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Background: In patients with symptomatic intracranial atherosclerotic stenosis (sICAS), recent evidence has suggested an association between artery-to-artery embolism (AAE) and cortical borderzone (CBZ) infarcts., Methods: We recruited patients with 50-99% anterior-circulation sICAS in this cohort. Stroke mechanisms were categorized as isolated parent artery atherosclerosis occluding penetrating artery (PAO), isolated AAE, isolated hypoperfusion, and mixed mechanisms, using two classification systems. In Classification I, the probable stroke mechanisms of internal borderzone and CBZ infarcts were both hypoperfusion, which were respectively hypoperfusion and AAE in Classification II. Other classification criteria were the same. We investigated and compared the predictive values of the two systems in predicting 90-day and 1-year recurrent ischemic stroke in the same territory (SIT)., Results: Among 145 patients (median age 62 years), 101 (69.7%) were males. We found significant difference in the proportions of baseline stroke mechanisms between these two systems (p < 0.001). Eleven (7.6%) and 19 (13.1%) patients respectively had 90-day or 1-year recurrent SIT. Classification II better predicted the risk of 90-day recurrent SIT than Classification I, when patients were divided into 4 groups according to baseline stroke mechanisms (p = 0.029), or by the presence of hypoperfusion (p < 0.001). The two classification systems had comparable predictive values for 1-year recurrent SIT., Conclusions: In medically treated sICAS patients, considering AAE rather than hypoperfusion as the stroke mechanism for CBZ infarcts could better predict early recurrent SITs., Competing Interests: Declarations. Conflict of Interest: The authors declare no competing interests., (© 2025. The Author(s).)

There may be different mechanisms underlying internal (IBZ) and cortical (CBZ) borderzone infarcts in intracranial atherosclerotic stenosis. In 84 patients with symptomatic, 50-99% atherosclerotic stenosis of M1 middle cerebral artery (MCA-M1) with acute borderzone infarcts in diffusion-weighted imaging, we classified the infarct patterns as isolated IBZ (n = 37), isolated CBZ (n = 31), and IBZ+CBZ (n = 16) infarcts. CT angiography-based computational fluid dynamics models were constructed to quantify translesional, post-stenotic to pre-stenotic pressure ratio (PR) in the MCA-M1 lesion. Those with IBZ infarcts were more likely to have a low PR (indicating impaired antegrade flow across the lesion) than those without (p = 0.012), and those with CBZ infarcts were more likely to have coexisting small cortical infarcts (indicating possible embolism) than those without (p = 0.004). In those with isolated IBZ or CBZ infarcts, low PR was independently associated with isolated IBZ infarcts (adjusted odds ratio = 4.223; p = 0.026). These two groups may also have different trajectories in the stroke risks under current medical treatment regimen, with a higher risk of same-territory ischemic stroke recurrence within 3 months in patients with isolated IBZ infarcts than isolated CBZ infarcts (17.9% versus 0.0%; log-rank p = 0.023), but similar risks later in 1 year., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: Symptomatic intracranial atherosclerotic stenosis (sICAS) is associated with a considerable risk of recurrent stroke despite contemporarily optimal medical treatment. Severity of luminal stenosis in sICAS and its haemodynamic significance quantified with computational fluid dynamics (CFD) models were associated with the risk of stroke recurrence. We aimed to develop and compare stroke risk prediction nomograms in sICAS, based on vascular risk factors and these metrics., Methods: Patients with 50%-99% sICAS confirmed in CT angiography (CTA) were enrolled. Conventional vascular risk factors were collected. Severity of luminal stenosis in sICAS was dichotomised as moderate (50%-69%) and severe (70%-99%). Translesional pressure ratio (PR) and wall shear stress ratio (WSSR) were quantified via CTA-based CFD modelling; the haemodynamic status of sICAS was classified as normal (normal PR&WSSR), intermediate (otherwise) and abnormal (abnormal PR&WSSR). All patients received guideline-recommended medical treatment. We developed and compared performance of nomograms composed of these variables and independent predictors identified in multivariate logistic regression, in predicting the primary outcome, recurrent ischaemic stroke in the same territory (SIT) within 1 year., Results: Among 245 sICAS patients, 20 (8.2%) had SIT. The D 2 H 2 A nomogram, incorporating diabetes, dyslipidaemia, haemodynamic status of sICAS, hypertension and age ≥50 years, showed good calibration (P for Hosmer-Lemeshow test=0.560) and discrimination (C-statistic 0.73, 95% CI 0.60 to 0.85). It also had better performance in risk reclassification and provided larger net benefits in decision curve analysis, compared with nomograms composed of conventional vascular risk factors only, and plus the severity of luminal stenosis in sICAS. Sensitivity analysis in patients with anterior-circulation sICAS showed similar results., Conclusions: The D 2 H 2 A nomogram, incorporating conventional vascular risk factors and the haemodynamic significance of sICAS as assessed in CFD models, could be a useful tool to stratify sICAS patients for the risk of recurrent stroke under contemporarily optimal medical treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Newtonian fluid model has been commonly applied in simulating cerebral blood flow in intracranial atherosclerotic stenosis (ICAS) cases using computational fluid dynamics (CFD) modeling, while blood is a shear-thinning non-Newtonian fluid. We aimed to investigate the differences of cerebral hemodynamic metrics quantified in CFD models built with Newtonian and non-Newtonian fluid assumptions, in patients with ICAS., Methods: We built a virtual artery model with an eccentric 75% stenosis and performed static CFD simulation. We also constructed CFD models in three patients with ICAS of different severities in the luminal stenosis. We performed static simulations on these models with Newtonian and two non-Newtonian (Casson and Carreau-Yasuda) fluid models. We also performed transient simulations on another patient-specific model. We measured translesional pressure ratio (PR) and wall shear stress (WSS) values in all CFD models, to reflect the changes in pressure and WSS across a stenotic lesion. In all the simulations, we compared the PR and WSS values in CFD models derived with Newtonian, Casson, and Carreau-Yasuda fluid assumptions., Results: In all the static and transient simulations, the Newtonian/non-Newtonian difference on PR value was negligible. As to WSS, in static models (virtual and patient-specific), the rheological difference was not obvious in areas with high WSS, but observable in low WSS areas. In the transient model, the rheological difference of WSS areas with low WSS was enhanced, especially during diastolic period., Conclusion: Newtonian fluid model could be applicable for PR calculation, but caution needs to be taken when using the Newtonian assumption in simulating WSS especially in severe ICAS cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Lan, Abrigo, Ip, Soo, Zheng, Wong, Wang, Shi, Leung and Leng.)

