Safety of Antithrombotic Therapy within 24 Hours after Recombinant Tissue-Plasminogen Activator Treatment for Large-Artery Atherosclerosis Stroke: Insights from Emergent PTA/CAS Cases.

BACKGROUND: Antithrombotic therapy (AT) should generally be avoided within 24 hours after recombinant tissue-plasminogen activator (rt-PA) treatment but should be considered in patients with large-artery atherosclerosis (LAA) who undergo concomitant emergent endovascular treatment (EVT). The aim of the present study was to assess the safety of AT within 24 hours after rt-PA treatment in patients with hyperacute ischemic stroke due to LAA who received concomitant EVT. METHODS: From January 2013 through July 2019, consecutive patients with acute ischemic cerebrovascular disease due to LAA who were admitted within 6 hours from symptom onset were recruited. The patients were classified into six groups based on the reperfusion treatment and early (within 24 hours) AT from rt-PA treatment. Safety outcomes were compared among the groups. RESULTS: A total of 155 patients (35 women [23%], median age 74 [IQR 66-79] years; NIHSS score 3 [1-10]) were included in the present study. Of these, 73 (47%) received no reperfusion therapy, 24 (15%) received rt-PA treatment and early AT, seven (6%) received rt-PA without early AT, 26 (17%) received EVT only, six (4%) received both rt-PA and EVT without early AT, and 19 (12%) received rt-PA and EVT with early AT. AT was administered a median of 3.9 (1.6-8.0) hours after rt-PA in patients with rt-PA+EVT with early AT. AT within 24 hours after rt-PA and EVT treatment did not increase hemorrhagic complications (p > 0.05 for all). CONCLUSION: In this retrospective analyses, early AT administration for patients with hyperacute stroke due to LAA treated with rt-PA plus EVT did not increase hemorrhagic events.

Migraine-like headache with aura induced by a small infarct in the parieto-occipital cortex: A case report.

A 56-year-old right-handed man was referred to our hospital for evaluation of sudden-onset transient quadrantanopia, which was followed by throbbing headache consistent with migraine with aura (MA). Magnetic resonance imaging (MRI) of the right parieto-occipital cortex on admission showed a hyperintense region on diffusion-weighted imaging, which disappeared 7 days later. A small cortical infarct in the parieto-occipital cortex can cause MA-like headache, and the present infarct lesion was only detectable on MRI during the acute phase. Performing MRI for patients with suspected acute MA might help identify the cause of MA-like headache and ensure appropriate management of patients.

iPSC-derived mesenchymal stem cells attenuate cerebral ischemia-reperfusion injury by inhibiting inflammatory signaling and oxidative stress.

Induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs) hold great promise as a cell source for transplantation into injured tissues to alleviate inflammation. However, the therapeutic efficacy of iMSC transplantation for ischemic stroke remains unknown. In this study, we evaluated the therapeutic effects of iMSC transplantation on brain injury after ischemia-reperfusion using a rat transient middle cerebral artery occlusion model and compared its therapeutic efficacy with that of bone marrow mesenchymal stem cells (BMMSCs). We showed that iMSCs and BMMSCs reduced infarct volumes after reperfusion and significantly improved motor function on days 3, 7, 14, 28, and 56 and cognitive function on days 28 and 56 after reperfusion compared with the vehicle group. Furthermore, immunological analyses revealed that transplantation of iMSCs and BMMSCs inhibited microglial activation and expression of proinflammatory cytokines and suppressed oxidative stress and neuronal cell death in the cerebral cortex at the ischemic border zone. No difference in therapeutic effect was observed between the iMSC and BMMSC groups. Taken together, our results demonstrate that iMSC therapy can be a practical alternative as a cell source for attenuation of brain injury and improvement of neurological function because of the unlimited supply of uniform therapeutic cells.

Stroke in Patients With Common Noncancerous Gynecologic Diseases: A Multicenter Study in Japan.

