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Background: Early neurological deterioration (END) occurs in many patients with acute ischemic stroke due to a variety of causes. Although pharmacologically induced hypertension (PIH) and anticoagulants have been investigated in several clinical trials for the treatment of END, the efficacy and safety of these treatments remain unclear. Here, we investigated whether PIH or anticoagulation is better as a rescue therapy for the progression of END in patients with lacunar stroke., Methods: This study included patients with lacunar stroke who received rescue therapy with END within 3 days of symptom onset between April 2014 and August 2021. In the PIH group, phenylephrine was administered intravenously for 24 h and slowly tapered when symptoms improved or after 5 days of PIH. In the anticoagulation group, argatroban was administered continuously intravenously for 2 days and twice daily for next 5 days. We compared END recovery, defined as improvement in NIHSS from baseline, excellent outcomes (0 or 1 mRS at 3 months), and safety profile., Results: Among the 4818 patients with the lacunar stroke, END occurred in 147 patients. Seventy-nine patients with END received PIH (46.9%) and 68 patients (46.3%) received anticoagulation therapy. There was no significant difference in age (P = 0.82) and sex (P = 0.87) between the two groups. Compared to the anticoagulation group, the PIH group had a higher incidence of END recovery (77.2% vs. 51.5%, P < 0.01) and excellent outcomes (34.2% vs. 16.2%, P = 0.04). PIH was associated with END (HR 2.49; 95% CI 1.06-5.81, P = 0.04). PIH remained associated with END recovery (adjusted HR 3.91; 95% CI 1.19-12.90, P = 0.02). Safety outcomes, like hemorrhagic conversion and mortality, were not significantly different between the two groups., Conclusions: As a rescue therapy for the progression of END in lacunar stroke patients, PIH with phenylephrine was more effective with similar safety compared to anticoagulation with argatroban., (© 2024. The Author(s).)

Background: Lipid-lowering therapies are mainstays in reducing recurrence after acute ischemic stroke (AIS). Evolocumab, a Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, is a promising lipid-lowering agent known to decrease LDL cholesterol and mitigate vascular events alongside statins. However, its effects on the early functional outcomes post-mechanical thrombectomy (MT) remain unclear. This study aimed to assess the short-term effects and incidence of bleeding events after the early, off-label use of PCSK9 inhibitors in AIS patients undergoing MT., Methods: We retrospectively analyzed patients who had MT at a Regional Stroke Center from December 2018 to April 2023. Our primary outcome was discharge functional outcomes. Secondary outcomes included early neurologic deterioration (END), symptomatic intracerebral hemorrhage (sICH), 3-month functional outcomes, 3-month recurrence rate, and lipid profiles., Results: Of 261 patients (mean age 69.2 ± 11.7, men 42.9%), 42 were administered evolocumab peri-procedurally. While baseline characteristics were similar between the two groups, evolocumab group demonstrated improved discharge outcomes, with a lower mean NIHSS (8.8 ± 6.8 vs. 12.4 ± 9.8, p  = 0.02) and a higher percentage of patients with discharge mRS ≤ 3 (52.4% vs. 35.6%, p  = 0.041). The 3-month follow-up show a non-significant trend toward an improved outcome in the evolocumab group. Multivariable analysis indicated that evolocumab had a potential impact on favorable discharge outcomes (aOR 1.98[0.94-4.22] for mRS ≤ 3 and 0.47[0.27-0.84] for lower ordinal mRS). Notably, evolocuamb users exhibited fewer instances of END and sICH, although they do not reach statistical significance. Additionally, the evolocumab group demonstrated potential benefits in LDL cholesterol reduction over time., Conclusion: Early use of evolocumab in AIS patients undergoing MT appeared to be safe and associated with better early functional outcomes. The potential benefit of the PCSK9 inhibitor shown here warrants further prospective studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Hong, Yoon, Bae, Rha and Park.)

Background and Purpose: Sex differences in cerebral microbleeds (CMBs) are not well-known. We aimed to assess the impact of sex on the progression of CMBs., Methods: The CHALLENGE (Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes) database was analyzed. Out of 256 subjects, 189 participants with a follow-up brain scan were included in the analysis. The linear mixed-effect model was used to compare the 2-year changes in the number of CMBs between men and women., Results: A total of 65 men and 124 women were analyzed. There were no significant differences in the prevalence (70.8 vs. 71.8%; P = 1.000) and the median [interquartile range (IQR)] number of total CMBs [1 (0-7) vs. 2 (0-7); P = 0.810] at baseline between men and women. The median (IQR) increase over 2 years in the number of CMBs was statistically higher in women than in men [1 (0-2) vs. 0 (0-1), P = 0.026]. The multivariate linear mixed-effects model showed that women had a significantly greater increase in the number of total, deep, and lobar CMBs compared to men after adjusting for age and the baseline number of CMBs [estimated log-transformed mean of difference between women and men: 0.040 ( P = 0.028) for total CMBs, 0.037 ( P = 0.047) for deep CMBs, and 0.047 ( P = 0.009) for lobar CMBs]., Conclusion: The progression of CMB over 2 years was significantly greater in women than in men., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yoon, Rha, Park, Park, Kwon, Kim, Youn, Jeong, Han and Choi.)

