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BackgroundThe addition of antiplatelet therapy to anticoagulant therapy in patients with stroke with non-valvular atrial fibrillation (NVAF) and atherothrombotic disease may increase bleeding risk without reducing recurrent stroke risk.AimsTo evaluate the clinical benefits of anticoagulant monotherapy compared to combination therapy with anticoagulants and antiplatelet agents.Methods and designThis is an investigator-initiated prospective multicenter, randomized, open-label, parallel-group clinical trial. Patients with NVAF and atherothrombotic disease who have had a recent ischemic stroke or transient ischemic attack will be eligible to participate in this trial.Study outcomesThe primary outcome is a composite of ischemic cardiovascular events, including cardiovascular death, ischemic stroke, myocardial infarction, systemic embolism, ischemic events requiring urgent revascularization, and major bleeding events within 2 years after randomization.Sample size estimatesThis study will enroll 400 patients, 200 receiving anticoagulant monotherapy and 200 receiving combination therapy. This sample size will provide 90% power (one-sided p = 0.025) to detect a risk reduction in outcome events within 2 years, assuming event rates of 13 and 27% for each group, respectively, and a 10% loss to follow-up at a 2.5% significance level with one-sided log-rank tests at an interim analysis and a final analysis.DiscussionThis will be the first study to assess the net clinical benefit of oral anticoagulant monotherapy in ischemic stroke patients with NVAF and atherothrombosis.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT03062319, NCT03062319; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000029222, UMIN000025392; https://jrct.niph.go.jp/latest-detail/jRCTs051180202, jRCTs051180202.

Background Atrial fibrillation (AF) is known to be a strong risk factor for stroke. However, the risk of stroke recurrence in patients with cryptogenic stroke with AF detected after stroke by an insertable cardiac monitor (ICM) is not well known. We sought to evaluate the risk of ischemic stroke recurrence in patients with cryptogenic stroke with and without ICM‐detected AF. Methods and Results We retrospectively reviewed patients with cryptogenic stroke who underwent ICM implantation at 8 stroke centers in Japan. Cox regression models were developed using landmark analysis and time‐dependent analysis. We set the target sample size at 300 patients based on our estimate of the annualized incidence of ischemic stroke recurrence to be 3% in patients without AF detection and 9% in patients with AF detection. Of the 370 patients, 121 were found to have AF, and 110 received anticoagulation therapy after AF detection. The incidence of ischemic stroke recurrence was 4.0% in 249 patients without AF detection and 5.8% in 121 patients with AF detection (P=0.45). In a landmark analysis, the risk of ischemic stroke recurrence was not higher in patients with AF detected ≤90 days than in those without (hazard ratio, 1.47 [95% CI, 0.41–5.28]). In a time‐dependent analysis, the risk of ischemic stroke recurrence did not increase after AF detection (hazard ratio, 1.77 [95% CI, 0.70–4.47]). Conclusions The risk of ischemic stroke recurrence in patients with cryptogenic stroke with ICM‐detected AF, 90% of whom were subsequently anticoagulated, was not higher than in those without ICM‐detected AF.

BackgroundAnemia can occur due to an aspiration maneuver of blood with thrombi during mechanical thrombectomy (MT) for stroke. However, the association between postoperative anemia and stroke outcomes is unknown.MethodsIn a registry-based hospital cohort, consecutive patients with acute ischemic stroke who underwent MT were retrospectively recruited. Patients were divided into the following three groups according to their hemoglobin (Hb) concentrations within 24 h after MT; no anemia (Hb concentrations ≥13 g/dL for men and ≥ 12 g/dL for women), mild anemia (Hb concentrations of 11–13 g/dL and 10–12 g/dL, respectively), and moderate-to-severe anemia (Hb concentrations

Introduction We aimed to evaluate the efficacy and safety of mechanical thrombectomy (MT) for medium vessel occlusion (MeVO) with the disabling deficit. Methods The study period was from January 2011 to December 2022. Inclusion criteria were 1) within 24 hours of stroke onset, 2) prestroke mRS score ≤1, 3) NIHSS score ≥4 or disabling deficit (complete hemianopia (≥2 on NIHSS), severe aphasia (≥2 on NIHSS), visual sensory extinction (≥1 on NIHSS), significant weakness with NIHSS subscore of paralysis ≥2), 4) MeVO (MCA distal M2, M3, ACA A1, A2, A3, PCA P1, P2, and P3). Outcomes were compared between the MT and standard medical treatment (SMT) groups. Outcome was defined as the favorable outcome (mRS score 0‐2 at 90 days), death within 90 days, and symptomatic intracranial hemorrhage (SICH). Results Of all, 192 patients (72 women, median age 78 years, median NIHSS score 11 points) were enrolled, and 76.6% (n=147) had distal M2 occlusion. Compared to the SMT group (n=153), the MT group (n=39) had a significantly larger median Tmax>10 sec volume (median 25 mL vs. 5 mL, P 6‐sec volume (61 mL vs. 44 mL, P

Background It is unclear whether all patient subgroups with acute ischemic stroke have benefited from advances in reperfusion therapy. We investigated long‐term trends of reperfusion therapy and outcomes according to the stroke severity. Methods Patients with acute ischemic stroke registered in the prospective nationwide hospital‐based registry between 2000 and 2020 were examined. Baseline National Institutes of Health Stroke Scale (NIHSS) score ≥10 and ≤5 was considered to indicate possible large vessel occlusions and minor deficits, respectively. Secular changes were assessed per 5‐year cohorts (2000–2005, 2006–2010, 2011–2015, 2016–2020). Outcomes included favorable outcome (modified Rankin scale score 0–2 at discharge). Results Of 127 741 patients, NIHSS score was ≥10 in 31 747 patients (24.9%), 6–9 in 17 083 patients (13.4%), and ≤5 in 78 911 patients (61.8%). In patients with NIHSS score ≥10, intravenous thrombolysis frequency increased from 1.6% to 26.5% between the 2000 to 2005 and 2016 to 2020 cohorts; endovascular therapy frequency increased from 2.0% to 29.8%. Favorable outcomes increased over time (adjusted odds ratio per 1‐cohort, 1.254 [95% CI, 1.204–1.306]). In patients with NIHSS score 6–9, intravenous thrombolysis frequency increased from 0.5% to 16.4%, and endovascular therapy frequency increased from 1.1% to 9.0%. Favorable outcomes did not change over time (1.005 [0.966–1.046]). In patients with NIHSS score ≤5, intravenous thrombolysis frequency increased from 0.2% to 5.1%, and endovascular therapy frequency increased from 0.7% to 2.8%. Favorable outcomes decreased over time (0.954 [0.931–0.978]). Conclusions Use of reperfusion therapy has increased, particularly in patients with NIHSS score ≥10. Favorable outcomes significantly increased over time in patients with NIHSS score ≥10 but decreased in those with NIHSS score ≤5.

