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Purpose: Carotid artery web (CaW) is a rare focal fibromuscular dysplasia that can lead to embolic strokes with large vessel occlusion. This condition can be effectively treated with endovascular thrombectomy (EVT). Our study aims to assess the prevalence of CaW among patients with acute ischemic stroke (AIS) who underwent EVT and to compare the clinical characteristics of CaW with other carotid artery pathologies. Methods: We enrolled consecutive patients with AIS who underwent EVT at a single medical center and two regional teaching hospitals in Taiwan from September 2014 to December 2021. We compared CaW with carotid dissection (CaD) and carotid large artery atherosclerosis (CaLAA) in terms of patient demographics and thrombus histological findings. Results: Of the 576 AIS patients who underwent EVT, four (mean age: 50 years) were diagnosed with CaW, resulting in a prevalence of 0.69%. Among these four patients, three experienced successful reperfusion after EVT and achieved functional independence (defined as a modified Rankin Scale score ≤2) three months post-stroke. Importantly, none of the CaW patients suffered a recurrent stroke within one year. Patients with CaW were younger than those with CaD or CaLAA, and exhibited fewer vascular risk factors. Additionally, CaW was associated with distal occlusion sites. The thrombus composition in CaW patients was similar to that in CaD patients. Conclusion: In conclusion, CaW is a rare finding among Asian patients with carotid artery disease who undergo for AIS. It is more prevalent in younger patients with a limited number of vascular risk factors.

Abstract Despite recent findings indicating a paradoxical association between high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease (CVD) mortality, the impact of HDL-C on subsequent outcomes after ischemic stroke remains unclear. The study aims to investigate the relationships between HDL-C levels and post-stroke functional outcomes while examining the potential modifying influence of HDL-C-related single nucleotide polymorphisms identified through genome-wide association studies. This cohort study included 1,310 patients diagnosed with acute ischemic stroke (AIS), all of whom had their admission serum lipid profile and genotyping information. Participants were categorized into four groups based on gender and HDL-C level. Prognostic outcomes were assessed using a modified Rankin Scale (mRS) at 1, 3, and 12 months post-admission. Multivariate logistic regression and restricted cubic spline regression analysis were used to assess the associations between HDL-C levels and outcomes. The mean age of patients was 61.17 ± 12.08 years, and 69.31% were men. After adjusting confounders, patients with the highest HDL-C level group had a significantly higher risk of poor functional outcomes at 1, 3, and 12 months following stroke compared to the reference group. Restricted cubic splines depicted a nonlinear association between HDL-C levels and poor prognosis in both men and women. The ABCA1 gene rs2575876 AA genotype combined with abnormal HDL-C levels exhibited a significantly heightened risk of post-stroke adverse outcomes at 1 and 3 months compared to patients with normal HDL-C levels and GG + GA genotype. These findings suggest that the combined effects of ABCA1 genetic variants with either low or high HDL-C levels could further heighten this risk.

Background In direct oral anticoagulant (DOAC) users with stroke due to large artery occlusion, endovascular thrombectomy is an effective treatment when intravenous thrombolytic therapy is unsuitable. The purpose of this study is to investigate the association between emergent DOAC levels and endovascular thrombectomy outcomes. Methods Participants with atrial fibrillation, who had a premorbid modified Rankin Scale score of ≤3 and had undergone endovascular thrombectomy for acute stroke, were enrolled. Drug levels upon hospital arrival were measured in the prestroke DOAC users. Head noncontrast computed tomography and computed tomographic angiography images were used to quantify thrombus permeability. The primary outcome was functional independence at 3 months (modified Rankin Scale 0–2 or a return to premorbid status for patients with a premorbid modified Rankin Scale of 3). Results The study included 250 patients (antithrombotic agent nonusers, 42.0%; oral anticoagulant users, 34.0%; and antiplatelet users, 24.0%). The primary outcomes did not differ among the 3 groups. Among oral anticoagulant users, 78.8% were DOAC users. Of the 59 DOAC users with available drug level measurements, 62.7% had low levels (

Background: This study aimed to evaluate the performance of a modified U.S. (MUS) model for risk prediction of cardiovascular (CV) events in Asian patients and compare it to European and Japanese models. Methods: The MUS model, based on the US ACC/AHA 2018 lipid treatment guideline, was employed to stratify patients under primary or secondary prevention. Two multi-center prospective observational registry cohorts, T-SPARCLE and T-PPARCLE, were used to validate the scoring system, and the primary outcome was the time to first occurrence/recurrence of major adverse cardiac events (MACEs). The MUS model's performance was compared to other models from Europe and Japan. Results: A total of 10,733 patients with the mean age of 64.2 (SD: 11.9) and 36.5% female were followed up for a median of 5.4 years. The MUS model was validated, with an AUC score of 0.73 (95% CI 0.68–0.78). The European and Japanese models had AUC scores ranging from 0.6 to 0.7. The MUS model categorized patients into four distinct CV risk groups, with hazard ratios (HRs) as follows: very high- vs. high-risk group (HR = 1.91, 95% CI 1.53–2.39), high- vs. moderate-risk group (HR = 2.08, 95% CI 1.60–2.69), and moderate- vs. low-risk group (HR = 3.14, 95% CI 1.63–6.03). After adjusting for the MUS model, a history of atherosclerotic vascular disease (ASCVD) was not a significant predictor of adverse cardiovascular outcomes within each risk group. Conclusion: The MUS model is an effective tool for risk stratification in Asian patients with and without ASCVD, accurately predicting MACEs and performing comparably or better than other established risk models. Our findings suggest that patient management should focus on background risk factors instead of solely on primary or secondary prevention.

Abstract Lobar cerebral microbleeds are a characteristic neuroimaging finding in cerebral amyloid angiopathy (CAA) but can also be found in hypertensive arteriolosclerosis. We aimed to investigate whether CAA is more associated with intracortical lobar microbleeds than hypertensive arteriosclerosis. Ninety-one survivors of spontaneous intracerebral hemorrhage with at least one lobar microbleed were included and underwent brain MRI and amyloid PET. We categorized lobar microbleeds as intracortical, juxtacortical, or subcortical. We assessed the associations between the lobar microbleed categories and microangiopathy subtypes or cerebral amyloid load based on the Pittsburgh Compound-B PET standardized uptake value ratio (SUVR). Patients with CAA had a higher prevalence of intracortical lobar microbleeds (80.0% vs. 50.8%, P = 0.011) and lower prevalence of subcortical lobar microbleeds (13.3% vs. 60.1%, P

BackgroundHyperglycemia affects the outcomes of endovascular therapy (EVT) for acute ischemic stroke (AIS). This study compares the predictive ability of diabetes status and glucose measures on EVT outcomes using nationwide registry data.MethodsThe study included 1,097 AIS patients who underwent EVT from the Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke. The variables analyzed included diabetes status, admission glucose, glycated hemoglobin (HbA1c), admission glucose-to-HbA1c ratio (GAR), and outcomes such as 90-day poor functional outcome (modified Rankin Scale score ≥ 2) and symptomatic intracranial hemorrhage (SICH). Multivariable analyses investigated the independent effects of diabetes status and glucose measures on outcomes. A receiver operating characteristic (ROC) analysis was performed to compare their predictive abilities.ResultsThe multivariable analysis showed that individuals with known diabetes had a higher likelihood of poor functional outcomes (odds ratios [ORs] 2.10 to 2.58) and SICH (ORs 3.28 to 4.30) compared to those without diabetes. Higher quartiles of admission glucose and GAR were associated with poor functional outcomes and SICH. Higher quartiles of HbA1c were significantly associated with poor functional outcomes. However, patients in the second HbA1c quartile (5.6–5.8%) showed a non-significant tendency toward good functional outcomes compared to those in the lowest quartile (

Abstract Background Previous studies of do-not-resuscitate (DNR) or do-not-intubate (DNI) orders in stroke patients have primarily been conducted in North America or Europe. However, characteristics associated with DNR/DNI orders in stroke patients in Asia have not been reported. Methods Based on the Taiwan Stroke Registry, this nationwide cross-sectional study enrolled hospitalized stroke patients from 64 hospitals between 2006 and 2020. We identified characteristics associated with DNR/DNI orders using a two-level random effects model. Results Among the 114,825 patients, 5531 (4.82%) had DNR/DNI orders. Patients with acute ischemic stroke (AIS) had the highest likelihood of having DNR/DNI orders (adjusted odds ratio [aOR] 1.76, 95% confidence interval [CI] 1.61–1.93), followed by patients with intracerebral hemorrhage (ICH), and patients with subarachnoid hemorrhage (SAH) had the lowest likelihood (aOR 0.53, 95% CI 0.43–0.66). From 2006 to 2020, DNR/DNI orders increased in all three types of stroke. In patients with AIS, women were significantly more likely to have DNR/DNI orders (aOR 1.23, 95% CI 1.15–1.32), while patients who received intravenous alteplase had a lower likelihood (aOR 0.74, 95% CI 0.65–0.84). Patients with AIS who were cared for by religious hospitals (aOR 0.55, 95% CI 0.35–0.87) and patients with SAH who were cared for by medical centers (aOR 0.40, 95% CI 0.17–0.96) were significantly less likely to have DNR/DNI orders. Conclusions In Taiwan, DNR/DNI orders increased in stroke patients between 2006 and 2020. Hospital characteristics were found to play a significant role in the use of DNR/DNI orders.