Background and Objectives: Gynecologic diseases such as uterine fibroids, endometriosis, and adenomyosis are common in women of reproductive age. Case reports and small case series have reported ischemic stroke in women with such common noncancerous gynecologic diseases, and their cause of stroke is frequently attributed to cryptogenic stroke or unconventional mechanisms related to hypercoagulability. However, stroke etiology and prognosis are not well known. We assessed the prevalence of and stroke mechanisms related to common noncancerous gynecologic diseases using hospital-based clinical data. Methods: We retrospectively identified consecutive female patients with common noncancerous gynecologic diseases (uterine fibroids, endometriosis, and adenomyosis) diagnosed with ischemic stroke/transient ischemic attack (TIA) between the ages of 20 and 59 years admitted to 10 stroke centers in Japan by reviewing prospectively collected data between 2017 and 2019. The clinical, laboratory, and neuroimaging features were evaluated and compared between patients with conventional stroke mechanisms (CSMs) (large artery atherosclerosis, small vessel occlusion, cardioembolism, and other determined etiology) and non-CSMs (cryptogenic stroke and causes related to hypercoagulability such as nonbacterial thrombotic endocarditis and paradoxical embolism) according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Results: Of the 470 female patients with ischemic stroke/TIA, 39 (8%) (37 ischemic stroke and 2 TIA) had common noncancerous gynecologic diseases. The most common gynecologic diseases were uterine fibroids in 24 (62%) patients, followed by endometriosis in 9 (23%) and adenomyosis in 6 (15%). Twenty patients (51%) were assigned to the non-CSMs group, and 19 patients (49%) were assigned to the CSMs group. Adenomyosis and endometriosis were more frequent in the non-CSMs group than in the CSMs group. CA125 and D-dimer levels were higher in the non-CSMs group than in the CSMs group. Multiple vascular territory infarcts were frequent in patients with adenomyosis (60%) and endometriosis (43%) in the non-CSMs group. No stroke recurrence or death was observed within 3 months after discharge in both the CSMs and non-CSMs groups. Outcomes at 3 months after discharge were similar in both groups. Discussion: In patients with common noncancerous gynecologic diseases, hypercoagulopathy may play a role in the pathogenesis of ischemic stroke/TIA without CSMs.

Immunomodulatory amnion-derived mesenchymal stromal cells preserve muscle function in a mouse model of Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an incurable genetic disease characterized by degeneration and necrosis of myofibers, chronic inflammation, and progressive muscle weakness resulting in premature mortality. Immunosuppressive multipotent mesenchymal stromal cell (MSC) therapy could be an option for DMD patients. We focused on amnion-derived mesenchymal stromal cells (AMSCs), a clinically viable cell source owing to their unique characteristics, such as non-invasive isolation, mitotic stability, ethical acceptability, and minimal risk of immune reaction and cancer. We aimed to identify novel immunomodulatory effects of AMSCs on macrophage polarization and their transplantation strategies for the functional recovery of skeletal and cardiac muscles. METHODS: We used flow cytometry to analyze the expression of anti-inflammatory M2 macrophage markers on peripheral blood mononuclear cells (PBMCs) co-cultured with human AMSCs (hAMSCs). hAMSCs were intravenously injected into DMD model mice (mdx mice) to assess the safety and efficacy of therapeutic interventions. hAMSC-treated and untreated mdx mice were monitored using blood tests, histological examinations, spontaneous wheel-running activities, grip strength, and echocardiography. RESULTS: hAMSCs induced M2 macrophage polarization in PBMCs via prostaglandin E2 production. After repeated systemic hAMSC injections, mdx mice exhibited a transient downregulation of serum creatin kinase. Limited mononuclear cell infiltration and a decreased number of centrally nucleated fibers were indicative of regenerated myofibers following degeneration, suggesting an improved histological appearance of the skeletal muscle of hAMSC-treated mdx mice. Upregulated M2 macrophages and altered cytokine/chemokine expressions were observed in the muscles of hAMSC-treated mdx mice. During long-term experiments, a significant decrease in the grip strength in control mdx mice significantly improved in the hAMSC-treated mdx mice. hAMSC-treated mdx mice maintained running activity and enhanced daily running distance. Notably, the treated mice could run longer distances per minute, indicating high running endurance. Left ventricular function in DMD mice improved in hAMSC-treated mdx mice. CONCLUSIONS: Early systemic hAMSC administration in mdx mice ameliorated progressive phenotypes, including pathological inflammation and motor dysfunction, resulting in the long-term improvement of skeletal and cardiac muscle function. The therapeutic effects might be associated with the immunosuppressive properties of hAMSCs via M2 macrophage polarization. This treatment strategy could provide therapeutic benefits to DMD patients.

