Validation of a Simple Clinical Tool for Screening of Acute Lacunar Stroke - a substudy of the WAKE-UP trial.

INTRODUCTION: Lacunar stroke represents around a quarter of all ischemic strokes, however, their identification with Computed Tomography in the hyperacute setting is challenging. We aimed to validate a clinical score to identify lacunar stroke in the acute setting, independently, with data from the WAKE-UP trial using magnetic resonance imaging. METHODS: We analysed data from the WAKE-UP trial and extracted Oxfordshire Community Stroke Project (OCSP) classification. Lacunar score was defined by NIHSS<7 and OCSP lacunar syndrome. Assessment of lacunar infarct by two independent investigators was blinded to clinical data. We calculated sensitivity, specificity, negative and positive predictive value (NPV and PPV, respectively) of lacunar score. RESULTS: We included 503 patients in the analysis, mean (±SD) age 65.2 (±11.6), 325 (65%) males, median (IQR) NIHSS=6 (4-9); 108 (22%) lacunar infarcts were identified on MR, patients fulfilling lacunar score criteria were 120 (24%), of which 47 (44%) had a lacunar infarct. Lacunar score correctly identified 322 (82%) of patients without lacunar infarct. Patients with lacunar score had lower NIHSS (4 vs 7,p<0.001), higher systolic (157 mmHg vs 151 mmHg,p=0.001) and diastolic (86 mmHg vs 83 mmHg,p=0.013) blood pressure and smaller infarct volume (2.4 ml vs 9.5 ml,p<0.001). Performance of lacunar score was: sensitivity 0.44; specificity 0.82; PPV 0.39; NPV 0.84; accuracy 0.73. Assuming a prevalence of lacunar stroke of 13%, PPV lowered to 0.30 but NPV was 0.90. Lacunar score performed better for supratentorial lacunar infarcts. CONCLUSIONS: Lacunar score had a very good specificity and NPV for screening of lacunar stroke. Implementation of this simple tool into clinical practice may help hyperacute management and guide patient selection in clinical trials.

The PREMISE database of 20 Macaca fascicularis PET/MRI brain images available for research.

Non-human primate studies are unique in translational research, especially in neurosciences where neuroimaging approaches are the preferred methods used for cross-species comparative neurosciences. In this regard, neuroimaging database development and sharing are encouraged to increase the number of subjects available to the community, while limiting the number of animals used in research. Here we present a simultaneous positron emission tomography (PET)/magnetic resonance (MR) dataset of 20 Macaca fascicularis images structured according to the Brain Imaging Data Structure standards. This database contains multiple MR imaging sequences (anatomical, diffusion and perfusion imaging notably), as well as PET perfusion and inflammation imaging using respectively [15O]H2O and [11C]PK11195 radiotracers. We describe the pipeline method to assemble baseline data from various cohorts and qualitatively assess all the data using signal-to-noise and contrast-to-noise ratios as well as the median of intensity and the pseudo-noise-equivalent-count rate (dynamic and at maximum) for PET data. Our study provides a detailed example for quality control integration in preclinical and translational PET/MR studies with the aim of increasing reproducibility. The PREMISE database is stored and available through the PRIME-DE consortium repository.

Comparison of healthcare costs before and after a STEMI: A French national health data system-based cohort study.

BACKGROUND: Few studies have investigated real-world healthcare costs following a myocardial infarction (MI) and, to our knowledge, none after an ST-elevation MI (STEMI) specifically. Producing such data is important in order to help evaluate the economic burden of STEMI, but also to feed economic evaluation models and eventually show the economic interest of reducing STEMI incidence. The aim of this study was to estimate the healthcare cost in the year preceding and the year following a STEMI in France, in order to estimate the surplus in healthcare resource consumption after a STEMI. METHODS: This study was conducted from the healthcare system perspective. The individual data from the HIBISCUS-STEMI cohort, which included patients with acute STEMI undergoing primary percutaneous coronary intervention, were matched with the French national health data system (Système National des Données de Santé, SNDS) using a probabilistic method. All expenses (in- and out-hospital) presented for reimbursement were taken into account to estimate a mean annual healthcare cost. RESULTS: A total 258 patients from the HIBISCUS-STEMI cohort were included in this economic study. The total mean healthcare cost was estimated at €3516 before the STEMI, and at €9980 after the STEMI. Hospitalizations constituted the largest cost item, 27 % of the total cost before the STEMI and 41.8 % after the STEMI (Δ + 338.8 %). Follow-up and rehabilitative care represented the second largest cost item (25.9 % before and 18 % after the STEMI, Δ + 96.7 %). Treatments represented 19.4 % of the total cost before the STEMI and 17.2 % after (Δ + 150.8 %). CONCLUSIONS: This study shows a significant surplus (threefold) of healthcare resource consumption in the year following a STEMI compared to the year preceding the STEMI.