Background/purpose: Amiodarone increases exposure of direct oral anticoagulants (DOACs). We aimed to analyze the effects of concurrent amiodarone use on DOAC concentrations and clinical outcomes. Methods: Patients who were ≥20 years of age, had atrial fibrillation, and took DOAC were enrolled to provide trough and peak samples for DOAC concentration measurements using ultra-high-performance liquid chromatography-tandem mass spectrometry. The results were compared with concentrations reported in clinical trials to define above, within, or under the expected range. The outcomes of interest were major bleeding and any gastrointestinal bleeding. Multivariate logistic regression and Cox proportional hazards model were used to determine the impact of amiodarone on above-range concentration and clinical outcomes, respectively. Results: A total of 722 participants (420 men, 58.2%) were enrolled to provide 691 trough samples and 689 peak samples. Among them, 21.3% concurrently used amiodarone. The proportion of patients with above-range trough and peak concentrations was 16.4% and 30.2%, respectively, for amiodarone users, in contrast to 9.4% and 19.8% for amiodarone non-users. The use of amiodarone was associated with above-range trough and peak concentrations (odds ratio [OR] = 2.00 [1.16, 3.47] and 1.82 [1.19, 2.79], respectively). However, amiodarone was not a significant predictor of major bleeding or any gastrointestinal bleeding. Conclusion: Concurrent amiodarone use led to increased DOAC concentration but was not associated with a higher risk of major bleeding or any gastrointestinal bleeding. Therapeutic monitoring of DOAC users concurrently taking amiodarone may be recommended for patients with an additional risk of increased DOAC exposure.

Abstract Background To investigate the association between cerebral amyloid deposition and long‐term cognitive outcomes in patients with hemorrhagic small vessel disease (SVD) and survivors of intracerebral hemorrhage (ICH). Methods Patients experiencing an ICH without overt dementia were prospectively recruited (n = 68) for brain MRI and Pittsburgh compound B (PiB) positron emission tomography scans at baseline. Cognitive function was assessed using the mini‐mental status examination (MMSE) and clinical dementia rating after an overall median follow‐up of 3.8 years. A positive amyloid scan was defined as a global PiB standardized uptake value ratio >1.2. Associations between follow‐up cognitive outcomes and neuroimaging markers were explored using multivariable Cox regression models. Results PiB(+) patients were older (72.1 ± 7.8 vs. 59.9 ± 11.7, p = .002) and more frequently had cerebral amyloid angiopathy (CAA) (63.6% vs. 15.8%, p = .002) than PiB(−) patients. PiB(+) was associated with a higher risk of dementia conversion (32.9 vs. 4.0 per 100‐person‐years, hazard ratio [HR] = 15.7 [3.0–80.7], p = .001) and MMSE score decline (58.8 vs. 9.9 per 100‐person‐years, HR = 6.2 [1.9–20.0], p = .002). In the non‐CAA subgroup (n = 52), PiB(+) remained an independent predictor of dementia conversion, p = .04). In the Cox models, PiB(+) was an independent predictor of dementia conversion (HR = 15.8 [2.6–95.4], p = .003) and MMSE score decline (HR = 5.7 [1.6–20.3], p = .008) after adjusting for confounders. Conclusions Cerebral amyloid deposition potentially contributes to long‐term cognitive decline in SVD‐related ICH.

Background Endovascular thrombectomy (EVT) is the standard therapy for patients with acute ischemic stroke secondary to large‐artery occlusion. In January 2019, the Taiwan Stroke Society established a nationwide TREAT‐AIS (Taiwan Registry of Endovascular Thrombectomy for Acute Ischemic Stroke). Here, we provide the study design, current progress, and baseline data of TREAT‐AIS. Methods TREAT‐AIS is a multicenter prospective registration program in Taiwan. Patients aged ≥20 years who underwent EVT for acute ischemic stroke were recruited. The key items on the registration form were divided into general stroke demographics and EVT‐related sections. The main outcome of effectiveness was functional independence (modified Rankin Scale score, 0–2) at 3 months. The influence of sex on post‐EVT outcomes was also analyzed in the presented study. Results By the end of June 2022, there were 10 medical centers and 9 community hospitals participating in the TREAT‐AIS and a total of 1522 patients (mean±SD age, 71.2±13.6 years; men, 55.6%) being enrolled. The median National Institutes of Health Stroke Scale score on admission was 18 (interquartile range, 12–23). The major cause of stroke was cardioembolism (43.6%), followed by large‐artery atherosclerosis (36.8%) and an undetermined cause (15.4%). Functional independence at 3 months poststroke was achieved in 36.2% of the patients. Male patients were more likely to have functional independence at 3 months compared with female patients (40.4% versus 30.8%; P

Background: Long-chain ceramides are associated with the mechanisms and clinical outcomes of acute ischemic stroke (AIS). This study aimed to investigate the plasma ceramides and sphingosine-1-phosphate in AIS patients undergoing endovascular thrombectomy (EVT) and their associations with outcomes. Methods: Plasma samples were collected from 75 AIS patients who underwent EVT before (T1), immediately after (T2), and 24 h after (T3) the procedures and 19 controls that were matched with age, sex, and co-morbidities. The levels of ceramides with different fatty acyl chain lengths and sphingosine-1-phosphate were measured by UHPLC–ESI–MS/MS. A poor outcome was defined as a modified Rankin Scale score of 3–6 at 3 months after stroke. Results: The plasma levels of long-chain ceramides Cer (d18:1/16:0) at all three time points, Cer (d18:1/18:0) at T1 and T3, and Cer (d18:1/20:0) at T1 and very-long-chain ceramide Cer (d18:1/24:1) at T1 were significantly higher in AIS patients than those in the controls. In contrast, the plasma levels of sphingosine-1-phosphate in AIS patients were significantly lower than those in the controls at all three time points. Among the AIS patients, 34 (45.3%) had poor functional outcomes at 3 months poststroke. Multivariable analysis showed that higher levels of Cer (d18:1/16:0) and Cer (d18:1/18:0) at all three time points, Cer (d18:1/20:0) at T1 and T2, and Cer (d18:1/24:0) at T2 remained significantly associated with poor functional outcomes after adjustment for potential confounding factors. Conclusion: Plasma ceramides were elevated early in AIS patients with acute large artery occlusion. Furthermore, Cer (d18:1/16:0) and Cer (d18:1/18:0) could be early prognostic indicators for AIS patients undergoing EVT.

Hereditary cerebral cavernous malformations (CCMs) are characterized by clustered dilated capillary-like vessels in the brain. Autosomal dominant polycystic kidney disease (PKD) is characterized by renal cysts and extra-renal abnormalities. We report a Taiwanese family in which the index case exhibited coexisting phenotypes of both CCMs and PKD. The index case was a 55-year-old woman with known PKD who developed an intracerebral hemorrhage (ICH) in the right medulla. Neuroimaging revealed numerous microbleeds in the bilateral cerebrum and cerebellum. Radiological CCMs were suspected given the absence of other imaging markers of small vessel disease. A comprehensive panel of 183 cerebral vascular malformation genes were investigated through genome sequencing. A novel CCM2 frameshift variant (c.607_608delCT, p.Leu203Valfs∗53) causing a pathogenic premature stop codon, and a known PKD2 nonsense variant (c.2407C > T, p.Arg803∗), were found. Segregation analysis revealed that four siblings were affected by either isolated aforementioned PKD2 or CCM2 variant. Notably, radiological CCMs were exclusively found in siblings who had this CCM2 variant, and bilateral internal carotid artery aneurysms were restricted to one sibling who had the PKD2 variant but not the CCM2 variant. Our study expands the genetic spectrum of CCM2 and demonstrates unambiguous cosegregation of CCM2 and PKD2 variants with their respective phenotypes.

