ObjectivesCarotid atherosclerosis plays an essential role in the occurrence of ischemic stroke. This study aimed to investigate whether a larger burden of napkin-ring sign (NRS) plaques on... Show moreObjectivesCarotid atherosclerosis plays an essential role in the occurrence of ischemic stroke. This study aimed to investigate whether a larger burden of napkin-ring sign (NRS) plaques on cervicocerebral computed tomography angiography (CTA) increased the risk of acute ischemic stroke (AIS).MethodsThis retrospective, single-center, cross-sectional study enrolled patients with NRS plaques identified in the subclavian arteries, brachiocephalic trunk, carotid arterial system, and vertebrobasilar circulation on contrast-enhanced cervicocerebral CTA. Patients were divided into AIS and non-AIS groups based on imaging within 12 h of symptom onset. Univariate and multivariate logistic regression analyses were performed to determine the risk factor of AIS occurrence.ResultsA total of 202 patients (66.72 years ± 8.97, 157 men) were evaluated. Plaques with NRS in each subject of the AIS group (N = 98) were significantly more prevalent than that in the control group (N = 104) (1.96 ± 1.17 vs 1.41 ± 0.62). In the AIS group, there were substantially more NRS plaques on the ipsilateral side than contralateral side (1.55 ± 0.90 vs. 0.41 ± 0.66). NRS located on the ipsilateral side of the AIS showed an area under the receiver curve (AUC) of 0.86 to identify ischemic stroke. NRS plaque amounts were an independent risk factor for AIS occurrence (odds ratio, 1.86) after adjusting for other factors.ConclusionsIncreased incidence of napkin-ring sign plaques on cervicocerebral CTA was positively associated with AIS occurrence, which could aid in detecting asymptomatic atherosclerotic patients at high risk of AIS in routine screening or emergency settings. Show less
In this thesis, the role of migraine as a cardiovascular risk factor is investigated in different populations with a varying medical history, including stroke and polycystic ovary syndrome (PCOS).... Show moreIn this thesis, the role of migraine as a cardiovascular risk factor is investigated in different populations with a varying medical history, including stroke and polycystic ovary syndrome (PCOS). We focused primarily on women and sex-specific features, exploring both conventional and novel measures for vascular health. This thesis was written in the context of the CREW consortium. The aim of the CREW consortium, a cooperation of major medical centers in the Netherlands and commissioned by the Dutch Heart Institute, was to study female-specific cardiovascular pathophysiology. The CREW-MIST (Cardiovascular Riskprofile in Women – MIcrovascular STatus) project, which was part of this consortium, focused on migraine in relation to stroke in women. Female-specific factors such as sex hormone- and pregnancy-related disorders were included in our studies and we explored microvascular health through heart- and brain imaging and functional measurements of the vasculature. Show less
PurposeThe composition of thrombi retrieved during endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) due to large vessel occlusion (LVO) may differ depending on their origin. In this... Show morePurposeThe composition of thrombi retrieved during endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) due to large vessel occlusion (LVO) may differ depending on their origin. In this study, we investigated the association between thrombus composition and stroke etiology in a large population of patients from the Dutch MR CLEAN Registry treated with EVT in daily clinical practice.MethodsThe thrombi of 332 patients with AIS were histologically analyzed for red blood cells (RBC), fibrin/platelets (F/P), and white blood cells (leukocytes) using a machine learning algorithm. Stroke etiology was assessed using the Trial of Org 10,172 in acute stroke treatment (TOAST) classification.ResultsThe thrombi of cardioembolic origin contained less RBC and more F/P than those of non-cardioembolic origin (25.8% vs 41.2% RBC [p = 0.003] and 67.1% vs 54.5% F/P [p = 0.004]). The likelihood of a non-cardioembolic source of stroke increased with increasing thrombus RBC content (OR 1.02; [95% CI 1.00-1.06] for each percent increase) and decreased with a higher F/P content (OR 1.02; [95% CI 1.00-1.06]). Thrombus composition in patients with a cardioembolic origin and undetermined origin was similar.ConclusionThrombus composition is significantly associated with stroke etiology, with an increase in RBC and a decrease in F/P raising the odds for a non-cardioembolic cause. No difference between composition of cardioembolic thrombi and of undetermined origin was seen. This emphasizes the need for more extensive monitoring for arrhythmias and/or extended cardiac analysis in case of an undetermined origin. Show less
