Background: and Purpose The congestive heart failure, hypertension, age, diabetes, previous stroke/transient ischemic attack (CHA2DS2-VASc) and hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol (HAS-BLED) scores have been validated in estimating the risks of ischemic stroke and major bleeding, respectively, in patients with atrial fibrillation (AF). This study investigated stroke-specific predictors of major bleeding in patients with stroke and AF who were taking oral anticoagulants (OACs). Methods: Subjects were selected from patients enrolled in the Korean ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts (K-ATTENTION) nationwide multicenter registry between 2013 and 2015. Patients were excluded if they were not taking OACs, had no brain imaging data, or had intracranial bleeding directly related to the index stroke. Major bleeding was defined according to International Society of Thrombosis and Haemostasis criteria. Cox regression analyses were performed to assess the associations between clinical variables and major bleeding and Kaplan-Meier estimates were performed to analyze event-free survival. Results: Of a total of 3,213 patients, 1,414 subjects (mean age of 72.6 years, 52.5% males) were enrolled in this study. Major bleeding was reported in 34 patients during the median follow-up period of 1.73 years. Multivariable analysis demonstrated that initial National Institutes of Health Stroke Scale scores (hazard ratio [HR] 1.07, p=0.006), hypertension (HR 3.18, p=0.030), persistent AF type (HR 2.51, p=0.016), and initial hemoglobin level (HR 0.74, p=0.001) were independently associated with major bleeding risk. Except for hypertension, these associations remained significant after adjusting for the HAS-BLED score. Intracranial atherosclerosis presented a trend of association without statistical significance (HR 2.21, p=0.050). Conclusions This study found that major bleeding risk was independently associated with stroke-specific factors in anticoagulated patients with stroke and AF. This has the clinical implication that baseline characteristics of patients with stroke and AF should be considered in secondary prevention, which would bring the net clinical benefit of balancing recurrent stroke prevention with minimal bleeding complications.

Background: The Omicron variant has become the most prevalent SARS-CoV-2 variant. Omicron is known to induce milder lesions compared to the original Wuhan strain. Fatal infection of the Wuhan strain into the brain has been well documented in COVID-19 mouse models and human COVID-19 cases, but apparent infections into the brain by Omicron have not been reported in human adult cases or animal models. In this study, we investigated whether Omicron could spread to the brain using K18-hACE2 mice susceptible to SARS-CoV-2 infection. Results: K18-hACE2 mice were intranasally infected with 1 × 105 PFU of the original Wuhan strain and the Omicron variant of SARS-CoV-2. A follow-up was conducted 7 days post infection. All Wuhan-infected mice showed > 20% body weight loss, defined as the lethal condition, whereas two out of five Omicron-infected mice (40%) lost > 20% body weight. Histopathological analysis based on H&E staining revealed inflammatory responses in the brains of these two Omicron-infected mice. Immunostaining analysis of viral nucleocapsid protein revealed severe infection of neuron cells in the brains of these two Omicron-infected mice. Lymphoid depletion and apoptosis were observed in the spleen of Omicron-infected mice with brain infection. Conclusion Lethal conditions, such as severe body weight loss and encephalopathy, can occur in Omicron-infected K18-hACE2 mice. Our study reports, for the first time, that Omicron can induce brain infection with lymphoid depletion in the mouse COVID-19 model.

Background: and Purpose This study aimed to evaluate whether extracellular-vesicle-incorporated microRNAs (miRNAs) are potential biomarkers for cancer-related stroke. Methods: This cohort study compared patients with active cancer who had embolic stroke of unknown sources (cancer-stroke group) with patients with only cancer, patients with only stroke, and healthy individuals (control groups). The expression profiles of miRNAs encapsulated in plasma exosomes and microvesicles were evaluated using microarray and validated using quantitative real-time polymerase chain reaction. The XENO-QTM miRNA assay technology was used to determine the absolute copy numbers of individual miRNAs in an external validation cohort. Results: This study recruited 220 patients, of which 45 had cancer-stroke, 76 were healthy controls, 39 were cancer controls, and 60 were stroke controls. Three miRNAs (miR-205-5p, miR-645, and miR-646) were specifically incorporated into microvesicles in patients with cancer-related stroke, cancer controls, and stroke controls. The area under the receiver operating characteristic curves of these three miRNAs were 0.7692–0.8510 for the differentiation of patients with cancer-stroke from cancer-controls and 0.8077–0.8846 for the differentiation of patients with cancer-stroke from stroke controls. The levels of several miRNAs were elevated in the plasma exosomes of patients with cancer, but were lower than those in plasma microvesicles. An in vivo study showed that systemic injection of miR-205-5p promoted the development of arterial thrombosis and elevation of D-dimer levels. Conclusion Stroke due to cancer-related coagulopathy was associated with deregulated expression of miRNAs, particularly microvesicle-incorporated miR-205-5p, miR-645, and miR-646. Further prospective studies of extracellular-vesicle-incorporated miRNAs are required to confirm the diagnostic role of miRNAs in patients with stroke and to screen the roles of miRNAs in patients with cancer.

