Effects of wearable ankle robotics for stair and over-ground training on sub-acute stroke: a randomized controlled trial.

BACKGROUND: Wearable ankle robotics could potentially facilitate intensive repetitive task-specific gait training on stair environment for stroke rehabilitation. A lightweight (0.5 kg) and portable exoskeleton ankle robot was designed to facilitate over-ground and stair training either providing active assistance to move paretic ankle augmenting residual motor function (power-assisted ankle robot, PAAR), or passively support dropped foot by lock/release ankle joint for foot clearance in swing phase (swing-controlled ankle robot, SCAR). In this two-center randomized controlled trial, we hypothesized that conventional training integrated with robot-assisted gait training using either PAAR or SCAR in stair environment are more effective to enhance gait recovery and promote independency in early stroke, than conventional training alone. METHODS: Sub-acute stroke survivors (within 2 months after stroke onset) received conventional training integrated with 20-session robot-assisted training (at least twice weekly, 30-min per session) on over-ground and stair environments, wearing PAAR (n = 14) or SCAR (n = 16), as compared to control group receiving conventional training only (CT, n = 17). Clinical assessments were performed before and after the 20-session intervention, including functional ambulatory category as primary outcome measure, along with Berg balance scale and timed 10-m walk test. RESULTS: After the 20-session interventions, all three groups showed statistically significant and clinically meaningful within-group functional improvement in all outcome measures (p < 0.005). Between-group comparison showed SCAR had greater improvement in functional ambulatory category (mean difference + 0.6, medium effect size 0.610) with more than 56% independent walkers after training, as compared to only 29% for CT. Analysis of covariance results showed PAAR had greater improvement in walking speed than SCAR (mean difference + 0.15 m/s, large effect size 0.752), which was in line with the higher cadence and speed when wearing the robot during the 20-session robot-assisted training over-ground and on stairs. CONCLUSIONS: Robot-assisted stair training would lead to greater functional improvement in gait independency and walking speed than conventional training in usual care. The active powered ankle assistance might facilitate users to walk more and faster with their paretic leg during stair and over-ground walking. TRIAL REGISTRATION: ClinicalTrials.gov NCT03184259. Registered on 12 June 2017.

Translesional Pressure Gradient Alters Relationship Between Blood Pressure and Recurrent Stroke in Intracranial Stenosis.

Background and Purpose- There is debate over an optimal systolic blood pressure (SBP) in secondary stroke prevention of patients with symptomatic intracranial atherosclerotic stenosis (sICAS). We investigated whether translesional pressure gradient across sICAS would alter the relationship between SBP and risk of recurrent stroke in such patients. Methods- We recruited patients with sICAS (50%-99% stenosis) confirmed in computed tomography angiography. We simulated blood flow across sICAS with computed tomography angiography-based computational fluid dynamics models. Translesional pressure ratio (PR=Pressurepost-stenotic/Pressurepre-stenotic) was calculated in each case. Pressure ratio (PR) ≤ median was defined as low PR, indicating larger translesional pressure gradient across sICAS. All patients received optimal medical treatment. We investigated the interaction of translesional PR and mean SBP during follow-up (SBPFU) in determining the risk of the primary outcome, recurrent ischemic stroke in the same territory within 1 year. Results- Among 157 patients with sICAS, the median PR was 0.93. Multivariate Cox regression revealed significant PR-SBPFU interaction on the primary outcome (P=0.008): in patients with normal PR, risk of primary outcome significantly decreased with lower SBPFU (hazard ratio for 10 mm Hg decrement =0.46; P=0.018); however, in those with low PR, SBPFU≤130 mm Hg was associated with significantly increased risk of primary outcome, compared with 130

Hemodynamics and stroke risk in intracranial atherosclerotic disease.

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 = pressurepoststenotic /pressureprestenotic ) and translesional wall shear stress ratio (WSSR = WSSstenotic - throat /WSSprestenotic ) 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.

Autonomic Dysfunction Predicts Clinical Outcomes After Acute Ischemic Stroke: A Prospective Observational Study.

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.

