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Background: Identification of risk factors and causes of stroke is key to optimize treatment and prevent recurrence. Up to one-third of young patients with stroke have a cryptogenic stroke according to current classification systems (Trial of ORG 10172 in Acute Stroke Treatment [TOAST] and atherosclerosis, small vessel disease, cardiac pathology, other causes, dissection [ASCOD]). The aim was to identify risk factors and leads for (new) causes of cryptogenic ischemic stroke in young adults, using the pediatric classification system from the IPSS study (International Pediatric Stroke Study). Methods: This is a multicenter prospective cohort study conducted in 17 hospitals in the Netherlands, consisting of 1322 patients aged 18 to 49 years with first-ever, imaging confirmed, ischemic stroke between 2013 and 2021. The main outcome was distribution of risk factors according to IPSS classification in patients with cryptogenic and noncryptogenic stroke according to the TOAST and ASCOD classification. Results: The median age was 44.2 years, and 697 (52.7%) were men. Of these 1322 patients, 333 (25.2%) had a cryptogenic stroke according to the TOAST classification. Additional classification using the ASCOD criteria reduced the number patients with cryptogenic stroke from 333 to 260 (19.7%). When risk factors according to the IPSS were taken into account, the number of patients with no potential cause or risk factor for stroke reduced to 10 (0.8%). Conclusions: Among young adults aged 18 to 49 years with a cryptogenic ischemic stroke according to the TOAST classification, risk factors for stroke are highly prevalent. Using a pediatric classification system provides new leads for the possible causes in cryptogenic stroke, and could potentially lead to more tailored treatment for young individuals with stroke.

Background: Targeting a cerebral perfusion pressure optimal for cerebral autoregulation (CPPopt) has been gaining more attention to prevent secondary damage after acute neurological injury. Brain tissue oxygenation (PbtO 2 ) can identify insufficient cerebral blood flow and secondary brain injury. Defining the relationship between CPPopt and PbtO 2 after aneurysmal subarachnoid hemorrhage may result in (1) mechanistic insights into whether and how CPPopt-based strategies might be beneficial and (2) establishing support for the use of PbtO 2 as an adjunctive monitor for adequate or optimal local perfusion. Methods: We performed a retrospective analysis of a prospectively collected 2-center dataset of patients with aneurysmal subarachnoid hemorrhage with or without later diagnosis of delayed cerebral ischemia (DCI). CPPopt was calculated as the cerebral perfusion pressure (CPP) value corresponding to the lowest pressure reactivity index (moving correlation coefficient of mean arterial and intracranial pressure). The relationship of (hourly) deltaCPP (CPP−CPPopt) and PbtO 2 was investigated using natural spline regression analysis. Data after DCI diagnosis were excluded. Brain tissue hypoxia was defined as PbtO 2 Results: One hundred thirty-one patients were included with a median of 44.0 (interquartile range, 20.8–78.3) hourly CPPopt/PbtO2 datapoints. The regression plot revealed a nonlinear relationship between PbtO 2 and deltaCPP ( P 2 decrease with deltaCPP 2 with deltaCPP ≥0mmHg, although there was substantial individual variation. Brain tissue hypoxia (34.6% of all measurements) was more frequent with deltaCPP Conclusions: We found a nonlinear relationship between PbtO 2 and deviation of patients’ CPP from CPPopt in aneurysmal subarachnoid hemorrhage patients in the pre-DCI period. CPP values below calculated CPPopt were associated with lower PbtO 2 . Nevertheless, the nature of PbtO 2 measurements is complex, and the variability is high. Combined multimodality monitoring with CPP/CPPopt and PbtO 2 should be recommended to redefine individual pressure targets (CPP/CPPopt) and retain the option to detect local perfusion deficits during DCI (PbtO 2 ), which cannot be fulfilled by both measurements interchangeably.