Association between Living Conditions and the Risk Factors, Etiology, and Outcome of Ischemic Stroke in Young Adults.

Objective In recent decades, living conditions have changed drastically. However, there are few data regarding the interaction between living conditions and the risk of ischemic stroke (IS) in young adults. The present study explored the association between living conditions or marital status and the risk factors, etiology, and outcome of IS in young adults. Methods We prospectively enrolled patients with incident IS who were 20-49 years old from 37 clinical stroke centers. We collected the demographic data, living conditions, marital status, vascular risk factors, disease etiology, treatment, and outcomes at discharge. A comparison group was established using the official statistics of Japan. We categorized patients into the two groups based on living conditions: solitary group and cohabiting group. Clinical characteristics were then compared between living conditions. Results In total, 303 patients were enrolled (224 men; median age at the onset: 44 years old). Significant factors associated with the incidence of IS were as follows: solitary status, body mass index >30 kg/m2, current smoking, heavy alcohol consumption, hypertension, diabetes mellitus, and dyslipidemia. Furthermore, in the solitary group, the proportions of men, unmarried individuals, and current smokers were significantly higher than in the cohabiting group. In addition, poor outcomes (modified Rankin Scale ≥4) of IS were more common in the solitary group than in the cohabiting group. Conclusion Our study showed that not only conventional vascular risk factors but also living conditions, especially living alone while unmarried, were independent risk factors for IS in young adults.

Transgenic type2 diabetes mouse models for in vivo redox measurement of hepatic mitochondrial oxidative stress.

BACKGROUND: Oxidative stress is involved in the progression of diabetes and its associated complications. However, it is unclear whether increased oxidative stress plays a primary role in the onset of diabetes or is a secondary indicator caused by tissue damage. Previous methods of analyzing oxidative stress have involved measuring the changes in oxidative stress biomarkers. Our aim is to identify a novel approach to clarify whether oxidative stress plays a primary role in the onset of diabetes. METHODS: We constructed transgenic type 2 diabetes mouse models expressing redox-sensitive green fluorescent proteins (roGFPs) that distinguished between mitochondria and whole cells. Pancreas, liver, skeletal muscle, and kidney redox states were measured in vivo. RESULTS: Hepatic mitochondrial oxidation increased when the mice were 4 weeks old and continued to increase in an age-dependent manner. The increase in hepatic mitochondrial oxidation occurred simultaneously with weight gain and increased blood insulin levels before the blood glucose levels increased. Administering the oxidative stress inducer acetaminophen increased the vulnerability of the liver mitochondria to oxidative stress. CONCLUSIONS: This study demonstrates that oxidative stress in liver mitochondria in mice begins at the onset of diabetes rather than after the disease has progressed. GENERAL SIGNIFICANCE: RoGFP-expressing transgenic type 2 diabetes mouse models are effective and convenient tools for measuring hepatic mitochondrial redox statuses in vivo. These models may be used to assess mitochondria-targeting antioxidants and establish the role of oxidative stress in type 2 diabetes.