Background: There has been no comparison of the determinants of admission route between acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We examined whether factors associated with direct versus transferred-in admission to regional cardiocerebrovascular centers (RCVCs) differed between AIS and AMI., Methods: Using a nationwide RCVC registry, we identified consecutive patients presenting with AMI and AIS between July 2016 and December 2018. We explored factors associated with direct admission to RCVCs in patients with AIS and AMI and examined whether those associations differed between AIS and AMI, including interaction terms between each factor and disease type in multivariable models. To explore the influence of emergency medical service (EMS) paramedics on hospital selection, stratified analyses according to use of EMS were also performed., Results: Among the 17,897 and 8,927 AIS and AMI patients, 66.6% and 48.2% were directly admitted to RCVCs, respectively. Multivariable analysis showed that previous coronary heart disease, prehospital awareness, higher education level, and EMS use increased the odds of direct admission to RCVCs, but the odds ratio (OR) was different between AIS and AMI (for the first 3 factors, AMI > AIS; for EMS use, AMI < AIS). EMS use was the single most important factor for both AIS and AMI (OR, 4.72 vs. 3.90). Hypertension and hyperlipidemia increased, while living alone decreased the odds of direct admission only in AMI; additionally, age (65-74 years), previous stroke, and presentation during non-working hours increased the odds only in AIS. EMS use weakened the associations between direct admission and most factors in both AIS and AMI., Conclusions: Various patient factors were differentially associated with direct admission to RCVCs between AIS and AMI. Public education for symptom awareness and use of EMS is essential in optimizing the transportation and hospitalization of patients with AMI and AIS., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2022 The Korean Academy of Medical Sciences.)

Background Prehospital delay is an important contributor to poor outcomes in both acute ischemic stroke (AIS) and acute myocardial infarction (AMI). We aimed to compare the prehospital delay and related factors between AIS and AMI. Methods and Results We identified patients with AIS and AMI who were admitted to the 11 Korean Regional Cardiocerebrovascular Centers via the emergency room between July 2016 and December 2018. Delayed arrival was defined as a prehospital delay of >3 hours, and the generalized linear mixed-effects model was applied to explore the effects of potential predictors on delayed arrival. This study included 17 895 and 8322 patients with AIS and AMI, respectively. The median value of prehospital delay was 6.05 hours in AIS and 3.00 hours in AMI. The use of emergency medical services was the key determinant of delayed arrival in both groups. Previous history, 1-person household, weekday presentation, and interhospital transfer had higher odds of delayed arrival in both groups. Age and sex had no or minimal effects on delayed arrival in AIS; however, age and female sex were associated with higher odds of delayed arrival in AMI. More severe symptoms had lower odds of delayed arrival in AIS, whereas no significant effect was observed in AMI. Off-hour presentation had higher and prehospital awareness had lower odds of delayed arrival; however, the magnitude of their effects differed quantitatively between AIS and AMI. Conclusions The effects of some nonmodifiable and modifiable factors on prehospital delay differed between AIS and AMI. A differentiated strategy might be required to reduce prehospital delay.

Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial., Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics., Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26-115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P <0.001), modified Rankin Scale score >0 ( P <0.001), and current tobacco use ( P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS., Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02313909.

Background/aims: Atrial fibrillation (AF)-related stroke accounts for 20% of ischemic strokes. Rivaroxaban use in AF patients for preventing stroke and systemic embolism was approved in 2013 in Korea. This study was to investigate the safety and effectiveness of rivaroxaban use in Korean patients with non-valvular AF in a real-world setting., Methods: This was an analysis of the Korean patients in Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation in Asia-Pacific (XANAP), which was a prospective, observational cohort study including patients with non-valvular AF starting rivaroxaban treatment to prevent stroke or non-central nervous system systemic embolism (non-CNS SE), conducted in 10 Asian countries., Results: A total of 844 patients were enrolled in the Korean portion of the XANAP study. In XANAP Korea, the mean age was 70.1 years and 62.6% were males. The mean CHADS2 score was 2.5 and the mean CHA2DS2-VASc score was 3.8. 47% of the patients had experienced prior stroke or non-CNS SE or transient ischemic attack. 73.6% of the patients had CHADS2 score ≥ 2. Incidence proportions of 0.8% of the patients (1.1 per 100 patient-years) developed adjudicated treatment-emergent major bleeding. Death was observed in 1.2% of the patients. The incidence of non-major bleeding as well as thromboembolic event were 8.4% (11.6 per 100 patient-years) and 1.5% (2.0 per 100 patient-years), respectively., Conclusion: This study reaffirmed the consistent safety profile of rivaroxaban. We found consistent results with overall XANAP population for rivaroxaban in terms of safety in non-valvular AF patients for the prevention of stroke and non-CNS SE.

