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(1) Background : For acute ischemic strokes caused by large vessel occlusion, manually assessed thrombus volume and perviousness have been associated with treatment outcomes. However, the manual assessment of these characteristics is time-consuming and subject to inter-observer bias. Alternatively, a recently introduced fully automated deep learning-based algorithm can be used to consistently estimate full thrombus characteristics. Here, we exploratively assess the value of these novel biomarkers in terms of their association with stroke outcomes. (2) Methods : We studied two applications of automated full thrombus characterization as follows: one in a randomized trial, MR CLEAN-NO IV ( n = 314), and another in a Dutch nationwide registry, MR CLEAN Registry ( n = 1839). We used an automatic pipeline to determine the thrombus volume, perviousness, density, and heterogeneity. We assessed their relationship with the functional outcome defined as the modified Rankin Scale (mRS) at 90 days and two technical success measures as follows: successful final reperfusion, which is defined as an eTICI score of 2b-3, and successful first-pass reperfusion (FPS). (3) Results : Higher perviousness was significantly related to a better mRS in both MR CLEAN-NO IV and the MR CLEAN Registry. A lower thrombus volume and lower heterogeneity were only significantly related to better mRS scores in the MR CLEAN Registry. Only lower thrombus heterogeneity was significantly related to technical success; it was significantly related to a higher chance of FPS in the MR CLEAN-NO IV trial (OR = 0.55, 95% CI: 0.31-0.98) and successful reperfusion in the MR CLEAN Registry (OR = 0.88, 95% CI: 0.78-0.99). (4) Conclusions : Thrombus characteristics derived from automatic entire thrombus segmentations are significantly related to stroke outcomes.

Background: Computed tomography perfusion (CTP)-estimated core volume is associated with functional outcomes in acute ischemic stroke. This relationship might differ among patients, depending on brain volume., Materials and Methods: We retrospectively included patients from the MR CLEAN Registry. Cerebrospinal fluid (CSF) and intracranial volume (ICV) were automatically segmented on NCCT. We defined the proportion of the ICV and total brain volume (TBV) affected by the ischemic core as ICV core and TBV core . Associations between the core volume, ICV core , TBV core , and functional outcome are reported per interquartile range (IQR). We calculated the area under the curve (AUC) to assess diagnostic accuracy., Results: In 200 patients, the median core volume was 13 (5-41) mL. Median ICV and TBV were 1377 (1283-1456) mL and 1108 (1020-1197) mL. Median ICV core and TBV core were 0.9 (0.4-2.8)% and 1.7 (0.5-3.6)%. Core volume (acOR per IQR 0.48 [95%CI 0.33-0.69]), ICV core (acOR per IQR 0.50 [95%CI 0.35-0.69]), and TBV core (acOR per IQR 0.41 95%CI 0.33-0.67]) showed a lower likelihood of achieving improved functional outcomes after 90 days. The AUC was 0.80 for the prediction of functional independence at 90 days for the CTP-estimated core volume, the ICV core , and the TBV core ., Conclusion: Correcting the CTP-estimated core volume for the intracranial or total brain volume did not improve the association with functional outcomes in patients who underwent EVT.

