Association of covert brain infarct phenotype with stroke recurrence in first-ever manifest ischemic stroke according to etiology.

INTRODUCTION: Covert brain infarcts (CBI) are frequent incidental findings on MRI and associated with future stroke risk in patients without a history of clinically evident cerebrovascular events. However, the prognostic value of CBI in first-ever ischemic stroke patients is unclear and previous studies did not report on different etiological stroke subtypes. We aimed to test CBI phenotypes and their association with stroke recurrence in first-ever ischemic stroke patients according to stroke etiology. PATIENTS AND METHODS: This study is a pooled data analysis of two prospectively collected cohorts of consecutive first-ever ischemic stroke patients admitted to the comprehensive stroke centers of Bern (Switzerland) and Graz (Austria). CBI phenotypes were identified on brain MRI within 72 h after admission. All patients underwent a routine follow-up (median: 12 months) to identify stroke recurrence. RESULTS: Of 1577 consecutive ischemic stroke patients (median age: 71 years), 691 patients showed CBI on brain MRI (44%) and 88 patients had a recurrent ischemic stroke (6%). Baseline CBI were associated with stroke recurrence in multivariable analysis (HR 1.9, 95% CI 1.1-3.3). CBI phenotypes with the highest risk for stroke recurrence were cavitatory CBI in small vessel disease (SVD)-related stroke (HR 7.1, 95% CI 1.6-12.6) and cortical CBI in patients with atrial fibrillation (HR 3.0, 95% CI 1.1-8.1). DISCUSSION AND CONCLUSION: This study reports a ≈ 2-fold increased risk for stroke recurrence in first-ever ischemic stroke patients with CBI. The risk of recurrent stroke was highest in patients with cavitatory CBI in SVD-related stroke and cortical CBI in patients with atrial fibrillation.Subject terms: Covert brain infarcts, stroke.

Small vessel disease burden and risk of recurrent cerebrovascular events in patients with lacunar stroke and intracerebral haemorrhage attributable to deep perforator arteriolopathy.

INTRODUCTION: Deep perforator arteriolopathy (DPA) causes intracerebral haemorrhage (ICH) and lacunar strokes (LS). We compare patient characteristics, MRI findings and clinical outcomes among patients with deep ICH and LS. PATIENTS AND METHODS: We included patients with MRI-confirmed LS or ICH in the basal ganglia, thalamus, internal capsule or brainstem from the Bernese Stroke Registry. We assessed MRI small vessel disease (SVD) markers, SVD burden score, modified Rankin Scale (mRS) and ischaemic stroke or ICH at 3 months. RESULTS: We included 716 patients, 117 patients (16.3%) with deep ICH (mean age (SD) 65.1 (±15.2) years, 37.1% female) and 599 patients (83.7%) with LS (mean age (SD) 69.7 (±13.6) years, 39.9% female). Compared to LS, deep ICH was associated with a higher SVD burden score (median (IQR) 2 (1-2) vs 1 (0-2)), aORshift 3.19, 95%CI 2.15-4.75). Deep ICH patients had more often cerebral microbleeds (deep ICH: 71.6% vs LS: 29.2%, p < 0.001, median count (IQR) 4(2-12) vs 2(1-6)) and a higher prevalence of lacunes (deep ICH: 60.5% vs LS: 27.4% p < 0.001). At 3 months, deep ICH was associated with higher mRS (aORshift 2.16, 95%CI 1.21-3.87). Occurrence of ischaemic stroke was numerically but not significantly higher in deep ICH (4.3% vs 2.9%; p = 0.51). One patient (1.1%) with ICH but none with LS suffered ICH recurrence. DISCUSSION/CONCLUSION: DPA manifesting as ICH is associated with more severe MRI SVD burden and worse outcome compared to LS. The short-term risks of subsequent ischaemic stroke and recurrent ICH are similar in ICH and LS patients. This implies potential consequences for future secondary prevention strategies.

Association of Chronic Covert Cerebral Infarctions and White Matter Hyperintensities With Atrial Fibrillation Detection on Post-Stroke Cardiac Rhythm Monitoring: A Cohort Study.

