Search

Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function. Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function. Methods: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker). Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p-values interaction terms > 0.05). Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns.

Purpose Follow-up infarct volume (FIV) is moderately associated with functional outcome. We hypothesized that accounting for infarct location would strengthen the association of FIV with functional outcome. Methods We included 252 patients from the HERMES collaboration with follow-up diffusion weighted imaging. Patients received endovascular treatment combined with best medical management (n = 52%) versus best medical management alone (n = 48%). FIV was quantified in low, moderate and high modified Rankin Scale (mRS)-relevant regions. We used binary logistic regression to study the relation between the total, high, moderate or low mRS-relevant FIVs and favorable outcome (mRS Results Small lesions only occupied high mRS-relevant brain regions. Lesions additionally occupied lower mRS-relevant brain regions if FIV expanded. Higher FIV was associated with a higher risk of unfavorable outcome, as were volumes of tissue with low, moderate and high mRS relevance. In multivariable modeling, only the volume of high mRS-relevant infarct was significantly associated with favorable outcome. The c-statistic was highest (0.76) for the models that included high mRS-relevant FIV or the combination of high, moderate and low mRS-relevant FIV but was not significantly different from the model that included only total FIV (0.75). Conclusion This study confirms the association of FIV and unfavorable functional outcome but showed no strengthened association if lesion location was taken into account.

Background Sporadic cerebral small vessel disease (SVD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) share clinical and neuroimaging features and possibly vascular dysfunction(s). However few studies have included both conditions, assessed more than one vascular dysfunction simultaneously, or included more than one centre. The INVESTIGATE-SVDs study will assess several cerebrovascular dysfunctions with MRI in participants with sporadic SVD or CADASIL at three European centres. Methods We will recruit participants with sporadic SVDs (ischaemic stroke or vascular cognitive impairment) and CADASIL in Edinburgh, Maastricht and Munich. We will perform detailed clinical and neuropsychological phenotyping of the participants, and neuroimaging including structural MRI, cerebrovascular reactivity MRI (CVR: using carbon dioxide challenge), phase contrast MRI (arterial, venous and CSF flow and pulsatility), dynamic contrast-enhanced MRI (blood brain barrier (BBB) leakage) and multishell diffusion imaging. Participants will measure their blood pressure (BP) and its variability over seven days using a telemetric device. Discussion INVESTIGATE-SVDs will assess the relationships of BBB integrity, CVR, pulsatility and CSF flow in sporadic SVD and CADASIL using a multisite, multimodal MRI protocol. We aim to establish associations between these measures of vascular function, risk factors particularly BP and its variability, and brain parenchymal lesions in these two SVD phenotypes. Additionally we will test feasibility of complex multisite MRI, provide reliable intermediary outcome measures and sample size estimates for future trials.

Background and Purpose: Thrombectomy with stent retriever and direct aspiration are equally effective in the endovascular treatment of anterior circulation acute ischemic stroke. We report efficacy and safety of initial treatment technique per occlusion segment. Methods: For this study, we analyzed data from the MR CLEAN Registry, a prospective, observational study in all centers that perform endovascular therapy in the Netherlands. We used ordinal logistic regression analysis to compare clinical and technical results of first line direct aspiration treatment with that of stent retriever thrombectomy stratified for occlusion segment. Primary outcome measure was functional outcome at 3 months. Secondary outcome measures included reperfusion grade expressed as the extended Thrombolysis in Cerebral Infarction score, periprocedural complication risk, time to reperfusion, and mortality. Results: Of the 2282 included patients, 1658 (73%) were initially treated with stent retriever and 624 (27%) with aspiration. Four hundred sixty-two patients had an occlusion of the intracranial part of the carotid artery, 1349 of the proximal middle cerebral artery, and 471 of the distal parts of the middle cerebral artery. There was no difference in functional outcome between aspiration and stent retriever thrombectomy (odds ratio, 1.0 [95% CI, 0.9–1.2]) in any of the occlusion segments ( P value for interaction=0.2). Reperfusion rate was higher in the aspiration group (odds ratio, 1.4 [95% CI, 1.1–1.6]) and did not differ between occlusion segments ( P value for interaction=0.6). Procedure times were shorter in the aspiration group (minutes 50 versus 65 minutes; P Conclusions: In unselected patients with anterior circulation infarcts, we observed equal functional outcome of aspiration and stent retriever thrombectomy in all occlusion segments. When aspiration was the first line treatment modality, reperfusion rates were higher and procedure times shorter in all occlusion segments.

Background CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome.Methods In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1,2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 mu m(2)/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered.Findings We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0.47 [95% CI 0.30-0.72], p=0.0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0.77 [0.69-0.86] per 10 mL, p(interaction)=0.29; diffusion MRI OR 0.87 [0.81-0.94] per 10 mL, p(interaction)=0.94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low.Interpretation Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imagingto-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

Background Antiplatelet therapy may increase the risk of symptomatic intracranial hemorrhage after endovascular treatment for ischemic stroke but may also have a beneficial effect on functional outcome. The aim of this study is to compare safety and efficacy outcomes after endovascular treatment in patients with and without prior antiplatelet therapy. Methods We analyzed patients registered in the MR CLEAN Registry between March 2014 and November 2017, for whom data on antiplatelet therapy were available. We used propensity score nearest-neighbor matching with replacement to balance the probability of receiving prior antiplatelet therapy between the prior antiplatelet therapy and no prior antiplatelet therapy group and adjusted for baseline prognostic factors to compare these groups. Primary outcome was symptomatic intracranial hemorrhage. Secondary outcomes were 90-day functional outcome (modified Rankin Scale), successful reperfusion (extended thrombolysis in cerebral infarction score ≥2B) and 90-day mortality. Results Thirty percent ( n = 937) of the 3154 patients were on prior antiplatelet therapy, who were matched to 477 patients not on prior antiplatelet therapy. Symptomatic intracranial hemorrhage occurred in 74/937 (7.9%) patients on prior antiplatelet therapy and in 27/477 (5.6%) patients without prior antiplatelet therapy adjusted odds ratio 1.47, 95% confidence interval 0.86–2.49. No associations were found between prior antiplatelet therapy and functional outcome (adjusted common odds ratio 0.87, 95% confidence interval 0.65–1.16), successful reperfusion (adjusted odds ratio 1.23, 95% confidence interval 0.77–1.97), or 90-day mortality (adjusted odds ratio 1.15, 95% confidence interval 0.86–1.54). Conclusion We found no evidence of an association of prior antiplatelet therapy with the risk of symptomatic intracranial hemorrhage after endovascular treatment, nor on functional outcome, reperfusion, or mortality. A substantial beneficial or detrimental effect of antiplatelet therapy on clinical outcome cannot be excluded. A randomized clinical trial comparing antiplatelet therapy versus no antiplatelet therapy is needed.

