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Background and Purpose: Stem cell–based therapy is a promising approach to repair brain damage after stroke. This study was conducted to investigate changes in neuroimaging measures using stem cell–based therapy in patients with ischemic stroke. Methods: In this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct were assigned to the autologous mesenchymal stem cell (MSC) treatment or control group. Of 54 patients who completed the intervention, 31 for the MSC and 13 for the control groups were included in this neuroimaging analysis. Motor function was assessed before the intervention and 90 days after randomization using the Fugl-Meyer assessment scale. Neuroimaging measures included fractional anisotropy values of the corticospinal tract and posterior limb of the internal capsule from diffusion tensor magnetic resonance imaging and strength of connectivity, efficiency, and density of the motor network from resting-state functional magnetic resonance imaging. Results: For motor function, the improvement ratio of the Fugl-Meyer assessment score was significantly higher in the MSC group compared with the control group. In neuroimaging, corticospinal tract and posterior limb of the internal capsule fractional anisotropy did not decrease in the MSC group but significantly decreased at 90 days after randomization in the control group. Interhemispheric connectivity and ipsilesional connectivity significantly increased in the MSC group. Change in interhemispheric connectivity showed a significant group difference. Conclusions: Stem cell–based therapy can protect corticospinal tract against degeneration and enhance positive changes in network reorganization to facilitate motor recovery after stroke. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01716481.

ObjectiveTo evaluate the safety and efficacy of induced hypertension in patients with acute ischemic stroke.MethodsIn this multicenter randomized clinical trial, patients with acute noncardioembolic ischemic stroke within 24 hours of onset who were ineligible for revascularization therapy and those with progressive stroke during hospitalization were randomly assigned (1:1) to the control and intervention groups. In the intervention group, phenylephrine was administered intravenously to increase systolic blood pressure (SBP) up to 200 mm Hg. The primary efficacy endpoint was early neurologic improvement (reduction in NIH Stroke Scale [NIHSS] score of ≥2 points during the first 7 days). The secondary efficacy endpoint was a modified Rankin Scale score of 0 to 2 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage/edema, myocardial infarction, and death.ResultsIn the modified intention-to-treat analyses, 76 and 77 patients were included in the intervention and control groups, respectively. After adjustment for age and initial stroke severity, induced hypertension increased the occurrence of the primary (odds ratio 2.49, 95% confidence interval [CI] 1.25–4.96, p = 0.010) and secondary (odds ratio 2.97, 95% CI 1.32–6.68, p = 0.009) efficacy endpoints. Sixty-seven (88.2%) patients of the intervention group exhibited improvements in NIHSS scores of ≥2 points during induced hypertension (mean SBP 179·7 ± 19.1 mm Hg). Safety outcomes did not significantly differ between groups.ConclusionAmong patients with noncardioembolic stroke who were ineligible for revascularization therapy and those with progressive stroke, phenylephrine-induced hypertension was safe and resulted in early neurologic improvement and long-term functional independence.ClinicalTrials.gov identifierNCT01600235.Classification of evidenceThis study provides Class III evidence that for patients with acute ischemic stroke, therapeutic-induced hypertension increases the probability of early neurologic improvement.

ObjectiveTo test whether autologous modified mesenchymal stem cells (MSCs) improve recovery in patients with chronic major stroke.MethodsIn this prospective, open-label, randomized controlled trial with blinded outcome evaluation, patients with severe middle cerebral artery territory infarct within 90 days of symptom onset were assigned, in a 2:1 ratio, to receive preconditioned autologous MSC injections (MSC group) or standard treatment alone (control group). The primary outcome was the score on the modified Rankin Scale (mRS) at 3 months. The secondary outcome was to further demonstrate motor recovery.ResultsA total of 39 and 15 patients were included in the MSC and control groups, respectively, for the final intention-to-treat analysis. Mean age of patients was 68 (range 28–83) years, and mean interval between stroke onset to randomization was 20.2 (range 5–89) days. Baseline characteristics were not different between groups. There was no significant difference between the groups in the mRS score shift at 3 months (p = 0.732). However, secondary analyses showed significant improvements in lower extremity motor function in the MSC group compared to the control group (change in the leg score of the Motricity Index, p = 0.023), which was notable among patients with low predicted recovery potential. There were no serious treatment-related adverse events.ConclusionsIV application of preconditioned, autologous MSCs with autologous serum was feasible and safe in patients with chronic major stroke. MSC treatment was not associated with improvements in the 3-month mRS score, but we did observe leg motor improvement in detailed functional analyses.Classification of EvidenceThis study provides Class III evidence that autologous MSCs do not improve 90-day outcomes in patients with chronic stroke.ClinicalTrials.gov IdentifierNCT01716481.