Background We aimed to clarify which time‐to‐maximum of the tissue residue function (Tmax) mismatch ratio is useful in predicting anterior intracranial atherosclerotic stenosis (ICAS)–related large‐vessel occlusion (LVO) before endovascular therapy. Methods and Results Patients with ischemic stroke who underwent perfusion‐weighted imaging before endovascular therapy for anterior intracranial LVO were divided into those with ICAS‐related LVO and those with embolic LVO. Tmax ratios of >10 s/>8 s, >10 s/>6 s, >10 s/>4 s, >8 s/>6 s, >8 s/>4 s, and >6 s/>4 s were considered Tmax mismatch ratios. Binominal logistic regression was used to identify ICAS‐related LVO, and the adjusted odds ratio (aOR) and 95% CI for each Tmax mismatch ratio increase of 0.1 were calculated. A similar analysis was performed for ICAS‐related LVO with and without embolic sources, using embolic LVO as the reference. Of 213 patients (90 women [42.0%]; median age, 79 years), 39 (18.3%) had ICAS‐related LVO. The aOR (95% CI) per 0.1 increase in Tmax mismatch ratio in ICAS‐related LVO with embolic LVO as reference was lowest with Tmax mismatch ratio >10 s/>6 s (0.56 [0.43–0.73]). Multinomial logistic regression analysis also showed the lowest aOR (95% CI) per 0.1 increase in Tmax mismatch ratio with Tmax >10 s/>6 s (ICAS‐related LVO without embolic source: 0.60 [0.42–0.85]; ICAS‐related LVO with embolic source: 0.55 [0.38–0.79]). Conclusions A Tmax mismatch ratio of >10 s/>6 s was the optimal predictor of ICAS‐related LVO compared with other Tmax profiles, with or without an embolic source before endovascular therapy. Registration clinicaltrials.gov. Identifier NCT02251665.

BackgroundParoxysmal atrial fibrillation (AF) is a probable cause of cryptogenic stroke (CS), and its detection and treatment are important for the secondary prevention of stroke. Insertable cardiac monitors (ICMs) are clinically effective in screening for AF and are superior to conventional short-term cardiac monitoring. Japanese guidelines for determining clinical indications for ICMs in CS are stricter than those in Western countries. Differences between Japanese and Western guidelines may impact the detection rate and prediction of AF via ICMs in patients with CS. Available data on Japanese patients are limited to small retrospective studies. Furthermore, additional information about AF detection, including the number of episodes, cumulative episode duration, anticoagulation initiation (type and dose of regimen and time of initiation), rate of catheter ablation, role of atrial cardiomyopathy, and stroke recurrence (time of recurrence and cause of the recurrent event), was not provided in the vast majority of previously published studies. ObjectiveIn this study, we aim to identify the proportion and timing of AF detection and risk stratification criteria in patients with CS in real-world settings in Japan. MethodsThis is a multicenter, prospective, observational study that aims to use ICMs to evaluate the proportion, timing, and characteristics of AF detection in patients diagnosed with CS. We will investigate the first detection of AF within the initial 6, 12, and 24 months of follow-up after ICM implantation. Patient characteristics, laboratory data, atrial cardiomyopathy markers, serial magnetic resonance imaging findings at baseline, 6, 12, and 24 months after ICM implantation, electrocardiogram readings, transesophageal echocardiography findings, cognitive status, stroke recurrence, and functional outcomes will be compared between patients with AF and patients without AF. Furthermore, we will obtain additional information regarding the number of AF episodes, duration of cumulative AF episodes, and time of anticoagulation initiation. ResultsStudy recruitment began in February 2020, and thus far, 213 patients have provided written informed consent and are currently in the follow-up phase. The last recruited participant (May 2021) will have completed the 24-month follow-up in May 2023. The main results are expected to be submitted for publication in 2023. ConclusionsThe findings of this study will help identify AF markers and generate a risk scoring system with a novel and superior screening algorithm for occult AF detection while identifying candidates for ICM implantation and aiding the development of diagnostic criteria for CS in Japan. Trial RegistrationUMIN Clinical Trial Registry UMIN000039809; https://tinyurl.com/3jaewe6a International Registered Report Identifier (IRRID)DERR1-10.2196/39307

The Japanese National Plan for the Promotion of Measures Against Cerebrovascular and Cardiovascular Diseases was formulated on October 27, 2020. One purpose of this plan was to promote research on cerebrovascular and cardiovascular diseases. Therefore, it is necessary to clarify the actual status of stroke treatment in Japan and operate a national stroke database with high public interest completely and accurately. The Japan Stroke Data Bank (JSDB; https://strokedatabank.ncvc.go.jp/en/) was established by the Ministry of Health, Labor and Welfare Scientific Research in Shimane University (Shimane, Japan) in 1999 and was transferred to the National Cerebral and Cardiovascular Center (Osaka, Japan) as a part of the Cardiovascular Disease Registry in 2015. More than 200,000 of stroke cases have been registered using individual forms from more than 100 nationwide stroke centers over ~20 years. Since there are few large-scale stroke registries with nationwide coverage in Asia, including Japan, compared with those in Europe and North America, the role of the JSDB in the plan will be important in the future. To construct a high-quality stroke registry, we aimed to (1) collect detailed data through individual questionnaires for each participating stroke center, (2) link to external databases (e.g., insurance claims and public death registries), (3) improve the quality of treatment at participating hospitals through benchmarking, and (4) obtain stable funding through sustained support from government and academic societies. We also describe the history of the JSDB and changes in the trend of real-world stroke treatment in Japan based on the results of analysis of data in the JSDB.

Introduction We aim to investigate the difference in mechanical thrombectomy (MT) outcome for cancer‐related stroke (CRS) with active and inactive cancer. Methods Of the consecutive acute ischemic stroke (AIS) patients admitted to our institute from 2010 to 2021, patients with cancer who received MT within 24 hours of onset and were enrolled.Outcomes including the favorable outcome (modified Rankin Scale score of 0 to 2) at3 months, 1‐year,and death within 3 months or 1‐yearwere assessed between patients with active and inactive cancer among patients with cancer. The rate offirst pass effect (FPE, extendedThrombolysis in Cerebral Infarction[eTICI] 2c/3 after first pass) and final eTICI 2c/3 achievement were also assessed. Active cancer was defined as a cancer that was diagnosed within 6 months; required chemotherapy or surgical treatment within 6 months; or was recurrent, metastatic, or inoperable. Results Of 59 patients (26 women; median age, 80 years; median NIH Stroke Scale score[NIHSS] 17), 19 (32.2%) patients had an active cancer. Patients with active cancer has less atrial fibrillation (47% vs. 78%,P< 0.01) and higher medianD‐dimer(4.60μg/mLvs. 2.00μg/mL,P< 0.01). There were no significant differences in the favorable outcome at 3 months (26% vs. 45%,P = 0.26) and at 1 year (26% vs. 45%,P = 0.26) between both groups, but death within 3 months (32% vs. 5%,P< 0.01) and within 1 year (42% vs. 8%,P< 0.01) were more frequent in patients with active cancer than those with inactive cancer. Conclusions Long‐term clinical outcomes of patients with active cancer were worse than those with inactive cancer.

