Pathophysiology, Diagnosis, Prognosis, and Prevention of Poststroke Epilepsy: Clinical and Research Implications.

Poststroke epilepsy (PSE) is associated with higher mortality and poor functional and cognitive outcomes in patients with stroke. With the remarkable development of acute stroke treatment, there is a growing number of survivors with PSE. Although approximately 10% of patients with stroke develop PSE, given the significant burden of stroke worldwide, PSE is a significant problem in stroke survivors. Therefore, the attention of health policymakers and significant funding are required to promote PSE prevention research. The current PSE definition includes unprovoked seizures occurring more than 7 days after stroke onset, given the high recurrence risks of seizures. However, the pathologic cascade of stroke is not uniform, indicating the need for a tissue-based approach rather than a time-based one to distinguish early seizures from late seizures. EEG is a commonly used tool in the diagnostic work-up of PSE. EEG findings during the acute phase of stroke can potentially stratify the risk of subsequent seizures and predict the development of poststroke epileptogenesis. Recent reports suggest that cortical superficial siderosis, which may be involved in epileptogenesis, is a promising marker for PSE. By incorporating such markers, future risk-scoring models could guide treatment strategies, particularly for the primary prophylaxis of PSE. To date, drugs that prevent poststroke epileptogenesis are lacking. The primary challenge involves the substantial cost burden due to the difficulty of reliably enrolling patients who develop PSE. There is, therefore, a critical need to determine reliable biomarkers for PSE. The goal is to be able to use them for trial enrichment and as a surrogate outcome measure for epileptogenesis. Moreover, seizure prophylaxis is essential to prevent functional and cognitive decline in stroke survivors. Further elucidation of factors that contribute to poststroke epileptogenesis is eagerly awaited. Meanwhile, the regimen of antiseizure medications should be based on individual cardiovascular risk, psychosomatic comorbidities, and concomitant medications. This review summarizes the current understanding of poststroke epileptogenesis, its risks, prognostic models, prophylaxis, and strategies for secondary prevention of seizures and suggests strategies to advance research on PSE.

Cutoff value of the geniohyoid muscle mass to identify sarcopenic dysphagia by ultrasonography.

PURPOSE: Determining the strength and area of the swallowing muscles is important in patients with sarcopenic dysphagia. Although the normative data on the strength of the swallowing muscles have been reported, those of the area of the geniohyoid muscle are poorly investigated. We investigated the cross-sectional area of the geniohyoid muscle in Japanese subjects without dysphagia using ultrasonography to determine the normative and cut-off values. METHODS: 142 subjects without dysphagia were included. The older group (age ≥ 65 years) included 36 (women 27/men 9) subjects, and the younger group (age ≤ 39 years) included 106 (women 54/men 52) subjects. The cross-sectional area of the geniohyoid muscle was measured by ultrasound. The mean of the younger group-2 standard deviation (SD) was calculated and used as a cut-off value for low swallowing muscle mass. RESULTS: The mean (SD) of the area of the geniohyoid muscle of each group was as follows: older women group 167.2 (32.6) mm2, older men group 193.2 (49.5) mm2, younger women group 247.3 (37.4) mm2, younger men group 313.1 (59.2) mm2. The mean 2SD of the geniohyoid muscle area in the younger women group was 172.5 mm2 and in the younger men group 194.7 mm2. CONCLUSION: We found that the cut-off value of the ultrasonographic cross-sectional area of the geniohyoid muscle was 172.5 mm2 for women and 194.7 mm2 for men. These values could be used as cut-off values for the mass of the geniohyoid muscle to identify patients with sarcopenic dysphagia.

High pillow and spontaneous vertebral artery dissection: A case-control study implicating "Shogun pillow syndrome".