Background: The effects of thrombus imaging characteristics on procedural and clinical outcomes after ischemic stroke are increasingly being studied. These thrombus characteristics - for eg, size, location, and density - are commonly analyzed as separate entities. However, it is known that some of these thrombus characteristics are strongly related. Multicollinearity can lead to unreliable prediction models. We aimed to determine the distribution, correlation and clustering of thrombus imaging characteristics based on a large dataset of anterior-circulation acute ischemic stroke patients., Methods: We measured thrombus imaging characteristics in the MR CLEAN Registry dataset, which included occlusion location, distance from the intracranial carotid artery to the thrombus (DT), thrombus length, density, perviousness, and clot burden score (CBS). We assessed intercorrelations with Spearman's coefficient (ρ) and grouped thrombi based on 1) occlusion location and 2) thrombus length, density and perviousness using unsupervised clustering., Results: We included 934 patients, of which 22% had an internal carotid artery (ICA) occlusion, 61% M1, 16% M2, and 1% another occlusion location. All thrombus characteristics were significantly correlated. Higher CBS was strongly correlated with longer DT (ρ=0.67, p<0.01), and moderately correlated with shorter thrombus length (ρ=-0.41, p<0.01). In more proximal occlusion locations, thrombi were significantly longer, denser, and less pervious. Unsupervised clustering analysis resulted in four thrombus groups; however, the cohesion within and distinction between the groups were weak., Conclusions: Thrombus imaging characteristics are significantly intercorrelated - strong correlations should be considered in future predictive modeling studies. Clustering analysis showed there are no distinct thrombus archetypes - novel treatments should consider this thrombus variability., Competing Interests: Competing interests: This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 777072 (INSIST project), and the AMC medical Research BV, Amsterdam UMC, location AMC, under project No 21937. The MR CLEAN registry is partially funded by unrestricted grants from the Applied Scientific Institute for Neuromodulation (Toegepast Wetenschappelijk Instituut voor Neuromodulatie), Erasmus Medical Center, Amsterdam University Medical Center and Maastricht University Medical Center. HAM reports being a co-founder and shareholder of Nicolab, a company that focuses on the use of artificial intelligence for medical image analysis. CBLMM reports grants from European Commission during the conduct of the study; grants from CVON/Dutch Heart Foundation, TWIN Foundation, Health Evaluation Netherlands, and Stryker, outside the submitted work; and shareholder of Nicolab. DWJD reports unrestricted grants from Stryker, Penumbra, Medtronic, Cerenovus, Thrombolytic Science, LLC, Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences and Health, and Thrombolytic Science, LLC for research, paid to institution. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Thrombus radiomics (TR) describe complex shape and textural thrombus imaging features. We aimed to study the relationship of TR extracted from non-contrast CT with procedural and functional outcome in endovascular-treated patients with acute ischemic stroke., Methods: Thrombi were segmented on thin-slice non-contrast CT (≤1 mm) from 699 patients included in the MR CLEAN Registry. In a pilot study, we selected 51 TR with consistent values across two raters' segmentations (ICC >0.75). Random forest models using TR in addition or as a substitute to baseline clinical variables (CV) and manual thrombus measurements (MTM) were trained with 499 patients and evaluated on 200 patients for predicting successful reperfusion (extended Thrombolysis in Cerebral Ischemia (eTICI) ≥2B), first attempt reperfusion, reperfusion within three attempts, and functional independence (modified Rankin Scale (mRS) ≤2). Three texture and shape features were selected based on feature importance and related to eTICI ≥2B, number of attempts to eTICI ≥2B, and 90-day mRS with ordinal logistic regression., Results: Random forest models using TR, CV or MTM had comparable predictive performance. Thrombus texture (inverse difference moment normalized) was independently associated with reperfusion (adjusted common OR (acOR) 0.85, 95% CI 0.72 to 0.99). Thrombus volume and texture were also independently associated with the number of attempts to successful reperfusion (acOR 1.36, 95% CI 1.03 to 1.88 and acOR 1.24, 95% CI 1.04 to 1.49)., Conclusions: TR describing thrombus volume and texture were associated with more attempts to successful reperfusion. Compared with models using CV and MTM, TR had no added value for predicting procedural and functional outcome., Competing Interests: Competing interests: Amsterdam UMC received funds from Stryker for consultations by CBLMM and YBWEMR. Unrelated to this study, Amsterdam UMC received grants from the Netherlands Organization for Health Research and Development, Health Holland Top Sector LSH and Nicolab. Dr Dippel and AvdL report unrestricted grants from Stryker, Penumbra, Medtronic, Cerenovus, Thrombolytic Science, LLC, Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, and Health Holland Top Sector Life Sciences & Health for research, paid to institution. Maastricht University Medical Center received funds from Stryker, Cerenovus, Nicolab and Philips for consultation by WHvZ. NAT received funding from the AMC Medical Research. PRK is funded by INSIST: a European Union’s Horizon 2020 research and innovation program. YBWEMR is minor shareholder of Nicolab. HAM is co-founder and shareholder of Nicolab. CBLMM reports a grant from the TWIN Foundation. Unrelated to this study, CBLMM is a minor shareholder of Nicolab and reports grants from CVON/Dutch Heart Foundation, European Commission, Health Evaluation Netherlands, and Stryker, all paid to institution., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Computed tomography perfusion (CTP) is frequently used in the triage of ischemic stroke patients for endovascular thrombectomy (EVT). We aimed to quantify the volumetric and spatial agreement of the CTP ischemic core estimated with different thresholds and follow-up MRI infarct volume on diffusion-weighted imaging (DWI). Patients treated with EVT between November 2017 and September 2020 with available baseline CTP and follow-up DWI were included. Data were processed with Philips IntelliSpace Portal using four different thresholds. Follow-up infarct volume was segmented on DWI. In 55 patients, the median DWI volume was 10 mL, and median estimated CTP ischemic core volumes ranged from 10-42 mL. In patients with complete reperfusion, the intraclass correlation coefficient (ICC) showed moderate-good volumetric agreement (range 0.55-0.76). A poor agreement was found for all methods in patients with successful reperfusion (ICC range 0.36-0.45). Spatial agreement (median Dice) was low for all four methods (range 0.17-0.19). Severe core overestimation was most frequently (27%) seen in Method 3 and patients with carotid-T occlusion. Our study shows moderate-good volumetric agreement between ischemic core estimates for four different thresholds and subsequent infarct volume on DWI in EVT-treated patients with complete reperfusion. The spatial agreement was similar to other commercially available software packages.

