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Introduction: Subarachnoid hemorrhage (SAH) mortality is decreasing, but data on functional outcomes over time is lacking. Methods: We created trends of good (Glasgow Outcomes Scale [GOS] of 4 or 5) and optimal (GOS of 5) functional outcomes and mortality (GOS of 1) using linear regression in 15 SAH trials and registries from 1982 to 2014. Models adjusted for age, sex, history of hypertension, World Federation of Neurological Surgeons grade, Fisher grade, aneurysm size, location, and repair modality, and whether data was from a clinical trial or registry. Analyses were repeated separately for the clinical trials and registries. Missing data were handled with multiple imputation. Results: Overall, 13,343 SAH patients were included. 9,524 (71%) patients had good functional outcome, while 1,608 (12%) died. There was a 0.6% adjusted improvement (95% confidence interval [CI]: 0.5% to 0.7%; p Conclusions: SAH morbidity and mortality decreased from the 1980s to 2010s. This data can be helpful for researchers planning trials, clinicians discussing expected outcomes with patients and family members, and healthcare administrators planning resource utilization.

Introduction: The evaluation of ischemic core is important in acute cerebral infarction with large vessel occlusion. The ischemic core is thought to approximate the region that is difficult to receive collateral circulation. We classified the ischemic core distribution pattern into four types on the basis of the tendency of cerebral blood volume (CBV) decrease in the ischemic core, and examined the prognostic ability. Methods: We included M1 or ICA occlusion which completely recanalized (TICI3) by thrombectomy in our institute from January 2015 to May 2019. The ischemic core was defined as a region where CBV were reduced less than 1.9 ml/100cc. Ischemic core distribution pattern was classified into the following 4 types. Type A: absent of ischemic core. Type B: ischemic core is confined to the basal ganglia and white matter. Type C1: ischemic core is present in the cortex but less than half of MCA region. Type C2: ischemic core is present in the cortex, and more than half of MCA region. The patient characteristics, temporal parameters, ASPECTS and ischemic core distribution pattern were analyzed with mRS0-2 at discharge as a good outcome group. Results: A total of 47 cases (14 ICA, 33 M1) were included. Ischemic core distribution pattern correlated well with mRS at discharge (p Conclusions: The distribution pattern of ischemic core defined by reduced CBV have good correlation with outcome. There is a possibility that it can be used as a simple tool to predict prognosis using CT perfusion in anterior circulation acute large vessel occlusion.

Hypothesis: Our previous study, ADS reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of short-term neurological worsening in non-cardioembolic stroke patients. The aim of the present study is to investigate 1) whether the impact of cilostazol addition to aspirin differ among each stroke subtype, and 2) factors associated with neurological deterioration and/or stroke recurrence in order to find therapeutic target. Methods: This is a retrospective analysis using the ADS databank. Neurological worsening and the rates of stroke recurrence within 14 day of onset were evaluated. Stroke subtype included large-artery atherosclerosis (LAA), lacunae infarct (LI), branch atheromatous disease (BAD), other, and undetermined. Results: Data on 1,160 patients (773 [67%] men; median age, 69 [61-77] years, NIHSS score was 2 [1-4]) were analyzed. At discharge, 167 (14%) were diagnoses as having LAA; LI, 532 (46%); BAD, 173 (15%); other, 132 (11%); and undetermined, 156 (14%). Neurological deterioration and/or recurrence were seen in 130 (11%) patients, and the rates were not different between patients treated with DAPT and aspirin in any stroke subtypes: LAA, 19% (DAPT) vs. 11% (aspirin alone), (p=0.185); LI, 4% vs. 3% (p=0.645); BAD, 33% vs.34%, (p=0.872), other, 8% vs.14% (p=0.272); undetermined, 13% vs. 8% (p=0.301). When we evaluated factors related to the deterioration/recurrence, age (p1.5cm (p Conclusions: Dual antiplatelet therapy using cilostazol and aspirin does not reduce the rate of short-term neurological worsening in each clinical stroke subtype. Improvement of hyperacute therapy targeting the elder patients with elevated blood pressure, large infarct and intracranial stenosis/occlusion should be required.