INTRODUCTION: The underlying causes of spontaneous vertebral artery dissection (sVAD) remain insufficiently understood. This study aimed to determine whether high-pillow usage is associated with an increased risk of sVAD and evaluate the frequency of sVAD attributable to high-pillow usage. PATIENTS AND METHODS: This case-control study identified patients with sVAD and age- and sex-matched non-sVAD controls (case-to-control ratio: 1:1) treated at a certified comprehensive stroke center in Japan between 2018 and 2023. The pillow height used at the onset of the index disease was measured and classified into three categories between 12 and 15 cm boundaries. Univariable logistic regression was performed to assess the odds ratio (OR) with a 95% confidence interval (CI) of high-pillow usage for sVAD development. A subgroup of sVAD attributable to high-pillow usage was defined with the following three conditions: high-pillow usage (⩾12 or ⩾15 cm); no minor preceding trauma; and wake-up onset. RESULTS: Fifty-three patients with sVAD and 53 non-sVAD controls (42% women, median age: 49 years) were identified. High-pillow usage (⩾12 and ⩾15 cm) was more common in the sVAD group than in the non-sVAD group (34 vs 15%; OR = 2.89; 95%CI = 1.13-7.43 and 17 vs 1.9%; OR = 10.6; 95%CI = 1.30-87.3, respectively). The subgroup of sVAD attributed to high-pillow usage (⩾12 and ⩾15 cm) was found in 11.3% (95%CI = 2.7%-19.8%) and 9.4% (95%CI = 1.5%-17.3%), respectively. CONCLUSION: High-pillow usage was associated with an increased risk of sVAD and accounted for approximately 10% of all sVAD cases. This tentative subgroup of sVAD may represent a distinct spectrum of disease-Shogun pillow syndrome.

Periodic discharges plus fast activity on electroencephalogram predict worse outcomes in poststroke epilepsy.

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.

Pre-existing sarcopenia and swallowing outcomes in acute stroke patients.

BACKGROUND & AIMS: This study aimed to investigate the associations of pre-existing sarcopenia with swallowing function, oral intake level, and aspiration pneumonia in patients with acute stroke. METHODS: This observational study included patients (≥60 years of age) with acute ischemic stroke or intracerebral hemorrhage within 7 days of onset who were screened for sarcopenia, malnutrition, and swallowing difficulties in a stroke-care unit within 48 h of admission. Sarcopenia was defined by the Asian Working Group on Sarcopenia 2019 as having a low calf circumference, handgrip strength, and appendicular muscle mass index. The primary outcome was impaired oral intake (functional oral intake scale <5 points) at 3, 7, and 14 days after admission, and the secondary outcome was aspiration pneumonia during hospitalization. RESULTS: We enrolled 350 patients (median age of 77 years; 63% males) who underwent the aforementioned screening. Sarcopenia was diagnosed in 34% of patients, and malnutrition was found in 66% of patients with sarcopenia. When compared with the comparison group (defined as patients with either or both normal calf circumference and handgrip strength), the sarcopenia group had significantly lower tongue pressure and a higher prevalence of dysphagia. Sarcopenia was associated with functional oral intake scale <5 at 7 days (adjusted odds ratio [OR], 4.72; 95% confidence interval [CI], 1.91-11.71); p = 0.002) and 14 days (adjusted OR, 3.93; 95% CI, 1.47-10.53; p = 0.006) and with aspiration pneumonia during hospitalization (adjusted OR, 6.12; 95% CI, 1.63-22.94; p = 0.007). CONCLUSION: Acute stroke patients with sarcopenia may have weakness of the swallowing-related muscles which may lead to impaired oral intake and aspiration pneumonia.

Rapid Evaluation of Large Vessel Occlusion for Mechanical Thrombectomy Using Carotid Duplex Ultrasound.

Objectives This study clarified the usefulness of carotid duplex ultrasound (CDU) in evaluating large vessel occlusion (LVO) in patients with acute stroke planned to be treated with mechanical thrombectomy (MT). Methods This study was single-center, prospective, observational trial. If the ratio of end-diastolic velocity in the common carotid arteries was ≥1.4, or diastolic flow in the affected internal carotid artery (ICA) was absent on CDU, patients were immediately transferred to the angio-suite without additional cerebrovascular imaging. Clinical parameters, including time metrics and outcomes, were evaluated in participants. Patients We enrolled stroke patients with a National Institutes of Health Stroke Scale score ≥6 and Alberta Stroke Program Early CT score ≥6 in whom MT could be initiated within 6 hours of the stroke onset. Results Among 140 patients screened during the study period, 48 were ultimately enrolled. Twenty-seven patients were diagnosed with LVO by CDU alone. CDU offered 83% sensitivity and 82% specificity for identifying the occlusion of the ICA or M1 segment of the middle cerebral artery. Among the 29 total patients treated with MT, 20 (67%) showed a modified Rankin Scale score ≤2 at 90 days. The door-to-puncture time was significantly shorter in patients evaluated by CDU alone (34 minutes) than in those evaluated by magnetic resonance angiography after CDU (47.5 minutes, p<0.001). Conclusion CDU might reduce the time metrics for early initiation of MT with good sensitivity and specificity in identifying LVO.