Background: Intracranial arterial stenosis (ICAS) is an important cause of stroke worldwide. Separate reports in Caucasians and Asians with stroke/transient ischaemic attack (TIA) have suggested lower ICAS prevalence in Caucasians, but there has been no direct comparisons of the two ethnic groups with the same criteria to define ICAS., Methods: Acute minor stroke or TIA patients in two cohorts respectively recruiting patients in Oxford (2011-2018, predominantly Caucasians) and Hong Kong (2011-2015, predominantly Chinese) were compared. ICAS was defined as ≥50% stenosis/occlusion in any major intracranial artery in MR/CT angiography. Prevalence, distribution and risk factors of ICAS were compared between the two cohorts. We also systematically reviewed literature on ICAS prevalence in stroke/TIA patients in different populations., Results: Among 1287 patients from Oxford and 691 from Hong Kong (mean age 69 vs 66), ICAS prevalence was higher in Chinese than in Caucasians (43.0% vs 20.0%; OR 3.02; 95% CI 2.47 to 3.70; p<0.001), independent of age (age-adjusted OR 3.73; 95% CI 3.00 to 4.63; p<0.001) and vascular risk factors (multivariable-adjusted OR 3.21; 95% CI 2.56 to 4.02; p<0.001). This ethnic difference was greater (p interaction=0.005) at age <70 years (OR 5.33; 95% CI 3.79 to 7.50; p<0.001) than at ≥70 years (OR 2.81; 95% CI 2.11 to 3.74; p<0.001). ICAS prevalence increased with age and with vascular risk factors in both cohorts, with equivalent prevalence in Chinese aged <60 years and Caucasians aged ≥80, and in Chinese with no vascular risk factor and Caucasians with two vascular risk factors. ICAS locations also differed between Chinese and Caucasian patients., Conclusions: Chinese are more susceptible to ICAS than Caucasians, with an earlier onset age and a higher prevalence, independent of vascular risk factors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

This study aimed to develop a sensitive index from transcranial Doppler (TCD) signals for quantitatively evaluating the effects of long-term external counterpulsation (ECP) treatment on stroke rehabilitation. We recruited 27 patients with unilateral ischemic stroke and a good acoustic window within 7 days of stroke onset. 15 of them received 35 daily 1-hour ECP treatment (ECP group) and the others underwent conventional therapy without ECP treatment (No-ECP group). We monitored blood flow in middle cerebral arteries on both sides by TCD, and analyzed them via discrete wavelet analysis method. The overall changes of National Institutes of Health Stroke Scale (NIHSS) and Barthel Index were assessed. A 'big-wave' phenomenon was observed in TCD signals of patients in ECP group after 35 days' treatment, with significant fluctuation in frequency interval from 0.010 to 0.034 Hz as main feature. A new index, which was denoted as I , was derived from this phenomenon. The I was significantly higher for patients in ECP group than that for patients in No-ECP group after 35-days' treatment ( 0.01). And the I was positively correlated with NIHSS change in ECP group ( ). The new index could be used as an effective indicator for evaluating enhancement of endothelial metabolism and neurogenic activity after long-term ECP treatment.

Background and Purpose: This study aimed to assess the effect of baseline white matter hyperintensities (WMH) on 1-year stroke recurrence and the functional outcome for patients with intracranial atherosclerosis (ICAS). Methods: We analyzed 2,076 patients who were enrolled in the Chinese IntraCranial AtheroSclerosis (CICAS) study. ICAS and WMH were diagnosed by baseline magnetic resonance angiography. The primary outcomes were stroke recurrence and unfavorable functional outcome (modified Rankin Scale score 3-6) at 1 year. Results: Of the 2,076 patients included in this study, 1,370 (65.99%) were men, and the mean age was 61.70 years. In total, 224 (10.79%) patients had no WMH and no ICAS, 922 (44.41%) patients had WMH and no ICAS, 157 (7.56%) patients had ICAS and no WMH, and 773 (37.24%) had both WMH and ICAS. During the follow-up period, 87 patients had a recurrent stroke and 333 had unfavorable outcomes at 1 year. Compared to WMH (-) ICAS (-) group, the adjusted odd ratios and 95% confidence interval for unfavorable functional outcome were 0.791 (0.470-1.332; p = 0.3779) in the WMH (+) ICAS (-) group, 1.920 (1.024-3.600; p = 0.0421) in the WMH (-) ICAS (+) group, and 2.046 (1.230-3.403; p = 0.0058) in the WMH (+) ICAS (+) group. There was no significant difference in stroke recurrence risk among the four groups. Conclusion: ICAS coexisting with WMH may predict an unfavorable functional outcome at 1 year, but not stroke recurrence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Liu, Pu,Wang, Zou, Pan, Zhang, Soo, Leung, Zhao, Wong, Wang and Liu.)

Background: Intracranial atherosclerotic disease (ICAD) is globally a major ischaemic stroke subtype with high recurrence. Understanding the morphology of symptomatic ICAD plaques, largely unknown by far, may help identify vulnerable lesions prone to relapse., Methods: We prospectively recruited patients with acute ischaemic stroke or transient ischaemic attack attributed to high-grade ICAD (60%-99% stenosis). Plaque morphological parameters were assessed in three-dimensional rotational angiography, including surface contour, luminal stenosis, plaque length/thickness, upstream shoulder angulation, axial/longitudinal plaque distribution and presence of adjoining branch atheromatous disease (BAD). We compared morphological features of smooth, irregular and ulcerative plaques and correlated them with cerebral ischaemic lesion load downstream in MRI., Results: Among 180 recruited patients (median age=60 years; 63.3% male; median stenosis=75%), plaque contour was smooth (51 (28.3%)), irregular (101 (56.1%)) or ulcerative (28 (15.6%)). Surface ulcers were mostly at proximal (46.4%) and middle one-third (35.7%) of the lesions. Most (84.4%) plaques were eccentric, and half had their maximum thickness over the distal end. Ulcerative lesions were thicker (medians 1.6 vs 1.3 mm; p=0.003), had steeper upstream shoulder angulation (56.2° vs 31.0 ° ; p<0.001) and more adjoining BAD (83.3% vs 57.0%; p=0.033) than non-ulcerative plaques. Ulcerative plaques were significantly associated with coexisting acute and chronic infarcts downstream (35.7% vs 12.5%; adjusted OR 4.29, 95% CI 1.65 to 11.14, p=0.003). Sensitivity analyses in patients with anterior-circulation ICAD lesions showed similar results in the associations between the plaque types and infarct load., Conclusions: Ulcerative intracranial atherosclerotic plaques were associated with vulnerable morphological features and had a higher cumulative infarct load downstream., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Burning and stabbing pain in the feet and lower limbs can have a significant impact on the activities of daily living, including walking, climbing stairs and sleeping. Peripheral neuropathy in particular is often misdiagnosed or underdiagnosed because of a lack of awareness amongst both patients and physicians. Furthermore, crude screening tools, such as the 10-g monofilament, only detect advanced neuropathy and a normal test will lead to false reassurance of those with small fiber mediated painful neuropathy. The underestimation of peripheral neuropathy is highly prevalent in the South-East Asia region due to a lack of consensus guidance on routine screening and diagnostic pathways. Although neuropathy as a result of diabetes is the most common cause in the region, other causes due to infections (human immunodeficiency virus, hepatitis B or C virus), chronic inflammatory demyelinating polyneuropathy, drug-induced neuropathy (cancer chemotherapy, antiretrovirals and antituberculous drugs) and vitamin deficiencies (vitamin B 1 , B 6 , B 12 , D) should be actively excluded., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: Contrast enhancement is a vital feature of the intracranial atherosclerotic plaque on high-resolution magnetic resonance imaging (HRMRI), but its clinical significance is still unclear. We aimed to quantitatively assess plaque enhancement patterns in the middle cerebral artery (MCA) atherosclerotic plaque. Methods: We conducted a cross-sectional study by prospectively recruiting stroke or transient ischemic attack patients with >30% of MCA stenosis of either side. All patients underwent contrast-enhanced HRMRI scans. Enrolled patients were classified into acute phase (<4 weeks), subacute phase (4-12 weeks) and chronic phase (>12 weeks) groups based on the time interval from stroke onset to imaging scan. Plaque enhancement index was calculated for each MCA lesion at the maximal narrowing site. Results: We identified a total of 89 MCA plaques [53 (60%) symptomatic and 36 (40%) asymptomatic; 57 (64%) acute, 18 (20%) subacute and 14 (16%) chronic] in 58 patients on HRMRI. Among the acute lesions, symptomatic plaques had a significantly stronger plaque enhancement than asymptomatic plaques (symptomatic vs. asymptomatic: 38.9 ± 18.2 vs. 18.2 ± 16.2, p < 0.001). Among the symptomatic lesions, plaque enhancement diminished with increasing time after stroke onset (38.9 ± 18.2, 22.0 ± 22.8, and 5.0 ± 10.1 for acute, subacute, and chronic phase, respectively; p = 0.001). Conclusion: Plaque enhancement in the acute atherosclerotic plaque is closely related to recent ischemic events. In symptomatic atherosclerosis, plaque enhancement regresses over time after ischemic stroke, which may offer the potential to monitor the plaque activity in intracranial atherosclerosis using HRMRI., (Copyright © 2020 Yang, Abrigo, Soo, Wong, Wong, Leung, Chu and Chen.)