Converting MMSE to MoCA and MoCA 5-minute protocol in an educationally heterogeneous sample with stroke or transient ischemic attack.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is psychometrically superior over the Mini-mental State Examination (MMSE) for cognitive screening in stroke or transient ischemic attack (TIA). It is free for clinical and research use. The objective of this study is to convert scores from the MMSE to MoCA and MoCA-5-minute protocol (MoCA-5 min) and to examine the ability of the converted scores in detecting cognitive impairment after stroke or TIA. METHODS: A total of 904 patients were randomly divided into training (n = 623) and validation (n = 281) samples matched for demography and cognition. MMSE scores were converted to MoCA and MoCA-5 min using (1) equipercentile method with log-linear smoothing and (2) Poisson regression adjusting for age and education. Receiver operating characteristics curve analysis was used to examine the ability of the converted scores in differentiating patients with cognitive impairment. RESULTS: The mean education was 5.8 (SD = 4.6; ranged 0-20) years. The entire spectrum of MMSE scores was converted to MoCA and MoCA-5 min using equipercentile method. Relationship between MMSE and MoCA scores was confounded by age and education, and a conversion equation with adjustment for age and education was derived. In the validation sample, the converted scores differentiated cognitively impaired patients with area under receiver operating characteristics curve 0.826 to 0.859. CONCLUSION: We provided 2 methods to convert scores from the MMSE to MoCA and MoCA-5 min based on a large sample of patients with stroke or TIA having a wide range of education and cognitive levels. The converted scores differentiated patients with cognitive impairment after stroke or TIA with high accuracy.

The prognosis of acute symptomatic seizures after ischaemic stroke.

OBJECTIVE: Acute symptomatic seizure (AS) after ischaemic stroke is defined as a seizure occurring ≤7 days of the stroke. There remains a lack of information on the prognosis of AS after ischaemic stroke and how it should be treated. METHODS: We prospectively recruited patients after their incidents of ischaemic stroke from a population-based stroke registry. Stroke aetiology was defined according to Trial-of-ORG-10172 in acute-stroke treatment (TOAST). Patients were examined for any transient complete-occlusion with recanalisation (TCOR) and haemorrhagic transformation. The seizure outcomes were (1) acute clustering of seizures ≤7 days, (2) seizure recurrence associated with stroke recurrence beyond the 7-day period and (3) unprovoked seizure (US) >7 days. RESULTS: 104 patients (mean age 65 years/55% female) with AS after ischaemic stroke were identified (mean follow-up 6.17 years). Comparison of the group of patients with AS and those without seizures showed that patients with AS had significantly less large-vessel and small-vessel disease but more cardioembolisms (p<0.05) and a higher proportion of TCOR (p<0.01), multiple territory infarcts (p=0.007) and haemorrhagic transformations (p<0.01). Using Kaplan-Meier statistics, the risk of acute clustering of seizures ≤7 days was 22%, with a statistical trend for TCOR as a predictive factor (p=0.06). The risk of seizure recurrence associated with worsening/recurrence of stroke beyond 7 days was 13.5% at 2 years, 16.4% at 4 years and 18% at 8 years. Presence of >2 cardiovascular risk factors (p<0.05) and status epilepticus (P<0.05) are predictive risk factors on Cox regression model. The risk of US was 19% at 2 years, 25% at 4 years and 28% at 8 years with epileptiform EEG as a predictive factor (p<0.05). CONCLUSIONS: Seizure recurrence following AS after ischaemic stroke may appear as acute clustering. Afterwards, seizures may occur as often with a recurrent stroke as without one within 4.2 years. We recommend the use of antiepileptic agents for up to 4 years if the underlying stroke aetiology cannot be fully treated.

Sex Differences Do Not Exist in Outcomes among Stroke Patients with Intracranial Atherosclerosis in China: Subgroup Analysis from the Chinese Intracranial Atherosclerosis Study.

