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Cancer-associated ischemic stroke (CAS) refers to a hypercoagulation disorder related to malignant tumors, especially adenocarcinoma. Carbohydrate antigen (CA) 125 is a mucinous serum marker that might reflect hypercoagulation status, but the association between CA 125 and CAS is unclear across various types of cancer. The aim of this study was to investigate the associations among tumor markers, coagulation markers, and clinical factors in acute ischemic stroke (AIS) patients with active cancer. Consecutive AIS patients with active cancer (a diagnosis or ongoing active therapy for cancer within 6 months) were prospectively enrolled at four hospitals. D-dimer, C-reactive protein (CRP), carcinoembryonic antigen (CEA), CA19-9, and CA 125 levels were measured. Of 120 AIS patients with active cancer, 47 were diagnosed with CAS. CA 125 had the strongest correlations with D-dimer and CRP (ρ = 0.543, p

Background and purpose In this post-hoc analysis using acute dual study dataset, the impacts of cerebral microbleeds (MBs) after mild stroke on clinical outcome were investigated. Methods The number of MBs on admission was categorized as 1) no MBs, 2) MBs 1–4, 3) MBs 5–9, and 4) MBs ≥ 10. The efficacy outcome was defined as neurological deterioration and stroke recurrence within 14 days. Safety outcomes included ICH and/or SAH as well as extracranial hemorrhages. Results Of the 1102 patients, 780 (71%) had no MBs on admission, while 230 (21%) had MBs 1–4, 48 (4%) had MBs 5–9, and 44 (4%) had MBs ≥ 10. The number of MBs was not associated with the neurological deterioration and/or stroke recurrence (p = 0.934), ICH and/or SAH (p = 0.743), and extracranial hemorrhage (p = 0.205). Favorable outcome was seem in 84% in the No MBs group, 83% in the MBs 1–4, 94% in the MBs 5–9, and 85% in the MBs ≥ 10 (p = 0.304). Combined cilostazol and aspirin therapy did not alter any rates of efficacy and safety outcomes among the no MBs, MBs 1–4, MBs 5–9, and MBs ≥ 10 groups compared to aspirin alone (all p > 0.05). By multivariate regression analysis, a history of ICH and diastolic blood pressure were the independent parameters to all of the MBs criteria (presence, MBs ≥ 5, and MBs ≥ 10). Conclusions MBs did not alter the clinical outcome at 3 months of onset. Elevated diastolic blood pressure and a history of ICH were the essential parameters related to the MBs.

Background Isolated basilar artery dissection (IBAD) is a rare but important cause of ischemic stroke. Anti-thrombotic therapy is often used to treat IBAD-related ischemic stroke, but selected cases might need more aggressive treatment. There is no previous report of emergent stenting for IBAD-related ischemic stroke after intravenous thrombolysis. Case presentation A 53-year-old Japanese woman was admitted to our hospital with disturbance of consciousness, right hemiplegia, severe dysarthria, and total gaze paralysis. Brain magnetic resonance imaging revealed no ischemic lesion, but magnetic resonance angiography showed stenosis in the basilar artery. After initiation of intravenous thrombolysis, her neurological symptoms dramatically improved. Five hours later, however, her symptoms deteriorated again. Cerebral angiography showed IBAD. Emergent stenting was successfully performed. At 90 days after stroke onset, she had no significant disability, with a modified Rankin scale score of 1. Conclusions Emergent stenting can be an effective treatment for patients with IBAD-related ischemic stroke who are resistant to IV-rtPA.

Background and Purpose— The treatment and prognosis of acute large vessel occlusion with mild symptoms have not been sufficiently studied. The present study aimed to investigate the clinical or radiological predictors of clinical outcome in patients with stroke with mild symptoms due to acute large vessel occlusion. Methods— Of 2420 patients with acute large vessel occlusion in the RESCUE-Japan Registry 2 (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Registry 2), a multicenter prospective registry in Japan, patients with modified Rankin Scale scores of 0 to 2 before onset and initial National Institutes of Health Stroke Scale (NIHSS) scores of 0 to 5 were examined in post hoc analysis. We examined the clinical and radiological characteristics associated with a favorable outcome (modified Rankin Scale score, 0–2 at 90 days) using multivariate analysis, as well as the factors associated with a favorable outcome in patients treated with endovascular therapy. Results— We analyzed 272 patients (median age, 73 years; median NIHSS score on admission, 3). Eighty-six (31.6%) patients were treated with intravenous recombinant tissue-type plasminogen activator, 54 (19.9%) underwent endovascular therapy, and 208 (76.5%) showed a favorable outcome. In multivariate analysis, age P Conclusions— Younger age, lower initial NIHSS score, intravenous recombinant tissue-type plasminogen activator, and absence of hyperglycemia were independently associated with a favorable outcome in patients with acute large vessel occlusion with low NIHSS scores. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02419794.

Although carotid endarterectomy (CEA) is an established procedure, technical modifications are required when anatomical features are unusual. The present study aimed to determine the characteristics of diagnostic features, surgical management, and outcomes of patients with a twisted carotid bifurcation (TCB). We assessed 108 consecutive patients by cervical carotid echography (CCE) and black-blood magnetic resonance imaging (BB-MRI) before they underwent 115 CEA procedures. We classified carotid bifurcation (CB) anatomy based on anteroposterior findings of the internal carotid artery (ICA) and external carotid artery (ECA) determined by cerebral or three-dimensional computed tomographic angiography as follows. The ICA and ECA ran laterally and medially, respectively, in Type 1, overlapped in Type 2, and the ICA and ECA ran medially and laterally, respectively, in Type 3. We also classified the patients according to whether or not they had a TCB and compared their diagnostic findings, clinical characteristics, and surgical outcomes. The numbers of patients with Types 1, 2, and 3 were 74 (64.4%), 32 (27.8%), and 9 (7.8%), respectively, and 13 (11.3%) with a TCB included four patients with Type 2 and all nine patients with Type 3. The appearance of Type 3 differed from that of the other two types on CCE and BB-MR images. After correcting the anatomical location of a TCB, surgical duration and adverse event rates did not significantly differ between patients with and without a TCB. Patients with a TCB could safely undergo CEA after correcting the ICA to the normal position.

Background: The present study aimed to clarify the association between left atrial (LA) size and ischemic events after ischemic stroke or transient ischemic attack (TIA) in patients with nonvalvular atrial fibrillation (NVAF). Methods: Acute ischemic stroke or TIA patients with NVAF were enrolled. LA size was classified into normal LA size, mild LA enlargement (LAE), moderate LAE, and severe LAE. The ischemic event was defined as ischemic stroke, TIA, carotid endarterectomy, carotid artery stenting, acute coronary syndrome or percutaneous coronary intervention, systemic embolism, aortic aneurysm rupture or dissection, peripheral artery disease requiring hospitalization, or venous thromboembolism. Results: A total of 1,043 patients (mean age, 78 years; 450 women) including 1,002 ischemic stroke and 41 TIA were analyzed. Of these, 351 patients (34%) had normal LA size, 298 (29%) had mild LAE, 198 (19%) had moderate LAE, and the remaining 196 (19%) had severe LAE. The median follow-up duration was 2.0 years (interquartile range, 0.9–2.1). During follow-up, 117 patients (11%) developed at least one ischemic event. The incidence rate of total ischemic events increased with increasing LA size. Severe LAE was independently associated with increased risk of ischemic events compared with normal LA size (multivariable-adjusted hazard ratio, 1.75; 95% confidence interval, 1.02–3.00). Conclusion: Severe LAE was associated with increased risk of ischemic events after ischemic stroke or TIA in patients with NVAF.