Background Acute myocardial infarction (AMI) infrequently occurs after acute stroke. The Heart‐brain team approach has a potential to appropriately manage this poststroke cardiovascular complication. However, clinical outcomes of AMI complicating acute stroke (AMI‐CAS) with the heart‐brain team approach have not been characterized. The current study investigated cardiovascular outcomes in patients with AMI‐CAS managed by a heart‐brain team. Methods and Results We retrospectively analyzed 2390 patients with AMI at our institute (January 1, 2007–September 30, 2020). AMI‐CAS was defined as the occurrence of AMI within 14 days after acute stroke. Major adverse cerebral/cardiovascular events (cardiac‐cause death, nonfatal myocardial infarction, and nonfatal stroke) and major bleeding events were compared in subjects with AMI‐CAS and those without acute stroke. AMI‐CAS was identified in 1.6% of the subjects. Most AMI‐CASs (37/39=94.9%) presented ischemic stroke. Median duration of AMI from the onset of acute stroke was 2 days. Patients with AMI‐CAS less frequently received primary percutaneous coronary intervention (43.6% versus 84.7%; P

Background We investigated the impact of the p.R4810K variant of RNF213 (ring finger protein 213) gene, a susceptibility gene of moyamoya disease in East Asia, on the outer diameter of cervical parts of carotid and vertebral arteries (VAs). Methods We examined consecutive Japanese patients with ischemic stroke who underwent carotid ultrasonography between 2015 and 2019. Patient background and the carotid ultrasonography‐measured outer diameter of extracranial cervical arteries, including the common carotid artery, internal carotid artery, external carotid artery, and cervical VA, were compared between variant carriers and noncarriers. Outer diameters of each artery were defined as the mean distance from far to near wall adventitia of right and left target arteries using carotid ultrasonography. The average diameter of both cervical portions of common carotid arteries, internal carotid arteries, external carotid arteries, and the dominant side diameter of both cervical VAs were used. Results Of the 617 adult patients (204 women; median age, 74 years) analyzed, 26 (4.2%) carried the RNF213 p.R4810K variant. Variant carriers were significantly younger (P

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

Background We elucidated the safety of treatment with alteplase at 0.6 mg/kg within 24 hours for patients on direct oral anticoagulants (DOACs) before ischemic stroke onset. Methods and Results Consecutive patients with acute ischemic stroke who underwent intravenous thrombolysis using alteplase at 0.6 mg/kg from 2011 to 2021 were enrolled from our single‐center prospective stroke registry. We compared outcomes between patients taking DOACs and those not taking oral anticoagulants within 48 hours of stroke onset. The primary safety outcome was the rate of symptomatic intracranial hemorrhage with a ≥4‐point increase on the National Institutes of Health Stroke Scale score from baseline. The efficacy outcome was defined as 3‐month modified Rankin Scale score of 0 to 2 after stroke onset. Of 915 patients with acute ischemic stroke who received intravenous thrombolysis (358 women; median age, 76 years; median National Institutes of Health Stroke Scale score, 10), 40 patients took DOACs (6 took dabigatran, 8 took rivaroxaban, 16 took apixaban, and 10 took edoxaban) within 24 hours of onset and 753 patients did not take any oral anticoagulants. The rate of symptomatic intracranial hemorrhage was comparable between patients on DOACs and those not on oral anticoagulants (2.5% versus 2.4%, P=0.95). The rate of favorable outcomes was comparable between the 2 groups (59.4% versus 58.2%, P=0.46), although the admission National Institutes of Health Stroke Scale score was higher in patients on DOACs. No significant differences showed in any intracranial hemorrhage within 36 hours or mortality at 3 months. Conclusions Intravenous thrombolysis would be safely performed for patients on DOACs following the recommendations of the Japanese guidelines. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02251665.

Using dual single-photon emission computed tomography (SPECT) scanning, we recently found the postictal-interictal (P-I) subtraction method frequently detects prolonged postictal hyperperfusion in poststroke epilepsy (PSE) and thus may be valuable for auxiliary diagnosis. This study aimed to determine if the asymmetry method can localize hyperperfusion to reflect epileptic activity in PSE using a single postictal SPECT scan. Sixty-four patients with PSE who had undergone perfusion SPECT two times (postictal and interictal) were enrolled. We formulated a novel asymmetry method (subtraction analysis of reversed postictal SPECT from postictal SPECT, co-registered to magnetic resonance imaging) to identify paradoxical asymmetric increase, defined as a higher perfusion area adjacent to stroke lesions compared to the contralateral side. The postictal hyperperfusion area and detection rates were determined by the asymmetry and P-I subtraction methods independently. We subsequently calculated the sensitivity and specificity of the asymmetry method, compared to the gold standard P-I subtraction method. We also evaluated lateralization concordance between the asymmetry method and other clinical findings. Among 64 patients (median age, 75 years), prolonged postictal hyperperfusion was detected in 43 (67%) by the asymmetry, and 54 (84%) the P-I, method. The asymmetry method had high sensitivity (80%) and specificity (100%) in detecting postictal hyperperfusion, showing high lateralization concordance with seizure semiology (97%) and epileptiform electroencephalography findings (interictal/ictal epileptiform discharges or periodic discharges) (100%). The present study demonstrated the advantages of the objective asymmetry method for detecting prolonged hyperperfusion through using one postictal SPECT scan in PSE.

Abstract The detection of underlying atrial fibrillation (AF) has become increasingly possible by insertable cardiac monitoring (ICM). During hospitalization for cryptogenic stroke, factors related to the early and late development of AF have not been studied. CHALLENGE ESUS/CS is a multicenter registry of cryptogenic stroke patients undergoing transesophageal echocardiography. Twelve-lead electrocardiogram, continuous cardiac monitoring, and 24-h Holter electrocardiogram were all used for the detection of AF. Early and late detection of AF was determined with an allocation ratio of 1:1 among patients with AF. A total of 677 patients (68.7 ± 12.8 years; 455 men) were enrolled, and 64 patients developed AF during hospitalization. Four days after admission was identified as the approximate median day to classify early and late phases to detect AF: ≤ 4 days, 37 patients; > 4 days, 27 patients. Multiple logistic regression analysis showed that spontaneous echo contrast (SEC) (OR 5.91; 95% CI 2.19–15.97; p 3 cm in diameter (OR 3.28; 95% CI 1.35–7.97; p = 0.009) was associated with AF > 4 days. SEC and large infarctions were important predictors of in-hospital AF detection, particularly in the early and late stages, respectively; thus, they could serve as indications for recommending ICM.

Despite the remarkable progress in acute treatment for stroke, in-hospital stroke is still devastating. The mortality and neurological sequelae are worse in patients with in-hospital stroke than in those with community-onset stroke. The leading cause of this tragic situation is the delay in emergent treatment. To achieve better outcomes, early stroke recognition and immediate treatment are crucial. In general, in-hospital stroke is initially witnessed by non-neurologists, but it is sometimes challenging for non-neurologists to diagnose a patient’s state as a stroke and respond quickly. Therefore, understanding the risk and characteristics of in-hospital stroke would be helpful for early recognition. First, we need to know “the epicenter of in-hospital stroke”. Critically ill patients and patients who undergo surgery or procedures are admitted to the intensive care unit, and they are potentially at high risk for stroke. Moreover, since they are often sedated and intubated, evaluating their neurological status concisely is difficult. The limited evidence demonstrated that the intensive care unit is the most common place for in-hospital strokes. This paper presents a review of the literature and clarifies the causes and risks of stroke in the intensive care unit.