P2Y12 Reaction Units and Clinical Outcomes in Acute Large Artery Atherosclerotic Stroke: A Multicenter Prospective Study.

AIMS: We aimed to determine the association between acute platelet reactivity and clinical outcome in acute ischemic stroke (AIS) or transient ischemic attack (TIA) with large-artery atherosclerosis (LAA). METHODS: In this prospective, 16-multicenter study, we enrolled AIS/TIA patients with LAA receiving clopidogrel. We assessed the association of P2Y12 reaction units (PRU) 24 hours after initiation of antiplatelets with the CYP2C19 genotype and recurrent ischemic stroke within 90 days, and the difference between acute (≤ 7 days) and subacute (8-90 days) phases. RESULTS: Among the 230 AIS/TIA patients enrolled, 225 with complete outcome data and 194 with genetic results were analyzed. A higher PRU was significantly associated with recurrent ischemic stroke within 90 days (frequency, 16%), and within 7 days (10%). Twenty-nine patients (15%) belonged to a CYP2C19 poor metabolizer group (CYP2C19＊2/＊2, ＊2/＊3, or ＊3/＊3). Multivariable receiver-operating characteristic analysis showed a greater area-under-the-curve (AUC) in predicting recurrence within 7 days, compared to 8-90 days (AUC, 0.79 versus 0.64; p=0.07), with a cut-off PRU of 254. Multivariable analysis showed high PRU (≥ 254), which had a comparable predictive performance for recurrent ischemic stroke within 7 days (odds ratio, 6.82; 95% CI, 2.23-20.9; p＜0.001) to the CYP2C19 poor metabolizer genotype. The net reclassification improvement, calculated by adding high PRU (≥ 254) to a model including the CYP2C19 poor metabolizer genotype in the prediction of recurrence within 7 days, was 0.83 (p＜0.001). CONCLUSIONS: Acute PRU evaluation possesses predictive value for recurrent ischemic stroke, especially within 7 days in AIS/TIA with LAA.

Association of Cortical Superficial Siderosis with Post-Stroke Epilepsy.

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.

Interictal epileptiform discharges as a predictive biomarker for recurrence of poststroke epilepsy.

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.

Association of Existence of Sarcopenia and Poor Recovery of Swallowing Function in Post-Stroke Patients with Severe Deglutition Disorder: A Multicenter Cohort Study.

BACKGROUND: The effect of sarcopenia on the recovery of swallowing function, and the interaction among sarcopenia, nutrition care, and rehabilitation therapy are inconclusive. METHODS: This multicenter cohort study was conducted between November 2018 and October 2020 in convalescent rehabilitation hospitals in Japan and included post-stroke patients aged ≥65 years with dysphagia. All participants were assigned to sarcopenia and non-sarcopenia groups. The primary outcome was the achievement of ≥2 Food Intake Level Scale [FILS] gain, and the secondary outcomes included Functional Independence Measure (FIM) gain and efficiency. Considering the effect modification of energy intake and rehabilitation duration, logistic regression analyses were performed. RESULTS: Overall, 153 participants with (median age, 82 years; 57.5% women) and 40 without (median age 75 years; 35.0% women) sarcopenia were included. The non-sarcopenia group had more patients who achieved an FILS gain of ≥2 (75.0%) than the sarcopenia group (51.0%). Sarcopenia was independently associated with a poor FILS gain (odds ratio:0.34, 95% confidence intervals: 0.13-0.86) but not associated with FIM gain or efficiency. This association was not affected by the rehabilitation duration or energy intake. CONCLUSIONS: In conclusion, sarcopenia was negatively associated with the recovery of swallowing function in stroke patients without interaction by energy intake and rehabilitation duration.

Developing an Asymmetry Method for Detecting Postictal Hyperperfusion in Poststroke Epilepsy.