Background: Rescue treatment for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage can include induced hypertension (iHTN) and, in refractory cases, endovascular approaches, of which selective, continuous intraarterial nimodipine (IAN) is one variant. The combination of iHTN and IAN can dramatically increase vasopressor demand. In case of unsustainable doses, iHTN is often prioritized over IAN. However, evidence in this regard is largely lacking. We investigated the effects of a classical (iHTN+IAN) and modified (IAN only ) treatment protocol for refractory DCI in an observational study. Methods: Rescue treatment for DCI was initiated with iHTN (target >180 mm Hg systolic) and escalated to IAN in refractory cases. Until July 2018, both iHTN and IAN were offered in cases refractory to iHTN alone. After protocol modification, iHTN target was preemptively lowered to >120 mm Hg when IAN was initiated (IAN only ). Primary outcome was noradrenaline demand. Secondary outcomes included noradrenaline-associated complications, brain tissue oxygenation, DCI-related infarction and favorable 6-month outcome (Glasgow Outcome Scale 4–5). Results: N=29 and n=20 patients were treated according to the classical and modified protocol, respectively. Protocol modification resulted in a significant reduction of noradrenaline demand (iHTN+IAN 0.70±0.54 µg/kg per minute and IAN only 0.26±0.20 µg/kg per minute, P P P =0.95). Incidence of DCI-related infarction (45.0% versus 41.1%, odds ratio, 1.16 [0.37–3.66]; P =0.80) and favorable clinical outcome (55.6% versus 40.0%, odds ratio, 1.88 [0.55–6.39]; P =0.32) were similar. Brain tissue oxygenation was significantly higher with IANonly (26.6±12.8, 39.6±15.4 mm Hg; P Conclusions: Assuming the potential of iHTN to be exhausted in case of refractory hypoperfusion, additional IAN may serve as a last-resort measure to bridge hypoperfusion in the DCI phase. With close monitoring, preemptive lowering of pressure target after induction of IAN may be a safe alternative to alleviate total noradrenaline load and potentially reduce complication rate.

Supplemental Digital Content is available in the text., Background and Purpose: Optimal blood pressure (BP) management in the acute phase of ischemic stroke remains an unresolved issue. It is uncertain whether guidelines for BP management during and after intravenous alteplase can be extrapolated to endovascular treatment (EVT) for stroke due to large artery occlusion in the anterior circulation. We evaluated the associations between systolic BP (SBP) in the first 6 hours following EVT and functional outcome as well as symptomatic intracranial hemorrhage. Methods: Patients of 8 MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry centers, with available data on SBP in the 6 hours following EVT, were analyzed. We evaluated maximum, minimum, and mean SBP. Study outcomes were functional outcome (modified Rankin Scale) at 90 days and symptomatic intracranial hemorrhage. We used multivariable ordinal and binary regression analysis to adjust for important prognostic factors and studied possible effect modification by successful reperfusion. Results: Post-EVT SBP data were available for 1161/1796 patients. Higher maximum SBP (per 10 mm Hg increments) was associated with worse functional outcome (adjusted common odds ratio, 0.93 [95% CI, 0.88–0.98]) and a higher rate of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.17 [95% CI, 1.02–1.36]). The association between minimum SBP and functional outcome was nonlinear with an inflection point at 124 mm Hg. Minimum SBP lower and higher than the inflection point were associated with worse functional outcomes (adjusted common odds ratio, 0.85 per 10 mm Hg decrements [95% CI, 0.76–0.95] and adjusted common odds ratio, 0.81 per 10 mm Hg increments [95% CI, 0.71–0.92]). No association between mean SBP and functional outcome was observed. Successful reperfusion did not modify the relation of SBP with any of the outcomes. Conclusions: Maximum SBP in the first 6 hours following EVT is positively associated with worse functional outcome and an increased risk of symptomatic intracranial hemorrhage. Both lower and higher minimum SBP are associated with worse outcomes. A randomized trial to evaluate whether modifying post-intervention SBP results in better outcomes after EVT for ischemic stroke seems justified.