Specific inflammatory profile of acute ischemic stroke patients with left atrial enlargement.

Background: The inflammatory process underlying atrial myopathy may affect the inflammatory response activated in acute ischemic stroke (AIS). Objectives: We aimed to assess whether left atrial enlargement (LAE) as a marker of atrial myopathy is associated with a different profile of circulating inflammatory markers in AIS patients. Methods: HIBISCUS-STROKE is a cohort study including anterior circulation AIS patients treated with mechanical thrombectomy following MRI. Ten circulating inflammatory markers were measured at admission and 6, 24, and 48 h after admission. LAE was defined as a left atrial volume index (LAVi) ≥34 ml/m2. A multiple logistic regression model was performed to detect an independent association between the area under the curve (AUC) of these markers and LAE. Results: We included 143 patients. Of them, 85 (59.4%) had LAE. On univariable analysis, we found that patients with LAE had higher soluble form suppression of tumorigenicity 2 (sST2), soluble tumor necrosis factor receptor I (sTNFR1), and vascular cellular adhesion molecule-1 (VCAM-1) AUC, were older, mostly female, had a higher National Institutes of Health Stroke Scale (NIHSS) score and blood glucose level at admission, had more often hypertension, and a cardioembolic source of AIS, such as atrial fibrillation, while they were less frequently current smokers and had a lower rate of tandem occlusion than patients without LAE. On multivariable analysis, we found that among circulating inflammatory markers, only high VCAM-1 (OR: 9.13, 95% CI: 3.21-25.9) and sST2 (OR: 3.40, 95% CI: 1.68-6.86) AUC remained associated with LAE. Conclusions: High VCAM-1 and sST2 levels within the first 48 h are associated with LAE in AIS patients.

Blood-Brain Barrier Permeability and Kinetics of Inflammatory Markers in Acute Stroke Patients Treated With Thrombectomy.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate the relationship between baseline blood-brain barrier (BBB) permeability and the kinetics of circulating inflammatory markers in a cohort of acute ischemic stroke (AIS) patients treated with mechanical thrombectomy. METHODS: The CoHort of Patients to Identify Biological and Imaging markerS of CardiovascUlar Outcomes in Stroke includes AIS patients treated with mechanical thrombectomy after admission MRI and undergoing a sequential assessment of circulating inflammatory markers. Baseline dynamic susceptibility perfusion MRI was postprocessed with arrival time correction to provide K2 maps reflecting BBB permeability. After coregistration of apparent diffusion coefficient and K2 maps, the 90th percentile of K2 value was extracted within baseline ischemic core and expressed as a percentage change compared with contralateral normal-appearing white matter. Population was dichotomized according to the median K2 value. Univariable and multiple variable logistic regression analyses were performed to investigate factors associated with increased pretreatment BBB permeability in the whole population and in patients with symptom onset <6 hours. RESULTS: In the whole population (n = 105 patients, median K2 = 1.59), patients with an increased BBB permeability had higher serum levels of matrix metalloproteinase (MMP)-9 at H48 (p = 0.02), a higher C-reactive protein (CRP) serum level at H48 (p = 0.01), poorer collateral status (p = 0.01), and a larger baseline ischemic core (p < 0.001). They were more likely to have hemorrhagic transformation (p = 0.008), larger final lesion volume (p = 0.02), and worst neurologic outcome at 3 months (p = 0.04). The multiple variable logistic regression indicated that an increased BBB permeability was associated only with ischemic core volume (odds ratio [OR] 1.04, 95% CI 1.01-1.06, p < 0.0001). Restricting analysis to patients with symptom onset <6 hours (n = 72, median K2 = 1.27), participants with an increased BBB permeability had higher serum levels of MMP-9 at H0 (p = 0.005), H6 (p = 0.004), H24 (p = 0.02), and H48 (p = 0.01), higher CRP levels at H48 (p = 0.02), and a larger baseline ischemic core (p < 0.0001). The multiple variable logistic analysis showed that increased BBB permeability was independently associated with higher H0 MMP-9 levels (OR 1.33, 95% CI 1.12-1.65, p = 0.01) and a larger ischemic core (OR 1.27, 95% CI 1.08-1.59, p = 0.04). DISCUSSION: In AIS patients, increased BBB permeability is associated with a larger ischemic core. In the subgroup of patients with symptom onset <6 hours, increased BBB permeability is independently associated with higher H0 MMP-9 levels and a larger ischemic core.

