSCs group was significantly decreased at 2 weeks when compared to the PBS-only groups, but there were no differences between the FBS-hMSCs and SS-hMSCs groups. Brain atrophy was significantly decreased in the SS-hMSCs group compared to the other groups. In DTI, rFA and rFD values were significantly higher and rRD value was significant lower in the SS-hMSCs group and these microstructure/connectivity changes were correlated with T2-weighted morphological changes. T2-weighted volume alterations (ischemic lesion and brain atrophy), and DTI microstructural indices and rFD changes, were well matched with the results of behavioral assessment. These quantitative MRI measurements could be potential outcome predictors of functional recovery after treatment with stem cells for stroke.

Background The RNF213 (ring finger protein 213 gene) variant R4810K is a susceptibility allele not only for Moyamoya disease (MMD) but also for intracranial atherosclerosis (ICAS) in East Asian populations. We hypothesized that this variant would affect the distribution of ICAS and recurrence of cerebrovascular events. Methods and Results We conducted a prospective study of patients with ICAS and MMD using high‐resolution magnetic resonance imaging and RNF213 R4810K genotyping. Patients were included in the ICAS group when relevant plaques existed on high‐resolution magnetic resonance imagingand in the MMD group when they carried the variant and high‐resolution magnetic resonance imaging showed no plaques but characteristic features of MMD. We compared clinical and neuroimaging features of patients with ICAS‐RNF213+ with patients with ICAS‐RNF213− and of patients with MMD. Of 477 patients, 238 patients were in the ICAS group and 239 were in the MMD group. Among patients with ICAS, 79 patients (33.2%) were in the ICAS‐RNF213+ group and 159 (66.8%) in the ICAS‐RNF213− group. Tandem lesions were significantly more common in the ICAS‐RNF213+ group than in the ICAS‐RNF213− group (40.3% versus 72.2%, P

Background There is insufficient evidence on the effect of statins, particularly high‐intensity statins, in patients with acute ischemic stroke and atrial fibrillation. We investigated the impact of statins on the outcomes in these patients, including those who might be vulnerable to statin therapy and those without clinical atherosclerotic cardiovascular diseases. Methods and Results A total of 2153 patients with acute ischemic stroke and atrial fibrillation were enrolled in the present nationwide, multicenter, cohort study. The primary composite end point was the occurrence of net adverse clinical and cerebral events (NACCE; death from any cause, stroke, acute coronary syndrome, or major bleeding) over a 3‐year period based on statin intensity. NACCE rates were lower in patients receiving low‐ to moderate‐intensity (adjusted hazard ratio 0.64; 95% CI: 0.52‐0.78) and high‐intensity statins (hazard ratio 0.51; 95% CI 0.40‐0.66) than in those not receiving statin therapy. High‐intensity statins were associated with a lower risk for NACCE than low‐ to moderate‐intensity statins (hazard ratio 0.76; 95% CI 0.59‐0.96). Subgroup analyses showed that the differences in hazard ratio for 3‐year NACCE favored statin use across all subgroups, including older patients, those with low cholesterol levels, patients receiving anticoagulants, and patients without clinical atherosclerotic cardiovascular diseases. Magnified benefits of high‐intensity statins compared with low‐ to moderate‐intensity statins were observed in patients who underwent revascularization therapy and those under 75 years of age. Conclusions Statins, particularly high‐intensity statins, could reduce the risk for NACCE in patients with acute ischemic stroke and atrial fibrillation; this needs to be further explored in randomized controlled trials.

Cardiac amyloidosis is characterized by the extracellular fibril deposition of amyloid protein in the myocardium. Cerebral embolism caused by cardiac amyloidosis is rare. We report a case of 59-year-old woman with multiple myeloma who developed cerebral infarction probably related to cardiac involvement of amyloidosis, and discuss the pathophysiological mechanisms based on kidney biopsy and characteristic echocardiographic and cardiac magnetic resonance imaging features.

