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Objectives: Intracerebral hemorrhage (ICH) and cerebral microbleeds (CMB) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy are more common in East Asian populations than in people of white European ancestry. We hypothesized that the ethnic difference is explained by the East Asian‐specific NOTCH3 p.R75P mutation. Methods: This retrospective observational study included 118 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in Japanese and Korean cohorts. We investigated whether the p.R75P mutation is associated with symptomatic ICH and multiple CMB (>5) using quasi‐Poisson regression models. We predicted the NOTCH3 extracellular domain protein structures in silico and graded NOTCH3 extracellular domain immunostaining in skin vessels of some patients, with subsequent comparisons between p.R75P and other conventional mutations. Results: Among 63 Japanese patients (median age 55 years; 56% men), 15 had a p.R75P mutation, significantly associated with symptomatic ICH (adjusted relative risk 9.56, 95% CI 2.45–37.31), multiple CMB (3.00, 1.34–6.71), and absence of temporopolar lesions (4.91, 2.29–10.52) after adjustment for age, sex, hypertension, and antithrombotics. In the Korean cohort (n = 55; median age 55 years; 51% men), the p.R75P mutation (n = 13) was also associated with symptomatic ICH (8.11, 1.83–35.89), multiple CMB (1.90, 1.01–3.56), and absence of temporopolar lesions (2.32, 1.08–4.97). Structural analysis revealed solvent‐exposed free cysteine thiols in conventional mutations, directly causing aggregation, whereas a stereochemically incompatible proline residue structure in p.R75P lowers correct disulfide bond formation probability, indirectly causing aggregation. Pathologically, the p.R75P mutation resulted in less vascular NOTCH3 extracellular domain accumulation than the other conventional mutations. Interpretation: NOTCH3 p.R75P mutation is associated with hemorrhagic presentations, milder temporopolar lesions, and distinct mutant protein structure properties. ANN NEUROL 2024;95:1040–1054 [ABSTRACT FROM AUTHOR]

Objective: Postseizure functional decline is a concern in poststroke epilepsy (PSE). However, data on electroencephalogram (EEG) markers associated with functional decline are scarce. Thus, we investigated whether periodic discharges (PDs) and their specific characteristics are associated with functional decline in patients with PSE. Methods: In this observational study, patients admitted with seizures of PSE and who had scalp EEGs were included. The association between the presence or absence of PDs and postseizure short‐term functional decline lasting 7 days after admission was investigated. In patients with PD, EEG markers were explored for risk stratification of short‐term functional decline, according to the American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. The association between EEG markers and imaging findings and long‐term functional decline at discharge and 6 months after discharge, defined as an increase in the modified Rankin Scale score compared with the baseline, was evaluated. Results: In this study, 307 patients with PSE (median age = 75 years, range = 35–97 years, 64% males; hemorrhagic stroke, 47%) were enrolled. Compared with 247 patients without PDs, 60 patients with PDs were more likely to have short‐term functional decline (12 [20%] vs. 8 [3.2%], p <.001), with an adjusted odds ratio (OR) of 4.26 (95% confidence interval [CI] = 1.44–12.6, p =.009). Patients with superimposed fast‐activity PDs (PDs+F) had significantly more localized (rather than widespread) lesions (87% vs. 58%, p =.003), prolonged hyperperfusion (100% vs. 62%, p =.023), and a significantly higher risk of short‐term functional decline than those with PDs without fast activity (adjusted OR = 22.0, 95% CI = 1.87–259.4, p =.014). Six months after discharge, PDs+F were significantly associated with long‐term functional decline (adjusted OR = 4.21, 95% CI = 1.27–13.88, p =.018). Significance: In PSE, PDs+F are associated with sustained neuronal excitation and hyperperfusion, which may be a predictor of postseizure short‐ and long‐term functional decline. [ABSTRACT FROM AUTHOR]