Background The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not... Show moreBackground The effectiveness of alteplase for ischemic stroke treatment is limited, partly due to the occurrence of intracranial and extracranial hemorrhage. Mutant pro-urokinase (m-proUK) does not deplete fibrinogen and lyses fibrin only after induction with alteplase. Therefore, this treatment has the potential to be safer and more efficacious than treatment with alteplase alone. The aim of this study is to assess the safety and efficacy of thrombolytic treatment consisting of a small bolus alteplase followed by m-proUK compared with standard thrombolytic treatment with alteplase in patients presenting with ischemic stroke. Methods DUMAS is a multicenter, phase II trial with a prospective randomized open-label blinded end-point (PROBE) design, and an adaptive design for dose optimization. Patients with ischemic stroke, who meet the criteria for treatment with intravenous (IV) alteplase can be included. Patients eligible for endovascular thrombectomy are excluded. Patients are randomly assigned (1:1) to receive a bolus of IV alteplase (5mg) followed by a continuous IV infusion of m-proUK (40 mg/h during 60 min) or usual care with alteplase (0.9 mg/kg). Depending on the results of interim analyses, the dose of m-proUK may be revised to a lower dose (30 mg/h during 60 min) or a higher dose (50 mg/h during 60 min). We aim to include 200 patients with a final diagnosis of ischemic stroke. The primary outcome is any post-intervention intracranial hemorrhage (ICH) on neuroimaging at 24 h according to the Heidelberg Bleeding Classification, analyzed with binary logistic regression. Efficacy outcomes include stroke severity measured with the National Institutes of Health Stroke Scale (NIHSS) at 24 h and 5-7 days, score on the modified Rankin scale (mRS) assessed at 30 days, change (pre-treatment vs. post-treatment) in abnormal perfusion volume, and blood biomarkers of thrombolysis at 24 h. Secondary safety endpoints include symptomatic intracranial hemorrhage, death, and major extracranial hemorrhage. This trial will use a deferred consent procedure. Discussion When dual thrombolytic therapy with a small bolus alteplase and m-proUK shows the anticipated effect on the outcome, this will lead to a 13% absolute reduction in the occurrence of ICH in patients with ischemic stroke. Show less
Steen, W. van der; Ende, N.A.M. van der; Kranendonk, K.R. van; Chalos, V.; Brouwer, J.; Oostenbrugge, R.J. van; ... ; MR Clean Registry Investigators 2022
Introduction: Little is known about the timing of occurrence of symptomatic intracranial hemorrhage (sICH) after endovascular therapy (EVT) for acute ischemic stroke. A better understanding could... Show moreIntroduction: Little is known about the timing of occurrence of symptomatic intracranial hemorrhage (sICH) after endovascular therapy (EVT) for acute ischemic stroke. A better understanding could optimize in-hospital surveillance time points and duration. The aim of this study was to delineate the probability of sICH over time and to identify factors associated with its timing. Patients and methods: We retrospectively analyzed data from the Dutch MR CLEAN trial and MR CLEAN Registry. We included adult patients who underwent EVT for an anterior circulation large vessel occlusion within 6.5 h of stroke onset. In patients with sICH (defined as ICH causing an increase of > 4 points on the National Institutes of Health Stroke Scale [NIHSS]), univariable and multivariable linear regression analysis was used to identify factors associated with the timing of sICH. This was defined as the time between end of EVT and the time of first CT-scan on which ICH was seen as a proxy. Results: SICH occurred in 205 (6%) of 3391 included patients. Median time from end of EVT procedure to sICH detection on NCCT was 9.0 [IQR 2.9-22.5] hours, with a rapidly decreasing incidence after 24 h. None of the analyzed factors, including baseline NIHSS, intravenous alteplase treatment, and poor reperfusion at the end of the procedure were associated with the timing of sICH. Conclusion: SICHs primarily occur in the first hours after EVT, and less frequently beyond 24 h. Guidelines that recommend to perform frequent neurological assessments for at least 24 h after intravenous alteplase treatment can be applied to ischemic stroke patients treated with EVT. Show less