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 DVT was associated with a greater infarct volume in magnetic resonance imaging (beta, 13.14; 95% CI , 1.62–24.66; P =0.028). Presence of DVT (hazard ratio, 16.79; 95% CI, 2.05–137.75; P =0.009) and microembolic signal (hazard ratio, 8.16; 95% CI , 1.36–48.85; P =0.022) were independent predictors of poor 1‐year survival. Conclusions Patients with cancer‐associated embolic stroke of undetermined source have an elevated risk of associated venous thromboembolism and arterial thromboembolism, both of which have a significant negative impact on 1‐year survival. The results of this study may enhance our understanding of cancer‐associated stroke and improve risk stratification of patients with this disease. Clinical Trial Registration URL : https://www.clinicaltrials.gov/.Unique identifier: NCT 02212496

Background and Purpose Left atrial dysfunction has been reported in patients with patent foramen ovale (PFO). Here we investigated the role of left atrial dysfunction in the development of embolic stroke in patients with PFO. Methods We identified consecutive patients with embolic stroke of undetermined sources except for PFO (PFO+ESUS). Healthy subjects with PFO served as controls (PFO+control). A stratified analysis by 10-year age group and an age- and sex- matching analysis were performed to compare echocardiographic markers between groups. In the PFO+ESUS group, infarct patterns of PFO-related stroke were determined (cortical vs. cortico-subcortical) and analyzed in correlation with left atrial function parameters. Results A total of 118 patients and 231 controls were included. The left atrial volume indices (LAVIs) of the PFO+ESUS patients were higher than those of the PFO+controls in age groups of 40–49, 50–59, and 60–69 years (P28 mL/m2) LAVI was more associated with the cortical infarct pattern (P=0.043 for an acute infarction and P=0.024 for a chronic infarction, both adjusted for age and shunt amount). The degree of right-to-left shunting was not associated with infarct patterns, but with the posterior location of acute infarcts (P=0.028). Conclusions Left atrial enlargement was associated with embolic stroke in subjects with PFO. Left atrial physiology might contribute to the development of PFO-related stroke and need to be taken into consideration for optimal prevention of PFO-related stroke.

Background: Increased risk of acute ischemic stroke is observed among cancer patients. Hypercoagulability is commonly observed in cancer-associated stroke, and is thus considered as a possible mechanism. In this study, we aimed to demonstrate intravascular thrombosis and its clinical impact in patients with cancer-associated stroke. Methods: We enrolled consecutive patients with embolic stroke of unknown source (ESUS) with or without active cancer in Samsung Medical Center from August 2014 to March 2018. We evaluated the presence of intravascular thrombosis, i.e. intravenous and intra-arterial thrombosis, by investigating the presence of deep vein thrombosis (DVT), microembolic signal (MES) and coagulation abnormalities in all patients. Infarct volumes on diffusion-weighted imaging and death dates were also collected. Results: Of 142 patients screened, 118 were included in this study (cancer group, n=37; non-cancer group, n=81). Cancer group had a higher prevalence of intravascular thrombosis compared to non-cancer group (62.2% vs. 19.8%, p Conclusion: Our study results provide evidences of increased intravascular thrombosis and their clinical impact in patients with cancer-associated stroke. Our findings may enhance the understanding of cancer-associated stroke and risk stratification of patients.