Background and Purpose: High-serum glucose on admission is a predictor of poor outcome after stroke. We assessed the association between glucose concentrations and clinical outcomes in patients who underwent endovascular treatment. Methods: From the MR CLEAN Registry, we selected consecutive adult patients with a large vessel occlusion of the anterior circulation who underwent endovascular treatment and for whom admission glucose levels were available. We assessed the association between admission glucose and the modified Rankin Scale score at 90 days, symptomatic intracranial hemorrhage and successful reperfusion rates. Hyperglycemia was defined as admission glucose ≥7.8 mmol/L. We evaluated the association between glucose and modified Rankin Scale using multivariable ordinal logistic regression and assessed whether successful reperfusion (extended Thrombolysis in Cerebral Infarction 2b-3) modified this association. Results: Of 3637 patients in the MR CLEAN Registry, 2908 were included. Median admission glucose concentration was 6.8 mmol/L (interquartile range, 5.9–8.1) and 882 patients (30%) had hyperglycemia. Hyperglycemia on admission was associated with a shift toward worse functional outcome (median modified Rankin Scale score 4 versus 3; adjusted common odds ratio, 1.69 [95% CI, 1.44–1.99]), increased mortality (40% versus 23%; adjusted odds ratio, 1.95 [95% CI, 1.60–2.38]), and an increased risk of symptomatic intracranial hemorrhage (9% versus 5%; adjusted odds ratio, 1.94 [95% CI, 1.41–2.66]) compared with nonhyperglycemic patients. The association between admission glucose levels and poor outcome (modified Rankin Scale score 3–6) was J -shaped. Hyperglycemia was not associated with the rate of successful reperfusion nor did successful reperfusion modify the association between glucose and functional outcome. Conclusions: Increased admission glucose is associated with poor functional outcome and an increased risk of symptomatic intracranial hemorrhage after endovascular treatment.

Supplemental Digital Content is available in the text., Background and Purpose: Stroke is associated with an increased risk of dementia. To assist in the early identification of individuals at high risk of future dementia, numerous prediction models have been developed for use in the general population. However, it is not known whether such models also provide accurate predictions among stroke patients. Therefore, the aim of this study was to determine whether existing dementia risk prediction models that were developed for use in the general population can also be applied to individuals with a history of stroke to predict poststroke dementia with equivalent predictive validity. Methods: Data were harmonized from 4 stroke studies (follow-up range, ≈12–18 months poststroke) from Hong Kong, the United States, the Netherlands, and France. Regression analysis was used to test 3 risk prediction models: the Cardiovascular Risk Factors, Aging and Dementia score, the Australian National University Alzheimer Disease Risk Index, and the Brief Dementia Screening Indicator. Model performance or discrimination accuracy was assessed using the C statistic or area under the curve. Calibration was tested using the Grønnesby and Borgan and the goodness-of-fit tests. Results: The predictive accuracy of the models varied but was generally low compared with the original development cohorts, with the Australian National University Alzheimer Disease Risk Index (C-statistic, 0.66) and the Brief Dementia Screening Indicator (C-statistic, 0.61) both performing better than the Cardiovascular Risk Factors, Aging and Dementia score (area under the curve, 0.53). Conclusions: Dementia risk prediction models developed for the general population do not perform well in individuals with stroke. Their poor performance could have been due to the need for additional or different predictors related to stroke and vascular risk factors or methodological differences across studies (eg, length of follow-up, age distribution). Future work is needed to develop simple and cost-effective risk prediction models specific to poststroke dementia.

Background and Purpose— Type 2 diabetes mellitus (T2D) is associated with cognitive impairment and an increased risk of dementia, but the association between prediabetes and cognitive impairment is less clear, particularly in a setting of major cerebrovascular events. This article examines the impact of impaired fasting glucose and T2D on cognitive performance in a stroke population. Methods— Seven international observational studies from the STROKOG (Stroke and Cognition) consortium (n=1601; mean age, 66.0 years; 70% Asian, 26% white, and 2.6% African American) were included. Fasting glucose level (FGL) during hospitalization was used to define 3 groups, T2D (FGL ≥7.0 mmol/L), impaired fasting glucose (FGL 6.1–6.9 mmol/L), and normal (FGL Z scores were derived from standardized neuropsychological test scores. The cross-sectional association between glucose status and cognitive performance at 3 to 6 months poststroke was examined using linear mixed models, adjusting for age, sex, education, stroke type, ethnicity, and vascular risk factors. Results— Patients with T2D had significantly poorer performance in global cognition (SD, −0.59 [95% CI, −0.82 to −0.36]; P P =0.55) or in any cognitive domain. Conclusions— Diabetes mellitus, but not prediabetes, is associated with poorer cognitive performance in patients 3 to 6 months after stroke.