Objective: To assess whether post‐stroke epilepsy (PSE) is associated with neuroimaging findings of hemosiderin in a case–control study, and whether the addition of hemosiderin markers improves the risk stratification models of PSE. Methods: We performed a post‐hoc analysis of the PROgnosis of POST‐Stroke Epilepsy study enrolling PSE patients at National Cerebral and Cardiovascular Center, Osaka, Japan, from November 2014 to September 2019. PSE was diagnosed when one unprovoked seizure was experienced >7 days after the index stroke, as proposed by the International League Against Epilepsy. As controls, consecutive acute stroke patients with no history or absence of any late seizure or continuing antiseizure medications at least 3 months after stroke were retrospectively enrolled during the same study period. We examined cortical microbleeds and cortical superficial siderosis (cSS) using gradient‐echo T2*‐weighted images. A logistic regression model with ridge penalties was tuned using 10‐fold cross‐validation. We added the item of cSS to the existing models (SeLECT and CAVE) for predicting PSE and evaluated performance of new models. Results: The study included 180 patients with PSE (67 women; median age 74 years) and 1,183 controls (440 women; median age 74 years). The cSS frequency was higher in PSE than control groups (48.9% vs 5.7%, p < 0.0001). Compared with the existing models, the new models with cSS (SeLECT‐S and CAVE‐S) demonstrated significantly better predictive performance of PSE (net reclassification improvement 0.63 [p = 0.004] for SeLECT‐S and 0.88 [p = 0.001] for CAVE‐S at the testing data). Interpretation: Cortical superficial siderosis was associated with PSE, stratifying stroke survivors at high risk of PSE. ANN NEUROL 2023;93:357–370 [ABSTRACT FROM AUTHOR]

Objectives: Recent advancements in genome research have revealed not only the importance of variants associated with cerebrovascular diseases but also a notably high frequency of carriers harboring multiple variants, presenting with an elusive blended phenotype. In this study, we report the case of a 66-year-old man who experienced 3 stroke episodes over a 4-year period, starting at the age of 62 years. The patient presented with isolated infarcts in the left temporal pole with progressive stenosis in the ipsilateral middle cerebral artery based on large and small artery crosstalk., Methods: Exons 2-24 of the NOTCH3 gene were analyzed by direct genomic DNA sequencing. The presence of the p.Arg4810Lys variant of the ring finger protein 213 ( RNF213 ) gene was evaluated using real-time PCR., Results: Diagnoses of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and RNF213 -related vasculopathy were made based on the early-onset recurrent stroke episode, progressive intracranial artery stenosis, and presence of the heterozygous NOTCH3 p.Cys1250Arg and RNF213 p.Arg4810Lys variants., Discussion: Temporal pole infarcts could represent a blended phenotype of both variants. This case highlights the importance of large and small artery crosstalk and the pivotal role of genetic analysis in determining the pathogenesis of stroke and dementia., Competing Interests: The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patients with acute ischemic stroke and active cancer have more severe neurological symptoms, elevated risks of stroke recurrence, and death compared with the general population. We examined whether von Willebrand factor (vWF) antigen levels at stroke onset were associated with the poor outcomes of patients with stroke and cancer., Methods and Results: Using data from 90 patients with acute ischemic stroke and active cancer who were registered in the SCAN (Ischemic Stroke in Patients With Cancer and Neoplasia) study, a prospective multicenter, observational study in Japan, we divided patients into 2 groups according to their median vWF antigen levels (high, n=46; or low, n=44). The high-vWF group had a significantly higher initial National Institutes of Health Stroke Scale score (median, 7 [interquartile range, 3-11.25] versus 3 [interquartile range, 1-8.5]; P <0.05) and a significantly higher incidence of cryptogenic stroke (32 [70%] versus 16 [36%]; P <0.01) and venous thromboembolism (7 [15%] versus 0 [0%]; P <0.01), as well as multiple lesions (28 [62%] versus 12 [27%]; P <0.001), than the low-vWF group. We observed no significant difference in the rate of stroke recurrence within 1 year between the groups. However, increased vWF levels were an independent predictor of death within 1 year of stroke onset, after adjusting for potential confounders (odds ratio, 6.77 [95% CI, 1.49-30.78]; P <0.05)., Conclusions: Elevated vWF antigen levels were associated with adverse outcomes in patients with cancer-associated stroke and may represent a useful biomarker to guide future therapeutic interventions.