Cervical artery dissection is caused by the separation of the vessel wall layers following either a tear in the intima or rupture of the vasa vasorum, with bleeding within the media, and is a potential source of thromboembolism, resulting in cerebral ischemia. Cervical artery dissection can be traumatic or spontaneous; however, the exact pathophysiology of a dissection is rarely identified. We report a case of carotid artery dissection caused by stylocarotid artery syndrome (Eagle syndrome), treated by surgical resection of the styloid process.

Superficial siderosis is a rare disease of the central nervous system, which is characterized by chronic intrathecal hemorrhage leading to hemosiderin deposition on the leptomeninges and subpial layers of the brain and spinal cord. Patients with the syndrome typically present with sensorineural hearing loss, myelopathy, cerebellar ataxia, pyramidal signs, and cognitive impairment. The most common etiologies of the disease include bleeding of unknown cause, ruptured aneurysms, arteriovenous malformation, and traumatic injury of the brain. Here, we describe two patients diagnosed with superficial siderosis caused by spinal lesions, which is an unusual cause of chronic bleeding due to the presence of the disease.

Background and Purpose Patients with active cancer are at an increased risk for stroke. Hypercoagulability plays an important role in cancer-related stroke. We aimed to test whether 1) hypercoagulability is a predictor of survival, and 2) correction of the hypercoagulable state leads to better survival in patients with stroke and active cancer. Methods We recruited consecutive patients with acute ischemic stroke and active systemic cancer between January 2006 and July 2015. Hypercoagulability was assessed using plasma D-dimer levels before and after 7 days of anticoagulation treatment. The study outcomes included overall and 1-year survival. Plasma D-dimer levels before and after treatment were tested in univariate and multivariate Cox regression models. We controlled for systemic metastasis, stroke mechanism, age, stroke severity, primary cancer type, histology, and atrial fibrillation using the forward stepwise method. Results A total of 268 patients were included in the analysis. Patients with high (3rd–4th quartiles) pre-treatment plasma D-dimer levels showed decreased overall and 1-year survival (adjusted HR, 2.19 [95% CI, 1.46–3.31] and 2.70 [1.68–4.35], respectively). After anticoagulation treatment, post-treatment D-dimer level was significantly reduced and independently associated with poor 1-year survival (adjusted HR, 1.03 [95% CI, 1.01–1.05] per 1 μg/mL increase, P=0.015). The successful correction of hypercoagulability was a protective factor for 1-year survival (adjusted HR 0.26 [CI 0.10–0.68], P=0.006). Conclusions Hypercoagulability is associated with poor survival after stroke in patients with active cancer. Effective correction of hypercoagulability may play a protective role for survival in these patients.

Background and Purpose Perfusion-diffusion mismatch has been evaluated to determine whether the presence of a target mismatch helps to identify patients who respond favorably to recanalization therapies. We compared the impact on infarct growth of collateral status and the presence of a penumbra, using magnetic resonance perfusion (MRP) techniques. Methods Consecutive patients who were candidates for recanalization therapy and underwent serial diffusion-weighted imaging (DWI) and MRP were enrolled. A collateral flow map derived from MRP source data was generated by automatic post-processing. The impact of a target mismatch (Tmax>6 s/apparent diffusion coefficient (ADC) volume≥1.8, ADC volume10 s for ADC volume

Background An increased risk of acute ischemic stroke is recognized among patients with cancer. However, the mechanism behind cancer‐related stroke is unclear. In this study, we determined the presence of associated venous thromboembolism and arterial thromboembolism and their clinical impact on patients with cancer‐related stroke. Methods and Results Patients with embolic stroke of undetermined source with or without cancer were evaluated for venous thromboembolism (deep vein thrombosis [DVT] and/or pulmonary embolism) and arterial thromboembolism by using Doppler sonography to determine the presence of lower‐extremity DVT and the microembolic signal of the symptomatic cerebral circulation, respectively. Infarct volume was determined by diffusion‐weighted magnetic resonance imaging. The multivariable linear regression and Cox proportional hazard analysis were used to investigate the effect of DVT and microembolic signal on infarct volume and 1‐year survival, respectively. Of 142 screened patients, 118 were included (37 with, 81 without cancer). Those with cancer had a higher prevalence of DVT or microembolic signal than did the noncancer group (62.2% versus 19.8%; P