Postoperative rebleeding (PR) is one of the most severe complications of endoscopic surgery, often performed to remove spontaneous intracerebral hemorrhage (sICH). However, the risk factors for PR remain unclear. This study retrospectively investigated whether increased preoperative plasma plasmin-α2-plasmin inhibitor complex (PIC) levels, indicating activation of fibrinolysis, are associated with PR. A total of 101 patients underwent endoscopic surgery to evacuate sICH at our institution from January 2010 to June 2019, and 79 patients who underwent examinations of plasma PIC levels at admission with available radiographical data were included. Correlations between PR and increased plasma PIC levels were retrospectively evaluated. PR occurred in eight patients (10.1%), and high PIC levels (≥ 4 or 6 μg/ml) were significantly associated with PR. The sensitivities employing high PIC levels of ≥ 4 μg/ml and ≥ 6 μg/ml were both 0.63, and the specificities using the same PIC levels were 0.86 and 0.92, respectively. Multivariable analyses showed that high plasma PIC levels of ≥ 4 μg/ml (odds ratio (OR), 12.77; 95% confidence interval (CI), 1.65–98.77; p = 0.02) or ≥ 6 μg/ml (OR, 18.33; 95% CI, 2.32–144.82; p = 0.006) were independent predictors of PR. This study found that increased plasma PIC levels were associated with PR following the endoscopic evacuation of sICHs, indicating that increased plasma PIC levels could be potentially used to predict PR. Further studies are needed to establish new surgical strategies and adjuvant treatments to improve surgical outcomes in patients with sICH prone to PR.

Introduction: Mechanical thrombectomy (MT) for acute ischemic stroke has become a standard therapy, and the recanalization rate has significantly improved. However, some cases of unsuccessful recanalization still occur. We aimed to clarify patient factors associated with unsuccessful recanalization after MT for acute ischemic stroke. Methods: This was a single-center, retrospective study of 119 consecutive patients with anterior circulation acute ischemic stroke who underwent MT at our hospital between April 2015 and March 2019. Successful recanalization after MT was defined as modified Treatment in Cerebral Ischemia (mTICI) grade 2b or 3, and unsuccessful recanalization was defined as mTICI grades 0–2a. Several factors were analyzed to assess their effect on recanalization rates. Results: Successful recanalization was achieved in 88 patients (73.9%). The univariate analysis showed that female sex (38.6 vs. 67.7%, p = 0.007), a history of hypertension (53.4 vs. 83.9%, p = 0.003), and a longer time from groin puncture to recanalization (median 75 vs. 124 min, p < 0.001) were significantly associated with unsuccessful recanalization. The multivariate analysis confirmed that female sex (OR 3.18; 95% CI 1.12–9.02, p = 0.030), a history of hypertension (OR 4.84; 95% CI 1.32–17.8, p = 0.018), M2–3 occlusion (OR 4.26; 95% CI 1.36–13.3, p = 0.013), and the time from groin puncture to recanalization (per 10-min increase, OR 1.22; 95% CI 1.09–1.37, p < 0.001) were independently associated with unsuccessful recanalization. Conclusion: Female sex and a history of hypertension might be predictors of unsuccessful recanalization after MT for anterior circulation acute ischemic stroke. Further studies are needed to fully evaluate predictors of recanalization.

Objective Limited data exist regarding the comparative detailed clinical characteristics of patients with ischemic stroke (IS)/transient ischemic attack (TIA) and intracerebral hemorrhage (ICH) receiving oral anticoagulants (OACs). Methods The prospective analysis of stroke patients taking oral anticoagulants (PASTA) registry, a multicenter registry of 1,043 stroke patients receiving OACs [vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulant (NOACs)] across 25 medical institutions throughout Japan, was used. Univariate and multivariable analyses were used to analyze differences in clinical characteristics between IS/TIA and ICH patients with atrial fibrillation (AF) who were registered in the PASTA registry. Results There was no significant differences in cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia, smoking, or alcohol consumption (all p0.05), between IS/TIA and ICH among both NOAC and VKA users. Cerebral microbleeds (CMBs) [odds ratio (OR), 4.77; p0.0001] were independently associated with ICH, and high brain natriuretic peptide/N-terminal pro B-type natriuretic peptide levels (OR, 1.89; p=0.0390) were independently associated with IS/TIA among NOAC users. A history of ICH (OR, 13.59; p=0.0279) and the high prothrombin time-international normalized ratio (PT-INR) (OR, 1.17; p0.0001) were independently associated with ICH, and a history of IS/TIA (OR, 3.37; 95% CI, 1.34-8.49; p=0.0101) and high D-dimer levels (OR, 2.47; 95% CI, 1.05-5.82; p=0.0377) were independently associated with IS/TIA among VKA users. Conclusion The presence of CMBs, a history of stroke, natriuretic peptide and D-dimer levels, and PT-INR may be useful for risk stratification of either IS/TIA or ICH development in patients with AF receiving OACs.

Background Thrombosis is a dynamic process, and a thrombus undergoes physical and biochemical changes that may alter its response to reperfusion therapy. This study assessed whether thrombus age influenced reperfusion quality and outcomes after mechanical thrombectomy for cerebral embolism. Methods We retrospectively evaluated 185 stroke patients and thrombi that were collected during mechanical thrombectomy at three stroke centers. Thrombi were pathologically classified as fresh or older based on their granulocytes' nuclear morphology and organization. Thrombus components were quantified, and the extent of NETosis (the process of neutrophil extracellular trap formation) was assessed using the density of citrullinated histone H3-positive cells. Baseline patient characteristics, thrombus features, endovascular procedures, and functional outcomes were compared according to thrombus age. Results Fresh thrombi were acquired from 43 patients, and older thrombi were acquired from 142 patients. Older thrombi had a lower erythrocyte content (p Conclusion An older thrombus delays reperfusion after mechanical thrombectomy for ischemic stroke. Adding therapies targeting thrombus maturation may improve the efficacy of mechanical thrombectomy.

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Background and Purpose: IV alteplase at 0.6 mg/kg for acute wake-up and unclear onset strokes was recommended in Japanese stroke guidelines in March 2019. We determined the safety and effectiveness of this newly recommended thrombolysis in clinical practice. Methods: This is a multicenter observational study, enrolling acute ischemic stroke patients with a time last-known-well >4.5 h who have a mismatch between DWI and FLAIR treated with intravenous alteplase. The safety outcomes are intracranial hemorrhage (ICH) with neurological deterioration within 36 h after thrombolysis, all cause deaths within 90 days, and adverse events. The efficacy outcomes are functionally independence defined as a mRS score of 0-1 at 90 days, and NIHSS change at 24h from baseline. Results: Between 2019 March and 2020 March, 63 patients (33 females; age, 74±11y; premorbid functionally independence, 50 (82%); median NIHSS on admission, 11) were enrolled at 14 hospitals. Of them, 40 patients (63%) recognized stroke symptoms at wake-up time, and median time between last-known-well and admission was 6.5 h. Baseline MRA showed any vessel occlusion in 52 patients (88%). IV alteplase was disrupted in one patient. Two patients (3%) had symptomatic ICH (≥4 increase in NIHSS) within 36 h. NIHSS change was -5.1±8.1. Twenty-one patients (36%) had functionally independence at discharge and there was no death during acute hospitalization. Of the overall 63 patients, 22 also underwent mechanical thrombectomy (36%, 72±9y, median NIHSS 16), showing no symptomatic ICH, mean NIHSS change of -8.9±7.5, and 8 patients (42%) had functionally independence at discharge. Conclusions: In clinical practice, IV alteplase for wake-up and unclear onset stroke patients with DWI-FLAIR mismatch seemed to be safe and effective compared with previous randomized control trials. Mechanical thrombectomy could be combined with alteplase safely and effectively.