Background and Purpose Cerebral venous flow alterations potentially contribute to age-related white matter changes, but their role in small vessel disease has not been investigated. Methods This study included 297 patients with hypertensive intracerebral hemorrhages (ICH) who underwent magnetic resonance imaging. Cerebral venous reflux (CVR) was defined as the presence of abnormal signal intensity in the dural venous sinuses or internal jugular vein on time-of-flight angiography. We investigated the association between CVR, dilated perivascular spaces (PVS), and recurrent stroke risk. Results CVR was observed in 38 (12.8%) patients. Compared to patients without CVR those with CVR were more likely to have high grade (>20 in the number) dilated PVS in the basal ganglia (60.5% vs. 35.1%; adjusted odds ratio [aOR], 2.64; 95% confidence interval [CI], 1.25 to 5.60; P=0.011) and large PVS (>3 mm in diameter) (50.0% vs. 18.5%; aOR, 3.87; 95% CI, 1.85 to 8.09; P

The previously published 2017 Taiwan Lipid Guidelines for High Risk Patients becomes the standard guidance of dyslipidemia management for patients with atherosclerotic cardiovascular disease (ASCVD) in Taiwan. New clinical trials of lipid lowering therapy were published successively after 2017. The study results changed the treatment concept of ASCVD. Therefore, an update focusing on the lipid treatment strategy for patients with ASCVD becomes necessary. In this focused update of the 2017 guideline, the treatment targets of low-density lipoprotein cholesterol (LDL-C) for patients with ASCVD were modified. The algorithm of LDL-C lowering therapy was revised. The recommendations in this focused update were made mainly based on the scientific evidence from recently published clinical trials and endorsed by the major medical societies in Taiwan.

Background/Purpose: Several risk scores have been developed to predict symptomatic intracerebral hemorrhage (SICH) after acute reperfusion therapy for ischemic stroke. We compared the performance of established risk scores in predicting SICH after EVT under different SICH criteria. Methods: A total of 258 patients with anterior circulation large vessel occlusion who received EVT in two medical centers of Taiwan were recruited. Three definitions of SICH, the European Collaborative Acute Stroke Study II (ECASS II), ECASS III, and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), were used. The HAT, SITS-SICH, SEDAN, and TAG risk scores were applied. Logistic regression and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of each risk model. Results: In the 258 included patients (mean age, 71.9 ± 11.8 years; men, 48.1%), the observed rates of SICH according to ECASS II, ECASS III, and SITS-MOST criteria were 10.1%, 5.0%, and 4.7%, respectively. Higher glucose level (>160 mg/dL) and unsuccessful recanalization independently predicted SICH under all criteria. Among the different risk scores, only SEDAN and TAG consistently predicted SICH. SEDAN and TAG scores exhibited the highest AUC in predicting SICH for ECASS III (SEDAN 0.72, TAG 0.72) and SITS-MOST (SEDAN 0.73, TAG 0.70) criteria. Conclusion: Among various risk scores, the TAG and SEDAN scores best predict SICH after EVT. Higher glucose level and unsuccessful recanalization, which are included in the TAG and SEDAN scores, are independent risk factors of SICH in the present cohort, highlighting their detrimental effects.

BackgroundCerebral amyloid angiopathy-related inflammation (CAA-ri) is a clinical syndrome characterized by MRI findings of amyloid-related imaging abnormalities-edema (ARIA-E) suggestive of autoimmune and inflammatory reaction and hemorrhagic evidence of cerebral amyloid angiopathy. The longitudinal variation of amyloid PET and its imaging association with CAA-ri are undetermined. Moreover, tau PET in CAA-ri has been rarely investigated.MethodWe retrospectively described two cases of CAA-ri. We provided the temporal change of amyloid and tau PET in the first case, and the cross-sectional finding of amyloid and tau PET in the second case. We also performed a literature review of the imaging features of amyloid PET in reported cases of CAA-ri.ResultsIn the first case, an 88-year-old male presented with progressive consciousness and gait disturbances over 2 months. MRI showed disseminated cortical superficial siderosis. Amyloid PET prior to and after the CAA-ri revealed focally decreased amyloid load in the region of ARIA-E. In the second case, a 72-year-old male was initially suspected to have central nervous system cryptococcosis but later diagnosed with CAA-ri because of the characteristic MRI features and good response to corticosteroid treatment; a subsequent amyloid scan revealed positive amyloid deposition of the brain. Neither case suggested an association between the region of ARIA-E and higher amyloid uptake on PET before or after onset of CAA-ri. Our literature review revealed variable findings related to amyloid burden in post-inflammatory regions in previously reported CAA-ri cases with available amyloid PET. Our case is the first report of longitudinal changes on amyloid PET and show focal decreases in amyloid load after the inflammatory process.ConclusionThis case series highlights the need to better explore the potential of longitudinal amyloid PET in the understanding of the mechanisms of CAA-ri.

Background/Purpose: Recently optimized models for selecting the locations of hospitals capable of providing endovascular thrombectomy (EVT) did not consider the accuracy of the prehospital stroke scale assessment and possibility of secondary transport. Our study aimed to propose a new model for selecting existing hospitals with intravenous thrombolysis capability to become EVT-capable hospitals. Methods: A sequential order was provided to upgrade hospitals providing intravenous thrombolysis, using a mixed integer programming model based on current medical resource allocation. In addition, we drafted a centralized plan to redistribute existing EVT resources by redetermining locations of EVT-capable hospitals. Using historical data of 7679 on-scene patients with suspected stroke, the model was implemented to determine the hospital that maximizes the number of patients receiving EVT treatment within call-to-definitive-treatment time. Results: All suspected stroke patients were sent to EVT-capable hospitals directly under the current medical resource allocation model. After upgrading one additional hospital to become an EVT-capable hospital, the percentage of patients receiving definitive treatment within the standard call-to-definitive-treatment time was elevated from 68.82% to 72.97%. In the model, assuming that there is no hospital providing EVT, all patients suspected of stroke will be sent to EVT-capable hospitals directly after upgrading three or more hospitals to be able to provide treatment. Conclusion: All patients eligible for acute stroke treatment are sent to EVT-capable hospitals in the simulation under the current medical resource allocation model. This model can be utilized to provide insights for capacity redistribution in other regions.

Background/Purpose: Sphingolipids are major constituents of eukaryotic cell membranes and play key roles in cellular regulatory processes. Our recent results in an experimental stroke animal model demonstrated changes in sphingolipids in response to acute ischemic brain injury. This study aimed to investigate the plasma levels of sphingosine-1-phosphate (S1P) and ceramides in acute ischemic stroke (AIS) patients and their associations with functional outcomes. Methods: Plasma samples were collected from patients with AIS at

Abstract Subjects with comorbidities are at risk for neurodegeneration. There is a lack of a direct relationship between comorbidities and neurodegeneration. In this study, immunomagnetic reduction (IMR) assays were utilized to assay plasma Aβ1–42 and total tau protein (T-Tau) levels in poststroke (PS, n = 27), family history of Alzheimer’s disease (ADFH, n = 35), diabetes (n = 21), end-stage renal disease (ESRD, n = 41), obstructive sleep apnea (OSA, n = 20), Alzheimer’s disease (AD, n = 65). Thirty-seven healthy controls (HCs) were enrolled. The measured concentrations of plasma Aβ1–42 were 14.26 ± 1.42, 15.43 ± 1.76, 15.52 ± 1.60, 16.15 ± 1.05, 16.52 ± 0.59, 15.97 ± 0.54 and 20.06 ± 3.09 pg/mL in HC, PS, ADFH, diabetes, ESRD, OSA and AD groups, respectively. The corresponding concentrations of plasma T-Tau were 15.13 ± 3.62, 19.29 ± 8.01, 17.93 ± 6.26, 19.74 ± 2.92, 21.54 ± 2.72, 20.17 ± 2.77 and 41.24 ± 14.64 pg/mL. The plasma levels of Aβ1–42 and T-Tau in were significantly higher in the PS, ADFH, diabetes, ESRD and OSA groups than controls (Aβ1–42 in PS: 15.43 ± 1.76 pg/mL vs. 14.26 ± 1.42 pg/mL, p