Using dual single-photon emission computed tomography (SPECT) scanning, we recently found the postictal-interictal (P-I) subtraction method frequently detects prolonged postictal hyperperfusion in poststroke epilepsy (PSE) and thus may be valuable for auxiliary diagnosis. This study aimed to determine if the asymmetry method can localize hyperperfusion to reflect epileptic activity in PSE using a single postictal SPECT scan. Sixty-four patients with PSE who had undergone perfusion SPECT two times (postictal and interictal) were enrolled. We formulated a novel asymmetry method (subtraction analysis of reversed postictal SPECT from postictal SPECT, co-registered to magnetic resonance imaging) to identify paradoxical asymmetric increase, defined as a higher perfusion area adjacent to stroke lesions compared to the contralateral side. The postictal hyperperfusion area and detection rates were determined by the asymmetry and P-I subtraction methods independently. We subsequently calculated the sensitivity and specificity of the asymmetry method, compared to the gold standard P-I subtraction method. We also evaluated lateralization concordance between the asymmetry method and other clinical findings. Among 64 patients (median age, 75 years), prolonged postictal hyperperfusion was detected in 43 (67%) by the asymmetry, and 54 (84%) the P-I, method. The asymmetry method had high sensitivity (80%) and specificity (100%) in detecting postictal hyperperfusion, showing high lateralization concordance with seizure semiology (97%) and epileptiform electroencephalography findings (interictal/ictal epileptiform discharges or periodic discharges) (100%). The present study demonstrated the advantages of the objective asymmetry method for detecting prolonged hyperperfusion through using one postictal SPECT scan in PSE.

Clinical and imaging features of nonmotor onset seizure in poststroke epilepsy.

OBJECTIVE: Motivated by the challenges raised by diagnosing poststroke epilepsy (PSE), especially in nonmotor onset seizure (non-MOS), we aimed to investigate the features of non-MOS, including seizure sequences, patient characteristics, and electrophysiological and imaging findings in PSE. METHODS: This observational cohort study enrolled patients with PSE whose seizure onset was witnessed. According to the International League Against Epilepsy (ILAE) 2017 seizure classification, we classified seizure-onset symptoms into the non-MOS and MOS groups. We compared the different clinical characteristics between the two groups. RESULTS: Between 2011 and 2018, we enrolled 225 patients with PSE (median age, 75 years), consisting of 97 (43%) with non-MOS and 128 (57%) with MOS. Overall, 65 (67%) of the patients without MOS had no subsequent convulsions. Multivariable logistic regression analysis showed significant associations of non-MOS with absence of poststroke hemiparesis (adjusted odds ratio [OR], 1.88; 95% confidence interval [CI], 1.03-3.42), frontal stroke lobe lesions (OR, 2.11; 95% CI, 1.14-3.91), and putaminal stroke lesions (OR, 2.51; 95% CI, 1.22-5.18) as negative indicators. Postictal single-photon emission computed tomography (SPECT) detected prolonged hyperperfusion in the temporal lobe more frequently in the non-MOS than in the MOS group (48% vs 31%; p = .02). The detection rate was higher than spikes/sharp waves in scalp electroencephalography, both in the non-MOS group (72% vs 33%; p < .001) and the MOS group (68% vs 29%; p < .001). SIGNIFICANCE: This study provides the clinical features of non-MOS in patients with PSE. Compared with the patients with MOS, patients with non-MOS showed less likely subsequent convulsive seizures, highlighting the clinical challenges. Postictal perfusion imaging and negative indicators of the non-MOS type may help diagnose and stratify PSE.

Impact of Seizure Recurrence on 1-Year Functional Outcome and Mortality in Patients With Poststroke Epilepsy.