Vascular hyperintensities on baseline FLAIR images are associated with functional outcome in stroke patients with successful recanalization after mechanical thrombectomy.

PURPOSE: The purpose of this study was to assess the prognostic value of vascular hyperintensities on FLAIR images (VHF) at admission MRI in patients with acute ischemic stroke (AIS) achieving successful recanalization after mechanical thrombectomy. MATERIALS AND METHODS: Patients with AIS treated by mechanical thrombectomy following admission MRI from the single-center HIBISCUS-STROKE cohort were assessed for eligibility. VHF were categorized using a four-scale classification and were considered poor when grade < 3 (i.e., absence of distal VHF). Recanalization was considered successful when modified thrombolysis in cerebral infarction score was ≥ 2B Functional outcome was considered poor if modified Rankin scale (mRS) at three months was > 2. Univariable and multiple variable logistic regressions were performed to identify factors associated with poor functional outcome despite successful recanalization. RESULTS: A total of 108 patients were included. There were 65 men and 43 women with a median age of 70.5 years (interquartile range: 55.0, 81.0; age range: 22.0-93.0 years). Among them, 39 subjects (36.1%) had poor functional outcome at three months. Univariable logistic regressions indicated that poorly extended VHF (VHF grade < 3) were associated with a poor functional outcome (P = 0.008) as well as age, hypertension and diabetes, baseline National Institute of Health Stroke Scale (NIHSS) score, pre-stroke mRS, lack of intravenous thrombolysis, cerebral microangiopathy and the presence of microbleeds. Multivariable analysis confirmed that poor VHF status was independently associated with a poor functional outcome (odds ratio [OR], 4.26; 95% confidence interval [CI]: 1.55-12.99; P = 0.007) in combination with hypertension (OR, 1.25; 95% CI: 0.87-1.85; P = 0.02), baseline NIHSS score (OR, 1.09; 95% CI: 1.04-1.20; P = 0.03), pre-stroke mRS (OR, 2.05; 95% CI: 1.07-4.61; P = 0.05) and lack of intravenous thrombolysis (OR, 0.23; 95% CI: 0.08-0.61; P = 0.004). CONCLUSION: Poorly extended VHF (grade <3) at admission MRI are associated with a poor functional outcome at three months despite successful recanalization by mechanical thrombectomy.

More Than 50 Percent Reduction in LDL Cholesterol in Patients With Target LDL <70 mg/dL After a Stroke.

BACKGROUND: Whether a strategy to target an LDL (low-density lipoprotein) cholesterol <70 mg/dL is more effective when LDL is reduced >50% from baseline rather than <50% from baseline has not been investigated. METHODS: The Treat Stroke to Target trial was conducted in France and South Korea in 61 sites between March 2010 and December 2018. Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 mg/dL or 100±10 mg/dL, using statin and/or ezetimibe as needed. We used the results of repeated LDL measurements (median, 5 [2-6] per patient) during 3.9 years (interquartile range, 2.1-6.8) of follow-up. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time-varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients in the lower target group who had >50% LDL cholesterol reduction from baseline during the trial had a higher baseline LDL cholesterol and a lower LDL cholesterol achieved as compared to patients who had <50% LDL cholesterol reduction (155±32 and 62 mg/dL versus 121±34 and 74 mg/dL, respectively, P<0.001 for both). In the <70 mg/dL target group, patients with >50% LDL reduction had a significant reduction in the primary outcome as compared to the higher target group (hazard ratio, 0.61 [95% CI, 0.43-0.88]; P=0.007) and patients with <50% LDL reduction from baseline had little reduction (hazard ratio, 0.96 [95% CI, 0.73-1.26]; P=0.75). CONCLUSIONS: In this post hoc analysis of the TST trial, targeting an LDL cholesterol of <70 mg/dL reduced the risk of primary outcome compared with 100±10 mg/dL provided LDL cholesterol reduction from baseline was superior to 50%, thereby suggesting that the magnitude of LDL cholesterol reduction was as important to consider as the target level to achieve. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: https://clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

Reversibility of Diffusion-Weighted Imaging Lesions in Patients With Ischemic Stroke in the WAKE-UP Trial.

