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Whole exome sequencing (WES) has been used to detect rare causative variants in neurological diseases. However, the efficacy of WES in genetic diagnosis of clinically heterogeneous familial stroke remains inconclusive. We prospectively searched for disease-causing variants in unrelated probands with defined familial stroke by candidate gene/hotspot screening and/or WES, depending on stroke subtypes and neuroimaging features at a referral center. The clinical significance of each variant was determined according to the American College of Medical Genetics guidelines. Among 161 probands (mean age at onset 53.2 ± 13.7 years; male 63.4%), 33 participants (20.5%) had been identified with 19 pathogenic/likely pathogenic variants (PVs; WES applied 152/161 = 94.4%). Across subtypes, the highest hit rate (HR) was intracerebral hemorrhage (ICH, 7/18 = 38.9%), particularly with the etiological subtype of structural vasculopathy (4/4 = 100%, PVs in ENG, KRIT1, PKD1, RNF213); followed by ischemic small vessel disease (SVD, 15/48 = 31.3%; PVs in NOTCH3, HTRA1, HBB). In contrast, large artery atherosclerosis (LAA, 4/44 = 9.1%) and cardioembolism (0/11 = 0%) had the lowest HR. NOTCH3 was the most common causative gene (16/161 = 9.9%), presenting with multiple subtypes of SVD (n = 13), ICH (n = 2), or LAA (n = 1). Importantly, we disclosed two previously unreported PVs, KRIT1 p.E379* in a familial cerebral cavernous malformation, and F2 p.F382L in a familial cerebral venous sinus thrombosis. The contribution of monogenic etiologies was particularly high in familial ICH and SVD subtypes in our Taiwanese cohort. Utilizing subtype-guided hotspot screening and/or subsequent WES, we unraveled monogenic causes in 20.5% familial stroke probands, including 1.2% novel PVs. Genetic diagnosis may enable early diagnosis, management and lifestyle modification. Graphical Abstract Among 161 familial stroke probands, 33 (20.5%) had been identified pathogenic or likely pathogenic monogenic variants related to stroke. The positive hit rate among all subtypes was high in intracerebral hemorrhage (ICH) and ischemic small vessel disease (SVD). Notably, two previously unreported variants, KRIT1 p.E379* in a familial cerebral cavernous malformation and F2 p.F382L in familial cerebral venous sinus thrombosis, were disclosed. CVT cerebral venous thrombosis; HTN Hypertensive subtype; LAA large artery atherosclerosis; SV structural vasculopathy; U Undetermined.

BACKGROUND Young stroke incidence has increased worldwide with lifestyle changes. Etiology and risk factors for both ischemic and hemorrhagic stroke in young Asians remain underexplored. METHODS We retrospectively reviewed consecutive acute stroke patients aged 16-45 years admitted to the Taipei Veterans General Hospital between 2009 and 2019 to analyze etiologic subtypes, risk factors, and serial modified Rankin Scale scores for 1 year and compare the age groups of 16-30 and 31-45 years. RESULTS Among 670 young Taiwanese patients (mean age at onset 37.5 ± 7.0 years; male 65.1%), there were 366 nontraumatic spontaneous hemorrhagic stroke (including 259 intracerebral hemorrhage [ICH] and 107 subarachnoid hemorrhage, SAH), 292 ischemic stroke and 12 cerebral venous thromboses. Notably, ICH was more prevalent in patients aged 16-30 than in those aged 31-45 (54.8% vs 36.8%). Specifically, structural vasculopathy (e.g., arteriovenous malformation, cavernoma) was the most common etiologic subtype in patients aged 16-30 (p < 0.001), whereas hypertensive ICH was the most common subtype in patients aged 31-45 (p < 0.001). On the other hand, the top ischemic subtype for both age groups was other determined diseases (e.g., arterial dissection, autoimmune diseases, moyamoya disease, etc.) rather than large artery atherosclerosis. Hyperlipidemia, diabetes, and cigarette smoking were more common risk factors for infarction than ICH. Familial stroke patients whose first- or second-degree relatives had a stroke by age 80 (n = 104, 15.5%) had more infarctions than those without a familial stroke history. In multivariate analyses, initial stroke severity, and infarction type were important predictors of favorable outcomes after 3 months. At the 1-year follow-up, patients with ICH and SAH had worse functional outcomes and survival rates than those with infarction. CONCLUSION An aggressive approach to elucidate the etiology of stroke is indicated because structural vasculopathy-induced ICH and other determined infarction are distinctively prevalent in young adults, particularly those aged 16-30.