Abstract The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft–Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p

Abstract Background Timely endovascular thrombectomy (EVT) significantly improves outcomes in patients with acute ischemic stroke (AIS) with large vessel occlusion type. However, whether certain central nervous system-specific plasma biomarkers correlate with the outcomes is unknown. We evaluated the temporal changes and prognostic roles of the levels of these biomarkers in patients with AIS undergoing EVT. Methods We enrolled 60 patients who received EVT for AIS and 14 controls. The levels of plasma biomarkers, namely neurofilament light chain (NfL), glial fibrillary astrocytic protein (GFAP), tau, and ubiquitin C-terminal hydrolase L1 (UCHL1), were measured with an ultrasensitive single molecule array before, immediately after, and 24 h after EVT (T1, T2, and T3, respectively). The outcomes of interest were death or disability at 90 days (defined as a modified Rankin Scale score of 3–6) and types of hemorrhagic transformation (hemorrhagic infarction or parenchymal hemorrhage). Results Of the 180 blood samples from the 60 patients who received EVT, the plasma NfL, GFAP, and UCHL1 levels at T1 were significantly higher than those of the controls, and the levels of all four biomarkers were significantly higher at T3. Patients with parenchymal hemorrhage had a significantly higher rate of increase in GFAP (P interaction = 0.005) and UCHL1 (P interaction = 0.007) levels compared with those without parenchymal hemorrhage. In a multivariable analysis with adjustment for age, sex, National Institute of Health Stroke Scale score, history of atrial fibrillation, and recanalization status, higher NfL levels at T1 (odds ratio [OR] 2.05; 95% confidence interval [CI], 1.03–4.08), T2 (OR, 2.08; 95% CI, 1.05–4.01), and T3 (OR, 3.94; 95% CI, 1.44–10.79) were independent predictors of death or disability at 90 days. Conclusion Among patients with AIS who received EVT, those with hemorrhagic transformation exhibited significant increase in plasma GFAP and UCHL1 levels over time. Higher plasma NfL were predictive of unfavorable functional outcomes.

Abstract This pilot, randomized, open-label controlled study compared the basal–bolus regimens of insulin glargine (IG) and neutral protamine Hagedorn (NPH) insulin in stroke patients with hyperglycemia receiving intensive care. The study recruited acute stroke patients requiring intensive care within 72 h (h) of onset and had blood glucose > 200 mg/dL. 50 patients received IG (n = 26) or NPH (n = 24) with added short-acting prandial regular insulin over a 72-h period. The primary end point was the percentage of glucose within 80–180 mg/dL assessed through continuous glucose monitoring. The baseline characteristics were comparable, except the IG had higher glucose pre-randomization than the NPH (290.69 ± 82.31 vs. 246.04 ± 41.76 mg/dL, P = 0.021). The percentage of time with glucose between 80 and 180 mg/dL was 45.88 ± 27.04% in the IG and 53.56 ± 22.89% in the NPH (P = 0.341) and the percentage of glucose reduction was 31.47 ± 17.52% in the IG and 27.28 ± 14.56% in the NPH (P = 0.374). The percentage of time with glucose

Abstract Chinese have a higher stroke incidence and a different distribution of ischemic stroke (IS) subtypes as compared with Caucasians. Herein we aimed to investigate the prevalence and associations of major risk factors in IS and its subtypes in Chinese patients. From 2006 to 2011, we included 4953 acute IS patients consecutively recruited in National Taiwan University Hospital Stroke Registry (mean age 68 years; male 59%). For each risk factor, we accessed the proportion in all IS patients, and calculated odds ratios for each main IS subtype versus other subtypes. Multiple logistic regression models were used to adjust for confounders, and to examine the associations of risk factors with IS subtypes. Compared with other ischemic subtypes, large artery atherosclerotic and lacunar strokes were associated with hypertension, diabetes, and hyperlipidaemia, while cardioembolic strokes were associated with ischemic heart disease. Furthermore, the associations with hypertension and diabetes became stronger in lacunar strokes after adjusting for confounders, but not in other ischemic subtypes. Here we report the variable effects of risk factors on different IS subtypes in Chinese patients in Taiwan. Our findings could help shed light on different mechanisms of IS subtypes and provide targets to make more effective strategies for IS prevention.

Cryptogenic stroke comprises about one-quarter of ischemic strokes with high recurrence rate; however, studies specifically investigating the features and treatment of this stroke subtype are rare. The concept of ‘embolic stroke of undetermined source’ (ESUS) may facilitate the development of a standardized approach to diagnose cryptogenic stroke and improve clinical trials. Since recent large randomized control trials failed to demonstrate a reduction in stroke recurrence with anticoagulants, anti-platelet agents remain the first-line treatment for ESUS patients. Nevertheless, patients with high risk of stroke recurrence (e.g., those with repeated embolic infarcts despite aspirin treatment) require a more extensive survey of stroke etiology, including cardiac imaging and prolonged cardiac rhythm monitoring. Anticoagulant treatments may still benefit some subgroups of high-risk ESUS patients, such as those with multiple infarcts at different arterial territories without aortic atheroma, the elderly, or patients with high CHA2D2-VASc or HOVAC scores, atrial cardiopathy or patent foramen ovale. Several important ESUS clinical trials are ongoing, and the results are anticipated. With rapid progress in our understanding of ESUS pathophysiology, new subcategorizations of ESUS and assignment of optimal treatments for each ESUS subgroup are expected in the near future.

Background/purpose: Atrial fibrillation (AF) patients with a history of ischemic stroke or transient ischemic attack (TIA) carry excessive risk of recurrent stroke. Real-world data for the Asian population is scarce. This study aimed to investigate the thromboembolism and major bleeding risk of non-vitamin K antagonist oral anticoagulant (NOAC) therapy among Asian patients, and to identify the risk factors of recurrent stroke. Methods: This retrospective study recruited AF patients aged over 20 years, who had a previous stoke or TIA, and received NOAC therapy. Thromboembolic events were recurrent ischemic stroke or TIA, and the major bleeding events were classified according to the PLATO (Platelet Inhibition and Patient Outcomes) criteria. Results: A total of 361 patients (61.2% male) were enrolled for data analysis. The incidence rate for recurrent ischemic stroke or TIA was 3.6 (95% CI = 2.5 to 5.5) per 100 person-years, and 0.9 (95% CI = 0.4 to 1.7) per 100 person-years for major bleeding. Patients with recurrent ischemic stroke or TIA were more likely to have malignancy (hazard ratio [HR] for malignancy = 4.4, 95% CI = 1.9 to 10.3, p = 0.001) and concomitantly take enzyme inducing antiepileptic drugs (EIAED, HR = 8.1, 95% CI = 2.7 to 24.1, p

Background Simultaneous multivessel occlusions (MVOs) are a rare condition, which may be encountered during endovascular thrombectomy (EVT) for acute ischemic stroke. This study aimed to investigate the prevalence, associated factors, and outcome of patients with acute ischemic stroke and MVO who underwent EVT. Methods Consecutive patients with acute ischemic stroke who received EVT between September 2014 and April 2021 were included. Acute MVO was defined as simultaneous occlusions of ≥2 intracranial or extracranial major vessels in either bilateral anterior circulation or anterior plus posterior circulation. Patients’ baseline characteristics and outcome of MVO were analyzed. Results Of 602 patients with acute ischemic stroke (mean age, 71±13 years; male, 53.1%) who received EVT, 11 patients (1.8%) had acute MVO. The involved vessels included bilateral internal carotid arteries in 3, bilateral middle cerebral arteries in 4, vertebral artery and distal middle cerebral artery in 1, and internal carotid artery and distal posterior cerebral artery in 3 patients. Preadmission dependence (modified Rankin scale score >2), higher initial stroke severity, and posterior cerebral artery occlusion were more frequently found in MVO. The cause of MVO included large vessel atherosclerosis in 4, cardioembolic in 4, cancer‐related hypercoagulability in 2, and postpartum in 1 patient. Several patients had received simultaneous multitargeted EVT, but only 4 of them achieved optimal reperfusion in both vessels. Compared with patients without MVO, those with MVO had higher mortality (adjusted odds ratio, 6.75; 95% CI, 1.93–23.6) and poor functional outcome (common odds ratio for 1‐point improvement at modified Rankin scale, 0.14, 95% CI, 0.05–0.45) at 90 days. Conclusion Acute simultaneous MVO in patients who underwent EVT is a rare yet devastating condition. Multitarget mechanical thrombectomy to achieve reperfusion is challenging but still possible.