BACKGROUND: Reversibility of the diffusion-weighted imaging (DWI) lesion means that not all of the DWI lesion represents permanently injured tissue. We investigated DWI reversibility and the association with thrombolysis, reperfusion and functional outcome in patients from the WAKE-UP trial (Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-Up Stroke). METHODS: In this retrospective analysis of WAKE-UP, a randomized controlled trial (RCT) between September 2012 and June 2017 in Belgium, Denmark, France, Germany, Spain and United Kingdom, a convolutional neural network segmented the DWI lesions (b=1000 s/mm2) at baseline and follow-up (24 hours). We calculated absolute and relative DWI reversibility in 2 ways: first, a volumetric (baseline volume-24-hour volume >0) and second, a voxel-based (part of baseline lesion not overlapping with 24-hour lesion) approach. We additionally defined relative voxel-based DWI-reversibility >50% to account for coregistration inaccuracies. We calculated the odds ratio for reversibility according to treatment arm. We analyzed the association of reversibility with excellent functional outcome (modified Rankin Scale score of 0-1), in a multivariable model. RESULTS: In 363 patients, the median DWI volume was 3 (1-10) mL at baseline and 6 (2-20) mL at follow-up. Volumetric DWI reversibility was present in 19% (69/363) with a median absolute reversible volume of 1 mL (0-2) or 28% (14-50) relatively. Voxel-based DWI reversibility was present in 358/363 (99%) with a median absolute volume of 1 mL (0-2), or 22% (9-38) relatively. In 18% of the patients (67/363), relative voxel-based DWI reversibility >50% was present. Volumetric DWI reversibility and relative voxel-based DWI reversibility >50% was more frequent in patients treated with alteplase versus placebo (OR, 1.86 [95% CI, 1.09-3.17] and OR, 2.03 [95% CI, 1.18-3.50], respectively). Relative voxel-based DWI reversibility >50% was associated with excellent functional outcome (OR, 2.30 [95% CI, 1.17-4.51]). CONCLUSIONS: Small absolute volumes of DWI reversibility were present in a large proportion of randomized patients in the WAKE-UP trial. Reversibility was more often present after thrombolysis.

Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke. METHODS: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models. RESULTS: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57-0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60-1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome (P=0.443) or any hemorrhagic transformation (P=0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19-4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80-4.81]). CONCLUSIONS: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01525290.

Predictors of Early Neurological Improvement and Its Relationship to Thrombolysis Treatment and Long-Term Outcome in the WAKE-UP Study.

INTRODUCTION: The aims of this study were to evaluate the relationship of clinical and imaging baseline factors and treatment on the occurrence of early neurological improvement (ENI) in the WAKE-UP trial of MRI-guided intravenous thrombolysis in unknown onset stroke and to examine the association of ENI with long-term favorable outcome in patients treated with intravenous thrombolysis. METHODS: We analyzed data from all patients with at least moderate stroke severity, reflected by an initial National Institutes of Health Stroke Scale (NIHSS) score ≥4 randomized in the WAKE-UP trial. ENI was defined as a decrease in NIHSS of ≥8 or a decline to zero or 1 at 24 h after initial presentation to the hospital. Favorable outcome was defined as a modified Rankin Scale score of 0-1 at 90 days. We performed group comparison and multivariable analysis of baseline factors associated with ENI and performed mediation analysis to evaluate the effect of ENI on the relationship between intravenous thrombolysis and favorable outcome. RESULTS: ENI occurred in 93 out of 384 patients (24.2%) and was more likely to occur in patients who received treatment with alteplase (62.4% vs. 46.0%, p = 0.009), had smaller acute diffusion-weighted imaging lesion volume (5.51 mL vs. 10.9 mL, p ≤ 0.001), and less often large-vessel occlusion on initial MRI (7/93 [12.1%] versus 40/291 [29.9%], p = 0.014). In multivariable analysis, treatment with alteplase (OR 1.97, 95% confidence interval [CI] 0.954-1.100), lower baseline stroke volume (OR 0.965, 95% CI: 0.932-0.994), and shorter time from symptom recognition to treatment (OR 0.994, 95% CI: 0.989-0.999) were independently associated with ENI. Patients with ENI had higher rates of favorable outcome at 90-day follow-up (80.6% vs. 31.3%, p ≤ 0.001). The occurrence of ENI significantly mediated the association of treatment with a good outcome, with ENI at 24 h explaining 39.4% (12.9-96%) of the treatment effect. CONCLUSION: Intravenous alteplase increases the odds of ENI in patients with at least moderate stroke severity, especially when given early. In patients with large-vessel occlusion, ENI is rarely observed without thrombectomy. ENI represents a good surrogate early marker of treatment effect as more than a third of good outcome at 90 days is explained by ENI at 24 h.