BACKGROUND: To date, sex difference in outcomes among patients with intracranial atherosclerosis (ICAS) has rarely been discussed in China as well as in the world. This study aimed to estimate the sex difference in outcomes among patients with ICAS in Chinese cerebral ischemia patients. METHODS: We analyzed 1,335 men and women with ICAS who were enrolled in the Chinese Intracranial Atherosclerosis study. They were followed-up for ischemic stroke recurrence, any cause of death, cerebral vascular events (including transient ischemic attack, ischemic and hemorrhagic stroke), combined end points (including cerebral vascular events, angina or myocardial infarction, pulmonary embolism, peripheral vascular events), and unfavorable outcome (modified Rankin scale score of 3-6) at 1 year. RESULTS: During the follow-up period, 59 (13.44%) combined end points were documented in women and 107 (11.94%) in men. Of the combined end points, 47 were recurrent ischemic stroke events (14 in women and 33 in men), and 51 other causes of deaths (24 in women and 27 in men). There were 349 unfavorable end points (117 in women and 232 in men). The cumulative probability of death was higher in women, but after adjusting for age, diabetes mellitus, hypertension, family history of stroke, current smoker, heavy drinking, hyperhomocysteinemia, and heart disease, there was no significant difference. There was also a lack of difference in 1-year ischemic stroke recurrence, cerebral vascular events, combined end points, and unfavorable outcome between women and men at 1 year. CONCLUSIONS: These results suggest no sex difference in outcome among patients with ICAS in Chinese cerebral ischemia patients.

Cortical Microinfarcts in Patients with Middle Cerebral Artery Stenosis.

BACKGROUND: Cortical microinfarcts (CMIs) have been correlated to cognitive decline and dementia. It was previously considered only visible on microscope, but was recently reported to be visible on 3.0 Tesla magnetic resonance imaging (MRI) and linked to presence of intracranial stenosis. We aimed to investigate CMIs on 3.0 Tesla MRI in patients with M1 middle cerebral artery (MCA-M1) stenosis. METHODS: Patients with a recent non-cardioembolic ischemic stroke or transient ischemic attack and an atherosclerotic MCA-M1 stenosis were recruited. The severity of MCA stenosis was defined as moderate (50%-69%) or severe (70%-99% or focal flow void) on time-of-flight MR angiography (MRA). The distal to proximal signal intensity ratio (SIR) of MCA stenosis was measured on time-of-flight MRA to represent its hemodynamic significance. The presence of CMI(s) in the ipsilateral hemisphere was assessed on axial T1- or T2-weighted images and T2-weighted fluid-attenuated inversion-recovery images. RESULTS: Overall, 86 patients (mean age: 62.8 years; 77.9% males) were analyzed, 66 (76.7%) and 20 (23.3%), respectively, having moderate and severe MCA-M1 stenoses. The median SIR was .91. Forty-five (52.3%) patients had ipsilateral CMI(s). Multivariate logistic regression showed a history of dyslipidemia (odds ratio [OR] = 6.83, P = .008), and an SIR lower than the median (OR = 4.73, P = .014) were independently associated with presence of CMI(s) in ipsilateral hemisphere to an MCA-M1 stenosis. CONCLUSIONS: Patients with stroke and intracranial stenosis had a high burden of CMI. Except for a history of dyslipidemia, the hemodynamic significance of the arterial stenosis may contribute to the presence of ipsilateral CMI(s) in these patients, which warrants further investigation in prospective, longitudinal studies.

Evolution of intracranial atherosclerotic disease under modern medical therapy.

