Search

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. more...

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. more...

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. more...

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 more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

Background/Aims: Early neurological deterioration (END) is frequently observed and related to poor functional outcome in patients with single subcortical infarction (SSI). We evaluated the role of diffusion-perfusion mismatch (DPM) as a predictor of END and functional outcome in patients with SSI. Methods: We retrospectively analyzed data for 274 patients with acute SSI. DPM was positive in the presence of a lesion on the perfusion map that was larger than that on the corresponding slice on diffusion-weighted imaging. END was defined as an increase of Results: DPM was more frequently observed in the END (+) than in the END (-) group (21/35 (60.0%) vs. 50/239 (20.9%); p < 0.001). After adjusting for covariates, the presence of DPM and NIHSS score on admission were independently associated with END (DPM, OR 5.03, p < 0.001; NIHSS, OR 1.14, p = 0.033) and poor functional outcome (DPM, OR 2.44, p = 0.018; NIHSS, OR 1.48, p < 0.001). Conclusions: The DPM concept is applicable to prediction of END and functional disability in patients with SSI. more...

Background and Purpose— Recent randomized clinical trials (RCTs) have evaluated the benefit of new oral anticoagulants in reducing the risk of vascular events and bleeding complications in patients with atrial fibrillation (AF). However, abundant and strict enrollment criteria may limit the validity and applicability of results of RCTs to clinical practice. We estimated the eligibility for participation in RCTs of an unselected group of patients with AF. In addition, we compared features favoring new oral anticoagulant use between patients with versus without stroke. Randomized Evaluation of Long-Term Anticoagulation Therapy Methods— We applied enrollment criteria of 4 RCTs (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) to 695 patients with AF taking warfarin, prospectively and consecutively collected at a university medical center; 500 patients with and 195 patients without stroke. Time in therapeutic range and bleeding risk scheme (anticoagulation and risk factors in atrial fibrillation) were also measured. Results— The proportions of patients fulfilling the trial enrollment criteria varied, ranging from 39% to 72.8%, depending on the differences in indications/contraindications among studies and presence/absence of stroke. The main reasons for ineligibility for RCTs were hemorrhagic risk (anticoagulation and risk factors in atrial fibrillation [ATRIA] score) (10.8%–40.5%) and planned cardioversion (5.1%–7.7%) for nonstroke patients, and a low creatinine clearance (5.6%–9.2%) and higher risk of bleeding (15.2%–20.8%) for patients with stroke. When compared with nonstroke patients, patients with stroke showed a lower time in therapeutic range (54.4±42.8% versus 65.4±34.9%, especially with severe disability) and a high hemorrhagic risk (ATRIA score) (3.06±2.30 versus 2.18±2.16) ( P Conclusions— Patients enrolled in RCTs are partly representative of patients with AF in clinical practice. When time in therapeutic range and bleeding tendency with warfarin use were considered, the use of new oral anticoagulants was preferred in patients with stroke than in nonstroke patients, but they were more likely to be excluded in RCTs. more...

Objective Dedicated magnetic resonance (MR) imaging (MRI) sequences for evaluation of collaterals can be generated using MR perfusion (MRP) source data. We compared a novel collateral flow imaging technique with digital subtraction angiography (DSA) for determining collateral circulation in acute stroke and evaluated the ability of MR-based collateral flow maps to predict outcomes after recanalization therapy. Methods Consecutive patients who were candidates for endovascular treatment were enrolled. A collateral flow map derived from MRP source data was generated by manual or automatic postprocessing. Collateral grading based on the collateral flow map was performed and compared with grading based on DSA. Clinical and radiological outcomes were evaluated according to MR-based collateral grading and early reperfusion (ER) status. Results There was good correlation between MRI-based and DSA-based collateral grades (weighted κ-coefficient = 0.70). Collateral status and achievement of ER were the 2 main determinants of a favorable functional outcome and neurological improvement, in addition to infarct growth. Regardless of achievement of ER, better collaterals were significantly associated with a lower modified Rankin score at day 90 (p more...