Background To mitigate uncertainty that may arise in the judgment of emergency medical technicians when relying on a prehospital stroke scale at the scene, we propose a hospital selection protocol that considers the uncertainty of a prehospital stroke scale and the actual door‐to‐treatment durations, and we have developed a web‐based system to be used with mobile devices. Methods and Results This hospital selection protocol incorporates real‐time, estimated transport time obtained from Google Maps, historical median door‐to‐treatment duration at hospitals that only provide the standard intravenous thrombolysis treatment, and at hospitals with endovascular thrombectomy for probable large‐vessel occlusion cases. We have validated the efficiency of the proposed protocol and compared it with other strategies used by emergency medical technicians when deciding on a receiving hospital. Using the proposed protocol for the triage reduces the time from onset to receiving definitive treatment by nearly 11 minutes. We found that the nearest endovascular thrombectomy–capable hospital from the scene may not be the most ideal if the door‐to‐treatment durations are discriminative. The results show that, when the tolerable bypass transport threshold and administration time are reduced to 9 minutes and 30.5 minutes, respectively, 228 patients out of 7678 cases, whose receiving hospitals were changed to endovascular thrombectomy–capable hospitals, received definitive treatment in a shorter time. The results of our analysis give recommendations for appropriate allowable bypass transport time for regional planning. Conclusions By applying almost‐real value parameters, we have validated a web‐based model, which can be universally adapted for optimal, time‐saving hospital selection for patients with stroke.

Abstract Objective To develop an easily applicable screening score to guide NOTCH3 p.R544C genetic testing for patients who presented with acute ischemic cerebrovascular events in Taiwan. Methods 1734 patients who presented with ischemic cerebrovascular events were enrolled from the Formosa Stroke Genetic Consortium stroke registry and were screened for the NOTCH3 p.R544C mutation. Clinical and MRI characteristics of NOTCH3 p.R544C mutation carriers (n = 36) and a subset of noncarriers (n = 673) were tested in a logistic regression model to identify key features associated with the NOTCH3 p.R544C carrier status. Variables and their odds ratios in the regression model were used to develop the R544C screening score to predict positive NOTCH3 p.R544C test results. Results We constructed the R544C screening score using five clinical and imaging characteristics, including stroke onset before 50 years of age, the small vessel occlusion subtype, a family history of stroke/TIA in siblings, external capsule involvement, and advanced deep white matter hyperintensity. The area under the ROC curve of the screening score was 0.867 (95% CI = 0.810‐0.924). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 0.75, 0.88, 0.13, 0.99, and 0.88, respectively, for a cutoff score of 5 points. In addition, the R544C screening score was validated in another cohort composed of 235 stroke patients with comparable performance (area under the ROC curve = 0.957, 95% CI = 0.916‐0.997). Interpretations For Taiwanese patients presenting with acute ischemic cerebrovascular events, the R544C screening score is easily applicable and can efficiently select high‐risk patients for NOTCH3 p.R544C mutation test.

Abstract Background Stroke remains the most cumbersome disease burden in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to investigate whether plasma biomarkers can reflect disease severity and predict stroke recurrence in CADASIL patients. Methods Sixty-three CADASIL patients (mean age 58.9 ± 9.3 years old, male 63%) from a multicenter registry and 17 controls were recruited. Plasma biomarkers, namely neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), were measured using an ultra-sensitive single molecule array at baseline. Neuroimaging markers assessed included the Fazekas scale of white matter hyperintensity, numbers of lacunes, and cerebral microbleeds (CMBs). Cox proportional hazards regression models were applied to calculate the hazard ratio (HR) of plasma biomarkers at baseline for predicting incident stroke during follow-up. Results Plasma NfL, GFAP, and UCHL1 levels were significantly elevated in the CADASIL patients than in the controls. Among the CADASIL patients, both plasma NfL and GFAP levels positively correlated with the numbers of CMBs (r = 0.32 and r = 0.37, respectively; both p < 0.05). Higher plasma levels of NfL and GFAP were associated with any stroke (odds ratio 2.02, 95% confidence interval [CI] 1.06–3.87) and ICH (odds ratio 2.06, 95% CI 1.26–3.35) at baseline, respectively. Within a mean follow-up period of 3.1 ± 2.1 years, 10 patients (16%) had incident stroke and 6 of them were ICH. Higher baseline NfL (HR 1.93, 95% CI 1.19–3.13) predicted any incident stroke, whereas higher GFAP (HR 2.80, 95% CI 1.21–6.53) predicted incident ICH. Conclusions In CADASIL patients, plasma NfL can be a promising biomarker for monitoring incident stroke, whereas GFAP may have a role in cerebral hemorrhage.

Background: The application of non-vitamin K antagonist oral anticoagulant (NOAC) reduces the risk of intracerebral hemorrhage (ICH) in comparison with vitamin K antagonist (VKA). However, the features and outcomes of NOAC-associated ICH are still unclear, especially for Asian populations. Methods: We retrospectively analyzed 49 consecutive patients who had spontaneous ICH while using NOAC or VKA. We compared the clinical characteristics, ICH volume, 7-day and 3-month mortality, and functional outcomes at discharge and 3 months post-stroke using the modified Rankin Scale (mRS) between NOAC- and VKA-associated ICH. The clinical features, ICH volume, ICH location, and/or treatment methods were statistically adjusted. Results: Among the 49 ICH patients, 15 (30.6%) were using NOAC and 34 (69.4%) were taking VKA. There were no significant differences in the initial ICH volume between groups (mean volume 34.2 ± 43.8 vs. 59.4 ± 46.5 mL, p = 0.061). The percentage of early mortality (within 7 days post-ICH) was significantly lower in the NOAC group (13.3% vs. 44.1%; p = 0.047), but the 3-month mortality was similar (33.3% vs. 47.1%; p = 0.294). The functional outcome was equally poor in both groups at discharge (p = 0.670) and 3 months post-ICH (mean mRS score 4.7 ± 1.3 vs. 4.6 ± 1.7, p = 0.766). Conclusion: There were no significant differences in initial ICH volume, 90-day mortality, or functional outcomes between NOAC and VKA-associated ICH in Asians. Keywords: Intracerebral hemorrhage, Non-vitamin K antagonist oral anticoagulant, Outcome, Vitamin K antagonist

BackgroundThe efficacy and safety of intravenous alteplase administered 3–4.5 h after acute ischemic stroke have been demonstrated. However, whether responses differ between low-dose and standard-dose alteplase during this time window and whether certain subgroups benefit more remain unknown.Patients and MethodsThe current analysis was based on a multicenter matched-cohort study conducted in Taiwan. The treatment group comprised 378 patients receiving intravenous alteplase 3–4.5 h after stroke onset, and the control group comprised 378 age- and sex-matched patients who did not receive alteplase treatment during the same period. Standard- and low-dose alteplase was administered to patients at the physician's discretion.ResultsOverall, patients receiving alteplase exhibited more favorable outcomes than did controls [34.0 vs. 22.7%; odds ratio (OR): 1.75, 95% confidence interval (CI): 1.27–1.42], and the effectiveness was consistent in all subgroups. Although patients in the standard-dose group (n = 182) were younger than those in the low-dose (n = 192) group, the proportions of patients with favorable outcomes (36.3 vs. 31.8%; OR: 1.22, 95% CI: 0.80–1.88) and symptomatic hemorrhage (2.8 vs 4.2%; OR: 0.65, 95% CI: 0.21–2.02) were consistently comparable in a covariate-adjusted model and an age-matched cohort. In the subgroup analysis, patients with cardioembolism, atrial fibrillation, and hypercholesterolemia were more likely to achieve favorable outcomes after receiving standard-dose than low-dose alteplase.ConclusionIn the 3–4.5 h time window, the effectiveness and safety of standard-dose and low-dose alteplase may be comparable. A standard dose may be selected for patients with cardioembolism, atrial fibrillation, or hypercholesterolemia.