Background: Poststroke cognitive impairment is common, but the trajectory and magnitude of cognitive decline after stroke is unclear. We examined the course and determinants of cognitive change after stroke using individual participant data from the Stroke and Cognition Consortium. Methods: Nine longitudinal hospital-based cohorts from 7 countries were included. Neuropsychological test scores and normative data were used to calculate standardized scores for global cognition and 5 cognitive domains. One-step individual participant data meta-analysis was used to examine the rate of change in cognitive function and risk factors for cognitive decline after stroke. Stroke-free controls were included to examine rate differences. Based on the literature and our own data that showed short-term improvement in cognitive function after stroke, key analyses were restricted to the period beginning 1-year poststroke to focus on its long-term effects. Results: A total of 1488 patients (mean age, 66.3 years; SD, 11.1; 98% ischemic stroke) were followed for a median of 2.68 years (25th–75th percentile: 1.21–4.14 years). After an initial period of improvement through up to 1-year poststroke, decline was seen in global cognition and all domains except executive function after adjusting for age, sex, education, vascular risk factors, and stroke characteristics (−0.053 SD/year [95% CI, −0.073 to −0.033]; P P Conclusions: Patients with stroke experience cognitive decline that is faster than that of stroke-free controls from 1 to 3 years after onset. An increased rate of decline is associated with older age and recurrent stroke.

Background and Purpose— Patients with acute ischemic stroke treated with endovascular thrombectomy may be treated with repeat endovascular thrombectomy (rEVT) in case of recurrent large vessel occlusion. Data on safety and efficacy of these interventions is scarce. Our aim is to report on frequency, timing, and outcome of rEVT in a large nation-wide multicenter registry. Methods— In the Netherlands, all patients with endovascular thrombectomy have been registered since 2002 (MR CLEAN Pretrial registry, MR CLEAN Trial [Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands], and MR CLEAN Registry). We retrospectively reviewed these databases for anterior circulation rEVT cases. Patient characteristics, procedural data, and functional outcome (modified Rankin Scale at 90 days) were analyzed. Results— Of 3928 patients treated between 2002 and 2017, 27 (0.7%) underwent rEVT. Median time between first and second procedure was 78 (1–1122) days; 11/27 patients were re-treated within 30 days. Cardioembolism was the most common etiology (18 patients [67%]). In 19 patients (70%), recurrent occlusion occurred ipsilateral to previous occlusion. At 90 days after rEVT procedure, 44% of the patients had achieved functional independence (modified Rankin Scale score of 0–2), and 33% had died. Adverse events were 2/27 (7.4%) intracranial hemorrhage, 1/27 (3.7%) stroke progression, and 1/27 (3.7%) pneumonia. Conclusions— In this large nationwide cohort of patients with acute ischemic stroke treated with endovascular thrombectomy, rEVT was rare. Stroke cause was mainly cardio-embolic, and most recurrent large vessel occlusions in which rEVT was performed occurred ipsilateral. Although there probably is a selection bias on repeated treatment in case of recurrent large vessel occlusion, rEVT appears safe, with similar outcome as in single-treated cases.

Background and Purpose— Patients with cardiovascular disease are at increased risk for cognitive decline. We studied the occurrence and profile of cognitive impairment in 3 patient groups as exemplar conditions of hemodynamic disturbances at different levels of the heart-brain axis, including patients with heart failure (HF), carotid occlusive disease (COD), and patients with cognitive complaints and vascular brain injury on magnetic resonance imaging (possible vascular cognitive impairment [VCI]). Methods— In 555 participants (160 HF, 107 COD, 160 possible VCI, 128 reference participants; 68±9 years; 36% F; Mini-Mental State Examination 28±2), we assessed cognitive functioning with a comprehensive test battery. Test scores were transformed into z -scores. Compound z -scores were constructed for: memory, language, attention/psychomotor speed, executive functioning, and global cognitive functioning. We rated cognitive domains as impaired when z -score≤−1.5. Based on the number of impaired domains, patients were classified as cognitively normal, minor, or major cognitive impairment. We used general linear models and χ 2 tests to compare cognitive functioning between patient groups and the reference group. Results— Age, sex, and education adjusted global cognitive functioning z-score was lower in patients with COD (β [SE]=−0.46 [0.10], P P z -scores were lower in patients with COD and possible VCI compared with reference participants. Patients with HF had lower z-scores on attention/speed and language compared with reference participants. Cognitive impairment was observed in 18% of HF, 36% of COD, and 45% possible VCI. There was no difference in profile of impaired cognitive domains between patient groups. Memory and attention-psychomotor speed were most commonly affected, followed by executive functioning and language. Conclusions— A substantial part of patients with HF and COD had cognitive impairment, which warrants vigilance for the occurrence of cognitive impairment. These results underline the importance of an integrative approach in medicine in patients presenting with disorders in the heart-brain axis.