Background: Previous studies conflicted in the association between intracranial atherosclerotic stenosis (ICAS) and the severity of white matter changes (WMC). Aims: We aimed to investigate the relationships between the severity of luminal stenosis and the hemodynamic significance of middle cerebral artery (MCA) stenosis, and the severity of ipsilateral WMC. Methods: In this cross-sectional study, patients with a recent ischemic stroke or transient ischemic attack and a 50-99% MCA-M1 stenosis in the Chinese Intracranial Atherosclerosis study cohort were analyzed. The post- to pre-stenotic signal intensity ratio (SIR) was obtained in time-of-flight MR angiography (MRA) to represent the hemodynamic significance of MCA-M1 stenosis, with a lower SIR indicating a hemodynamically more severe lesion. The severity of ipsilesional WMC was assessed by an age-related WMC (ARWMC) scale in T2-weighted fluid attenuated inversion recovery MR imaging. The relationships between the degree of MCA-M1 stenosis, SIR, and ipsilesional ARWMC scale were analyzed. The MCA-M1 lesion with a higher percentage of stenosis was chosen for analyses in patients with bilateral MCA-M1 stenoses. Results: Among 180 subjects (mean age, 64 years), a lower SIR of MCA-M1 stenosis (Spearman correlation coefficient, -0.543; p < 0.001), but not the degree of stenosis ( p = 0.93), was significantly linearly correlated with a higher ipsilateral ARWMC. Multivariate ordinal logistic regression identified older age (OR = 1.037; 95% CI, 1.008-1.066; p = 0.011) and lower SIR (OR = 0.010; 95% CI, 0.002-0.058; p < 0.001) as independent predictors for more severe ipsilateral WMC. Conclusion: Patients with hemodynamically more severe ICAS are more likely to have more severe ipsilateral WMC. Longitudinal studies with sequential imaging exams may further reveal the impact of hemodynamic significance of ICAS on the development and progression of WMC., (Copyright © 2020 Fang, Leng, Pu, Zou, Pan, Song, Soo, Leung, Wang, Zhao, Wang, Wang,Wong, Liu and Xu.)

Background and Purpose- Poststroke autonomic dysfunction portended an unfavorable prognosis. We investigated whether blood pressure variability (BPV), heart rate variability, and baroreflex sensitivity might predict stroke functional outcome. Methods- We calculated BPV, heart rate variability, baroreflex slope, and baroreflex effectiveness index from a 5-minute beat-to-beat blood pressure and heart rate monitoring within 7 days from the stroke onset. We compared the parameters between patients with a good outcome (modified Rankin Scale score, 0-2) and those with a poor outcome. Results- Among 142 patients (mean age, 63.9±10.2 years; 88.0% men), functional outcome was good in 112 (78.9%) and poor in 30 (21.1%). There were significant differences in admission National Institutes of Health Stroke Scale, prior stroke, high-frequency systolic BPV, low/high-frequency ratio of BPV, baroreflex sensitivity-up, and baroreflex sensitivity-total between the 2 groups (all P <0.05). In multivariate analysis, National Institutes of Health Stroke Scale (OR, 1.672 [95% CI, 1.316-2.125]; P <0.001), low/high-frequency ratio of systolic BPV (OR, 0.493 [95% CI, 0.250-0.973]; P =0.041), and baroreflex effectiveness index-down (OR, 0.958 [95% CI, 0.924-0.992]; P =0.017) independently predicted a poor functional outcome. Conclusions- A decreased low/high-frequency ratio of systolic BPV and impaired baroreflex sensitivity predicted an unfavorable stroke outcome, in addition to the established prognostic factor such as the National Institutes of Health Stroke Scale.

We aimed to investigate the roles of antegrade residual flow and leptomeningeal collateral flow in sustaining cerebral perfusion distal to an intracranial atherosclerotic stenosis (ICAS). Patients with apparently normal cerebral perfusion distal to a symptomatic middle cerebral artery (MCA)-M1 stenosis were enrolled. Computational fluid dynamics models were built based on CT angiography to obtain a translesional pressure ratio (PR) to gauge the residual antegrade flow. Leptomeningeal collaterals (LMCs) were scaled on CT angiography. Cerebral perfusion metrics were obtained in CT perfusion maps. Among 83 patients, linear regression analyses revealed that both translesional PR and LMC scale were independently associated with relative ipsilesional mean transit time (rMTT). Subgroup analyses showed that ipsilesional rMTT was significantly associated with translesional PR ( p  < 0.001) rather than LMC scale in those with a moderate (50-69%) MCA stenosis, which, however, was only significantly associated with LMC scale ( p  = 0.051) in those with a severe (70-99%) stenosis. Antegrade residual flow and leptomeningeal collateral flow have complementary effects in sustaining cerebral perfusion distal to an ICAS, while cerebral perfusion may rely more on the collateral circulation in those with a severe stenosis.

Aim: Though combination of clopidogrel added to aspirin has been compared to aspirin alone in patients with stroke or transient ischemic attack, limited data exists on the relative efficacy and safety between clopidogrel and aspirin monotherapy in patients with a recent ischemic stroke. We aimed to compare clopidogrel versus aspirin monotherapy in this population., Methods: PubMed, Embase, and CENTRAL databases were searched from inception to May 2018 to identify clinical trials and observational studies comparing clopidogrel versus aspirin for secondary prevention in patients with recent ischemic stroke within 12 months. Pooled effect estimates were calculated using a random effects model and were reported as risk ratios with 95% confidence intervals., Results: Five studies meeting eligibility criteria were included in the analysis. A total of 29,357 adult patients who had recent ischemic stroke received either clopidogrel ( n = 14, 293) or aspirin ( n = 15, 064) for secondary prevention. Pairwise meta-analysis showed a statistically significant risk reduction in the occurrence of major adverse cardiovascular and cerebrovascular events (risk ratio 0.72 [95% CI, 0.53-0.97]), any ischemic or hemorrhagic stroke (0.76 [0.58, 0.99), and recurrent ischemic stroke (0.72 [0.55, 0.94]) in patients who received clopidogrel versus aspirin. The risk of bleeding was also lower for clopidogrel versus aspirin (0.57 [0.45, 0.74]). There was no difference in the rate of all-cause mortality between the two groups., Conclusions: The analysis showed lower risks of major adverse cardiovascular or cerebrovascular events, recurrent stroke, and bleeding events for clopidogrel monotherapy compared to aspirin. These findings support clinical benefit for single antiplatelet therapy with clopidogrel over aspirin for secondary prevention in patients with recent ischemic stroke., Competing Interests: Maurizio Paciaroni received honoraria as a member of the speaker bureau of Aspen, Sanofi-Aventis, Boehringer Ingelheim, Bayer, Bristol Meyer Squibb, Daiiki Sankyo and Pfizer. Birsen Ince has received honoraria from Pfizer and Sanofi-Aventis within the past 36 months, outside the submitted work. Kursad Kutluk has received honoraria from Boehringer Ingelheim, Pfizer and Sanofi-Aventis within the past 36 months, outside the submitted work. Dara Paek, Jung Min Han, and Michael del Aguila report employment by Doctor Evidence at the time in which this research was conducted, who was contracted by Sanofi to perform the analysis. Shalini Girotra reports employment by Sanofi. All other authors have nothing to disclose., (Copyright © 2019 Maurizio Paciaroni et al.)