Background: Preclinical studies showed that stroke induces a process of recovery via the activation of MSCs, and culture methods for MSCs using stroke patient’s serum obtained during the acute phase of a stroke could constitute a novel MSC activation method. The present trial was conducted to test whether modified MSCs with autologous serum improve the recovery in patients with chronic stroke. Methods: In this prospective, randomized controlled trial, patients with moderate-to-severe disabling middle cerebral artery territory infarct observed within 90 days of the onset of symptoms were assigned, in a 2:1 ratio, to receive MSC therapy (intervention group) or standard care alone (control group), and followed for 3 months. The primary outcome was the score on the mRS at 3 months of treatment. Results: Totals of 39 and 15 patients completed the follow-up in the intervention and control groups, respectively. The mean interval between stroke onset to randomization was 20.2±17.2 days. The mean age was 63.4±13.9 and median NIHSS score was 11 [IQR, 8-17] in the study population. The baseline characteristics were well balanced in the two groups. The median mRS score at day 90 was 3 [IQR, 3-4] in the intervention group and 4 [IQR, 3-4] in the treatment group (P = 0.879). Proportional odds ratio for good functional outcome (mRS at 3 months of treatment) with the stem cell treatment was 0.65 (95% confidence interval, 0.18-2.44; P = 0.529), after adjusting for age, gender, and initial NIHSS scores. In secondary efficacy endpoint, no significant difference was found in the two groups measured by global Fugl-Meyer assessment. However, Fugl-Meyer score in the lower motor function showed significant improvement in the intervention group (delta between baseline and 90-day, 2.3 vs. 4.7; P Conclusions: Among patients with chronic stroke, treatment with autologous preconditioned MSC was feasible but did not improve long-term functional outcome. Further studies are needed to select responders to MSC therapies and to improve efficacy of stem cell therapeutics.

Objective We sought to identify the clinical outcome and predictors for ischemic stroke recurrence in adults with symptomatic moyamoya disease (MMD). Methods We analyzed 104 adult MMD patients with ischemic stroke or TIA registered at our institution. All patients underwent digital subtraction angiography and single photon emission computed tomography to measure disease severity and cerebral vascular reserve (CVR). A Cox regression model was used to identify predictors of recurrent ischemic stroke. Results Fifty-nine patients were non-surgically treated and 45 patients were surgically treated. In the non-surgical group, the Kaplan–Meier estimate of ischemic stroke recurrence was 1.6% in the first year and 11.8% in the 5th year. Hypertension (hazard ratio [HR] = 0.07, 95% confidence interval [CI] 0.01–0.99), diabetes (HR = 35.16, 95% CI 2.61–474.16), presence of steno-occlusive lesion in posterior cerebral arteries (HR = 17.53, 95% CI 2.02–152.43), and extended or global decreased CVR (HR = 13.62, 95% CI 1.55–119.84) were independent predictors of recurrence. In the surgical group, the Kaplan–Meier estimate of ischemic stroke recurrence was 24.4% in the first year and 24.4% in the 5th year. Half of the recurred patients experienced recurrent ischemic strokes postoperatively. Diabetes was the only predictor of recurrent ischemic stroke (HR = 6.17, 95% CI 1.31–29.14). Conclusions In non-surgically treated MMD, PCA stenosis and CVR were identified as predictors of ischemic stroke recurrence. Diabetes was an independent predictor of recurrent ischemic stroke in both non-surgical and surgically treated MMD groups.

Background and Purpose— Good collateral flow is an important predictor for favorable responses to recanalization therapy and successful outcomes after acute ischemic stroke. Magnetic resonance perfusion–weighted imaging (MRP) is widely used in patients with stroke. However, it is unclear whether the perfusion parameters and thresholds would predict collateral status. The present study evaluated the relationship between hypoperfusion severity and collateral status to develop a predictive model for good collaterals using MRP parameters. Methods— Patients who were eligible for recanalization therapy that underwent both serial diffusion-weighted imaging and serial MRP were enrolled into the study. A collateral flow map derived from MRP source data was generated through automatic postprocessing. Hypoperfusion severity, presented as proportions of every 2-s T max strata to the entire hypoperfusion volume ( T max≥2 s), was compared between patients with good and poor collaterals. Prediction models for good collaterals were developed with each T max strata proportion and cerebral blood volumes. Results— Among 66 patients, 53 showed good collaterals based on MRP-based collateral grading. Although no difference was noted in delays within 16 s, more severe T max delays ( T max 16–18 s , T max 18–22 s , T max 22–24 s , and T max >24 s ) were associated with poor collaterals. The probability equation model using T max strata proportion demonstrated high predictive power in a receiver operating characteristic analysis (area under the curve=0.9303; 95% confidence interval, 0.8682–0.9924). The probability score was negatively correlated with the volume of infarct growth ( P =0.030). Conclusions— Collateral status is associated with more severe T max delays than previously defined. The present T max severity–weighted model can determine good collaterals and subsequent infarct growth.