Background The aim of this study was to determine the associations of cerebral small vessel disease (SVD) burden with renal dysfunction and albuminuria in patients taking oral antithrombotic agents. Methods and Results Patients who newly started or continued taking oral antiplatelets or anticoagulants were enrolled in a prospective, multicenter, observational study. Obligatorily acquired multimodal magnetic resonance imaging at registration with prespecified imaging conditions was assessed for cerebral microbleeds, white matter hyperintensities, enlarged basal ganglia perivascular spaces, or lacunes, and an ordinal SVD score was calculated (range, 0–4). Multivariable adjusting covariates were age, sex, hypertension, diabetes, dyslipidemia, current smoking, drinking, and estimated glomerular filtration rate (eGFR). Of 5324 patients (1762 women; median age, 73 years), 4797 (90.1%) patients were taking oral antithrombotic agents for secondary stroke prevention. Cerebral microbleeds were present in 32.7%, confluent white matter hyperintensities in 51.8%, extensive basal ganglia perivascular spaces in 38.9%, and lacunes in 59.4%. Median SVD score was 2. Compared with eGFR category G1 (eGFR ≥90 mL/min per 1.73 m2), adjusted odds ratios for SVD score increment were 1.63 (95% CI, 1.11–2.39) at category G4 (eGFR 15–

Background Extended thrombolysis in cerebral infarction (eTICI) 2c/3 reperfusion after mechanical thrombectomy (MT) is associated with better stroke outcomes than eTICI 2b. Whether additional MT attempt after achieving eTICI 2b (beyond 2b attempt) leads to better outcomes is unknown. Methods Consecutive patients with acute anterior circulation stroke who achieved eTICI 2b during MT were divided into 2 groups: those who further tried MT (beyond‐2b group) and those without (nonbeyond‐2b group). The patients who directly achieved eTICI 2c/3 without experiencing 2b (direct‐2c/3 group) were also studied. The outcomes included the reperfusion status, favorable outcome (3‐month modified Rankin scale score of 0–2), neurological improvement (a ≥10‐point decrease of the National Institutes of Health Stroke Scale score from baseline or the score of 0) at 24 hours and symptomatic intracranial hemorrhage. Results Of 308 patients, 50 were in the beyond‐2b group, 87 in the nonbeyond‐2b group, and the remaining 171 in the direct‐2c/3 group. Perfusion of middle cerebral artery branches supplying the primary motor cortex was worse in the beyond‐2b than the nonbeyond‐2b group at the time of eTICI 2b (P=0.007). Favorable outcome was similarly common (48% for each, P=0.40). Neurological improvement was more frequent (52% versus 37%; P=0.04) and symptomatic intracranial hemorrhage tended to be more common (6% versus 1%, P=0.11) in the beyond‐2b than the nonbeyond‐2b group. Eighteen patients (36%) in the beyond‐2b group finally achieved eTICI 2c/3; 10 of these (56%) and 14 of the remaining 32 (44%) had favorable outcome (P=0.83). The former rate was similar to that in the direct‐2c/3 group (58%; P=0.99). Conclusions Patients undergoing additional MT attempt after achieving eTICI 2b had numerically but not significantly more symptomatic intracranial hemorrhage and showed a similar level of functional outcome at 3 months than those who did not. When eTICI 2c/3 was finally achieved by additional attempts, functional outcome was similar with that of patients who directly achieved eTICI 2c/3 without experiencing 2b. Clinical Trial Registration Information URL: https://www.clinicaltrials.gov. Unique identifier: NCT02251665.

BackgroundThe optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated.MethodsFrom data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months.ResultsAmong the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54).ConclusionsInfarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke.Clinical trial registrationUnique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.

Background We retrospectively compared early‐ (

Objectives: Acute ischemic stroke (AIS) is a significant and devastating complication in patients with end-stage renal disease on hemodialysis (ESRD/HD). Since one-third of AIS in ESRD/HD patients occurs during or soon after dialysis, patients are more likely to present within the time window when intravenous thrombolysis (IVT) can be performed. IVT may improve prognosis in ESRD/HD patients with AIS. However, ESRD/HD patients have been excluded from large trials and may have been withheld from IVT due to concerns about bleeding complications. To date, there is no clear evidence and firm guidance on the safety and efficacy of IVT in ESRD/HD patients with AIS. This narrative review aimed to evaluate critical scientific data on the benefits and risks of IVT use in patients with ESRD/HD and AIS. Materials and Methods: We searched the electronic database of PubMed for studies evaluating the relationship between AIS, ESRD/HD, and IVT. Reference sections and additional publications were also searched manually. Studies on AIS in patients with ESRD/HD requiring maintenance dialysis that referred to IVT were included. Results: In total, 560 studies were found in the PubMed electronic database during the period covered, of which 10 met the selection criteria. IVT for AIS in ESRD/HD patients could improve neurological outcomes and be safely performed even with the possibility of hemorrhagic complications associated with hypertension. Despite the high complication and mortality rates in ESRD/HD patients with AIS after IVT, the association with IVT was unclear. Conclusions: IVT for AIS in ESRD/HD patients may improve outcomes and should not be withheld based solely on ESRD/HD status.

Introduction: The ring finger protein 213 gene (RNF213) has been identified as a susceptibility gene for moyamoya disease, and the p.R4810K polymorphism as a founder variant commonly found in East Asian patients. 1 A recent large case‐control study including over 46,958 Japanese subjects reported that the RNF213 p.R4810K variant was a strong risk factor for Japanese cerebral infarction: the variant was found in 5.2% of patients with non‐cardioembolic stroke and in 2.1% of healthy controls. 2 Mechanical thrombectomy (MT) is a standard treatment for acute ischemic stroke due to occlusion of the internal carotid artery and M1 segment of the middle cerebral artery, but in East Asians, about 15–25% of LVOs for which MT was performed were reportedly caused by intracranial atherosclerotic disease (ICAD). 3 RNF213 p.R4810K variant may be involved to some extent in ICAD‐related LVO of Asian patients undergoing MT. In this study, we aimed to investigate the impact of RNF213 p.R4810K variant on EVT for anterior circulation LVO stroke. Methods: Of the consecutive ischemic stroke patients from 2011 to 2021 seen in our institute, patients who underwent EVT for acute occlusion of the intracranial ICA or M1 segment of MCA and signed a consent form for RNF213 genotyping were included. Outcomes were instant re‐occlusion, final modified Thrombolysis in Cerebral Infarction (mTICI) ≥2b reperfusion, early re‐occlusion, and modified Rankin Scale (mRS) score 0–2 at 90 days. Instant re‐occlusion was defined as occurrence of re‐occlusion during the procedure, whereas early re‐occlusion as re‐occlusion detected on magnetic resonance angiography within 2 weeks after confirmation of successful reperfusion at the end of the procedure. 4 Results: Of the 277 patients (128 women [46.2%]; median age, 76 years) analyzed, 10 (3.6%) patients had the RNF213 p.R4810K variant. The variant carriers were younger (67 years vs. 76 years, P