Objective: To investigate whether hemodynamic features of symptomatic intracranial atherosclerotic stenosis (sICAS) might correlate with the risk of stroke relapse, using a computational fluid dynamics (CFD) model., Methods: In a cohort study, we recruited patients with acute ischemic stroke attributed to 50 to 99% ICAS confirmed by computed tomographic angiography (CTA). With CTA-based CFD models, translesional pressure ratio (PR = pressure poststenotic /pressure prestenotic ) and translesional wall shear stress ratio (WSSR = WSS stenotic - throat /WSS prestenotic ) were obtained in each sICAS lesion. Translesional PR ≤ median was defined as low PR and WSSR ≥4th quartile as high WSSR. All patients received standard medical treatment. The primary outcome was recurrent ischemic stroke in the same territory (SIT) within 1 year., Results: Overall, 245 patients (median age = 61 years, 63.7% males) were analyzed. Median translesional PR was 0.94 (interquartile range [IQR] = 0.87-0.97); median translesional WSSR was 13.3 (IQR = 7.0-26.7). SIT occurred in 20 (8.2%) patients, mostly with multiple infarcts in the border zone and/or cortical regions. In multivariate Cox regression, low PR (adjusted hazard ratio [HR] = 3.16, p = 0.026) and high WSSR (adjusted HR = 3.05, p = 0.014) were independently associated with SIT. Patients with both low PR and high WSSR had significantly higher risk of SIT than those with normal PR and WSSR (risk = 17.5% vs 3.0%, adjusted HR = 7.52, p = 0.004)., Interpretation: This work represents a step forward in utilizing computational flow simulation techniques in studying intracranial atherosclerotic disease. It reveals a hemodynamic pattern of sICAS that is more prone to stroke relapse, and supports hypoperfusion and artery-to-artery embolism as common mechanisms of ischemic stroke in such patients. Ann Neurol 2019;85:752-764., (© 2019 American Neurological Association.)

With over 2 million new cases annually, stroke is associated with the highest disability-adjusted life-years lost of any disease in China. The burden is expected to increase further as a result of population ageing, an ongoing high prevalence of risk factors (eg, hypertension), and inadequate management. Despite improved access to overall health services, the availability of specialist stroke care is variable across the country, and especially uneven in rural areas. In-hospital outcomes have improved because of a greater availability of reperfusion therapies and supportive care, but adherence to secondary prevention strategies and long-term care are inadequate. Thrombolysis and stroke units are accepted as standards of care across the world, including in China, but bleeding-risk concerns and organisational challenges hamper widespread adoption of this care in China. Despite little supporting evidence, Chinese herbal products and neuroprotective drugs are widely used, and the increased availability of neuroimaging techniques also results in overdiagnosis and overtreatment of so-called silent stroke. Future efforts should focus on providing more balanced availability of specialised stroke services across the country, enhancing evidence-based practice, and encouraging greater translational research to improve outcome of patients with stroke., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Purpose: Cerebral microbleeds (CMBs), which predict future intracerebral haemorrhage (ICH), may guide anticoagulant decisions for atrial fibrillation (AF). We aimed to evaluate the risk of warfarin-associated ICH in Chinese patients with AF with CMBs., Methods: In this prospective, observational, multicentre study, we recruited Chinese patients with AF who were on or intended to start anticoagulation with warfarin from six hospitals in Hong Kong. CMBs were evaluated with 3T MRI brain at baseline. Primary outcome was clinical ICH at 2-year follow-up. Secondary outcomes were ischaemic stroke, systemic embolism, mortality of all causes and modified Rankin Scale ≥3. Outcome events were compared between patients with and without CMBs., Results: A total of 290 patients were recruited; 53 patients were excluded by predefined criteria. Among the 237 patients included in the final analysis, CMBs were observed in 84 (35.4%) patients, and 11 had ≥5 CMBs. The mean follow-up period was 22.4±10.3 months. Compared with patients without CMBs, patients with CMBs had numerically higher rate of ICH (3.6% vs 0.7%, p=0.129). The rate of ICH was lower than ischaemic stroke for patients with 0 to 4 CMBs, but higher for those with ≥5 CMBs. CMB count (C-index 0.82) was more sensitive than HAS-BLED (C-index 0.55) and CHA2DS2-VASc (C-index 0.63) scores in predicting ICH., Conclusions: In Chinese patients with AF on warfarin, presence of multiple CMBs may be associated with higher rate of ICH than ischaemic stroke. Larger studies through international collaboration are needed to determine the risk:benefit ratio of oral anticoagulants in patients with AF of different ethnic origins., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: The risk of recurrent stroke following a transient ischemic attack (TIA) or minor stroke is high, despite of a significant reduction in the past decade. In this study, we investigated the feasibility of using artificial neural network (ANN) for risk stratification of TIA or minor stroke patients. Methods: Consecutive patients with acute TIA or minor ischemic stroke presenting at a tertiary hospital during a 2-year period were recruited. We collected demographics, clinical and imaging data at baseline. The primary outcome was recurrent ischemic stroke within 1 year. We developed ANN models to predict the primary outcome. We randomly down-sampled patients without a primary outcome to 1:1 match with those with a primary outcome to mitigate data imbalance. We used a 5-fold cross-validation approach to train and test the ANN models to avoid overfitting. We employed 19 independent variables at baseline as the input neurons in the ANN models, using a learning algorithm based on backpropagation to minimize the loss function. We obtained the sensitivity, specificity, accuracy and the c statistic of each ANN model from the 5 rounds of cross-validation and compared that of support vector machine (SVM) and Naïve Bayes classifier in risk stratification of the patients. Results: A total of 451 acute TIA or minor stroke patients were enrolled. Forty (8.9%) patients had a recurrent ischemic stroke within 1 year. Another 40 patients were randomly selected from those with no recurrent stroke, so that data from 80 patients in total were used for 5 rounds of training and testing of ANN models. The median sensitivity, specificity, accuracy and c statistic of the ANN models to predict recurrent stroke at 1 year was 75%, 75%, 75%, and 0.77, respectively. ANN model outperformed SVM and Naïve Bayes classifier in our dataset for predicting relapse after TIA or minor stroke. Conclusion: This pilot study indicated that ANN may yield a novel and effective method in risk stratification of TIA and minor stroke. Further studies are warranted for verification and improvement of the current ANN model.

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare that the study was supported by grants from the Ministry of Science and Technology of the People’s Republic of China (2016YFC0901001, 2016YFC0901002, 2017YFC1310901, 2018YFC1311700 and 2018YFC1311706), and grants from Beijing Municipal Commission of Health and Family Planning (No 2016-1-2041, SML20150502).

Leukoaraiosis (LA) is frequently found in ischemic stroke patients, especially when those patients have intracranial atherosclerosis (ICAS). However, previous studies regarding an association of LA with cerebral large artery atherosclerosis showed conflicting results, and the relationship of LA with ICAS is uncertain. This study aimed to explore the association between LA and cerebral large artery atherosclerosis in Chinese patients with cerebral ischemia. Data were derived from the Chinese Intracranial Atherosclerosis (CICAS) study. Patients diagnosed with an ischemic stroke or transient ischemic attack (TIA) within 7 days of symptom onset were included. The analysis of magnetic resonance imaging (MRI) focused on severity of LA in periventricular and deep white matter; type of cerebral large artery stenosis; and the number, severity, and distribution of ICAS lesions. ICAS was defined as an occlusion or more than 50% stenosis of intracranial vessels on magnetic resonance angiography. Among 2420 patients included, distinct LA was observed in 898 (37.11%) patients, and the rate of LA increased significantly with an increased number of risk factors. Multivariate analysis revealed that LA was independently associated with ICAS (odds ratio [OR], 1.388; 95% confidence interval [CI], 1.132-1.702; P =0.0016). In the subgroup analysis of ICAS, LA was more frequently observed in multiple lesions (OR, 1.342; 95% CI, 1.060-1.699; P =0.0146), occlusive lesions (OR, 1.554; 95% CI, 1.214-1.998; P =0.0005), and lesions in the posterior circulation (OR, 1.360; 95% CI, 1.003-1.846; P =0.0481). In this nationwide prospective study, LA was associated with symptomatic ICAS, patients with multiple ICAS lesions, occlusive lesions, and atherosclerotic lesions in the posterior circulation were more likely to coexist with LA.

