The obstetrical consequences of ischemic stroke in women of childbearing age.

PURPOSE: Although recurrence risk is a major concern for women having had an ischemic stroke (IS) and who are planning a pregnancy, studies on recurrence risk and pregnancy outcomes are scarce and heterogeneous. METHODS: This retrospective study assessed women aged 15-44 years with a diagnosis of ischemic stroke admitted in the Lyon Stroke Centre, France, between January 2009 and December 2013. The primary outcome was stroke recurrence during pregnancy or the post-partum period. Secondary outcomes were pregnancy complications. RESULTS: Overall, 104 women with a prior ischemic stroke were included. Mean age at the time of the stroke was 36 ± 6.7 years old. Stroke etiology was large-artery atherosclerosis for 1 woman, cardioembolism for 23 women, and undetermined for 55 women. No antiphospholipid syndrome was found. Among them, 29 women had 58 subsequent pregnancies. Overall, there were three IS recurrence (2.9%), but none occurred during pregnancy. There were 27 miscarriages (47% of pregnancies), two pre-eclampsia (3%), and one stillbirth (1.7%). CONCLUSIONS: We observed no recurrence of IS during pregnancy. The study also highlighted that the risk of miscarriages was higher than general population and that of stillbirth should be further studied.

Interrater reliability in neurology objective structured clinical examination across specialties.

PURPOSE: To assess interrater reliability and examiners' characteristics, especially specialty, associated with scoring of neurology objective structured clinical examination (OSCE). MATERIAL AND METHODS: During a neurology mock OSCE, five randomly chosen students volunteers were filmed while performing 1 of the 5 stations. Video recordings were scored by physicians from the Lyon and Clermont-Ferrand university teaching hospitals to assess students performance using both a checklist scoring and a global rating scale. Interrater reliability between examiners were assessed using intraclass coefficient correlation. Multivariable linear regression models including video recording as random effect dependent variable were performed to detect factors associated with scoring. RESULTS: Thirty examiners including 15 (50%) neurologists participated. The intraclass correlation coefficient of checklist scores and global ratings between examiners were 0.71 (CI95% [0.45-0.95]) and 0.54 (CI95% [0.28-0.91]), respectively. In multivariable analyses, no factor was associated with checklist scores, while male gender of examiner was associated with lower global rating (ß coefficient = -0.37; CI 95% [-0.62-0.11]). CONCLUSIONS: Our study demonstrated through a video-based scoring method that agreement among examiners was good using checklist scoring while moderate using global rating scale in neurology OSCE. Examiner's specialty did not affect scoring whereas gender was associated with global rating scale.

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.

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.

Relevance of National Institutes of Health Stroke Scale subitems for best revascularization therapy in minor stroke patients with large vessel occlusion: An observational multicentric study.

BACKGROUND AND PURPOSE: The best management of acute ischemic stroke patients with a minor stroke and large vessel occlusion is still uncertain. Specific clinical and radiological data may help to select patients who would benefit from endovascular therapy (EVT). We aimed to evaluate the relevance of National Institutes of Health Stroke Scale (NIHSS) subitems for predicting the potential benefit of providing EVT after intravenous thrombolysis (IVT; "bridging treatment") versus IVT alone. METHODS: We extracted demographic, clinical, risk factor, radiological, revascularization and outcome data of consecutive patients with M1 or proximal M2 middle cerebral artery occlusion and admission NIHSS scores of 0-5 points, treated with IVT ± EVT between May 2005 and March 2021, from nine prospectively constructed stroke registries at seven French and two Swiss comprehensive stroke centers. Adjusted interaction analyses were performed between admission NIHSS subitems and revascularization modality for two primary outcomes at 3 months: non-excellent functional outcome (modified Rankin Scale score 2-6) and difference in NIHSS score between 3 months and admission. RESULTS: Of the 533 patients included (median age 68.2 years, 46% women, median admission NIHSS score 3), 136 (25.5%) initially received bridging therapy and 397 (74.5%) received IVT alone. Adjusted interaction analysis revealed that only facial palsy on admission was more frequently associated with excellent outcome in patients treated by IVT alone versus bridging therapy (odds ratio 0.47, 95% confidence interval 0.24-0.91; p = 0.013). Regarding NIHSS difference at 3 months, no single NIHSS subitem interacted with type of revascularization. CONCLUSIONS: This retrospective multicenter analysis found that NIHSS subitems at admission had little value in predicting patients who might benefit from bridging therapy as opposed to IVT alone. Further research is needed to identify better markers for selecting EVT responders with minor strokes.

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.