Introduction: The survey of atrial fibrillation (AF) is routinely recommended in acute stroke case, even in patients without AF on admission, because the AF leads to a sever stroke. Cilostazol is often used for stroke patients without AF in Japan; however, it has the adverse events of palpitation due to the vessels dilatation by increased nitric oxide. We hypothesized that administration of cilostazol may clarify the burden AF in stroke patients without AF. Methods: From our prospective randomized control study, (randomized to dual antiplatelet therapy using cilostazol and aspirin or aspirin alone targeted patients for non-cardioembolic stroke [ADS]), patients assessed the presence of AF were retrospectively analyzed. Presence of AF was detected using ECG monitoring and Holter ECG. All patients were divided into the AF group and the non-AF group and imaging and laboratory findings were compared between the 2 groups. Multivariate regression analysis was conducted to evaluate the independent factors related to new AF. Results: 1194 patients (793 [66%] men; median age [IQR] of 69 [61-77] years, NIHSS score 2 [1-4], onset-to-admission 10.8 [4.7-20.5] hours) patients were included. AF was newly detected in 41 patients (3 by ECG, 21 by the ECG monitoring and 17 by the Holter ECG) during hospitalization. Patients randomized to the combined cilostazol and aspirin therapy frequently had the AF than those to aspirin alone (29/596 [5%] vs. 12/598 [2%], p=0.007). AF group was older than the non-AF group (76 [72-82] vs. 68 [60-77] years, p1.5cm) (p Conclusion: Administration of cilostazol increases the detectability of AF in acute non-cardioembolic stroke.

Purpose: Cerebral hyperperfusion syndrome (CHS) is a rare devastating complication associated with hyperperfusion after carotid endarterectomy. Single photon emission computed tomography (SPECT) is usually used with acetazolamide challenge to measure the cerebrovascular reserve (CVR), and a decreased CVR is indicative of a high risk of post CEA hyperperfusion. However, acetazolamide administration can rarely cause serious adverse effects, and thus, alternative methods may be required. Perfusion computed tomography (PCT) is a rapid, more accessible modality, which can be acquired with CT angiography. PCT seems to be useful as a screening tool in identifying groups at high-risk of hyperperfusion, but its usefulness has not sufficiently investigated. Our purpose was to clarify the relationship between hyperperfusion and the preoperative PCT parameters of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Method: We included patients who underwent carotid endarterectomy in our hospital from 2014 December to 2018 April. PCT was obtained preoperatively and on postoperative day 1. Hyperperfusion is defined as a postoperative CBF of the middle cerebral artery area which has increased twice that of the preoperative value. CHS was defined as any symptom and imaging findings related with hyperperfusion, which include headache, seizure, neurological dysfunction, and any intracranial hemorrhage in the related area. Preoperative CBF, CBV, MTT and other patient characteristics are statistically analyzed between a hyperperfusion group and non-hyperperfusion group. Result: There are 73 patients who underwent CEA during the study period, and hyperperfusion was observed in 5 cases, from which 2 were considered as CHS. In the hyperperfusion group, the preoperative CBF was significantly lower (p=0.0008), and the CBV and MTT significantly higher (p=0.0196, p=0.0002). ROC analysis showed that the PCT parameters with the maximal area under the receiver-operating characteristic curve for hyperperfusion was preoperative MTT with an optimal threshold at 8.0 seconds (sensitivity 100%, specificity 100%). Conclusion: Patient with prolonged preoperative MTT tend to develop hyperperfusion, which is related to CHS.