FLAMES with Elevated Myelin Basic Protein Followed by Myelitis.

The pathophysiology of unilateral cortical fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions in anti-myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis with seizures (FLAMES) is unclear. A 26-year-old man was referred because of a seizure. FLAIR showed an increased signal intensity and swelling of the right frontal cortex. His symptoms and imaging abnormalities were improved after intravenous methylprednisolone therapy. MOG antibody was detected both in serum and cerebrospinal fluid (CSF). Therefore, the patient was diagnosed with FLAMES. Myelin basic protein (MBP) was elevated in CSF. The high MBP value in the CSF in the present case suggested that demyelination as well as inflammation can occur in some FLAMES patients.

Randomised placebo-controlled multicentre trial to evaluate the efficacy and safety of JTR-161, allogeneic human dental pulp stem cells, in patients with Acute Ischaemic stRoke (J-REPAIR).

INTRODUCTION: JTR-161 is a novel allogeneic human cell product consisting of dental pulp stem cells isolated from the extracted teeth of healthy adults. It is currently under development as a cell-based therapy for ischaemic stroke. The aim of this study is to evaluate the safety and efficacy of JTR-161 in patients with acute ischaemic stroke when given as a single intravenous administration within 48 hours of symptom onset. METHODS AND ANALYSIS: This is a first-in-human, randomised, double-blind, placebo-controlled, multicentre, phase 1/2 clinical trial to be conducted in Japan (from January 2019 to July 2021). Patients with a clinical diagnosis of anterior circulation ischaemic stroke with a National Institutes of Health Stroke Scale (NIHSS）score of 5-20 at baseline were enrolled. Patients previously treated with recombinant tissue-type plasminogen activator and/or endovascular thrombectomy were allowed to be enrolled. The study consists of three cohorts: cohorts 1 and 2 (each eight patients) and cohort 3 (60 patients). Subjects were randomly assigned to receive either JTR-161 or placebo in a 3:1 ratio in cohorts 1 and 2, and in a 1:1 ratio in cohort 3. The number of cells administered was increased sequentially from 1×108 (cohort 1) to 3 x 108 (cohort 2). In cohort 3, the higher tolerated dose among the two cohorts was administered. The primary endpoint is the proportion of patients who achieve an excellent outcome as defined by all of the following criteria at day 91 in cohort 3: modified Rankin Scale ≤1, NIHSS ≤1 and Barthel Index ≥95. ETHICS AND DISSEMINATION: The protocol and informed consent form were approved by the institutional review board at each participating study site. A manuscript with the results of the primary study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04608838; JapicCTI-194570 and Clinical Trials. gov.

Dental-Pulp Stem Cells as a Therapeutic Strategy for Ischemic Stroke.

Regenerative medicine aims to restore human functions by regenerating organs and tissues using stem cells or living tissues for the treatment of organ and tissue defects or dysfunction. Clinical trials investigating the treatment of cerebral infarction using mesenchymal stem cells, a type of somatic stem cell therapy, are underway. The development and production of regenerative medicines using somatic stem cells is expected to contribute to the treatment of cerebral infarction, a central nervous system disease for which there is no effective treatment. Numerous experimental studies have shown that cellular therapy, including the use of human dental pulp stem cells, is an attractive strategy for patients with ischemic brain injury. This review describes the basic research, therapeutic mechanism, clinical trials, and future prospects for dental pulp stem cell therapy, which is being investigated in Japan in first-in-human clinical trials for the treatment of patients with acute cerebral ischemia.

The Effect of Aging and Small-Vessel Disease Burden on Hematoma Location in Patients with Acute Intracerebral Hemorrhage.