Background and aims: Atrial fibrillation (AF) is a major cause of ischemic stroke; however, detailed clinical data and prognostic factors for stroke patients with AF are lacking in Korea. We aimed to investigate clinical information and factors associated with functional outcomes of stroke patients with AF from the Korean nationwide ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts (K-ATTENTION) database.Methods: From January 2013 to December 2015, consecutive clinical information from acute stroke patients with AF or history of AF was collected from 11 centers in Korea. Collected data included demographics, risk factors, pre-stroke medication, stroke severity, stroke subtypes, concomitant cerebral atherosclerosis, brain image findings, recanalization therapy, discharge medication, and functional outcome at 3 months after index stroke.Results: A total of 3,213 stroke patients (mean age, 73.6 ± 9.8 years; female, 48.6%) were included. The mean CHA2DS2-VASc score was 4.9. Among the 1,849 (57.5%) patients who had brain image and functional outcome data, poor outcome (modified Rankin scale > 2) was noted in 53.1% (981/1,849) of patients. After adjusting for age, sex, and variables that had a p < 0.05 in univariate analysis or well-known factors for functional outcome, presence of asymptomatic extracranial cerebral atherosclerosis [odd ratio (OR): 1.96, 95% confidence interval (CI): 1.36–2.82, p = 0.001] and less frequent prior stroke statin intake (OR: 0.69, 95% CI: 0.49–0.98, p = 0.038) were associated with poor functional outcome.Conclusion: Our results suggest that presence of non-relevant extracranial cerebral atherosclerosis may affect poor functional outcome and prior stroke statin therapy may be feasible in Korean stroke patients with AF.

Background Intracranial atherosclerotic stroke is prevalent in Asians. We hypothesized that patients with the ring finger protein 213 (RNF213) variant, a susceptibility locus for moyamoya disease in Asians, have different neuroimaging characteristics in terms of the vessel wall and hemodynamics. Methods and Results We analyzed consecutive patients with ischemic events in middle cerebral artery distribution and relevant plaques of the distal internal carotid artery or proximal middle cerebral artery on high‐resolution magnetic resonance imaging. Patients with carotid/cardiac sources of embolism or moyamoya disease were excluded. High‐resolution magnetic resonance imaging features (eg, outer vessel diameters and plaque characteristics) and fractional flow (as measured by adjusted signal intensity ratio on time‐of‐flight magnetic resonance angiography) were compared between RNF213 p.Arg4810Lys variant carriers and noncarriers. Among 144 patients included, 44 (29.9%) had the RNF213 variant. Clinical characteristics, including age, sex, body mass index, and vascular risk factors, were not significantly different between RNF213 variant carriers and noncarriers. However, the outer vessel diameter was smaller in RNF213 variant carriers than in noncarriers (P

Background and Purpose: Despite the recent growing interest in the cancer–stroke association, the long-term effect, and organ-specific association with stroke incidence in subjects with cancer have not been clearly defined.Methods: Data were obtained from the Korean National Health Insurance Service National Sample Cohort database between 2002 and 2015. To investigate the effects of cancer on stroke incidence, subjects were classified into cancer and non-cancer groups based on the period after cancer diagnosis and origin organ of cancer. To minimize the effects of selection bias, we performed a propensity score matching analysis with covariates of demographic data, vascular risk factors, antithrombotics use and statin use. Incident stroke was diagnosed based on operational definition and classified into ischemic stroke and hemorrhagic stroke.Results: Data of 20,707 subjects with cancer and 675,594 without cancer were analyzed for 7 follow-up years. The subjects with cancer had higher risk of any stroke (subdistribution hazard ratio [SHR], 1.13; 95% confidence interval [CI], 1.02–1.26; p = 0.0181) than those without cancer. Similar trend was found for ischemic stroke (SHR, 1.17; 95% CI, 1.05–1.31; p = 0.0054), but not for hemorrhagic stroke. The risk of stroke was increased in subjects with cancer in the digestive organ, respiratory and intrathoracic organ, and “others (such as breast and female and male reproductive organs)” in 3 years; however, the association disappeared thereafter except those with “others” cancer. Chemotherapy increased the risk of ischemic stroke (SHR 1.21; 95% CI, 1.03–1.41).Conclusions: Cancer increases the risk of stroke at 3 years after the diagnosis of cancer, and the effect was maintained for 7 years. The association between cancer and stroke incidence depends on the organ from which the cancer originated and chemotherapy.