Background and Purpose— Hyperglycemia is a negative prognostic factor after acute ischemic stroke but is not known whether glucose is associated with the effects of endovascular thrombectomy (EVT) in patients with large-vessel stroke. In a pooled-data meta-analysis, we analyzed whether serum glucose is a treatment modifier of the efficacy of EVT in acute stroke. Methods— Seven randomized trials compared EVT with standard care between 2010 and 2017 (HERMES Collaboration [highly effective reperfusion using multiple endovascular devices]). One thousand seven hundred and sixty-four patients with large-vessel stroke were allocated to EVT (n=871) or standard care (n=893). Measurements included blood glucose on admission and functional outcome (modified Rankin Scale range, 0–6; lower scores indicating less disability) at 3 months. The primary analysis evaluated whether glucose modified the effect of EVT over standard care on functional outcome, using ordinal logistic regression to test the interaction between treatment and glucose level. Results— Median (interquartile range) serum glucose on admission was 120 (104–140) mg/dL (6.6 mmol/L [5.7–7.7] mmol/L). EVT was better than standard care in the overall pooled-data analysis adjusted common odds ratio (acOR), 2.00 (95% CI, 1.69–2.38); however, lower glucose levels were associated with greater effects of EVT over standard care. The interaction was nonlinear such that significant interactions were found in subgroups of patients split at glucose < or >90 mg/dL (5.0 mmol/L; P =0.019 for interaction; acOR, 3.81; 95% CI, 1.73–8.41 for patients < 90 mg/dL versus 1.83; 95% CI, 1.53–2.19 for patients >90 mg/dL), and glucose < or >100 mg/dL (5.5 mmol/L; P =0.004 for interaction; acOR, 3.17; 95% CI, 2.04–4.93 versus acOR, 1.72; 95% CI, 1.42–2.08) but not between subgroups above these levels of glucose. Conclusions— EVT improved stroke outcomes compared with standard treatment regardless of glucose levels, but the treatment effects were larger at lower glucose levels, with significant interaction effects persisting up to 90 to 100 mg/dL (5.0–5.5 mmol/L). Whether tight control of glucose improves the efficacy of EVT after large-vessel stroke warrants appropriate testing.

Background and Purpose: Cerebral white matter signal abnormalities (WMSAs) are a significant radiological marker associated with brain and vascular aging. However, understanding their clinical impact is limited because of their pathobiological heterogeneity. We determined whether use of robust reliable automated procedures can distinguish WMSA classes with different clinical consequences. Methods: Data from generally healthy participants aged >50 years with moderate or greater WMSA were selected from the Human Connectome Project-Aging (n=130). WMSAs were segmented on T1 imaging. Features extracted from WMSA included total and regional volume, number of discontinuous clusters, size of noncontiguous lesion, contrast of lesion intensity relative to surrounding normal appearing tissue using a fully automated procedure. Hierarchical clustering was used to classify individuals into distinct classes of WMSA. Radiological and clinical variability was evaluated across the individual WMSA classes. Results: Class I was characterized by multiple, small, lower-contrast lesions predominantly in the deep WM; class II by large, confluent lesions in the periventricular WM; and class III by higher-contrast lesions restricted to the juxtaventricular WM. Class II was associated with lower myelin content than the other 2 classes. Class II was more prevalent in older subjects and was associated with a higher prevalence of hypertension and lower physical activity levels. Poor sleep quality was associated with a greater risk of class I. Conclusions: We classified heterogeneous subsets of cerebral white matter lesions into distinct classes that have different clinical risk factors. This new method for identifying classes of WMSA will be important in understanding the underlying pathophysiology and in determining the impact on clinical outcomes.

Background and Purpose— Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions. Methods— Eleven CAA cases (median [IQR] age=69 years [65–79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68–92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere. Results— Our results demonstrated increased IgG positivity in the frontotemporal ( P =0.044) and parietooccipital ( P =0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions ( P =0.005 and P =0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-β–positive vessels (Spearman ρ=0.71, P =0.015 and Spearman ρ=0.73, P =0.011, respectively). Moreover, the percentage of fibrin and IgG-positive vessels, but not amyloid-β–positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman ρ=0.77, P =0.005 and Spearman ρ=0.70, P =0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds. Conclusions— Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAA-related brain injury.

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.

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.