Introduction: From the results of NASCET and ECST, surgical treatment for carotid artery near occlusion (NO) has not been as effective as of that for severe stenosis. A meta-analysis published in 2015 supported surgical treatment for NO, but this is still controversial because recent large prospective studies such as CREST or ICSS exclude NO. Method: We conducted a retrospective single center case-controlled study in Japan. Among all NO cases from May 2006 to May 2017, we selected those who had internal carotid artery (ICA) without collapse, with collapse but with detection of vascular lumen from neck to intracranium by angiography and MRI, and without mechanical changes of vessel wall. We excluded patients who had ICA with full collapse and without the possibility for expansion. The carotid artery endarterectomy (CEA) or carotid artery stenting (CAS) was performed according to plaque character, position, and expectancy of expansion. The primary outcome was ipsilateral stroke within 90 days after surgery. Secondary outcomes included restenosis of more than 50%, and perioperative complications (postoperative procedural DWI positive, myocardial infarction, death). Result: In the eligible 60 patients, 56 were male, and the median age was 73±6.3. The number of symptomatic lesions and string signs were 27 and 5, and the CEA and CAS groups consisted of 33 and 27 patients, respectively. There was no significant difference between each group in the patient backgrounds other than the age and follow-up period (71 and 76 [p = 0.0093], 63 and 39 months, respectively [p = 0.0185]). Ipsilateral stroke within 90 days after surgery occurred in 0 and 4 patients (p = 0.0328), and restenosis in 7 (3 needed additional CAS) and 3 patients (p = 0.490). The postoperative DWI positive was 7 and 11 (p = 0.095), and all of them were asymptomatic or transient. There were no cases of perioperative myocardial infarction, and perioperative death occurred in 1 patient. Conclusion: CEA group had the advantage of procedural safety but also the risk of restenosis. In CAS group, we can expect good expansions of ICA, but perioperative complications are relatively high. Our results suggest that there exist specific factors including surgical indication which lead to good outcome by surgical treatment.

Hypothesis: The aim of the present study was to investigate the efficacy and safety of antiplatelet (aspirin plus cilostazol) dual therapy for non-cardioembolic stroke patients within 48 h of symptom onset. Methods: ADS is an investigator initiated, a prospective, multicenter (34 hospitals in Japan), randomized, and an aspirin-controlled study. Acute stroke patients with non-cardioembolic stroke within 48 hours of onset were studied. Only patients with preadmission mRS score 0-2 were included. Subjects were randomly allocated to the combination therapy with aspirin 81-200mg plus cilostazol 200mg (Dual group) and the single therapy with aspirin 81-200mg (Aspirin group) for 14 days. After the 14 days, all patients took the cilostazol 200mg for 3 months. Primary outcomes include 1) the neurological worsening within 14 day of onset; and 2) the rates of transient ischemic attack (TIA), stroke recurrence, intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH) within 14 days of onset. Secondary outcome included mRS score at 3 months after stroke. Results: 1,201 patients (796 [66%] men; median age [interquartile range], 69 [61-77] years) were randomized 1:1 to either the dual group or the aspirin group. Initial National Institutes of Health Stroke Scale score was similar as 2 (1-4) in both groups (p=0.617). As a primary outcome, the neurological worsening within 14 days was similarly observed in the dual and in the aspirin group (10.5% vs. 9.7%, P=0.701). The rates of TIA and stroke recurrence in the dual and in the aspirin group were also similar as 0.2% vs. 0.2% (p=1.000), and 1.2% vs. 1.3% (p=1.000), respectively. As a safety outcome, each group had one patient with ICH (0.2% vs. 0.2%, p=1.000). Only 1 patient (0.2%) in the dual group complained of SAH within 14 days of stroke onset, though it was asymptomatic (p=1.000). Regarding the secondary outcome, although preadmission mRS score of 0 was infrequent in the dual group (84% vs. 89%, p=0.054), the rate of mRS 0-1 at 3 months seemed to be frequent in the dual group than aspirin group (69% vs. 64% p=0.075). Conclusions: Dual antiplatelet therapy using cilostazol and aspirin does not reduce the rate of short-term neurological worsening. However, this combined therapy may improve the clinical outcome at 3 months of onset.