Background: Cerebral intravoxel incoherent motion (IVIM) imaging assumes two components. However, more compartments are likely present in pathologic tissue. We hypothesized that spectral analysis using a nonnegative least-squares (NNLS) approach can detect an additional, intermediate diffusion component, distinct from the parenchymal and microvascular components, in lesion-prone regions. Purpose: To investigate the presence of this intermediate diffusion component and its relation with cerebral small vessel disease (cSVD)-related lesions. Study Type: Prospective cross-sectional study. Population: Patients with cSVD (n = 69, median age 69.8) and controls (n = 39, median age 68.9). Field Strength/Sequence: Whole-brain inversion recovery IVIM acquisition at 3.0T. Assessment: Enlarged perivascular spaces (PVS) were rated by three raters. White matter hyperintensities (WMH) were identified on a fluid attenuated inversion recovery (FLAIR) image using a semiautomated algorithm. Statistical Tests: Relations between IVIM measures and cSVD-related lesions were studied using the Spearman's rank order correlation. Results: NNLS yielded diffusion spectra from which the intermediate volume fraction f int was apparent between parenchymal diffusion and microvasular pseudodiffusion. WMH volume and the extent of MRI-visible enlarged PVS in the basal ganglia (BG) and centrum semiovale (CSO) were correlated with f int in the WMHs, BG, and CSO, respectively. f int was 4.2 ± 1.7%, 7.0 ± 4.1% and 13.6 ± 7.7% in BG and 3.9 ± 1.3%, 4.4 ± 1.4% and 4.5 ± 1.2% in CSO for the groups with low, moderate, and high number of enlarged PVS, respectively, and increased with the extent of enlarged PVS (BG: r = 0.49, P < 0.01; CSO: r = 0.23, P = 0.02). f int in the WMHs was 27.1 ± 13.1%, and increased with the WMH volume (r = 0.57, P < 0.01). Data Conclusion: We revealed the presence of an intermediate diffusion component in lesion-prone regions of cSVD and demonstrated its relation with enlarged PVS and WMHs. In tissue with these lesions, tissue degeneration or perivascular edema can lead to more freely diffusing interstitial fluid contributing to f int. Level of Evidence: 2. Technical Efficacy: Stage 2. J. Magn. Reson. Imaging 2020;51:1170–1180.

Introduction: Outcomes after endovascular treatment (EVT) for acute ischemic stroke are highly time dependent, but whether active reduction of time to treatment leads to better outcome has not been demonstrated. We compared data of the two subsequent MR CLEAN Registry cohorts, comprising all patients in the Netherlands who had EVT for acute ischemic stroke from 2014-2017, for a trend in time to treatment and its association with outcome. Methods: We compared workflow, successful reperfusion (eTICI 2B-3), NIHSS at 24h, functional outcome (mRS) at 90 days, occurrence of symptomatic intracranial hemorrhage (sICH) and mortality in patients with ischemic stroke and a proximal intracranial occlusion in the anterior circulation included in the second cohort of the Registry (June 2016-November 2017; n = 1779) to those in patients included in the first cohort (March 2014-June 2016; n = 1526) using logistic regression. Results: Baseline NIHSS was 16 in both cohorts. Times from onset-to-groin and onset-to-reperfusion were shorter in the second cohort than in the first (185 versus 210 minutes; p Discussion: Our data show that outcomes after EVT in routine clinical practice are improving, likely attributable to improved workflow and experience.

Introduction: Intracranial hemorrhage after acute ischemic stroke patients manifests as natural progression or as a complication of treatment with potential subsequent neurological deterioration. Currently it is unclear whether these hemorrhagic transformations (HT) contribute to the poorer functional outcomes observed in patients with large infarcts. The purpose of this study is to assess the association of HT with follow-up infarct volume (FIV) and functional outcome at 90 days after AIS. Additionally, we determined whether the development of HT was associated with a diminished endovascular therapy (EVT) effect. Methods: All patients from the HERMES collaboration with follow-up imaging were included. HERMES is pooled data from seven randomized controlled trials that assessed the efficacy and safety of EVT compared to usual care. Patients with HT were identified according to the ECASS classification and FIV was assessed on CT or MRI. Infarct and hemorrhage were included in the FIV. We assessed functional outcome using the modified Rankin Scale 90 days after stroke onset. Ordinal logistic regression with adjustment for potential confounders was used to determine the association of HT and FIV with functional outcome. Results: Of all included patients with follow-up imaging (n=1665), 42% had HT (n=698). Before and after adjustment for confounders HT and FIV were associated with a shift in the direction of poorer functional outcome (aOR:0.71,95%CI:0.58-0.86 and aOR:0.99,95%CI:0.99-0.99). EVT was beneficial in patients with and without HT, but effect was greater in patients without (aOR:1.70,95%CI:1.27-2.28 vs. aOR:2.51,95%CI:1.97-3.20)(figure 1.) Conclusions: In this analysis, patients with HT after AIS were less likely to have good functional outcome compared to those without HT, independent of the FIV. While the EVT effect was slightly diminished in patients who developed HT, EVT was always of significant benefit.

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Ang II infusion is associated with increased permeability of the blood-brain barrier (BBB) and chronic activation of microglia. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF-1R inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory were assessed during an Object Location task and a Morris Water Maze task (MWM). At the end of the study, microglia depletion efficacy and BBB leakages were assessed using flow cytometry and immunohistochemistry.Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, but not in Ang II mice treated with PLX5622. Histological and flow cytometry analyses revealed almost complete ablation of microglia upon CSF1R inhibition, while brain resident perivascular macrophages, were reduced by 60%. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment.Conclusion: Our results show that depletion of microglia, and less so PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. This novel finding supports the critical role of brain immune cells, and most in particular microglia, in the pathogenesis of hypertension-related cognitive impairment.

ObjectiveTo compare outcomes after endovascular treatment (EVT) for acute ischemic stroke with 3 different types of anesthetic management in clinical practice, as anesthetic management may influence functional outcome.MethodsData of patients with an anterior circulation occlusion, included in the Dutch nationwide, prospective Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry between March 2014 and June 2016, were analyzed. Patients were divided into 3 groups defined by anesthetic technique performed during EVT: local anesthesia only (LA), general anesthesia (GA), or conscious sedation (CS). Primary outcome was the modified Rankin Scale score at 90 days. To compare functional outcome between groups, we estimated a common odds ratio (OR) with ordinal logistic regression, adjusted for age, sex, prestroke modified Rankin Scale score, baseline NIH Stroke Scale score, collaterals, and time from onset to arrival at intervention center.ResultsA total of 1,376 patients were included. Performed anesthetic technique was LA in 821 (60%), GA in 381 (28%), and CS in 174 (13%) patients. Compared to LA, both GA and CS were associated with worse functional outcome on the modified Rankin Scale score at 90 days (GA cORadj 0.75; 95% confidence interval [CI] 0.58–0.97; CS cORadj 0.45; 95% CI 0.33–0.62). CS was associated with worse functional outcome than GA (cORadj 0.60; 95% CI 0.42–0.87).ConclusionsLA is associated with better functional outcome than systemic sedation in patients undergoing EVT for acute ischemic stroke. Whereas LA had a clear advantage over CS, this was less prominent compared to GA.Classification of evidenceThis study provides Class III evidence that for patients with acute ischemic stroke undergoing EVT, LA improves functional outcome compared to GA or CS.

Introduction: We examined the role of hemodynamic dysfunction in cognition by relating cerebral blood flow (CBF), measured with arterial spin labeling (ASL), to cognitive functioning, in patients with heart failure (HF), carotid occlusive disease (COD), and patients with cognitive complaints and vascular brain injury on magnetic resonance imaging (MRI; ie, possible vascular cognitive impairment [VCI]).Methods: We included 439 participants (124 HF; 75 COD; 127 possible VCI; 113 reference participants) from the Dutch multi-center Heart-Brain Study. We used pseudo-continuous ASL to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and four cognitive domains.Results: CBF values were lowest in COD, followed by VCI and HF, compared to reference participants. This did not explain cognitive impairment, as we did not find an association between CBF and cognitive functioning.Discussion: We found that reduced CBF is not the major explanatory factor underlying cognitive impairment in patients with hemodynamic dysfunction along the heart-brain axis.