Background and Purpose— The capillary index score (CIS) is based on the hypothesis that areas lacking capillary blush on pretreatment cerebral digital subtraction angiograms correspond to nonviable cerebral tissue. Methods— Pretreatment digital subtraction angiograms and post-treatment noncontrast enhanced computed tomographic scans from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) trial were evaluated for areas lacking capillary blush and with tissue hypodensity, respectively. Because the superior and middle zones of the CIS correspond to the 7 cerebral cortex regions of the Alberta Stroke Program Early CT (ASPECT) score, capillary blush was scored in these 2 zones (0–2), called sub-CIS, and compared with the ASPECT score in these 7 regions (0–7), called hypodensity score. The presence and extent of hypodensity were compared between sub-CIS zones with contingency tables and nonparametric comparisons between groups, respectively. Results— On the basis of a sample size of 50 subjects, 100% with sub-CIS P =0.004). The extent of hypodensity (numeric hypodensity score) was significantly lower for sub-CIS=2 than 0 or 1 ( P =0.02). For 42 subjects with revascularization data, the presence and extent of hypodensity were significantly lower for sub-CIS=2 plus good revascularization than for other combinations of sub-CIS and revascularization ( P =0.02 and 0.01, respectively). Conclusions— The absence of capillary blush on pretreatment digital subtraction angiogram seems to correspond to nonviable cerebral tissue. Successful revascularization reduces the chance of tissue hypodensity (infarction), when capillary blush is present. Clinical Trial Registration— URL: http://www.trialregister.nl . Unique identifier: NTR number 1804. URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

Background and Purpose— Recent randomized trials have proven the benefit of intra-arterial treatment (IAT) with retrievable stents in acute ischemic stroke. Patients with poor or absent collaterals (preexistent anastomoses to maintain blood flow in case of a primary vessel occlusion) may gain less clinical benefit from IAT. In this post hoc analysis, we aimed to assess whether the effect of IAT was modified by collateral status on baseline computed tomographic angiography in the Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN). Methods— MR CLEAN was a multicenter, randomized trial of IAT versus no IAT. Primary outcome was the modified Rankin Scale at 90 days. The primary effect parameter was the adjusted common odds ratio for a shift in direction of a better outcome on the modified Rankin Scale. Collaterals were graded from 0 (absent) to 3 (good). We used multivariable ordinal logistic regression analysis with interaction terms to estimate treatment effect modification by collateral status. Results— We found a significant modification of treatment effect by collaterals ( P =0.038). The strongest benefit (adjusted common odds ratio 3.2 [95% confidence intervals 1.7–6.2]) was found in patients with good collaterals (grade 3). The adjusted common odds ratio was 1.6 [95% confidence intervals 1.0–2.7] for moderate collaterals (grade 2), 1.2 [95% confidence intervals 0.7–2.3] for poor collaterals (grade 1), and 1.0 [95% confidence intervals 0.1–8.7] for patients with absent collaterals (grade 0). Conclusions— In MR CLEAN, baseline computed tomographic angiography collateral status modified the treatment effect. The benefit of IAT was greatest in patients with good collaterals on baseline computed tomographic angiography. Treatment benefit appeared less and may be absent in patients with absent or poor collaterals. Clinical Trial Registration— URL: http://www.trialregister.nl and http://www.controlled-trials.com . Unique identifier: (NTR)1804 and ISRCTN10888758, respectively.

Background and Purpose— Intra-arterial treatment by means of retrievable stents has been proven safe and effective. In MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), the choice of the type of thrombectomy device was left to the discretion of the interventionist. The aim of this study was to explore the differences in functional outcome, neurological recovery, reperfusion, extent of infarction, and adverse events according to stent type and make. Methods— The primary outcome was functional outcome at 90 days, assessed with the modified Rankin Scale (mRS). Neuroimaging outcomes included occlusion on computed tomographic angiography at 24 hours, infarct volume at 5 to 7 days, and modified thrombolysis in cerebral infarction scores. Safety outcomes included death within 90 days and any symptomatic intracerebral hemorrhage. We analyzed possible interactions between stent type and treatment with multiple regression models. Treatment effects were adjusted for patient age, stroke severity, and collateral score. Results— Of the 500 patients included in the trial, 233 were allocated to intervention. Of these, 124 (53%) were first treated with Trevo (adjusted common odds ratio for shift on the mRS [acOR, 1.98; 95% confidence interval, 1.30–2.92]), 31 (13%) with Solitaire (acOR, 1.90; 95% confidence interval, 0.97–3.73), 40 (17%) with other retrievable stents or mechanical devices (acOR, 0.96; 95% confidence interval, 0.51–3.93], and 38 (16%) could not be treated. There was no interaction between device and treatment effect on functional outcome and all other secondary and safety outcomes. Conclusions— We found no evidence for a differential effect of thrombectomy for acute ischemic stroke by type of stent. Clinical Trial Registration— URL: http://www.isrctn.com . Unique identifier: ISRCTN10888758.