Spatio-Temporal Characterization of Brain Inflammation in a Non-human Primate Stroke Model Mimicking Endovascular Thrombectomy.

Reperfusion therapies in acute ischemic stroke have demonstrated their efficacy in promoting clinical recovery. However, ischemia/reperfusion injury and related inflammation remain a major challenge in patient clinical management. We evaluated the spatio-temporal evolution of inflammation using sequential clinical [11C]PK11195 PET-MRI in a non-human primate (NHP) stroke model mimicking endovascular thrombectomy (EVT) with a neuroprotective cyclosporine A (CsA) treatment. The NHP underwent a 110-min transient endovascular middle cerebral artery occlusion. We acquired [11C]PK11195 dynamic PET-MR imaging at baseline, 7 and 30 days after intervention. Individual voxel-wise analysis was performed thanks to a baseline scan database. We quantified [11C]PK11195 in anatomical regions and in lesioned areas defined on per-occlusion MR diffusion-weighted imaging and perfusion [15O2]H2OPET imaging. [11C]PK11195 parametric maps showed a clear uptake overlapping the lesion core at D7, which further increased at D30. Voxel-wise analysis identified individuals with significant inflammation at D30, with voxels located within the most severe diffusion reduction area during occlusion, mainly in the putamen. The quantitative analysis revealed that thalamic inflammation lasted until D30 and was significantly reduced in the CsA-treated group compared to the placebo. In conclusion, we showed that chronic inflammation matched ADC decrease at occlusion time, a region exposed to an initial burst of damage-associated molecular patterns, in an NHP stroke model mimicking EVT. We described secondary thalamic inflammation and the protective effect of CsA in this region. We propose that major ADC drop in the putamen during occlusion may identify individuals who could benefit from early personalized treatment targeting inflammation.

Is the optimal Tmax threshold identifying perfusion deficit volumes variable across MR perfusion software packages? A pilot study.

PURPOSE: Accurate quantification of ischemic core and ischemic penumbra is mandatory for late-presenting acute ischemic stroke. Substantial differences between MR perfusion software packages have been reported, suggesting that the optimal Time-to-Maximum (Tmax) threshold may be variable. We performed a pilot study to assess the optimal Tmax threshold of two MR perfusion software packages (A: RAPID®; B: OleaSphere®) by comparing perfusion deficit volumes to final infarct volumes as ground truth. METHODS: The HIBISCUS-STROKE cohort includes acute ischemic stroke patients treated by mechanical thrombectomy after MRI triage. Mechanical thrombectomy failure was defined as a modified thrombolysis in cerebral infarction score of 0. Admission MR perfusion were post-processed using two packages with increasing Tmax thresholds (≥ 6 s, ≥ 8 s and ≥ 10 s) and compared to final infarct volume evaluated with day-6 MRI. RESULTS: Eighteen patients were included. Lengthening the threshold from ≥ 6 s to ≥ 10 s led to significantly smaller perfusion deficit volumes for both packages. For package A, Tmax ≥ 6 s and ≥ 8 s moderately overestimated final infarct volume (median absolute difference: - 9.5 mL, interquartile range (IQR) [- 17.5; 0.9] and 0.2 mL, IQR [- 8.1; 4.8], respectively). Bland-Altman analysis indicated that they were closer to final infarct volume and had narrower ranges of agreement compared with Tmax ≥ 10 s. For package B, Tmax ≥ 10 s was closer to final infarct volume (median absolute difference: - 10.1 mL, IQR: [- 17.7; - 2.9]) versus - 21.8 mL (IQR: [- 36.7; - 9.5]) for Tmax ≥ 6 s. Bland-Altman plots confirmed these findings (mean absolute difference: 2.2 mL versus 31.5 mL, respectively). CONCLUSIONS: The optimal Tmax threshold for defining the ischemic penumbra appeared to be most accurate at ≥ 6 s for package A and ≥ 10 s for package B. This implies that the widely recommended Tmax threshold ≥ 6 s may not be optimal for all available MRP software package. Future validation studies are required to define the optimal Tmax threshold to use for each package.