Background and purpose: While computer-aided diagnosis (CAD) tools are widely used in stroke imaging routines already, their influence on actual decision-making is still underexplored. We analyzed the effect of a simulated CAD tool on ASPECT-Scoring on acute-stroke CT-scans with respect to experience level. Materials and methods: Baseline CT scans of 100 stroke patients from the MR CLEAN trial with consensus-ASPECTS as ground truth were independently ASPECTS graded by three readers with different levels of experience. Weeks later the same CTs were re-analyzed with additional displaying of simulated ASPECTS (s-ASPECTS, by adding or subtracting 2 points from the ground truth). Readers were told that the score was generated by an automatic ASPECT-Scoring algorithm. The influence of the displayed s-ASPECTS on the readers’ second ASPECT-Scoring was analyzed by using a linear mixed model and the reliability was assessed. Performance was measured as the absolute difference between readers ASPECTS and consensus-ASPECTS. Results: The influence of the s-ASPECTS on the second ASPECT-Scoring was the lowest for the reader with the most experience in neuroradiology, while the other readers were significantly more influenced. All readers veered further away from the ground truth in their second ASPECT-Scoring with the s-ASPECTS, though not significantly. Overall interrater reliability was excellent (ICC = 0.94 [0.92–0.96]). Conclusions: ASPECT-Scoring may be significantly influenced by simulated ASPECTS displayed by a suboptimal CAD tool, especially in readers with less experience, and performance tends to decrease. Keywords: Computed tomography, Ischemic stroke, Diagnostic method, Alberta stroke program early CT score, Machine learning

Rupture of a vulnerable carotid plaque is one of the leading causes of stroke. Carotid magnetic resonance imaging (MRI) is able to visualize all the main hallmarks of plaque vulnerability. Various MRI sequences have been developed in the last two decades to quantify carotid plaque burden and composition. Often, a combination of multiple sequences is used. These MRI techniques have been extensively validated with histological analysis of carotid endarterectomy specimens. High agreement between the MRI and histological measures of plaque burden, intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), fibrous cap (FC) status, inflammation and neovascularization has been demonstrated. Novel MRI sequences allow to generate three-dimensional isotropic images with a large longitudinal coverage. Other new sequences can acquire multiple contrasts using a single sequence leading to a tremendous reduction in scan time. IPH can be easily identified as a hyperintense signal in the bulk of the plaque on strongly T(1)-weighted images, such as magnetization-prepared rapid acquisition gradient echo images, acquired within a few minutes with a standard neurovascular coil. Carotid MRI can also be used to evaluate treatment effects. Several meta-analyses have demonstrated a strong predictive value of IPH, LRNC, thinning or rupture of the FC for ischemic cerebrovascular events. Recently, in a large meta-analysis based on individual patient data of asymptomatic and symptomatic individuals with carotid artery stenosis, it was shown that IPH on MRI is an independent risk predictor for stroke, stronger than any known clinical risk parameter. Expert recommendations on carotid plaque MRI protocols have recently been described in a white paper. The present review provides an overview of the current status and applications of carotid plaque MR imaging and its future potential in daily clinical practice.

CT Perfusion (CTP) imaging has gained importance in the diagnosis of acute stroke. Conventional perfusion analysis performs a deconvolution of the measurements and thresholds the perfusion parameters to determine the tissue status. We pursue a data-driven and deconvolution-free approach, where a deep neural network learns to predict the final infarct volume directly from the native CTP images and metadata such as the time parameters and treatment. This would allow clinicians to simulate various treatments and gain insight into predicted tissue status over time. We demonstrate on a multicenter dataset that our approach is able to predict the final infarct and effectively uses the metadata. An ablation study shows that using the native CTP measurements instead of the deconvolved measurements improves the prediction., Accepted for publication in Medical Image Analysis

Background and purposeInfarct volume is a valuable outcome measure in treatment trials of acute ischemic stroke and is strongly associated with functional outcome. Its manual volumetric assessment is, however, too demanding to be implemented in clinical practice.ObjectiveTo assess the value of convolutional neural networks (CNNs) in the automatic segmentation of infarct volume in follow-up CT images in a large population of patients with acute ischemic stroke.Materials and methodsWe included CT images of 1026 patients from a large pooling of patients with acute ischemic stroke. A reference standard for the infarct segmentation was generated by manual delineation. We introduce three CNN models for the segmentation of subtle, intermediate, and severe hypodense lesions. The fully automated infarct segmentation was defined as the combination of the results of these three CNNs. The results of the three-CNNs approach were compared with the results from a single CNN approach and with the reference standard segmentations.ResultsThe median infarct volume was 48 mL (IQR 15–125 mL). Comparison between the volumes of the three-CNNs approach and manually delineated infarct volumes showed excellent agreement, with an intraclass correlation coefficient (ICC) of 0.88. Even better agreement was found for severe and intermediate hypodense infarcts, with ICCs of 0.98 and 0.93, respectively. Although the number of patients used for training in the single CNN approach was much larger, the accuracy of the three-CNNs approach strongly outperformed the single CNN approach, which had an ICC of 0.34.ConclusionConvolutional neural networks are valuable and accurate in the quantitative assessment of infarct volumes, for both subtle and severe hypodense infarcts in follow-up CT images. Our proposed three-CNNs approach strongly outperforms a more straightforward single CNN approach.

BackgroundMechanical thrombectomy with stent retrievers has proved to be safe and effective in endovascular treatment of acute ischemic stroke. Direct aspiration has shown revascularization rates comparable to those of stent retrievers in the recent ASTER and COMPASS trials. However, the efficacy of aspiration in routine clinical practice has not yet been shown.ObjectiveTo show that aspiration has clinical and technical outcomes equal to those of stent retriever thrombectomy in daily clinical practice.MethodsWe analysed data of patients with a large vessel occlusion of the anterior circulation registered in the Dutch MR CLEAN Registry between March 2014 and June 2016. Primary outcome was functional outcome measured with the modified Rankin Scale (mRS) score. Secondary outcomes were reperfusion grade, periprocedural complication rate, and procedure duration. Association of treatment technique with functional outcome was estimated with univariable and multivariable ordinal logistic regression analysis and expressed as a common OR (cOR) for a shift towards better outcome on the mRS.ResultsAs first-line treatment, 207 of 1175 patients (17.6%) were treated with direct aspiration, and 968 (82.4%) by a stent retriever. We observed no differences in functional outcome (adjusted cOR=1.020 (95% CI 0.68 to 1.52)) and periprocedural complications. Successful reperfusion (extended Thrombolysis in Cerebral Infarction ≥2b) was similar. Duration of the procedure was shorter with aspiration (57 min (IQR 35–73) vs 70 min (IQR 47–95), pConclusionDirect aspiration shows clinical outcomes equal to those of stent retriever thrombectomy in our large multicenter real-life cohort. We found no difference in complication rates and shorter procedure times for aspiration.