Background and Purpose Advantages of new oral anticoagulations may be greater in atrial fibrillation (AF) patients of poor anticoagulation control with warfarin. The SAMe-TT2R2 scoring system, based on clinical variables, was recently developed to aid in identifying these patients. In this study, we investigated the association of this clinical composite score with genetic factors related warfarin dosing and the quality of anticoagulation control. Methods Clinical and genetic data were collected from 380 consecutive Korean patients with AF (CHA2DS2-VASc score, 3.5±1.8) who were followed for an average of 4 years. We evaluated factors associated with time in therapeutic range (TTR, INR 2-3), including the CYP2C9 and VKORC1 genotypes and the SAMe-TT2R2 score (Sex female, Age two co-morbidities], Treatment [interacting drugs, e.g., amiodarone], Tobacco use within 2 years [doubled], and Race non-white [doubled]). Results The average SAMe-TT2R2 score was 3.4±0.9, range 2-7; and 153 patients (40.2%) had SAMe-TT2R2 scores ≥4. Time in specific INR ranges varied depending on the VKORC1 genotype but not with the CYP2C9 genotype or the SAMe-TT2R2 score. TTR was higher in patients with the VKORC1 1173C>T than in VKORC1 TT (61.7±16% vs. 56.7±17.4%, P=0.031). Multivariate testing showed that VKORC1 genotype but not the SAMe-TT2R2 score was significantly associated with labile INRs. There was no correlation between the SAMe-TT2R2 scores and pharmacogenetic data. Conclusions A genetic factor, but none of the common clinical and demographic factors, as combined in the SAMe-TT2R2 score, was associated with the quality of anticoagulation control in Korean patients with AF.

Background: In this multicentre, randomised controlled trial, we evaluated the safety and efficacy of induced hypertension in patients with acute ischaemic stroke. Methods: Patients with acute non-cardioembolic ischaemic stroke within 24 hours of onset who were ineligible for revascularisation therapy and those with progressive stroke during hospitalization were randomly assigned (1:1) to the control and intervention groups. In the intervention group, phenylephrine was intravenously administered to increase systolic blood pressure (SBP) up to 200 mmHg. The primary efficacy endpoint was early neurological improvement (reduction in NIHSS score ≥ 2 points during the first 7 days). The secondary efficacy endpoint was a modified Rankin scale score of 0-2 at 90 days. Safety outcomes included symptomatic intracranial haemorrhage/oedema, myocardial infarction, and death. Findings: Totals of 76 and 77 patients were included in the intervention and control groups, respectively. Relative to the control group, patients in the intervention group were younger, exhibited higher baseline NIHSS values, and were more likely to experience progressive stroke and large vessel occlusion. Sixty-seven (88·2%) patients of the intervention group exhibited improvements in NIHSS scores ≥2 during induced hypertension (mean SBP: 179·7±19·1 mmHg). After adjusting for age and initial stroke severity, induced hypertension increased the occurrence of the primary (odds ratio: 2·49; 95% CI: 1·25-4·96; P=0·010) and secondary efficacy endpoints (odds ratio: 2·97; 95% CI: 1·32-6·68; P=0·009). The numbers needed to treat were 3·7 and 8·4 for the primary and secondary endpoints, respectively. Safety outcomes did not significantly differ between groups. Interpretation: Among patients with non-cardioembolic stroke who were ineligible for revascularisation therapy and those with progressive stroke, phenylephrine-induced hypertension was safe and resulted in early neurological improvement and long-term functional independence (class IB evidence). Clinical Trial Number: This trial is registered with ClinicalTrials.gov (NCT01600235). Funding: Samsung Medical Center and IlDong Pharma, Inc. Seoul, South Korea. Declaration of Interests: All authors declare no competing interests. Ethic Approval Statement: Patients from eight sites in South Korea were enrolled between June 2012 and December 2017. The trial was approved by the appropriate national regulatory authorities and relevant ethnics committee at each participating site. All participants provided written informed consent.