Background: Thrombus formation is a dynamic process and the structure of thrombus changes with time. We examined the effect of thrombus age on the quality of reperfusion and prognosis in mechanical thrombectomy for acute ischemic stroke. Methods: We examined 185 patients who underwent mechanical thrombectomy in 3 stroke centers between January 2015 and December 2019, and pathologically evaluated their retrieved thrombi. Thrombi were classified according to histologically accepted definitions as: fresh, with intact granulocytes; and older, with organization or lytic changes characterized by areas of colliquation necrosis and karyorrhexis of granulocytes. The extent of neutrophil extracellular trap formation (NETosis) in thrombi was assessed on the basis of the density of citrullinated histone H3 positive particles. Baseline characteristics, time to successful reperfusion (eTICI 2b or more), thrombus feature, and functional outcome were compared between the patients with fresh and older thrombi. Results: Fresh thrombi were obtained from 43 patients (23%), and older thrombi, from 142 patients (77%). The stroke subtypes and onset-to-puncture time did not significantly differ between the two groups. The erythrocyte content was higher, whereas the density of macrophages and extent of NETosis were lower in the fresh thrombi. Fresh thrombi were associated with shorter time from puncture to recanalization (median, 48 vs. 62 min, P = 0.004; Figure), and fewer passes before reperfusion (median, 1 vs. 2; P < 0.001). In the multivariate analysis, favorable outcome (mRS ≤ 2) was observed more often in patients with fresh thrombi (adjusted OR, 2.76; 95% CI, 1.20-6.32). Conclusions: An older thrombus necessitated longer procedure time and more device passes, which deteriorate the functional outcome of patients with acute ischemic stroke. Thrombus maturation may contribute to resistance to mechanical thrombectomy.

Background Statins have been associated with reduced recurrence and better functional outcomes in patients with acute ischemic stroke. However, the effect of statins in patients with acute large vessel occlusion (LVO) is not well scrutinized. Methods and Results RESCUE (Recovery by Endovascular Salvage for Cerebral Ultra‐Acute Embolism)‐Japan Registry 2, a physician‐initiated registry, enrolled 2420 consecutive patients with acute LVO who were admitted to 46 centers across Japan within 24 hours of onset. We compared patients with and without statin use after acute LVO onset (statin group and nonstatin group, respectively) in terms of the modified Rankin scale at 90 days. We estimated that the odds ratios for the primary outcome was modified Rankin scale and we estimated the odds ratios for a 1‐scale lower modified Rankin scale adjusting for confounders. After excluding 12 patients without LVO and 9 patients without follow‐up, the mean age of 2399 patients was 75.9 years; men accounted for 55% of patients. Statins were administered to 447 (19%) patients after acute LVO onset. Patients in the statin group had more atherothrombotic cerebral infarctions (34.2% versus 12.1%, P P P P =0.02). The mortality at 90 days was lower in the statin group (4.7%) than the nonstatin group (12.5%; P P =0.02). Conclusions Statin administration after acute LVO onset is significantly associated with better functional outcome and mortality at 90 days.

Background Our previous trial acute dual 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. Present post-hoc analysis investigated whether the impact of combined cilostazol and aspirin differed among stroke subtypes and factors associated with neurological deterioration and/or stroke recurrence. Methods Using the ADS registry, the rate of neurological deterioration, defined as clinical worsening and/or recurrent stroke, including transient ischemic attack was calculated. Stroke subtypes included large-artery atherosclerosis (LAA), small vessel occlusion (SVO), other determined etiology (Others), and undetermined etiology of stroke (Undetermined). Results Data of 1022 patients were analyzed. Deterioration was seen in 104 (10%) patients, and the rates were not markedly different between patients treated with DAPT vs. aspirin in any stroke subtypes: LAA, 19% vs. 11%, (p=0.192); SVO, 10% vs. 10% (p=1.000); Others, 6% vs. 6% (p=1.000); Undetermined, 11% vs. 8% (p=0.590). Diabetes mellitus was the independent factor associated with deterioration (odds ratio 4.360, 95% confidence interval 1.139–16.691, p=0.032) in the LAA group. Age (1.030 [1.004–1.057], p=0.026), systolic blood pressure (1.012 [1.003–1.022], p=0.010), and infarct size (2.550 [1.488–4.371], p=0.001) were associated with deterioration in SVO group, and intracranial stenosis/occlusion was associated with it in the Undetermined group (3.744 [1.138–12.318], p=0.030). Conclusions Combined cilostazol and aspirin did not reduce the rate of short-term neurological deterioration in any clinical stroke subtype. The characteristics of patients whose condition deteriorates in the acute period may differ based on the stroke subtypes.

The Japanese Society of Neurology has held an annual workshop for stroke education since September 2018 for young members of the society and medical students to take an interest in stroke medicine and stroke research and to contribute to conquest of stroke, a national disease. The third annual workshop will be held in the National Cerebral and Cardiovascular Center, Osaka in September 2020 also with the support of the Japan Stroke Society. Designated lecturers are preparing for presentation of their own devising. Here, brief abstracts of educational lectures and special statements on career formation of vascular neurologists are introduced.

Background and Purpose— Disease management is a healthcare strategy that includes self-management education and treatment coordination. We conducted a randomized controlled trial to determine whether a disease management program intervention could improve risk factor profiles and, thus, reduce the recurrence of stroke and other cardiovascular diseases. Methods— This study is a prospective randomized, open-label, parallel group study involving outpatients with a history of stroke. Between September 2010 and November 2012, we enrolled patients aged between 40 and 80 years who experienced their last ischemic stroke event or transient ischemic attack within 1 year. After stratifying by the ischemic stroke subtype, 321 subjects (67.5±8.5 years, 95 female) were randomly assigned to either the disease management program intervention group (n=156) or the usual care group (n=165). The primary end point of this study was the difference in the Framingham risk score (general cardiovascular disease 10-year risk) from baseline. The secondary end points of this study included stroke recurrence, onset of cardiovascular disease, all-cause mortality, and all vascular events. Results— Regarding the primary end point, there was no significant difference in the changes in the Framingham risk score at any follow-up time between the groups. The incidence of stroke recurrence tended to be lower in the disease management program intervention group, although no significant difference was found (hazard ratio, 0.49; 95% CI, 0.19–1.29). Conclusions— We were unable to demonstrate a clear benefit of disease management program intervention. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02121327.