Background: Both basal collaterals (BC) and cortical microvascularization (CM) on angiography have been suggested as moyamoya disease (MMD)-specific findings; however, it is unknown whether the vascular network represents compensatory mechanisms for vascular occlusion or aberrant active neovascularization. Methods: We investigated the grade of antegrade MCA flow, the degree of BC, and the presence of CM on conventional angiography in relation to disease severity in pediatric MMD. CM was defined as enlarged and winding distal cortical arteries and categorized into anterior or posterior CM depending on their sources. Findings from basal and acetazolamide stress brain perfusion SPECT studies were also evaluated. Results: A total of 172 pediatric patients with MMD were enrolled in this study. As the severity of MMD increased, the grade of antegrade MCA flow gradually diminished. While the degree of BC peaked at Suzuki stage 3-4, CM was frequently observed at early MMD stages. About two-thirds of hemispheres with normal antegrade MCA flow on angiography and normal perfusion status on SPECT had anterior and/or posterior CM. Both anterior and posterior CM gradually decreased with the advancement of MMD. Conclusion: Our findings from a large cohort of angiographically confirmed pediatric MMD patients indicate that neovascularization may occur before significant hemodynamic impairment in MMD. more...

Background: Some ischemic strokes in patients with atrial fibrillation (AF) are caused by noncardioembolic etiologies (AF-unrelated stroke), but not AF itself (AF-related stroke). However, most clinical trials on the risk of stroke in AF have not distinguished between these. We investigated the frequency and features of AF-unrelated versus AF-related strokes in patients with AF plus ischemic stroke. We hypothesized that certain clinical factors, including chronicity of AF, treatment at the time of stroke onset and echocardiographic findings, may help to discriminate between AF-related and AF-unrelated strokes. The mechanisms and antithrombotic medications at the time of stroke recurrence in the two groups were also examined. Methods: Consecutive patients with ischemic stroke within 7 days of symptom onset and with AF were included. Patients were classified according to the previously published criteria. Clinical factors including CHADS2 and CHA2DS2-VASc scores and transthoracic echocardiographic (TTE) findings were evaluated. Results: Of 522 patients, 424 (81.2%) were grouped as AF-related stroke and the remaining 90 (17.2%) were classified as AF-unrelated stroke. Among the patients with AF-unrelated stroke, 51 (9.8%) were categorized as possible large artery atherosclerosis and 38 (7.3%) as possible small artery occlusion; 1 patient (0.2%) was assigned to miscellaneous cause. The AF-related and AF-unrelated strokes had similar CHADS2 and CHA2DS2-VASc scores. However, compared to AF-unrelated stroke, AF-related stroke was independently associated with female sex (odds ratio, OR, 2.19; 95% confidence interval, CI, 1.18-4.05), sustained AF (OR, 2.09; 95% CI, 1.21-3.59), inadequate anticoagulation at stroke onset (OR, 3.21; 95% CI, 1.33-7.75) and left ventricular dysfunction on TTE (OR, 2.84; 95% CI, 1.40-5.74). We identified 26 patients who experienced 2 strokes during the study period. The initial stroke subtype was a strong predictor of the recurrent stroke mechanism (p < 0.001). Among 17 events of AF-related recurrent stroke in these subpopulation, only 2 strokes (11.8%) occurred in a setting of adequate anticoagulation, whereas 4 out of 9 patients (44.4%) who had AF-unrelated strokes at recurrence were sufficiently anticoagulated at the time of admission (p = 0.138). Conclusion: AF is not always a culprit of stroke in patients with AF plus ischemic stroke; approximately one sixth of these cases are unrelated to AF and have distinct characteristics compared to AF-related stroke. There are significant differences in terms of some clinical and TTE parameters between AF-related and AF-unrelated stroke. Future studies are warranted to optimize strategies for risk stratification, treatment and prevention of stroke in these patients. more...

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. more...

Background Paradoxical embolism has been documented as a mechanism of cryptogenic embolic stroke. We investigated the frequency of right-to-left shunt in patients with cryptogenic embolic stroke and evaluated the factors associated with diffusion-weighted imaging (DWI) lesion pattern. Methods We analyzed data on 157 consecutive patients with acute ischemic stroke because of presumed cryptogenic embolism. Agitated saline transcranial Doppler study was conducted in all patients to detect right-to-left shunt. We evaluated the association of the amount (microemboli ≥20 vs. ≥20) and activity (spontaneous vs. after Valsalva maneuver only) of right-to-left shunt with diffusion-weighted imaging lesion patterns. Results Right-to-left shunt was observed in 96 (61·1%) patients. The multiplicity and distribution of diffusion-weighted imaging lesions did not differ depending on the amount and activity of right-to-left shunt. However, the size of diffusion-weighted imaging lesions differed depending on the amount of right-to-left shunt ( P = 0·019). Right-to-left shunt was more frequently observed in patients with small (Conclusions Our results indicate that the amount of right-to-left shunt determines the Diffusion-weighted imaging lesion patterns and suggest that mechanisms of stroke other than paradoxical mechanism may play an important role in patients with large cryptogenic embolic stroke. more...

