Fronto-thalamic networks and the left ventral thalamic nuclei play a key role in aphasia after thalamic stroke.

Thalamic aphasia results from focal thalamic lesions that cause dysfunction of remote but functionally connected cortical areas due to language network perturbation. However, specific local and network-level neural substrates of thalamic aphasia remain incompletely understood. Using lesion symptom mapping, we demonstrate that lesions in the left ventrolateral and ventral anterior thalamic nucleus are most strongly associated with aphasia in general and with impaired semantic and phonemic fluency and complex comprehension in particular. Lesion network mapping (using a normative connectome based on fMRI data from 1000 healthy individuals) reveals a Thalamic aphasia network encompassing widespread left-hemispheric cerebral connections, with Broca's area showing the strongest associations, followed by the superior and middle frontal gyri, precentral and paracingulate gyri, and globus pallidus. Our results imply the critical involvement of the left ventrolateral and left ventral anterior thalamic nuclei in engaging left frontal cortical areas, especially Broca's area, during language processing.

Depressive symptoms and anti-N-methyl-D-aspartate-receptor GluN1 antibody seropositivity in the PROSpective cohort with incident stroke.

Background: Anti-NMDA-receptor GluN1 antibodies (NMDAR1-abs) are present in an autoimmune encephalitis with severe neuropsychiatric symptoms. We aimed to estimate the impact of serum NMDAR1-abs on depressive symptoms years after first-ever ischemic stroke (IS). Methods: Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B; NCT01363856). Serum NMDAR1-abs (IgM/IgA/IgG) were measured within 7 days after IS using cell-based assays. We defined seropositivity as titers ≥1:10, thereof low titers as ≤1:100 and high titers as >1:100. We used the Center for Epidemiological Studies-Depression (CES-D) scale to measure depressive symptoms at year one, two and three following IS. We calculated crude and confounder adjusted weighted generalized linear models to quantify the impact of NMDAR1-abs on CES-D assessed at three annual time-points. Results: NMDAR1-abs were measured in 583 PROSCIS-B IS patients (mean age = 67 [SD = 13]; 42%female; median NIHSS = 2 [IQR = 1-4]) of whom 76 (13%; IgM: n = 49/IgA: n = 43/IgG: n = 2) were seropositive, 55 (9%) with low and 21 (4%) with high titers. CES-D regarded over all follow-up time-points was higher in seropositive patients (ßcrude = 2.56 [95%CI = -0.34 to 5.45]; ßadjusted = 2.26 [95%CI = -0.68 to 5.20]) and effects were highest in patients with high titer (low titers: ßcrude = 1.42 [95%CI = -1.79 to 4.62], ßadjusted = 0.53 [95%CI = -2.47 to 3.54]; high titers: ßcrude = 5.85 [95%CI = 0.20 to 11.50]; ßadjusted = 7.20 [95%CI = 0.98 to 13.43]). Conclusion: Patients with serum NMDAR1-abs (predominantly IgM&IgA) suffer more severe depressive symptoms after mild-to-moderate IS compared to NMDAR1-abs seronegative patients.

Machine learning-based prediction of clinical outcomes after first-ever ischemic stroke.

Background: Accurate prediction of clinical outcomes in individual patients following acute stroke is vital for healthcare providers to optimize treatment strategies and plan further patient care. Here, we use advanced machine learning (ML) techniques to systematically compare the prediction of functional recovery, cognitive function, depression, and mortality of first-ever ischemic stroke patients and to identify the leading prognostic factors. Methods: We predicted clinical outcomes for 307 patients (151 females, 156 males; 68 ± 14 years) from the PROSpective Cohort with Incident Stroke Berlin study using 43 baseline features. Outcomes included modified Rankin Scale (mRS), Barthel Index (BI), Mini-Mental State Examination (MMSE), Modified Telephone Interview for Cognitive Status (TICS-M), Center for Epidemiologic Studies Depression Scale (CES-D) and survival. The ML models included a Support Vector Machine with a linear kernel and a radial basis function kernel as well as a Gradient Boosting Classifier based on repeated 5-fold nested cross-validation. The leading prognostic features were identified using Shapley additive explanations. Results: The ML models achieved significant prediction performance for mRS at patient discharge and after 1 year, BI and MMSE at patient discharge, TICS-M after 1 and 3 years and CES-D after 1 year. Additionally, we showed that National Institutes of Health Stroke Scale (NIHSS) was the top predictor for most functional recovery outcomes as well as education for cognitive function and depression. Conclusion: Our machine learning analysis successfully demonstrated the ability to predict clinical outcomes after first-ever ischemic stroke and identified the leading prognostic factors that contribute to this prediction.

Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke.

Clonal hematopoiesis (CH) is common among older people and is associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort With Incident Stroke-Berlin study using error-corrected targeted sequencing. The primary composite end point (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. A total of 348 somatic mutations with a variant allele frequency ≥1% were identified in 236 of 581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = .01) and white matter lesion (P < .001). CH-positive patients showed increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6), interferon gamma, high-sensitivity C-reactive protein, and vascular cell adhesion molecule 1. CH-positive patients had a higher risk for the primary CEP (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.04-2.31; P = .03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR, 1.30; 95% CI, 1.04-1.62; P = .022) in multivariable Cox regression. Although our data show that, in particular, larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a proinflammatory profile, opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

White matter hyperintensities are an independent predictor of cognitive decline 3 years following first-ever stroke-results from the PROSCIS-B study.

BACKGROUND: White matter hyperintensities (WMH) are the result of cerebral small vessel disease and may increase the risk of cognitive impairment (CI), recurrent stroke, and depression. We aimed to explore the association between selected cerebrovascular risk factors (CVRF) and WMH load as well as the effect of increased WMH burden on recurrent vascular events, CI, and depression in first-ever ischemic stroke patients. METHODS: 431 from the PROSpective Cohort with Incident Stroke (PROSCIS) were included; Age-Related White Matter Changes (ARWMC) score was used to assess WMH burden on FLAIR. The presence of CVRF (defined via blood pressure, body-mass-index, and serological markers of kidney dysfunction, diabetes mellitus, and hyperlipoproteinemia) was categorized into normal, borderline, and pathological profiles based on commonly used clinical definitions. The primary outcomes included recurrent vascular events (combined endpoint of recurrent stroke, myocardial infarction and/or death), CI 3 years post-stroke, and depression 1-year post-stroke. RESULTS: There was no clear association between CVRF profiles and WMH burden. High WMH lesion load (ARWMC score ≥ 10) was found to be associated with CI (adjusted OR 1.05 [95% CI 1.00-1.11]; p < 0.02) in a mixed-model analysis. Kaplan-Meier survival analysis showed a visible increase in the risk of recurrent vascular events following stroke; however, after adjustment, the risk was non-significant (HR 1.5 [95% CI 0.76-3]; p = 0.18). WMH burden was not associated with depression 1-year post stroke (adjusted OR 0.72 [95% CI 0.31-1.64]; p = 0.44). CONCLUSION: Higher WMH burden was associated with a significant decline in cognition 3 years post-stroke in this cohort of first-ever stroke patients.

Differentiation of Cerebral Neoplasms with Vessel Size Imaging (VSI).

PURPOSE: Cerebral neoplasms of various histological origins may show comparable appearances on conventional Magnetic Resonance Imaging (MRI). Vessel size imaging (VSI) is an MRI technique that enables noninvasive assessment of microvasculature by providing quantitative estimates of microvessel size and density. In this study, we evaluated the potential of VSI to differentiate between brain tumor types based on their microvascular morphology. METHODS: Using a clinical 3T MRI scanner, VSI was performed on 25 patients with cerebral neoplasms, 10 with glioblastoma multiforme (GBM), 8 with primary CNS lymphoma (PCNSL) and 7 with cerebral lung cancer metastasis (MLC). Following the postprocessing of VSI maps, mean vessel diameter (vessel size index, vsi) and microvessel density (Q) were compared across tumors, peritumoral areas, and healthy tissues. RESULTS: The MLC tumors have larger and less dense microvasculature compared to PCNSLs in terms of vsi and Q (p = 0.0004 and p < 0.0001, respectively). GBM tumors have higher yet non-significantly different vsi values than PCNSLs (p = 0.065) and non-significant differences in Q. No statistically significant differences in vsi or Q were present between GBMs and MLCs. GBM tumor volume was positively correlated with vsi (r = 0.502, p = 0.0017) and negatively correlated with Q (r = -0.531, p = 0.0007). CONCLUSION: Conventional MRI parameters are helpful in differentiating between PCNSLs, GBMs, and MLCs. Additionally incorporating VSI parameters into the diagnostic protocol could help in further differentiating between PCNSLs and metastases and potentially between PCNSLs and GBMs. Future studies in larger patient cohorts are required to establish diagnostic cut-off values for VSI.

Evolution of Blood-Brain Barrier Permeability in Subacute Ischemic Stroke and Associations With Serum Biomarkers and Functional Outcome.