Background and Purpose: Patients undergoing carotid artery stenting (CAS) who show low responsiveness to clopidogrel may have a higher risk of peri-procedural embolic events. This study aimed to compare the effectiveness and safety of clopidogrel and ticlopidine plus Ginkgo biloba in clopidogrel-resistant patients undergoing CAS.Methods: In this multi-center, randomized, controlled trial, we used platelet reactivity test to select patients undergoing CAS who showed clopidogrel resistance, and compared treatments using clopidogrel and ticlopidine plus ginkgo. The primary outcome was the incidence of new ischemic lesion in the ipsilateral hemisphere of CAS. Detection of microembolic signal on transcranial Doppler was the secondary outcome. The clinical outcomes were also monitored.Results: This trial was discontinued after 42 patients were randomized after preplanned interim sample size re-estimation indicated an impractical sample size. The primary endpoint occurred in 12/22 patients (54.5%) in the clopidogrel group and 13/20 patients (65.0%) in the ticlopidine–ginkgo group (P = 0.610). No significant differences in the presence of microembolic signal (15.0 vs. 11.8%, P = 0.580), clinical outcomes (ischemic stroke or transient ischemic attack, 0.0 vs. 5.5%; acute myocardial infarction 0.0 vs. 0.0%; all-cause death, 4.5 vs. 0.0%), or incidence of adverse events were found in the two groups. In terms of resistance to clopidogrel, treatment with ticlopidine–ginkgo significantly increased the P2Y12 Reaction Units (difference, 0.0 [−0.3–3.0] vs. 21.0 [6.0–35.0], P < 0.001).Conclusions: In patients who showed clopidogrel resistance, ticlopidine–ginkgo treatment was safe and increased P2Y12 Reaction Units; however, compared to clopidogrel, it failed to improve surrogate and clinical endpoints in patients undergoing CAS. This multimodal biomarker-based clinical trial is feasible in neurointerventional research.Clinical Trial Registration:http://www.clinicaltrials.gov. Unique identifier: NCT02133989.

Revascularization therapies have been established as the treatment mainstay for acute ischemic stroke. However, a substantial number of patients are either ineligible for revascularization therapy, or the treatment fails or is futile. At present, non-contrast computed tomography is the first-line neuroimaging modality for patients with acute stroke. The use of magnetic resonance imaging (MRI) to predict the response to early revascularization therapy and to identify patients for delayed treatment is desirable. MRI could provide information on stroke pathophysiologies, including the ischemic core, perfusion, collaterals, clot, and blood–brain barrier status. During the past 20 years, there have been significant advances in neuroimaging as well as in revascularization strategies for treating patients with acute ischemic stroke. In this review, we discuss the role of MRI and post-processing, including machine-learning techniques, and recent advances in MRI-based triage for revascularization therapies in acute ischemic stroke.

The objective of this study was to investigate the potential benefits of statin therapy initiation in acute stroke in patients with active cancer. This study was conducted in two parts. First, data from patients who are presented with stroke and active cancer were obtained from prospectively collected multicenter hospital-based stroke registries. Patients were classified into statin user and non-user groups; the statin group was further divided into low-potency and high-potency statin subgroups. The primary outcome was time to mortality. Second, we obtained data from the Korean National Health Information Service-National Sample Cohort (NHIS-NSC) database for external validation and analyzed the effect of statins on mortality, taking compliance into consideration. For the stroke registry cohort, statin use was independently associated with reduced mortality in a multivariable model [hazard ratio (HR) = 0.675, 95% confidence interval (CI) = 0.457–0.996]. There was no interaction between statin use and cancer characteristics, vascular risk factors, or laboratory findings. A dose-dependent relationship between statin use and survival was also demonstrated. Analysis of the NHIS-NSC database found a similar association between statin therapy and reduced mortality (adjusted HR = 0.64, 95% CI = 0.45–0.90) and this effect persisted even after controlling for the adherence of statin use (HR = 0.60, 95% CI = 0.41–0.89). Statin therapy could be associated with reduced mortality in patients with acute stroke and active cancer.