Background Cerebrovascular diseases are common comorbidities in patients with cancer. Although active cancer causes ischemic stroke by multiple pathological conditions, including thromboembolism attributable to Trousseau syndrome, the relationship between stroke and inactive cancer is poorly known. The aim of this study was to elucidate the different underlying pathogeneses of cryptogenic stroke in active and inactive patients with cancer, with detailed investigation by transesophageal echocardiography. Methods and Results CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke Clarified by Transesophageal Echocardiography for Embolic Stroke of Undetermined Source/Cryptogenic Stroke) registry is a multicenter registry including data of patients initially diagnosed as having cryptogenic stroke and undergoing transesophageal echocardiography. Patients were divided into active cancer, inactive cancer, and noncancer groups, and their clinical features were compared. Of the total 667 enrolled patients (age, 68.7±12.8 years; 455 men), 41 (6.1%) had active cancer, and 51 (7.5%) had a history of inactive cancer. On multinomial logistic regression analysis, infarctions in multiple vascular territories (odds ratio [OR], 2.73; 95% CI, 1.39–5.40) and CRP (C‐reactive protein) (OR, 1.10; 95% CI, 1.01–1.19) were independently associated with active cancer, whereas age (OR, 1.05; 95% CI, 1.01–1.08), contralateral carotid stenosis from the index stroke lesion (OR, 4.05; 95% CI, 1.60–10.27), calcification of the aortic valve (OR, 2.10; 95% CI, 1.09–4.05), and complicated lesion of the aortic arch (OR, 2.13; 95% CI, 1.11–4.10) were significantly associated with inactive cancer. Conclusions Patients with cancer were not rare in cryptogenic stroke. Although patients with active cancer had more multiple infarctions, patients with inactive cancer had more atherosclerotic embolic sources potentially causing arteriogenic strokes. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000032957.

Background To clarify differences in clinical significance of intracardiac thrombi in nonvalvular atrial fibrillation‐associated stroke as identified by transesophageal echocardiography (TEE) and transthoracic echocardiography (TTE). Methods and Results Using patient data on nonvalvular atrial fibrillation‐associated ischemic stroke between 2011 and 2014 from 15 South Korean stroke centers (n=4841) and 18 Japanese centers (n=1192), implementation rates of TEE/TTE, and detection rates of intracardiac thrombi at each center were correlated. The primary outcome was recurrent ischemic stroke at 1 year after the onset. A total of 5648 patients (median age, 75 years; 2650 women) were analyzed. Intracardiac thrombi were detected in 75 patients (1.3%) overall. Thrombi were detected in 7.8% of patients with TEE (either TEE alone or TEE+TTE: n=679) and in 0.6% of those with TTE alone (n=3572). Thrombus detection rates varied between 0% and 14.3% among centers. As TEE implementation rates at each center increased from 0% to 56.7%, thrombus detection rates increased linearly (detection rate [%]=0.11×TEE rate [%]+1.09 [linear regression], P

Abstract Background and purpose The management of post‐stroke epilepsy (PSE) should ideally include prevention of both seizure and adverse effects; however, an optimal antiseizure medications (ASM) regimen has yet been established. The purpose of this study is to assess seizure recurrence, retention, and tolerability of older‐generation and newer‐generation ASM for PSE. Methods This prospective multicenter cohort study (PROgnosis of Post‐Stroke Epilepsy [PROPOSE] study) was conducted from November 2014 to September 2019 at eight hospitals. A total of 372 patients admitted and treated with ASM at discharge were recruited. Due to the non‐interventional nature of the study, ASM regimen was not adjusted and followed standard hospital practices. The primary outcome was seizure recurrence in patients receiving older‐generation and newer‐generation ASM. The secondary outcomes were the retention and tolerability of ASM regimens. Results Of the 372 PSE patients with ASM at discharge (median [IQR] age, 73 [64–81] years; 139 women [37.4%]), 36 were treated with older‐generation, 286 with newer‐generation, and 50 with mixed‐generation ASM. In older‐ and newer‐generation ASM groups (n = 322), 98 patients (30.4%) had recurrent seizures and 91 patients (28.3%) switched ASM regimen during the follow‐up (371 [347–420] days). Seizure recurrence was lower in newer‐generation, compared with the older‐generation, ASM (hazard ratio [HR], 0.42, 95%CI 0.27–0.70; p = .0013). ASM regimen withdrawal and change of dosages were lower in newer‐generation ASM (HR, 0.34, 95% CI 0.21–0.56, p

Background To explore how the clinical impact of heart rate (HR) and heart rate variabilities (HRV) during the initial 24 hours after acute intracerebral hemorrhage (ICH) contribute to worse clinical outcomes. Methods and Results In the ATACH‐2 (Antihypertensive Treatment in Intracerebral Hemorrhage 2) trial, the HR was recorded for every 15 minutes from baseline to 1 hour and hourly during the initial 24 hours post‐randomization. We calculated the following: mean, standard deviation, coefficient of variation, successive variation, and average real variability (ARV). Outcomes were hematoma expansion at 24 hours and unfavorable functional outcome, defined as modified Rankin Scale score 4 to 6 at 90 days. Of the 1000 subjects in ATACH‐2, 994 with available HR data were included in the analyses. Overall, 262 experienced hematoma expansion, and 362 had unfavorable outcomes. Increased mean HR was linearly associated with unfavorable outcome (per 10 bpm increase adjusted odds ratio [aOR], 1.31, 95% CI, 1.14–1.50) but not with hematoma expansion, while HR‐ARV was associated with hematoma expansion (aOR, 1.06, 95% CI, 1.01–1.12) and unfavorable outcome (aOR, 1.07, 95% CI, 1.01–1.3). Every 10‐bpm increase in mean HR increased the probability of unfavorable outcome by 4.3%, while every 1 increase in HR‐ARV increased the probability of hematoma expansion by 1.1% and unfavorable outcome by 1.3%. Conclusions Increased mean HR and HR‐ARV within the initial 24 hours were independently associated with unfavorable outcome in acute ICH. Moreover, HR‐ARV was associated with hematoma expansion at 24 hours. This may have future therapeutic implications to accommodate HR and HRV in acute ICH. Registration URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01176565.

IntroductionDysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models. In addition, vascular abnormalities in the circle of Willis are associated with cerebrovascular disease. Here, we evaluated the relationship between the East Asian founder variant RNF213 p.R4810K and consequent anatomical variations in the circle of Willis in cerebrovascular disease.Patients and MethodsThe present study is an observational cross-sectional study. It included patients with acute anterior circulation non-cardioembolic stroke admitted to our institution within 7 days of symptom onset or last-known-well from 2011 to 2019, and those who participated in the National Cerebral and Cardiovascular Center Biobank. We compared anatomical variations of the vessels constituting the circle of Willis between RNF213 p.R4810K (c.14429G > A) variant carriers and non-carriers using magnetic resonance angiography and assessed the association between the variants and the presence of the vessels constituting the circle of Willis. Patients with moyamoya disease were excluded.ResultsFour hundred eighty-one patients [146 women (30%); median age 70 years; median baseline National Institutes of Health Stroke Scale score 5] were analyzed. The RNF213 p.R4810K variant carriers (n = 25) were more likely to have both posterior communicating arteries (PComAs) than the variant non-carriers (n = 456) (56% vs. 13%, P < 0.01). Furthermore, variant carriers were less likely to have an anterior communicating artery (AComA) than non-carriers (68% vs. 84%, P = 0.04). In a multivariate logistic regression analysis, the association of RNF213 p.R4810K variant carriers with the presence of both PComAs and the absence of AComA remained significant.ConclusionOur findings suggest that the RNF213 p.R4810K variant is an important factor in determining anatomical variations in the circle of Willis.

Abstract Background Patients with vascular Ehlers-Danlos syndrome (EDS) occasionally suffer from arterial dissection. Eagle syndrome, which is caused by an elongated styloid process and also causes arterial dissection, is difficult to diagnose and could sometimes be overlooked. Little is known of the coexistence of these two diseases, and treatment strategy is not established. Here, we present a case of bilateral internal carotid artery (ICA) dissection due to Eagle syndrome in a patient with vascular EDS. Case presentation A 30-year-old man was admitted to our hospital because of sudden onset of mild sensory disturbance in his left limbs. He had a history of Ehlers-Danlos syndrome (EDS) and also had left cervical internal carotid artery (ICA) dissection 3 years before. Diffusion-weighted imaging showed acute cerebral infarcts in the right hemisphere. Cervical computed tomography angiography (CTA) revealed the right ICA narrowing at the cervical portion in addition to the previous left cervical ICA dissection. Cervical magnetic resonance imaging (MRI) revealed double-lumen and intramural hematoma at the narrowing portion of the right cervical ICA, which indicates arterial dissection. CT also revealed bilateral elongated styloid processes which are close to each side of cervical ICA. We diagnosed him as bilateral ICA dissection due to bilateral Eagle syndrome. Considering vascular complications due to vascular EDS, we performed closer follow-up with transoral carotid ultrasonography (TOCU). In 4 months, his right ICA dissection gradually improved without stroke recurrence or deterioration of dissection. Conclusions Since patients with vascular EDS easily develop arterial dissection, Eagle syndrome may be overlooked. Clinicians should consider Eagle syndrome in the case of vascular EDS with extracranial ICA dissection and close follow-up should be prioritized in cases of Eagle syndrome with vascular EDS.

Abstract Background Simultaneous cerebral and myocardial infarction is called cardiocerebral infarction (CCI), and is rarely encountered. Because of the narrow time window and complex pathophysiology, CCI is challenging to immediately diagnose and treat. Case presentation A 73-year-old woman suddenly developed right hemiplegia and severe aphasia. Twelve-lead electrocardiography showed tachycardic atrial fibrillation without any significant ST-T change. Magnetic resonance imaging revealed a proximal middle cerebral artery occlusion. She was immediately treated with alteplase at the dosage approved for ischemic stroke followed by mechanical thrombectomy as bridging therapy, and complete recanalization was achieved. Aphasia improved and she began to complain of chest pain, and reported that she had experienced chest discomfort just prior to right limb weakness. Coronary angiography showed a partial filling defect in the right coronary artery with rapid and adequate distal flow, for which percutaneous coronary intervention was not required. Alteplase was suggested to have effectively resolved the coronary emboli. The occlusions of the cerebral and coronary arteries were assumed to have occurred nearly simultaneously and cardiogenic embolism due to atrial fibrillation was considered as the most likely etiology. Conclusions As seen in the present case, CCI may benefit from immediate treatment with intravenous tissue plasminogen activator (IV-tPA). Although which of percutaneous coronary intervention or cerebral thrombectomy should be performed first remains unclear, we must decide whether to rescue the brain or heart first in each patient within a limited window of time. This dilemma has recently become evident in this era with mechanical thrombectomy strongly established as an effective intervention for acute ischemic stroke. Close cooperation between stroke physicians and cardiologists is becoming more important.

Computerized tomography (CT) or magnetic resonance imaging (MRI) is indispensable for diagnosing acute ischemic stroke (AIS) patients who are candidates for recombinant tissue plasminogen activator (rt-PA) therapies, but further investigation concerning appropriate selection of therapy following advanced imaging including perfusion imaging has not yet been done. The 2018 AHA guidelines have recommended not to perform excessive time-consuming imaging before rt-PA. Here we describe two cases in which reperfusion therapy was decided based on advanced imaging. The first case was a 70-year-old woman with complaints of total aphasia and right unilateral spatial neglect. Her MRI revealed no apparent high signal area in diffusion-weighted image (DWI), and her magnetic resonance angiography (MRA) showed no large vessel occlusion. Subsequent perfusion-weighted image (PWI) analysis showed a unilateral perfusion deficit in the left middle cerebral artery (MCA) region. The other case was an 88-year-old man with complaints of minor unilateral spatial neglect, right conjugate deviation of the eyes, and dysarthria. His MRI also revealed no apparent high signal area in DWI, and MRA showed slight stenosis in the right middle MCA. Subsequent PWI analysis showed a unilateral perfusion deficit in the right MCA region. In both cases, intravenous rt-PA therapy was administered after the diagnosis of AIS and the patients responded well to the reperfusion therapy. When DWI is performed too early, detecting the ischemic core and differentiating between a diagnosis of stroke and stroke mimics is sometimes difficult. Evaluation of perfusion abnormalities in acute cases can be performed quickly, as shown in these cases. Although rt-PA can be given just by non-contrast CT with no hemorrhage, advanced imaging may be an option to identify difficult-to-diagnose patients who require reperfusion therapy.

Introduction: The usefulness of the blind exchange with mini-pinning (BEMP) technique has recently been reported for mechanical thrombectomy in patients with stroke owing to medium vessel occlusion (MeVO). The Tron stent retriever can be delivered and deployed through a 0.0165-inch microcatheter. This retriever has potential as an effective and safe treatment for acute ischemic stroke (AIS) due to occlusion of the M2 segment of the middle cerebral artery (MCA). Here, we report the outcomes of the BEMP technique using Tron stent retrievers for M2 occlusion thrombectomy.Methods: Consecutive patients with AIS owing to M2 occlusion who underwent the BEMP technique using 2 × 15-mm or 4 × 20-mm Tron stent retrievers were included. The technique involves deploying a Tron stent retriever through a 0.0165-inch microcatheter, followed by microcatheter removal and blind navigation of a 3MAX or 4MAX aspiration catheter over the bare Tron delivery wire until the aspiration catheter reaches the clot. A Tron stent retriever is inserted into the aspiration catheter like a cork and subsequently pulled as a unit. We assessed procedural outcomes [first-pass expanded thrombolysis in cerebral infarction (eTICI) score 2c/3 and 2b/2c/3], safety outcomes [symptomatic intracranial hemorrhage (sICH)], and clinical outcomes (good outcome rate defined as modified Rankin Scale score 0–2 at 90 days and mortality at 90 days).Results: Eighteen M2 vessels were treated in 15 patients (six female, median age: 80 years, and median National Institutes of Health Stroke Scale score: 18). The BEMP technique was performed successfully in all cases. Whether to use a 3MAX or 4MAX catheter was determined by considering one of the following target vessels: dominant, non-dominant, or co-dominant M2 (3MAX, n = 9; 4MAX, n = 9). The first-pass eTICI 2c/3 and 2b/2c/3 rates were 47 (7/15) and 60% (9/15), respectively; sICH was not observed. Seven patients (47%) achieved good outcomes, and one patient (7%) died within 90 days.Conclusions: The Tron stent retriever was safely and effectively used in the BEMP technique for acute MCA M2 occlusion and can be combined with a 0.0165-inch microcatheter, which may be useful for treating MeVO, in general.