Background: Ischemic events caused by carotid artery stenosis are affected not only by stenosis but also by the instability of plaque. In symptomatic low-grade stenosis cases medical treatment is generally performed, but there are cases with repeated recurrence. The purpose of this study is to clarify the clinical features and long-term outcomes in cases of symptomatic low-grade stenosis. Methods: We included seventy-one symptomatic patients with carotid low-grade stenosis ( Results: The mean stenosis rate, rSI and ERR on admission were 20.4, 1.75 and 1.96, respectively. Seventy percent of cases involved intraplaque hemorrhage and positive remodeling. During a mean of 52-months follow-up, a recurrence of ischemic events was confirmed in 33 cases (46%), from which the duration until recurrence was within 7 days (33%), 3 months (18%), 1 year (18%), 2 years (21%), and over 2 years (15%). Nine cases had impending stroke, 3 of which were associated with major artery occlusion. CEA was performed in 28 cases (39%) for impending stroke (25%), recurrence of ischemic events (46%), asymptomatic infarction (7%), and stenosis rate progression (11%). During a mean of 47-months follow-up after CEA, 2 cases of death (fetal intracerebral hemorrhage, asphyxia) and one case of brain stem lacunar infarction were observed, but an ipsilateral ischemic event was not observed. Conclusion: Most of the symptomatic patients with low-grade stenosis had both intraplaque hemorrhage and positive remodeling. The risk of recurrence and stenosis progression was high. CEA might have had a preventive effect against ischemic events in low-grade stenosis.

Backgrounds and Purpose— Predictive value of reflux of anterior spinal artery for recurrent posterior circulation ischemia in bilateral vertebral arteries steno-occlusive disease was evaluated. Methods— We retrospectively reviewed 55 patients with symptomatic posterior circulation stroke caused by bilateral stenotic (>70%) lesions of the vertebral artery. We investigated any correlation of clinical and angiographic characteristics including collateral flow patterns, with recurrent stroke. Risk factors for poor 3-month functional outcome were also evaluated. Results— Recurrent posterior circulation stroke was observed in 15 (27.3%) patients. Multivariable analysis using Cox proportional hazards model showed anterior spinal artery reflux as a significant risk factor for stroke recurrence (adjusted hazard ratio, 19.3 [95% confidence interval, 5.35–69.9]; P P =0.028). Conclusions— In patients with symptomatic bilateral vertebral artery occlusive disease, anterior spinal artery reflux predicted recurrent posterior circulation stroke and poor functional outcome.

Introduction: Plasma D-dimer levels elevate during acute stage of aneurysmal subarachnoid hemorrhage (SAH) and are associated with poor functional outcomes. However, the mechanism in which D-dimer elevation on admission affects functional outcomes remains unknown. Hypothesis: We hypothesize that D-dimer levels on admission are correlated with systemic complications rather than neurological complications, and therefore have an additive predictive value on conventional risk factors for poor functional outcomes. Methods: A total of 187 patients with aneurymal SAH were retrospectively analyzed from a single center, observational cohort database. Correlations of plasma D-dimer levels on admission with patients’ characteristics, initial presentation, neurological complications, and systemic complications were identified. We also evaluated additive value of D-dimer elevation on admission for poor functional outcomes by comparing predictive models with and without D-dimer. Result and Conclusions: D-dimer elevation on admission was associated with increasing age, women, and severity of SAH. Patients with higher D-dimer levels had increased likelihood of nosocomial infections (OR 1.22 [95% CI 1.07-1.39], p = 0.004), serum sodium disorders (OR 1.11 [95% CI 1.01-1.23], p = 0.033), and cardiopulmonary complications (OR 1.20 [95% CI 1.04-1.37], p = 0.01) by multivariable analysis. D-dimer elevation was an independent risk factor of poor functional outcomes (modified Rankin scale 3-6, OR 1.50 [95% CI 1.15-1.95], p = 0.003). A novel prediction model with D-dimer had significantly better discrimination ability for poor outcomes than conventional models without D-dimer, evaluated by C statistics, net reclassification improvement, and integrated discrimination improvement methods. These results suggest that elevated D-dimer levels on admission were independently correlated with systemic complications, and had an additive value for outcome prediction on conventional risk factors after aneurysmal SAH.