Martens, L.G.; Luo, J.; Wermer, M.J.H.; Dijk, K.W. van; Hagg, S.; Grassmann, F.; ... ; Heemst, D. van 2022
Background and aims: Mitochondrial dysfunction is associated with increased reactive oxygen species (ROS) that are thought to drive disease risk, including stroke. We investigated the association... Show moreBackground and aims: Mitochondrial dysfunction is associated with increased reactive oxygen species (ROS) that are thought to drive disease risk, including stroke. We investigated the association between mtDNA abundance, as a proxy measure of mitochondrial function, and incident stroke, using multivariable-adjusted survival and Mendelian Randomization (MR) analyses. Methods: Cox-proportional hazard model analyses were conducted to assess the association between mtDNA abundance, and incident ischemic and hemorrhagic stroke over a maximum of 14-year follow-up in European -ancestry participants from UK Biobank. MR was conducted using independent (R-2 < 0.001) lead variants for mtDNA abundance (p < 5 x 10(-8)) as instrumental variables. Single-nucleotide polymorphism (SNP)-ischemic stroke associations were derived from three published open source European-ancestry results databases (cases/ controls): MEGASTROKE (60,341/454,450), UK Biobank (2404/368,771) and FinnGen (10,551/202,223). MR was performed per study, and results were subsequently meta-analyzed. Results: In total, 288,572 unrelated participants (46% men) with mean (SD) age of 57 (8) years were included in the Cox-proportional hazard analyses. After correction for considered confounders (BMI, hypertension, cholesterol, T2D), no association was found between low versus high mtDNA abundance and ischemic (HR: 1.06 [95% CI: 0.95, 1.18]) or hemorrhagic (HR: 0.97 [95% CI: 0.82, 1.15]) stroke. However, in the MR analyses after removal of platelet count-associated SNPs, we found evidence for an association between genetically-influenced mtDNA abundance and ischemic stroke (odds ratio, 1.17; confidence interval, 1.03, 1.32). Conclusions: Although the results from both multivariable-adjusted prospective and basis MR analyses did not show an association between low mtDNA and increased risk of ischemic stroke, in-depth MR sensitivity analyses may suggest evidence for a causal relationship. Show less
Wolff, L.; Su, J.H.; Loon, D. van; Es, A. van; Doormaal, P.J. van; Majoie, C.; ... ; MR CLEAN Investigators 2022
Purpose Outcome of endovascular treatment in acute ischemic stroke patients is depending on the collateral circulation maintaining blood flow to the ischemic territory. We evaluated the inter-rater... Show morePurpose Outcome of endovascular treatment in acute ischemic stroke patients is depending on the collateral circulation maintaining blood flow to the ischemic territory. We evaluated the inter-rater reliability and accuracy of raters and an automated algorithm for assessing the collateral score (CS, range: 0-3) in acute ischemic stroke patients. Methods Baseline CTA scans with an intracranial anterior occlusion from the MR CLEAN study (n=500) were used. For each core lab CS, ten CTA scans with sufficient quality were randomly selected. After a training session in collateral scoring, all selected CTA scans were individually evaluated for a visual CS by three groups: 7 radiologists, 13 junior and 9 senior radiology residents. Two additional radiologists scored CS to be used as reference, with a third providing a CS to produce a 2 out of 3 consensus CS in case of disagreement. An automated algorithm was also used to compute CS. Inter-rater agreement was reported with intraclass correlation coefficient (ICC). Accuracy of visual and automated CS were calculated. Results 39 CTA scans were assessed (1 corrupt CTA-scan excluded). All groups showed a moderate ICC (0.689-0.780) in comparison to the reference standard. Overall human accuracy was 65 +/- 7% and increased to 88 +/- 5% for dichotomized CS (0-1, 2-3). Automated CS accuracy was 62%, and 90% for dichotomized CS. No significant difference in accuracy was found between groups with different levels of expertise. Conclusion After training, inter-rater reliability in collateral scoring was not influenced by experience. Automated CS performs similar to residents and radiologists in determining a collateral score. Show less