BACKGROUND AND OBJECTIVES: The functional outcome and mortality of patients with poststroke epilepsy (PSE) have not been assessed in a prospective study. Previous reports have suggested that patients with PSE may suffer from prolonged functional deterioration after a seizure. In this study, we prospectively investigated the functional outcome and mortality of patients with PSE and analyzed the effect of seizure recurrence on the outcomes. METHODS: This is part of the Prognosis of Post-Stroke Epilepsy study, a multicenter, prospective observational cohort study, where 392 patients with PSE (at least 1 unprovoked seizure more than 7 days after the onset of the last symptomatic stroke) were followed for at least 1 year at 8 hospitals in Japan. This study included only PSE patients with a first-ever seizure and assessed their functional decline and mortality at 1 year. Functional decline was defined as an increase in modified Rankin Scale (mRS) score at 1 year compared with baseline, excluding death. The associations between the seizure recurrence and the outcomes were analyzed statistically. RESULTS: A total of 211 patients (median age of 75 years; median mRS score of 3) were identified. At 1 year, 50 patients (23.7%) experienced seizure recurrence. Regarding outcomes, 25 patients (11.8%) demonstrated functional decline and 20 (9.5%) had died. Most patients died of pneumonia or cardiac disease (7 patients each), and no known causes of death were directly related to recurrent seizures. Seizure recurrence was significantly associated with functional decline (odds ratio [OR] 2.96, 95% CI 1.25-7.03, p = 0.01), even after adjusting for potential confounders (adjusted OR 3.26, 95% CI 1.27-8.36, p = 0.01), but not with mortality (OR 0.79, 95% CI 0.25-2.48, p = 0.68). Moreover, there was a significant trend where patients with more recurrent seizures were more likely to have functional decline (8.7%, 20.6%, and 28.6% in none, 1, and 2 or more recurrent seizures, respectively; p = 0.006). DISCUSSION: One-year functional outcome and mortality of patients with PSE were poor. Seizure recurrence was significantly associated with functional outcome, but not with mortality. Further studies are needed to ascertain whether early and adequate antiseizure treatment can prevent the functional deterioration of patients with PSE.

A Nationwide Multi-Center Questionnaire Survey on the Real-World State and Clinical Management of Poststroke Dementia in Japan.

BACKGROUND: Poststroke dementia (PSD) is a serious problem for stroke survivors. However, there is still limited data on the real-world state and clinical management of PSD worldwide, and several countries already have a super-aged society. OBJECTIVE: We conducted a nationwide questionnaire survey to examine the real-world state and management of PSD in Japan. METHODS: A survey was conducted in the top 500 Japanese hospitals regarding the number of stroke patients treated between July 2018 and August 2019. Thirteen questions regarding PSD were mailed to doctors responsible for stroke management. RESULTS: Responses were obtained from 251 hospitals (50.2%). The chief doctors responsible for stroke management answered the questionnaires. The median numbers of patients admitted annually with stroke in the departments of neurology and neurosurgery in the hospitals were 281.0 (interquartile range [IQR], 231.8-385.3) and 253.5 (IQR, 210.0-335.3), respectively, and most hospitals were acute care hospitals. Executive dysfunction was the most common cognitive dysfunction (10.9%), followed by amnesia (9.5%) and apathy (4.1%). Surprisingly, many stroke survivors lived alone at home (23.7%). Montreal Cognitive Assessment was significantly uncommon compared to Mini-Mental State Examination (p < 0.01). Furthermore, objective evaluation tests for behavioral and psychological symptoms of dementia were not often performed. Cognitive rehabilitation treatments were performed more often and earlier than drug treatments. The first drug of choice for PSD was predominantly donepezil (79.1%), followed by galantamine (6.1%), cilostazol (4.9%), memantine (2.5%), and rivastigmine (1.8%). CONCLUSION: Our study provides real-world evidence for the state of clinical practice related to PSD in Japan.

Influence of Renal Impairment and Genetic Subtypes on Warfarin Control in Japanese Patients.

The genotypes of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) can influence therapeutic warfarin doses. Conversely, nongenetic factors, especially renal function, are associated with warfarin maintenance doses; however, the optimal algorithm for considering genes and renal dysfunction has not been established. This single-center prospective cohort study aimed to evaluate the factors affecting warfarin maintenance doses and develop pharmacogenetics-guided algorithms, including the factors of renal impairment and others. To commence, 176 outpatients who were prescribed warfarin for thromboembolic stroke prophylaxis in the stroke center, were enrolled. Patient characteristics, blood test results, dietary vitamin K intake, and CYP2C9 and VKORC1 (-1639G>A) genotypes were recorded. CYP2C9 and VKORC1 (-1639G>A) genotyping revealed that 80% of the patients had CYP2C9 *1/*1 and VKORC1 mutant AA genotypes. Multiple linear regression analysis demonstrated that the optimal pharmacogenetics-based model comprised age, body surface area, estimated glomerular filtration rate (eGFR), genotypes, vitamin K intake, aspartate aminotransferase levels, and alcohol intake. eGFR exercised a significant impact on the maintenance doses, as an increase in eGFR of 10 mL/min/1.73 m2 escalated the warfarin maintenance dose by 0.6 mg. Reduced eGFR was related to lower warfarin maintenance doses, independent of VKORC1 and CYP2C9 genotypes in Japanese patients.