Background: A thrombus in the M1 segment of the middle cerebral artery (MCA) can occlude this main stem only or extend into the M1-M2 bifurcation. The occlusion pattern may affect endovascular treatment (EVT) success, as a bifurcated thrombus may be more prone to fragmentation during retrieval., Objective: To investigate whether bifurcated thrombus patterns are associated with EVT procedural and clinical outcomes., Methods: Occlusion patterns of MCA thrombi on CT angiography from MR CLEAN Registry patients were classified into three groups: main stem occlusion, bifurcation occlusion extending into one M2 branch, and bifurcation occlusion extending into both M2 branches. Procedural parameters, procedural outcomes (reperfusion grade and embolization to new territory), and clinical outcomes (24-48 hour National Institutes of Health Stroke Scale [NIHSS FU ] score, change in NIHSS scores between 24 and 48 hours and baseline ∆ [NIHSS], and 90-day modified Rankin Scale [mRS] scores) were compared between occlusion patterns., Results: We identified 1023 patients with an MCA occlusion of whom 370 (36%) had a main stem occlusion, 151 (15%) a single branch, and 502 (49%) a double branch bifurcation occlusion. There were no statistically significant differences in retrieval method, procedure time, number of retrieval attempts, reperfusion grade, and embolization to new territory between occlusion patterns. Patients with main stem occlusions had lower NIHSS FU scores than patients with single (7 vs 11, p=0.01) or double branch occlusions (7 vs 9, p=0.04). However, there were no statistically significant differences in ∆ NIHSS or in 90-day mRS scores., Conclusions: In our population, EVT procedural and long-term clinical outcomes were similar for MCA bifurcation occlusions and MCA main stem occlusions., Competing Interests: Competing interests: This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 777072 (INSIST project), and the AMC medical Research BV, Amsterdam UMC, location AMC, under project No 21937. The MR CLEAN registry is partially funded by unrestricted grants from the Applied Scientific Institute for Neuromodulation (Toegepast Wetenschappelijk Instituut voor Neuromodulatie), Erasmus Medical Center, Amsterdam University Medical Center and Maastricht University Medical Center. HAM reports co-founder and shareholder of Nicolab, a company that focuses on the use of artificial intelligence for medical image analysis. CBLMM reports grants from European Commission during the conduct of the study; grants from CVON/Dutch Heart Foundation, TWIN Foundation, and Stryker, outside the submitted work; and shareholder of Nicolab. IGHJ reports shareholder of Nicolab. DWJD and AvdL report unrestricted grants from Stryker, Penumbra, Medtronic, Cerenovus, Thrombolytic Science, LLC, Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organization for Health Research and Development, Health Holland Top Sector Life Sciences and Health, and Thrombolytic Science, LLC for research, paid to institution. BvdW received funds from Bayer and LivaNova for consultancy, paid to his institution, and grants from the Dutch Heart Foundation, the Horizon 2020 programme, and Stryker, paid to his institution, all outside the work submitted. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Computed tomography perfusion (CTP) is frequently performed during the diagnostic workup of acute ischemic stroke patients. Yet, ischemic core estimates vary widely between different commercially available software packages. We assessed the volumetric and spatial agreement of the ischemic core on CTP with the follow-up infarct on diffusion-weighted imaging (DWI) using an automated software., Methods: We included successfully reperfused patients who underwent endovascular treatment (EVT) with CTP and follow-up DWI between November 2017 and September 2020. CTP data were processed with a fully automated software using relative cerebral blood flow (rCBF) < 30% to estimate the ischemic core. The follow-up infarct was segmented on DWI imaging data, which were acquired at approximately 24 h. Ischemic core on CTP was compared with the follow-up infarct lesion on DWI using intraclass correlation coefficient (ICC) and Dice similarity coefficient (Dice)., Results: In 59 patients, the median estimated core volume on CTP was 16 (IQR 8-47) mL. The follow-up infarct volume on DWI was 11 (IQR 6-42) mL. ICC was 0.60 (95% CI 0.33-0.76), indicating moderate volumetric agreement. Median Dice was 0.20 (IQR 0.01-0.35). The median positive predictive value was 0.24 (IQR 0.05-0.57), and the median sensitivity was 0.3 (IQR 0.13-0.47). Severe core overestimation on computed tomography perfusion > 50 mL occurred in 4/59 (7%) of the cases., Conclusions: In patients with successful reperfusion after EVT, CTP-estimated ischemic core showed moderate volumetric and spatial agreement with the follow-up infarct lesion on DWI, similar to the most used commercially available CTP software packages. Severe ischemic core overestimation was relatively uncommon., (© 2022. The Author(s).)

Good collateral status in acute ischemic stroke patients is an important indicator for good outcomes. Perfusion imaging potentially allows for the simultaneous assessment of local perfusion and collateral status. We combined multiple CTP parameters to evaluate a CTP-based collateral score. We included 85 patients with a baseline CTP and single-phase CTA images from the MR CLEAN Registry. We evaluated patients' CTP parameters, including relative CBVs and tissue volumes with several time-to-maximum ranges, to be candidates for a CTP-based collateral score. The score candidate with the strongest association with CTA-based collateral score and a 90-day mRS was included for further analyses. We assessed the association of the CTP-based collateral score with the functional outcome (mRS 0-2) by analyzing three regression models: baseline prognostic factors (model 1), model 1 including the CTA-based collateral score (model 2), and model 1 including the CTP-based collateral score (model 3). The model performance was evaluated using C-statistic. Among the CTP-based collateral score candidates, relative CBVs with a time-to-maximum of 6-10 s showed a significant association with CTA-based collateral scores ( p = 0.02) and mRS ( p = 0.05) and was therefore selected for further analysis. Model 3 most accurately predicted favorable outcomes (C-statistic = 0.86, 95% CI: 0.77-0.94) although differences between regression models were not statistically significant. We introduced a CTP-based collateral score, which is significantly associated with functional outcome and may serve as an alternative collateral measure in settings where MR imaging is not feasible.