BackgroundThis study aimed to investigate the association between the carotid ultrasound results and 1-yr mortality of patients with neurological deficits in the emergency department (ED).MethodsThis study included patients with neurological symptoms who presented to the ED between January 1, 2009 and December 31, 2018, and underwent sonographic imaging of the bilateral carotid bulb, common carotid artery (CCA), internal carotid artery (ICA), and external carotid arteries. A stenosis degree of >50% was defined as significant carotid stenosis. Carotid plaque score (CPS) was calculated by adding the score of stenosis severity of all segments. The association between carotid ultrasound results and 1-yr mortality was investigated using the Cox regression model.ResultsThe analysis included 7,961 patients (median age: 69 yr; men: 58.7%). Among them, 247 (3.1%) passed away from cardiovascular (CV)-related causes, and 746 (9.4%) died within a year. The mortality group presented with more significant carotid stenosis of the carotid bulb, CCA, or ICA and had a higher median CPS. A higher CPS was associated with a greater 1-yr all-cause mortality (adjusted hazard ratio [aHR] = 1.08; 95% confidence interval [CI] = 1.03-1.13; p = 0.001; log-rank p < 0.001) and CV-related mortality (aHR = 1.13; 95% CI = 1.04-1.22; p = 0.002, log-rank p < 0.001). Significant stenosis of either carotid artery segment did not result in a higher risk of 1-yr mortality.ConclusionsWe comprehensively investigated the utility of carotid ultrasound parameters on predicting mortality in this 10-yr population-based cohort, which included over 7,000 patients with acute neurological deficits presented to the ED. The result showed that CPS could be used as risk stratification tools for 1-yr all-cause and CV mortality.

Objective: Lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased intracerebral hemorrhage (ICH) risk. However, reverse causality and residual confounding has not attracted public attention. Therefore, we assessed whether people with LDL-C have increased risk of mortality adjusting for potential confounders using two large Taiwan cohorts.Methods: The Mei-Jhao (MJ) cohort has 414,372 adults participating in a medical screening program with 378 ICH deaths within 15 years of follow-up (1994–2008). Cox proportional hazards regressions estimated hazard death ratios according to LDL-C levels. We identified 4,606 ICH patients from the Taiwan Stroke Registry (TSR) and analyzed the impact of LDL-C on 3-month mortality.Results: Low cholesterol (LDL-C

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by mutations in NOTCH3, is the most common cause of hereditary cerebral small vessel disease. Whether it will involve systemic vasculopathy such as retinal vessel remains unknown. Optical coherence tomography angiography (OCT-A) is a noninvasive technique for visualising retinal blood flow. We analysed vessel density and retinal thickness in patients with CADASIL and investigated their correlations with disease severity.MethodsThis prospective study enrolled 35 patients with CADASIL (59 eyes) and 35 healthy controls (54 eyes). OCT-A was used to measure the vessel density of the macular region and the thickness of retinal layers. Patients with CADASIL were divided into stroke (n = 20) and nonstroke (n = 15) subgroups and underwent cognition and gait speed evaluation. Neuroimaging markers of cortical thickness, white matter hyperintensity, lacunae, and cerebral microbleeds were examined through brain magnetic resonance imaging.ResultsThe OCT-A parameters, including vessel density, were comparable between the patients with CADASIL and the controls. In patients with CADASIL, vessel density in the superficial retinal plexus in the macula as was inner retinal thickness was significantly lower in the stroke than the nonstroke subgroup. Macular vessel density and inner retinal thickness were positively correlated with gait speed, while negatively correlated with number of lacunae.ConclusionsOCT-A is potentially a useful tool for evaluating disease severity, ischaemic burden, and neurodegeneration in patients with advanced CADASIL.

Ischemic stroke with a mismatch between diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) or T2-weighted images indicates onset within 4.5 h, but the pathological substrates in the DWI-T2 mismatch and T2(+) areas remain elusive. In this study, proteomics was used to explore (1) the protein expression profiles in the T2(+), mismatch, and contralateral areas, and (2) the protein with the highest expression in the T2(+) area in the brains of male Sprague-Dawley rats within 4.5 h after middle cerebral artery occlusion (MCAO). The expression of the candidate protein was further validated in (1) rat brain subjected to MCAO, (2) rat primary cortical neuronal culture with oxygen-glucose deprivation (OGD), and (3) infarcted human brain tissues. This study showed that apoptosis was observed in the T2(+) and mismatch regions and necroptosis in the T2(+) region of rat brains after MCAO. We identified capping protein regulator and myosin 1 linker 3 (CARMIL3) as the candidate molecule in the T2(+) and mismatch areas, exclusively in neurons, predominantly in the cytoplasm, and most abundant in the mismatch area. The CARMIL3(+) neurons and neurites in the mismatch and T2(+) areas were larger than those in the control area, and associated with (1) increased expression of sulfonylurea receptor 1 (SUR1), indicating edema, (2) accumulation of p62, indicating impaired autophagy, and (3) increase in 8-hydroxy-2′-deoxyguanosine (8-OHdG), indicating oxidative stress. The increased expression of CARMIL3 was validated in a cell model of cortical neurons after OGD and in infarcted human brain tissues. In conclusion, this study shows that the mismatch and T2(+) areas within 4.5 h after ischemia are characterized by upregulated expression of CARMIL3 in neurons, particularly the mismatch area, which is associated with neuronal edema, impaired autophagy, and oxidative stress, indicating that CARMIL3 serves as a molecular signature of brain ischemia.

Background Conventional prognostic scores usually require predefined clinical variables to predict outcome. The advancement of natural language processing has made it feasible to derive meaning from unstructured data. We aimed to test whether using unstructured text in electronic health records can improve the prediction of functional outcome after acute ischemic stroke. Methods and Results Patients hospitalized for acute ischemic stroke were identified from 2 hospital stroke registries (3847 and 2668 patients, respectively). Prediction models developed using the first cohort were externally validated using the second cohort, and vice versa. Free text in the history of present illness and computed tomography reports was used to build machine learning models using natural language processing to predict poor functional outcome at 90 days poststroke. Four conventional prognostic models were used as baseline models. The area under the receiver operating characteristic curves of the model using history of present illness in the internal and external validation sets were 0.820 and 0.792, respectively, which were comparable to the National Institutes of Health Stroke Scale score (0.811 and 0.807). The model using computed tomography reports achieved area under the receiver operating characteristic curves of 0.758 and 0.658. Adding information from clinical text significantly improved the predictive performance of each baseline model in terms of area under the receiver operating characteristic curves, net reclassification improvement, and integrated discrimination improvement indices (all P

Background and Purpose: Edoxaban exposure varies across different ethnicities. The purpose of our study was to examine the risk factors associated with high or low edoxaban concentrations in Asian populations.Methods: Participants with atrial fibrillation who were undergoing edoxaban therapy were enrolled. Peak (1–4 h after edoxaban administration) and trough (24 ± 4 h from the last edoxaban dose) blood samples were collected to measure edoxaban concentrations using ultrahigh-performance liquid chromatography with tandem mass spectrometry. The edoxaban concentrations were compared to those observed in clinical trials to define a higher- or lower-than-expected range. Multivariate logistic regression was used to analyze the risk factors associated with high or low edoxaban concentrations.Results: Eighty participants (49 men, 61.3%) were enrolled and provided 78 trough and 76 peak samples. Twenty participants (25.6%) were determined to have low trough concentrations, which was associated with higher creatinine clearance and the use of the 30 mg regimen (odds ratio [OR] and 95% confidence interval [CI], 1.06 [1.01, 1.11], p = 0.01 and 5.77 [1.34, 24.75], p = 0.02, respectively). In contrast, 21 participants (27.6%) had high peak concentrations, which was associated with an off-label overdosing regimen (OR = 4.68 [1.23, 17.70], p = 0.02).Conclusion: Our study identified factors associated with increased or decreased edoxaban exposure. The measurement of edoxaban concentration may be recommended for patients with selected characteristics.