Background and Purpose: In the setting of acute ischemic stroke, increased blood-brain barrier permeability (BBBP) as a sign of injury is believed to be associated with increased risk of poor outcome. Pre-clinical studies show that selected serum biomarkers including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), matrix metallopeptidases (MMP), and vascular endothelial growth factors (VEGFs) may play a role in BBBP post-stroke. In the subacute phase of stroke, increased BBBP may also be caused by regenerative mechanisms such as vascular remodeling and therefore may improve functional recovery. Our aim was to investigate the evolution of BBBP in ischemic stroke using contrast-enhanced (CE) magnetic resonance imaging (MRI) and to analyze potential associations with blood-derived biomarkers as well as functional recovery in subacute ischemic stroke patients. Methods: This is an exploratory analysis of subacute ischemic stroke patients enrolled in the BAPTISe study nested within the randomized controlled PHYS-STROKE trial (interventions: 4 weeks of aerobic fitness training vs. relaxation). Patients with at least one CE-MRI before (v1) or after (v2) the intervention were eligible for this analysis. The prevalence of increased BBBP was visually assessed on T1-weighted MR-images based on extent of contrast-agent enhancement within the ischemic lesion. The intensity of increased BBBP was assessed semi-quantitatively by normalizing the mean voxel intensity within the region of interest (ROI) to the contralateral hemisphere ("normalized CE-ROI"). Selected serum biomarkers (high-sensitive CRP, IL-6, TNF-α, MMP-9, and VEGF) at v1 (before intervention) were analyzed as continuous and dichotomized variables defined by laboratory cut-off levels. Functional outcome was assessed at 6 months after stroke using the modified Rankin Scale (mRS). Results: Ninety-three patients with a median baseline NIHSS of 9 [IQR 6-12] were included into the analysis. The median time to v1 MRI was 30 days [IQR 18-37], and the median lesion volume on v1 MRI was 4 ml [IQR 1.2-23.4]. Seventy patients (80%) had increased BBBP visible on v1 MRI. After the trial intervention, increased BBBP was still detectable in 52 patients (74%) on v2 MRI. The median time to v2 MRI was 56 days [IQR 46-67]. The presence of increased BBBP on v1 MRI was associated with larger lesion volumes and more severe strokes. Aerobic fitness training did not influence the increase of BBBP evaluated at v2. In linear mixed models, the time from stroke onset to MRI was inversely associated with normalized CE-ROI (coefficient -0.002, Standard Error 0.007, p < 0.01). Selected serum biomarkers were not associated with the presence or evolution of increased BBBP. Multivariable regression analysis did not identify the occurrence or evolution of increased BBBP as an independent predictor of favorable functional outcome post-stroke. Conclusion: In patients with moderate-to-severe subacute stroke, three out of four patients demonstrated increased BBB permeability, which decreased over time. The presence of increased BBBP was associated with larger lesion volumes and more severe strokes. We could not detect an association between selected serum biomarkers of inflammation and an increased BBBP in this cohort. No clear association with favorable functional outcome was observed. Trial registration: NCT01954797.

No Association Between Thrombus Perviousness and Cardioembolic Stroke Etiology in Basilar Artery Occlusion Stroke.

Background: Thrombus perviousness (TP) quantified by thrombus attenuation increase (TAI) assessed on acute non-contrast computed tomography (NCCT) and CT angiography (CTA) may be associated with stroke etiology in anterior circulation ischemic stroke. We investigated whether TP is associated with stroke etiology and recanalization after mechanical thrombectomy in patients with acute basilar artery occlusion (BAO). Methods: Eighty patients with complete BAO and in-house acute imaging from a prospectively maintained database were included. Two raters independently segmented the complete thrombus on co-registered NCCT and CTA to determine TAI in Hounsfield units (HUCTA-HUNCCT); averaged values of the raters were used for analysis. Recanalization to modified treatment in cerebral ischemia (mTICI) score 2b/3 was considered successful, and 90-day modified Rankin Scale score 0-2 was considered favorable. Results: TAI did not differ between patients with different stroke etiologies; median TAI in patients with cardioembolic stroke (n = 36) was -0.47 (interquartile range -4.08 to 7.72), 1.94 (-8.14 to 10.75) in patients with large artery atherosclerosis (LAA; n = 25), and -0.99 (-6.49 to 5.40) in patients with stroke of undetermined origin (n = 17; p = 0.955). Binary logistic regression analyses did not identify TAI as an independent indicator of cardioembolic stroke (adjusted odds ratio [OR] vs. LAA stroke: 1.0 [95% CI: 0.95-1.0], p = 0.751). There was no association with successful recanalization (adjusted OR 1.4 [0.70-2.7], p = 0.345) or favorable outcome (adjusted OR 1.1 [95% CI: 0.94-1.2], p = 0.304). Conclusion: In contrast to proximal middle cerebral artery occlusions, TP in BAO patients is not associated with cardioembolic stroke etiology. Larger confirmatory studies to establish the potential role of TP for clinical applications should focus on patients with anterior circulation stroke.