Purpose: We aimed to study the association of non-contrast CT (NCCT) thrombus density with procedural and clinical outcomes in patients with acute ischemic stroke who underwent endovascular treatment (EVT). Since thrombus density is associated with thrombus location, we focused on M1 occlusions only., Methods: Patients with available thin-slice (< 2.5 mm) NCCT were included from a nationwide registry. Regression models were used to assess the relation between thrombus density (per Hounsfield unit [HU]) and the following outcomes. For reperfusion grade, adjusted common odds ratios (acOR) indicated a 1-step shift towards improved outcome per HU increase in thrombus density. For the binary outcomes of first-pass reperfusion (first-pass extended thrombolysis in cerebral infarction [eTICI] 2C-3, FPR), functional independence [90-day modified Rankin Scale (mRS) score of 0-2] and mortality), aORs were reported. Adjusted β coefficients (aβ) were reported for 24-h NIHSS and procedure duration in minutes. Outcome differences between first-line treatment devices (stent retriever versus aspiration) were assessed with interaction terms., Results: In 566 patients with M1 occlusions, thrombus density was not associated with reperfusion (acOR 1.01, 95% CI 0.99-1.02), FPR (aOR 1.01, 95% CI 0.99-1.03), mortality (aOR 0.98, 95% CI 0.95-1.00), 24-h NIHSS (aβ - 0.7%, 95% CI - 1.4-0.2), or procedure duration (aβ 0.27, 95% CI - 0.05-0.58). In multivariable analysis, thrombus density was associated with functional independence (aOR 1.02, 95% CI 1.00-1.05). No interaction was found between thrombus density and first-line treatment device for any outcome., Conclusion: In patients with M1 occlusions, thrombus density was not clearly associated with procedural and clinical outcomes after EVT., (© 2022. The Author(s).)

Background and Objective: Computed tomography perfusion (CTP) is widely used in the evaluation of acute ischemic stroke patients for endovascular thrombectomy (EVT). The stability of CTP core estimation is suboptimal and varies between software packages. We aimed to quantify the volumetric and spatial agreement between the CTP ischemic core and follow-up infarct for four ischemic core estimation approaches using syngo.via., Methods: We included successfully reperfused, EVT-treated patients with baseline CTP and 24h follow-up diffusion weighted magnetic resonance imaging (DWI) (November 2017-September 2020). Data were processed with syngo.via VB40 using four core estimation approaches based on: cerebral blood volume (CBV)<1.2mL/100mL with and without smoothing filter, relative cerebral blood flow (rCBF)<30%, and rCBF<20%. The follow-up infarct was segmented on DWI., Results: In 59 patients, median estimated CTP core volumes for four core estimation approaches ranged from 12-39 mL. Median 24h follow-up DWI infarct volume was 11 mL. The intraclass correlation coefficient (ICC) showed moderate-good volumetric agreement for all approaches (range 0.61-0.76). Median Dice was low for all approaches (range 0.16-0.21). CTP core overestimation >10mL occurred least frequent (14/59 [24%] patients) using the CBV-based core estimation approach with smoothing filter., Conclusions: In successfully reperfused patients who underwent EVT, syngo.via CTP ischemic core estimation showed moderate volumetric and spatial agreement with the follow-up infarct on DWI. In patients with complete reperfusion after EVT, the volumetric agreement was excellent. A CTP core estimation approach based on CBV<1.2 mL/100mL with smoothing filter least often overestimated the follow-up infarct volume and is therefore preferred for clinical decision making using syngo.via., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: HAM is co-founder and shareholder of Nicolab. BJE reports grants from Stryker Neurovascular and personal fees from Dekra and Novartis outside the submitted work. CBLMM is shareholder of Nicolab and reports grants from TWIN, CVON/Dutch Heart Foundation, and Stryker outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declare no support from any organization or financial relationships with any organizations that might have an interest in the submitted work. All authors declare no other relationships or activities that could appear to have influenced the submitted work.

Infarct volume (FIV) on follow-up diffusion-weighted imaging (FU-DWI) is only moderately associated with functional outcome in acute ischemic stroke patients. However, FU-DWI may contain other imaging biomarkers that could aid in improving outcome prediction models for acute ischemic stroke. We included FU-DWI data from the HERMES, ISLES, and MR CLEAN-NO IV databases. Lesions were segmented using a deep learning model trained on the HERMES and ISLES datasets. We assessed the performance of three classifiers in predicting functional independence for the MR CLEAN-NO IV trial cohort based on: (1) FIV alone, (2) the most important features obtained from a trained convolutional autoencoder (CAE), and (3) radiomics. Furthermore, we investigated feature importance in the radiomic-feature-based model. For outcome prediction, we included 206 patients: 144 scans were included in the training set, 21 in the validation set, and 41 in the test set. The classifiers that included the CAE and the radiomic features showed AUC values of 0.88 and 0.81, respectively, while the model based on FIV had an AUC of 0.79. This difference was not found to be statistically significant. Feature importance results showed that lesion intensity heterogeneity received more weight than lesion volume in outcome prediction. This study suggests that predictions of functional outcome should not be based on FIV alone and that FU-DWI images capture additional prognostic information.