Background and Purpose: Vasa vasorum (VV) have been believed to be rare or non-existent in small-caliber intracranial arteries. In a series of human cerebral artery specimens, we identified and examined the distribution of VV in association with co-existing intracranial atherosclerosis., Methods: We obtained cerebral artery specimens from 32 consecutive autopsies of subjects aged 45 years or above. We scrutinized middle cerebral artery (MCA), vertebral artery (VA), and basilar artery (BA) for the presence of adventitial VV. We described the distribution of VV, and the characteristics of co-existing atherosclerotic lesions., Results: Among 157 intracranial arteries, adventitial VV were present in 74 of the 157 specimens (47%), involving MCA (n=13, 18%), BA (n=14, 19%), and VA (n=47, 64%). Although qualitatively these 74 adventitial VV distributed similarly in arteries with or without atherosclerotic lesions (disease-free arteries n=4/8; arteries of pre-atherosclerosis n=17/42; and arteries of progressive atherosclerosis n=53/107), the presence of adventitial VV in intracranial VA was associated with a heavier plaque load (1.72±1.66 mm2 vs. 0.40±0.32 mm2, P<0.001), severer luminal stenosis (25%±21% vs. 12%±9%, P=0.002), higher rate of concentric lesions (79% vs. 36%, P=0.002), and denser intraplaque calcification (44% vs. 0%, P=0.003). Histologically, intracranial VA with VV had a larger diameter (3.40±0.79 mm vs. 2.34±0.58 mm, P<0.001), thicker arterial wall (0.31±0.13 mm vs. 0.23±0.06 mm, P=0.002), and a larger intima-media (0.19±0.09 mm vs. 0.13± 0.04 mm, P=0.003) than VA without VV., Conclusion: s Our study demonstrated the distribution of adventitial VV within brain vasculature and association between vertebral VV and progressive atherosclerotic lesions with a heavier plaque load and denser intraplaque calcification.

Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique that serves as treatment tool to neurological disorders. However, the mechanism of how the stimulation modulates ongoing brain activity and connectivity is still not fully understood. Simultaneous acquisition of neuroimaging data together with brain stimulation could allow a noninvasive examination of the brain dynamic changes during the process. In this pilot study, concurrent tDCS and fMRI was conducted in a healthy subject. Dynamic functional connectivity and effective connectivity were used to reveal the information flow. The results demonstrated that tDCS duration has important effects on the brain connectivity and the causal relationships among the brain regions. These results might reflect the fundamental mechanism of brain processing under the external stimulation.

Collateral circulation plays a vital role in sustaining blood flow to the ischaemic areas in acute, subacute or chronic phases after an ischaemic stroke or transient ischaemic attack. Good collateral circulation has shown protective effects towards a favourable functional outcome and a lower risk of recurrence in stroke attributed to different aetiologies or undergoing medical or endovascular treatment. Over the past decade, the importance of collateral circulation has attracted more attention and is becoming a hot spot for research. However, the diversity in imaging methods and criteria to evaluate collateral circulation has hindered comparisons of findings from different cohorts and further studies in exploring the clinical relevance of collateral circulation and possible methods to enhance collateral flow. The statement is aimed to update currently available evidence and provide evidence-based recommendations regarding grading methods for collateral circulation, its significance in patients with stroke and methods under investigation to improve collateral flow., Competing Interests: Competing interests: None declared.

Purpose: Intracranial artery calcification (IAC) has been demonstrated to be correlated with ischemic stroke, cognitive decline, and other vascular events by accumulating evidences from both Western and Asian populations. The proposed study aimed to investigate its potential mechanisms by evaluating the blood flow velocity and pulsatility index (PI) of cerebral arteries., Methods: Consecutive ischemic stroke patients admitted to the Prince of Wales Hospital were recruited after excluding those with atrial fibrillation or poor temporal window. Quantitative measurements of IAC severity were assessed on brain CT scans. Transcranial Doppler (TCD) ultrasonography was performed to evaluate the blood flow velocity of the middle cerebral artery (MCA) and vertebral-basilar artery (VBA)., Results: In total, 318 patients were analyzed. Spearman's correlation analysis demonstrated both high MCA systolic flow velocity and high MCA PI were correlated with IAC Agatston score, p < 0.001 individually. Similar correlation was also found between IAC Agatston score and high VBA velocity/high VBA PI, p ≤ 0.001 individually. Multiple logistic regression analysis showed IAC Agatston score was an independent risk factor for high MCA velocity (OR 1.533; 95% CI 1.235-1.903), high VBA velocity (OR 1.964; 95% CI 1.381-2.794), and high VBA PI (OR 1.200; 95% CI 1.016-1.418), respectively., Conclusion: Heavier IAC might cause generalized artery flow velocity changes and increased pulsatility index, which may indicate high resistance within cerebrovasculature.

Objectives: Stenosis of the intracranial large arteries, especially the middle cerebral artery (MCA), is common in the Chinese population. We conducted a case-control study to investigate clinical and apolipoprotein E (ApoE) gene polymorphism of MCA atherosclerosis in the Chinese population., Materials and Methods: Polymerase chain reaction-based protocols were used to identify the genotypes of polymorphisms in ApoE genes. Clinical parameters and the genotypes of polymorphisms in the ApoE genes were compared in patients with and without MCA stenosis. The ApoE exon ε4 genotypes with risk factors were compared in the patients with and without MCA stenosis., Results: In total, 337 ischemic stroke patients were recruited, 156 cases with and 181 without MCA stenosis. Univariate analysis showed that the levels of systolic blood pressure and pulse pressure were higher in the MCA-stenosis group. There were no significant differences in the genotype and allele frequencies of the ApoE polymorphism observed between patients with and without MCA stenosis. However, there was a trend that the MCA-stenosis group tended to have more of genotype ε4/ε4 (3.8% vs. 0.6%, P=0.052) than the non-MCA-stenosis group. There was no effect of ApoE genotype and genotype-by-environment interactions on ischemic stroke susceptibility., Conclusions: This present study indicated that the hypertension (ie, systolic blood pressure and pulse pressure) and the ApoEε4/ε4 genotype may be associated with the occurrence of MCA stenosis in the ischemic stroke Chinese patients.

Background and Purpose: MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke., Methods: Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24., Results: Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0-1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation., Conclusions: More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: Computational fluid dynamics (CFD) allows noninvasive fractional flow (FF) computation in intracranial arterial stenosis. Removal of small artery branches is necessary in CFD simulation. The consequent effects on FF value needs to be judged., Methods: An idealized vascular model was built with 70% focal luminal stenosis. A branch with one third or one half of the radius of the parent vessel was added at a distance of 5, 10, 15 and 20 mm to the lesion. With pressure and flow rate applied as inlet and outlet boundary conditions, CFD simulations were performed. Flow distribution at bifurcations followed Murray's law. By including or removing side branches, five patient-specific intracranial artery models were simulated. Transient simulation was performed on a patient-specific model, with a larger branch for validation. Branching effect was considered trivial if the FF difference between paired models (branches included or removed) was within 5%., Results: Compared with the control model without a branch, in all idealized models the relative differences of FF was within 2%. In five pairs of cerebral arteries (branches included/removed), FFs were 0.876 and 0.877, 0.853 and 0.858, 0.874 and 0.869, 0.865 and 0.858, 0.952 and 0.948. The relative difference in each pair was less than 1%. In transient model, the relative difference of FF was 3.5%., Conclusion: The impact of removing side branches with radius less than 50% of the parent vessel on FF measurement accuracy is negligible in static CFD simulations, and minor in transient CFD simulation., (Copyright © 2018. Published by Elsevier Inc.)