Background From 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 Results A 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 P P NIHSS score, lesion size (≥20 mm), multiple (≥3) lesions, and involvement of posterior circulation or multiple vascular territories differentiated the 3 groups (pseudo, R 2 =0.656). The prediction ability of this model was validated in the external validation cohort (n=117, area under the curve 0.78). Conclusions Our data indicate that patients with cryptogenic embolic stroke show distinct clinical and radiological features depending on the underlying causes.

Background: Moyamoya disease (MMD) is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 (RNF213) was identified as a susceptibility gene for MMD in East Asian. However, the pathogenesis of MMD is still unclear. Methods: We prospectively analyzed clinical data for 139 patients with MMD (108 definite MMD, 31 probable MMD) and 61 patients with intracranial atherosclerotic stroke (ICAS), and 68 healthy subjects. We compared the genetic (RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor [VEGF] and receptor [VEGFR2], and antagonizing cytokine [endostatin]) and endothelial dysfunction (asymmetric dimethylarginine [ADMA], nitric oxide and its metabolites [nitrite and nitrate]), between patients with MMD and ICAS. We then performed the path analysis to evaluate whether a certain protein biomarker mediates the association the genetic and MMD. Results: Caveolin-1 level was decreased in patients with MMD and this level was markedly decreased in RNF213 variant carriers. Circulating factor such as VEGF and receptor were not different among the groups. Markers for endothelial dysfunction were significantly higher in patients with ICAS, but normal in MMD. The path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 level that led to MMD. The level of combined marker of MMD (caveolin-1) and ICAS (ADMA, marker for endothelial dysfunction) predicted MMD with a good sensitivity and specificity. Conclusions: Our results indicate that MMD is primarily caveolae disorder, dysregulation of endothelial vesicular trafficking and signal transduction, but not related to endothelial dysfunction or dysregulation of circulating cytokines.

Background/Aims: To enable the diagnosis of moyamoya disease (MMD), detection of distal internal carotid artery stenosis and hazy network of basal collaterals (BCs) are required. This study aimed at evaluating the factors that could determine the degree of BCs in patients with angiographically confirmed MMD. Methods: We analyzed 146 consecutive patients with MMD (age 26.2 ± 19.6, range 1-75). The degree of BCs (%) was measured based on conventional angiography. Factors associated with the degree of BCs, including clinico-radiological and genetic factors (p.Arg4810Lys variant), were analyzed. Results: The degree of BCs varied among MMD patients and significantly decreased with an increase in the age of diagnosis of MMD (coefficient -1.55; p < 0.001). Although the degree of BC development depends on the MMD stage (Suzuki stage), it is less prominent in adult-onset (>18 years) MMD compared to childhood MMD. The presence of p.Arg4810Lys variant, types of MMD (bilateral vs. unilateral) and stroke (ischemic, hemorrhagic, or asymptomatic), shrinkage (outer diameter) of intracranial vessels, external carotid collateral status, and cortical neovascularization were not associated with the degree of BCs. Conclusion: Although prominent BCs are required for diagnosis of MMD, BCs are decreased with aging, suggesting that angiogenic capacity is altered in adult onset MMD compared to childhood MMD.

Background Moyamoya disease is a unique cerebrovascular occlusive disease of unknown etiology. Ring finger protein 213 ( RNF213) was identified as a susceptibility gene for Moyamoya disease in East Asian countries. However, the pathogenesis of Moyamoya disease remains unclear. Methods We prospectively analyzed clinical data for 139 patients with Moyamoya disease (108 bilateral Moyamoya disease, 31 unilateral Moyamoya disease), 61 patients with intracranial atherosclerotic stroke, and 68 healthy subjects. We compared the genetic ( RNF213 variant) and protein biomarkers for caveolae (caveolin-1), angiogenesis (vascular endothelial growth factor (VEGF) and receptor (VEGFR2), and antagonizing cytokine (endostatin)) and endothelial dysfunction (asymmetric dimethylarginine (ADMA), and nitric oxide and its metabolites (nitrite and nitrate)) between patients with Moyamoya disease and intracranial atherosclerotic stroke. We then performed path analysis to evaluate whether a certain protein biomarker mediates the association between genes and Moyamoya disease. Results Caveolin-1 level was decreased in patients with Moyamoya disease and markedly decreased in RNF213 variant carriers. Circulating factors such as VEGF and VEGFR2 did not differ among the groups. Markers for endothelial dysfunction were significantly higher in patients with intracranial atherosclerotic stroke but normal in those with Moyamoya disease. Path analysis showed that the presence of the RNF213 variant was associated with caveolin-1 levels that could lead to Moyamoya disease. The level of combined marker of Moyamoya disease (caveolin-1) and intracranial atherosclerotic stroke (ADMA, an endothelial dysfunction marker) predicted Moyamoya disease with good sensitivity and specificity. Conclusion Our results suggest that Moyamoya disease is a caveolae disorder but is not related to endothelial dysfunction or dysregulation of circulating cytokines.