Introduction: Endovascular therapy (EVT) is established as first-line treatment for acute ischemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation. For basilar artery occlusion, recent randomized clinical trials demonstrated not only equipoise but also advantages for EVT under particular circumstances. It remains unclear whether EVT offers an advantage over best medical management (BMM) including thrombolysis (IVT) in isolated occlusion of the proximal posterior cerebral artery (PCAO).Methods: Patients with AIS due to PCAO proven by CT or MR angiography were retrospectively identified from local databases at four comprehensive stroke centers in Germany, USA, and Taiwan between 2012 and 2020. Demographic and clinical data were collected, and imaging characteristics including pretherapeutic, interventional, and follow-up imaging were reviewed locally at each center. Patients were grouped according to therapy, i.e., BMM including IVT alone vs. BMM and EVT. Efficacy endpoints were early neurological improvement (ENI) after 24 h or at discharge, good outcome (modified Rankin scale 0–2) after 3 months, as well as hemorrhagic complications and in-house deaths as safety endpoints.Results: We included 130 patients of whom 23 (17.7%) received EVT. EVT patients had more proximal occlusions (69.9 vs. 43%, p = 0.023) and had a better premorbid function [premorbid mRS, 0 (0–4) vs. 1 (0–3), p < 0.01] when compared to BMM patients. IVT showed a trend toward being less performed in the EVT group (21.7 vs. 41.1%, p = 0.1), while other baseline parameters were balanced. Successful reperfusion was achieved in 52% of EVT patients. ENI was more frequent in the EVT group (61 vs. 35.5%, p = 0.034). Good outcome at 90 days and safety endpoints did not differ. In a bivariate analysis, ENI was independently predicted by the use of EVT (OR, 2.76; CI, 1.055–7.04) and the baseline National Institutes of Health Stroke Scale (NIHSS) (OR, 1.082; CI, 1.027–1.141 per point increase).Discussion: EVT in isolated PCAO appears safe and feasible. Positive effects on clinical outcome are primarily on ENI but also depend on the initial stroke severity. Further prospective or randomized studies are needed to better describe the potential long-term clinical benefits of EVT for PCAO as compared with best medical management.

Background/purpose: Dabigatran is effective in preventing ischemic stroke and systemic embolism in patients with atrial fibrillation. Although the therapeutic window for dabigatran is wide, its pharmacokinetic properties can differ between specific populations. This study aimed to establish a real-life plasma dabigatran concentration database and investigate potential factors affecting this concentration in Asians. Methods: Patients under dabigatran therapy were recruited. Plasma dabigatran concentration was determined in trough and peak blood samples by using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Factors affecting the dabigatran concentration were investigated. Results: A total of 46 patients (33 male, 71.7%) were prospectively enrolled. Most of them were receiving a low dose regimen (110 mg twice daily, n = 38, 82.6%). The trough and peak concentrations were significantly correlated (p 3 points, and HAS-BLED score ≥3 points. Multiple linear regression analysis identified body weight and serum creatinine as key factors predicting trough concentration (p = 0.003 and 0.005, respectively). Importantly, drug adherence was the only independent factor associated with low trough concentration, defined as the lowest 20th percentile in our study cohort (n = 10, hazard ratio = 9.07; 95% CI, 1.12 to 73.22; p = 0.004). Conclusion: Dabigatran monitoring may be considered for patients at risk of overexposure, especially those with low body weight and renal insufficiency, and also for detecting those with extremely low drug concentration. Keywords: Adherence, Atrial fibrillation, Dabigatran, Drug concentration, Ischemic stroke, Pharmacokinetics

Background and Purpose: Real-world laboratory monitoring of dabigatran activity is challenging. The purpose of the present study was to demonstrate the feasibility and accuracy of finger prick sampling with dried blood spot (fpDBS) cards in measuring the dabigatran concentration.Material and Methods: Patients >20 years of age with atrial fibrillation and receiving dabigatran therapy for more than 7 days were included in the study. Peak and trough dabigatran concentrations were collected by simultaneous finger prick and venous puncture. The dabigatran concentration was measured by ultra-high performance liquid chromatography with tandem mass spectrometry. Our previously developed post-column infused internal standard (PCI-IS) method was applied to estimate the blood spot volume on fpDBS and to calibrate the drug concentration. Deming regression was used to analyze the correlation between dabigatran concentration on fpDBS cards and in plasma samples, followed by Bland–Altman analysis to compare the bias between two sampling techniques.Results: A total of 33 patients were enrolled and contributed 66 plasma and 55 fpDBS dabigatran samples. The average patient age was 74.6 ± 7.9 years, mean creatinine clearance 58.1 ± 18.3 mL/min, and CHA2DS2-VASc score 3.5 ± 1.6 points. The dabigatran concentration ranged from 41.8–1421.7 ng/mL. The plasma and DBS dabigatran concentrations correlated well (r = 0.98), and the conversion factor for fpDBS to plasma dabigatran concentration was 1.28. The Bland–Altman analysis showed that 94.5% of the fpDBS-predicted concentration fell within 20% of bias.Conclusions: The study showed that fpDBS measurement of dabigatran concentration is reliable and can be applied in clinical scenarios.

Background/purpose: Details of the communication between the caller and dispatcher have not been reported previously in Taiwan. This study aimed to: (1) understand the details of the communication between the caller and dispatcher among the calls for stroke patients, (2) identify factors associated with stroke recognition by dispatchers, and (3) evaluate the association between stroke recognition by dispatchers and stroke management. Methods: We conducted a retrospective observational study involving patients with stroke or transient ischemic stroke transported by the emergency medical service, and arriving at 9 hospitals in Taipei within 3 h of symptom onset from January 1, 2013 to February 28, 2014. Patients were excluded if tape-recording data or prehospital information were not available. Data of the enrolled patients were reviewed. We used stroke dispatch determination as the surrogate for stroke recognition by dispatchers. Multivariable logistic regression was used to identify the factors associated with stroke dispatch determination. Results: A total of 507 patients were included. In approximately 50% of cases, callers were close family members. Ninety-one patients (17.9%) had stroke dispatch determination. After adjustment, stroke reported spontaneously, any symptom included in the Cincinnati Prehospital Stroke Scale reported spontaneously, and dispatcher adherence to the protocol, were associated with stroke dispatch determination significantly. Stroke dispatch determination was associated with receiving pre-arrival notification, shorter door-to-computed tomography time, and thrombolytic therapy. Conclusion: The dispatchers should spend more time identifying stroke patients by following the dispatch protocol. Recognition of stroke by dispatchers was associated with improved stroke care. Keywords: Stroke, Dispatch, Thrombolytic therapy

Background/purpose: Endovascular thrombectomy has been strongly recommended for treatment of acute ischemic stroke (AIS) with large vessel occlusion. This study aimed to evaluate its efficacy and safety in an Asian population from a single center in Taiwan. Methods: Patients who experienced AIS and received endovascular thrombectomy during the period of September 2014 to September 2016 at National Taiwan University Hospital were included. Factors related to favorable outcome, defined as modified Rankin scale 0–2 at 90 days after stroke, were analyzed. Results: During the study period, 65 patients (mean age, 71.9 ± 12.4 years; 44.6% females) received endovascular thrombectomy, including 33 who received intravenous thrombolysis before the endovascular treatment. A significant trend of increasing thrombectomy therapy was observed. The median National Institutes of Health Stroke Scale (NIHSS) score on admission was 19 (interquartile range, 15–26). The sites of vessel occlusion were middle cerebral artery in 47 (72.3%) patients, intracranial internal carotid artery in 8 (12.4%), anterior cerebral artery in 1 (1.5%), and basilar artery in 9 (13.8%). The median times from stroke onset to groin puncture and from groin puncture to recanalization time were 200 and 29.5 min, respectively. Successful revascularization was achieved in 41 (63.1%) patients. Two (3.1%) patients had symptomatic hemorrhagic transformation. At 90 days, 25 (38.5%) patients achieved favorable outcome. A shorter time from onset to puncture, and successful recanalization were independent predictors of favorable outcome. Conclusion: This study demonstrated the therapeutic promise of endovascular thrombectomy for treatment of AIS with large vessel occlusion in a clinical setting. Keywords: Acute ischemic stroke, Outcome, Thrombectomy, Thrombolysis

Background: Enhancing detection of undiagnosed atrial fibrillation (AF) in hospitalized patients with a recent ischemic stroke is important because of the treatment implications; especially since presence of paroxysmal AF may not be picked up in a single 12-lead electrocardiogram (ECG) test. While several trials have shown improved detection of AF with prolonged ECG monitoring, this strategy is associated with relatively high cost, labor intensity, and patient inconvenience, thereby making it challenging to routinely implement in all hospitals. Fortunately, conventional 24-h Holter monitoring and repeated 12-lead ECGs are readily available to detect paroxysmal AF in all hospitals, but is unclear which is the better strategy for evaluating undiagnosed AF. The objective of his study is to conduct a randomized trial of serial 12-lead ECGs vs. 24-hour Holter monitoring in the detection of AF in ischemic stroke patients without known AF. Methods and analysis: We plan to enroll 1200 participants from six hospitals in Taiwan. Patients will be eligible for enrollment if they are admitted for an acute ischemic stroke within 2 days, are ≥65 years of age, and have no known AF by history or on baseline ECG at admission. We will randomly assign participants in a 1:1 ratio to undergo daily 12-lead ECG once daily for 5 days (intervention group) or 24-h Holter monitoring (control group). Primary outcome is newly detected AF on a 12-lead ECG or AF lasting ≥30 s on Holter monitoring. Trial registration number: ClinicalTrials.gov Identifier: NCT02578979.