Background and Purpose: Central autonomic dysfunction increases stroke morbidity and mortality. We aimed to investigate whether poststroke autonomic dysfunction graded by Ewing battery can predict clinical outcome., Methods: In this prospective observational study, we assessed autonomic function of ischemic stroke patients within 7 days from symptom onset by Ewing battery. On the basis of the magnitude of autonomic dysfunction, we stratified patients into significant (definite, severe, or atypical) or minor (normal or early) autonomic function impairment groups and correlated the impairment with the 3-month modified Rankin Scale score (good outcome: modified Rankin Scale score 0≈2; poor outcome: modified Rankin Scale score 3≈6)., Results: Among the 150 patients enrolled (mean age, 66.4±9.9 years; 70.7% males), minor autonomic dysfunction was identified in 36 patients (24.0%), and significant autonomic dysfunction was identified in 114 patients (76.0%) based on Ewing battery. In 3 months, a poor functional outcome was found in 32.5% of significant group patients compared with 13.9% in the minor group ( P =0.031). Crude odds ratios of the magnitude of autonomic dysfunction and 3-month unfavorable functional outcome after acute ischemic stroke were 2.979 (95% confidence interval, 1.071-8.284; P =0.036). After adjusting for confounding variables with statistical significance between the 2 functional outcome subgroups identified in univariate analysis (including sex and National Institutes of Health Stroke Scale score on admission), the magnitude of autonomic dysfunction still independently predicted an unfavorable outcome, with an odds ratio of 3.263 (95% confidence interval, 1.141-9.335; P =0.027)., Conclusions: Autonomic dysfunction gauged by Ewing battery predicts poor functional outcome after acute ischemic stroke., (© 2017 American Heart Association, Inc.)

Background: Anterior and posterior circulation atherosclerosis differ in vascular risk factors and stroke mechanisms. However, few studies have compared the pathological features between these lesions. Using a series of intracranial artery specimens, we characterized the intracranial atherosclerotic lesions and compared pathological features among different arteries of the intracranial vasculature., Methods: Intracranial large arteries of 32 consecutively recruited autopsy cases of Chinese adults aged 45 years or older were examined pathologically using routine histology and immunostaining, to characterize the pathological features of the atherosclerotic lesions. We analyzed middle cerebral arteries (MCAs) (both left and right), vertebral arteries (VAs) (side more affected), and basilar arteries (BAs)., Results: Progressive atherosclerotic lesions were present in 91(71%) of the 128 arteries examined. Features of complicated plaques were infrequently detected: plaque hemorrhage was encountered in 12%, neovasculature in 12%, lumen thrombi in 13%, macrophage infiltration in 20%, and calcification in 25% of arteries. Luminal narrowing of MCA was the most severe, followed by VA; the BA least stenotic (37 ± 25 vs. 30 ± 24 vs. 20 ± 20%, all p  < 0.05). MCA had more eccentric (vs. concentric) plaques than VA (69 vs. 25%, p  = 0.003) and BA (69 vs. 38%; p  = 0.03). Lumen thrombi were more frequent in BA, and calcification most commonly occurred in VA atherosclerotic lesions., Conclusion: Intracranial atherosclerotic plaques were commonly present in this sample, but the lesions generally lacked features of complicated plaques. MCA lesions had demonstrable differences compared with VA and BA lesions. Further studies are needed to determine whether these characteristics indicate a distinctive atherosclerotic phenotype for the intracranial vasculature.

Intracranial atherosclerosis is one of the leading causes of ischemic stroke and occurs more commonly in patients of Asian, African or Hispanic origin than in Caucasians. Although the histopathology of intracranial atherosclerotic disease resembles extracranial atherosclerosis, there are some notable differences in the onset and severity of atherosclerosis. Current understanding of intracranial atherosclerotic disease has been advanced by the high-resolution magnetic resonance imaging (HRMRI), a novel emerging imaging technique that can directly visualize the vessel wall pathology. However, the pathological validation of HRMRI signal characteristics remains a key step to depict the plaque components and vulnerability in intracranial atherosclerotic lesions. The purpose of this review is to describe the histological features of intracranial atherosclerosis and to state current evidences regarding the validation of MR vessel wall imaging with histopathology.

Aim: To examine the safety and efficacy of mesenchymal stem cell (MSC) therapy for intracerebral haemorrhage with neurological dysfunctions for a year., Methods: MSC were ex vivo expanded from 29 mL (17-42 mL) autologous bone marrow. Patients were randomized to have two intravenous injections of autologous MSC or placebos in four weeks apart. Neurological functions and clinical outcomes were monitored before treatment and at 12 th , 16 th , 24 th , 36 th and 60 th week upon completion of the treatment., Results: A mean of 4.57 × 10 7 (range: 1.43 × 10 7 -8.40 × 10 7 ) MSC per infusion was administered accounting to 8.54 × 10 5 (2.65 × 10 5 -1.45 × 10 6 ) per kilogram body weight in two occasions. There was neither adverse event at time of administration nor sign of de novo tumour development among patients after monitoring for a year post MSC therapy. Neuro-restoration and clinical improvement in terms of modified Barthel index, functional independence measure and extended Glasgow Outcome Scale were evident among patients having MSC therapy compared to patients receiving placebos., Conclusion: Intravenous administration of autologous bone marrow-derived MSC is safe and has the potential of improving neurological functions in chronic stroke patients with severe disability., Competing Interests: Conflict-of-interest statement: All authors declared that no conflict of interest exists.

Background and Purpose: Posterior circulation ischemic stroke (IS) is generally considered an illness with a poor prognosis. However, there are no effective rating scales to predict recurrent stroke following it. Therefore, our aim was to identify clinical or radiological measures that could assist in predicting recurrent cerebral ischemic episodes., Methods: We prospectively enrolled 723 noncardiogenic posterior circulation IS patients with onset of symptoms <7 days. Stroke risk factors, admission symptoms and signs, topographical distribution and responsible cerebral artery of acute infarcts, and any recurrent IS or transient ischemic attack (TIA) within 1 year were assessed. Cox regression was used to identify risk factors associated with recurrent IS or TIA within the year after posterior circulation IS., Results: A total of 40 patients (5.5%) had recurrent IS or TIA within 1 year of posterior circulation IS. Multivariate Cox regression identified chief complaint with dysphagia (hazard ratio [HR], 4.16; 95% confidence interval [CI], 1.69-10.2; P =0.002), repeated TIAs within 3 months before the stroke (HR, 15.4; 95% CI, 5.55-42.5; P <0.0001), responsible artery stenosis ≥70% (HR, 7.91; 95% CI, 1.00-62.6; P =0.05), multisector infarcts (HR, 5.38; 95% CI, 1.25-23.3; P =0.02), and not on antithrombotics treatment at discharge (HR, 3.06; 95% CI, 1.09-8.58; P =0.03) as independent predictors of recurrent IS or TIA., Conclusions: Some posterior circulation IS patients are at higher risk for recurrent IS or TIA. Urgent assessment and preventive treatment should be offered to these patients as soon as possible., (© 2017 American Heart Association, Inc.)