Aims The bleeding risk of current antithrombotic strategies in clinical settings, including recently developed agents, needs to be clarified. Methods and Design In an investigator-initiated, prospective, multicentre, observational study, patients with cerebrovascular or cardiovascular diseases who were taking oral antiplatelet or anticoagulant agents were enrolled. Compulsory multimodal magnetic resonance images were acquired at baseline to assess cerebral small vessel disease. Six-month follow-up will be performed for two years. The primary outcome is major bleeding as defined by the International Society on Thrombosis and Hemostasis. Results Between October 2016 and March 2019, 5306 patients (71.7 ± 11.2 years old, 1762 women) were enrolled. Previous intracranial haemorrhage was documented in 181 patients (3.4%), cerebrovascular disease (including asymptomatic) requiring antithrombotic therapy in 5006 patients (94.3%), and atrial fibrillation in 1061 patients (20.0%). At entry, 3726 patients (70.2%) were taking antiplatelet agents alone, including 551 (10.4%) using dual antiplatelet agents, 1317 (24.8%) taking anticoagulants alone, and the remaining 263 (5.0%) taking both. The leading antiplatelet agent was clopidogrel (2014 patients), and the leading combination of dual antiplatelet medication was clopidogrel plus aspirin (362). Use of direct oral anticoagulants (1029 patients, 19.4%) exceeded warfarin use (554, 10.4%). The number of pivotal bleeding events exceeded 200 in April 2020. Conclusions This study is expected to provide the incidence of bleeding complications of recent oral antithrombotics in clinical practice and identify their associations with underlying small vessel disease and other biomarkers. Novel risk stratification models for bleeding risk will be able to be created based on the study results.

Carotid revascularization may be considered for severe stenosis, but its use for symptomatic mild stenosis (50%) with vulnerable plaque or ulcer remains uncertain. The characteristics of patients with symptomatic mild stenosis who underwent revascularization are reviewed.The subjects of this study were 18 patients with symptomatic mild stenosis (50%) on angiography from among 175 patients who underwent revascularization in our department. The plaques were evaluated by black-blood magnetic resonance imaging (BB-MRI) and ultrasonography (US) and classified into 2 types: type 1 (n = 15), a lesion with an ulcer or mobile plaque or thrombosis on angiography or US; and type 2 (n = 3), a lesion without any of the above. Fourteen patients underwent carotid endarterectomy (CEA), and 4 patients underwent carotid artery stenting.The stenosis on angiography was 27.2% ± 10.7 (5%-41%), and the area carotid artery stenosis rate on US was 69.8 ± 14.5% (44.5%-97%). The stenosis rate of these 2 methods was not at all correlated. In type 1 plaque that underwent CEA, 10 of 11 patients had vulnerable plaque by histopathology, and 1 patient had thrombus on the plaque by operative findings. In type 2 plaque that underwent CEA, all patients had vulnerable plaque by histopathology. During the follow-up period, none of the patients had restenosis or stroke.The findings of US and BB-MRI in patients with symptomatic mild stenosis (50%) on angiography are important for determining treatment. If BB-MRI or US shows the findings of vulnerable plaque in mild stenosis, surgical treatment may be considered for these patients.

BACKGROUND We determined the 2-year long-term risk-benefit profile in patients with stroke or transient ischemic attack (TIA) receiving warfarin or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry in Japan.Methods and Results:NVAF patients within 7 days after onset of ischemic stroke/TIA were enrolled in 18 stroke centers. Outcome measures included ischemic and bleeding events and death in the 2-year follow-up period. We enrolled 1,116 patients taking either warfarin (650 patients) or DOACs (466 patients) at acute hospital discharge. DOAC users were younger and had lower National Institutes of Health Stroke Scale, CHADS2and discharge modified Rankin Scale scores than warfarin users (P

Background The mechanism of progressive neurological deficit in patients with recent small subcortical infarcts has not yet been clarified. Inflammatory biomarkers and the use of cilostazol may be associated with this phenomenon. Methods Between May 2013 and April 2014, we evaluated consecutive first-ever patients with stroke due to recent small subcortical infarcts within 48 hours of onset. We divided patients into 2 groups according to the use of antiplatelet agents (cilostazol with or without aspirin versus aspirin alone). Plasma biomarkers such as matrix metalloproteinase-9, interleukin-6, high sensitive C-reactive protein, and amyloid β precursor protein (APP770, indicating endothelial dysfunction) were measured twice: (1) within 24 hours; and (2) 1 week after their admission. Multivariable logistic regression analyses were performed to identify the variables independently associated with progressive neurological deficit and poor functional outcome. Results We analyzed 41 patients (male: 63.4%, mean age: 70.8 years). Most of the patients (90%) who were treated with cilostazol were concomitantly treated with aspirin. Matrix metalloproteinase-9 and high sensitive C-reactive protein were higher in patients with progressive neurological deficit compared with those without. APP770 were more likely to be decreased in cilostazol group compared with aspirin group. Multivariable analyses show that traditional risk factors such as age and National Institutes of Health Stroke Scale scores were independently associated with both progressive neurological deficit and poor functional outcome. Conclusions Inflammatory biomarkers may be associated with progressive neurological deficit. Early initiation of cilostazol may decrease the levels of plasma biomarkers.

Background and Purpose— Stroke is the most frequent severe clinical event in patients with Fabry disease. We aimed to evaluate the cerebral magnetic resonance imaging findings of patients with Fabry disease and assess their association with future stroke risk after enzyme replacement therapy (ERT) induction. Methods— We retrospectively reviewed the magnetic resonance imaging findings of 25 patients with Fabry disease. Of these, 12 adult patients without prior stroke or ERT were enrolled to evaluate the association between baseline magnetic resonance imaging findings and stroke occurrence after ERT initiation. We assessed white matter hyperintensities, periventricular hyperintensities, and basilar artery diameter as neuroimaging markers. Results— The mean age of participants was 38.8±16.8 years. Fourteen patients (56.0%) were women. White matter hyperintensities and periventricular hyperintensities were observed in 15 and 13 cases, respectively. The mean basilar artery diameter was 3.2±0.55 mm. Two patients demonstrated old infarct lesions. Three of 12 patients in whom ERT was initiated had symptomatic stroke after baseline magnetic resonance imaging. Of these, 2 developed stroke within 6-month post-ERT initiation. The baseline basilar artery diameter was larger in patients who developed stroke than in those who did not (4.0±0.40 versus 2.9±0.49 mm, P =0.02). Conclusions— Basilar artery diameter may be associated with stroke risk after ERT initiation among Japanese patients with Fabry disease.