Background: The ratio of intracranial cerebrospinal fluid (CSF) volume to intracranial volume (ICV) has been identified as a potential predictor of malignant edema formation in patients with acute... Show moreBackground: The ratio of intracranial cerebrospinal fluid (CSF) volume to intracranial volume (ICV) has been identified as a potential predictor of malignant edema formation in patients with acute ischemic stroke. Aims: We aimed to evaluate the added value of the CSF/ICV ratio in a model to predict malignant edema formation in patients who underwent endovascular treatment. Methods: We included patients from the MR CLEAN Registry, a prospective national multicenter registry of patients who were treated with endovascular treatment between 2014 and 2017 because of acute ischemic stroke caused by large vessel occlusion. The CSF/ICV ratio was automatically measured on baseline thin-slice noncontrast CT. The primary outcome was the occurrence of malignant edema based on clinical and imaging features. The basic model included the following predictors: age, National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT score, occlusion of the internal carotid artery, collateral score, time between symptom onset and groin puncture, and unsuccessful reperfusion. The extended model included the basic model and the CSF/ICV ratio. The performance of the basic and the extended model was compared with the likelihood ratio test. Results: Malignant edema occurred in 40 (6%) of 683 patients. In the extended model, a lower CSF/ICV ratio was associated with the occurrence of malignant edema (odds ratio (OR) per percentage point, 1.2; 95% confidence interval (CI) 1.1-1.3, p < 0.001). Age lost predictive value for malignant edema in the extended model (OR 1.1; 95% CI 0.9-1.5, p = 0.372). The performance of the extended model was higher than that of the basic model (p < 0.001). Conclusions: Adding the CSF/ICV ratio improves a multimodal prediction model for the occurrence of malignant edema after endovascular treatment. Show less
Objectives Thrombus computed tomography (CT) characteristics might be used to assess histopathologic thrombus composition in patients treated with endovascular thrombectomy (EVT) for acute ischemic... Show moreObjectives Thrombus computed tomography (CT) characteristics might be used to assess histopathologic thrombus composition in patients treated with endovascular thrombectomy (EVT) for acute ischemic stroke (AIS). We aimed to assess the variability in thrombus composition that could be predicted with combined thrombus CT characteristics. Methods Thrombi of patients enrolled in the MR CLEAN Registry between March 2014 and June 2016 were histologically analyzed with hematoxylin-eosin staining and quantified for percentages of red blood cells (RBCs) and fibrin/platelets. We estimated the association between general qualitative characteristics (hyperdense artery sign [HAS], occlusion location, clot burden score [CBS]) and thrombus composition with linear regression, and quantified RBC variability that could be explained with individual and combined characteristics with R-2. For patients with available thin-slice (<= 2.5 mm) imaging, we performed similar analyses for general and quantitative characteristics (HAS, occlusion location, CBS, [relative] thrombus density, thrombus length, perviousness, distance from ICA-terminus). Results In 332 included patients, the presence of HAS (a beta 7.8 [95% CI 3.9-11.7]) and shift towards a more proximal occlusion location (a beta 3.9 [95% CI 0.6-7.1]) were independently associated with increased RBC and decreased fibrin/platelet content. With general characteristics, 12% of RBC variability could be explained; HAS was the strongest predictor. In 94 patients with available thin-slice imaging, 30% of RBC variability could be explained; thrombus density and thrombus length were the strongest predictors. Conclusions Quantitative thrombus CT characteristics on thin-slice admission CT improve prediction of thrombus composition and might be used to further guide clinical decision-making in patients treated with EVT for AIS in the future. Show less