Background and Purpose— The clinical significance of microembolic signals (MES) in the posterior circulation remains unclear. The aim of this study was to investigate the sources and consequences of MES in acute posterior circulation cerebral ischemia. Methods— We evaluated a total of 140 consecutive patients (93 males, mean age 62.9 years) who had acute posterior circulation cerebral ischemia. The MES monitoring was conducted at the basilar artery through the suboccipital window for a 30-minute period. Results— MES were detected in 18 (12.9%) of the 140 patients. Clinical characteristics and laboratory data did not differ between the MES-positive and MES-negative groups. Intracranial vertebrobasilar artery (VBA) stenosis was independently associated with the presence of MES (odds ratio, 9.85; 95% confidence interval, 1.22–79.48; P =0.032), whereas the patients with vertebral artery stenosis that was limited to the extracranial portion did not show an association. Microembolic signals occurred significantly more frequently in patients with severe degree of VBA stenosis compared to those with nonsignificant stenosis (odds ratio, 9.88; 95% confidence interval, 1.23–79.07; P =0.031). In a subgroup analysis of the 79 patients who had lesions on diffusion-weighted images and relevant VBA stenosis, the MES-positive group showed more frequent embolic infarction ( P =0.010) and multiple lesion patterns ( P =0.007) than single perforating infarctions. Conclusions— In acute posterior circulation cerebral ischemia, intracranial and severe VBA stenosis is associated with MES and may be its root causes. The presence of MES in VBA stenosis suggests that multiple and embolic type infarctions are the mechanisms of stroke. more...

Background and Purpose— The clinical significance of sulcal effacement has been widely investigated in CT studies, but the results are controversial. In this study, we evaluated the presence of perisylvian sulcal effacement (PSE) on fluid attenuation inversion recovery MRI and hypothesized that PSE may be related to collateral flow status together with hyperintense vessels on fluid attenuation inversion recovery in hyperacute stroke. In addition, we investigated whether an association between PSE and clinical outcome could be found in these patients. Methods— Consecutive patients with acute middle cerebral artery infarcts within 6 hours of symptom onset were included. All patients had internal carotid artery or middle cerebral artery occlusion and underwent MRI including FLAIR. The presence of PSE and hyperintense vessels on fluid attenuation inversion recovery and the collateral status and occurrence of early recanalization (ER) on conventional angiography were evaluated. Results— Of 139 patients, 79 (56.8%) had PSE. Multivariate testing revealed PSE was independently associated with collateral status. The association between hyperintense vessels and collaterals was different depending on PSE. Compared to PSE-positive and ER-negative patients, PSE-negative and ER-negative patients (odds ratio, 4.11; 95% confidence interval, 1.12–15.17) and PSE-negative and ER-positive patients (odds ratio, 34.62; 95% confidence interval, 5.75–208.60), but not PSE-positive and ER-positive patients, were more likely to experience favorable clinical outcomes (modified Rankin Scale score ≤2 at 3 months). Conclusions— PSE is independently associated with collateral status in patients with acute middle cerebral artery stroke. Moreover, PSE in conjunction with recanalization status can predict clinical outcomes in these patients. more...

Background and Purpose— The significance of asymptomatic coronary artery atherosclerosis burden (CAB) in the interpretation of stroke biomarker results is unknown. We investigated biomarker values to determine if they are related to cerebral atherosclerosis with consideration of CAB. Methods— We prospectively recruited patients with noncardioembolic ischemic cerebrovascular disease who had no history of coronary artery disease. Patient-based vascular assessment was conducted using MRA for the cerebral arteries and cardiac CT angiography for the coronary arteries. Biomarkers including the C-reactive protein and homocysteine were measured. Results— A total of 178 patients were included in the study. The extracranial carotid stenosis was associated with the highest quartile of C-reactive protein (OR, 2.24; 95% CI, 1.04–4.55), whereas age was the only predictor of the highest quartile of homocysteine (OR, 1.06; 95% CI, 1.02–1.11). However, with consideration of CAB, CAB (≥2 segments with ≥50% stenosis) remained the only independent predictor for the highest quartile of C-reactive protein (OR, 8.69; 95% CI, 2.41–31.30) and homocysteine (OR, 11.44; 95% CI, 2.61–50.11). Conclusions— Our data emphasize the importance of CAB in biomarker studies of patients with ischemic stroke. more...