Background and Purpose— The Montreal Cognitive Assessment (MoCA) is nowadays recommended for the screening of poststroke cognitive impairment. However, little is known about the temporal evolution of MoCA-assessed cognition after stroke. The objective of this study was to examine the temporal pattern of overall and domain-specific cognition at 2 and 6 months after stroke using the MoCA and to identify patient groups at risk for cognitive impairment at 6 months after stroke. Methods— Prospective cohort study in which 324 patients were administered the MoCA at 2 and 6 months post stroke. Cognitive impairment was defined as MoCA Results— Between 2 and 6 months post stroke, mean MoCA score improved from 23.7 (3.9) to 24.7 (3.5), P P Conclusions— Although cognitive improvement is seen ≤6 months post stroke, long-term cognitive deficits are prevalent. Identifying patients at risk of cognitive impairment is, therefore, important as well as targeting interventions to this group.

Background and Purpose— Cerebral small vessel disease (CSVD) may be caused by endothelial dysfunction, whereas endothelial progenitor cells (EPC) may attenuate endothelial dysfunction. Their vitality is lower in CSVD. A subset of lymphocytes, angiogenic T-cells, is capable to stimulate EPC function. The purpose of our study was to explore the relation between CSVD manifestations, angiogenic T-cells, and EPC in hypertensive patients with CSVD. Methods— We compared 32 essential hypertensive patients with CSVD (white matter lesions, asymptomatic lacunar infarcts, or microbleeds on 1.5-Tesla MRI) to 29 age-matched and sex-matched hypertensive controls. We counted angiogenic T-cells (CD3 + /CD31 + /CD184 + ) and putative EPC (CD31 + /CD34 + /CD45 - /KDR + ) by flow cytometry and determined EPC vitality by in vitro cluster formation. Results— Putative EPC numbers were lower in hypertensive individuals with CSVD than in those without (10±7 . 10 3 /mL versus 13±6 . 10 3 /mL [median±interquartile range]; P =0.011). Angiogenic T-cell numbers were also lower in hypertensive individuals with CSVD than in those without (0.56±0.25 . 10 9 /mL versus 0.78±0.50 . 10 9 /mL; P =0.008). Higher angiogenic T-cell numbers independently related to absence of CSVD (odds ratio, 0.088; 95% confidence interval, 0.012–0.627). Conclusions— Our data suggest that angiogenic T-cells and putative EPC independently relate to radiological CSVD manifestations in hypertensive patients.

Background and Purpose— Elevated blood pressure (BP) is associated with the presence of cerebral microbleeds (CMBs) in cross-sectional studies. However, longitudinal studies did not show a convincing relationship. We aimed to determine the association between elevated BP levels and the occurrence of new CMBs after a 2-year follow-up in first-ever lacunar stroke patients using ambulatory BP monitoring. Methods— Ninety-six first-ever lacunar stroke patients underwent brain MRI and ambulatory BP monitoring at baseline and after 2-year follow-up. We used logistic regression analyses to assess the association of BP levels with new CMBs. Results— We found new CMBs in 17 patients (18%). Higher 24-hour, day and night systolic BP (odds ratio, 2.69; 95% confidence interval, 1.40–5.21 per SD increase for 24-hour BP) and diastolic BP (odds ratio, 2.13; 95% confidence interval, 1.15–3.90 per SD increase for 24-hour BP) at baseline were associated with the development of new CMBs independent of age and sex. BP levels decreased during follow-up in both patients with and without new CMBs. Unlike BP levels at baseline, there was no difference in BP levels at follow-up between patients with and without new CMBs. Conclusions— Both higher systolic and diastolic BP levels were associated with the development of new CMBs in a population of lacunar stroke patients. Decrease of BP levels during follow-up did not halt progression of CMBs; however, it remains to be determined whether (early) intervention with antihypertensive drugs can slow down progression of CMBs.