Background This study was conducted to explore the association of different phenotypes, count, and location of chronic covert brain infarctions (CBIs) with detection of atrial fibrillation (AF) on prolonged post-stroke cardiac rhythm monitoring (PCM). Methods and Results We conducted a cohort single-center study of consecutive first-ever ischemic stroke or transient ischemic attack patients undergoing PCM between January 2015 and December 2017. We blindly rated CBI phenotypes according to established definitions and white matter hyperintensities (WMHs) according to the age-related white matter changes rating scale. We used (multiple) regression models to assess the association of the imaging biomarkers and incident AF on PCM. A total of 795 patients (median [interquartile range]) aged 69 (57-78) years, 41% women, median National Institutes of Health Stroke Scale score 2 (0-5), median PCM duration 14 (7-14) days, and AF detection in 61 patients (7.7%) were included. On univariate analysis, WMHs (per point odds ratio, 1.35 [95% CI, 1.03-1.78]) but not CBIs (odds ratio, 0.90 [95% CI, 0.52-1.56]) were associated with AF detection. Neither CBI phenotype, count, nor location were associated with AF detection. After adjustment for age, hypertension, and stroke severity, neither increasing WMHs (per point adjusted odds ratio, 0.85 [95% CI, 0.60-1.20]) nor CBIs (adjusted odds ratio, 0.60 [95% CI, 0.33-1.09]) were independently associated with AF detection. Conclusions Although WMHs and CBIs represent surrogate biomarkers of vascular risk factors, neither WMHs nor CBIs, including their phenotypes, count, and location, were independently associated with AF detection on PCM. In patients with manifest ischemic stroke or transient ischemic attack, the presence of imaging biomarkers of chronic ischemic injury does not seem promising to further refine prediction tools for AF detection on PCM.

Chronic cerebral infarctions and white matter lesions link to long-term survival after a first ischemic event: A cohort study.

BACKGROUND AND PURPOSE: To investigate the association of different phenotypes, count, and locations of chronic covert brain infarctions (CBI) with long-term mortality in patients with first-ever manifest acute ischemic stroke (AIS) or transient ischemic attack (TIA). Additionally, to analyze their potential interaction with white matter hyperintensities (WMH) and predictive value in addition to established mortality scores. METHODS: Single-center cohort study including consecutive patients with first-ever AIS or TIA with available MRI imaging from January 2015 to December 2017. Blinded raters adjudicated CBI phenotypes and WMH (age-related white matter changes score) according to established definitions. We compared Cox regression models including prespecified established predictors of mortality using Harrell's C and likelihood ratio tests. RESULTS: A total of 2236 patients (median [interquartile range] age: 71 [59-80] years, 43% female, National Institutes of Health Stroke Scale: 2 [1-6], median follow-up: 1436 days, 21% death during follow-up) were included. Increasing WMH (per point adjusted Hazard Ratio [aHR] = 1.29 [1.14-1.45]), but not CBI (aHR = 1.21 [0.99-1.49]), were independently associated with mortality. Neither CBI phenotype, count, nor location was associated with mortality and there was no multiplicative interaction between CBI and WMH (p > .1). As compared to patients without CBI or WMH, patients with moderate or severe WMH and additional CBI had the highest hazards of death (aHR = 1.62 [1.23-2.13]). The Cox regression model including CBI and WMH had a small but significant increment in Harrell's C when compared to the model including 14 clinical variables (0.831 vs. 0.827, p < .001). DISCUSSION: WMH represent a strong surrogate biomarker of long-term mortality in first-ever manifest AIS or TIA patients. CBI phenotypes, count, and location seem less relevant. Incorporation of CBI and WMH slightly improves predictive capacity of established risk scores.

Development of a Score for Prediction of Occult Malignancy in Stroke Patients (Occult-5 Score).