Background: Intracranial carotid artery calcification (ICAC) on computed tomography (CT) is a marker of atherosclerosis and an independent predictor of vascular events including stroke. While vitamin K antagonists (VKAs) are used to prevent embolic stroke, they have been shown to increase levels of both coronary and extracoronary artery calcification. This has not been studied for (intracranial) carotid arteries. The aim of this study is to investigate the association between VKA use and degree of ICAC. We tested our hypothesis in a cohort of patients with nontraumatic intracerebral hemorrhage (ICH) of which a substantial part used VKAs. Materials and Methods: We retrospectively semiquantified ICAC on brain unenhanced CT of consecutive adult patients with nontraumatic ICH. Assessment was performed blinded to clinical characteristics and status of VKA use. We used a 5-point visual scale and dichotomized degree of ICAC in low and high degree. Patient demographics, VKA use, duration of VKA treatment, as well as known risk factors for intracranial calcification were collected. Univariable and multivariable logistic regression analyses were performed to investigate the association between ICAC and VKA use. Results: Three hundred and seventy-six nontraumatic ICH patients were included of whom 77 were using VKAs (20.5%) with a median treatment duration of 35 months. Any degree of ICAC was detected in 289 patients (76.9%). Univariable analysis showed that a high degree of ICAC was significantly associated with older age [odds ratio (OR), 1.06, 95% confidence interval (CI), 1.03-1.08], hypertension (OR, 2.14; 95% CI, 1.27-3.62), diabetes mellitus (OR, 2.38; 95% CI, 1.27-4.49), and the use of VKAs (OR, 1.84; 95% CI, 1.06-3.20). In multivariable regression analysis, only older age was significantly associated with a higher degree of ICAC (OR, 1.05; 95% CI, 1.02-1.08), while VKA use was not (OR, 1.22; 95% CI, 0.67-2.24). Conclusions: Our findings do not support VKA use as an independent risk factor for higher ICAC degree in patients with ICH. We could not confirm the concerns about VKA use and intracranial carotid vascular calcification. We suggest further research in other cohorts with VKA users such as patients with ischemic stroke and atrial fibrillation.

Objective Post-stroke depression (PSD) and post-stroke apathy (PSA) are both associated with adverse outcome after stroke. This study aimed to examine whether personality traits predict the course of PSD and PSA. Methods In this prospective cohort study, 240 stroke patients completed the NEO Five Factor Inventory, Montgomery-Asberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months post-stroke. Neuropsychiatric assessment was repeated at 6- and 12-month follow-up after initial testing. Results Linear mixed models showed that high neuroticism scores were associated with higher depression levels at baseline, and this association remained stable at follow-up. High extraversion scores and high conscientiousness scores were associated with lower apathy levels at baseline. For neuroticism, a significant interaction with time was found, with higher neuroticism scores at baseline being associated with an increase in apathy scores from 6-month to 12-month follow-up. Prospective analyses showed that high extraversion predicted low apathy levels at 6-month and 12-month follow-up independent of its relations with baseline depression and apathy. High neuroticism predicted high apathy levels at 12-month follow-up, whereas high agreeableness and high openness predicted high apathy levels and low apathy levels, respectively, at 6-month follow-up. None of the personality traits predicted depression scores at follow-up. Conclusion Personality traits are associated with the development and sustainability of PSD and PSA. The traits associated with PSD and PSA were different, providing support for the independence of these constructs. The findings highlight the importance to take personality traits into account as a potential vulnerability factor for PSD and PSA.

ObjectiveThe effect of intra-arterial treatment (IAT) for acute ischemic stroke is highly time-dependent. We investigated the delay of IAT and factors associated with such delay.MethodsMR CLEAN was a randomized trial of IAT plus usual care versus usual care alone (n=500). With multivariable linear regression, we analyzed the effect of intravenous treatment, general anesthesia, off-hours and inter-hospital transfer on time to admission to the emergency department (ED) of the intervention center and time to treatment. Furthermore, we assessed compliance with a target of 75 min for time from ED to treatment, and calculated the potential absolute increase in the number of patients with a good outcome (modified Rankin Scale score ≤2) if this target had been achieved in all treated patients.ResultsInter-hospital transfer prolonged time to ED by 140 min (95% CI 129 to 150) but reduced time from ED to treatment by 77 min (95% CI 64 to 91). Time from ED to treatment was increased by 19 min by general anesthesia (95% CI 5 to 33) and total time was increased by 23 min during off-hours (95% CI 6 to 40). The in-hospital target was achieved in 11.5% (22/192) of patients. Full compliance with the target time of 75 min from ED to treatment would have increased the proportion of patients with a good outcome by 7.6% (95% CI 6.7% to 8.5%).ConclusionInter-hospital transfer is an important cause of delay in the delivery of IAT and every effort should be made to avoid transfers and reduce transfer-related delay. Furthermore, in-hospital workflow should be optimized to improve functional outcome after IAT.

Objective To examine the influence of vascular cognitive impairment (VCI) on the course of poststroke depression (PSD) and poststroke apathy (PSA). Methods Included were 250 stroke patients who underwent neuropsychological and neuropsychiatric assessment 3 months after stroke (baseline) and at a 6- and 12-month follow-up after baseline. Linear mixed models tested the influence of VCI in at least one cognitive domain (any VCI) or multidomain VCI (VCI in multiple cognitive domains) at baseline and domain-specific VCI at baseline on levels of depression and apathy over time, with random effects for intercept and slope. Results Almost half of the patients showed any VCI at baseline, and any VCI was associated with increasing apathy levels from baseline to the 12-month follow-up. Patients with multidomain VCI had higher apathy scores at the 6- and 12-month follow-up compared with patients with VCI in a single cognitive domain. Domain-specific analyses showed that impaired executive function and slowed information processing speed went together with increasing apathy levels from baseline to 6- and 12-month follow-up. None of the cognitive variables predicted the course of depressive symptoms. Conclusion Baseline VCI is associated with increasing apathy levels from baseline to the chronic stroke phase, whereas no association was found between baseline VCI and the course of depressive symptoms. Health professionals should be aware that apathy might be absent early after stroke but may evolve over time in patients with VCI.

ObjectiveTo examine, first, whether the co-occurrence of executive dysfunction (ED) and poststroke depression (PSD) shows different associations with neuroimaging markers and the course of depression and executive function, and second, whether it is associated with a different course on other cognitive domains and quality of life.MethodsThe present study included 245 stroke patients (35.9% female, mean age 67.5 years (SD=11.9). All patients completed neuropsychological and neuropsychiatric assessment 3 months poststroke, which were repeated at 6-month and 12-month follow-up. A subset (n=186) received 3-Tesla brain MRI at baseline to evaluate lesion-related imaging markers, white matter hyperintensity volume, global brain atrophy and total cerebral small vessel disease burden.ResultsPatients with ‘depression–executive dysfunction syndrome’ (DES) showed higher white matter hyperintensity volumes compared with all other groups and more frequently showed left-sided lesions compared with ED only and PSD only. They also had more frequently old infarcts and higher total cerebral small vessel disease burden compared with PSD only and patients with neither ED nor PSD, and more global brain atrophy compared with PSD only. Longitudinal analyses showed that patients with DES had a more chronic course of depressive symptoms relative to PSD only, and a stable pattern of worse cognitive performance similar to patients with ED only.ConclusionsThe co-occurrence of ED and PSD is associated with a worse prognosis of depression, persistent cognitive impairment and a higher amount of vascular and degenerative brain pathology. Future studies are needed to examine whether these patients represent a more severe subtype within the PSD spectrum.Clinical trial registrationNCT02585349;Results.

The Framingham Stroke Risk Profile (FSRP) was developed to predict clinical stroke. We investigated if FSRP is associated with more "silent" effects of cerebrovascular disease, namely progression of cerebral small vessel disease (cSVD)-related brain damage and cognitive performance in hypertensive patients. Ninety patients with essential hypertension underwent a brain MRI scan and FSRP assessment at baseline, and a second brain MRI scan and neuropsychological assessment at 9-year follow-up. We visually rated progression of cSVD-related MRI markers. FSRP was associated with progressive periventricular white matter hyperintensities (P = .017) and new microbleeds (P = .031), but not after correction for the FSRP age component. FSRP was associated with lower overall cognitive performance (P

BACKGROUND: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care.METHODS: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered.FINDINGS: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09-2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75-3·10, pINTERPRETATION: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons.FUNDING: Medtronic.