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 < 2) after 90 days. The strength of association was evaluated using the c-statistic., 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., (© 2021. The Author(s).)

Residual blood flow distal to an arterial occlusion in patients with acute ischemic stroke (AIS) is associated with favorable patient outcome. Both collateral flow and thrombus permeability may contribute to such residual flow. We propose a method for discriminating between these two mechanisms, based on determining the direction of flow in multiple branches distal to the occluding thrombus using dynamic Computed Tomography Angiography (dynamic CTA). We analyzed dynamic CTA data of 30 AIS patients and present patient-specific cases that identify typical blood flow patterns and velocities. We distinguished patterns with anterograde (N = 10), retrograde (N = 9), and both flow directions (N = 11), with a large variability in velocities for each flow pattern. The observed flow patterns reflect the interplay between permeability and collaterals. The presented method characterizes distal flow and provides a tool to study patient-specific distal tissue perfusion.

Background: The value of administering intravenous alteplase before endovascular treatment (EVT) for acute ischemic stroke has not been studied extensively, particularly in non-Asian populations., Methods: We performed an open-label, multicenter, randomized trial in Europe involving patients with stroke who presented directly to a hospital that was capable of providing EVT and who were eligible for intravenous alteplase and EVT. Patients were randomly assigned in a 1:1 ratio to receive EVT alone or intravenous alteplase followed by EVT (the standard of care). The primary end point was functional outcome on the modified Rankin scale (range, 0 [no disability] to 6 [death]) at 90 days. We assessed the superiority of EVT alone over alteplase plus EVT, as well as noninferiority by a margin of 0.8 for the lower boundary of the 95% confidence interval for the odds ratio of the two trial groups. Death from any cause and symptomatic intracerebral hemorrhage were the main safety end points., Results: The analysis included 539 patients. The median score on the modified Rankin scale at 90 days was 3 (interquartile range, 2 to 5) with EVT alone and 2 (interquartile range, 2 to 5) with alteplase plus EVT. The adjusted common odds ratio was 0.84 (95% confidence interval [CI], 0.62 to 1.15; P = 0.28), which showed neither superiority nor noninferiority of EVT alone. Mortality was 20.5% with EVT alone and 15.8% with alteplase plus EVT (adjusted odds ratio, 1.39; 95% CI, 0.84 to 2.30). Symptomatic intracerebral hemorrhage occurred in 5.9% and 5.3% of the patients in the respective groups (adjusted odds ratio, 1.30; 95% CI, 0.60 to 2.81)., Conclusions: In a randomized trial involving European patients, EVT alone was neither superior nor noninferior to intravenous alteplase followed by EVT with regard to disability outcome at 90 days after stroke. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by the Collaboration for New Treatments of Acute Stroke consortium and others; MR CLEAN-NO IV ISRCTN number, ISRCTN80619088.)., (Copyright © 2021 Massachusetts Medical Society.)

Background and Purpose: Thrombus perviousness estimates residual flow along a thrombus in acute ischemic stroke, based on radiological images, and may influence the benefit of endovascular treatment for acute ischemic stroke. We aimed to investigate potential endovascular treatment (EVT) effect modification by thrombus perviousness., Methods: We included 443 patients with thin-slice imaging available, out of 1766 patients from the pooled HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set of 7 randomized trials on EVT in the early window (most within 8 hours). Control arm patients (n=233) received intravenous alteplase if eligible (212/233; 91%). Intervention arm patients (n=210) received additional EVT (prior alteplase in 178/210; 85%). Perviousness was quantified by thrombus attenuation increase on admission computed tomography angiography compared with noncontrast computed tomography. Multivariable regression analyses were performed including multiplicative interaction terms between thrombus attenuation increase and treatment allocation. In case of significant interaction, subgroup analyses by treatment arm were performed. Our primary outcome was 90-day functional outcome (modified Rankin Scale score), resulting in an adjusted common odds ratio for a one-step shift towards improved outcome. Secondary outcomes were mortality, successful reperfusion (extended Thrombolysis in Cerebral Infarction score, 2B–3), and follow-up infarct volume (in mL)., Results: Increased perviousness was associated with improved functional outcome. After adding a multiplicative term of thrombus attenuation increase and treatment allocation, model fit improved significantly (P=0.03), indicating interaction between perviousness and EVT benefit. Control arm patients showed significantly better outcomes with increased perviousness (adjusted common odds ratio, 1.2 [95% CI, 1.1–1.3]). In the EVT arm, no significant association was found (adjusted common odds ratio, 1.0 [95% CI, 0.9–1.1]), and perviousness was not significantly associated with successful reperfusion. Follow-up infarct volume (12% [95% CI, 7.0–17] per 5 Hounsfield units) and chance of mortality (adjusted odds ratio, 0.83 [95% CI, 0.70–0.97]) decreased with higher thrombus attenuation increase in the overall population, without significant treatment interaction., Conclusions: Our study suggests that the benefit of best medical care including alteplase, compared with additional EVT, increases in patients with more pervious thrombi.