Background and Purpose: Blood pressure (BP) control is strongly recommended, but BP control rate has not been well studied in patients with stroke. We evaluated the BP control rate with fimasartan-based antihypertensive therapy initiated in patients with recent cerebral ischemia., Methods: This multicenter, prospective, single-arm trial involved 27 centers in South Korea. Key inclusion criteria were recent cerebral ischemia within 90 days and high BP [systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg]. BP lowering was initiated with fimasartan. BP management during the follow-up was at the discretion of the responsible investigators. The primary endpoint was the target BP goal achievement rate (<140/90 mm Hg) at 24 weeks. Key secondary endpoints included achieved BP and BP changes at each visit, and clinical events (ClinicalTrials.gov Identifier: NCT03231293)., Results: Of 1,035 patients enrolled, 1,026 were included in the safety analysis, and 951 in the efficacy analysis. Their mean age was 64.1 years, 33% were female, the median time interval from onset to enrollment was 10 days, and the baseline SBP and DBP were 162.3±16.0 and 92.2±12.4 mm Hg (mean±SD). During the study period, 55.5% of patients were maintained on fimasartan monotherapy, and 44.5% received antihypertensive therapies other than fimasartan monotherapy at at least one visit. The target BP goal achievement rate at 24-week was 67.3% (48.6% at 4-week and 61.4% at 12-week). The mean BP was 139.0/81.8±18.3/11.7, 133.8/79.2±16.4/11.0, and 132.8/78.5±15.6/10.9 mm Hg at 4-, 12-, and 24-week. The treatment-emergent adverse event rate was 5.4%, including one serious adverse event., Conclusions: Fimasartan-based BP lowering achieved the target BP in two-thirds of patients at 24 weeks, and was generally well tolerated., Competing Interests: All the investigators received research grant based on the study contracts for the number of subjects enrolled and/or for the conduct of the study from Boryung Pharmaceutical Co., Ltd., Seoul, Korea., (Copyright © 2021 Korean Neurological Association.)

Blood pressure variability (BPV) is associated with higher cardiovascular morbidity risks; however, its association with cognitive decline remains unclear. We investigated whether higher BPV is associated with faster declines in cognitive function in ischemic stroke (IS) patients. Cognitive function was evaluated between April 2010 and August 2015 using the Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment in 1,240 Korean PICASSO participants. Patients for whom baseline and follow-up cognitive test results and at least five valid BP readings were available were included. A restricted maximum likelihood-based Mixed Model for Repeated Measures was used to compare changes in cognitive function over time. Among a total of 746 participants (64.6 ± 10.8 years; 35.9% female). Baseline mean-MMSE score was 24.9 ± 4.7. The median number of BP readings was 11. During a mean follow-up of 2.6 years, mean baseline and last follow-up MMSE scores were 25.4 ± 4.8 vs. 27.8 ± 4.4 (the lowest BPV group) and 23.9 ± 5.2 vs. 23.2 ± 5.9 (the highest BPV group). After adjusting for multiple variables, higher BPV was independently associated with faster cognitive decline over time. However, no significant intergroup difference in cognitive changes associated with mean systolic BP was observed. Further research is needed to elucidate how BPV might affect cognitive function.

No study yet has compared the longitudinal course and prognosis between subcortical vascular cognitive impairment patients with and without genetic component. In this study, we compared the longitudinal changes in cerebral small vessel disease markers and cognitive function between subcortical vascular mild cognitive impairment (svMCI) patients with and without NOTCH3 variant [ NOTCH3 (+) svMCI vs. NOTCH3 (-) svMCI]. We prospectively recruited patients with svMCI and screened for NOTCH3 variants by sequence analysis for mutational hotspots in the NOTCH3 gene. Patients were annually followed-up for 5 years through clinical interviews, neuropsychological tests, and brain magnetic resonance imaging. Among 63 svMCI patients, 9 (14.3%) had either known mutations or possible pathogenic variants. The linear mixed effect models showed that the NOTCH3 (+) svMCI group had much greater increases in the lacune and cerebral microbleed counts than the NOTCH3 (-) svMCI group. However, there were no significant differences between the two groups regarding dementia conversion rate and neuropsychological score changes over 5 years., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yoon, Kim, Kim, Ki, Lee, Rha, Na and Seo.)

Competing Interests: The authors have no potential conflicts of interest to disclose.

Background and Purpose- Although cilostazol has shown less hemorrhagic events than aspirin, only marginal difference was observed in hemorrhagic stroke events among patients at high risk for cerebral hemorrhage. To identify patients who would most benefit from cilostazol, this study analyzed interactions between treatment and subgroups of the PICASSO trial (Prevention of Cardiovascular Events in Asian Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage). Methods- Ischemic stroke patients with a previous intracerebral hemorrhage or multiple microbleeds were randomized to treatment with cilostazol or aspirin and followed up for a mean 1.8 years. Efficacy, defined as the composite of any stroke, myocardial infarction, and vascular death, and safety, defined as the incidence of hemorrhagic stroke, were analyzed in the 2 groups. Interactions between treatment and age, sex, presence of hypertension and diabetes mellitus, index of high-risk cerebral hemorrhage, and white matter lesion burden were analyzed for primary and key secondary outcomes. Changes in vital signs and laboratory results were compared in the 2 groups. Results- Among all 1534 patients enrolled, a significant interaction between treatment group and index of high risk for cerebral hemorrhage on hemorrhagic stroke ( P for interaction, 0.03) was observed. Hemorrhagic stroke was less frequent in the cilostazol than in the aspirin group in patients with multiple microbleeds (1 versus 13 events; hazard ratio, 0.08 [95% CI, 0.01-0.61]; P =0.01). A marginal interaction between treatment group and white matter change on any stroke ( P for interaction, 0.08) was observed. Cilostazol reduced any stroke significantly in patients with mild (5 versus 16 events; hazard ratio, 0.36 [95% CI, 0.13-0.97]; P =0.04)-to-moderate (16 versus 32 events; hazard ratio, 0.50 [95% CI, 0.29-0.92]; P =0.03) white matter changes. Heart rate and HDL (high-density lipoprotein) cholesterol level were significantly higher in the cilostazol group than in the aspirin group at follow-up. Conclusions- Cilostazol may be more beneficial for ischemic stroke patients with multiple cerebral microbleeds and before white matter changes are extensive. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01013532.