Background: and Purpose The natural course of adult-onset moyamoya disease (MMD) is unknown, and there is no medical treatment that halts its progression. We hypothesized that progressive shrinkage of large intracranial arteries occurs in adult-onset MMD, and that cilostazol inhibits this process. Methods: Serial high-resolution magnetic resonance imaging (HR-MRI) was performed on 66 patients with MMD: 30 patients received cilostazol, 21 received other antiplatelets, and 15 received no antiplatelets or had poor compliance to them. Serial HR-MRI was performed (interval between MRI scans: 29.67±18.02 months, mean±SD), and changes in outer diameter, luminal stenosis, and vascular enhancement were measured. Factors affecting HR-MRI changes were evaluated, including vascular risk factors and the ring finger protein 213 gene variant. Results: The progression of stenosis to occlusion, recurrent ischemic stroke, and the development of new stenotic segments were observed in seven, seven, and three patients, respectively. Serial HR-MRI indicated that the degree of stenosis increased with negative remodeling (outer diameter shrinkage). Patients who received cilostazol presented significantly larger outer diameters and lower degrees of stenosis compared with other groups (p=0.005 and p=0.031, respectively). After adjusting for clinical and genetic factors, only cilostazol use was independently associated with negative remodeling (odds ratio=0.29, 95% confidence interval=0.10–0.84, p=0.023). While vascular enhancement was observed in most patients (61 patients), the progression of enhancement or the occurrence of new vascular enhancement was rarely observed on follow-up HR-MRI (6 and 1 patients, respectively). Conclusions Adult-onset MMD induces progressive shrinkage of large intracranial arteries, which cilostazol treatment may prevent. Further randomized clinical trials are warranted.

A 12-year-old neutered male Golden Retriever presented with a progressively enlarging mass in the submandibular region. Histopathological diagnosis confirmed lymphangiosarcoma with metastasis to the liver and spleen. The pleomorphic neoplastic endothelial cells of the tumor grow directly on bundles of dermal collagen, forming numerous clefts and interconnecting channels that are devoid of conspicuous hematic elements. As lymphangiosarcoma is an uncommon malignant neoplasm, the number of previously reported cases and information of the tumor is limited. The present report describes the clinical history and histopathological diagnosis of a progressive lymphangiosarcoma in the submandibular region with metastases in a dog.

Background: and Purpose Previous studies have assessed the relationship between cerebral vessel tortuosity and intracranial aneurysm (IA) based on two-dimensional brain image analysis. We evaluated the relationship between cerebral vessel tortuosity and IA according to the hemodynamic location using three-dimensional (3D) analysis and studied the effect of tortuosity on the recurrence of treated IA. Methods: We collected clinical and imaging data from patients with IA and disease-free controls. IAs were categorized into outer curvature and bifurcation types. Computerized analysis of the images provided information on the length of the arterial segment and tortuosity of the cerebral arteries in 3D space. Results: Data from 95 patients with IA and 95 controls were analyzed. Regarding parent vessel tortuosity index (TI; P<0.01), average TI (P<0.01), basilar artery (BA; P=0.02), left posterior cerebral artery (P=0.03), both vertebral arteries (VAs; P<0.01), and right internal carotid artery (P<0.01), there was a significant difference only in the outer curvature type compared with the control group. The outer curvature type was analyzed, and the occurrence of an IA was associated with increased TI of the parent vessel, average, BA, right middle cerebral artery, and both VAs in the logistic regression analysis. However, in all aneurysm cases, recanalization of the treated aneurysm was inversely associated with increased TI of the parent vessels. Conclusions TIs of intracranial arteries are associated with the occurrence of IA, especially in the outer curvature type. IAs with a high TI in the parent vessel showed good outcomes with endovascular treatment.