INTRODUCTION: Intracerebral hemorrhage (ICH) is a devastating hemorrhagic event and is associated with high mortality or severe neurological sequelae. Age-associated differences in hematoma location for nonlobar ICH are not well known. The aims of the present study were to elucidate the relationship between age and hematoma location and to assess the differences in small-vessel disease (SVD) burden as a potential surrogate marker for longstanding hypertension among various hematoma locations. METHODS: From September 2014 through July 2019, consecutive patients with acute, spontaneous ICH were retrospectively enrolled from a prospective registry. Magnetic resonance imaging was performed during admission, and the total SVD burden score (including microbleeds, lacunes, enlarged perivascular spaces, and white matter hyperintensities) was calculated. The relationships of hematoma location with aging and SVD burden were assessed by using multivariate logistic regression analyses. RESULTS: A total of 444 patients (156 women [35%]; median age 69 [interquartile range 59-79] years; National Institutes of Health Stroke Scale score 9 [17][3-17]) were enrolled in the present study. Multivariate logistic regression analyses showed that advanced age was independently associated with thalamic (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.19-1.84, p < 0.001 for 10-year increment) and lobar hemorrhage (OR: 1.58, 95% CI: 1.19-2.09, p = 0.002) and was independently and negatively related to putaminal hemorrhage (OR: 0.55, 95% CI: 0.44-0.68, p < 0.001). The total SVD burden score was independently and positively associated with thalamic hemorrhage (OR: 1.27, 95% CI: 1.01-1.59, p = 0.045) and negatively with lobar hemorrhage (OR: 0.74, 95% CI: 0.55-0.99, p = 0.042), even after adjusting by age, but not with putaminal hemorrhage (OR: 0.91, 95% CI: 0.73-1.14, p = 0.395). CONCLUSION: Putaminal, thalamic, and lobar hemorrhages are prone to occur in specific ages and SVD states: putaminal in young patients, thalamic in old and high SVD burden patients, and lobar hemorrhages in old and low SVD burden patients. Susceptibility to bleeding with aging or severe SVD accumulation seems to differ considerably among brain locations.

Recent Advances in Cell-Based Therapies for Ischemic Stroke.

Stroke is the most prevalent cardiovascular disease worldwide, and is still one of the leading causes of death and disability. Stem cell-based therapy is actively being investigated as a new potential treatment for certain neurological disorders, including stroke. Various types of cells, including bone marrow mononuclear cells, bone marrow mesenchymal stem cells, dental pulp stem cells, neural stem cells, inducible pluripotent stem cells, and genetically modified stem cells have been found to improve neurological outcomes in animal models of stroke, and there are some ongoing clinical trials assessing their efficacy in humans. In this review, we aim to summarize the recent advances in cell-based therapies to treat stroke.

Risk factors, etiology, and outcome of ischemic stroke in young adults: A Japanese multicenter prospective study.

PURPOSE: This study aimed to evaluate the risk factors, etiology, and outcomes of ischemic stroke (IS) in Japanese young adults. METHODS: This was a prospective multicenter study. We enrolled patients aged 16 to 55 years with IS within seven days of the onset of symptoms. We assessed the demographic data, risk factors, stroke etiology, and outcome at discharge. The clinical characteristics were compared between sexes and among age groups. RESULTS: We prospectively enrolled 519 patients (median age, 48 years: 139 females). The mean National Institute of Health Stroke Scale score was 3.6 ± 0.2. The most common risk factors were hypertension (HT) (55%), dyslipidemia (DL) (47%), and current smoking (42%). Body mass index, incidence of current smoking, and heavy alcohol consumption were higher in males. The prevalence of current smoking, HT, DL, and diabetes mellitus increased with aging. The most common etiologic subgroup of IS was small vessel disease (145/510, 28%). Intracranial arterial dissection (IAD) was the most common among the other determined causes (56/115, 49%). The outcome at discharge was relatively good (mRS 0-1, 71.7%); however, poor outcome (mRS ≥ 4) was observed at an incidence of 9.5%. CONCLUSIONS: Most young adults with IS had modifiable risk factors, of which prevalence increased with age. This emphasizes lifestyle improvement to prevent IS in the young population. Furthermore, we indicated that the incidence rate of IAD was high among the other determined causes.