Background and Purpose: Whether pharmacologically altered high-density lipoprotein cholesterol (HDL-C) affects the risk of cardiovascular events is unknown. Recently, we have reported the Prevention of Cardiovascular Events in Asian Patients with Ischaemic Stroke at High Risk of Cerebral Haemorrhage (PICASSO) trial that demonstrated the non-inferiority of cilostazol to aspirin and superiority of probucol to non-probucol for cardiovascular prevention in ischemic stroke patients (clinicaltrials.gov: NCT01013532). We aimed to determine whether on-treatment HDL-C changes by cilostazol and probucol influence the treatment effect of each study medication during the PICASSO study., Methods: Of the 1,534 randomized patients, 1,373 (89.5%) with baseline cholesterol parameters were analyzed. Efficacy endpoint was the composite of stroke, myocardial infarction, and cardiovascular death. Cox proportional hazards regression analysis examined an interaction between the treatment effect and changes in HDL-C levels from randomization to 1 month for each study arm., Results: One-month post-randomization mean HDL-C level was significantly higher in the cilostazol group than in the aspirin group (1.08 mmol/L vs. 1.00 mmol/L, P<0.001). The mean HDL-C level was significantly lower in the probucol group than in the non-probucol group (0.86 mmol/L vs. 1.22 mmol/L, P<0.001). These trends persisted throughout the study. In both study arms, no significant interaction was observed between HDL-C changes and the assigned treatment regarding the risk of the efficacy endpoint., Conclusions: Despite significant HDL-C changes, the effects of cilostazol and probucol treatment on the risk of cardiovascular events were insignificant. Pharmacologically altered HDL-C levels may not be reliable prognostic markers for cardiovascular risk.

Endovascular recanalization therapy (ERT) has been a standard of care for patients with acute ischemic stroke due to large artery occlusion (LAO) within 6 hours after onset, since five landmark ERT trials conducted by 2015 demonstrated its clinical benefit. Recently, two randomized clinical trials demonstrated that ERT, even in the late time window of up to 16 hours or 24 hours after last known normal time, improved the outcome of patients who had a target mismatch, defined as either clinical-core mismatch or perfusion-core mismatch, which prompted the update of national guidelines in several countries. Accordingly, to provide evidence-based and up-to-date recommendations for ERT in patients with acute LAO in Korea, the Clinical Practice Guidelines Committee of the Korean Stroke Society decided to revise the previous Korean Clinical Practice Guidelines of Stroke for ERT. For this update, the members of the writing group were appointed by the Korean Stroke Society and the Korean Society of Interventional Neuroradiology. After thoroughly reviewing the updated evidence from two recent trials and relevant literature, the writing members revised recommendations, for which formal consensus was achieved by convening an expert panel composed of 45 experts from the participating academic societies. The current guidelines are intended to help healthcare providers, patients, and their caregivers make well-informed decisions and to improve the quality of care regarding ERT. The ultimate decision for ERT in a particular patient must be made in light of circumstances specific to that patient.

Recent clinical trials demonstrated the clinical benefit of endovascular treatment (EVT) in patients with acute ischemic stroke due to large vessel occlusion. These trials confirmed that good outcome after EVT depends on the time interval from symptom onset to reperfusion and that in-hospital delay leads to poor clinical outcome. However, there has been no universally accepted in-hospital workflow and performance benchmark for rapid reperfusion. Additionally, wide variety in workflow for EVT is present between each stroke centers. In this consensus statement, Korean Society of Interventional Neuroradiology and Korean Stroke Society Joint Task Force Team propose a standard workflow to reduce door-to-reperfusion time for stroke patients eligible for EVT. This includes early stroke identification and pre-hospital notification to stroke team of receiving hospital in pre-hospital phase, the transfer of stroke patients from door of the emergency department to computed tomography (CT) room, warming call to neurointervention (NI) team for EVT candidate prior to imaging, NI team preparation in parallel with thrombolysis, direct transportation from CT room to angiography suite following immediate decision of EVT and standardized procedure for rapid reperfusion. Implementation of optimized workflow will improve stroke time process metrics and clinical outcome of the patient treated with EVT.

