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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. 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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Vertebrobasilar artery dissection (VBD) have unknown mechanism. • More than 1/4 of VBD stroke have high leukocyte and neutrophil counts. • Higher leukocyte/neutrophil counts in VBD than large artery atherosclerosis stroke [ABSTRACT FROM AUTHOR]

Background: Basilar artery branch atheromatous disease (BABAD), in which basilar artery atheroma occludes penetrating arteries at their origin, is a common etiology of posterior circulation stroke (PCS). It is currently unknown whether white matter hyperintensity(WMH), a marker of small vessel disease(SVD), is associated with BABAD.Methods: The present study analyzed data from patients with PCS who were enrolled in the Taipei Veterans General Hospital Stroke Registry between January 1, 2010 and February 28, 2014. WMH severity was rated using the Scheltens scale. We used multivariate analyses to: (1) compare the severity of WMH between patients with BABAD, patients with large-artery > 50% atherosclerotic stenosis-related PCS(LAA), and non-stroke subjects(NS); and (2) evaluate the relationship between WMH severity and the 3-month prognosis of patients with BABAD.Results: The study pool included 151 BABAD, 97 LAA, and 78 non-stroke patients. Multivariate analyses adjusting for age, sex, and vascular risk factors showed that compared to patients with LAA [Odds ratio(OR) = 0.51, p = 0.037] and NS (OR = 0.40, p = 0.004), patients with BABAD (OR = 1) had greater WMH severity (score ≥ 50th percentile) in periventricular, but not subcortical, regions. Moreover, greater periventricular WMH severity predicted poor 3-month functional outcomes (modified Rankin Scale > 3) with an OR of 3.21 (p = 0.028) in BABAD patients.Conclusions: We are the first to show a significant association between WMH and BABAD that is independent of vascular risk factors and atherosclerotic large-artery disease. Our results suggest that small vessel abnormalities other than lipohyalinosis may be involved in BABAD pathophysiology. A future management strategy should include both large and small vessel protection. [ABSTRACT FROM AUTHOR]

Background: Posterior circulation ischemic stroke (PCS) caused by arterial dissection (AD-PCS) was rarely discussed. The present study aimed to evaluate the clinical characteristics and predictors of poor outcomes in AD-PCS patients. Methods: A total of 286 PCS patients were recruited from Taipei Veterans General Hospital Stroke Registry (between January 1, 2012 and February 28, 2014). Clinical/image data of recruited PCS patients were reviewed by stroke specialists who reached a consensus on the stroke etiologies. Data of AD-PCS patients were analyzed. Results: Seventy-four patients (65.8 ± 15.6 years, 56 (75.7%) men) were determined as AD-PCS. Headache and neck pain at admission were only presented in 18.9 and 6.8% of patients, respectively. The location of AD was initiated in the vertebral artery (66.2%), basilar artery (27.0%), posterior inferior cerebellar artery (5.4%) and posterior cerebral artery (1.4%). The involvement of intracranial arteries was present in the majority of patients (97.3%). Of the patients, 9.5% died, and 29.7% had poor functional outcomes (modified Rankin Scale ≥4) at 3-month. Conscious change independently predicted mortality at 3 months. Quadriparesis, National Institutes of Health Stroke Scale (NIHSS) score >8 and infarct lesions involving >1 category were independent predictors for poor functional outcomes at 3 months. Conclusion: AD is an important etiology of PCS. Physicians should be more vigilant in recognizing AD-PCS. Intracranial arteries are more important in AD-PCS; very few patients of AD-PCS had dissection solely in extracranial arteries. Short-term outcomes of AD-PCS were not favorable. Conscious change, quadriparesis, NIHSS score >8 and infarct lesions involving >1 category were independent predictors for poor outcomes. Patients presenting these factors should be monitored closely. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]