RNF213 p.R4810K (c.14429G > A) Variant Determines Anatomical Variations of the Circle of Willis in Cerebrovascular Disease.

INTRODUCTION: Dysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models. In addition, vascular abnormalities in the circle of Willis are associated with cerebrovascular disease. Here, we evaluated the relationship between the East Asian founder variant RNF213 p.R4810K and consequent anatomical variations in the circle of Willis in cerebrovascular disease. PATIENTS AND METHODS: The present study is an observational cross-sectional study. It included patients with acute anterior circulation non-cardioembolic stroke admitted to our institution within 7 days of symptom onset or last-known-well from 2011 to 2019, and those who participated in the National Cerebral and Cardiovascular Center Biobank. We compared anatomical variations of the vessels constituting the circle of Willis between RNF213 p.R4810K (c.14429G > A) variant carriers and non-carriers using magnetic resonance angiography and assessed the association between the variants and the presence of the vessels constituting the circle of Willis. Patients with moyamoya disease were excluded. RESULTS: Four hundred eighty-one patients [146 women (30%); median age 70 years; median baseline National Institutes of Health Stroke Scale score 5] were analyzed. The RNF213 p.R4810K variant carriers (n = 25) were more likely to have both posterior communicating arteries (PComAs) than the variant non-carriers (n = 456) (56% vs. 13%, P < 0.01). Furthermore, variant carriers were less likely to have an anterior communicating artery (AComA) than non-carriers (68% vs. 84%, P = 0.04). In a multivariate logistic regression analysis, the association of RNF213 p.R4810K variant carriers with the presence of both PComAs and the absence of AComA remained significant. CONCLUSION: Our findings suggest that the RNF213 p.R4810K variant is an important factor in determining anatomical variations in the circle of Willis.

Antiseizure medications for post-stroke epilepsy: A real-world prospective cohort study.

BACKGROUND AND PURPOSE: The management of post-stroke epilepsy (PSE) should ideally include prevention of both seizure and adverse effects; however, an optimal antiseizure medications (ASM) regimen has yet been established. The purpose of this study is to assess seizure recurrence, retention, and tolerability of older-generation and newer-generation ASM for PSE. METHODS: This prospective multicenter cohort study (PROgnosis of Post-Stroke Epilepsy [PROPOSE] study) was conducted from November 2014 to September 2019 at eight hospitals. A total of 372 patients admitted and treated with ASM at discharge were recruited. Due to the non-interventional nature of the study, ASM regimen was not adjusted and followed standard hospital practices. The primary outcome was seizure recurrence in patients receiving older-generation and newer-generation ASM. The secondary outcomes were the retention and tolerability of ASM regimens. RESULTS: Of the 372 PSE patients with ASM at discharge (median [IQR] age, 73 [64-81] years; 139 women [37.4%]), 36 were treated with older-generation, 286 with newer-generation, and 50 with mixed-generation ASM. In older- and newer-generation ASM groups (n = 322), 98 patients (30.4%) had recurrent seizures and 91 patients (28.3%) switched ASM regimen during the follow-up (371 [347-420] days). Seizure recurrence was lower in newer-generation, compared with the older-generation, ASM (hazard ratio [HR], 0.42, 95%CI 0.27-0.70; p = .0013). ASM regimen withdrawal and change of dosages were lower in newer-generation ASM (HR, 0.34, 95% CI 0.21-0.56, p < .0001). CONCLUSIONS: Newer-generation ASM possess advantages over older-generation ASM for secondary prophylaxis of post-stroke seizures in clinical practice.

Study Protocol for a Randomized, Double-Blind, Placebo-Controlled, Phase-II Trial: AdrenoMedullin for Ischemic Stroke Study.