Brush sign and collateral supply as potential markers of large infarct growth after successful thrombectomy.

OBJECTIVES: To investigate the relationships between brush sign and cerebral collateral status on infarct growth after successful thrombectomy. METHODS: HIBISCUS-STROKE cohort includes acute ischemic stroke patients treated with thrombectomy after MRI triage and undergoing a day-6 MRI including FLAIR images to quantify final infarct volume (FIV). Successful reperfusion was defined as a modified thrombolysis in cerebral infarction score ≥ 2B. Infarct growth was calculated by subtracting FIV from baseline ischemic core after co-registration and considered large (LIG) when > 11.6 mL. Brush sign was assessed on T2*-weighted-imaging and collaterals were assessed using the hypoperfusion intensity ratio, which is the volume of Time-To-Tmax (Tmax) ≥ 10 s divided by the volume of Tmax ≥ 6 s. Good collaterals were defined by a hypoperfusion intensity ratio < 0.4. RESULTS: One hundred and twenty-nine patients were included, of whom 45 (34.9%) had a brush sign and 63 (48.8%) good collaterals. Brush sign was associated with greater infarct growth (p = 0.01) and larger FIV (p = 0.02). Good collaterals were associated with a smaller baseline ischemic core (p < 0.001), larger penumbra (p = 0.04), and smaller FIV (p < 0.001). Collateral status was not significantly associated with brush sign (p = 0.20) or with infarct growth (p = 0.67). Twenty-eight (22.5%) patients experienced LIG. Univariate regressions indicated that brush sign (odds ratio (OR) = 4.8; 95% confidence interval (CI): [1.9;13.3]; p = 0.004) and hemorrhagic transformation (OR = 1.7; 95%CI: [1.2;2.6]; p = 0.04) were predictive of LIG. In multivariate regression, only the brush sign remained predictive of LIG (OR = 5.2; 95%CI: [1.8-16.6], p = 0.006). CONCLUSIONS: Brush sign is a predictor of LIG after successful thrombectomy and cerebral collateral status is not. KEY POINTS: • Few predictors of ischemic growth are known in ischemic stroke patients achieving successful mechanical thrombectomy. • Our results suggest that the brush sign-a surrogate marker of severe hypoperfusion-is independently associated with large ischemic growth (> 11.6 mL) after successful thrombectomy whereas cerebral collateral status does not.

Patient-Reported Quality of Life After Intravenous Alteplase for Stroke in the WAKE-UP Trial.

BACKGROUND AND OBJECTIVES: Intravenous alteplase improves functional outcome after acute ischemic stroke. However, little is known about the effects on self-reported health-related quality of life (HRQoL). METHODS: WAKE-UP was a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in stroke with unknown onset time. HRQoL was assessed using the EuroQol five-dimensional questionnaire (EQ-5D) at 90 days, comprising the EQ-5D index and the EQ visual analogue scale (VAS). Functional outcome was assessed by the modified Rankin Scale (mRS). We calculated the effect of treatment on EQ-5D index and EQ VAS using multiple linear regression models. Mediation analysis was performed on stroke survivors to explore the extent to which the effect of alteplase on HRQoL was mediated by functional outcome. RESULTS: Among 490 stroke survivors, the EQ-5D index was available for 452 (92.2%), of whom 226 (50%) were assigned to treatment with alteplase and 226 (50%) to placebo. At 90 days, mean EQ-5D index was higher, reflecting a better health state, in patients randomized to treatment with alteplase than with placebo (0.75 vs 0.67) with an adjusted mean difference of 0.07 (95% CI 0.02-0.12, p = 0.005). In addition, mean EQ VAS was higher with alteplase than with placebo (72.6 vs 64.9), with an adjusted mean difference of 7.6 (95% CI 3.9-11.8, p < 0.001). Eighty-five percent of the total treatment effect of alteplase on the EQ-5D index was mediated using the mRS score while there was no significant direct effect. By contrast, the treatment effect on the EQ VAS was mainly through the direct pathway (60%), whereas 40% was mediated by the mRS. DISCUSSION: Assessment of patient-reported outcome measures reveals a potential benefit of intravenous alteplase for HRQoL beyond improvement of functional outcome. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov number, NCT01525290; EudraCT number, 2011-005906-32.

Sex differences in imaging and clinical characteristics of patients from the WAKE-UP trial.