Background and Purpose: Following the positive results from recent trials on endovascular therapy (EVT), bridging therapy (intravenous alteplase plus EVT) is increasingly being used for the treatment of acute ischemic stroke. However, the optimal dose of intravenous alteplase remains unknown in centers where bridging therapy is actively performed. The optimal dose for eventual recanalization and positive clinical outcomes in patients receiving bridging therapy also remains unknown., Methods: In this prospective Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) sub-study, we explored the outcomes following treatment with two different doses (low- [0.6 mg/kg] or standard-dose [0.9 mg/kg]) of intravenous alteplase across 12 Korean centers where EVT is actively performed. The primary endpoint was a favorable outcome at 90 days (modified Rankin Scale scores 0 to 1). Secondary endpoints included symptomatic intracerebral hemorrhage (ICH) in all patients, and the recanalization rate and favorable outcome in patients who underwent cerebral angiography for EVT (ClinicalTrials.gov, number NCT01422616)., Results: Of 351 patients, the primary outcome occurred in 46% of patients in both the standard-(80/173) and low-dose (81/178) groups (odds ratio [OR], 1.14; 95% confidence interval [CI], 0.72 to 1.81; P =0.582), although ICHs tended to occur more frequently in the standard-dose group (8% vs. 3%, P =0.056). Of the 67 patients who underwent cerebral angiography, there was no significant difference in favorable functional outcome between the standard- and low-dose groups (39% vs. 21%; OR, 2.39; 95% CI, 0.73 to 7.78; P =0.149)., Conclusions: There was no difference in functional outcome between the patients receiving different doses of alteplase in centers actively performing bridging therapy.

Background and Purpose: The quality of anticoagulation is critical for ensuring the benefit of warfarin, but this has been less well studied in Korean ischemic stroke patients with atrial fibrillation (AF)., Methods: This study retrospectively analyzed the data of patients who had an AF-related ischemic stroke and were treated with long-term warfarin therapy in 16 Korean centers. The quality of warfarin therapy was primarily assessed by the time in therapeutic range [TTR; international normalized ratio (INR), 2.0-3.0] and additionally by the proportion of INR values within the therapeutic range., Results: The long-term warfarin-treated cohort comprised 1,230 patients. They were aged 70.1±9.7 years (mean±SD), 42.5% were female, and their CHA₂DS₂-VASc score was 4.75±1.41. The TTR analysis included 33,941 INR measurements for 27,487 months: per patients, 27.6 (SD, 22.4) INR measurements for 22.4 (SD, 12.9) months. The mean TTR of individual patients was 49.1% (95% confidence interval, 47.9-50.3%), and the TTR quartiles were <34.5, 34.5-49.1, 49.1-64.5%, and >64.5%. None of the 16 centers achieved a mean TTR of >60%. Of all INR measurements, 44.6% were within the therapeutic range, 41.7% were <2.0, and 13.7% were >3.0., Conclusions: In Korean ischemic stroke patients who had AF, the quality of warfarin therapy was low and might be inadequate to effectively prevent recurrent stroke or systemic embolism., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2017 Korean Neurological Association)

Objective: We performed this study to assess the effect of an antiplatelet agent on the progression of white matter hyperintensities (WMH)., Methods: From August 2003 to May 2005, we consecutively enrolled patients who underwent brain magnetic resonance imaging (MRI) for health check-up purposes and showed no significant findings other than WMH of any degree. Patients were divided into two groups based on whether or not they received antiplatelet therapy. All patients had a follow-up brain MRI after 5 years and WMH volume change was measured using imaging analysis software. To minimize selection bias potentially arising from antiplatelet treatment assignment, analyses were inverse probability weighted., Results: Among the 93 patients who met the inclusion criteria, 54 patients (58.1%) were grouped as the antiplatelet group (AG), and the remaining 39 patients (41.9%) as the non-antiplatelet group (NAG). After inverse propensity weighting, all baseline characteristics were similar between the two groups, and antiplatelet treatment did not show any significant effect on the total WMH volume change (p = 0.957)., Conclusion: Antiplatelet medication may not alter the progression of WMH.

Background and Purpose: In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence., Methods: In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding., Results: Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77-1.35; P=0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P=0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group., Conclusions: Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00814268., (© 2016 American Heart Association, Inc.)

Patients with severe stroke due to acute large cerebral artery occlusion are likely to be severely disabled or dead without timely reperfusion. Previously, intravenous tissue plasminogen activator (IV-TPA) within 4.5 hours after stroke onset was the only proven therapy, but IV-TPA alone does not sufficiently improve the outcome of patients with acute large artery occlusion. With the introduction of the advanced endovascular therapy, which enables more fast and more successful recanalization, recent randomized trials consecutively and consistently demonstrated the benefit of endovascular recanalization therapy (ERT) when added to IV-TPA. Accordingly, to update the recommendations, we assembled members of the writing committee appointed by the Korean Stroke Society, the Korean Society of Interventional Neuroradiology, and the Society of Korean Endovascular Neurosurgeons. Reviewing the evidences that have been accumulated, the writing members revised recommendations, for which formal consensus was achieved by convening a panel composed of 34 experts from the participating academic societies. The current guideline provides the evidence-based recommendations for ERT in patients with acute large cerebral artery occlusion regarding patient selection, treatment modalities, neuroimaging evaluation, and system organization.