Background: and Purpose To evaluate the outcome events and bleeding complications of the European Society of Cardiology (ESC) guideline-matched oral anticoagulant therapy for patients with acute ischemic stroke and atrial fibrillation (AF). Methods: Patients with acute ischemic stroke and AF from a nationwide multicenter registry (Korean ATrial fibrillaTion EvaluatioN regisTry in Ischemic strOke patieNts [K-ATTENTION]) between January 2013 and December 2015 were included in the study. Patients were divided into the ESC guideline-matched and the non-matched groups. The primary outcome was recurrence of any stroke during the 90-day follow-up period. Secondary outcomes were major adverse cerebrovascular and cardiovascular events, ischemic stroke, intracranial hemorrhage, acute coronary syndrome, allcause mortality, and major hemorrhage. Propensity score matching and logistic regression analyses were performed to assess the effect of the treatments administered. Results: Among 2,321 eligible patients, 1,126 patients were 1:1 matched to the ESC guidelinematched and the non-matched groups. As compared with the non-matched group, the ESC guideline-matched group had a lower risk of any recurrent stroke (1.4% vs. 3.4%; odds ratio [OR], 0.41; 95% confidence interval [CI], 0.18 to 0.95). The risk of recurrent ischemic stroke was lower in the ESC guideline-matched group than in the non-matched group (0.9% vs. 2.7%; OR, 0.32; 95% CI, 0.11 to 0.88). There was no significant difference in the other secondary outcomes between the two groups. Conclusions ESC guideline-matched oral anticoagulant therapy was associated with reduced risks of any stroke and ischemic stroke as compared with the non-matched therapy.

Background: and Purpose Previous studies have assessed the relationship between cerebral vessel tortuosity and intracranial aneurysm (IA) based on two-dimensional brain image analysis. We evaluated the relationship between cerebral vessel tortuosity and IA according to the hemodynamic location using three-dimensional (3D) analysis and studied the effect of tortuosity on the recurrence of treated IA. Methods: We collected clinical and imaging data from patients with IA and disease-free controls. IAs were categorized into outer curvature and bifurcation types. Computerized analysis of the images provided information on the length of the arterial segment and tortuosity of the cerebral arteries in 3D space. Results: Data from 95 patients with IA and 95 controls were analyzed. Regarding parent vessel tortuosity index (TI; P<0.01), average TI (P<0.01), basilar artery (BA; P=0.02), left posterior cerebral artery (P=0.03), both vertebral arteries (VAs; P<0.01), and right internal carotid artery (P<0.01), there was a significant difference only in the outer curvature type compared with the control group. The outer curvature type was analyzed, and the occurrence of an IA was associated with increased TI of the parent vessel, average, BA, right middle cerebral artery, and both VAs in the logistic regression analysis. However, in all aneurysm cases, recanalization of the treated aneurysm was inversely associated with increased TI of the parent vessels. Conclusions TIs of intracranial arteries are associated with the occurrence of IA, especially in the outer curvature type. IAs with a high TI in the parent vessel showed good outcomes with endovascular treatment.

Systemic cancer and ischemic stroke are common conditions and two of the most frequent causes of death among the elderly. The association between cancer and stroke has been reported worldwide. Stroke causes severe disability for cancer patients, while cancer increases the risk of stroke. Moreover, cancer-related stroke is expected to increase due to advances in cancer treatment and an aging population worldwide. Because cancer and stroke share risk factors (such as smoking and obesity) and treatment of cancer can increase the risk of stroke (e.g., accelerated atherosclerosis after radiation therapy), cancer may accelerate conventional stroke mechanisms (i.e., atherosclerosis, small vessel disease, and cardiac thrombus). In addition, active cancer and chemotherapy may enhance thrombin generation causing stroke related to coagulopathy. Patients with stroke due to cancer-related coagulopathy showed the characteristics findings of etiologic work ups, D-dimer levels, and infarct patterns. In this review, we summarized the frequency of cancer-related stroke among patients with ischemic stroke, mechanisms of stroke with in cancer patients, and evaluation and treatment of cancer-related stroke. We discussed the possibility of cancer-related stroke as a stroke subtype, and presented the most recent discoveries in the pathomechanisms and treatment of stroke due to cancer-related coagulopathy.