Background and Purpose— Collaterals sustain the penumbra before recanalization and offset infarct growth, yet the influence of baseline collateral flow on recanalization after endovascular therapy remains relatively unexplored. Methods— We analyzed consecutive patients who received endovascular therapy for acute cerebral ischemia from 2 distinct study populations. We assessed the relationship between pretreatment collateral grade and vascular recanalization (Thrombolysis In Myocardial Ischemia [TIMI] scale). In addition, we assessed infarct growth on serial MRI. Results— A total of 222 patients was included, 138 from the United States and 84 from South Korea. Complete revascularization occurred in 14.1% (11 of 78) patients with poor pretreatment collateral grades, whereas it was observed in 25.2% (26 of 103) patients with good collaterals and 41.5% (17 of 41) patients with excellent collaterals ( P P =0.012). Conclusions— Our data indicate that angiographic collateral grade determines the recanalization rate after endovascular revascularization therapy. When therapeutic revascularization was achieved, beneficial effects were not observed in patients with poor collaterals. Angiographic collateral grade may therefore help guide treatment decision-making in acute cerebral ischemia. more...

Background and Purpose— Carotid artery stenosis is an important etiologic factor of stroke related to coronary artery bypass surgery. We evaluated clinical and laboratory factors to identify biomarkers for pre-existing carotid artery stenosis in patients undergoing coronary artery bypass surgery. Methods— Between June 2006 and September 2008, 811 patients aged ≥50 years underwent preoperative carotid artery duplex scanning as part of a preoperative assessment for nonemergency cardiac procedures. Of these, 54 patients with previous stroke or transient ischemic attack were excluded. The association between various biomarkers and carotid artery stenosis was analyzed by multiple logistic regression analysis. The receiver operating characteristic curves were generated and analyzed to compare diagnostic performance and optimum diagnostic cutoff levels of biomarkers. Results— A total of 757 patients was included in the study. The prevalence of asymptomatic carotid stenosis of ≥50% and ≥70% was 26.4% and 8.6%, respectively. In multivariate analysis, plasma levels of apolipoprotein B (apoB):apoA-I, lipoprotein(a), and homocysteine were independently associated with carotid stenosis of ≥50%: the OR (95% CI) for apoB/apoA-I, lipoprotein(a), and homocysteine in the highest versus lowest quartile was 2.07 (1.18 to 3.66), 2.17 (1.16 to 4.05), and 2.13 (1.20 to 3.79), respectively. Receiver operating characteristic curve analysis indicated area under the curve values of 0.708 (apoB:apoA-I), 0.678 (lipoprotein[a]), and 0.689 (homocysteine). The sensitivity, specificity, positive and negative predictive values (%) for diagnosis of carotid stenosis ≥50% were 80.0, 50.4, 38.0, and 86.9 for apoB:apoA-I; 47.0, 78.9, 46.1, and 79.5 for lipoprotein(a); and 69.3, 62.1, 41.2, and 84.1 for homocysteine, respectively. Conclusion— Our findings indicated that plasma levels of apoB/apoA-I, lipoprotein(a), and homocysteine can predict asymptomatic carotid stenosis in patients undergoing coronary artery bypass surgery. more...

Background: Perfusion-weighted imaging (PWI) is rarely used to evaluate cases of posterior circulation infarctions. We evaluated clinical outcomes, diffusion-weighted imaging (DWI) patterns and angiographic findings in patients experiencing medullary infarctions according to PWI results. Methods: Data from consecutive patients with acute ischemic lesions primarily involving the medulla were analyzed. All patients underwent MRI including DWI, PWI and MR angiography. The patients were grouped according to the presence or absence of a perfusion delay in the medulla and/or inferior cerebellum. Results: Among 35 patients, all but 1 had a PWI of interpretable quality. Of these 34 patients, 18 had a normal perfusion status, while 16 had perfusion defects in the medulla and/or inferior cerebellum. The abnormal PWI group had poor clinical outcomes at 7 days and 1 month after the onset of symptoms. There was no difference in DWI patterns between these 2 groups. The angiographic findings demonstrated that a stenosis of ≧50% or an occlusion of the ipsilesional vertebral artery was frequently observed in the abnormal PWI group (p = 0.001). Multivariate analysis revealed that abnormal PWI and DWI patterns were independently associated with poor early and late outcomes following medullary infarctions. Conclusions: PWI may be a feasible modality for assessing the perfusion status of the posterior circulation and predicting clinical outcomes following medullary infarctions. more...