Purpose: Snakebite is an emergency which causes local symptoms such as pain and edema around the bite. Systemic symptoms may also develop, such as dizziness or renal failure, and may even cause death. The purpose of this research was to assess the validity and safety of snakebite protocol for surgery when treating snakebite patients., Materials and Methods: Retrospective research was performed on patients who were admitted after being treated at the emergency center from January 2008 to December 2012. When necessary, debridement was also performed, and 46 of 111 patients (41.4%) underwent debridement. Those who had received debridement without antivenom administration due to a positive skin reaction test were classified as group A, and group B received antivenom and delayed debridement. We reviewed the emergency and admission charts of the patients in each group and recorded and compared their age, sex, bite site, severity of local and general symptoms, time to receive antivenin, and complications., Results: Of the ten patients (21.7%) in group A, two (66.6%) developed cellulites, and one of them experienced skin necrosis, resulting in a skin graft. In group B, there were 36 patients (78.2%), 19 (52.7%) of whom developed cellulitis. Skin necrosis occurred in two patients, and one of these patients received a skin graft. Compartment syndrome was found in one patient, and fasciotomy and a skin graft were performed., Conclusion: The treatment protocol implemented to treat snakebite patients admitted to the emergency center during this research was safely and properly followed during surgical treatment.

Background and Purpose: Recent randomized clinical trials (RCTs) have demonstrated benefits of endovascular recanalization therapy (ERT) contrary to earlier trials. We aimed to estimate the benefits of ERT added to standard therapy in acute ischemic stroke., Methods: From a literature search of RCTs testing ERT, we performed a meta-analysis to estimate an overall efficacy and safety of ERT for all trials, stent-retriever trials, and RCTs comparing ERT and intravenous tissue plasminogen activator (IV-TPA)., Results: We identified 15 relevant RCTs including 2,899 patients. For all trials, ERT was associated with increased good outcomes (odds ratio [OR] 1.79; 95% confidence interval [CI] 1.34, 2.40; P<0.001) compared to the control. ERT also increased no or minimal disability outcomes, good neurological recovery, good activity of daily living, and recanalization. ERT did not significantly increase symptomatic intracranial hemorrhage (SICH) (OR 1.19; 95% CI 0.83, 1.69; P=0.345) or death (OR 0.87; 95% CI 0.71, 1.05; P=0.151). In contrast, ERT significantly reduced extreme disability or death (OR 0.77; 95% CI 0.61, 0.97; P=0.025). Restricting to five stent-retriever trials comparing ERT plus IV-TPA vs. IV-TPA alone, the benefit was even greater for good outcome (OR 2.39; 95% CI 1.88, 3.04; P<0.001) and extreme disability or death (OR 0.57; 95% CI 0.41, 0.78; P=0.001). Restricting to eight RCTs comparing ERT (plus IV-TPA in six trials) with IV-TPA alone showed similar efficacy and safety., Conclusions: This updated meta-analysis shows that ERT substantially improves clinical outcomes and reduces extreme disability or death without significantly increasing SICH compared to standard therapy.

Cardioembolic stroke related to nonvalvular atrial fibrillation is associated with a high recurrence rate and high mortality and morbidity. In this population, therefore, optimal anticoagulant therapy is required to prevent the occurrence of second stroke. Oral anticoagulant, warfarin has been traditionally used, but it is greatly limited by its narrow efficacy window, complex pharmacokinetics, and multiple drug interactions, thus requiring frequent blood monitoring. Recently, oral anticoagulants targeted for a specific coagulation component have been newly developed and tested in large clinical trials. Dabigatran, direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban, inhibitors of factor Xa harbor great merits of rapid action time, short half-life, stable plasma concentration, and little drug interaction. Recently, large randomized clinical trials and meta-analyses have been published to show the efficacy and safety of the new oral anticoagulants compared with warfarin. Based on the results from recent clinical trials, we revised recommendations to apply optimal anticoagulant therapy in patients with nonvalvular atrial fibrillation and ischemic stroke or transient ischemic attack.

The purpose of this clinical practice guideline (CPG) is to provide current and comprehensive recommendations for the medical and surgical management of primary intracerebral hemorrhage (ICH). Since the release of the first Korean CPGs for stroke, evidence has been accumulated in the management of ICH, such as intracranial pressure control and minimally invasive surgery, and it needs to be reflected in the updated version. The Quality Control Committee at the Korean Society of cerebrovascular Surgeons and the Writing Group at the Clinical Research Center for Stroke (CRCS) systematically reviewed relevant literature and major published guidelines between June 2007 and June 2013. Based on the published evidence, recommendations were synthesized, and the level of evidence and the grade of the recommendation were determined using the methods adapted from CRCS. A draft guideline was scrutinized by expert peer reviewers and also discussed at an expert consensus meeting until final agreement was achieved. CPGs based on scientific evidence are presented for the medical and surgical management of patients presenting with primary ICH. This CPG describes the current pertinent recommendations and suggests Korean recommendations for the medical and surgical management of a patient with primary ICH.

Flail arm syndrome (FAS), an atypical presentation of amyotrophic lateral sclerosis (ALS), is characterized by progressive, predominantly proximal, weakness of upper limbs, without involvement of the lower limb, bulbar, or respiratory muscles. When encountering a patient who presents with this symptomatic profile, possible diagnoses include upper limb onset ALS (UL-ALS), and FAS. The lack of information regarding FAS may make differential diagnosis between FAS and UL-ALS difficult in clinical settings. The aim of this study was to compare clinical and electromyographic findings from patients diagnosed with FAS with those from patients diagnosed with UL-ALS. To accomplish this, 18 patients with FAS and 56 patients with UL-ALS were examined. Significant differences were observed between the 2 groups pertaining to the rate of fasciculation, patterns of predominantly affected muscles, and the Medical Research Council scale of the weakest muscle. The presence of upper motor neuron signs and lower motor neuron involvement evidenced through electromyography showed no significant between-group differences.