D-dimer levels are used in several clinical settings, such as in predicting venous thrombosis, cardioembolic stroke and cancer status. In the present study, we investigated the associations between plasma D-dimer levels at admission, clinical characteristics and mortality at discharge in cryptogenic stroke patients. We also investigated whether D-dimer levels can predict long-term outcomes in those patients, including those with and without right-to-left shunt (RLS). Acute cryptogenic stroke patients (n = 295, 72 ± 13 years old) were consecutively enrolled and retrospectively analyzed. We defined the cryptogenic stroke as an undetermined etiology according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Plasma D-dimer levels at admission were evaluated. Assessments for RLS were performed using saline contrast-transcranial Doppler ultrasonography or contrast-transesophageal echography. Survivors (at discharge) underwent follow-up for up to 3 years after stroke onset. Of the total enrolled cohort, 17 patients died at discharge. D-dimer levels correlated with initial National Institutes of Health Stroke Scale (NIHSS) score (r = 0.391, P

Background: We aimed to clarify associations between pre-admission risk scores (CHADS2, CHA2DS2-VASc, and HAS-BLED) and 2-year clinical outcomes in ischemic stroke or transient ischemic attack (TIA) patients with non-valvular atrial fibrillation (NVAF) using a prospective, multicenter, observational registry. Methods: From 18 Japanese stroke centers, ischemic stroke or TIA patients with NVAF hospitalized within 7 days after onset were enrolled. Outcome measures were defined as death/disability (modified Rankin Scale score ≥3) at 2 years, 2-year mortality, and ischemic or hemorrhagic events within 2 years. Results: A total of 1,192 patients with NVAF (527 women; mean age, 78 ± 10 years), including 1,141 ischemic stroke and 51 TIA, were analyzed. Rates of death/disability, mortality, and ischemic or hemorrhagic events increased significantly with increasing pre-admission CHADS2 (p for trend p for trend = 0.024 for events), CHA2DS2-VASc (p for trend p for trend = 0.004 for death/disability, p for trend p for trend = 0.024 for events) scores. Pre-admission CHADS2 (OR per 1 point, 1.52; 95% CI 1.35–1.71; p p p = 0.016 for events), CHA2DS2-VASc (1.55, 1.41–1.72, p < 0.001; 1.21, 1.12–1.30, p < 0.001; 1.17, 1.07–1.27, p < 0.001; respectively), and HAS-BLED (1.33, 1.17–1.52, p < 0.001; 1.23, 1.10–1.38, p < 0.001; 1.18, 1.05–1.34, p = 0.008; respectively) scores were independently associated with all outcome measures. Conclusions: In ischemic stroke or TIA patients with NVAF, all pre-admission risk scores were independently associated with death/disability at 2 years and 2-year mortality, as well as ischemic or hemorrhagic events within 2 years.

Background and Purpose: The characteristics of direct oral anticoagulant (DOAC)-related intracerebral hemorrhage (ICH) have not been fully clarified. We planned to recruit patients prospectively and to investigate the characteristics and outcomes in patients with ICH receiving direct oral anticoagulant (DOAC) and warfarin treatment. Methods: The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke patients receiving OAC. Patient enrollment started in April 2016 at 25 tertiary centers across Japan. We compared imaging, clinical characteristics, and discharge modified Rankin Scale (mRS) between DOAC- and warfarin-related ICH patients with atrial fibrillation (AF). Results: A total of 154 patients (51 women; median age 77 [quartiles 69-87] years) were analyzed. Of these, 111 patients (72%) received prior DOAC treatment and the remaining 43 (28%) received prior warfarin treatment (Fig. A, B and C). There were no relevant differences in clinical and hematoma characteristics between DOAC- and warfarin-related ICH regarding baseline hematoma volume (median [quartiles]: DOAC, 11 [5-23] mL vs. warfarin, 12 [5-30] mL; P =0.95), rate of hematoma expansion (DOAC, 12/111 [11%] vs. warfarin, 4/43 [9%]; P =0.80), rate of subcortical hemorrhage (DOAC, 15/111 [11%] vs. warfarin, 10/43 [9%]; P =0.80) and the proportion of patients with unfavorable outcome (mRS, 4-6: DOAC 76/108 [70%] vs. warfarin 23/38 [61%]; P =0.26). Cerebral microbleeds (CMBs) were detected more frequently in DOAC group than in warfarin (47/76 [62%] vs. 11/32 [34%]; P Conclusions: Our results showed that there were no significant differences in hematoma characteristics and functional outcome among AF patients with DOAC- or warfarin-related ICH.

Background and Purpose: The characteristics of patients with stroke prior receiving direct oral anticoagulant (DOAC) have not been fully clarified. We planned to recruit patients prospectively and to investigate the characteristics and outcomes in stroke patients taking DOAC and warfarin treatment prior to the event. Methods: The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke patients receiving OAC. Patient enrollment started in April 2016 at 25 tertiary centers across Japan. We compared clinical characteristics and discharge modified Rankin Scale (mRS) between DOAC-and warfarin-treatment in patients with atrial fibrillation (AF). Results: A total of 580 patients (231 women; median age 80 [quartiles 73-84] years) were analyzed (Fig. A). Of these, 365 patients (63%) received prior DOAC treatment and the remaining 215 (37%) received prior warfarin treatment (Fig. B and C). There were significant differences in clinical characteristics and outcome between DOAC-and warfarin-treatment prior to the event regarding initial NIHSS score (median [quartiles]: DOAC, 4 [2-16] vs. warfarin, 9 [3-21]; P =0.0001), rate of medium-large size of infarct (DOAC, 202/340 [59%] versus warfarin, 152/203 [75%]; P =0.0003) and the proportion of patients with favorable outcome (mRS, 0-3: DOAC 218/354 [62%] vs. warfarin 108/212 [49%]; P =0.0036). Subclassification according to DOAC dosing revealed patients with low-dose (259/365; 71%) to be older and to have a higher NIHSS score compared with regular dose (low-dose, 5 [2-17] vs. regular-dose, 3 [1-11]; P =0.0023) (Fig. D). Type of DOAC agent did not result in relevant differences in clinical characteristics or outcome (Fig. E). Conclusions: Our results showed that patients with DOAC treatment before the event showed smaller infarct size, milder initial stroke severity, and favorable outcome compared to patients with warfarin.

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.

Background: Cerebral arterial dissection is considered a rare disease, but recent advances in diagnostic imaging have increased the likelihood of its diagnosis. In particular, Black-Blood (BB) MRI T1 weighted imaging (BB-MRI) enables the diagnosis of cerebral arterial dissection by reducing the signal in the vascular lumen and detecting a high signal from the hematoma in the false lumen. However, the changes in the hematoma over time are still unknown. In this study, these changes were investigated retrospectively. Methods: This study included patients who were admitted to the Stroke Department of the Japanese Red Cross Okayama Hospital from April 2015 to May 2019 and diagnosed with cerebral arterial dissection at discharge based on the imaging criteria of the spontaneous cervicocephalic arterial dissections study-Japan (SCADS-J). The ratios of the signal intensity from the arterial dissection sites to the signal intensity from the normal blood vessel walls (BB-ratio = dissected vessel wall T1 value/normal vessel wall T1 value) were calculated based on when the B-MRI images were taken. The period from the onset of the disease was analyzed. Results: During this study, 646 acute stroke patients were hospitalized, and cerebral arterial dissection was confirmed at discharge in 16 patients (mean age, 57 years; 14 men) based on the diagnostic imaging criteria of the SCADS-J. For the 12 patients who underwent BB-MRI within 1 week of onset, the BB-ratio increased over the first week and peaked at a median of 10.5 days (1st IQR 8.75-3rd 15.25), with a mean BB-ratio of 3.35 (SD 1.00). Discussion: The signal intensity of the BB-MRI T1 weighted images for intramural hematoma increased 1 week after the onset of cerebral arterial dissection. Therefore, diagnoses must account for the length of time elapsed since disease onset.