Background and Purpose— High blood pressure (BP) is associated with poor outcome and the occurrence of symptomatic intracranial hemorrhage in acute ischemic stroke. Whether BP influences the benefit or safety of intra-arterial treatment (IAT) is not known. We aimed to assess the relation of BP with functional outcome, occurrence of symptomatic intracranial hemorrhage and effect of IAT. Methods— This is a post hoc analysis of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). BP was measured at baseline, before IAT or stroke unit admission. We estimated the association of baseline BP with the score on the modified Rankin Scale at 90 days and safety parameters with ordinal and logistic regression analysis. Effect of BP on the effect of IAT was tested with multiplicative interaction terms. Results— Systolic BP (SBP) had the best correlation with functional outcome. This correlation was U-shaped; both low and high baseline SBP were associated with poor functional outcome. Higher SBP was associated with symptomatic intracranial hemorrhage (adjusted odds ratio, 1.25 for every 10 mm Hg higher SBP [95% confidence interval, 1.09–1.44]). Between SBP and IAT, there was no interaction for functional outcome, symptomatic intracranial hemorrhage, or other safety parameters; the absolute benefit of IAT was evident for the whole SBP range. The same was found for diastolic BP. Conclusions— BP does not affect the benefit or safety of IAT in patients with acute ischemic stroke caused by proximal intracranial vessel occlusion. Our data provide no arguments to withhold or delay IAT based on BP. Clinical Trial Registration— URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

Contains fulltext : 182353.pdf (Publisher’s version ) (Open Access) Seizures after intracerebral hemorrhage are repeatedly seen. Whether the development of seizures after intracerebral hemorrhage affects survival in the long term is unknown. This study aims to determine the relation between seizures (i.e., with and without anti-epileptic therapy) and long-term mortality risk in a large patient population with intracerebral hemorrhage. We retrospectively included patients with a non-traumatic ICH in all three hospitals in the South Limburg region in the Netherlands between January 1st 2004 and December 31st 2009, and we assessed all-cause mortality until March 14th 2016. Patient who did not survive the first seven days after intracerebral hemorrhage were excluded from analyses. We used Cox multivariate analyses to determine independent predictors of mortality. Of 1214 patients, 783 hemorrhagic stroke patients fulfilled the inclusion criteria, amongst whom 37 (4.7%) patients developed early seizures (within 7 days after hemorrhage) and 77 (9.8%) developed late seizures (more than 7 days after hemorrhage). Seizure development was not significantly related to mortality risk after correction for conventional vascular risk factors and hemorrhage severity. However, we found a small but independent relation between the use of anti-epileptic drugs and a lower long-term mortality (HR = 0.32, 95% CI 0.11-0.91). In our large population, seizures and epilepsy did not relate independently to an increased mortality risk after hemorrhage.

Item does not contain fulltext BACKGROUND: Intra-arterial treatment in acute ischemic stroke is safe and effective as recently shown in several randomized clinical trials. The level of experience of the interventionist performing the IAT procedure has not been studied. The present study investigates effects of interventionists' experience on technical aspects of the procedure and clinical outcome of the patient. METHODS: In this study of 313 patients with a proximal intracranial arterial anterior circulation occlusion, treated in the Netherlands from 2002 until participation in the Multicenter Randomized Clinical trial of Endovascular treatment for acute ischemic stroke (MR CLEAN), data were collected retrospectively. The association of the senior interventionists' experience with duration of the procedure, adverse events, recanalization, neurological outcome, and functional outcome at discharge was analyzed. Multiple regression models adjusted for age, sex, stroke severity, carotid terminus occlusion, use of a retrievable stent and onset to door time were used. RESULTS: No association between interventionists' experience and recanalization, neurological outcome, or functional outcome was observed in a strict selection of patients. This strict selection include a start of intra-arterial treatment within 6h, no coagulation disturbances, systolic blood pressure

Background and Purpose— Cerebral small vessel disease (SVD) is associated with cognitive impairment. This may be because of decreased microstructural integrity and microvascular perfusion, but data on these relationships are scarce. We determined the relationship between cognition and microvascular perfusion and microstructural integrity in SVD patients, using intravoxel incoherent motion imaging—a diffusion-weighted magnetic resonance imaging technique designed to determine microvascular perfusion and microstructural integrity simultaneously. Methods— Seventy-three patients with SVD and 39 controls underwent intravoxel incoherent motion imaging and neuropsychological assessment. Parenchymal diffusivity D (a surrogate measure of microstructural integrity) and perfusion-related measure fD* were calculated for the normal appearing white matter, white matter hyperintensities, and cortical gray matter. The associations between cognitive performance and D and fD* were determined. Results— In SVD patients, multivariable analysis showed that lower fD* in the normal appearing white matter and cortical gray matter was associated with lower overall cognition ( P =0.03 and P =0.002, respectively), lower executive function ( P =0.04 and P =0.01, respectively), and lower information-processing speed ( P =0.04 and P =0.01, respectively). D was not associated with cognitive function. In controls, no association was found between D , fD* , and cognition. Conclusions— In SVD patients, lower cognitive performance is associated with lower microvascular perfusion in the normal appearing white matter and cortical gray matter. Our results support recent findings that both cortical gray matter and normal appearing white matter perfusion may play a role in the pathophysiology of cognitive dysfunction in SVD. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR3786.

Purpose Increased blood–brain barrier (BBB) permeability has been shown to play a significant role in the pathophysiology of cerebrovascular disease and it may provide an early functional marker of progression or treatment effects. The aim of the study was to investigate the test–retest reproducibility and influencing factors of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in measuring subtle leakage in patients with cerebrovascular disease. Material and Methods DCE-MRI (3T) was performed on two separate days in 16 patients (age 66 ± 9 years) with cerebrovascular disease, prospectively. The leakage rate was quantified for white matter (WM) and gray matter (GM) using the Patlak graphical approach with individual vascular input functions (VIFs). Furthermore, the influence of session-averaged VIFs, the average of the VIFs obtained on two days, and shorter scan times (range 5–25 minutes) on the reproducibility were evaluated in WM and GM. Results Coefficients of variation (CV) ≤14.4% (WM and GM), intraclass correlation coefficients (ICCs) of 0.77 (WM) and 0.49 (GM), were observed for the leakage rate. Session-averaged VIFs hardly affected these results (CV ≤13.4%). The repeatability coefficients (RCs) of the leakage rate decreased from 2.7·10−3 to 0.4·10−3 min−1 in WM (P < 0.01) and 4.4·10−3 to 0.9·10−3 min−1 in GM (P < 0.01) with increasing scan time (range 5–25 minutes). Conclusion Based on the moderate CVs and moderate-to-excellent ICCs, we demonstrate that measuring subtle BBB leakage using DCE-MRI is moderate-to-excellent reproducible. Longer scan times improve the reproducibility. The provided RCs at various scan times may assist future clinical studies investigating BBB leakage using DCE-MRI. Level of Evidence: 2 J. Magn. Reson. Imaging 2017