Background and Purpose: Intracranial atherosclerotic stenosis (ICAS) is considered as a major cause of stroke. The carotid intima-media thickness (CIMT), which accurately reflects the burden of generalized atherosclerosis, is also associated with stroke. The aim of this study was to determine the association between the CIMT and ICAS responses to medical treatment., Methods: This study constituted part of the "Trial of cilostazol in symptomatic intracranial arterial stenosis"-2 that evaluated the ICAS response after randomized antiplatelet treatment. Magnetic resonance angiography and CIMT measurement were performed at baseline and after 7 months of treatment. CIMT was measured using semiautomated software, and was presented as maximum (CIMT-max) and average (CIMT-ave) values. The change in CIMT was compared relative to the ICAS response (i.e., progression, no-change, and regression). Ordinal logistic regression and analysis of covariance (ANCOVA) were used to analyze the association between the responses., Results: Among the 101 enrolled patients, 85 underwent follow-up CIMT measurement. CIMT increased most in the ICAS progression group (CIMT-max: 0.09±0.23, CIMT-ave: 0.04±0.12), and to a lesser degree in the no-change group (CIMT-max: 0.02±0.16, CIMT-ave: 0.02±0.11), but decreased in patients with ICAS regression (CIMT-max: -0.04±0.11, CIMT-ave: -0.03±0.07; CIMT-max: p=0.010, CIMT-ave: p=0.015). Ordinal logistic regression analysis demonstrated that the change in CIMT-max was independently associated with the ICAS response (p=0.032). However, the ANCOVA revealed that the reverse was not true, in that the ICAS response was not independently associated with the change in CIMT after adjusting for confounding factors., Conclusions: The ICAS response may be associated with the CIMT response to medical treatment.

Background and Purpose: Predictors of progression of intracranial atherosclerotic stenosis have not been clearly identified. We investigated whether poststroke changes in lipid profiles would affect the prognosis of symptomatic intracranial atherosclerotic stenosis., Methods: This is a substudy of Trial of cilOstazol in Symptomatic intracranial Stenosis 2 (TOSS-2). From 10 centers we enrolled 230 subjects with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or basilar artery. At baseline and 7 months after stroke, subjects underwent MR angiogram and assessment of cardiovascular risk factors including lipoprotein levels. Progression of intracranial atherosclerotic stenosis was determined by comparing stenosis on the baseline and follow-up MR angiograms., Results: Cilostazol treatment was more frequently seen in the nonprogression group (109 of 198 [55.1%]) than in the progression group (11 of 32 [34.4%]). At 7 months after stroke when compared with baseline, low-density lipoprotein cholesterol and total cholesterol levels decreased in both groups. However, only nonprogressors showed increase in high-density lipoprotein cholesterol levels between baseline and follow-up. Changes in apolipoprotein B/apolipoprotein A-I levels were not different between the groups, although apolipoprotein B/A-I at 7 months was higher in progressors than in nonprogressors. Remnant lipoprotein cholesterol levels decreased in nonprogressors, whereas they did not change in progressors. In multivariable analyses, after adjusting for cilostazol treatment and remnant lipoprotein cholesterol reduction or apolipoprotein B/A-I at 7 months, high-density lipoprotein cholesterol elevation remained as a significant predictor for the nonprogression., Conclusions: This is the first prospective multicenter study to demonstrate that high-density lipoprotein cholesterol elevation, along with remnant lipoprotein cholesterol reduction and low apolipoprotein B/A-I, is associated with prevention of angiographic progression of symptomatic intracranial atherosclerotic stenosis., Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00130039.

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

Background: Delayed arrival at hospital is one of the major obstacles in enhancing the rate of thrombolysis therapy in patients with acute ischemic stroke. Our study aimed to investigate factors associated with prehospital delay after acute ischemic stroke in Korea., Methods: A prospective, multicenter study was conducted at 14 tertiary hospitals in Korea from March 2009 to July 2009. We interviewed 500 consecutive patients with acute ischemic stroke who arrived within 48 hours. Univariate and multivariate analyses were performed to evaluate factors influencing prehospital delay., Results: Among the 500 patients (median 67 years, 62% men), the median time interval from symptom onset to arrival was 474 minutes (interquartile range, 170-1313). Early arrival within 3 hours of symptom onset was significantly associated with the following factors: high National Institutes of Health Stroke Scale (NIHSS) score, previous stroke, atrial fibrillation, use of ambulance, knowledge about thrombolysis and awareness of the patient/bystander that the initial symptom was a stroke. Multivariable logistic regression analysis indicated that awareness of the patient/bystander that the initial symptom was a stroke (OR 4.438, 95% CI 2.669-7.381), knowledge about thrombolysis (OR 2.002, 95% CI 1.104-3.633) and use of ambulance (OR 1.961, 95% CI 1.176-3.270) were significantly associated with early arrival., Conclusions: In Korea, stroke awareness not only on the part of patients, but also of bystanders, had a great impact on early arrival at hospital. To increase the rate of thrombolysis therapy and the incidence of favorable outcomes, extensive general public education including how to recognize stroke symptoms would be important.