Early Cognitive Assessment Following Acute Stroke: Feasibility and Comparison between Mini-Mental State Examination and Montreal Cognitive Assessment.

OBJECTIVES: Cognitive assessment is not performed routinely in the acute stroke setting. We investigated factors associated with cognitive impairment and the differences between the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores in patients with acute stroke. METHODS: In this prospective study, 881 consecutive patients (median age, 73 years) with acute stroke were enrolled. Clinical characteristics, such as education, vascular risk factors, premorbid cognitive status using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), and stroke severity, were assessed. Cognitive performance was measured using MMSE and MoCA within 5 days of stroke onset. RESULTS: Both MMSE and MoCA were feasible in 621 (70.5%) patients. Factors independently associated with nonfeasibility were age (odds ratio [OR]: 1.05; 95% confidence interval [CI]: 1.02-1.08), IQCODE score (OR: 1.02; 95%CI: 1.00-1.04), and National Institutes of Health Stroke Scale (NIHSS) score (OR, 1.16; 95%CI, 1.12-1.20). Impaired MoCA (with a cut-off <26/30) performance was observed in 544 of 621 (87.6%) patients. Factors independently associated with cognitive impairment were age (OR: 1.06; 95%CI: 1.03-1.10) and NIHSS score (OR: 1.34; 95%CI: 1.14-1.57). Eighty percent of patients with normal MMSE scores had an impaired MoCA score (MMSE-MoCA mismatch). The differences were highest in the visuospatial (94.8% versus 65.3%; P < .0001), recall (76.6% versus 35.6%; P < .0001), abstraction (82.5% versus 49.8%; P < .0001), and language (72.3% versus 65.9%; P < .0001) domains between the normal MMSE and MoCA group and MMSE-MoCA mismatch group. CONCLUSIONS: The MoCA can be particularly useful in patients with cognitive deficits undetectable on the MMSE in the acute stroke phase.

Reducing door-to-reperfusion time in acute stroke endovascular therapy using magnetic resonance imaging as a screening modality.

BACKGROUND: The feasibility of performing MRI first for patients with suspected hyperacute stroke in real-world practice has not been fully examined. Moreover, most past studies of reducing door-to-reperfusion time (DRT) in endovascular treatment (EVT) were conducted using CT. The aim of this study was to evaluate the feasibility of an MRI-first policy and to examine the effects of a quality improvement (QI) process for reducing DRT using MRI. METHODS: From January 2013 to December 2018, consecutive patients with acute stroke who came to hospital directly and were treated with emergent EVT were prospectively enrolled into the present study. In principle, MRI was performed first for patients with suspected acute stroke. A step-by-step QI process for decreasing DRT was adopted during this period. Time metrics for EVT were compared between specific time periods. RESULTS: A total of 180 patients (71 women; median age 76 years (range 69-64); National Institutes of Health Stroke Scale score 17 (range 10-23)) were included in the present study. More patients in the late phase were managed with the MRI-first policy (p<0.001). DRT (199 min in Phase 1, 135 min in Phase 2, 129 min in Phase 3, and 121 min in Phase 4, p<0.001) was significantly reduced across the phases. The percentage of patients with DRT <120 min increased significantly across time periods (p<0.001). Symptomatic intracerebral hemorrhage did not increase across phases (p=0.575). CONCLUSION: An MRI-first policy was feasible, and DRT decreased considerably with a step-by-step QI process. This process may be applicable to other hospitals.

Accurate etiology diagnosis in patients with stroke and atrial fibrillation: A role for brain natriuretic peptide.