Introduction: The correlation between the composition of thrombi retrieved by mechanical thrombectomy (MT) and stroke etiology is inconclusive. We describe a case with atherosclerotic components in thrombi retrieved by MT for acute internal carotid artery (ICA) occlusion.Case Presentation: A 69-year-old man with acute onset of global aphasia and right hemiplegia was transferred to our institute. His baseline National Institutes of Health Stroke Scale score was 24. Magnetic resonance imaging demonstrated acute ischemic stroke in the left parietal lobe. Magnetic resonance angiography revealed occlusion of the left ICA. MT was attempted for acute left ICA occlusion. The initial angiography showed occlusion of the proximal ICA, while intraprocedural angiography revealed a large thrombus that extended from the cervical ICA to the intracranial ICA. Successful reperfusion was achieved by five passes using stent retrievers and an aspiration catheter. A large volume of red thrombus was retrieved by each pass. The final angiogram showed successful reperfusion with modified Thrombolysis in Cerebral Ischemia grade 2b and severe stenosis in the proximal ICA. Neck magnetic resonance imaging showed severe left ICA stenosis with a vulnerable plaque. Hence, his stroke etiology was determined as large artery atherosclerosis. Histopathological examination of the retrieved thrombi revealed atheromatous components, including cholesterol clefts, foam cells, and a necrotic core.Conclusions: Atherosclerotic components in retrieved thrombi might provide useful clues for diagnosing stroke pathogenesis. Further studies are warranted to clarify the utility of assessing atheromatous components in retrieved thrombi in diagnosing stroke etiology.

BackgroundThere is currently no validated risk prediction model for recurrent events among patients with acute ischemic stroke (AIS) and atrial fibrillation (AF). Considering that the application of conventional risk scores has contextual limitations, new strategies are needed to develop such a model. Here, we set out to develop and validate a comprehensive risk prediction model for stroke recurrence in AIS patients with AF.MethodsAIS patients with AF were collected from multicenter registries in South Korea and Japan. A developmental dataset was constructed with 5648 registered cases from both countries for the period 2011‒2014. An external validation dataset was also created, consisting of Korean AIS subjects with AF registered between 2015 and 2018. Event outcomes were collected during 1 year after the index stroke. A multivariable prediction model was developed using the Fine-Gray subdistribution hazard model with non-stroke mortality as a competing risk. The model incorporated 21 clinical variables and was further validated, calibrated, and revised using the external validation dataset.ResultsThe developmental dataset consisted of 4483 Korean and 1165 Japanese patients (mean age, 74.3 ± 10.2 years; male 53%); 338 patients (6%) had recurrent stroke and 903 (16%) died. The clinical profiles of the external validation set (n = 3668) were comparable to those of the developmental dataset. The c-statistics of the final model was 0.68 (95% confidence interval, 0.66 ‒0.71). The developed prediction model did not show better discriminative ability for predicting stroke recurrence than the conventional risk prediction tools (CHADS2, CHA2DS2-VASc, and ATRIA).ConclusionsNeither conventional risk stratification tools nor our newly developed comprehensive prediction model using available clinical factors seemed to be suitable for identifying patients at high risk of recurrent ischemic stroke among AIS patients with AF in this modern direct oral anticoagulant era. Detailed individual information, including imaging, may be warranted to build a more robust and precise risk prediction model for stroke survivors with AF.

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small vessel disease, with reported frequencies of 2-5/100,000 individuals. Recently, it has been reported that some patients with NOTCH3 gene mutations show atypical clinical symptoms of CADASIL. Assuming that CADASIL is underdiagnosed in some cases of lacunar infarction, this study was designed to examine the prevalence of NOTCH3 gene mutations in the patients at highest risk who were admitted for lacunar infarctions.Methods: From January 2011 to April 2018, 1,094 patients with lacunar infarctions were admitted to our hospital, of whom 31 patients without hypertension but with white matter disease (Fazekas scale 2 or 3) were selected and genetically analyzed for NOTCH3 gene mutations (Phase 1). Furthermore, 54 patients, who were 60 years or younger, were analyzed for NOTCH3 mutations (Phase 2). NOTCH3 exons 2–24, which encode the epidermal growth factor-like repeat domain of the NOTCH3 receptor, were analyzed for mutations by direct sequencing of genomic DNA.Results: Three patients presented NOTCH3 p.R75P mutations: two in the Phase 1 and one in the Phase 2 cohort. Among patients aged 60 years or younger and those without hypertension but with moderate-to-severe white matter lesions, the carrier frequency of p.R75P was 3.5% (3/85), which was significantly higher than that in the Japanese general population (4.7KJPN) (odds ratio [95% CI] = 58.2 [11.6–292.5]). All three patients with NOTCH3 mutations had family histories of stroke, and the average patient age was 51.3 years. All three patients also showed white matter lesions in the external capsule but not in the temporal pole. The CADASIL and CADASIL scale-J scores of the three patients were 6, 17, 7 (mean, 10.0) and 13, 20, 10 (mean, 14.3), respectively.Conclusion: Among patients hospitalized for lacunar infarctions, the p.R75P prevalence may be higher than previously estimated. The NOTCH3 p.R75P mutation may be underdiagnosed in patients with early-onset lacunar infarctions due to the atypical clinical and neuroimaging features of CADASIL. Early-onset, presence of family history of stroke, external capsule lesions, and absence of hypertension may help predict underlying NOTCH3 mutations despite no temporal white matter lesions.