Objective: We analyzed the diffusion and perfusion characteristics of acute MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode) lesions in a large series to investigate the controversial changes of the apparent diffusion coefficient (ADC) that were reported in prior studies., Materials and Methods: We analyzed 44 newly appearing lesions during 28 stroke-like episodes in 13 patients with MELAS. We performed a visual assessment of the MR images including the ADC and perfusion maps, comparison of the ADC between the normal and abnormal areas, comparison of % ADC between the 44 MELAS lesions and the 30 acute ischemic infarcts. In addition, the patterns of evolution on follow-up MR images were analyzed., Results: Decreased, increased, and normal ADCs were noted in 16 (36%), 16 (36%), and 12 (27%) lesions, respectively. The mean % ADC was 102 ± 40.9% in the MELAS and 64 ± 17.8% in the acute vascular infarcts (p < 0.001), while perfusion imaging demonstrated hyper-perfusion in six acute MELAS lesions. On follow-up images, resolution, progression, and tissue loss were noted in 10, 4, and 17 lesions, respectively., Conclusion: The cytotoxic edema gradually evolves following an acute stroke-like episode in patients with MELAS, and this may overlap with hyper-perfusion and vasogenic edema. The edematous swelling may be reversible or it may evolve to encephalomalacia, suggesting irreversible damage.

Background: Some studies suggest low temperatures can affect mortality, especially deaths associated with circulatory and respiratory conditions., Methods: We investigated the association between ischemic stroke onset and decrease in temperature in 545 patients over a 3-year period (January 1998 to December 2000) in Incheon, Korea. We used a case-crossover study design to assess changes in the risk of ischemic stroke during a brief hazard period after exposure to decrease in temperature. For each subject, the case period was matched to 2 control periods exactly 1 week before and after onset of the ischemic stroke., Results: Decreased ambient temperature was associated with risk of acute ischemic stroke. The strongest effect was seen on day after exposure to cold weather. The odds ratio (OR) for an interquartile range decrease in temperature was 2.9 (95% confidence interval [CI] = 1.5-5.3). The risk period was 24-48 hours after cold exposure. Risk estimates associated with decreased temperature were greater in the winter than in the summer. Women, persons greater than 65 years of age, nonobese persons, and those with previous hypertension or hypercholesterolemia were more susceptible to cold-induced ischemic stroke., Conclusions: These results suggest that stroke occurrence rises with decreasing temperature, and that even a moderate decrease in temperature can increase the risk of ischemic stroke. Susceptible people should take steps to protect themselves from cold, especially in the winter.

Ovarian hyperstimulation syndrome is a serious complication of ovulation induction and has a diverse clinical spectrum from edema to thromboembolism. Antiphospholipid antibody syndrome, one of the well known hypercoagulable states, can be also manifested as an arterial or venous thrombosis and recurrent spontaneous abortion. Sometimes a patient with antiphospholipid antibodies might not notice a miscarriage and seek for assisted reproduction treatment, which harbors a chance of developing ovarian hyperstimulation syndrome. If this happens, the ovarian hyperstimulation syndrome can exacerbate the thrombotic complication of underlying antiphospholipid antibody syndrome, resulting in a catastrophic vascular event. The authors experienced a case of middle cerebral artery infarct, which developed during ovarian hyperstimulation syndrome in a 33-yr-old woman with a previous history of fetal loss. An elevated titer of anticardiolipin antibodies was noticed and persisted thereafter. The authors suggest screening tests for the presence of antiphospholipid antibodies before controlled ovarian hyperstimulation.

We investigated the single- and multiple dose pharmacokinetics of a new controlled-release formulation (Orfil retard enteric coated tablet) of valproic acid in comparison with those of the plain tablet as a reference. Twelve healthy volunteers were given each formulation of 300 mg in the single-dose study. In the steady-state multiple-dose study, twelve epileptic patients received 1200 mg/day of the reference drug (300 mg 9 AM, 300 mg 3 PM, 600 mg 9 PM) and the test formulation (600 mg 9 AM, 600 mg 9 PM) with at least one week interval in cross-over manner. The AUC values of the test controlled release formulation were 91.7% (95% confidence interval: 78.4-100.4%) of the reference drug in the single-dose study and 98.2% (95% confidence interval: 86.2%-109.9%) in the steady-state study. The AUC's of the two formulations were not significantly different by ANOVA test. The Cmax and Tmax values of the test formulation were significantly different from the values of the reference in single-(Tmax: 158.4%, Cmax: 52.5% of the reference) and multiple-dose study (Tmax: 153.5% of the reference). The MRT values of the test formulation were also significantly greater (129.4% of the reference) in the single-dose study. Regarding the controlled-release characteristics of the test formulation, fluctuation index and percentage fluctuation of the twice a day dosage regimen of the test formulation were comparable with those of the thrice a day dosage regimen of the conventional tablet. Area deviation was even smaller in the test regimen of the controlled release formulation.(ABSTRACT TRUNCATED AT 250 WORDS)