In Taiwan, the prevalence of hyperlipidemia increased due to lifestyle and dietary habit changes. Low density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein cholesterol (non-HDL-C) are all significant predicting factors of coronary artery disease in Taiwan. We recognized that lipid control is especially important in patients with existed atherosclerotic cardiovascular diseases (ASCVD), including coronary artery disease (CAD), ischemic stroke and peripheral arterial disease (PAD). Because the risk of ASCVD is high in patients with diabetes mellitus (DM), chronic kidney disease (CKD) and familial hypercholesterolemia (FH), lipid control is also necessary in these patients. Lifestyle modification is the first step to control lipid. Weight reduction, regular physical exercise and limitation of alcohol intake all reduce triglyceride (TG) levels. Lipid-lowering drugs include HMG-CoA reductase inhibitors (statins), cholesterol absorption inhibitors (ezetimibe), proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, nicotinic acids (niacin), fibric acids derivatives (fibrates), and long-chain omega-3 fatty acids. Statin is usually the first line therapy. Combination therapy with statin and other lipid-lowering agents may be considered in some clinical settings. For patients with acute coronary syndrome (ACS) and stable CAD, LDL-C < 70 mg/dL is the major target. A lower target of LDL-C 40 in men and >50 mg/dL in women in DM. LDL-C increased CV risk in patients with CKD. In adults with glomerular filtration rate (GFR) < 60 mL/min/1.73m2 without chronic dialysis (CKD stage 3–5), statin therapy should be initiated if LDL-C ≥ 100 mg/dL. Ezetimibe can be added to statin to consolidate the CV protection in CKD patients. Mutations in LDL receptor, apolipoprotein B and PCSK9 genes are the common causes of FH. Diagnosis of FH usually depends on family history, clinical history of premature CAD, physical findings of xanthoma or corneal arcus and high levels of LDL-C. In addition to conventional lipid lowering therapies, adjunctive treatment with mipomersen, lomitapide, or PCSK9 inhibitors become necessary to further reduce LDL-C in patients with FH. Overall, these recommendations are to help the health care professionals in Taiwan to treat hyperlipidemia with current scientific evidences. We hope the prescription rate of lipid lowering drugs and control rate of hyperlipidemia in high risk patients could be increased by implementation of the clinical guidelines. The major purpose is to improve clinical outcomes of these high risk patients through the control of hyperlipidemia.

Abstract Background Estrogen plays an important role as an anti-inflammatory and neuroprotective agent in ischemic stroke. In this study, we analyzed the effect of a polygenic risk score (PRS) constructed using inflammatory genes and estradiol levels on the risk of ischemic stroke. Methods This case-control study was conducted with 624 ischemic stroke patients and 624 age- and gender-matched controls. The PRS estimated the polygenic contribution of inflammatory genes from ischemic stroke susceptibility loci. Estradiol levels were measured using a radioimmunoassay. High and low estradiol levels were defined according to the log-transformed median estradiol levels in female and male controls. Results Subjects in the fourth quartile of the PRS had a significant 1.57-fold risk of ischemic stroke (95% confidence interval [CI], 1.12 ~ 2.19), after adjusting for covariates compared to individuals in the lowest quartile. Compared to individuals with high estradiol levels and a low PRS as the reference group, those exposed to low estradiol levels and a high PRS had an increased risk of ischemic stroke (odds ratio, 3.35; 95% CI, 1.79 ~ 6.28). Similar results were also observed in males when the analysis was stratified by gender. Conclusions Our data suggest that the PRS can be useful in evaluating a high risk of ischemic stroke among patients, especially those exposed to low estradiol levels.

Background and Objectives: Intravenous recombinant tissue plasminogen activator (rt-PA) has been approved for acute ischemic stroke (AIS) within 3 h after onset and the treatment was then extended to 4.5 h. However, the Food and Drug Administration did not approve the indication in the expanded time window. This retrospective, matched cohort study aims to investigate the effectiveness and safety of rt-PA in AIS at 3–4.5 h after onset.Materials and Methods: The treatment group included AIS patients receiving rt-PA at 3–4.5 h after onset, otherwise complying with the regulation, in the stroke registries in 16 hospitals between 2008 and 2017. The control group included age- and sex-matched patients not receiving intravenous thrombolysis from the same registries, excluding those with contraindications. The primary outcome was modified Rankin Scale (mRS) 0–1 at day 90. The safety outcomes were any intracerebral hemorrhage (ICH), early neurological deterioration and 3-month mortality.Results: Each group had 374 patients. There were 34.0% of patients with 3-month mRS 0-1 in the treatment group vs. 22.7% in the control group with an odds ratio of 1.75 (95% confidence intervals, 1.27 to 2.42, P = 0.001). There was no difference in symptomatic ICH, early neurological deterioration and 3-month mortality rates between two groups. The 3-month mRS and symptomatic ICH did not differ significantly in patients receiving standard dose or low dose of rt-PA.Conclusions: Our results support the prescription of rt-PA in AIS patients 3–4.5 h after onset as an effective and tolerable treatment in their functional recovery.

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease caused by β -amyloid (Aβ) deposition at the leptomeningeal vessel walls. It is a common cause of spontaneous intracerebral hemorrhage and a frequent comorbidity in Alzheimer’s disease. The high recurrent hemorrhage rate in CAA makes it very important to recognize this disease to avoid potential harmful medication. Imaging studies play an important role in diagnosis and research of CAA. Conventional computed tomography and magnetic resonance imaging (MRI) methods reveal anatomical alterations, and remains as the most reliable tool in identifying CAA according to modified Boston criteria. The vascular injuries of CAA result in both hemorrhagic and ischemic manifestations and related structural changes on MRI, including cerebral microbleeds, cortical superficial siderosis, white matter hyperintensity, MRI-visible perivascular spaces, and cortical microinfarcts. As imaging techniques advance, not only does the resolution of conventional imaging improve, but novel skills in functional and molecular imaging studies also enable in vivo analysis of vessel physiological changes and underlying pathology. These modern tools help in early detection of CAA and may potentially serve as sensitive outcome markers in future clinical trials. In this article, we reviewed past studies of CAA focusing on utilization of various conventional and novel imaging techniques in both research and clinical aspects.

ObjectiveIn-hospital stroke (IHS) is an uncommon but serious medical emergency. Early recanalization through endovascular thrombectomy (EVT) may offer a vital therapeutic choice. This study compared the clinical features and outcomes between IHS and community-onset stroke (COS).MethodsFrom a single-center registry of 2813 patients with ischemic stroke, those who had received EVT for acute ischemic stroke were included and classified into the IHS and COS groups based on their stroke onset scenario. We compared the outcomes including successful recanalization, symptomatic intracranial hemorrhage, functional independence (modified Rankin Scale score, 0-2) at 90 days, and mortality between the two groups.ResultsA total of 24 patients with IHS (mean age, 70 years; 54% men) and 105 patients with COS (mean age, 73 years; 47% men) were included. The most frequently reported reasons for admission in patients with IHS were cardiovascular and oncological diseases. The initial National Institutes of Health Stroke Scale (NIHSS) scores and main occluded vessels were similar between the two groups. Patients with IHS received a higher number of active malignancy diagnoses, were more likely to withhold antithrombotic agents, and exhibited higher prestroke functional dependency. The median onset-to-puncture time was 192 min in IHS and 217 min in COS (P = 0.15). The percentages of successful recanalization (79% vs 71%), symptomatic hemorrhage (0% vs 9%), functional independence (42% vs 40%), and mortality (17% vs 12%) were comparable between the two groups. After adjustment for covariates, initial NIHSS scores and successful recanalization were the most important predictors for functional independence at 90 days.ConclusionsDespite having disadvantages at baseline, patients with IHS could still benefit from timely EVT to achieve favorable outcomes. A well-designed acute stroke protocol tailored for IHS should be developed.