BACKGROUND AND PURPOSE: Malignancy associated acute ischemic stroke (AIS) requires specific diagnostic work-up, treatment and prevention to improve outcome. This study aimed to develop a biomarker-based score for prediction of occult malignancy in AIS patients. METHODS: Single-center cross-sectional study including consecutive AIS patients treated between July 2017 and November 2018. Patients with active malignancy at presentation, or diagnosed within 1 year thereafter and patients free of malignancy, were included and malignancy associated biomarkers were assessed. LASSO analyses of logistic regression were performed to determine biomarkers predictive of active malignancy. Predictors were derived from a predictive model for active malignancy. A comparison between known and unknown (=occult) malignancies when the index stroke occurred was used to eliminate variables not associated with occult malignancy. A predictive score (OCCULT-5 score) for occult malignancy was developed based on the remaining variables. RESULTS: From 1001 AIS patients, 61 (6%) presented an active malignancy. Thirty-nine (64%) were known and 22 (36%) occult. Five variables were included in the final OCCULT-5 score: age ≥ 77 years, embolic stroke of undetermined source, multi-territorial infarcts, D-dimer levels ≥ 820 µ/gL, and female sex. A score of ≥ 3 predicted an underlying occult malignancy with a sensitivity of 64%, specificity of 73%, positive likelihood ratio of 2.35 and a negative likelihood ratio of 0.50. CONCLUSIONS: The OCCULT-5 score might be useful to identify patients with occult malignancy. It may thus contribute to a more effective and timely treatment and thus lead to a positive impact on overall outcome.

Chronic Covert Brain Infarctions and White Matter Hyperintensities in Patients With Stroke, Transient Ischemic Attack, and Stroke Mimic.

Background This study was conducted to compare frequencies of chronic brain infarctions (CBIs) and white matter hyperintensities (WMHs) as well as their associations with established early recurrence risk scores in patients with transient ischemic attack (TIA) and stroke mimics compared with ischemic stroke. Methods and Results Single-center cohort study including consecutive patients with TIA, stroke mimics, and acute ischemic stroke, with available magnetic resonance imaging from January 2015 to December 2017. Blinded raters adjudicated WMH (age-related white matter changes score) and CBI according to established definitions. A total of 2112 patients (median [Q1-Q3] age 71 [59-80] years, 43% women, National Institutes of Health Stroke Scale score of 2 [1-7], 80% ischemic stroke, 18% TIA, 2% stroke mimics) were included. While CBIs were present in only 10% of patients with stroke mimic, they were detected in 28% of TIAs and 38% of ischemic strokes (P<0.001). WMHs were less pronounced (0, 0-1) in patients with stroke mimic, but there was no difference between TIA (1, 1-2) and ischemic stroke (0, 1-2) patients. CBIs (adjusted odds ratio, 0.3; 95% CI, 0.1-0.9) were associated with a lower rate of stroke mimic as the final diagnosis, while WMHs were not (adjusted odds ratio per point, 1.3; 95% CI, 0.7-2.2). WMH (ß per point, 0.4; 95% CI, 0.3-0.6) and presence of CBI (ß, 0.6; 95% CI, 0.3-0.9) were associated with a higher cardiovascular risk profile according to the ABCD3-I score. The accuracy of prediction was good for high-risk TIA (cross-validated area under the receiver operating characteristic curve, 0.89; 95% CI, 0.79-0.93) on the basis of brain imaging, age, and sex. Conclusions CBI and WMH differ between patients with stroke mimic and patients with TIA/ischemic stroke and are closely associated with established recurrence risk scores. Prospective studies need to clarify whether including brain frailty markers may contribute to the refinement of current management algorithms and risk stratifications.

Heterogeneity of the Relative Benefits of TICI 2c/3 over TICI 2b50/2b67 : Are there Patients who are less Likely to Benefit?

PURPOSE: Incomplete reperfusion after mechanical thrombectomy (MT) is associated with a poor outcome. Rescue therapy would potentially benefit some patients with an expanded treatment in cerebral ischemia score (eTICI) 2b50/2b67 reperfusion but also harbors increased risks. The relative benefits of eTICI 2c/3 over eTICI 2b50/67 in clinically important subpopulations were analyzed. METHODS: Retrospective analysis of our institutional database for all patients with occlusion of the intracranial internal carotid artery (ICA) or the M1/M2 segment undergoing MT and final reperfusion of ≥eTICI 2b50 (903 patients). The heterogeneity in subgroups of different time metrics, age, National Institutes of Health Stroke Scale (NIHSS), number of retrieval attempts, Alberta Stroke Programme Early CT Score (ASPECTS) and site of occlusion using interaction terms (pi) was analyzed. RESULTS: The presence of eTICI 2c/3 was associated with better outcomes in most subgroups. Time metrics showed no interaction of eTICI 2c/3 over eTICI 2b50/2b67 and clinical outcomes (onset to reperfusion pi = 0.77, puncture to reperfusion pi = 0.65, onset to puncture pi = 0.63). An eTICI 2c/3 had less consistent association with mRS ≤2 in older patients (>82 years, pi = 0.038) and patients with either lower NIHSS (≤9) or very high NIHSS (>19, pi = 0.01). Regarding occlusion sites, the beneficial effect of eTICI 2c/3 was absent for occlusions in the M2 segments (aOR 0.73, 95% confidence interval [CI] 0.33-1.59, pi = 0.018). CONCLUSION: Beneficial effect of eTICI 2c/3 over eTICI 2b50/2b67 only decreased in older patients, M2-occlusions and patients with either low or very high NIHSS. Improving eTICI 2b50/2b67 to eTICI 2c/3 in those subgroups may be more often futile.