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.

Gut microbiota and stroke: New avenues to improve prevention and outcome.

Despite major recent therapeutic advances, stroke remains a leading cause of disability and death. Consequently, new therapeutic targets need to be found to improve stroke outcome. The deleterious role of gut microbiota alteration (often mentioned as "dysbiosis") on cardiovascular diseases, including stroke and its risk factors, has been increasingly recognized. Gut microbiota metabolites, such as trimethylamine-N-oxide, short chain fatty acids and tryptophan, play a key role. Evidence of a link between alteration of the gut microbiota and cardiovascular risk factors exists, with a possible causality link supported by several preclinical studies. Gut microbiota alteration also seems to be implicated at the acute phase of stroke, with observational studies showing more non-neurological complications, higher infarct size and worse clinical outcome in stroke patients with altered microbiota. Microbiota targeted strategies have been developed, including prebiotics/probiotics, fecal microbiota transplantation, short chain fatty acid and trimethylamine-N-oxide inhibitors. Research teams have been using different time windows and end-points for their studies, with various results. Considering the available evidence, it is believed that studies focusing on microbiota-targeted strategies in association with conventional stroke care should be conducted. Such strategies should be considered according to three therapeutic time windows: first, at the pre-stroke (primary prevention) or post-stroke (secondary prevention) phases, to enhance the control of cardiovascular risk factors; secondly, at the acute phase of stroke, to limit the infarct size and the systemic complications and enhance the overall clinical outcome; thirdly, at the subacute phase of stroke, to prevent stroke recurrence and promote neurological recovery.

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.

Inhibition of alkaline phosphatase impairs dyslipidemia and protects mice from atherosclerosis.

Calcium accumulation in atherosclerotic plaques predicts cardiovascular mortality, but the mechanisms responsible for plaque calcification and how calcification impacts plaque stability remain debated. Tissue-nonspecific alkaline phosphatase (TNAP) recently emerged as a promising therapeutic target to block cardiovascular calcification. In this study, we sought to investigate the effect of the recently developed TNAP inhibitor SBI-425 on atherosclerosis plaque calcification and progression. TNAP levels were investigated in ApoE-deficient mice fed a high-fat diet from 10 weeks of age and in plaques from the human ECLAGEN biocollection (101 calcified and 14 non-calcified carotid plaques). TNAP was inhibited in mice using SBI-425 administered from 10 to 25 weeks of age, and in human vascular smooth muscle cells (VSMCs) with MLS-0038949. Plaque calcification was imaged in vivo with 18F-NaF-PET/CT, ex vivo with osteosense, and in vitro with alizarin red. Bone architecture was determined with µCT. TNAP activation preceded and predicted calcification in human and mouse plaques, and TNAP inhibition prevented calcification in human VSMCs and in ApoE-deficient mice. More unexpectedly, TNAP inhibition reduced the blood levels of cholesterol and triglycerides, and protected mice from atherosclerosis, without impacting the skeletal architecture. Metabolomics analysis of liver extracts identified phosphocholine as a substrate of liver TNAP, who's decreased dephosphorylation upon TNAP inhibition likely reduced the release of cholesterol and triglycerides into the blood. Systemic inhibition of TNAP protects from atherosclerosis, by ameliorating dyslipidemia, and preventing plaque calcification.

Time to treatment with bridging intravenous alteplase before endovascular treatment:subanalysis of the randomized controlled SWIFT-DIRECT trial.

BACKGROUND: We hypothesized that treatment delays might be an effect modifier regarding risks and benefits of intravenous thrombolysis (IVT) before mechanical thrombectomy (MT). METHODS: We used the dataset of the SWIFT-DIRECT trial, which randomized 408 patients to IVT+MT or MT alone. Potential interactions between assignment to IVT+MT and expected time from onset-to-needle (OTN) as well as expected time from door-to-needle (DTN) were included in regression models. The primary outcome was functional independence (modified Rankin Scale (mRS) 0-2) at 3 months. Secondary outcomes included mRS shift, mortality, recanalization rates, and (symptomatic) intracranial hemorrhage at 24 hours. RESULTS: We included 408 patients (IVT+MT 207, MT 201, median age 72 years (IQR 64-81), 209 (51.2%) female). The expected median OTN and DTN were 142 min and 54 min in the IVT+MT group and 129 min and 51 min in the MT alone group. Overall, there was no significant interaction between OTN and bridging IVT assignment regarding either the functional (adjusted OR (aOR) 0.76, 95% CI 0.45 to 1.30) and safety outcomes or the recanalization rates. Analysis of in-hospital delays showed no significant interaction between DTN and bridging IVT assignment regarding the dichotomized functional outcome (aOR 0.48, 95% CI 0.14 to 1.62), but the shift and mortality analyses suggested a greater benefit of IVT when in-hospital delays were short. CONCLUSIONS: We found no evidence that the effect of bridging IVT on functional independence is modified by overall or in-hospital treatment delays. Considering its low power, this subgroup analysis could have missed a clinically important effect, and exploratory analysis of secondary clinical outcomes indicated a potentially favorable effect of IVT with shorter in-hospital delays. Heterogeneity of the IVT effect size before MT should be further analyzed in individual patient meta-analysis of comparable trials. TRIAL REGISTRATION NUMBER: URL: https://www. CLINICALTRIALS: gov ; Unique identifier: NCT03192332.