Background: Stroke evolution frequently occurs during the first week after stroke. However, the association between the type of stroke evolution and baseline perfusion severity has not been investigated. Methods: We analyzed clinical and serial MRI data on patients with acute middle cerebral artery infarcts. Multimodal MRIs were acquired before treatment and on day 7. Time to peak (Tmax) perfusion lesion maps were then generated, and changes in the day 7 diffusion-weighted imaging (DWI) were classified; new lesions were defined as new DWI lesions not contiguous with initial abnormalities, and infarct growth as enlargement of DWI lesions. Results: Among 74 patients (mean age 64.2 years), 51 received recanalization therapy. The day 7 DWI revealed the presence of new lesions in 39 cases (52.7%) and infarct growth (mean ± SD 20.0 ± 4.3 ml) in 52. No correlation was observed between new lesion and infarct growth (r = 0.029, p = 0.805). Most new lesions were multiple and small, located in cortical/superficial areas and within the mild perfusion delay (2 ≤ Tmax < 4 s) regions, whereas infarct growth generally occurred within the severer perfusion delay regions. Multiple regression analysis revealed that large mild perfusion delay was independently associated with new lesions, whereas large initial DWI lesions and a severer perfusion delay (4 ≤ Tmax < 8 s) were associated with infarct growth. In terms of treatment, endovascular therapy was associated with new lesions, whereas the degree of angiographic recanalization was inversely associated with infarct growth. Conclusions: The types of stroke evolution differed depending on the baseline hypoperfusion severity, and the mode and effect of recanalization therapy. A poor correlation was observed between new lesions and infarct growth. more...

Background: Recently, the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) and the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) trialists suggested that diffusion-perfusion magnetic resonance imaging (MRI) can classify patients into 4 subgroups likely to differentially experience benefit or harm from reperfusion therapies. However, there is a lack of data comparing MR mismatch profiles between different race-ethnic groups. In addition, clinical factors affecting MR mismatch profiles are not well described. Methods: We analyzed clinical and pretreatment MRI data of patients from 2 geographically and ethnically distinct study populations (Seoul, South Korea, and Los Angeles, Calif., USA) who are eligible for recanalization therapy. Diffusion-perfusion mismatch regions were classified among the 4 DEFUSE MR profiles: target mismatch, no mismatch, small lesion and malignant. Results: A total of 147 South Korean and 162 Southern Californian subjects (64.2% Whites) were included. Pretreatment MRIs revealed that the MR mismatch profiles were different in the 2 study populations (p < 0.001). Target mismatch was more prevalent in Southern Californian subjects (67.9%) compared with South Korean subjects (58.5%), whereas the small lesion pattern was more prevalent in the latter (9.9 vs. 23.1%). After adjusting for covariables, 3 features independently decreased the likelihood of presence of target mismatch: history of diabetes (OR 0.369, 95% CI 0.196–0.694), small versus large arterial occlusion (OR 0.052, 95% CI 0.01–0.255) and largest size (highest tertile) of diffusion-weighted imaging (DWI) lesion volume (OR 0.516, 95% CI 0.266–0.999). The one feature independently increasing target mismatch likelihood was intermediate size (middle tertile) DWI volume (OR 2.977, 95% CI 1.431–6.195). Conclusions: Target mismatch profiles are present in 55–70% of patients. Target mismatch is less common in patients with diabetes, small vessel occlusion, Asian ethnicity and extensive DWI lesions, and more common in patients with DWI lesions of intermediate size. more...

Most clinical trials have focused on the presence of perfusion- and diffusion-weighted imaging (PWI–DWI) mismatch by more than 20%, and different stroke subtypes were lumped together. We hypothesized that intracranial large artery atherosclerotic stroke (IC-LAA) would show different PWI–DWI and magnetic resonance angiography (MRA)–DWI mismatch profiles, compared with other stroke subtypes. Consecutive patients underwent pretreatment multiparametric magnetic resonance imaging for the acute middle cerebral artery infarcts within 6 h of symptom onset. We assessed the difference in the DWI–PWI mismatch ratio, severity of hypoperfusion, and MRA–DWI mismatch among the stroke subtypes. Of 86 patients, 19 (22.1%) had IC-LAA; 42 (48.8%) cardioembolic stroke, 15 (17.4%) extracranial-LAA, and 10 (11.6%) had cryptogenic embolic stroke. Although the volume of the penumbra was not different among the groups, the mismatch ratio was higher (P=0.003) and the severity of hypoperfusion was lower in the IC-LAA group (P=0.001). The MRA–DWI mismatch was more prevalent in the IC-LAA group than in other groups ( P < 0.001). Collateral grading, assessed in 41 patients, was more likely to be intermediate/excellent in the IC-LAA group ( P < 0.001). Multivariate testing revealed that a larger mismatch ratio and less severe hypoperfusion, and MRA–DWI mismatch were independently associated with IC-LAA. Our data show that patients with IC-LAA had different mismatch profiles, which were related to better collaterals, compared with other subtypes. more...

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. more...

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. more...