Objective: Stent retriever (SR) angioplasty is an adjunctive technique for acute large vessel occlusion stroke due to underlying intracranial atherosclerotic disease (ICAD-LVO). Prolonged SR deployment maintains blood flow distal to the atherosclerotic lesion until the antiplatelet agent has exerted its effect. Although SR angioplasty for ICAD-LVO has been reported, few reports are available on SR angioplasty for medium vessel occlusion stroke due to underlying ICAD (ICAD-MeVO). Here, we describe a case of SR angioplasty for acute occlusion of the left M2 segment of the middle cerebral artery (MCA) due to underlying ICAD., Case Presentation: A 79-year-old man with a history of left MCA M2 segment stenosis presented with motor aphasia and dysarthria. Diffusion-weighted MRI showed no high-signal intensity areas, and MRA showed occlusion of the left MCA M2 segment. The patient was diagnosed with ICAD-MeVO. After performing an MRI, the patient's symptoms progressed to total aphasia. SR angioplasty was performed for the occlusion of the left M2 segment of the MCA. Diffusion-weighted MRI the day after the procedure showed a small area of high-signal intensity exclusively in the left putamen, while MRA confirmed recanalization of the left MCA M2 segment. Aphasia improved after the procedure. No re-occlusion was observed for 90 days, and the modified Rankin Scale score at 90 days was 2., Conclusion: SR angioplasty appears to be a safe option for managing MCA M2 segment occlusion., (©2024 The Japanese Society for Neuroendovascular Therapy.)

Background Limited data exist on the prognostic factors for patients with ischemic stroke and active cancer. Methods and Results We conducted a prospective, multicenter, observational study in Japan, including patients with acute ischemic stroke and active cancer, to investigate the prognostic factors. We followed up the patients for 1 year after stroke onset. The patients were divided into 2 groups according to cryptogenic stroke and known causes (small-vessel occlusion, large-artery atherosclerosis, cardioembolism, and other determined cause), and survival was compared. The hazard ratios (HRs) and 95% CIs for mortality were calculated using Cox regression models. We identified 135 eligible patients (39% women; median age, 75 years). Of these patients, 51% had distant metastasis. A total of 65 (48%) and 70 (52%) patients had cryptogenic stroke and known causes, respectively. Patients with cryptogenic stroke had significantly shorter survival than those with known causes (HR [95% CI], 3.11 [1.82-5.32]). The multivariable Cox regression analysis revealed that distant metastasis, plasma D-dimer levels, venous thromboembolism (either deep venous thrombosis or pulmonary embolism) complications at stroke onset were independent predictors of mortality after adjusting for potential confounders. Cryptogenic stroke was associated with prognosis in univariable analysis but was not significant in multivariable analysis. The plasma D-dimer levels stratified the prognosis of patients with ischemic stroke and active cancer. Conclusions The prognosis of patients with acute ischemic stroke and active cancer varied considerably depending on stroke mechanism, distant metastasis, and coagulation abnormalities. The present study confirmed that coagulation abnormalities were crucial in determining the prognosis of such patients.

Poststroke epilepsy is a major ischaemic/haemorrhagic stroke complication. Seizure recurrence risk estimation and early therapeutic intervention are critical, given the association of poststroke epilepsy with worse functional outcomes, quality of life and greater mortality. Several studies have reported risk factors for seizure recurrence; however, in poststroke epilepsy, the role of EEG in predicting the risk of seizures remains unclear. This multicentre observational study aimed to clarify whether EEG findings constitute a risk factor for seizure recurrence in patients with poststroke epilepsy. Patients with poststroke epilepsy were recruited from the PROgnosis of POst-Stroke Epilepsy study, an observational multicentre cohort study. The enrolled patients with poststroke epilepsy were those admitted at selected hospitals between November 2014 and June 2017. All patients underwent EEG during the interictal period during admission to each hospital and were monitored for seizure recurrence over 1 year. Board-certified neurologists or epileptologists evaluated all EEG findings. We investigated the relationship between EEG findings and seizure recurrence. Among 187 patients with poststroke epilepsy (65 were women with a median age of 75 years) admitted to the lead hospital, 48 (25.7%) had interictal epileptiform discharges on EEG. During the follow-up period (median, 397 days; interquartile range, 337-450 days), interictal epileptiform discharges were positively correlated with seizure recurrence (hazard ratio, 3.82; 95% confidence interval, 2.09-6.97; P < 0.01). The correlation remained significant even after adjusting for age, sex, severity of stroke, type of stroke and generation of antiseizure medications. We detected periodic discharges in 39 patients (20.9%), and spiky/sharp periodic discharges were marginally associated with seizure recurrence (hazard ratio, 1.85; 95% confidence interval, 0.93-3.69; P = 0.08). Analysis of a validation cohort comprising 187 patients with poststroke epilepsy from seven other hospitals corroborated the association between interictal epileptiform discharges and seizure recurrence. We verified that interictal epileptiform discharges are a risk factor for seizure recurrence in patients with poststroke epilepsy. Routine EEG may facilitate the estimation of seizure recurrence risk and the development of therapeutic regimens for poststroke epilepsy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)