CYP2C19 loss-of-function single-nucleotide polymorphisms (SNPs) are associated with poor responses of clopidogrel in secondary prevention of ischemic stroke (IS). It is still unclear whether these SNPs, which may result in poor cytochrome P450 2C19 (CYP2C19) enzymatic activity, affect the occurrence of IS and its subtypes. The present study evaluated the relationship between the CYP2C19 loss-of-function alleles and IS.Eight hundred sixty-eight patients with IS and 557 nonstroke (NS) control individuals were prospectively recruited. Stroke etiologies, including large-artery atherosclerosis (LAA), cardioembolism (CE), and small-vessel occlusion (SVO), were determined. The two most common CYP2C19 loss-of-function alleles worldwide, CYP2C19*2 and CYP2C19*3, were investigated by genotyping. Patients with two loss-of-function alleles of the CYP2C19 genes were classified as poor metabolizers.Our population has a high frequency of CYP2C19 loss-of-function alleles, mostly contributed by CYP2C19*2, being present in 51.3% to 57.5% of patients with IS of different etiologies and 53.1% of NS individuals. The proportions of CYP2C19 poor metabolizers within NS group and each IS group with disparate etiology are similar (NS 73 [13.1%]; LAA 44 [14.2%], p = 0.623; CE 26 [14.0%], p = 0.541; SVO 38 [13.3%], p = 0.443). Nevertheless, the frequencies of CYP2C19*3 allele were different among the NS and different IS subgroups. Multivariate analyses adjusting for age, sex, and vascular risk factors revealed that CYP2C19*3 allele was a protective factor for SVO (odds ratio [OR] = 0.5, 95% confidence interval [CI] = 0.3 to 0.9, p = 0.015 [vs NS], OR = 0.5, 95% CI = 0.3 to 0.8, p = 0.010 [vs LAA and CE]).The CYP2C19 poor metabolizer is not associated with IS and its subtypes. Furthermore, CYP2C19*3 may be a protective factor for SVO and its mechanism warrants further investigation.

Background and aims Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60–89, 30–59, 15–29, and Results Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR Conclusions After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

Background: With the popularity of MRI use, vertebrobasilar artery dissection (VBD) has been found more frequently in patients with posterior circulation ischemic stroke (PCS). The relationship between VBD and atherosclerosis is unknown. The present study aimed to prove the hypothesis that PCS with pure VBD (p-VBD) and with VBD and accompanied cervical or cerebral artery atherosclerosis (a-VBD) have distinct manifestations. Methods: Patients with VBD-related PCS who were prospectively enrolled in the Taipei Veterans General Hospital Stroke Registry between January 1, 2010 and August 31, 2014 were recruited for the present study. Patients who had (1) atherosclerotic plaques with or without stenotic flow in cervical arteries on Duplex ultrasonography or (2) focal >30% stenosis in cerebral arteries other than the dissecting region (usually in arterial bifurcations which are prone to atheroma formation) on brain MRA were defined as a-VBD. Results: There were 91 patients (67 [73.6%] males, mean age 65.5 years [SD = 15.2, range, 21–91]) with VBD-related PCS recruited for the present study; 31 were a-VBD and 60 were p-VBD. The results showed that there were significant differences in onset age, frequency of cigarette smoking, dissecting vascular involvement, and infarct locations between the 2 groups. In addition, compared with p-VBD, the a-VBD group had poorer functional recovery at 3 months and 1 year, respectively, which was independent of age, sex, vascular risk factors, stroke severity at admission, and treatment options. Conclusion: VBD-related PCS with and without accompanied atherosclerosis had different manifestations and should be regarded as distinct arterial diseases.

We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients.From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013.Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of 120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of 120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively.Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or 120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.