Objectives Outcome of endovascular treatment in acute ischemic stroke patients depends on collateral circulation to provide blood supply to the ischemic territory. We evaluated the performance of a... Show moreObjectives Outcome of endovascular treatment in acute ischemic stroke patients depends on collateral circulation to provide blood supply to the ischemic territory. We evaluated the performance of a commercially available algorithm for assessing the collateral score (CS) in acute ischemic stroke patients. Methods Retrospectively, baseline CTA scans (<= 3-mm slice thickness) with an intracranial carotid artery (ICA), middle cerebral artery segment M1 or M2 occlusion, from the MR CLEAN Registry (n = 1627) were evaluated. All CTA scans were evaluated for visual CS (0-3) by eight expert radiologists (reference standard). A Web-based AI algorithm quantified the collateral circulation (0-100%) for correctly detected occlusion sides. Agreement between visual CS and categorized automated CS (0: 0%, 1: > 0- <= 50%, 2: > 50- < 100%, 3: 100%) was assessed. Area under the curve (AUC) values for classifying patients in having good (CS: 2-3) versus poor (CS: 0-1) collaterals and for predicting functional independence (90-day modified Rankin Scale 0-2) were computed. Influence of CTA acquisition timing after contrast material administration was reported. Results In the analyzed scans (n = 1024), 59% agreement was found between visual CS and automated CS. An AUC of 0.87 (95% CI: 0.85-0.90) was found for discriminating good versus poor CS. Timing of CTA acquisition did not influence discriminatory performance. AUC for predicting functional independence was 0.66 (95% CI 0.62-0.69) for automated CS, similar to visual CS 0.64 (95% CI 0.61-0.68). Conclusions The automated CS performs similar to radiologists in determining a good versus poor collateral score and predicting functional independence in acute ischemic stroke patients with a large vessel occlusion. Show less
Amini, M.; Hartog, S.J. den; Leeuwen, N. van; Eijkenaar, F.; Kuhrij, L.S.; Stolze, L.J.; ... ; PERFEQTOS Investigators 2021
Background: Although the provision of performance feedback to healthcare professionals based on data from quality registries is common practice in many fields of medicine, observational studies of... Show moreBackground: Although the provision of performance feedback to healthcare professionals based on data from quality registries is common practice in many fields of medicine, observational studies of its effect on the quality of care have shown mixed results. The objective of this study is to evaluate the effect of performance feedback on the quality of care for acute ischemic stroke.Methods: PERFEQTOS is a stepped wedge cluster randomized trial in 13 hospitals in the Netherlands providing endovascular thrombectomy for ischemic stroke. The primary outcome is the hospital's door-to-groin time. The study starts with a 6-month period in which none of the hospitals receives the performance feedback intervention. Subsequently, every 6 months, three or four hospitals are randomized to cross over from the control to the intervention conditions, until all hospitals receive the feedback intervention. The feedback intervention consists of a dashboard with quarterly reports on patient characteristics, structure, process, and outcome indicators related to patients with ischemic stroke treated with endovascular thrombectomy. Hospitals can compare their present performance with their own performance in the past and with other hospitals. The performance feedback is provided to local quality improvement teams in each hospital, who define their own targets on specific indicators and develop performance improvement plans. The impact of the performance feedback and improvement plans will be evaluated by comparing the primary outcome before and after the intervention.Discussion: This study will provide evidence on the effectiveness of performance feedback to healthcare providers. The results will be actively disseminated through peer-reviewed journals, conference presentations, and various stakeholder engagement activities. Show less
Introduction: Early detection of large vessel occlusion (LVO) is essential to facilitate fast endovascular treatment. CT angiography (CTA) is used to detect LVO in suspected stroke patients. We... Show moreIntroduction: Early detection of large vessel occlusion (LVO) is essential to facilitate fast endovascular treatment. CT angiography (CTA) is used to detect LVO in suspected stroke patients. We aimed to assess the accuracy of CTA evaluations in daily clinical practice in a large cohort of suspected stroke patients. Patients and methods: We used data from the PRESTO study, a multicenter prospective observational cohort study that included suspected stroke patients between August 2018 and September 2019. Baseline CTAs were re-evaluated by an imaging core laboratory and compared to the local assessment. LVO was defined as an occlusion of the intracranial internal carotid artery, M1 segment, or basilar artery. Medium vessel occlusion (MeVO) was defined as an A1, A2, or