Introduction: Radiological thrombus characteristics are associated with patient outcomes and treatment success after acute ischemic stroke. These characteristics could be expected to undergo time-dependent changes due to factors influencing thrombus architecture like blood stasis, clot contraction, and natural thrombolysis. We investigated whether stroke onset-to-imaging time was associated with thrombus length, perviousness, and density in the MR CLEAN Registry population. Methods: We included 245 patients with M1-segment occlusions and thin-slice baseline CT imaging from the MR CLEAN Registry, a nation-wide multicenter registry of patients who underwent endovascular treatment for acute ischemic stroke within 6.5 h of onset in the Netherlands. We used multivariable linear regression to investigate the effect of stroke onset-to-imaging time (per 5 min) on thrombus length (in mm), perviousness and density (both in Hounsfield Units). In the first model, we adjusted for age, sex, intravenous thrombolysis, antiplatelet use, and history of atrial fibrillation. In a second model, we additionally adjusted for observed vs. non-observed stroke onset, CT-angiography collateral score, direct presentation at a thrombectomy-capable center vs. transfer, and stroke etiology. We performed exploratory subgroup analyses for intravenous thrombolysis administration, observed vs. non-observed stroke onset, direct presentation vs. transfer, and stroke etiology. Results: Median stroke onset-to-imaging time was 83 (interquartile range 53-141) min. Onset to imaging time was not associated with thrombus length nor perviousness (β 0.002; 95% CI -0.004 to 0.007 and β -0.002; 95% CI -0.015 to 0.011 per 5 min, respectively) and was weakly associated with thrombus density in the fully adjusted model (adjusted β 0.100; 95% CI 0.005-0.196 HU per 5 min). The subgroup analyses showed no heterogeneity of these findings in any of the subgroups, except for a significantly positive relation between onset-to-imaging time and thrombus density in patients transferred from a primary stroke center (adjusted β 0.18; 95% CI 0.022-0.35). Conclusion: In our population of acute ischemic stroke patients, we found no clear association between onset-to-imaging time and radiological thrombus characteristics. This suggests that elapsed time from stroke onset plays a limited role in the interpretation of radiological thrombus characteristics and their effect on treatment results, at least in the early time window., Competing Interests: Erasmus MC received funds from Stryker by AL. Amsterdam UMC received funds from Stryker for consultations by CM and YR. MUMC received funds from Stryker and Codman for consultations by WZ. CM reports grants from the TWIN Foundation, the CVON/Dutch Heart Foundation, the European Commission. HM is cofounder and shareholder of Nico.lab. CM, MC, and YR own stock in Nico.lab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tolhuisen, Kappelhof, Dutra, Jansen, Guglielmi, Dippel, van Zwam, van Oostenbrugge, van der Lugt, Roos, Majoie, Caan, Marquering and the MR CLEAN Registry Investigators.)

Objective: Calcified cerebral emboli (CCE) are a rare cause of acute ischemic stroke. The authors aimed to assess the association of CCE with functional outcome, successful reperfusion, and mortality. Furthermore, they aimed to assess the effectiveness of intravenous alteplase treatment and endovascular treatment (EVT), as well as the best first-line EVT approach in patients with CCE., Methods: The Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry is a prospective, observational multicenter registry of patients treated with EVT for acute ischemic stroke in 16 intervention hospitals in the Netherlands. The association of CCE with functional outcome, reperfusion, and mortality was evaluated using logistic regression models. Univariable comparisons were made to determine the effectiveness of intravenous alteplase treatment and the best first-line EVT approach in CCE patients., Results: The study included 3077 patients from the MR CLEAN Registry. Fifty-five patients (1.8%) had CCE. CCE were not significantly associated with worse functional outcome (adjusted common OR 0.71, 95% CI 0.44-1.15), and 29% of CCE patients achieved functional independence. An extended Thrombolysis in Cerebral Infarction score ≥ 2B was significantly less often achieved in CCE patients compared to non-CCE patients (adjusted OR [aOR] 0.52, 95% CI 0.28-0.97). Symptomatic intracranial hemorrhage occurred in 8 CCE patients (15%) vs 171 of 3022 non-CCE patients (6%; p = 0.01). The median improvement on the National Institutes of Health Stroke Scale (NIHSS) was 2 in CCE patients versus 4 in non-CCE patients (p = 0.008). CCE were not significantly associated with mortality (aOR 1.16, 95% CI 0.64-2.12). Intravenous alteplase use in CCE patients was not associated with functional outcome or reperfusion. In CCE patients with successful reperfusion, stent retrievers were more often used as the primary treatment device (p = 0.04)., Conclusions: While patients with CCE had significantly lower reperfusion rates and less improvement on the NIHSS after EVT, CCE were not significantly associated with worse functional outcome or higher mortality rates. Therefore, EVT should still be considered in this specific group of patients.