Background and PurposeAn elevated intracellular calcium level is known to be a major initiator and activator of ischemic cell death pathway; however, in recent studies, elevated serum calcium levels have been associated with better clinical outcomes and smaller cerebral infarct volumes. The pathophysiological role played by calcium in ischemic stroke is largely unknown.MethodsAcute stroke patients from a prospective stroke registry, consecutively admitted during October 2002-September 2008, were included. Significant associations between the modified Rankin scale distribution at discharge and serum calcium or albumin-corrected calcium were identified using ordinal logistic regression analysis. Cox proportional hazard models were used for survival analysis.ResultsMean serum calcium and albumin-corrected calcium levels of the 1,915 participants on admission were 8.97±0.58 mg/dL and 9.07±0.49 mg/dL, respectively. Second [adjusted odds ratio 1.32 (95% confidence interval 1.07-1.61)] and third [1.24 (1.01-1.53)] tertiles of serum calcium level and the third [1.24 (1.01-1.53)] tertile of albumin-corrected calcium level were found to be independent risk factors for a poor discharge outcome. Significant relationships were observed with serum calcium [1.19 (1.03-1.38)] and albumin-corrected calcium [1.21(1.01-1.44)] as linear variables. However, only albumin-corrected calcium was associated with long-term mortality, third tertile [adjusted hazard ratio 1.40 (1.07-1.83)], and increase by 1 mg/dL [1.46 (1.16-1.84)].ConclusionsElevated albumin-corrected serum calcium levels are associated with a poorer short-term outcome and greater risk of long-term mortality after acute ischemic stroke.

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by stenosis of the internal carotid arteries with compensatory development of collateral vessels. Although a founder variant of RNF213, p.Arg4810Lys (c.14429G>A, rs112735431), is a major genetic risk factor for MMD in East Asians, the frequency and disease susceptibility of other variants in this gene remain largely unknown. In the present study, we investigated the association of RNF213 variants with MMD in Korean patients and population controls.For all RNF213 variants listed in the Human Gene Mutation Database (HGMD) as disease-causing or likely disease-causing mutations for MMD, genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Genetic data from 264 adult patients with MMD were analyzed and compared with two control populations comprised of 622 and 1,100 Korean individuals, respectively.Among the 30 RNF213 variants that were listed in the HGMD, p.Arg4810Lys was identified in 67.4% (178/264) of patients with MMD and showed a significantly higher allele frequency than in the controls, giving an odds ratio of 63.29 (95% confidence interval, 33.11-120.98) for the 622 controls and 48.55 (95% confidence interval, 31.00-76.03) for the 1100 controls. One additional variant, p.Ala5021Val (c.15062C>T, rs138130613), was identified in 0.8% (2/264) of patients; however, the allele frequencies were not significantly different from those in the controls.These results suggest that, in our cohort of Korean patients, the p.Arg4810Lys is the only variant that is strongly associated with MMD among the 30 RNF213 variants listed in the HGMD.