Background and Purpose— We aimed to compare outcomes of ischemic stroke patients with nonvalvular atrial fibrillation between earlier and later initiation of direct oral anticoagulants (DOACs) after stroke onset. Methods— From data for 1192 nonvalvular atrial fibrillation patients with acute ischemic stroke or transient ischemic attack in a prospective, multicenter, observational study, patients who started DOACs during acute hospitalization were included and divided into 2 groups according to a median day of DOAC initiation after onset. Outcomes included stroke or systemic embolism, major bleeding, and death at 3 months, as well as those at 2 years. Results— DOACs were initiated during acute hospitalization in 499 patients in median 4 (interquartile range, 2–7) days after onset. Thus, 223 patients (median age, 74 [interquartile range, 68–81] years; 78 women) were assigned to the early group (≤3 days) and 276 patients (median age, 75 [interquartile range, 69–82] years; 101 women) to the late (≥4 days) group. The early group had lower baseline National Institutes of Health Stroke Scale score and smaller infarcts than the late group. The rate at which DOAC administration persisted at 2 years was 85.2% overall, excluding patients who died or were lost to follow-up. Multivariable Cox shared frailty models showed comparable hazards between the groups at 2 years for stroke or systemic embolism (hazard ratio, 0.86 [95% CI, 0.47–1.57]), major bleeding (hazard ratio, 1.39 [95% CI, 0.42–4.60]), and death (hazard ratio, 0.61 [95% CI, 0.28–1.33]). Outcome risks at 3 months also did not significantly differ between the groups. Conclusions— Risks for events including stroke or systemic embolism, major bleeding, and death were comparable whether DOACs were started within 3 days or from 4 days or more after the onset of nonvalvular atrial fibrillation–associated ischemic stroke or transient ischemic attack. Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01581502.

Background We hypothesized that administration of cilostazol may clarify the occult atrial fibrillation (AF) during hospitalization in mild stroke patients, who has no history of AF. Methods From our prospective non-cardioembolic stroke study, randomized to dual antiplatelet therapy using cilostazol and aspirin or aspirin alone trial (ADS), data on the presence or absence of AF were retrospectively analyzed. In the ADS, during hospitalization, as a routine examination, presence of AF was investigated using electrocardiogram (ECG), ECG monitoring and Holter ECG. Multivariate regression analysis was conducted to evaluate the independent parameters related to the AF. Clinical outcome at 3 months was evaluated using modified Rankin Scale (mRS) score. Results Data on 1194 patients (793 [66%] men; median age [interquartile range] of 69 [61–77] years, National Institutes of Health Stroke Scale score 2 [1–4], onset-to-admission 10.8 [4.7–20.5] hours) were retrospectively analyzed. AF was newly detected in 41 (3%) patients (3 by ECG, 21 by the ECG monitoring and 17 by the Holter ECG) during hospitalization. Patients treated with combined cilostazol and aspirin therapy frequently had the AF than those took aspirin alone (5% vs. 2%, p = .007). Multivariate regression analysis showed that cilostazol administration was one of the independent factors for new-AF (odds ratio 2.672, 95%CI: 1.205–5.927, p = .016). The frequency of mRS 0-1 was 68% in the new-AF group and 67% in the non-AF group (p = 1.000). Conclusion Cilostazol therapy may increase the detectability of AF in acute non-cardioembolic stroke, though the new-AF was not related to clinical outcome at 3 months.

Background We aimed to develop quality indicators (QIs) related to primary and comprehensive stroke care and examine the feasibility of their measurement using the existing Diagnosis Procedure Combination (DPC) database. Methods and results We conducted a systematic review of domestic and international studies using the modified Delphi method. Feasibility of measuring the QI adherence rates was examined using a DPC-based nationwide stroke database (396,350 patients admitted during 2013-2015 to 558 hospitals participating in the J-ASPECT study). Associations between adherence rates of these QIs and hospital characteristics were analyzed using hierarchical logistic regression analysis. We developed 17 and 12 measures as QIs for primary and comprehensive stroke care, respectively. We found that measurement of the adherence rates of the developed QIs using the existing DPC database was feasible for the 6 QIs (primary stroke care: early and discharge antithrombotic drugs, mean 54.6% and 58.7%; discharge anticoagulation for atrial fibrillation, 64.4%; discharge antihypertensive agents, 51.7%; comprehensive stroke care: fasudil hydrochloride or ozagrel sodium for vasospasm prevention, 86.9%; death complications of diagnostic neuroangiography, 0.4%). We found wide inter-hospital variation in QI adherence rates based on hospital characteristics. Conclusions We developed QIs for primary and comprehensive stroke care. The DPC database may allow efficient data collection at low cost and decreased burden to evaluate the developed QIs.

Background The aim of the present study was to investigate the efficacy and safety of antiplatelet (aspirin plus cilostazol) dual therapy for patients with noncardioembolic stroke within 48 hours of symptom onset. Methods and Results The ADS (Acute Aspirin Plus Cilostazol Dual Therapy for Non‐Cardiogenic Stroke Patients Within 48 Hours of Symptom Onset ) study is an investigator‐initiated, prospective, multicenter (34 hospitals in Japan), randomized, open‐label, and aspirin‐controlled trial. Acute stroke patients with noncardioembolic stroke within 48 hours of onset were studied. The subjects were randomly allocated to combination therapy with aspirin 81 to 200 mg plus cilostazol 200 mg (dual group) and single therapy with aspirin 81 to 200 mg (aspirin group) for 14 days. After the 14 days, all patients took the cilostazol 200 mg for 3 months. A primary efficacy outcome was defined as any one of the following occurring (neurological deterioration, symptomatic stroke recurrence, or transient ischemic attack) within 14 days. A primary safety outcome included intracerebral hemorrhage and subarachnoid hemorrhage. Between May 2011 and June 2017, 1201 patients (796 [66%] men; median age, 69 [61–77] years) randomized 1:1 to either the dual group or the aspirin group were analyzed. Initial National Institutes of Health Stroke Scale score was 2 (1–4) in both groups ( P =0.830). A primary efficacy outcome was observed in 11% in the dual group and 11% in the aspirin group ( P =0.853). A primary safety outcome occurred in 2 (0.3%) in the dual group and in 1 (0.2%) in the aspirin group ( P =0.624). Conclusions Dual antiplatelet therapy using cilostazol and aspirin was safe but did not reduce the rate of short‐term neurological worsening. Clinical Trial Registration URL : umin.ac.jp/ctr/index/htm. Unique identifier: UMIN 000004950.

Objective:\ud It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed.\ud \ud Methods:\ud We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).\ud \ud Results:\ud We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585).\ud \ud Interpretation:\ud Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group.