Thrombus permeability determines blood flow through the occluding thrombus in acute ischemic stroke (AIS) patients. The quantification of thrombus permeability is challenging since it cannot be directly measured nor derived from radiological imaging data. As a proxy of thrombus permeability, thrombus perviousness has been introduced, which assesses the amount of contrast agent that has penetrated the thrombus on single-phase computed tomography angiography (CTA). We present a method to assess thrombus permeability rather than perviousness. We follow a three-step approach: (1) we propose a theoretical channel-like structure model describing the thrombus morphology. Using Darcy's law, we provide an analytical description of the permeability for this model. According to the channel-like model, permeability depends on the number of channels in the thrombus, the radius of the occluded artery, and the void fraction representing the volume available for the blood to flow; (2) we measure intra-thrombus blood flow and velocity on dynamic CTA; and (3) we combine the analytical model with the dynamic CTA measurements to estimate thrombus permeability. Analysis of dynamic CTA data from 49 AIS patients showed that the median blood velocity in the thrombus was 0.58 (IQR 0.26-1.35) cm/s. The median flow within the thrombus was 3.48 · 10 -3 (IQR 1.71 · 10 -3 -9.21 · 10 -3 ) ml/s. Thrombus permeability was of the order of 10 -3 -10 -5 mm 2 , depending on the number of channels in the thrombus. The channel-like thrombus model offers an intuitive way of modelling thrombus permeability, which can be of interest when studying the effect of thrombolytic drugs., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Infarct 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., Objective: To 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 Methods: We 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., Results: The 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., Conclusion: Convolutional 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., Competing Interests: Competing interests: RSB, AMMB, HAM, and CBLMM are cofounders and shareholder of Nico Laboratory. EP is a shareholder of Nico Laboratory., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose- If a relationship between stroke etiology and thrombus computed tomography characteristics exists, assessing these characteristics in clinical practice could serve as a useful additional diagnostic tool for the identification of stroke subtype. Our purpose was to study the association of stroke etiology and thrombus computed tomography characteristics in patients with acute ischemic stroke due to a large vessel occlusion. Methods- For 1429 consecutive patients enrolled in the MR CLEAN Registry, we determined stroke cause as defined by the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria. The association of stroke etiology with the hyperdense artery sign, clot burden score, and thrombus location was estimated with univariable and multivariable binary and ordinal logistic regression. Additionally, for 367 patients with available thin-section imaging, we assessed the association of stroke etiology with absolute and relative thrombus attenuation, distance from internal carotid artery-terminus to thrombus, thrombus length, and thrombus attenuation increase with univariable and multivariable linear regression. Results- Compared with cardioembolic strokes, noncardioembolic strokes were associated with presence of hyperdense artery sign (odds ratio, 2.2 [95% CI, 1.6-3.0]), lower clot burden score (common odds ratio, 0.4 [95% CI, 0.3-0.6]), shift towards a more proximal thrombus location (common odds ratio, 0.2 [95% CI, 0.2-0.3]), higher absolute thrombus attenuation (β, 3.6 [95% CI, 0.9-6.4]), decrease in distance from the ICA-terminus (β, -5.7 [95% CI, -8.3 to -3.0]), and longer thrombi (β, 8.6 [95% CI, 6.5-10.7]), based on univariable analysis. Thrombus characteristics of strokes with undetermined cause were similar to those of cardioembolic strokes. Conclusions- Thrombus computed tomography characteristics of cardioembolic stroke are distinct from those of noncardioembolic stroke. Additionally, our study supports the general hypothesis that many cryptogenic strokes have a cardioembolic cause. Further research should focus on the use of thrombus computed tomography characteristics as a diagnostic tool for stroke cause in clinical practice.

Background and Purpose- Due to chronic hypoperfusion, cervical atherosclerosis may promote cerebral collateral circulation. We hypothesized that patients with ischemic stroke due to cervical carotid atherosclerosis have a more extensive collateral circulation and better outcomes than patients with cardioembolism. We tested this hypothesis in a population of patients who underwent endovascular treatment for large vessel occlusion. Methods- From the MR-CLEAN Registry (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), we selected consecutive adult endovascular treatment patients (March 2014 to June 2016) with acute ischemic stroke due to anterior circulation large vessel occlusion and compared patients with cervical carotid artery stenosis >50% to those with cardioembolic etiology. The primary outcome was collateral score, graded on a 4-point scale. Secondary outcomes included the modified Rankin Scale (mRS) score and mortality at 90 days. We performed multivariable regression analyses and adjusted for potential confounders. Results- Of 1627 patients in the Registry, 190 patients with cervical carotid atherosclerosis and 476 with cardioembolism were included. Patients with cervical carotid atherosclerosis were younger (median 69 versus 76 years, P <0.001), more often male (67% versus 47%, P <0.001), more often had an internal carotid artery terminus occlusion (33% versus 18%, P <0.001), and a lower prestroke mRS (mRS score, 0-2; 96% versus 85%, P <0.001), than patients with cardioembolism. Stroke due to cervical carotid atherosclerosis was associated with higher collateral score (adjusted common odds ratio, 1.67 [95% CI, 1.17-2.39]) and lower median mRS at 90 days (adjusted common odds ratio, 1.45 [95% CI, 1.03-2.05]) compared with cardioembolic stroke. There was no statistically significant difference in proportion of mRS 0-2 (aOR, 1.36 [95% CI, 0.90-2.07]) or mortality at 90 days (aOR, 0.80 [95% CI, 0.48-1.34]). Conclusions- Patients with stroke due to cervical carotid atherosclerosis had a more extensive cerebral collateral circulation and a slightly better median mRS at 90 days than patients with cardioembolic stroke.