Background Early-onset adult stroke has not been fully characterized in Asians. Objectives We investigated the etiologic subtypes, risk factors and 1-year outcomes of early-onset stroke (16 – 55 years of age) in a Taiwanese cohort. Methods We retrospectively reviewed consecutive patients with acute stroke admitted to the Taipei Veterans General Hospital in Taiwan between 2009 and 2017. Patients were classified by age of onset (≤ or > 55) and etiologic subtypes and regularly followed for 1 year. Results Among all stroke patients (n=8155), 17.6% (n=1310) were early-onset, who had slightly more spontaneous hemorrhagic stroke (50.8%) than ischemic stroke (49.2%). The most common etiologic subtypes of hemorrhagic stroke were hypertensive intracerebral hemorrhage (ICH), subarachnoid hemorrhage and undetermined ICH. The most common subtypes of infarction were large artery atherosclerosis, other determined diseases (52.5% arterial dissection) and embolic stroke of undetermined source. Smoking, alcohol overdrink, obesity, ischemic heart disease and family history of stroke were more in the early-onset than the elderly patients. The early-onset patients with familial stroke (n=87, 6.6%) were more males and more commonly had infarction than those without familial stroke. Monogenic diseases accounted for 5.7% of young familial stroke. At 1-year follow-up, the early-onset patients with infarction displayed greater functional improvements but more stroke recurrence than those with ICH. Conclusions Hypertensive hemorrhagic stroke and large artery atherosclerosis or dissection occlusion are characteristically common etiologies of young stroke in Taiwan. Early-onset infarction had higher recurrence yet better 1-year outcomes than early-onset ICH. Patients with familial versus non-familial aggregation had more ischemic infarction and monogenic diseases.

Introduction Vertebrobasilar artery dissection(VBD) is a common etiology of posterior circulation stroke(PCS). However, the etiology of VBD itself remains unclear. The present study aimed to test whether inflammation is involved in the mechanism of VBD by evaluating its relationship with total and differential leukocyte counts. Methods Patients with PCS caused by VBD or by large artery atherosclerosis(LAA) were recruited between January 1, 2012 and December 31, 2014 from the Taipei Veterans General Hospital. Age- and sex-matched non-stroke(NS) volunteers were also included. Univariate and multivariate analyses were performed to compare total/differential leukocyte counts among VBD, LAA, and NS groups. Results One-hundred-one patients with VBD [average age: 64.8(15.1) years; 77(76.2%) males], 70 with LAA [average age: 73.9(10.6) years; 44(62.9%) males], and 202 NS [average age: 64.8(15.1) years; 77(76.2%) males] patients were included in the present study. Compared with the NS and LAA groups, respectively, the VBD group had significantly higher total leukocyte and neutrophil counts and frequency of high leukocyte (>10,000 × 106/L) and high neutrophil (>8000 × 106/L) counts. Multivariate analyses, adjusted for age, sex, and vascular risk factors, showed that the VBD group, compared with the other groups, had an odds-ratio of 5.04 (95% confidence interval:2.43–10.43) and 5.90 (2.70–12.92) with respect to the prevalence of high leukocyte and high neutrophil counts. Conclusion VBD was associated with high leukocyte and neutrophil counts. Our results support that inflammation and neutrophil-related pathophysiology might be involved in the mechanism of VBD; however, the causal relationship would need further investigations.

Background Taiwan's NHI Administration proposed a nationwide postacute care-cerebral vascular disease (PAC-CVD) program, which transfers stroke patients at postacute phase in medical centers to community hospitals. Its aim is mainly to prevent a prolonged stay in medical centers, which usually results in higher medical costs. The present study evaluated the 3-months functional outcomes of stroke patients receiving PAC-CVD. Methods We retrogradely retrieved patients' data from Stroke Registry of a Northern medical center. Patients admitted between January 2014 and March 2018 were screened. We included patients receiving PAC-CVD and age/sex/stroke severity/functional status-matched acute stroke patients (regular rehabilitation group). Baseline clinical characteristics and 3-months functional outcomes were analyzed. We defined 3-months mRS 0 to 2 as better, 3 to 4 as same, and 5 to 6 as worse functional recovery. Results One-hundred-and-seventy-three patients receiving PAC-CVD and 173 matched controls (68.2 ± 14.0-years-old, 68.5% ± 11.22% men) were recruited. All patients were with mRS 3 to 4 at discharge from our medical center. The distributions of 3-months functional recovery in two groups were as follows: better/same/worse 3-months functional outcomes, PAC-CVD = 40.4%/57.8%/1.8%; controls (regular rehabilitation) = 33.9%/50.3%/5.8%. Multivariate analyses adjusted for age, sex, NIHSS, and cardiovascular risk factors were performed to evaluate whether PAC-CVD predicted better or poor functional outcomes. The results showed that compared with controls, PAC-CVD group had similar frequency of better functional recovery (odds ratio [OR] = 0.97, 95% CI = 0.54-1.74, p = 0.924) but less frequency of worse functional outcomes (OR = 0.08, 95% CI = 0.008-0.84, p = 0.035). Conclusion About one-third of patients with mRS 3 to 4 recovered well in 3-months after stroke in both PAC-CVD and regular rehabilitation groups. Our results showed that PAC-CVD program can significantly decrease functional decline after acute stroke.

