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Objective The underlying pathophysiology varies according to stroke subtype. However, stroke heterogeneity among patients with systemic lupus erythematosus (SLE) remains unstudied. We hypothesized that the contribution of SLE to stroke might vary according to its subtype and investigated the associations of SLE and various stroke subtypes. Methods Diagnostic codes and electronic medical records were used to identify 70 patients with SLE who developed acute cerebral infarction or intracerebral hemorrhaging at four tertiary referral hospitals between 2008 and 2018. Intracerebral hemorrhaging was classified as lobar or deep, while cerebral infarction was classified according to the SSS-TOAST criteria. Physician notes were used to identify SLE activity, and their prevalences were compared among stroke subtypes. Outcomes were collected from the patients' medical records. Results The most common stroke subtype in patients with SLE was that of undetermined causes (31%), followed by small artery occlusion (16%), cardioaortic embolism (13%), other causes (11%), lobar hemorrhaging (10%), deep hemorrhaging (10%), and large artery atherosclerosis (9%). Stroke onset occurred during a period of high SLE activity in 21 patients (30%). The proportion of patients with high SLE activity varied according to stroke subtype (p=0.039) and was highest for cerebral infarction with undetermined causes. Stroke recurrence or death was observed in 40% of patients within 5 years after the initial stroke onset. Conclusion The contributions of SLE to stroke varied significantly according to the stroke subtype. Given the unfavorable prognosis, close stroke subtype-specific observation by rheumatologists and stroke specialists is recommended after stroke events.

Background: The “1-3-6-12-day rule” for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity. Methods: The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0–7), moderate (8–15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation. Results: In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)—initiating DOACS within 1, 2, 3, and 4 days, respectively—than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27–0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27–0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data. Conclusions: In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Background: Cerebral small vessel disease (SVD) has received attention as a risk stratification tool for antithrombotic-related intracranial hemorrhage but may also be a predictor for bleeding in other organs. Purpose: To determine the excess risk of antithrombotic-related bleeding due to cerebral SVD burden. Methods: Patients with cerebrovascular or cardiovascular diseases taking oral antithrombotic agents were prospectively enrolled from 52 hospitals across Japan between 2016 and 2019. Multimodal brain MRI was acquired at baseline for all patients under prespecified conditions. All MRI examinations were interpreted by a central diagnostic radiology committee for cerebral microbleeds, lacunes, white matter hyperintensities, and enlarged basal ganglia perivascular spaces, for calculation of a total SVD score (range 0-4). The primary outcome was major bleeding during 2-year follow-up. Secondary outcomes included bleeding in each site and ischemic events. Event risks according to SVD score were estimated with multivariable Cox proportional hazards models. Results: Of the analyzed 5250 patients (1736 women; median age, 73 years; 9933 patient-years follow-up), antiplatelets and anticoagulants were administered at baseline in 3948 and 1565, respectively. Median of the total SVD score was 2 (IQR 1-3). As SVD score increased, advanced age, hypertension, anemia, and chronic kidney disease were more prevalent (P Conclusions: The total SVD score was predictive for intracranial hemorrhage and probably for extracranial bleeding, suggesting a broader clinical relevance of cerebral SVD as a marker for safe implementation of antithrombotic therapy.

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.

Thrombosis with thrombocytopenia syndrome (TTS) induced by the coronavirus disease 2019 vaccine is characterized by thrombocytopenia and thrombosis. Positivity for the anti-platelet factor 4-antibody is related to TTS pathophysiology, similar to heparin-induced thrombocytopenia. Although TTS is very rare, with an incidence of almost 1/100,000 cases, physicians need to keep in mind this adverse reaction that can lead to serious symptoms and death. Prompt treatment should be initiated in cases of suspected TTS.