BACKGROUND AND PURPOSE: Sex-based differences in acute ischemic stroke are a well-known phenomenon. We aimed to explore these differences between women and men in the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial. METHODS: We compared baseline demographic and imaging characteristics (visual fluid-attenuated inversion recovery [FLAIR] positivity, relative FLAIR signal intensity, collateral status) between women and men in all screened patients. In randomized patients (i.e., those with diffusion-weighted imaging (DWI)-FLAIR mismatch), we evaluated a modifying role of sex on the treatment effect of alteplase in multivariable logistic regression, with treatment adjusted for National Institute of Health Stroke Scale (NIHSS) score and age. Dependent variables were modified Rankin Scale (mRS) score of 0-1 at 90 days and distribution of mRS scores at 90 days. RESULTS: Of 1362 screened patients, 529 (38.8%) were women. Women were older than men, had higher baseline NIHSS scores and smoked less frequently. FLAIR positivity of the DWI lesion was equally present in women (174/529, 33.1%) and men (273/833, 33.3%; p = 1.00) and other imaging variables also did not differ between the sexes. In a total of 503 randomized patients, of whom 178 were women (35.4%), sex did not modify the treatment effect of alteplase on mRS score 0-1 or on the total distribution of mRS scores. CONCLUSION: As in many other stroke trials, more men than women were included in the WAKE-UP trial, but the presence of a visual DWI-FLAIR mismatch and the relative FLAIR signal intensity did not differ between the sexes. The treatment effect of alteplase was not modified by sex.

Assessment of three MR perfusion software packages in predicting final infarct volume after mechanical thrombectomy.

AIMS: To evaluate the performance of three MR perfusion software packages (A: RAPID; B: OleaSphere; and C: Philips) in predicting final infarct volume (FIV). METHODS: This cohort study included patients treated with mechanical thrombectomy following an admission MRI and undergoing a follow-up MRI. Admission MRIs were post-processed by three packages to quantify ischemic core and perfusion deficit volume (PDV). Automatic package outputs (uncorrected volumes) were collected and corrected by an expert. Successful revascularization was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) score ≥2B. Uncorrected and corrected volumes were compared between each package and with FIV according to mTICI score. RESULTS: Ninety-four patients were included, of whom 67 (71.28%) had a mTICI score ≥2B. In patients with successful revascularization, ischemic core volumes did not differ significantly from FIV regardless of the package used for uncorrected and corrected volumes (p>0.15). Conversely, assessment of PDV showed significant differences for uncorrected volumes. In patients with unsuccessful revascularization, the uncorrected PDV of packages A (median absolute difference -40.9 mL) and B (median absolute difference -67.0 mL) overestimated FIV to a lesser degree than package C (median absolute difference -118.7 mL; p=0.03 and p=0.12, respectively). After correction, PDV did not differ significantly from FIV for all three packages (p≥0.99). CONCLUSIONS: Automated MRI perfusion software packages estimate FIV with high variability in measurement despite using the same dataset. This highlights the need for routine expert evaluation and correction of automated package output data for appropriate patient management.

Association of Blood Biomarkers of Inflammation With Penumbra Consumption After Mechanical Thrombectomy in Patients With Acute Ischemic Stroke.

BACKGROUND AND OBJECTIVES: The objective of this study was to assess the relationship between blood biomarkers of inflammation and lesion growth within the penumbra in acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT). METHODS: The HIBISCUS-STROKE cohort enrolled patients admitted in the Lyon Stroke Center for an anterior circulation AIS treated with MT after brain MRI assessment. Lesion growth within the penumbra was assessed on day 6 MRI using a voxel-based nonlinear coregistration method and dichotomized into low and high according to the median value. C-reactive protein, interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1, soluble tumor necrosis factor receptor I, soluble form suppression of tumorigenicity 2 (sST2), soluble P-selectin, vascular cellular adhesion molecule-1, and matrix metalloproteinase-9 were measured in sera at 4 time points within the first 48 hours. Reperfusion was considered as successful if Thrombolysis in Cerebral Infarction score was 2b/2c/3. A multiple logistic regression model was performed to detect any association between area under the curve (AUC) of these biomarkers within the first 48 hours and a high lesion growth within the penumbra. RESULTS: Ninety patients were included. The median lesion growth within the penumbra was 2.3 (0.7-6.2) mL. On multivariable analysis, a high sST2 AUC (OR 3.77, 95% CI 1.36-10.46), a high baseline DWI volume (OR 3.65, 95% CI 1.32-10.12), and a lack of successful reperfusion (OR 0.19, 95% CI 0.04-0.92) were associated with a high lesion growth within the penumbra. When restricting analyses to patients with successful reperfusion (n = 76), a high sST2 AUC (OR 5.03, 95% CI 1.64-15.40), a high baseline DWI volume (OR 3.74, 95% CI 1.22-11.53), and a high penumbra volume (OR 3.25, 95% CI 1.10-9.57) remained associated with a high lesion growth within the penumbra. DISCUSSION: High sST2 levels within the first 48 hours are associated with a high lesion growth within the penumbra.