Serum biomarkers are associated with hemorrhagic transformation and brain edema after cerebral infarction. However, whether serum biomarkers predict hemorrhagic transformation in large vessel occlusion stroke even after mechanical thrombectomy, which has become widely used, remains uncertain. In this prospective study, we enrolled patients with large vessel occlusion stroke in the anterior circulation. We analyzed 91 patients with serum samples obtained on admission. The levels of matrix metalloproteinase-9 (MMP-9), amyloid precursor protein (APP) 770, endothelin-1, S100B, and claudin-5 were measured. We examined the association between serum biomarkers and hemorrhagic transformation within one week. Fifty-four patients underwent mechanical thrombectomy, and 17 patients developed relevant hemorrhagic transformation (rHT, defined as hemorrhagic changes ≥ hemorrhagic infarction type 2). Neither MMP-9 (no rHT: 46 ± 48 vs. rHT: 15 ± 4 ng/mL, P = 0.30), APP770 (80 ± 31 vs. 85 ± 8 ng/mL, P = 0.53), endothelin-1 (7.0 ± 25.7 vs. 2.0 ± 2.1 pg/mL, P = 0.42), S100B (13 ± 42 vs. 12 ± 15 pg/mL, P = 0.97), nor claudin-5 (1.7 ± 2.3 vs. 1.9 ± 1.5 ng/mL, P = 0.68) levels on admission were associated with subsequent rHT. When limited to patients who underwent mechanical thrombectomy, the level of claudin-5 was higher in patients with rHT than in those without (1.2 ± 1.0 vs. 2.1 ± 1.7 ng/mL, P = 0.0181). APP770 levels were marginally higher in patients with a midline shift ≥ 5 mm than in those without (79 ± 29 vs. 97 ± 41 ng/mL, P = 0.084). The predictive role of serum biomarkers has to be reexamined in the mechanical thrombectomy era because some previously reported serum biomarkers may not predict hemorrhagic transformation, whereas the level of APP770 may be useful for predicting brain edema.

Background and Objective Endogenous neurogenesis is associated with functional recovery after stroke, but the roles it plays in such recovery processes are unknown. This study aims to clarify the roles of endogenous neurogenesis in functional recovery and motor map reorganization induced by rehabilitative therapy after stroke by using a rat model of cerebral ischemia (CI). Methods Ischemia was induced via photothrombosis in the caudal forelimb area of the rat cortex. First, we examined the effect of rehabilitative therapy on functional recovery and motor map reorganization, using the skilled forelimb reaching test and intracortical microstimulation. Next, using the same approaches, we examined how motor map reorganization changed when endogenous neurogenesis after stroke was inhibited by cytosine-β- d -arabinofuranoside (Ara-C). Results Rehabilitative therapy for 4 weeks after the induction of stroke significantly improved functional recovery and expanded the rostral forelimb area (RFA). Intraventricular Ara-C administration for 4-10 days after stroke significantly suppressed endogenous neurogenesis compared to vehicle, but did not appear to influence non-neural cells (e.g., microglia, astrocytes, and vascular endothelial cells). Suppressing endogenous neurogenesis via Ara-C administration significantly inhibited (~50% less than vehicle) functional recovery and RFA expansion (~33% of vehicle) induced by rehabilitative therapy after CI. Conclusions After CI, inhibition of endogenous neurogenesis suppressed both the functional and anatomical markers of rehabilitative therapy. These results suggest that endogenous neurogenesis contributes to functional recovery after CI related to rehabilitative therapy, possibly through its promotion of motor map reorganization, although other additional roles cannot be ruled out.

Motor map reorganization is believed to be one mechanism underlying rehabilitation-induced functional recovery. Although the ipsilesional secondary motor area has been known to reorganize motor maps and contribute to rehabilitation-induced functional recovery, it is unknown how the secondary motor area is reorganized by rehabilitative training. In the present study, using skilled forelimb reaching tasks, we investigated neural network remodeling in the rat rostral forelimb area (RFA) of the secondary motor area during 4weeks of rehabilitative training. Following photothrombotic stroke in the caudal forelimb area (CFA), rehabilitative training led to task-specific recovery and motor map reorganization in the RFA. A second injury to the RFA resulted in reappearance of motor deficits. Further, when both the CFA and RFA were destroyed simultaneously, rehabilitative training no longer improved task-specific recovery. In neural tracer studies, although rehabilitative training did not alter neural projection to the RFA from other brain areas, rehabilitative training increased neural projection from the RFA to the lower spinal cord, which innervates the muscles in the forelimb. Double retrograde tracer studies revealed that rehabilitative training increased the neurons projecting from the RFA to both the upper cervical cord, which innervates the muscles in the neck, trunk, and part of the proximal forelimb, and the lower cervical cord. These results suggest that neurons projecting to the upper cervical cord provide new connections to the denervated forelimb area of the spinal cord, and these new connections may contribute to rehabilitation-induced task-specific recovery and motor map reorganization in the secondary motor area.

Background and Purpose— Eosinophil counts are thought to be associated with atherosclerosis and aortic arch plaques. However, whether these associations exist among patients with acute ischemic stroke remains unclear. We aimed to evaluate the association between absolute eosinophil count (AEC) and aortic arch plaques among these patients. Methods— Consecutive acute ischemic stroke patients undergoing transesophageal echocardiography were retrospectively analyzed. Complex aortic arch plaques (CAPs) were defined as plaques ≥4 mm in thickness, with ulcer, or with mobile component. Results— A total of 430 patients (289 male, mean age 69.8±11.4 years) were enrolled. Patients with CAPs (n=169) showed higher mean AEC than those without (167±174/µL versus 127±127/µL; P =0.007). Multivariate analysis showed that increased AEC was independently associated with the presence of CAPs (odds ratio, 2.09; 95% confidence interval, 1.21–3.65). Conclusions— Among patients with acute ischemic stroke, increased AEC was independently associated with the presence of CAPs. Our results suggest that AEC may be a useful predictor for the presence of CAPs in these patients.

Administration of intravenous recombinant tissue plasminogen activator (rt-PA) and mechanical thrombectomy (MT) have become standard therapeutic approaches for acute internal carotid artery and middle cerebral artery M1 segment occlusion (ICA/M1O). However, clinical deterioration of the condition is still observed in some cases.We aimed to identify patients' factors associated with exacerbation. This was a single-center, retrospective study of 35 consecutive patients with acute ICA/M1O who underwent rt-PA/rt-PA and MT at our hospital between January 2016 and September 2019. We divided patients into two groups based on the total NIHSS score at discharge: the "improvement" and "exacerbation" groups. Clinical characteristics, laboratory data, and imaging findings were compared between the groups.The improvement group (13 patients [37%]) had a lower mean age (70 vs. 81 years, p = 0.02), National Institutes of Health Stroke Scale score (NIHSS, 13 vs. 19, p = 0.02), and C-reactive protein (CRP) levels (0.24 vs. 0.92 mg/dl, p0.01) than the exacerbation group (22 patients [63%]). Receiver operating characteristic curve analysis revealed the cut-off age to be 79 (sensitivity 76.9%, specificity 72.7%), NIHSS score to be 20 (sensitivity 92.3%, specificity 63.6%), and CRP to be 0.14 mg/dl (sensitivity 69.2%, specificity 81.8%). Multivariate analysis confirmed a CRP level of0.14 mg/dl (odds ratio, 10.16; 95% confidence interval 1.38-75.13; p = 0.01) to be independently associated with clinical deterioration at discharge.A CRP level of0.14 mg/dl is a strong predictor of clinical deterioration at discharge in patients with acute ICA/M1O undergoing recanalization therapy.