Development of direct oral anticoagulants and their antidotes has led to the need to reconsider the eligibility of acute stroke patients who have been taking oral anticoagulants for intravenous thrombolysis. Officially authorized Japanese guidelines on this issue were revised twice at the time of approval for clinical use of direct oral anticoagulants and idarucizumab, a specific reversal agent for dabigatran. A unique recommendation in the latest Japanese clinical guides was that thrombolysis can be recommended if the time of the last dose of direct oral anticoagulants exceeds 4 hours and if commonly available anticoagulation markers are normal or subnormal, i.e., international normalized ratio of prothrombin time

Background Malignant profiles were identified by imaging profiles and unfavorable outcomes that have poor response to reperfusion therapy. Many trials have used this profile in their inclusion criteria including large‐vessel occlusion acute ischemic stroke trials. We aimed to redefine the cutoff values for malignant profile in acute ischemic stroke patients with large‐vessel occlusion regardless of reperfusion therapy. Methods and Results Consecutive acute ischemic stroke patients with anterior large‐vessel occlusion were prospectively extracted from the National Cerebral and Cardiovascular Center Stroke Registry between March 2014 and December 2017. Diffusion‐Weighted Imaging‐Alberta Stroke Program Early Computed Tomography Score (DWI‐ASPECTS) and diffusion‐weighted imaging lesion ischemic core volume (VolDWI) were measured in acute ischemic stroke patients with large‐vessel occlusion with or without treatment. Unfavorable outcome was defined as a modified Rankin Scale score 5 to 6 at 3 months, and optimal DWI‐ASPECTS and VolDWI for unfavorable outcome were assessed. In total, 198 patients (111 men, 77±13 years old) were enrolled. Median DWI‐ASPECTS was 7 (5‐9), and median VolDWI was 55 (6‐134) mL. Among the patients, 72 (36%) patients underwent reperfusion therapy, and 83 (42%) had unfavorable outcomes. The threshold values for a malignant profile on receiver operating characteristic curve analysis for DWI‐ASPECTS and VolDWI were 4 (area under the curve 0.78, P

Background We aimed to clarify associations between prior anticoagulation and short‐ or long‐term clinical outcomes in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Methods and Results A total of 1189 ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation who were hospitalized within 7 days after onset were analyzed. Of these, 813 patients (68.4%) received no prior anticoagulation, 310 (26.1%) received prior warfarin treatment with an international normalized ratio (INR)

BackgroundThe crushed-tablet rivaroxaban concentration has been previously reported to be lower than the non-crushed concentration. However, the rivaroxaban concentration of fine granules has not yet been investigated. The anticoagulation intensity of rivaroxaban with fine granules, tablets, and crushed tablets was compared in acute stroke patients to assess the efficacy of each form.Methods and findingsHospitalized patients over 75 years old with acute stroke who started taking rivaroxaban from April 2012 to September 2017 were included. Blood samples were drawn just before and 4 hours after taking rivaroxaban on a median of 5 days after treatment initiation for concentration measurements (C0h, C4h) based on an anti-factor Xa chromogenic assay. Of 114 patients (49 female, 83±5 years old), 97 had ischemic strokes, 9 had transient ischemic attacks, and 8 had intracerebral hemorrhages. Rivaroxaban was administered a median of 7 days after onset. Of these, 38 patients were given the 15 mg dose, and 76 were given the 10 mg dose. In the 15 mg dose group, C0h was significantly higher in the fine granule group than in the crushed tablet group, with no significant difference compared to the tablet group [C0h: 27.6±6.8 vs 4.0±4.1 (P = 0.01) vs. 33.3±25.2 ng/ml, (P = 0.51), respectively], as was C4h [223.0±66.6 vs 103.0±79.5 (P = 0.02) vs. 229.5±121.6 ng/ml (P = 0.88)]. In the 10 mg dose group, C0h was significantly higher in the fine granule group than in the crushed tablet group and comparable to that in the tablet group [23.2±7.9 vs 7.5±6.2 (PConclusionsThe rivaroxaban concentration with fine granules was consistent with that in the tablet group and higher than that in the crushed tablet group.

BackgroundThe purpose of this study was to examine the relationships between glucose parameters obtained by continuous glucose monitoring and clinical outcomes in acute stroke patients. Methods and ResultsConsecutive patients with acute ischemic stroke or intracerebral hemorrhage within 24 hours after onset were included. A continuous glucose monitoring device (iPro2) was attached for the initial 72 hours after emergent admission. Eight glucose parameters were obtained from continuous glucose monitoring: maximum, minimum, mean, and SD of blood glucose levels, as well as area under the curve more than 8 mmol/L of blood glucose, distribution time more than 8 mmol/L of blood glucose, coefficient of variation (%CV), and presence of time less than 4 mmol/L over 72 hours. The primary outcome measure was death or dependency at 3 months (modified Rankin Scale score ≥3). One hundred patients with acute ischemic stroke (n=58) or intracerebral hemorrhage (n=42) were included. Blood glucose levels varied between 5.2±1.4 and 11.4±3.2 mmol/L over 72 hours, with area under the curve more than 8 mmol/L of blood glucose of 0.7±1.4 min×mmol/L, distribution time more than 8 mmol/L of blood glucose of 31.7±32.7%, coefficient of variation of 15.5±5.4%, and presence of hypoglycemia in 20% of overall patients. Mean glucose level (adjusted odds ratio, 1.60, 95% confidence interval, 1.12–2.28/1 mmol/L), area under the curve more than 8 mmol/L of blood glucose (2.13, 1.12–4.02/1 min×mmol/L), and distribution time more than 8 mmol/L of blood glucose (1.25, 1.05–1.50/10%) were related to death or dependency for overall patients, as well as for acute ischemic stroke patients (2.05, 1.15–3.65; 2.38, 1.04–5.44; 1.85, 1.10–3.10, respectively). ConclusionsHigh mean glucose levels, distribution time more than 8 mmol/L of blood glucose, and areas under the curve more than 8 mmol/L of blood glucose during the initial 72 hours of acute stroke were associated with death or dependency at 3 months.

Abstract A 70‐year‐old woman developed acute cerebral infarction. Transthoracic echocardiography showed a large mobile mass in the left atrium, suggesting cardiac myxoma as the most likely diagnosis. Surgical exploration revealed a papillary fibroelastoma originating from the coumadin ridge, which is fairly rare but important as a source of cerebral embolization.

Background and PurposeFactors associated with early arrival may vary according to the characteristics of the hospital. We investigated the factors associated with early hospital arrival in two different stroke centers located in Korea and Japan.MethodsConsecutive patients with ischemic stroke arrived hospital within 48 hours of onset between January 2011 and December 2012 were identified and the clinical and time variables were retrieved from the prospective stroke registries of Severance Hospital of Yonsei University Health System (YUHS; Seoul, Korea) and National Cerebral and Cardiovascular Center (NCVC; Osaka, Japan). Subjects were dichotomized into early (time from onset to arrival ≤4.5 hours) and late (>4.5 hours) arrival groups. Univariate and multivariate analyses were performed to evaluate factors associated with early hospital arrival.ResultsA total of 1,966 subjects (992 from YUHS; 974 from NCVC) were included in this study. The median time from onset to arrival was 6.1 hours [interquartile range, 1.7-17.8 hours]. In multivariate analysis, the factors associated with early arrival were atrial fibrillation (Odds ratio [OR], 1.505; 95% confidence interval [CI], [1.168-1.939]), higher initial National Institute of Health Stroke Scale scores (OR, 1.037; 95% CI [1.023-1.051]), onset during daytime (OR, 2.799; 95% CI [2.173-3.605]), and transport by an emergency medical service (OR, 2.127; 95% CI [1.700-2.661]). These factors were consistently associated with early arrival in both hospitals.ConclusionsDespite differences between the hospitals, there were common factors related to early arrival. Efforts to identify and modify these factors may promote early hospital arrival and improve stroke outcome.