OBJECTIVES: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke in several animal models. After a phase I study in healthy volunteers, two phase II trials of AM for inflammatory bowel diseases have been recently completed. The current AdrenoMedullin For Ischemic Stroke (AMFIS) study aims to assess the safety and efficacy of AM in patients with acute ischemic stroke. MATERIALS AND METHODS: The AMFIS study is an investigator-initiated, randomized, double-blind, phase-II trial. AM or placebo will be administered to patients with non-cardioembolic ischemic stroke within 24 h after stroke onset. In the first cohort of the AMFIS study, patients will be randomly allocated to the investigation treatment A (30 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). In the second cohort, patients will be assigned to the investigation treatment B (56 µg/kg of AM in total for 7 days, n = 20) or placebo group (n = 10). RESULTS: Serious adverse events related to the protocol treatment will be evaluated as the primary outcome. All adverse events will be analyzed as the secondary outcome. Regarding efficacy endpoints, the change in National Institutes of Health Stroke Scale and modified Rankin Scale scores will be compared between investigation treatment and placebo groups. CONCLUSIONS: AM is expected to be a safe and effective treatment for ischemic stroke.

A Nationwide Multi-Center Questionnaire Survey on the Real-World State and Issues Regarding Post-Stroke Complications in Japan.

OBJECTIVES: Post-stroke complications affect stroke survivors across the world, although data on them are limited. We conducted a questionnaire survey to examine the real-world state and issues regarding post-stroke complications in Japan, which represents a super-aged society. MATERIALS AND METHODS: In 2018, a nationwide multi-center questionnaire survey was conducted in the top 500 Japanese hospitals regarding the number of stroke patients treated. Three questionnaires regarding post-stroke complications were mailed to the doctors responsible for stroke management. RESULTS: Responses were obtained from 251 hospitals (50.2%). The chief doctors responsible for stroke management answered the questionnaires. The number of stroke patients in the departments of neurology and neurosurgery was 338.3 ± 195.3 and 295.8 ± 121.8. Hospitals were classified using the categories secondary (n =142) and tertiary hospitals (n = 106); most hospitals were acute hospitals. Dementia was the most common complication (30.9%), followed by dysphagia (29.3%), and apathy (16.3%). Dementia was thought to be more common by neurologists than neurosurgeons, while apathy and bladder-rectal disorder were thought to be more common by neurosurgeons than neurologists (p = 0.001). The most difficult complication to treat was dysphagia (40.4%), followed by dementia (33.9%), epilepsy (4.1%), and fall (4.1%). Dementia was considered to lack clinical evidence regarding treatment (32.8%), followed by dysphagia (25.3%), and epilepsy (14.1%). Epilepsy was considered to lack clinical evidence among hospitals with a larger number of stroke cases (p = 0.044). CONCLUSION: This study revealed the current state and issues regarding post-stroke complications in Japan. Clinicians should be aware of the importance of post-stroke complications, although data on them remain unsatisfactory.

Visualizing prolonged hyperperfusion in post-stroke epilepsy using postictal subtraction SPECT.

Diagnosis of post-stroke epilepsy is often challenging because of a low incidence of epileptiform abnormalities on electroencephalography (EEG). Hence, this study evaluated whether postictal subtraction single-photon emission computed tomography (SPECT) could visualize epileptic activity and act as a diagnostic modality in post-stroke epilepsy. Fifty post-stroke epilepsy patients, who had undergone Tc-99m-ECD SPECT twice (postictal and interictal), were enrolled. The postictal hyperperfusion area was identified by subtraction (postictal-interictal) SPECT and classified into two distribution types: superficial or deep-seated. Laterality and distribution of postictal hyperperfusion on subtraction SPECT were compared with stroke lesions, seizure symptoms, and epileptiform EEG findings. Forty-three of the 50 patients (86%) had hyperperfusion on subtraction SPECT and 26 (52%) had epileptiform EEG findings. Subtraction SPECT showed prolonged postictal hyperperfusion despite the relatively long interval between seizure end and postictal SPECT (median: 19.1 h, range: 2.2-112.5 h). The laterality of the hyperperfusion area had a high concordance rate with the laterality of stroke lesions (97.7%), seizure symptoms (91.9%), and epileptiform EEG findings (100%). Scalp EEG identified epileptiform activity more frequently in superficial type of SPECT, but less frequently in deep-seated type (both, P = 0.03). Postictal SPECT can be complementary to scalp EEG in endorsing the diagnosis and location of post-stroke epilepsy.