Background and Purpose— The effect of enzyme replacement therapy (ERT) on cerebrovascular complications remains largely unexplored. We aimed to investigate the relationship between basilar artery (BA) diameter and long-term ERT in patients with Fabry disease. Methods— We obtained baseline magnetic resonance imaging data from 30 patients (40.5±16.3 years, male: 14) in the single institution; among them, 21 patients prospectively had follow-up magnetic resonance imaging assessments. The short axis of BA diameter was measured at the midpons level on axial T2-weighted images. Brain magnetic resonance imaging measurements included markers of cerebral small vessel disease (lacunas, white matter hyperintensities, and cerebral microbleeds). We assessed variables associated with baseline BA diameter and annual BA diameter change using linear regression analyses. Results— Hypertension, left ventricular hypertrophy, estimated glomerular filtration rate, and white matter hyperintensities correlated with the initial BA diameter. After a mean interval of 7.2±4.6 years, the annual BA diameter change correlated positively with severe white matter hyperintensities and inversely with the duration of ERT (β=−0.48, P =0.033). After stratifying patients by sex, a significant correlation between the duration of ERT and BA diameter was found only in men (β=−0.72, P =0.019). Conclusions— Our results show a possible relationship between ERT and changes in BA diameter. Future studies to elucidate the clinical impact of BA changes as a potential surrogate marker are needed.

The relationship between noncontrast computed tomography (CT) markers, which predict the expansion of spontaneous intracerebral hemorrhage (sICH) under conservative treatment, and postoperative rebleeding (PR) after treatment by directly removing the sICH is unknown. This study investigated the relationship between noncontrast CT markers and PR in patients with sICH treated by endoscopic surgery.The study population included 92 patients with available data who underwent endoscopic surgery for sICH at our institution from January 2010 to September 2018. The correlations between PR and preoperative noncontrast CT markers, including the blend sign, hypodensities, black hole sign, heterogeneous density, and island signs, were retrospectively evaluated.In 5 of the 18 patients (27.8%) with the blend sign, PR developed, whereas only 5 of 74 patients (6.8%) without the blend sign developed PR. In the univariate regression analyses, manifestation of hydrocephalus (odds ratio [OR], 8.75; 95% confidence interval [CI], 2.15-35.68; P = 0.002), presence of the blend sign (OR, 5.31; 95% CI, 1.34-20.97; P = 0.02), and insertion of external ventricular drainage (OR, 13.88; 95% CI, 3.22-59.77; P0.001) were significant risk factors. The other radiographic markers were not associated with PR. In a multivariate analysis, the presence of the blend sign (OR, 22.07; 95% CI, 2.18-223.60; P = 0.009) was the only independent predictor of PR.The blend sign is likely to be a strong predictor for PR in patients who undergo endoscopic surgery for sICH. To improve the prognosis of patients with sICH, further studies are needed to establish new treatment strategies and surgical procedures.

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 ) INR ≥2 on admission, and the remaining 38 (3.2%) received prior direct oral anticoagulant treatment. Prior warfarin treatment was associated with a lower risk of death or disability at 3 months compared with no prior anticoagulation ( INR P =0.001; INR ≥2: adjusted odds ratio: 0.40; 95% CI, 0.16–0.97; P =0.043) but was not associated with a lower risk of death or disability at 2 years. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years compared with no prior anticoagulation (adjusted hazard ratio: 2.94; 95% CI, 1.20–6.15; P =0.021). Conclusions Prior warfarin treatment was associated with a lower risk of death or disability at 3 months but was not associated with a lower risk of death or disability at 2 years in ischemic stroke or transient ischemic attack patients with nonvalvular atrial fibrillation. Prior warfarin treatment with an INR ≥2 on admission was associated with a higher risk of ischemic events within 2 years. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01581502.

Background: Improving the quality of stroke care is an urgent issue worldwide. To facilitate the measurement of quality of stroke care in Japan, we aimed to develop the Close The Gap-Stroke initiative in the J-ASPECT Study. Methods and Results: Quality indicators (QIs) were developed by a multidisciplinary board between 2015 and 2017. The process involved a systematic review of domestic and international studies related to primary and comprehensive stroke care. Adherence rates for the defined QIs were calculated for 8,826 patients with acute ischemic stroke from 227 hospitals between 2013 to 2015. Seventeen and 12 measures were identified as QIs for primary and comprehensive stroke care (PSC and CSC), respectively. We analyzed adherence rates of all 17 QIs for PSC and 8 QIs for CSC related with acute ischemic stroke. We found NIHSS documentation (91.0 %), CT/MRI performed within 25min and 24hr (80.9 % and 99.1 %), evaluation of extracranial vascular imaging (90.4 %), treated in stroke unit (57.4 %), tPA administration (89.5 %), tPA performed within 1hr (37.4 %), early and discharge antithrombotics medication (75.1 % and 49.0 %), discharge anticoagulation for atrial fibrillation patients (76.2 %), discharge statin medication (32.7 %), discharge antihypertensive agents (54.3 %), deep vein thrombosis prophylaxis (34.5 %), early rehabilitation (57.0 %), dysphagia screening (76.6 %), smoking cessation (59.8 %) and stroke education (71.4 %) for primary stroke care; and median time to multimodal CT or MR brain and vascular imaging (33 min), proper endovascular recanalization (81.7 %), tPA before endovascular recanalization (65.7 %), TICI grade 2b/3 after endovascular recanalization (73.0 %), median time of door to puncture (105 min), symptomatic intracranial hemorrhage after thrombolytic or endovascular therapy (7.45 %), 90 days mRS documentation after thrombolytic or endovascular therapy (60.8 %), occurrence of complication within 24 hours of diagnostic neuroangiography (7.27 %) for comprehensive stroke care. Conclusion: This is a promising first step to measure the QIs related to primary and comprehensive stroke care at a national level in Japan.

Background: Retinal ischemia might be mainly caused by carotid stenosis and warning sign for ischemic stroke. Retinal ischemia is rare condition, therefore it is uncertain what lead to ischemic stroke in retinal-ischemic-patient. Methods: We retrospectively identified 128 patients who diagnosed retinal ischemia at 3 hospitals using each hospital stroke database collected from April 1st 2004 to Jun 30th 2016. We extracted data as patient sex, age, comorbidities and checked medical record for detecting recurrent of ischemic stroke and retinal ischemia. Logistic regression analysis was performed to analyze the effect of various factors on the recurrent of ischemic stroke. Results: The mean age of the patients at admission was 69 years old, and 93 patients (73%) was men. Seventy nine patients were diagnosed amaurosis fugax and 49 were retinal embolism. More than one visual defect attack had seen in 25 patients. One hundred twenty three patients were done cerebral MRI and DWI positive ischemic lesion was revealed in 12patients.Carotid stenosis were detected in 38 patients, patent foramen ovale were 40 patients, atrial fibrillation were 8 patients, complicated aortic plaque were 36 patients, and cancer were 25 patients. Mean follow-up period was 645 days and 6 patients had ischemic stroke, 4 had retinal ischemia and 18 underwent surgical intervention (carotid endarterectomy 12, carotid stenting 4, extracranial to intracranial bypass 2). Multivariable analysis found that the prevalence of ischemic stroke was significantly increased in DWI positive (odds ratio 10.9, confidence interval 1.7-69.6), under treatment cancer (10.0, 1.2-85.0), more than one visual attack (2.8, 1.1-7.3). Conclusion: DWI positive ischemic lesion on cerebral MRI was risk factor for ischemic stroke in retinal ischemic patients. We should consider to do MRI on retinal ischemic patients.