Cerebral autoregulation (CA) is a protective mechanism that maintains cerebral blood flow at a relatively constant level despite fluctuations of cerebral perfusion pressure or arterial blood pressure. It is a universal physiological mechanism that may involve myogenic, neural control as well as metabolic regulations of cerebral vasculature in response to changes in pressure or cerebral blood flow. Traditionally, CA has been represented by a sigmoid curve with a wide plateau between about 50 mm Hg and 170 mm Hg of steady-state changes in mean arterial pressure, defined as static CA. With the advent of transcranial Doppler, measurement of cerebral blood flow in response to transient changes in arterial pressure has been used to assess dynamic CA. However, a gold standard for measuring CA is not currently available. Stroke has been the leading cause of long-term adult disability throughout the world. A better understanding of CA and its response to pathological derangements can help assess the severity of stroke, guide management decisions, assess response to interventions and provide prognostic information. The objective of this review is to provide a comprehensive insight about physiology of autoregulation, measurement methodologies and clinical applications in stroke to help build a consensus for what should be included in an internationally agreed protocol for CA testing and monitoring, and to promote its translation into clinical bedside practice for stroke management., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Whether dynamic cerebral autoregulation (dCA) is impaired focally in the affected hemisphere or bilaterally in both the affected and nonaffected hemispheres after ischemic stroke remains controversial. We therefore investigated the pattern of dCA in acute ischemic stroke patients with different subtypes., Methods: Sixty acute ischemic stroke patients with unilateral anterior circulation infarct [30 with large artery atherosclerosis (LAA), 13 with small vessel disease (SVD), and 17 with coexisting LAA and SVD] and 16 healthy controls were enrolled. Spontaneous arterial blood pressure and cerebral blood flow velocity fluctuations in both bilateral middle cerebral arteries using transcranial Doppler were recorded over 10 minutes. Transfer function analysis was applied to obtain autoregulatory parameters, autoregulation index (ARI), phase difference (PD), and gain., Results: PD was significantly lower on both the ipsilateral and contralateral sides in the LAA group (ipsilateral, 30.74 degrees; contralateral, 29.17 degrees) and the coexisting LAA and SVD group (20.23 degrees; 13.10 degrees) than that in healthy controls (left side, 51.66 degrees; right side, 58.48 degrees) (all P < .05), but there were no significant differences between the 2 sides when compared with each other in all groups. However, in the coexisting LAA and SVD group, phase on both sides was significantly lower when compared with that in the LAA and SVD groups, respectively. The results of ARI were consistent with the findings in PD., Conclusions: The results indicate that dCA is bilaterally impaired in acute ischemic patients with LAA, and the coexisting SVD may aggravate the bilateral impairment of dCA., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the relation between neuroticism and fatigue in Chinese patients with stroke., Design: Cross-sectional study., Setting: Acute stroke unit., Participants: Survivors of ischemic stroke (N=191) recruited from the acute stroke unit between May 1, 2010, and September 1, 2011., Interventions: Not applicable., Main Outcome Measures: The personality trait of neuroticism was measured with the neuroticism subscale of the Chinese version of the NEO Five-Factor Inventory. The level of fatigue was measured with the Fatigue Assessment Scale. The National Institutes of Health Stroke Scale, Geriatric Depression Scale, Barthel Index, and Mini-Mental State Examination were administered to obtain demographic and clinical information., Results: Fatigue severity 3 months after stroke positively correlated with Geriatric Depression Scale and NEO Five-Factor Inventory neuroticism scores and negatively correlated with the Barthel Index score., Conclusions: Neuroticism, independent of depressive symptoms, is a predictor of fatigue severity 3 months after stroke. Interventions such as psychological screening programs are warranted for early detection of patients at high risk of poststroke depression., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

The role of the infarct location in the development of poststroke agitation (PSA) is largely unknown. This study examined the association between the locations of infarcts and PSA at 9 months following the index stroke in 213 patients with the Chinese version of the Neuropsychiatric Inventory. Compared with the non-PSA group, PSA patients had a higher number and volume of acute pontine infarcts. Ventral pontine and lateral cerebellar infarcts were independent predictors of PSA in the multivariate analysis.

Background and Objective: Aggression and agitation are common after a stroke. The association between agitation/aggression following stroke and Health-Related Quality of Life (HRQoL) in stroke survivors is unknown. This study aimed to examine the association between agitation/aggression and HRQoL in Chinese stroke survivors., Methods: Three hundred and twenty-four stroke patients entered this cross-sectional study. Agitation/aggression was assessed using the Chinese version of Neuropsychiatric Inventory (CNPI). HRQoL was measured with the Stroke Specific Quality of Life (SSQoL)., Results: Three months after the index stroke, agitation/aggression was found in 60 (18.5%) patients. In the agitation/aggression group, 44 patients (73.3%) showed passive agitation/aggression, whereas 16 (26.7%) displayed passive and active agitation/aggression. No patients showed only active agitation/aggression. Patients with agitation/aggression were more likely to have history of diabetes and greater severity of depression, as well as lower SSQoL total score and Personality Changes and Social Role scores. Controlling for diabetes and depression severity did not alter the above results. The Energy and Thinking scores of the SSQoL were significantly lower in the passive/active agitation/aggression group relative to the passive agitation/aggression group (adjusted for CNPI aggression/agitation score)., Conclusion: In this study sample, agitation/aggression was preponderantly of the passive type and was associated with poorer HRQoL independently from depression or medical conditions. Patients with both passive and active agitation/aggression had lower Quality of Life (QoL) than patients with only passive agitation/aggression. The causality of the association between low QoL and agitation/aggression needs to be explored in future studies.

Opinion Statement: The thalamus plays an important role in different brain functions including memory, emotions, sleep-wake cycle, executive functions, mediating general cortical alerting responses, processing of sensory (including taste, somatosensory, visual, and auditory) information and relaying it to the cortex, and sensorimotor control. Thalamic stroke, both in isolation and in combination with infarcts involving other structures, are not rare. The functional complexity of the thalami nuclei and the not uncommon normal variations of arteries supply the thalamus induce wide variations in presentation of thalami infarcts. In patients with an unusual collection of deficits difficult to explain by a single lesion, in particular where there is impaired vigilance, thalamic disease should be considered which may mimic several different neurological conditions. By researching the literature, we found that the characteristic stroke syndrome of paramedian thalamic infarction is probably underdiagnosed. In addition to thalamic infarct, thalamic lesions can be caused by deep cerebral venous thrombosis with neuropsychological and radiological features that should be considered in the differential diagnosis of intracranial artery occlusion or bleeding, especially in young patients.