Objective Stroke research and clinical trials have focused mainly on anterior circulation stroke (ACS). Since clinical characteristics, mechanisms, and outcomes of posterior circulation stroke (PCS) have been reported different from ACS, more PCS studies are required, particularly researching the etiologies, to help establish an optimal management strategy. Methods The present study analyzed patients of PCS who were consecutively admitted and registered in Taipei Veterans General Hospital Stroke Registry between 1 January 2012 to 28 February 2014. We demonstrated the distribution of etiologies, compared the clinical characteristics/outcomes among different etiology groups, and used univariate/multivariate analyses to identify the predictors for poor functional outcome (modified Rankin Scale ≥5) at discharge and 3 month. Results About 286 patients of PCS were included for analyses. Basilar artery atheromatous branch occlusive disease (BABO, 28.0%) and large artery dissection (25.9%) were the two most common etiologies, followed by large artery atherosclerotic stenosis/occlusion (LAA, 20.6%), cardioembolism (CE, 18.5%) and small vessel disease (7.0%). Age, vascular risk factors, infarct locations and patterns, and outcomes were different among these five etiology groups. Multivariate analyses showed that age >70 y/o (discharge/3 month, OR, 95% CI: 3.05, 1.23–7.56/8.39, 2.32–30.33), admission NIH Stroke Scale >9 (19.50, 8.69–43.75/13.45, 5.59–32.39), and etiology (LAA versus BABO: 5.00, 1.58–15.83/4.00, 1.19–13.4; CE versus BABO: 3.36, 1.02–11.09/4.66, 1.40–15.46) were independently associated with poor functional outcome. Interpretation The etiologies of PCS are heterogeneous and shown to be associated with functional outcomes. Our results have shed lights on future pathophysiological research and designs of clinical trials for PCS.

Intracranial vertebrobasilar artery dissection (iVBD) is an important etiology for posterior circulation ischemic stroke (PCS); however, its long-term functional outcome has been seldom reported. The present study aimed to elucidate the functional outcomes and the predictors of poor functional recovery at 1-year after iVBD-caused PCS.Patients with iVBD-caused PCS who had been recruited in the Stroke Registry of Taipei Veterans General Hospital between January 1, 2012 to February 28, 2014 were included. Multivariate analysis was used to detect predictors for poor 1-year functional recovery [modified Rankin Scale (mRS) ≥ 4].Sixty patients [age: 66.3±15.1 years; 45(75%) men] were included. At 1-year after stroke, 61.7% of patients had good functional status (mRS 0-1); however, 21.6% of patients were disabled (mRS≥4). Multivariate analyses showed that older age, cigarette-smoking history and low basilar-artery (BA) flow velocity were significantly associated with poor functional recovery independent of stroke severity at admission. The results also revealed a synergistic effect of cigarette-smoking and low BA flow on poor 1-year functional recovery: patients with both, a history of cigarette-smoking and low BA flow (≤24cm/s) had an odds ratio of 276.1 (p=0.007) leading to poor 1-year functional recovery, versus patients with neither cigarette-smoking history nor low BA flow.Our results suggest that adequate blood flow may be key to functional recovery after iVBDcaused PCS. Methods to improve blood flow and tissue perfusion after iVBD-caused PCS should be considered in the future clinical studies with the purpose to improve functional recovery in these patients.