Purpose To assess parameter agreement of volume transfer coefficient (Ktrans) between two vascular regions and to study the correlation with microvessel density on histology. The dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameter Ktrans is frequently used to study atherosclerotic plaque microvasculature. Ktrans has been reported using different descriptive statistics (mean, median, 75th percentile) either for the whole vessel wall or the adventitia in previous studies. Materials and Methods DCE-MRI parameter agreement was analyzed in 110 symptomatic patients with ≥2 mm carotid plaque that underwent a 3T carotid DCE-MRI examination. Ktrans was estimated in the entire vessel wall and adventitia. Twenty-three patients underwent carotid endarterectomy and were used for comparison with histological quantification of microvessel density of the plaque using CD31 immunohistochemistry. DCE-MRI parameters in the vessel wall regions were compared using Pearson's correlation coefficient, Bland–Altman analysis, and a two-sided paired samples t-test. Correlation of the DCE-MRI parameters with histology was studied using the Pearson's correlation coefficient. Results Median adventitial Ktrans was 5% higher (P = 0.003) than entire vessel wall Ktrans, with no differences for other descriptive statistics. Vessel wall and adventitial Ktrans showed similar moderately strong correlations with plaque microvessel density on histology (Pearson's ρ: 0.59–0.65 [P < 0.003] and 0.52–0.64 [P < 0.011], respectively). Conclusion The similar moderately strong correlations for vessel wall and adventitial Ktrans with microvessel density on histology suggested that both regions reflected plaque microvessel density. Care should to be taken when comparing absolute values between studies. Future studies incorporating thresholds for risk stratification need to agree upon standardization of DCE-MRI parameters. Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1053–1059.

Objective:As blood–brain barrier (BBB) dysfunction may occur in normal aging but may also play a pivotal role in the pathophysiology of cerebral small vessel disease (cSVD), we used dynamic contrast-enhanced (DCE)–MRI to quantify the rate and the spatial extent of BBB leakage in patients with cSVD and age- and sex-matched controls to discern cSVD-related BBB leakage from aging-related leakage.Methods:We performed structural brain MRI and DCE-MRI in 80 patients with clinically overt cSVD and 40 age- and sex-matched controls. Using the Patlak pharmacokinetic model, we calculated the leakage rate. The mean leakage rate and relative leakage volume were calculated using noise-corrected histogram analysis. Leakage rate and leakage volume were compared between patients with cSVD and controls for the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter.Results:Multivariable linear regression analyses adjusting for age, sex, and cardiovascular risk factors showed that the leakage volume of the NAWM, WMH, and CGM was significantly larger in patients with cSVD compared with controls. No significant difference was found for leakage rate in any of the tissue regions.Conclusion:We demonstrated a larger tissue volume with subtle BBB leakage in patients with cSVD than in controls. This was shown in the NAWM, WMH, and CGM, supporting the generalized nature of cSVD.

Background and Purpose— Ischemic lesion volume (ILV) assessed by follow-up noncontrast computed tomography correlates only moderately with clinical end points, such as the modified Rankin Scale (mRS). We hypothesized that the association between follow-up noncontrast computed tomography ILV and outcome as assessed with mRS 3 months after stroke is strengthened when taking the mRS relevance of the infarct location into account. Methods— An anatomic atlas with 66 areas was registered to the follow-up noncontrast computed tomographic images of 254 patients from the MR CLEAN trial (Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands). The anatomic brain areas were divided into brain areas of high, moderate, and low mRS relevance as reported in the literature. Based on this distinction, the ILV in brain areas of high, moderate, and low mRS relevance was assessed for each patient. Binary and ordinal logistic regression analyses with and without adjustment for known confounders were performed to assess the association between the ILVs of different mRS relevance and outcome. Results— The odds for a worse outcome (higher mRS) were markedly higher given an increase of ILV in brain areas of high mRS relevance (odds ratio, 1.42; 95% confidence interval, 1.31–1.55 per 10 mL) compared with an increase in total ILV (odds ratios, 1.16; 95% confidence interval, 1.12–1.19 per 10 mL). Regression models using ILV in brain areas of high mRS relevance instead of total ILV showed a higher quality. Conclusions— The association between follow-up noncontrast computed tomography ILV and outcome as assessed with mRS 3 months after stroke is strengthened by accounting for the mRS relevance of the affected brain areas. Future prediction models should account for the ILV in brain areas of high mRS relevance.

Background Health-related quality of life measured with the EuroQol Group 5-Dimension Self-Report Questionnaire was one of the secondary outcomes in the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN). We reported no statistically significant difference in EuroQol Group 5-Dimension Self-Report Questionnaire score between the intervention and control groups, but deaths were not included. Aims Reanalyze the effect of intra-arterial treatment for large vessel occlusion in acute ischemic stroke patients on health-related quality of life in more detail. We now include patients who died during follow-up. Methods The EuroQol Group 5-Dimension Self-Report Questionnaire questionnaires were obtained 90 days after treatment. We used the Dutch tariff to derive a utility index from the EuroQol Group 5-Dimension Self-Report Questionnaire score. Treatment effect was estimated with the Mann–Whitney U test and linear regression. The effect of treatment on the distribution of EuroQol Group 5-Dimension Self-Report Questionnaire dimension scores was assessed with ordinal logistic regression. Results We obtained EuroQol Group 5-Dimension Self-Report Questionnaire scores from 457 (91.7%) of the 500 patients, including 108 who died before follow-up. Median EuroQol Group 5-Dimension Self-Report Questionnaire score in the intervention group was 0.57, and 0.39 in the control group (p = 0.03). Treatment effect estimated with linear regression was 0.07 (95%CI: −0.001 to 0.143). Treatment specifically affected EuroQol Group 5-Dimension Self-Report Questionnaire dimensions “mobility” (OR: 0.43, 95%CI: 0.29–0.66), “self-care” (OR: 0.60, 95%CI: 0.41–0.89), and “usual activities” (OR: 0.53, 95%CI: 0.36–0.79). Conclusion Treatment had a limited effect on quality of life, as measured with the EuroQol Group 5-Dimension Self-Report Questionnaire. Nevertheless, patients with acute ischemic stroke caused by an intracranial occlusion in the anterior circulation, who had intra-arterial treatment, experience better health-related quality of life than patients without intra-arterial treatment. Trial Registration URL: http://www.isrctn.com/ISRCTN10888758 Unique identifier: ISRCTN10888758

Aims: Endovascular thrombectomy (EVT) improves outcome after acute ischaemic stroke (AIS) caused by an intracranial occlusion. The aim of the present study was to determine whether atrial fibrillation (AF) modifies the effect of EVT.Methods and results: MR CLEAN was a randomised clinical trial of EVT plus usual care vs. usual care alone for patients with an intracranial occlusion. The primary outcome was the modified Rankin scale (mRS) score at 90 days. The primary effect parameter was the adjusted common odds ratio (acOR), estimated with ordinal logistic regression and adjusted for age and stroke severity at baseline. Treatment effect modification by AF was assessed using a multiplicative interaction variable. We included all 500 patients. In total, 135 (27%) had AF. These patients were older, had a worse pre-stroke mRS score and were less often treated with IV alteplase. In patients without AF, the estimated treatment effect was similar to the overall treatment effect (acOR 1.9, 95% CI: 1.3 to 2.7). In patients with AF, the treatment effect appeared lower (acOR 1.0, 95% CI: 0.6 to 1.9). The interaction of treatment effect and AF was not significant (p=0.09, after adjustment p=0.12).Conclusions: This study did not show significant difference in the EVT effect between acute stroke patients with and those without AF.