M2 occlusion. We calculated the accuracy, sensitivity, and specificity to detect LVO and LVO+MeVO, using the core laboratory evaluation as reference standard. Results: We included 656 patients. The core laboratory detected 89 LVOs and 74 MeVOs in 155 patients. Local observers missed 6 LVOs (7%) and 28 MeVOs (38%), of which 23 M2 occlusions. Accuracy of LVO detection was 99% (95% CI: 98-100%), sensitivity 93% (95% CI: 86-97%), and specificity 100% (95% CI: 99-100%). Accuracy of LVO+MeVO detection was 95% (95% CI: 93-96%), sensitivity 79% (95% CI: 72-85%), and specificity 99% (95% CI: 98-100%). Discussion and Conclusion: CTA evaluations in daily clinical practice are highly accurate and LVOs are adequately recognized. The detection of MeVOs seems more challenging. The evolving EVT possibilities emphasize the need to improve CTA evaluations in the acute setting. Show less
Background Brain atrophy is suggested to impair the potential for functional recovery after acute ischemic stroke. We assessed whether the effect of endovascular treatment is modified by brain... Show moreBackground Brain atrophy is suggested to impair the potential for functional recovery after acute ischemic stroke. We assessed whether the effect of endovascular treatment is modified by brain atrophy in patients with acute ischemic stroke due to large vessel occlusion. Methods We used data from MR CLEAN, a multicenter trial including patients with acute ischemic stroke due to anterior circulation large vessel occlusion randomized to endovascular treatment plus medical care (intervention) versus medical care alone (control). We segmented total brain volume (TBV) and intracranial volume (ICV) on baseline non-contrast computed tomography (n = 410). Next, we determined the degree of atrophy as the proportion of brain volume in relation to head size (1 - TBV/ICV) x 100%, analyzed as continuous variable and in tertiles. The primary outcome was a shift towards better functional outcome on the modified Rankin Scale expressed as adjusted common odds ratio. Treatment effect modification was tested using an interaction term between brain atrophy (as continuous variable) and treatment allocation. Results We found that brain atrophy significantly modified the effect of endovascular treatment on functional outcome (P for interaction = 0.04). Endovascular treatment led to larger shifts towards better functional outcome in the higher compared to the lower range of atrophy (adjusted common odds ratio, 1.86 [95% CI: 0.97-3.56] in the lowest tertile vs. 1.97 [95% CI: 1.03-3.74] in the middle tertile vs. 3.15 [95% CI: 1.59-6.24] in the highest tertile). Conclusion Benefit of endovascular treatment is larger in the higher compared to the lower range of atrophy, demonstrating that advanced atrophy should not be used as an argument to withhold endovascular treatment. Show less
Treurniet, K.M.; LeCouffe, N.E.; Kappelhof, M.; Emmer, B.J.; Es, A.C.G.M. van; Boiten, J.; ... ; MR CLEAN-NO IV Investigators 2021
BackgroundEndovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior... Show moreBackgroundEndovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO.MethodsMR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients >= 18years of age with a pre-stroke mRS <3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included.DiscussionIVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT.Trial registrationwww.isrctn.com: ISRCTN80619088. Registered on 31 October 2017. Show less
The research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the... Show moreThe research described in this thesis was aimed at identifying and understanding biological mechanisms and molecular pathways involved in the pathophysiology of stroke and migraine, including the detrimental connection between them. The thesis consists of two parts. Part 1 describes multiple experimental stroke research projects in mice in which we set out to: (I) improve the methodology of stroke research, and (II) unravel the stroke-migraine connection using diff erent research strategies, methods, and transgenic mouse models. The mouse models express human pathogenic mutations found in CADASIL, RVCL-S and FHM1 and represent the clinical spectrum of monogenic disorders linking ischemic stroke and migraine. Part 2 includes multiple clinical projects in which we set out to study a large cohort of ischemic stroke patients with and without migraine in search for means to investigate stroke characteristics and vascular pathology. Show less
Goyal, M.; Orlov, K.; Jensen, M.E.; Taylor, A.; Majoie, C.; Jayaraman, M.; ... ; Ospel, J.M. 2020