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 hypercoagulability using D-dimer levels may be a useful marker for predicting outcomes in ischemic stroke patients with cancer, other biological markers for predicting outcomes are unclear. We aimed to investigate the associations between several biological markers and short-term or long-term outcomes among ischemic stroke patients with cancer.Consecutive acute ischemic stroke patients with cancer (n = 309) were registered. Biological markers such as hemoglobin, albumin, C-reactive protein and D-dimer levels were assessed. Stroke outcomes, namely, a 3-month modified Rankin Scale score indicating poor functional outcome (mRS score of 3-6) and 1-year survival, were assessed.Of the 277 patients who could be assessed for 3 months outcome, 131 patients (47.3%) had a poor outcome at 3 months. Multivariable analysis revealed that increased D-dimer levels and decreased albumin levels were independently associated with poor stroke outcomes (adjusted odds ratio [aOR]: 1.04, 95% confidence interval [CI]: 1.00-1.08, and aOR: 0.50, 95% CI: 0.31-0.80, respectively). Of 309 patients, 70 patients (22.7%) died during the follow-up period (median, 241 days). Multivariate Cox proportional hazard analyses showed that high D-dimer levels and hypoalbuminemia were independently associated with mortality (adjusted hazard ratio [aHR]: 2.65, 95% CI: 1.37-5.12, and aHR: 2.29, 95% CI: 1.21-4.49, respectively). The effect of each biological marker on mortality was notably observed among patients with active cancer but not among those with nonactive cancer.Low albumin levels were independently associated with short- and long-term outcomes, as were D-dimer levels, in acute ischemic stroke patients with cancer.

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.

The present study was performed to evaluate the ganglion cell complex (GCC) thickness as well as the significance map and analyse the time course of the change in GCC thickness in patients with homonymous hemianopia due to posterior cerebral artery (PCA) territory stroke using spectral-domain optical coherence tomography. This study included 40 control subjects and 11 patients with unilateral PCA territory stroke. The GCC parameters were quantified using a custom-built software programme. The GCC data, centred on the macula, was divided vertically into hemianopic and unaffected sides. GCC parameters were calculated using an average of those from both eyes. The relationship between the GCC parameters and the time after stroke was determined by regression analyses. The GCC parameters in the hemi-retinae corresponding to the affected hemifields significantly differed between the hemianopes and the control group. The area under the receiver operating characteristics curve of the GCC significance map areas was significantly high. A regression analysis revealed a significant relationship between the time after stroke and both the GCC significance map areas (r = 0.791, p = .004) and GCC thickness (r = −0.736, p = .010) on the hemianopic side. The GCC parameters on the hemianopic side were reduced in patients with acquired occipital homonymous hemianopia, and the reduction was slowly progressive probably due to transsynaptic retrograde degeneration of the retinal ganglion cells. A significance map analysis provides additional OCT parameters that could be used to investigate the effect of retrogeniculate lesions on the inner retina of patients.

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.

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.

An 87-year-old woman was admitted to our hospital because of speech disturbance and right facio-pharyngo-glosso-masticatory diplegia. She had bronchial asthma, was previously diagnosed with cerebral infarction, had experienced two events of convulsive status epilepticus, and was undergoing treatment with theophylline, levetiracetam, and clopidogrel. Head diffusion-weighted magnetic resonance imaging revealed a high-signal area in the left crus posterior capsula interna. For this, we administered cilostazol along with her regular medicines. On day 14, she had tonic-clonic convulsions, extending from the right upper and lower limbs to the whole body. Subsequently, cilostazol was discontinued, and the dose of levetiracetam was increased. However, she developed severe tonic-clonic seizures with right sensory aphasia and right hemiplegia, for which an increased dose of lacosamide was added. When theophylline was discontinued 5 days after the onset of convulsions, the blood concentration of theophylline was 9.7μg/mL. After theophylline was discontinued, tonic-clonic convulsions improved. The disturbance of consciousness and right hemiparesis were improved after one week, while the disturbance of sensory aphasia was improved after one month. We suspect that cerebral infarction may have aggravated the central nervous system damage caused by theophylline, thereby resulting in aminophylline-related non-convulsive status epilepticus. (Received 20 July 2020; Accepted 27 October 2020; Published 1 March 2021).