Introduction Cerebral small vessel disease (cSVD) is associated with microvascular and parenchymal alterations. Intravoxel incoherent motion (IVIM) MRI has been proposed to simultaneously measure both the microvascular perfusion and parenchymal diffusivity. This study aimed to evaluate the application of IVIM in cSVD to assess the microvasculature and parenchymal microstructure. Methods Seventy-three patients with cSVD (age 70 ± 11 y) and thirty-nine controls (age 69 ± 12 y) underwent IVIM imaging (3T). Group differences of the perfusion volume fraction f and the parenchymal diffusivity D were investigated using multivariable linear regression accounted for age, sex and cardiovascular factors. To examine the relation between the IVIM measures and the disease severity on structural MRI, white matter hyperintensity (WMH) load served as surrogate measure of the disease severity. Results Patients had a larger f (p, Highlights • The application of IVIM in cSVD was investigated. • IVIM shows a predicted microstructure impairment in cSVD. • Unexpected increased perfusion volume fraction is observed using IVIM. • Perfusion volume fraction and parenchymal diffusivity increase with disease severity. • IVIM imaging may provide a potential surrogate marker for the progression of cSVD.

Background: Poststroke fatigue (PSF) is a form of pathological fatigue that can develop after stroke and has a negative impact on functional outcome. PSF is associated with poststroke depression (PSD), which in turn shows similarities with poststroke apathy (PSA). This study aimed at disentangling the temporal associations between PSF and PSD and between PSF and PSA. Methods: A total of 250 stroke patients were included, of which 243 completed the Fatigue Severity Scale, Montgomery-Åsberg Depression Rating Scale, and Apathy Evaluation Scale at 3 months poststroke, with follow-up measurements at 6 and 12 months after initial testing. Linear mixed models and linear regressions were performed to evaluate the temporal associations between PSF and PSD, and between PSF and PSA. Results: PSF was present in 119 patients (49%), of whom 62 patients also had PSD (26%), and 21 patients (9%) also had PSA. At baseline, PSF patients showed higher depression levels, which remained stable at follow-up. PSD patients had higher fatigue levels compared with no-PSD patients at baseline, which remained stable at follow-up. No association between apathy and fatigue was found at baseline and no interaction with time was found. Change in fatigue from baseline to 12-month follow-up was associated with change in depression and with change in apathy. Conclusions: Bidirectional associations were found between PSF and PSD. In treatment and rehabilitation programs, early focus on the presence of PSD and PSF is important, since these conditions tend to persist. As there are currently more treatment options for PSD, attention for PSD is important and might also have a beneficial effect on PSF.

Background and Purpose— A high clot burden score (CBS) is associated with favorable outcome after intravenous treatment for acute ischemic stroke. The added benefit of intra-arterial treatment might be less in these patients. The aim of this exploratory post hoc analysis was to assess the relation of CBS with neurological improvement and endovascular treatment effect. Methods— For 499 of 500 patients in the MR CLEAN study (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the CBS was determined. Ordinal logistic regression models with and without main baseline prognostic variables were used to assess the association between CBS (continuous or dichotomized at CBS of 6) and a shift toward better outcome on the modified Rankin Scale. The model without main baseline prognostic variables only included treatment allocation and CBS. Models with and without a multiplicative interaction term of CBS and treatment were compared using the χ 2 test to assess treatment effect modification by CBS. Results— Higher CBS was associated with a shift toward better outcome on the modified Rankin Scale; adjusted common odds ratio per point CBS was 1.12 (95% confidence interval, 1.04–1.20]. Dichotomized CBS had an adjusted common odds ratio of 1.67 (95% confidence interval, 1.12–2.51). Both effect estimates were slightly attenuated by adding baseline prognostic variables. The addition of the interaction terms did not significantly improve the fit of the models. There was a small and insignificant increase of intra-arterial treatment efficacy in the high CBS group. Conclusions— A higher CBS is associated with improved outcome and may be used as a prognostic marker. We found no evidence that CBS modifies the effect of intra-arterial treatment. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR1804. URL: http://www.controlled-trials.com . Unique identifier: ISRCTN10888758.

Contains fulltext : 208975.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1.34 years [IQR 0.19-2.44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1.35 (95% CI 1.20-1.50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2.45 (1.82-3.29) for intracranial haemorrhage and 1.23 (1.08-1.40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4.55 [95% CI 3.08-6.72] for intracranial haemorrhage vs 1.47 [1.19-1.80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5.52 [3.36-9.05] vs 1.43 [1.07-1.91]; and for >/=20 cerebral microbleeds, aHR 8.61 [4.69-15.81] vs 1.86 [1.23-1.82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for >/=20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Background Rupture of a vulnerable carotid atherosclerotic plaque is an important underlying cause of ischemic stroke. Increased leaky plaque microvasculature may contribute to plaque vulnerability. These immature microvessels may facilitate entrance of inflammatory cells into the plaque. The objective of the present study is to investigate whether there is a difference in plaque microvasculature (the volume transfer coefficient K trans ) between the ipsilateral symptomatic and contralateral asymptomatic carotid plaque using noninvasive dynamic contrast‐enhanced magnetic resonance imaging. Methods and Results Eighty‐eight patients with recent transient ischemic attack or ischemic stroke and ipsilateral >2 mm carotid plaque underwent 3 T magnetic resonance imaging to identify plaque components and to determine characteristics of plaque microvasculature. The volume transfer coefficient K trans , indicative for microvascular density, flow, and permeability, was calculated for the ipsilateral and asymptomatic plaque, using a pharmacokinetic model (Patlak). Presence of a lipid‐rich necrotic core, intraplaque hemorrhage, and a thin and/or ruptured fibrous cap was assessed on multisequence magnetic resonance imaging . We found significantly lower K trans in the symptomatic carotid plaque compared with the asymptomatic side (0.057±0.002 min −1 versus 0.062±0.002 min −1 ; P =0.033). There was an increased number of slices with intraplaque hemorrhage (0.9±1.6 versus 0.3±0.8, P =0.002) and lipid‐rich necrotic core (1.4±1.9 versus 0.8±1.4, P =0.016) and a higher prevalence of plaques with a thin and/or ruptured fibrous cap (32% versus 17%, P =0.023) at the symptomatic side. Conclusions K trans was significantly lower in symptomatic carotid plaques, indicative for a decrease of plaque microvasculature in symptomatic plaques. This could be related to a larger amount of necrotic tissue in symptomatic plaques. Clinical Trial Registration URL : http://www.clinicaltrials.gov.uk . Unique identifier: NCT 01208025.

Supplemental Digital Content is available in the text., Background and Purpose— It is unclear whether endovascular treatment (EVT) is beneficial for patients with acute ischemic stroke with occlusion of the M2 segment of the middle cerebral artery. We aimed to compare functional outcomes, technical aspects, and complications of EVT between patients with acute ischemic stroke because of M2 and M1 occlusions in clinical practice. Furthermore, outcome and complications after EVT in dominant and nondominant caliber M2 division occlusions were studied. Methods— Data were obtained from the MR CLEAN Registry (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) which is an ongoing observational study in 16 Dutch centers performing EVT in the Netherlands. Functional outcome was measured with the modified Rankin Scale score at 90 days. Neurological recovery (delta National Institutes of Health Stroke Scale), successful reperfusion rates (extended Thrombolysis in Cerebral Infarction ≥2B), and safety outcomes were also investigated. Associations between occlusion location and outcome were analyzed with ordinal logistic regression models, with adjustment for other prognostic factors. Results— In total, 244 (24%) patients with an M2 and 759 (76%) patients with an M1 occlusion who underwent EVT were analyzed. Functional outcomes were not significantly different between patients with M2 versus M1 occlusions (adjusted common odds ratio, 1.24; 95% CI, 0.87–1.73). Occurrence of symptomatic intracerebral hemorrhage was also similar for M2 and M1 occlusions (6.6% versus 5.9%; P=0.84). Further analysis about dominance of an M2 branch was performed in 175 (72%) patients. Neurological recovery was comparable (mean delta National Institutes of Health Stroke Scale, −2±10 for dominant M2, −5±5 for nondominant M2, and −4±9 [P=0.24] for M1 occlusions). Furthermore, the effect of reperfusion status on functional outcome was comparable between occlusion divisions (common odds ratio, 1.27; 95% CI, 1.06–1.53 for dominant M2; common odds ratio, 1.32; 95% CI, 0.93–1.87 for nondominant M2; and common odds ratio, 1.35; 95% CI, 1.24–1.46 for M1 occlusions). Conclusions— Outcomes and complication rates after EVT were similar in patients with M2 and M1 occlusions. Although based on observational data and a limited sample size, a similar association of reperfusion status with functional outcome for all subgroups provides no evidence that patients with either a dominant or a nondominant M2 occlusion should be routinely excluded from EVT.