OBJECTIVE: Understanding how symptomatic intracranial atherosclerotic disease (ICAD) evolves with current medical therapy may inform secondary stroke prevention. METHODS: In a prospective academic-initiated study, we recruited 50 patients (mean age = 63.4 ± 9.0 years) with acute strokes attributed to high-grade (≥70%) intracranial atherosclerotic stenosis for 3-dimensional rotational angiograms before and after intensive medical therapy for 12 months. Treatment targets included low-density lipoprotein ≤ 70mg/dl, glycosylated hemoglobin (HbA1c) ≤ 6.5%, and systolic blood pressure ≤ 140 mmHg. We analyzed infarct topography and monitored microembolic signal in recurrent strokes. The reference group was a published cohort of 143 ICAD patients. RESULTS: Overall, the stenoses regressed from 79% at baseline (interquartile range [IQR] = 71-87%) to 63% (IQR = 54-74%) in 1 year (p < 0.001). Specifically, the qualifying lesions (n = 49) regressed (stenosis reduced >10%) in 24 patients (49%), remained quiescent (stenosis same or ±10%) in 21 patients (43%), and progressed (stenosis increased >10%) in 4 patients (8%). There was no difference in intensity of risk factor control between groups of diverging clinical or angiographic outcomes. Higher HbA1c at baseline predicted plaque regression at 1 year (odds ratio = 4.4, 95% confidence interval = 1.4-14.5, p = 0.006). Among the 6 patients with recurrent strokes pertaining to the qualifying stenosis, 5 patients had solitary or rosarylike acute infarcts along the internal or anterior border zones, and 2 patients showed microembolic signals in transcranial Doppler ultrasound. INTERPRETATION: A majority of symptomatic high-grade intracranial plaques had regressed or remained quiescent by 12 months under intensive medical therapy. Artery-to-artery thromboembolism with impaired washout at border zones was a common mechanism in stroke recurrence.

Diminished Signal Intensities Distal to Intracranial Arterial Stenosis on Time-of-Flight MR Angiography Might Indicate Delayed Cerebral Perfusion.

BACKGROUND: Intracranial arterial stenosis (ICAS) is a predominant cause of ischemic stroke in Asia. Changes in the signal intensities (SIs) across ICAS lesions on time-of-flight magnetic resonance angiography (TOF-MRA) have been indicated to partially reflect the hemodynamic significance of the lesions, which we aimed to verify by correlating it with cerebral perfusion features provided by CT perfusion (CTP) imaging. METHODS: Ischemic stroke or transient ischemic attack patients with unilateral symptomatic stenosis (≥50%) of intracranial internal carotid artery or middle cerebral artery (MCA) were included in this study. Change of SIs across an ICAS lesion on TOF-MRA was calculated by the distal and proximal SI ratio (SIR). Cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) within the MCA territory of ipsilateral and contralateral hemispheres were evaluated on the CTP images at the basal ganglia level. Relative CBV, CBF and MTT were defined as ratios of the values obtained from ipsilateral and contralateral hemispheres. The relationships between SIR and CTP parameters were analyzed. RESULTS: Fifty subjects (74% male, mean age 62) were recruited. Overall, the mean SIR was 0.77 ± 0.17. SIR of ICAS was significantly, linearly and negatively correlated with ipsilateral CBV (r = -0.335, p = 0.017), ipsilateral MTT (r = -0.301, p = 0.034), and ipsilateral/contralateral MTT ratio (r = -0.443, p = 0.001). CONCLUSIONS: Diminished SIs distal to ICAS on TOF-MRA might be associated with delayed ipsilateral cerebral perfusion. Changes of the SIs across ICAS lesions on TOF-MRA may be a simple marker to reflect cerebral perfusion changes in patients with symptomatic ICAS.

Delayed-onset dementia after stroke or transient ischemic attack.

INTRODUCTION: Patients surviving stroke without immediate dementia are at high risk of delayed-onset dementia. Mechanisms underlying delayed-onset dementia are complex and may involve vascular and/or neurodegenerative diseases. METHODS: Dementia-free patients with stroke and/or transient ischemic attack (TIA; n = 919) were studied for 3 years prospectively, excluding those who developed dementia 3 to 6 months after stroke and/or TIA. RESULTS: Forty subjects (4.4%) developed dementia during the study period. Imaging markers of severe small vessel disease (SVD), namely presence of ≥3 lacunes and confluent white matter changes; history of hypertension and diabetes mellitus independently predicted delayed-onset dementia after adjustment for age, gender, and education. Only 6 of 31 (19.4%) subjects with delayed cognitive decline harbored Alzheimer's disease-like Pittsburg compound B (PiB) retention. Most PiB cases (16/25, 64%) had evidence of severe SVD. DISCUSSION: Severe SVD contributes importantly to delayed-onset dementia after stroke and/or TIA. Future clinical trials aiming to prevent delayed-onset dementia after stroke and/or TIA should target this high-risk group.

Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in China: the Chinese Intracranial Atherosclerosis (CICAS) Study.

BACKGROUND AND PURPOSE: We aimed to establish the prevalence, characteristics, and outcomes of intracranial atherosclerosis (ICAS) in China by a large, prospective, multicenter study. METHODS: We evaluated 2864 consecutive patients who experienced an acute cerebral ischemia<7 days after symptom onset in 22 Chinese hospitals. All patients underwent magnetic resonance angiography, with measurement of diameter of the main intracranial arteries. ICAS was defined as ≥50% diameter reduction on magnetic resonance angiography. RESULTS: The prevalence of ICAS was 46.6% (1335 patients, including 261 patients with coexisting extracranial carotid stenosis). Patients with ICAS had more severe stroke at admission and stayed longer in hospitals compared with those without intracranial stenosis (median National Institutes of Health Stroke Scale score, 3 versus 5; median length of stay, 14 versus 16 days; both P<0.0001). After 12 months, recurrent stroke occurred in 3.27% of patients with no stenosis, in 3.82% for those with 50% to 69% stenosis, in 5.16% for those with 70% to 99% stenosis, and in 7.27% for those with total occlusion. Cox proportional hazards regression analyses showed that the degree of arterial stenosis, age, family history of stroke, history of cerebral ischemia or heart disease, complete circle of Willis, and National Institutes of Health Stroke Scale score at admission were independent predictors for recurrent stroke at 1 year. The highest rate of recurrence was observed in patients with occlusion with the presence of ≥3 additional risk factors. CONCLUSIONS: ICAS is the most common vascular lesion in patients with cerebrovascular disease in China. Recurrent stroke rate in our study was lower compared with those of previous clinical trials but remains unacceptably high in a subgroup of patients with severe stenosis.

Evaluation of carotid angioplasty and stenting for radiation-induced carotid stenosis.

BACKGROUND AND PURPOSE: We aimed to evaluate the procedural safety, clinical, and angiographic outcome of carotid angioplasty and stenting for high-grade (≥70%) radiation-induced carotid stenosis (RIS) using atherosclerotic stenosis (AS) as a control. METHODS: In this 6-year prospective nonrandomized study, we compared the carotid angioplasty and stenting outcome of 65 consecutive patients (84 vessels) with RIS with that of a control group of 129 consecutive patients (150 vessels) with AS. Study end points were 30-day periprocedural stroke or death, ipsilateral ischemic stroke, technical success, procedural characteristics, instent restenosis (ISR; ≥50%) and symptomatic ISR. RESULTS: The median follow-up was 47.3 months (95% confidence interval, 26.9-61.6). Imaging assessment was available in 74 vessels (RIS) and 120 vessels (AS) in 2 years. Comparing RIS group with AS group, the rates of periprocedural stroke or death were 1.5% (1/65) versus 1.6% (2/129; P=1); ipsilateral ischemic stroke rates were 4.6% (3/65) versus 4.7% (6/129; P=1); the annual risks of ipsilateral ischemic stroke were 1.2% (3 patient/254.7 patient year) versus 1.2% (6 patient/494.2 patient year; P=0.89); technical success rates were both 100%. Stenting of common carotid artery and the use of multiple stents was more common in the RIS group (P=0 in both cases); ISR rates were 25.7% (19/74) versus 4.2% (5/120; P<0.001); symptomatic ISR rates were 6.8% (5/74) versus 0.8% (1/120; P=0.031). CONCLUSIONS: The safety, effectiveness, and technical difficulty of carotid angioplasty and stenting for RIS are comparable with that for AS although it is associated with a higher rate of ISR. CLINICAL TRIAL REGISTRATION: This trial was not registered as enrollment started in 2006.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Angiographic features, collaterals, and infarct topography of symptomatic occlusive radiation vasculopathy: a case-referent study.