Background: Intracranial arterial calcification (ICAC) is frequently detected on head computed tomography and has been found to be associated with ischemic stroke by recent clinical studies., Aims: Based on a hospital-based study, we aimed to compare the occurrence of cerebral microembolic signals (MES) among stroke patients with different degrees of ICAC, which may indicate the potential mechanisms linking ICAC and ischemic stroke in intracranial atherosclerosis patients., Methods: This is a post-hoc analysis of our previous clinical study in 2005-2007, recruiting consecutive ischemic stroke patients with middle cerebral artery territory infarctions and good temporal window for MES monitoring. The degrees of ICAC in the Circle of Willis, especially calcification in the ipsilateral intracranial internal carotid artery (iICA), were evaluated both qualitatively and quantitatively on unenhanced head computed tomography., Results: Among the 68 recruited patients, MES was detected in 26 patients (38.24%). The overall degree of ICAC in the Circle of Willis was similar between patients with and without MES. For calcification in ipsilateral iICA, the presence of MES was more frequent in the high extent group (widest arc of calcification ≥90°) than in the low extent group (54.2% versus 29.5%, P = .046). Logistic regression found that a high extent ipsilateral iICA calcification was an independent risk factor of MES (odds ratio: 3.134; 95% confidence interval, 1.029-9.543; P = .044)., Conclusions: MES is frequently detected in patients with a high extent of ipsilateral iICA calcification, which suggests that a high extent of iICA calcification indicates artery vulnerability and accounts for the occurrence of microemboli in the corresponding artery., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Though dysfunction of neuromuscular junction (NMJ) is associated with congenital myasthenic syndrome (CMS), the proteins involved in neuromuscular transmission have not been completely identified. In this study, we aimed to identify a novel CMS gene in a consanguineous family with limb-girdle type CMS. Homozygosity mapping of the novel CMS gene was performed using high-density single-nucleotide polymorphism microarrays. The variants in CMS gene were identified by whole-exome sequencing (WES) and Sanger sequencing. A 20 MB-region of homozygosity (ROH) was mapped on chromosome 6q15-21. This was the only ROH that present in all clinically affected siblings and absent in all clinically unaffected siblings. WES showed a novel variant of AK9 gene located in this ROH. This variant was a start-gain mutation and introduced a cryptic 5'-UTR signal in intron 5 of the AK9 gene. The normal splicing signal would be interfered by the cryptic translation signal leading to defective splicing. Another 25 MB-ROH was found on chromosome 11p13-q12 in all siblings. WES showed a homozygous RAPSN pathogenic variant in this ROH. Since RAPSN-associated limb-girdle type CMS was only manifested in AK9 homozygous variant carriers, the disease phenotype was of digenic inheritance, and was determined by the novel disease modifier AK9 which provides NTPs for N-glycosylation. This is the first time that this specific genotype-phenotype correlation is reported. Importantly, the AK9-associated nucleotide deficiency may replete by dietary supplements. Since AK9 is a disease modifier, enhancing N-glycosylation by increasing dietary nucleotides may be a new therapeutic option for CMS patients.

Background and Purpose: In the SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes), ticagrelor was not superior to aspirin. Because of differences in patient demographics and stroke disease pattern in Asia, outcomes of ticagrelor versus aspirin were assessed among Asian patients in a prespecified exploratory analysis., Methods: Baseline demographics, treatment effects, and safety of ticagrelor and aspirin were assessed among Asian patients. Differences in outcomes between groups were assessed using Cox proportional hazard model., Results: A total of 3858 (29.2%) SOCRATES participants were recruited in Asia. Among the Asian patients, the primary end point event occurred in 186 (9.6%) of the 1933 patients treated with ticagrelor, versus 224 (11.6%) of the 1925 patients treated with aspirin (hazard ratio, 0.81; 95% confidence interval, 0.67-0.99). The exploratory P value for treatment-by-region interaction was 0.27. The primary end point event rate in the Asian subgroup was numerically higher than that in the non-Asian group (10.6% versus 5.7%; nominal P<0.01). Among the Asian patients, the rate of PLATO (Platelet Inhibition and Patient Outcomes)-defined major bleeding was similar in the ticagrelor group and the aspirin group (0.6% versus 0.8%; hazard ratio, 0.76; 95% confidence interval, 0.36-1.61)., Conclusions: The event rates were numerically higher in the Asian patients. Among the Asian patients with acute stroke or transient ischemic attacks, there was a trend toward a lower hazard ratio in reducing risk of the primary end point of stroke, myocardial infarction, or death in the ticagrelor group., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994720., (© 2016 American Heart Association, Inc.)

Background: Intracranial arterial stenosis (ICAS) is the dominant cause for ischemic stroke worldwide, with hemodynamic compromise as a crucial contributor. Prolonged perfusion is commonly observed in ICAS patients on CT perfusion (CTP) maps, while the clinical significance of this perfusion pattern has not been elucidated., Method: Patients having symptomatic ICAS of 50-99% stenosis with sustained downstream cerebral blood flow (CBF) were enrolled in this study. Prolonged perfusion was defined as increased mean transit time (MTT) in vascular territories of the target ICAS on CTP maps. The primary clinical outcome was recurrence of ipsilateral ischemic stroke, and secondary outcome was any ipsilateral ischemic events at 2 years follow-up., Results: Of the 95 patients (median age 61y; 70% males) with symptomatic ICAS, 29 patients (30.5%) had prolonged perfusion. Such delayed perfusion was persistent in a majority of patients according to the 1-year imaging follow-up. The prolongation of cerebral perfusion was associated with subsequent risk for ipsilateral ischemic stroke (HR 7.01; 95% CI 1.86-26.46; p = 0.004), but not for any ipsilateral ischemic events (HR 1.52; 95% CI 0.63-3.68; p = 0.348). Further comparison of perfusion measures showed lower CBF (p = 0.034) and higher MTT (p = 0.064) in patients with recurrent ischemic stroke, but not in those with recurrent transient ischemic attack (TIA). Among patients with recurrent stroke, a majority had multiple infarcts along the borderzone regions., Conclusion: In patients with symptomatic ICAS, persistent prolonged cerebral perfusion might contribute to the relapse of ischemic stroke, but not TIA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: CT perfusion (CTP) imaging provides quantitative evaluation of cerebral perfusion flow and volume. Our previous findings showed that benign oligemia caused by intracranial large artery disease may be existent in subacute stroke., Aims: We aimed at comparing the topographic patterns and clinical outcome of stroke patients with and without persistent benign oligemia as defined by CTP imaging., Methods: Consecutive ischemic stroke patients who were referred for CTP in 2009 were screened. The topographic patterns (cortical, borderzone or perforating artery territory infarcts) were assessed by diffusion-weighted imaging (DWI). The clinical outcome was defined by modified Rankin score at 6 months after stroke onset., Results: Totally, 26 stroke patients were recruited. Benign oligemia in subacute stage was detected in 15 patients. The occurrence of borderzone infarction was higher in stroke patients with benign oligemia than those without (p = 0.036)., Conclusions: The topographic pattern of DWI may be different between the intracranial arterial disease patients with and without benign oligemia on CTP in subacute stroke., (© 2016 S. Karger AG, Basel.)

Objective: To determine associations between cerebral microbleed (CMB) burden with recurrent ischemic stroke (IS) and intracerebral hemorrhage (ICH) risk after IS or TIA., Methods: We identified prospective studies of patients with IS or TIA that investigated CMBs and stroke (ICH and IS) risk during ≥3 months follow-up. Authors provided aggregate summary-level data on stroke outcomes, with CMBs categorized according to burden (single, 2-4, and ≥5 CMBs) and distribution. We calculated absolute event rates and pooled risk ratios (RR) using random-effects meta-analysis., Results: We included 5,068 patients from 15 studies. There were 115/1,284 (9.6%) recurrent IS events in patients with CMBs vs 212/3,781 (5.6%) in patients without CMBs (pooled RR 1.8 for CMBs vs no CMBs; 95% confidence interval [CI] 1.4-2.5). There were 49/1,142 (4.3%) ICH events in those with CMBs vs 17/2,912 (0.58%) in those without CMBs (pooled RR 6.3 for CMBs vs no CMBs; 95% CI 3.5-11.4). Increasing CMB burden increased the risk of IS (pooled RR [95% CI] 1.8 [1.0-3.1], 2.4 [1.3-4.4], and 2.7 [1.5-4.9] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively) and ICH (pooled RR [95% CI] 4.6 [1.9-10.7], 5.6 [2.4-13.3], and 14.1 [6.9-29.0] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively)., Conclusions: CMBs are associated with increased stroke risk after IS or TIA. With increasing CMB burden (compared to no CMBs), the risk of ICH increases more steeply than that of IS. However, IS absolute event rates remain higher than ICH absolute event rates in all CMB burden categories., (© 2016 American Academy of Neurology.)