BACKGROUND: Atrial fibrillation (AF) is the leading cause of cardioembolic stroke (CES), and patients with stroke and AF are frequently assumed to have CES. However, strokes presumably due to atherosclerotic pathophysiologies in large or small vessels can also occur in patients with AF. The aims of the present study were to clarify the prevalence of and factors related to a non-cardioembolic etiology in acute stroke patients with AF. METHODS: From March 2011 through May 2017, consecutive acute ischemic stroke patients with AF were retrospectively recruited. The concomitant presence of non-cardioembolic features (small vessel occlusion [SVO] or large artery atherosclerosis [LAA]) on imaging was evaluated. The frequency of and factors associated with co-existing SVO/LAA features were assessed. RESULTS: A total of 560 consecutive patients with AF and acute stroke (237 women; median age 78 [IQR 71-85] years; NIHSS score 9 [3-20]) were enrolled. Of these, 42 (7.5%) had co-existing SVO/LAA features. Multivariable logistic regression analysis showed that the brain natriuretic peptide level (BNP, OR 0.78, p = .030 per 100 pg/mL increase) was independently and negatively associated with co-existing SVO/LAA features and receiver operating characteristic curve analysis revealed the practical cut-off BNP value was 130 pg/mL (sensitivity 54% and specificity 68%). CONCLUSION: SVO/LAA features were found in 7.5% of acute stroke patients with AF. A relatively low BNP level on admission was independently associated with co-existing SVO/LAA features. Thorough examination for a more appropriate etiology may be particularly necessary in acute stroke patients with AF and a relatively low BNP level.

Ischemic stroke during anticoagulant interruption by healthcare professionals in stroke patients with atrial fibrillation.

BACKGROUND: Anticoagulant therapy often requires temporary interruption. Nevertheless, the frequency and clinical characteristics of stroke patients who develop stroke during anticoagulant interruption are not fully known. METHODS: From March 2011 through May 2017, consecutive acute ischemic stroke patients with AF who were admitted to our stroke unit were retrospectively recruited. Patients who developed ischemic stroke during anticoagulant interruption were defined as those who developed ischemic stroke within 30 days from anticoagulant interruption. The frequency and clinical characteristics of patients during anticoagulant interruption were analyzed. RESULTS: A total of 561 patients with AF and acute ischemic stroke (237 women; median age 78 [IQR 71-85] years) were admitted during the study period. Of these, 21 (3.7%, 12 patients discontinued vitamin K antagonist [VKA] and 9 discontinued direct oral anticoagulants [DOACs]) patients were admitted during the period of anticoagulant interruption. Severity and functional outcomes in stroke patients during anticoagulant interruption were not different from those without anticoagulant treatment. The number of days between anticoagulant interruption and stroke onset was shorter in patients who discontinued DOACs (3 [3-5] days) than in those who discontinuedVKAs (10 [7-20] days, p = .004). The major reason for interruption was planning of invasive procedures (52%). Guideline deviations were suspected in 82% of such cases. CONCLUSION: Patients developing stroke during anticoagulant interruption accounted for 3.7% of stroke patients with AF. Strokes occurred relatively early after interruption, especially in patients who discontinued DOACs. Guideline deviations was frequent.

Visualizing the Distribution of Matrix Metalloproteinases in Ischemic Brain Using In Vivo 19F-Magnetic Resonance Spectroscopic Imaging.

Matrix metalloproteinases (MMPs) damage the neurovascular unit, promote the blood-brain barrier (BBB) disruption following ischemic stroke, and play essential roles in hemorrhagic transformation (HT), which is one of the most severe side effects of thrombolytic therapy. However, no biomarkers have presently been identified that can be used to track changes in the distribution of MMPs in the brain. Here, we developed a new 19F-molecular ligand, TGF-019, for visualizing the distribution of MMPs in vivo using 19F-magnetic resonance spectroscopic imaging (19F-MRSI). We demonstrated TGF-019 has sufficient sensitivity for the specific MMPs suspected in evoking HT during ischemic stroke, i.e., MMP2, MMP9, and MMP3. We then utilized it to assess those MMPs at 22 to 24 hours after experimental focal cerebral ischemia on MMP2-null mice, as well as wild-type mice with and without the systemic administration of the recombinant tissue plasminogen activator (rt-PA). The 19F-MRSI of TGN-019-administered mice showed high signal intensity within ischemic lesions that correlated with total MMP2 and MMP9 activity, which was confirmed by zymographic analysis of ischemic tissues. Based on the results of this study, 19F-MRSI following TGN-019 administration can be used to assess potential therapeutic strategies for ischemic stroke.