BACKGROUND AND PURPOSE: Occlusive radiation vasculopathy (ORV) predisposes head-and-neck cancer survivors to ischemic strokes. METHODS: We analyzed the digital subtraction angiography acquired in 96 patients who had first-ever transient ischemic attack or ischemic strokes attributed to ORV. Another age-matched 115 patients who had no radiotherapy but symptomatic high-grade (>70%) carotid stenoses were enrolled as referent subjects. Digital subtraction angiography was performed within 2 months from stroke onset and delineated carotid and vertebrobasilar circulations from aortic arch up to intracranial branches. Two reviewers blinded to group assignment recorded all vascular lesions, collateral status, and infarct pattern. RESULTS: ORV patients had less atherosclerotic risk factors at presentation. In referent patients, high-grade stenoses were mostly focal at the proximal internal carotid artery. In contrast, high-grade ORV lesions diffusely involved the common carotid artery and internal carotid artery and were more frequently bilateral (54% versus 22%), tandem (23% versus 10%), associated with complete occlusion in one or both carotid arteries (30% versus 9%), vertebral artery (VA) steno-occlusions (28% versus 16%), and external carotid artery stenosis (19% versus 5%) (all P<0.05). With comparable rates of vascular anomaly, ORV patients showed more established collateral circulations through leptomeningeal arteries, anterior communicating artery, posterior communicating artery, suboccipital/costocervical artery, and retrograde flow in ophthalmic artery. In terms of infarct topography, the frequencies of cortical or subcortical watershed infarcts were similar in both groups. CONCLUSIONS: ORV angiographic features and corresponding collaterals are distinct from atherosclerotic patterns at initial stroke presentation. Clinical decompensation, despite more extensive collateralization, may precipitate stroke in ORV.

Prognostic value of inflammatory mediators in 1-year outcome of acute ischemic stroke with middle cerebral artery stenosis.

BACKGROUND AND PURPOSE: Inflammation exists in inception, progression, and reperfusion of acute ischemic stroke. Insightful understanding of correlation in inflammatory mediators and stroke severity with intracranial artery stenosis may improve rational stroke therapy. METHODS: We prospectively recruited 977 patients with acute noncardioembolic ischemic stroke with MCA stenosis by MRA as none to mild (<50%), moderate (50-69%), severe (70-99%), or occlusive (100%). The peripheral levels of WBC, homocysteine (HCY), and high sensitivity C-reactive protein (hs-CRP) were recorded. All patients were assessed of 1-year outcome by mRS as favorable (0-2) or poor (3-6). RESULTS: The levels of WBC, HCY, and hs-CRP had no significant differences in patients with categorized MCA stenosis (all P > 0.05). Higher levels of WBC, HCY, and hs-CRP were found in patients with 1-year poor outcome (all P < 0.05), but only hs-CRP is an independent predictor (OR 1.06, 95% CI 1.027-1.093, P = 0.0003). The combination of any two of increased hs-CRP (>3 mg/L), WBC (>6.91 × 10(9)/L), and HCY (>15 µ mol/L) had higher power in predicting 1-year poor outcome than the single elevated mediator. CONCLUSIONS: Elevated hs-CRP independently predicts 1-year poor outcome in acute stroke. The combination of increased hs-CRP, WBC, or HCY had a stronger predictive value in poor outcome than individual elevated mediator.

Risk stratification in symptomatic intracranial atherosclerotic disease with conventional vascular risk factors and cerebral haemodynamics.

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 D2H2A 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 D2H2A 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.

Association of Alternative Anticoagulation Strategies and Outcomes in Patients With Ischemic Stroke While Taking a Direct Oral Anticoagulant.