Background: The predictors of symptom development in asymptomatic carotid stenosis are still unclear. We sought to identify factors associated with symptom development in asymptomatic carotid stenosis using multimodal imaging technique. Methods: We retrospectively collected patients who had carotid artery revascularization procedures (carotid endarterectomy [CEA] or carotid artery stenting [CAS]) from April 2007 to May 2013. Patients who had event of cerebral ischemic stroke during 6 months before CEA or CAS were categorized as a symptomatic carotid stenosis. Results from carotid Duplex sonography, CT angiography, brain MRI and MRA, perfusion-weighted MRI (PWI), and demographic profiles were compared. Multivariate logistic regression analysis was performed to identify factors associated with symptom carotid stenosis. Results: A total of 684 patients (asymptomatic 58%, symptomatic 42%) with carotid stenosis more than 50% were included. The presence of ischemic heart diseases, peripheral artery occlusive disease and use of statin were higher in the asymptomatic carotid stenosis. On Duplex scan, ulceration, echolucent plaque, and heterogeneous components of plaque were more frequent in symptomatic carotid stenosis. Angiographic data showed the length of plaque was longer in symptomatic carotid stenosis. Presence of deep white matter hyperintensity, FLAIR vessel sign and GRE vessel sign were more frequently observed in symptomatic carotid stenosis. Patients with symptomatic carotid stenosis had increased cerebral blood flow, cerebral blood volume (CBV), and delayed time to peak when compared to the asymptomatic stenosis. Multivariate analysis revealed length of plaque (>20mm), deep white matter hyperintensity and increased CBV were associated with symptomatic carotid stenosis (Odd ratio [OR]=2.339, 95% confidence interval [CI] 1.312-4.169, P=0.004; OR=2.315, 95% CI 1.160-4.619, P=0.017; OR=2.242, 95% CI 1.127-4.463, P=0.021, respectively). Conclusion: Plaque burden, deep white matter hyperintensity, and increased CBV were independent predictors of symptom development in carotid stenosis. Multimodal imaging may be useful to identify high risk patients of ischemic stroke among asymptomatic carotid stenosis.

Background Both Moyamoya disease (MMD) and intracranial atherosclerotic stenosis (ICAS) are more prevalent in Asians than in Westerners. We hypothesized that a substantial proportion of patients with adult-onset MMD were misclassified as having ICAS, which may in part explain the high prevalence of intracranial atherosclerotic stroke in Asians. Method We analyzed 352 consecutive patients with ischemic events within the MCA distribution and relevant intracranial arterial stenosis, but no demonstrable carotid or cardiac embolism sources. Conventional angiography was performed in 249 (70.7%) patients, and the remains underwent MRA. The occurrence of the c.14429G>A (p.Arg4810Lys) variant in ring finger protein 213 (RNF213) was analyzed. This gene was recently identified as a susceptibility gene for MMD in East Asians. Results The p.Arg4810Lys variant was observed in half of patients with intracranial stenosis (176 of 352, 50.0%), in no healthy control subjects (n = 51), and in 3.2% of stroke control subjects (4 of 124 patients with other etiologies). The presence of basal collaterals, bilateral involvement on angiography, and absence of diabetes were independently associated with the presence of the RNF213 variant. Among 131 patients who met all three diagnostic criteria and were diagnosed with MMD, three-fourths (75.6%) had this variant. However, a significant proportion of patients who met two criteria (57.7%), one criterion (28.6%), or no criteria (20.0%) also had this variant. Some of them developed typical angiographic findings of MMD on follow-up angiography. Conclusions Careful consideration of MMD is needed when diagnosing ICAS because differential therapeutic strategies are required for these diseases and due to the limitations of the current diagnostic criteria for MMD.