Introduction: Intraplaque hemorrhage (IPH) has been reported to be a characteristic feature of a vulnerable plaque, indicated by an area of high signal intensity on carotid MRI. It has been reported that symptomatic low-grade stenosis with IPH is strongly associated with ischemic events, but there are limited data regarding the dynamics of the carotid plaque signal. The aim of this study was to assess the time-dependent change of carotid plaque in the symptomatic patient with low-grade stenosis. Methods: Thirty-eight symptomatic patients with carotid low-grade stenosis (0.31 between time points was considered significant. We then investigated changes in rSI and subsequent ipsilateral ischemic events. Result: Of the 38 patients, there were strong-positive and positive plaque at baseline in 22 and 12 patients, respectively. During a mean follow-up period of 42.5 months, 26 positive plaques (74%) at baseline kept an rSI of >1.25, and all of 4 negative plaques at baseline changed positive. Strong-positive plaques at baseline showed a lower tendency to be negative than positive plaque (p=0.08). Twenty-one of the 38 patients (55%) experienced a total of 26 recurrent ischemic events. In patients who experienced recurrent ischemic events, 19 plaques (73%) were strong-positive and 5 plaques (19%) were positive. Compared to the most recent carotid MRI, rSI at the event was stable in 18 patients (69%) and increased in 8 patients (31%). Conclusions: Most symptomatic plaque with low-grade stenosis retained its hyperintensity after ischemic events and had a high rate of subsequent ipsilateral ischemic events. A sustaining high signal intensity might be associated with an increased risk of subsequent ischemic events. Follow-up observation by carotid MRI has the potential to increase the accuracy of stroke risk stratification in the management of carotid low-grade stenosis.

Background and Purpose— About one half of those who develop adult-onset moyamoya disease experience intracranial hemorrhage. Despite the extremely high frequency of rebleeding attacks and poor prognosis, measures to prevent rebleeding have not been established. The purpose of this study is to determine whether extracranial–intracranial bypass can reduce incidence of rebleeding and improve patient prognosis. Methods— This study was a multicentered, prospective, randomized, controlled trial conducted by 22 institutes in Japan. Adult patients with moyamoya disease who had experienced intracranial hemorrhage within the preceding year were given either conservative care or bilateral extracranial–intracranial direct bypass and were observed for 5 years. Primary and secondary end points were defined as all adverse events and rebleeding attacks, respectively. Results— Eighty patients were enrolled (surgical, 42; nonsurgical, 38). Adverse events causing significant morbidity were observed in 6 patients in the surgical group (14.3%) and 13 patients in the nonsurgical group (34.2%). Kaplan–Meier survival analysis revealed significant differences between the 2 groups (3.2%/y versus 8.2%/y; P =0.048). The hazard ratio of the surgical group calculated by Cox regression analysis was 0.391 (95% confidence interval, 0.148–1.029). Rebleeding attacks were observed in 5 patients in the surgical group (11.9%) and 12 in the nonsurgical group (31.6%), significantly different in the Kaplan–Meier survival analysis (2.7%/y versus 7.6%/y; P =0.042). The hazard ratio of the surgical group was 0.355 (95% confidence interval, 0.125–1.009). Conclusions— Although statistically marginal, Kaplan–Meier analysis revealed the significant difference between surgical and nonsurgical group, suggesting the preventive effect of direct bypass against rebleeding. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/index.htm . Unique identifier: C000000166.

Background: Assessment of plaque vulnerability is important in evaluating the future risk of stroke. Plaque characteristics and plaque volume are important components of plaque vulnerability. Expansive remodeling (ER) is one of the criteria for vulnerable plaque in the coronary arteries, and influences the plaque volume. The aim of this study is risk stratification of carotid plaque through the evaluation of quantitative ER and MRI plaque signal intensity. Methods: We studied and obtained both pre-operation carotid MRI T1-weighted axial and long axis images of 72 patients who underwent carotid endarterectomy or carotid aretery stenting. ER ratio (ERR) was calculated from the ratio of the linear diameter of the artery at the thickest segment of the plaque to the diameter of the artery beyond any poststenotic dilatation on the long axis image on carotid MRI. We also calculated relative plaque signal intensity (rSI) from the axial image and grouped the patients as follows: Group A, rSI≥1.4 and ERR≥1.8; Group B, rSI Results: Of the 72 patientis, the number of patients in each group was as follows: Group A, 20 patients; B, 12 patients; C, 19 patients; D, 21 patients. Fifteen patients (75%) in Group A, 6 patients (50%) in Group B, 8 patients (42%) in Group C and 7 patients (33%) in Group D had ischemic events within 6 months. Ischemic events in Group A was significantly higher than in Group C and D (p Conclusion: The combined assessment of plaque characterization with MRI and morphological evaluation using ERR are useful in risk stratification for carotid lesions.