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.

Cerebrovascular disease and vasculitis-related diseases have been reported as systemic complications of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A proposed underlying mechanism is that SARS-CoV-2 infects vascular endothelial cells via the angiotensin-converting enzyme 2 (ACE2) and causes inflammation. Cerebrovascular disease and vasculitis are often observed in severe COVID-19 cases, and they may be associated with critical systemic conditions, such as the cytokine storm and thrombotic tendencies. Several other mechanisms have been proposed, and diverse pathological conditions may be associated with COVID-19-related cerebrovascular disease and vasculitis. Clarifying the pathophysiology and establishing a better therapeutic regimen will facilitate favorable outcomes.

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.

Prescribing under-dose direct oral anticoagulants (DOACs) for non-valvular atrial fibrillation (NVAF) is alerted to increase cardiovascular events or death. However, the association between dose selection of DOACs and the clinical course remains unclear. This study aimed to propose a novel criterion for selecting the DOAC dose and investigate clinical characteristics of ischemic stroke (IS) under this criterion.We assessed the pooled prospective multicenter registry data of stroke patients taking anticoagulant agents, including IS patients with NVAF and prior DOAC usage. The recommended dose according to the reduction criteria of each DOAC and the selected dose were identified for each patient, and patients were categorized into four groups: no alternative low-dose, selecting low-dose appropriately with all DOACs applicable for reduction criteria; selected low-dose, selecting low-dose appropriately or inappropriately despite at least one DOAC inapplicable for reduction criteria; selected standard-dose, appropriate standard-dose use; and absolute over-dose, inappropriate standard-dose regardless of criteria. We investigated the effects of dose selection of DOACs on short-term poor functional outcomes.322 patients were included in the analysis. The prevalence of no alternative low-dose, selected low-dose, selected standard-dose, and absolute over-dose was 74 (23%), 144 (45%), 89 (27%), and 15 (5%), respectively. Multivariable analysis found that the selected low-dose group showed significantly poorer functional outcomes than the selected standard-dose group only in patients without renal dysfunction (OR, 2.60; 95% CI, 1.17-6.00; P = 0.0186).Selecting a low dose DOAC might be associated with poor functional outcomes in patients without renal dysfunction.

Atrial fibrillation (AF) includes paroxysmal and sustained (persistent or permanent) AF, and both forms are considered risk factors for ischemic stroke. This study aimed to investigate the differences in stroke severity at admission between patients with paroxysmal AF and sustained AF when treated with direct oral anticoagulants (DOACs).Using data from DOAC-treated 300 nonvalvular patients with AF and acute anterior circulation stroke who were registered in the Multicenter Prospective Analysis of Stroke Patients Taking Oral Anticoagulants study, patients were divided into two groups, namely, paroxysmal AF and sustained AF. We compared the clinical characteristics between the two groups and determined the effect of these two types of AF on stroke severity on admission.Of 300 patients, 246 (males, n = 149; median age, 80 years) and 54 (males, n = 32; median age, 78 years) were assigned to the sustained AF and paroxysmal AF groups, respectively. The sustained AF group had a higher proportion of severe stroke (National Institutes of Health Stroke Scale score,20) on admission (22.0% vs. 5.7%, p = 0.006) and internal carotid artery occlusion (11.4% vs. 1.9%, p = 0.03) compared to the paroxysmal AF group. Multivariate analysis showed that sustained AF was independently associated with severe stroke on admission (odds ratio 4.31, 95% confidence interval 1.24-15.0, p = 0.02).Sustained AF was associated with a higher severity of stroke accompanied with major vessel occlusion than paroxysmal AF, even prior to DOACs treatment. Registration https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034958.

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