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.

CNN-LSTM Based Multimodal MRI and Clinical Data Fusion for Predicting Functional Outcome in Stroke Patients.

Clinical outcome prediction plays an important role in stroke patient management. From a machine learning point-of-view, one of the main challenges is dealing with heterogeneous data at patient admission, i.e. the image data which are multidimensional and the clinical data which are scalars. In this paper, a multimodal convolutional neural network - long short-term memory (CNN-LSTM) based ensemble model is proposed. For each MR image module, a dedicated network provides preliminary prediction of the clinical outcome using the modified Rankin scale (mRS). The final mRS score is obtained by merging the preliminary probabilities of each module dedicated to a specific type of MR image weighted by the clinical metadata, here age or the National Institutes of Health Stroke Scale (NIHSS). The experimental results demonstrate that the proposed model surpasses the baselines and offers an original way to automatically encode the spatio-temporal context of MR images in a deep learning architecture. The highest AUC (0.77) was achieved for the proposed model with NIHSS. Clinical Relevance- - We present the first deep learning approach predicting the clinical outcome of stroke patients treated by mechanical thrombectomy which integrates imaging data at the voxel level with key clinical metadata. Combining clinical and imaging data to evaluate the potential benefit from therapy closely mirrors the clinical decision process. Our promising results suggest our predictive model could assist in acute stroke management.

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.

Safety and efficacy of prophylactic levetiracetam for prevention of epileptic seizures in the acute phase of intracerebral haemorrhage (PEACH): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage. METHODS: The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding. FINDINGS: Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0·16, 95% CI 0·03-0·94, p=0·043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group. INTERPRETATION: Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage. FUNDING: French Ministry of Health.

Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial.

BACKGROUND: Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke. METHODS: In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants. FINDINGS: Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [91%] of 201 vs 199 [96%] of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047). INTERPRETATION: Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients. FUNDING: Medtronic and University Hospital Bern.

Leukoaraiosis Distribution and Cerebral Collaterals: A Systematic Review and Meta-Analysis.

Background and Objective: Microvascular failure might result in the collapse of cerebral collaterals. However, controversy remains regarding the role of leukoaraiosis (LA) in collateral recruitment. We, therefore, performed a systematic review and meta-analysis of the association between LA and cerebral collaterals. Methods: Ovid Medline, PubMed, Embase, Web of Science, and three Chinese databases were searched from inception to August 2021. Two types of cerebral collaterals, including Circle of Willis (CoW) and leptomeningeal collaterals (LC), were investigated separately. Random effect models were used to calculate the pooled odds ratio (OR). Meta-regression and subgroup analyses were performed to explore the potential sources of heterogeneity. Results: From 14 studies (n = 2,451) that fulfilled our inclusion criteria, data from 13 could be pooled for analysis. Overall, there was a significant association between severe LA and incomplete CoW (pooled OR 1.66, 95% CI 1.18-2.32, p = 0.003), with low heterogeneity (I 2 = 5.9%). This association remained significant in deep LA (pooled OR 1.48, 95% CI 1.04-2.11, p = 0.029, I 2 = 0), but not periventricular LA. Similarly, there was a significant association between LA and LC (pooled OR 1.73, 95% CI 1.03-2.90, p = 0.037), but with high heterogeneity (I 2 = 67.2%). Meta-regression indicated a negative association of sample size with the effect sizes (p = 0.029). In addition, most of the studies (7/9) included into the analysis of the relationship of severe LA with poor LC enrolled subjects with large vessel occlusion stroke, and this relationship remained significant when pooling the seven studies, but with high heterogeneity. Conclusion: Severe LA is associated with a higher prevalence of poor collaterals. This association is robust for CoW but weak for LC. Further studies are required to explore the underlying mechanisms.