Introduction: Accurate assessment of brain reperfusion during endovascular treatment helps determining whether adjuvant intervention is necessary. The gold standard for reperfusion scales are the modified and extended Treatment in Cerebral Ischemia (mTICI and eTICI) scale. However, these scales are coarse and highly dependent on the observer, which may result in imprecise rating of reperfusion status. In this study, we developed a semi-automated quantitative reperfusion measure (qTICI) that was based on eTICI methodology using deep learning. Methods: Digital subtraction angiography (DSA) images of 67 acute ischemic stroke patients with proximal occlusions were collected from the MRCLEAN registry, including only patients who were eTICI graded by an independent core lab and had follow-up 90 days-modified Rankin Scale (mRS) scores. Both DSA projections, anteroposterior and lateral, were used. We trained a patch-based multi-path convolutional neural network to segment the perfusion area. The ground truths of perfusion segmentation were constructed using heuristic, intensity thresholding after vessel removal, which were inspected for their accuracy by a neuroradiologist. The target downstream territory was manually segmented based on the treated occlusion location by two neurointerventionalists. qTICI was formulated as a ratio between the area of perfusion and target downstream territory. We compared performance between qTICI and eTICI in relation with functional outcome, dichotomized as favorable (mRS 0-2) and unfavorable outcome (mRS 3-6). Results: Our study showed that the multi-path convolutional neural network was able to reproduce the ground truth perfusion segmentation with an average Dice score of 0.91. qTICI correlated significantly with eTICI (p Conclusions: qTICI provided a quantitative and semi-automated perfusion assessment with strong association with functional outcome.

Background: The 90-day modified Rankin Scale (mRS) is the most commonly used primary outcome measure in stroke treatment trials, but has drawbacks, including the potential loss of subjects due to prolonged follow-up. An alternative may be the NIH Stroke Scale (NIHSS) early after stroke, which is frequently used as a secondary outcome measure. The aim of this study was to evaluate whether the NIHSS assessed within one week after trial inclusion could serve as a primary outcome measure for trials of acute ischaemic stroke treatment. Methods: We used the Prentice criteria to evaluate NIHSS 1 day and 5-7 days after trial inclusion as primary outcome measures in two trials of endovascular treatment (EVT): the positive MR CLEAN and the neutral IMS III. The four Prentice criteria evaluate a surrogate endpoint against a true endpoint (Figure). We adjusted for age, baseline NIHSS, collateral score, and time of symptom onset to randomization. Results: The Prentice criteria were met for NIHSS at 1 day and 5-7 days in MR CLEAN (n=500). We found a significant treatment effect of EVT on the mRS and on the NIHSS at 1 day and 5-7 days. After adjustment for NIHSS at 1 day and 5-7 days, the effect of EVT on mRS decreased from common odds ratio 1·69 (95%CI: 1·22-2·33) to respectively 1·33 (95%CI: 0·95-1·85) and 1·21 (95%CI: 0·86-1·72). In IMS III (n=656) there was no treatment effect on NIHSS at 1 day (p=0.56) and 5-7 days (p=0.28), coinciding with the absence of a treatment effect on mRS. Conclusion: NIHSS is able to replace the mRS at 90 days as a measure of treatment effect. NIHSS within one week after trial inclusion may be used as a primary outcome measure in trials of acute ischemic stroke treatment, particularly in phase II(b) trials. This could minimize loss to follow-up, and reduce trial duration and costs.

Introduction: CT Perfusion (CTP) imaging allows estimations of the ischemic core and penumbra. We hypothesize that a deep learning approach improves upon classic deconvolution analysis. Method: We trained a deep neural network to predict the final infarct volume based on the native CTP images, time to reperfusion and reperfusion status in a derivation cohort (MR CLEAN study). Given a CTP scan, prediction of the final infarct with simulated treatment parameters (instant reperfusion or no reperfusion at all), allows estimation of core and perfusion lesion. The model was validated in a five-fold cross-validation on the derivation cohort and, without retraining, on an external dataset (CRISP study). We calculated the mean absolute difference (MAD) between the volumes of the predicted core/perfusion lesion and true final infarct in reperfusers and non-reperfusers (based on 24h MRA and mTICI at the end of the procedure: 0 vs 2B-3) and compared these to the volume estimations of CTP processing by IschemaView RAPID. We assumed the measured final infarct to correspond to the core at baseline in reperfused patients and to the perfusion lesion in non-reperfused patients. Results: In the derivation cohort the deep learning prediction improved core prediction in reperfusers (MAD of 34 ml vs 66 ml, p Conclusion: We developed and validated a deep learning based method which improved volume estimations compared to classic CTP processing.

The presence of intraplaque haemorrhage (IPH) has been related to plaque rupture, is associated with plaque progression, and predicts cerebrovascular events. However, the mechanisms leading to IPH are not fully understood. The dominant view is that IPH is caused by leakage of erythrocytes from immature microvessels. The aim of the present study was to investigate whether there is an association between atherosclerotic plaque microvasculature and presence of IPH in a relatively large prospective cohort study of patients with symptomatic carotid plaque. One hundred and thirty-two symptomatic patients with ≥2 mm carotid plaque underwent cardiovascular magnetic resonance (CMR) of the symptomatic carotid plaque for detection of IPH and dynamic contrast-enhanced (DCE)-CMR for assessment of plaque microvasculature. Ktrans, an indicator of microvascular flow, density and leakiness, was estimated using pharmacokinetic modelling in the vessel wall and adventitia. Statistical analysis was performed using an independent samples T-test and binary logistic regression, correcting for clinical risk factors. A decreased vessel wall Ktrans was found for IPH positive patients (0.051 ± 0.011 min− 1 versus 0.058 ± 0.017 min− 1, p = 0.001). No significant difference in adventitial Ktrans was found in patients with and without IPH (0.057 ± 0.012 min− 1 and 0.057 ± 0.018 min− 1, respectively). Histological analysis in a subgroup of patients that underwent carotid endarterectomy demonstrated no significant difference in relative microvessel density between plaques without IPH (n = 8) and plaques with IPH (n = 15) (0.000333 ± 0.0000707 vs. and 0.000289 ± 0.0000439, p = 0.585). A reduced vessel wall Ktrans is found in the presence of IPH. Thus, we did not find a positive association between plaque microvasculature and IPH several weeks after a cerebrovascular event. Not only leaky plaque microvessels, but additional factors may contribute to IPH development. NCT01208025 . Registration date September 23, 2010. Retrospectively registered (first inclusion September 21, 2010). NCT01709045 , date of registration October 17, 2012. Retrospectively registered (first inclusion August 23, 2011).