Yield of Dual Therapy With Statin and Ezetimibe in the Treat Stroke to Target Trial.

BACKGROUND: In atherosclerotic stroke, lipid-lowering treatment with a target LDL (low-density lipoprotein) cholesterol of <70 compared with 100±10 mg/dL reduced the risk of subsequent cardiovascular events. This post hoc analysis explored the relative effects of the combination of statin and ezetimibe (dual therapy) and statin monotherapy in achieving the lower LDL cholesterol target and in reducing the risk of major vascular events, as compared with the higher target group. METHODS: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned to a target LDL cholesterol of <70 or 100±10 mg/dL, using statin and/or ezetimibe as needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization, and vascular death. Cox regression model including lipid-lowering therapy as a time varying variable, after adjustment for randomization strategy, age, sex, index event (stroke or transient ischemic attack), and time since the index event. RESULTS: Among 2860 patients enrolled, patients who were on dual therapy during the trial in the lower target group had a higher baseline LDL cholesterol as compared to patients on statin monotherapy (141±38 versus 131±36, respectively, P<0.001). In patients on dual therapy and on statin monotherapy, the achieved LDL cholesterol was 66.2 and 64.1 mg/dL respectively, and the primary outcome was reduced during dual therapy as compared with the higher target group (HR, 0.60 [95% CI, 0.39-0.91]; P=0.016) but not during statin monotherapy (HR, 0.92 [95% CI, 0.70-1.20]; P=0.52), with no significant increase in intracranial bleeding. CONCLUSIONS: In the TST trial (Treat Stroke to Target), targeting an LDL cholesterol of < 70 mg/dL with a combination of statin and ezetimibe compared with 100±10 mg/dL consistently reduced the risk of subsequent stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01252875. URL: clinicaltrialsregister.eu; Unique identifier: EUDRACT2009-A01280-57.

Early effect of thrombolysis on structural brain network organisation after anterior-circulation stroke in the randomized WAKE-UP trial.

The symptoms of acute ischemic stroke can be attributed to disruption of the brain network architecture. Systemic thrombolysis is an effective treatment that preserves structural connectivity in the first days after the event. Its effect on the evolution of global network organisation is, however, not well understood. We present a secondary analysis of 269 patients from the randomized WAKE-UP trial, comparing 127 imaging-selected patients treated with alteplase with 142 controls who received placebo. We used indirect network mapping to quantify the impact of ischemic lesions on structural brain network organisation in terms of both global parameters of segregation and integration, and local disruption of individual connections. Network damage was estimated before randomization and again 22 to 36 h after administration of either alteplase or placebo. Evolution of structural network organisation was characterised by a loss in integration and gain in segregation, and this trajectory was attenuated by the administration of alteplase. Preserved brain network organization was associated with excellent functional outcome. Furthermore, the protective effect of alteplase was spatio-topologically nonuniform, concentrating on a subnetwork of high centrality supported in the salvageable white matter surrounding the ischemic cores. This interplay between the location of the lesion, the pathophysiology of the ischemic penumbra, and the spatial embedding of the brain network explains the observed potential of thrombolysis to attenuate topological network damage early after stroke. Our findings might, in the future, lead to new brain network-informed imaging biomarkers and improved prognostication in ischemic stroke.

Inflammatory profile and white matter hyperintensity burden in acute ischemic stroke patients.

Inflammation is involved in small vessel disease (SVD). We aim to clarify whether inflammation related to white matter hyperintensities (WMH), a key component of SVD, may affect the inflammatory response in acute ischemic stroke (AIS) patients. For this, we sequentially measured 10 circulating inflammatory markers and assessed WMH burden on admission MRI in AIS patients treated with thrombectomy. Of 149 patients, 57 (38.3%) had a high WMH burden (Fazekas≥3). A high WMH burden was associated with 4 markers levels but this association did not remain following multivariable analyses. WMH burden is not associated with a specific inflammatory profile in AIS.