Phenotypes of Chronic Covert Brain Infarction in Patients With First-Ever Ischemic Stroke: A Cohort Study.

BACKGROUND AND PURPOSE: The aim of this study was to assess the rate of chronic covert brain infarctions (CBIs) in patients with acute ischemic stroke (AIS) and to describe their phenotypes and diagnostic value. METHODS: This is a single-center cohort study including 1546 consecutive patients with first-ever AIS on magnetic resonance imaging imaging from January 2015 to December 2017. The main study outcomes were CBI phenotypes, their relative frequencies, location, and association with vascular risk factors. RESULTS: Any CBI was present in 574/1546 (37% [95% CI, 35%-40%]) of patients with a total of 950 CBI lesions. The most frequent locations of CBI were cerebellar in 295/950 (31%), subcortical supratentorial in 292/950 (31%), and cortical in 213/950 (24%). CBI phenotypes included lacunes (49%), combined gray and white matter lesions (30%), gray matter lesions (13%), and large subcortical infarcts (7%). Vascular risk profile and white matter hyperintensities severity (19% if no white matter hyperintensity, 63% in severe white matter hyperintensity, P<0.001) were associated with presence of any CBI. Atrial fibrillation was associated with cortical lesions (adjusted odds ratio, 2.032 [95% CI, 1.041-3.967]). Median National Institutes of Health Stroke Scale scores on admission were higher in patients with an embolic CBI phenotype (median National Institutes of Health Stroke Scale, 5 [2-10], P=0.025). CONCLUSIONS: CBIs were present in more than a third of patients with first AIS. Their location and phenotypes as determined by MRI were different from previous studies using computed tomography imaging. Among patients suffering from AIS, those with additional CBI represent a vascular high-risk subgroup and the association of different phenotypes of CBIs with differing risk factor profiles potentially points toward discriminative AIS etiologies.

Stent-Based Retrieval Techniques in Acute Ischemic Stroke Patients with and Without Susceptibility Vessel Sign.

BACKGROUND AND PURPOSE: Randomized controlled trials have challenged the assumption that reperfusion success after mechanical thrombectomy varies depending on the retrieval techniques applied; however, recent analyses have suggested that acute ischemic stroke (AIS) patients showing susceptibility vessel sign (SVS) may respond differently. We aimed to compare different stent retriever (SR)-based thrombectomy techniques with respect to interventional outcome parameters depending on SVS status. METHODS: We retrospectively reviewed 497 patients treated with SR-based thrombectomy for anterior circulation AIS. Imaging was conducted using a 1.5 T or 3 T magnetic resonance imaging (MRI) scanner. Logistic regression analyses were performed to test for the interaction of SVS status and first-line retrieval technique. Results are shown as percentages, total values or adjusted odds ratio (aOR) with 95% confidence intervals (CI). RESULTS: An SVS was present in 87.9% (n = 437) of patients. First-line SR thrombectomy was used to treat 293 patients, whereas 204 patients were treated with a combined approach (COA) of SR and distal aspiration. An additional balloon-guide catheter (BGC) was used in 273 SR-treated (93.2%) and 89 COA-treated (43.6%) patients. On logistic regression analysis, the interaction variable of SVS status and first-line retrieval technique was not associated with first-pass reperfusion (aOR 1.736, 95% CI 0.491-6.136; p = 0.392), overall reperfusion (aOR 3.173, 95% CI 0.752-13.387; p = 0.116), periinterventional complications, embolization into new territories, or symptomatic intracerebral hemorrhage. The use of BGC did not affect the results. CONCLUSION: While previous analyses indicated that first-line SR thrombectomy may promise higher rates of reperfusion than contact aspiration in AIS patients with SVS, our data show no superiority of any particular SR-based retrieval technique regardless of SVS status.

Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Cerebral microbleeds (CMBs) are common in patients with acute ischemic stroke and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown. METHODS: We performed a prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke trial criteria 22 to 36 hours after treatment. RESULTS: Of 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99-5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59-1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07-2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence (p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution. DISCUSSION: In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm ratio in patients with a larger number of CMBs. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days.

Early Neurologic Deterioration in Lacunar Stroke: Clinical and Imaging Predictors and Association With Long-term Outcome.

OBJECTIVE: To determine the rate and predictors of early neurological deterioration (END) in patients with lacunar strokes as well as its implications for management and outcome. METHODS: We enrolled consecutive patients with MRI-defined lacunar stroke who presented within 12 hours after symptom onset from a prospective stroke database (2015-2019). END was defined as any persisting increase in National Institutes of Health Stroke Scale (NIHSS) score of ≥2 points within 24 hours after admission and favorable outcome as modified Rankin Scale (mRS) of 0-2 at 90 days. We assessed the association of END with clinical and imaging variables, acute treatment and outcome using multivariable regression, calculating adjusted odds ratios. RESULTS: Sixty-one of 365 (16.7%) patients with acute lacunar stroke (median age 71.8 years, 39.5% female, median NIHSS score on admission 3) had END. Lower NIHSS score on admission (per point, aOR 0.81, p=0.006), capsular warning syndrome (aOR 7.00, p<0.001), ventral pontine infarct (aOR 3.49, p=0.008) and hypoperfusion on imaging (aOR 2.13, p=0.026) were associated with END. Acute dual antiplatelet therapy was associated with reduced risk of END (aOR 0.10, p=0.04). Patients with END had less favorable outcome at 90 days (aOR 0.13 p<0.001), but intravenous thrombolysis (IVT) was associated with favorable outcome at 90 days (aOR 3.95, p=0.002). CONCLUSION: One in six patients with lacunar stroke has END and patients at high risk of END can be identified using radiological and clinical variables. Targeted therapeutic trials for this population seem justified. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that early neurologic deterioration in patients with acute lacunar stroke predicts poorer functional outcome at 90 days as determined by the modified Rankin Scale.

Safety and Angiographic Efficacy of Intra-Arterial Fibrinolytics as Adjunct to Mechanical Thrombectomy: Results from the INFINITY Registry.

BACKGROUND AND PURPOSE: Data on safety and efficacy of intra-arterial (IA) fibrinolytics as adjunct to mechanical thrombectomy (MT) are sparse. METHODS: INtra-arterial FIbriNolytics In ThrombectomY (INFINITY) is a retrospective multi-center observational registry of consecutive patients with anterior circulation large-vessel occlusion ischemic stroke treated with MT and adjunctive administration of IA fibrinolytics (alteplase [tissue plasminogen activator, tPA] or urokinase [UK]) at 10 European centers. Primary outcome was the occurrence of symptomatic intracranial hemorrhage (sICH) according to the European Cooperative Acute Stroke Study II definition. Secondary outcomes were mortality and modified Rankin Scale (mRS) scores at 3 months. RESULTS: Of 5,612 patients screened, 311 (median age, 74 years; 44.1% female) received additional IA after or during MT (194 MT+IA tPA, 117 MT+IA UK). IA fibrinolytics were mostly administered for rescue of thrombolysis in cerebral infarction (TICI) 0-2b after MT (80.4%, 250/311). sICH occurred in 27 of 308 patients (8.8%), with an increased risk in patients with initial TICI0/1 (adjusted odds ratio [aOR], 2.3; 95% confidence interval [CI], 1.1 to 5.0 per TICI grade decrease) or in those with intracranial internal carotid artery occlusions (aOR, 3.7; 95% CI, 1.2 to 12.5). In patients with attempted rescue of TICI0-2b and available angiographic follow-up, 116 of 228 patients (50.9%) showed any angiographic reperfusion improvement after IA fibrinolytics, which was associated with mRS ≤2 (aOR, 3.1; 95% CI, 1.4 to 6.9). CONCLUSIONS: Administration of IA fibrinolytics as adjunct to MT is performed rarely, but can improve reperfusion, which is associated with better outcomes. Despite a selection bias, an increased risk of sICH seems possible, which underlines the importance of careful patient selection.