Background and PurposeIn order to improve inter-rater reliability and minimize diagnosis of undetermined etiology for stroke subtype classification, using a stroke registry, we developed and implemented a magnetic resonance imaging (MRI)-based algorithm for acute ischemic stroke subtype classification (MAGIC).MethodsWe enrolled patients who experienced an acute ischemic stroke, were hospitalized in the 14 participating centers within 7 days of onset, and had relevant lesions on MR-diffusion weighted imaging (DWI). MAGIC was designed to reflect recent advances in stroke imaging and thrombolytic therapy. The inter-rater reliability was compared with and without MAGIC to classify the Trial of Org 10172 in Acute Stroke Treatment (TOAST) of each stroke patient. MAGIC was then applied to all stroke patients hospitalized since July 2011, and information about stroke subtypes, other clinical characteristics, and stroke recurrence was collected via a web-based registry database.ResultsThe overall intra-class correlation coefficient (ICC) value was 0.43 (95% CI, 0.31-0.57) for MAGIC and 0.28 (95% CI, 0.18-0.42) for TOAST. Large artery atherosclerosis (LAA) was the most common cause of acute ischemic stroke (38.3%), followed by cardioembolism (CE, 22.8%), undetermined cause (UD, 22.2%), and small-vessel occlusion (SVO, 14.6%). One-year stroke recurrence rates were the highest for two or more UDs (11.80%), followed by LAA (7.30%), CE (5.60%), and SVO (2.50%).ConclusionsDespite several limitations, this study shows that the MAGIC system is feasible and may be helpful to classify stroke subtype in the clinic.

BackgroundFrom a therapeutic viewpoint, it is important to differentiate the underlying causes of embolism in patients with cryptogenic stroke, such as aortic arch atheroma, patent foramen ovale, and paroxysmal atrial fibrillation. We investigated the clinical and radiological characteristics of these 3 common causes of cryptogenic embolism to develop models for decision making in etiologic workups. Methods and ResultsA total of 321 consecutive patients with acute infarcts from cryptogenic embolism were included. Patients were divided into 3 groups—aortic arch atheroma (n=40), patent foramen ovale (n=153), and paroxysmal atrial fibrillation (n=128)—based on extensive cardiologic workups. We used a multinomial logistic regression analysis to detect the clinical and diffusion‐weighted imaging factors associated with the probability of aortic arch atheroma, patent foramen ovale, and paroxysmal atrial fibrillation. Clinical and radiological features differed among the groups. The patent foramen ovale group had a healthy vascular risk factor profile and showed posterior circulation involvement compared with other groups (P

Cancer and stroke, which are known to be associated with one another, are the most common causes of death in the elderly. However, the pathomechanisms that lead to stroke in cancer patients are not well known. Circulating extracellular vesicles (EVs) play a role in cancer-associated thrombosis and tumor progression. Therefore, we hypothesized that cancer cell-derived EVs cause cancer-related coagulopathy resulting in ischemic stroke.Serum levels of D-dimer and EVs expressing markers for cancer cells (epithelial cell adhesion molecule [CD326]), tissue factor (TF [CD142]), endothelial cells (CD31+CD42b-), and platelets (CD62P) were measured using flow cytometry in (a) 155 patients with ischemic stroke and active cancer (116 - cancer-related, 39 - conventional stroke mechanisms), (b) 25 patients with ischemic stroke without cancer, (c) 32 cancer patients without stroke, and (d) 101 healthy subjects.The levels of cancer cell-derived EVs correlated with the levels of D-dimer and TF+ EVs. The levels of cancer cell-derived EVs (CD326+ and CD326+CD142+) were higher in cancer-related stroke than in other groups (P

BACKGROUND:Both intracranial atherosclerotic stenosis (ICAS) and moyamoya disease (MMD) are prevalent in Asians. We hypothesized that the Ring Finger protein 213 gene polymorphism (RNF213), a susceptibility locus for MMD in East Asians, is also a susceptibility gene for ICAS in patients whose diagnosis had been confirmed by conventional angiography (absence of basal collaterals) and high-resolution MRI (HR-MRI, presence of plaque). METHODS:We analyzed 532 consecutive patients with ischemic events in the middle cerebral artery (MCA) distribution and relevant stenotic lesion on the distal internal carotid artery or proximal MCA, but no demonstrable carotid or cardiac embolism sources. Additional angiography was performed on 370 (69.5%) patients and HR-MRI on 283 (53.2%) patients. RESULTS:Based on angiographic and HR-MRI findings, 234 patients were diagnosed with ICAS and 288 with MMD. The RNF213 variant was observed in 50 (21.4%) ICAS patients and in 119 (69.1%) MMD patients. The variant was observed in 25.2% of patients with HR-MRI-confirmed ICAS. Similarly, 15.8% of ICAS patients in whom MMD was excluded by angiography had this variant. Among the ICAS patients, RNF213 variant carriers were younger and more likely to have a family history of MMD than non-carriers were. Multivariate testing showed that only the age of ICAS onset was independently associated with the RNF213 variant (odds ratio, 0.97; 95% CI, 0.944-0.99). CONCLUSIONS:RNF213 is a susceptibility gene not only for MMD but also for ICAS in East Asians. Further studies are needed on RNF213 variants in ICAS patients outside East Asian populations.