BACKGROUND AND OBJECTIVES: Ischemic stroke despite a direct oral anticoagulant (DOAC) is increasingly common and portends a high risk of subsequent ischemic stroke. The efficacy and safety of antithrombotic regimens after the condition are unclear. We aimed to compare the outcomes of patients with ischemic stroke despite DOACs with and without an alternative antithrombotic regimen and determine the risk factors of recurrent ischemic stroke while on anticoagulation. METHODS: In a population-based, propensity score-weighted, retrospective cohort study, we compared the clinical outcomes of DOAC-to-warfarin switch, DOAC-to-DOAC switch (DOACswitch), or addition of antiplatelet agents, with those of unchanged DOAC regimen (DOACsame) among patients with nonvalvular atrial fibrillation (NVAF) who developed the first ischemic stroke despite a DOAC from January 1, 2015, to December 31, 2020, in Hong Kong. The primary outcome was recurrent ischemic stroke. Secondary outcomes were intracranial hemorrhage, acute coronary syndrome, and death. We performed competing risk regression analyses to compare the clinical endpoints and determined the predictors of recurrent ischemic stroke in an unweighted multivariable logistic regression model. RESULTS: During the 6-year study period, among 45,946 patients with AF on a DOAC as stroke prophylaxis, 2,908 patients developed ischemic stroke despite a DOAC. A total of 2,337 patients with NVAF were included in the final analyses. Compared with DOACsame, warfarin (aHR 1.96, 95% CI 1.27-3.02, p = 0.002) and DOACswitch (aHR 1.62, 95% CI 1.25-2.11, p < 0.001) were associated with an increased risk of recurrent ischemic stroke. In the DOACsame group, adjunctive antiplatelet agent was not associated with a reduced risk of recurrent ischemic stroke. Diabetes mellitus, concurrent cytochrome P450/P-glycoprotein (CYP/P-gp) modulators, and large artery atherosclerotic disease (LAD) were predictors of recurrent ischemic stroke. DISCUSSION: In patients with NVAF with ischemic stroke despite a DOAC, the increased risk of recurrent ischemic stroke with switching to warfarin called for caution against such practice, while the increased ischemic stroke with DOAC-to-DOAC switch demands further studies. Adjunctive antiplatelet agent did not seem to reduce ischemic stroke relapse. Because diabetes mellitus, the use of CYP/P-gp modulators, and LAD were predictors of recurrent ischemic stroke, further investigations should evaluate whether strict glycemic control, DOAC level monitoring, and routine screening for carotid and intracranial atherosclerosis may reduce ischemic stroke recurrence in these patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with NVAF experiencing an ischemic stroke while being treated with a DOAC, continuing treatment with that DOAC is more effective at preventing recurrent ischemic stroke than switching to a different DOAC or to warfarin.

Cerebral Hemodynamics Underlying Artery-to-Artery Embolism in Symptomatic Intracranial Atherosclerotic Disease.

Artery-to-artery embolism (AAE) is a common stroke mechanism in intracranial atherosclerotic disease (ICAD), associated with a considerable risk of recurrent stroke. We aimed to investigate cerebral hemodynamic features associated with AAE in symptomatic ICAD. Patients with anterior-circulation, symptomatic ICAD confirmed in CT angiography (CTA) were recruited. We classified probable stroke mechanisms as isolated parent artery atherosclerosis occluding penetrating artery, AAE, hypoperfusion, and mixed mechanisms, largely based on infarct topography. CTA-based computational fluid dynamics (CFD) models were built to simulate blood flow across culprit ICAD lesions. Translesional pressure ratio (PR = Pressurepost-stenotic/Pressurepre-stenotic) and wall shear stress ratio (WSSR = WSSstenotic-throat/WSSpre-stenotic) were calculated, to reflect the relative, translesional changes of the two hemodynamic metrics. Low PR (PR ≤ median) and high WSSR (WSSR ≥ 4th quartile) respectively indicated large translesional pressure and elevated WSS upon the lesion. Among 99 symptomatic ICAD patients, 44 had AAE as a probable stroke mechanism, 13 with AAE alone and 31 with coexisting hypoperfusion. High WSSR was independently associated with AAE (adjusted OR = 3.90; P = 0.022) in multivariate logistic regression. There was significant WSSR-PR interaction on the presence of AAE (P for interaction = 0.013): high WSSR was more likely to associate with AAE in those with low PR (P = 0.075), but not in those with normal PR (P = 0.959). Excessively elevated WSS in ICAD might increase the risk of AAE. Such association was more prominent in those with large translesional pressure gradient. Hypoperfusion, commonly coexisting with AAE, might be a therapeutic indicator for secondary stroke prevention in symptomatic ICAD with AAE.