Purpose There is little data and lack of consensus regarding antiplatelet management for intracranial stenting due to underlying intracranial atherosclerosis in the setting of endovascular... Show morePurpose There is little data and lack of consensus regarding antiplatelet management for intracranial stenting due to underlying intracranial atherosclerosis in the setting of endovascular treatment (EVT). In this DELPHI study, we aimed to assess whether consensus on antiplatelet management in this situation among experienced experts can be achieved, and what this consensus would be. Methods We used a modified DELPHI approach to address unanswered questions in antiplatelet management for intracranial stenting due to underlying atherosclerosis in the setting of EVT. An expert-panel (19 neurointerventionalists from 8 countries) answered structured, anonymized on-line questionnaires with iterative feedback-loops. Panel-consensus was defined as agreement >= 70% for binary closed-ended questions/>= 50% for closed-ended questions with > 2 response options. Results Panel members answered a total of 5 survey rounds. They acknowledged that there is insufficient data for evidence-based recommendations in many aspects of antiplatelet management for intracranial stenting due to underlying atherosclerosis in the setting of EVT. They believed that antiplatelet management should follow a standardized regimen, irrespective of imaging findings and reperfusion quality. There was no consensus on the timing of antiplatelet-therapy initiation. Aspirin was the preferred antiplatelet agent for the peri-procedural period, and oral Aspirin in combination with a P2Y12 inhibitor was the favored postprocedural regimen. Conclusion Data on antiplatelet management for intracranial stenting due to underlying atherosclerosis in the setting of EVT are limited. Panel-members in this study achieved consensus on postprocedural antiplatelet management but did not agree upon a preprocedural and intraprocedural antiplatelet regimen. Further prospective studies to optimize antiplatelet regimens are needed. Show less
Background: Despite evidence of a quite large beneficial effect of endovascular treatment (EVT) for ischemic stroke caused by anterior circulation large vessel occlusion, many patients do not... Show moreBackground: Despite evidence of a quite large beneficial effect of endovascular treatment (EVT) for ischemic stroke caused by anterior circulation large vessel occlusion, many patients do not recover even after complete recanalization. To some extent, this may be attributable to incomplete microvascular reperfusion, which can possibly be improved by antiplatelet agents and heparin. It is unknown whether periprocedural antithrombotic medication in patients treated with EVT improves functional outcome. The aim of this study is to assess the effect of acetylsalicylic acid (ASA) and unfractionated heparin (UFH), alone, or in combination, given to patients with an ischemic stroke caused by an intracranial large vessel occlusion in the anterior circulation during EVT.Methods: MR CLEAN-MED is a multicenter phase III trial with a prospective, 2 x 3 factorial randomized, open label, blinded end-point (PROBE) design, which aims to enroll 1500 patients. The trial is designed to evaluate the effect of intravenous ASA (300 mg), UFH (low or moderate dose), both or neither as adjunctive therapy to EVT. We enroll adult patients with a clinical diagnosis of stroke (NIHSS >= 2) and with a confirmed intracranial large vessel occlusion in the anterior circulation on CTA or MRA, when EVT within 6 h from symptom onset is indicated and possible. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days. Treatment effect on the mRS will be estimated with ordinal logistic regression analysis, with adjustment for main prognostic variables. Secondary outcomes include stroke severity measured with the NIHSS at 24 h and at 5-7 days, follow-up infarct volume, symptomatic intracranial hemorrhage (sICH), and mortality.Discussion: Clinical equipoise exists whether antithrombotic medication should be administered during EVT for a large vessel occlusion, as ASA and/or UFH may improve functional outcome, but might also lead to an increased risk of sICH. When one or both of the study treatments show the anticipated effect on outcome, we will be able to improve outcome of patients treated with EVT by 5%. This amounts to more than 50 patients annually in the Netherlands, more than 1800 in Europe, and more than 1300 in the USA. Show less