Background: Lacunar infarctions account for up to 25% of all ischemic strokes and, thus, constitute a numerically important subgroup. It is important that the two pathogeneses of lacunar infarction, that is, small-vessel occlusion and branch atheromatous disease, be differentiated because prognoses and treatment strategies differ. The authors evaluated the presence of branch atheromatous plaque in parent arteries that supply lacunar infarcts by high-resolution magnetic resonance imaging (HR-MRI). Methods: HR-MRI was performed in 15 patients with (1) a clinical presentation consistent with classical lacunar syndromes; (2) an acute lacunar infarction by diffusion-weighted imaging, measuring ≤20 mm in maximal diameter; (3) a magnetic resonance angiography showing a normal middle cerebral artery or basilar artery supplying the ischemic lesion, and (4) no other obvious etiology for small-vessel distribution ischemic stroke. Results: The median time of vessel wall imaging after index events was 4 days (range, 2–15 days). Six of the 15 patients had a lacunar infarction in the middle cerebral artery territory, and 9 had a lesion in the basilar artery territory. HR-MRI detected underlying atheromatous plaques in 9 patients (60%) with a lacunar infarction. In these 9 patients, asymptomatic intracranial atherosclerotic stenosis was more frequent compared to patients without branch atheromatous plaque (55.6 vs. 16.7%). In pontine infarctions, ischemic lesions that extended to the pial base of the pons were more frequent in patients with branch atheromatous plaques (83.3 vs. 33.3%), and all the ischemic lesions and atheromatous plaques were on the same side (right, n = 2; left, n = 4). All plaques responsible for acute symptomatic lacunar infarction were enhanced in contrast-enhanced T1-weighted HR-MR images. Conclusions: HR-MRI results enabled underlying symptomatic branch atheromatous disease to be detected in lacunar infarction patients. The experience gained during this study indicates that HR-MRI better delineates intracranial arterial lesions, suggesting that its use will lead to a further understanding of the mechanisms involved in stroke.

Background: Carotid intima-media thickness (IMT) has been widely used as a surrogate of early atherosclerosis. However, the characteristics of patients in cohort-based studies of carotid IMT are very heterogeneous. We evaluated the carotid intima, media, and IMT in really normal (RN) subjects who had no coronary artery disease or other coronary risk factors. Methods: Among the 3041 patients (male:female=1819:1222, mean age=61±11 years) who have undergone carotid ultrasound at our institution since 2003, 124 patients (male:female=84:40, mean age 54±12 years) who had no coronary artery stenosis confirmed by coronary angiography and no diabetes, hypertension, hypercholesterolemia, or renal dysfunction were enrolled in this study. The carotid intima, media, and IMT were compared between the general population group and the RN subjects. Results: Right maximal, mean IMT, intimal thickness, and medial thickness were 0.93±0.25, 0.78±0.16, 0.24±0.36, and 0.51±0.15mm in RN subjects, respectively. The left maximal, mean IMT, intimal thickness, and medial thickness were 0.92±0.33, 0.79±0.24, 0.23±0.03, and 0.55±0.24mm, respectively. The maximal and mean IMT and medial thickness of both carotid arteries were significantly higher in subjects from the general population. Conclusion: In a large Korean cohort for carotid IMT, the carotid medial thickness and IMT were significantly related to atherosclerotic risk factors. We must be careful in defining the normal reference values of carotid IMT due to heterogeneous characteristics in the population.