Characteristics of Acute Spontaneous Intracerebral Hemorrhage in Patients Receiving Oral Anticoagulants.

OBJECTIVE: We investigated the precise clinical and radiologic characteristics of intracerebral hemorrhage associated with direct oral anticoagulant use. METHODS: Patients with acute spontaneous intracerebral hemorrhage admitted to our department from September 2014 to November 2017 were retrospectively analyzed. Clinical and neuroradiological characteristics of patients with direct oral anticoagulant-related intracerebral hemorrhage, and effects of prior treatment on the severity at admission and on outcome at discharge were assessed. RESULTS: Of the 301 enrolled patients (103 women; median age 68 years), 261 received no oral anticoagulants (86.8%), 20 received warfarin (6.6%), and 20 received direct oral anticoagulants (DOACs) (6.6%). Median initial National Institutes of Health Stroke Scale scores differed significantly among the groups (P = .0283). Systolic blood pressure (P = .0031) and estimated glomerular filtration rate (P = .0019) were significantly lower in the oral anticoagulant-related intracerebral hemorrhage group than in other groups. Total small vessel disease scores were significantly higher in the oral anticoagulant-related intracerebral hemorrhage group than in the warfarin group (P = .0413). Multivariate analysis revealed that prior oral anticoagulant treatment (odds ratio: 0.21, 95% confidence interval: 0.05-0.96, P = .0445) was independently negatively associated with moderate-to-severe neurological severity (stroke scale score ≥10) after adjusting for intracerebral hemorrhage location and various risk factors. There were significant differences in hematoma volume in the basal ganglia (P = .0366). CONCLUSIONS: DOAC-related intracerebral hemorrhage may occur particularly in patients with a high risk of bleeding; however, they had a milder initial neurological severity than those with warfarin-related intracerebral hemorrhage, possibly due to relatively smaller hematoma volume, especially in the basal ganglia.

Safety of Anticoagulant Therapy Including Direct Oral Anticoagulants in Patients With Acute Spontaneous Intracerebral Hemorrhage.

BACKGROUND: Because the efficacy and safety of anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) are not fully known, present study aimed to elucidate the current status and the safety of anticoagulant therapy, mainly direct oral anticoagulants (DOACs), for acute ICH and anticoagulant-indicated patients. Methods and Results: From September 2014 through March 2017, consecutive patients with acute (<7 days from onset), spontaneous ICH were retrospectively enrolled from a prospective registry. Whether to start anticoagulation was at the attending physicians' discretion, and thromboembolic or hemorrhagic events during hospitalization were analyzed. A total of 236 patients (80 women [34%]; median age 69 [interquartile range 61-79] years; National Institutes of Health stroke scale score 7 [3-16]) were enrolled. Of them, 47 patients (20%) had an indication for anticoagulant therapy (33 had atrial fibrillation, 14 developed deep vein thrombosis), and 41 of 47 patients (87%) were actually treated with anticoagulant therapy (DOACs were used in 34 patients) after a median of 7 days from ICH onset. There was neither hematoma expansion nor excessive hemorrhagic complications during hospitalization after starting anticoagulant therapy. CONCLUSIONS: Anticoagulant therapy was conducted for approximately 90% of anticoagulation-indicated patients after a median of 7 days from ICH onset. The predominant anticoagulant medications were DOACs. Anticoagulant therapy started from the acute phase of ICH should be safe.