Treatment selection is becoming increasingly more important in acute ischemic stroke patient care. Clinical variables and radiological image biomarkers (old age, pre-stroke mRS, NIHSS, occlusion location, ASPECTS, among others) have an important role in treatment selection and prognosis. Radiological biomarkers require expert annotation and are subject to inter-observer variability. Recently, Deep Learning has been introduced to reproduce these radiological image biomarkers. Instead of reproducing these biomarkers, in this work, we investigated Deep Learning techniques for building models to directly predict good reperfusion after endovascular treatment (EVT) and good functional outcome using CT angiography images. These models do not require image annotation and are fast to compute. We compare the Deep Learning models to Machine Learning models using traditional radiological image biomarkers. We explored Residual Neural Network (ResNet) architectures, adapted them with Structured Receptive Fields (RFNN) and auto-encoders (AE) for network weight initialization. We further included model visualization techniques to provide insight into the network's decision-making process. We applied the methods on the MR CLEAN Registry dataset with 1301 patients. The Deep Learning models outperformed the models using traditional radiological image biomarkers in three out of four cross-validation folds for functional outcome (average AUC of 0.71) and for all folds for reperfusion (average AUC of 0.65). Model visualization showed that the arteries were relevant features for functional outcome prediction. The best results were obtained for the ResNet models with RFNN. Auto-encoder initialization often improved the results. We concluded that, in our dataset, automated image analysis with Deep Learning methods outperforms radiological image biomarkers for stroke outcome prediction and has the potential to improve treatment selection., (Copyright © 2019. Published by Elsevier Ltd.)

Background and Purpose- Thrombus imaging characteristics have been reported to be useful to predict functional outcome and reperfusion in acute ischemic stroke. However, conflicting data about this subject exist in patients undergoing endovascular treatment. Therefore, we aimed to evaluate whether thrombus imaging characteristics assessed on computed tomography are associated with outcomes in patients with acute ischemic stroke treated by endovascular treatment. Methods- The MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry is an ongoing, prospective, and observational study in all centers performing endovascular treatment in the Netherlands. We evaluated associations of thrombus imaging characteristics with the functional outcome (modified Rankin Scale at 90 days), mortality, reperfusion, duration of endovascular treatment, and symptomatic intracranial hemorrhage using univariable and multivariable regression models. Thrombus characteristics included location, clot burden score (CBS), length, relative and absolute attenuation, perviousness, and distance from the internal carotid artery terminus to the thrombus. All characteristics were assessed on thin-slice (≤2.5 mm) noncontrast computed tomography and computed tomography angiography, acquired within 30 minutes from each other. Results- In total, 408 patients were analyzed. Thrombus with distal location, higher CBS, and shorter length were associated with better functional outcome (adjusted common odds ratio, 3.3; 95% CI, 2.0-5.3 for distal M1 occlusion compared with internal carotid artery occlusion; adjusted common odds ratio, 1.15; 95% CI, 1.07-1.24 per CBS point; and adjusted common odds ratio, 0.96; 95% CI, 0.94-0.99 per mm, respectively) and reduced duration of endovascular procedure (adjusted coefficient B, -14.7; 95% CI, -24.2 to -5.1 for distal M1 occlusion compared with internal carotid artery occlusion; adjusted coefficient B, -8.5; 95% CI, -14.5 to -2.4 per CBS point; and adjusted coefficient B, 7.3; 95% CI, 2.9-11.8 per mm, respectively). Thrombus perviousness was associated with better functional outcome (adjusted common odds ratio, 1.01; 95% CI, 1.00-1.02 per Hounsfield units increase). Distal thrombi were associated with successful reperfusion (adjusted odds ratio, 2.6; 95% CI, 1.4-4.9 for proximal M1 occlusion compared with internal carotid artery occlusion). Conclusions- Distal location, higher CBS, and shorter length are associated with better functional outcome and faster endovascular procedure. Distal thrombus is strongly associated with successful reperfusion, and a pervious thrombus is associated with better functional outcome.

Virtual planning of open cranial vault reconstruction is used to simulate and define an pre-operative plan for craniosynostosis surgery. However, virtual planning techniques are subjective and dependent on the experience and preferences of the surgical team. To develop an objective automated 3D pre-operative planning technique for open cranial vault reconstructions, we used curvature maps for the shape comparison of the patient's skull with an age-specific reference skull. We created an average skull for the age-group of 11-14 months. Also, we created an artificial test object and selected a cranial CT-scan of an 11 months old trigonocephaly patient as test case. Mesh data of skulls were created using marching cubes and raycasting. Curvature maps were computed using quadric surface fitting. The shape comparison was tested for the test object and the average skull. Finally, shape comparison was performed for the trigonocephalic skull with the average skull. Similar shapes and the area on the patient's skull that maximally corresponded in shape with the reference shape were correctly identified. This study showed that curvature maps allow the comparison of craniosynostosis skulls with age-appropriate average skulls and a first step towards an objective user-independent pre-operative planning technique for open cranial vault reconstructions is made.