The smoking paradox in ischemic stroke patients treated with intra-arterial thrombolysis in combination with mechanical thrombectomy-VISTA-Endovascular.

BACKGROUND: The smoking-paradox of a better outcome in ischemic stroke patients who smoke may be due to increased efficacy of thrombolysis. We investigated the effect of smoking on outcome following endovascular therapy (EVT) with mechanical thrombectomy alone versus in combination with intra-arterial (IA-) thrombolysis. METHODS: The primary endpoint was defined by three-month modified Rankin Scale (mRS). We performed a generalized linear model and reported relative risks (RR) for smoking (adjustment for age, sex, hypertension, atrial fibrillation, stroke severity, time to EVT) in patient data stemming from the Virtual International Stroke Trials Archive-Endovascular database. RESULTS: Among 1,497 patients, 740(49.4%) were randomized to EVT; among EVT patients, 524(35.0%) received mechanical thrombectomy alone and 216(14.4%) received it in combination with IA-thrombolysis. Smokers (N = 396) had lower mRS scores (mean 2.9 vs. 3.2; p = 0.02) and mortality rates (10% vs. 17.3%; p<0.001) in univariate analysis. In all patients and in patients treated with mechanical thrombectomy alone, smoking had no effect on outcome in regression analyses. In patients who received IA-thrombolysis (N = 216;14%), smoking had an adjusted RR of 1.65 for an mRS≤1 (95%CI 0.77-3.55). Treatment with IA-thrombolysis itself led to reduced RR for favorable outcome (adjusted RR 0.30); interaction analysis of IA-thrombolysis and smoking revealed that non-smokers with IA-thrombolysis had mRS≤2 in 47 cases (30%, adjusted RR 0.53 [0.41-0.69]) while smokers with IA-thrombolysis had mRS≤2 in 23 cases (38%, adjusted RR 0.61 [0.42-0.87]). CONCLUSIONS: Smokers had no clear clinical benefit from EVT that incorporates IA-thrombolysis.

Magnetic resonance imaging-based changes in vascular morphology and cerebral perfusion in subacute ischemic stroke.

MRI-based vessel size imaging (VSI) allows for in-vivo assessment of cerebral microvasculature and perfusion. This exploratory analysis of vessel size (VS) and density (Q; both assessed via VSI) in the subacute phase of ischemic stroke involved sixty-two patients from the BAPTISe cohort ('Biomarkers And Perfusion--Training-Induced changes after Stroke') nested within a randomized controlled trial (intervention: 4-week training vs. relaxation). Relative VS, Q, cerebral blood volume (rCBV) and -flow (rCBF) were calculated for: ischemic lesion, perilesional tissue, and region corresponding to ischemic lesion on the contralateral side (mirrored lesion). Linear mixed-models detected significantly increased rVS and decreased rQ within the ischemic lesion compared to the mirrored lesion (coefficient[standard error]: 0.2[0.08] p = 0.03 and -1.0[0.3] p = 0.02, respectively); lesion rCBF and rCBV were also significantly reduced. Mixed-models did not identify time-to-MRI, nor training as modifying factors in terms of rVS or rQ up to two months post-stroke. Larger lesion VS was associated with larger lesion volumes (ß 34, 95%CI 6.2-62; p = 0.02) and higher baseline NIHSS (ß 3.0, 95%CI 0.49-5.3;p = 0.02), but was not predictive of six-month outcome. In summary, VSI can assess the cerebral microvasculature and tissue perfusion in the subacute phases of ischemic stroke, and may carry relevant prognostic value in terms of lesion volume and stroke severity.

Association Between Thrombus Perviousness Assessed on Computed Tomography and Stroke Cause.

BACKGROUND AND PURPOSE: A recent study proposed that thrombus perviousness (TP)-the degree to which contrast agents penetrate the thrombus in an occluded vessel measured on noncontrast computed tomography (NCCT) and CT angiography-may be associated with cardioembolic stroke cause with high specificity. Our aim was to investigate which clinical and laboratory parameters affect measures of TP and to validate its diagnostic accuracy in an independent cohort of patients with acute ischemic stroke. METHODS: Seventy-five patients from a prospectively maintained database with proximal occlusions of the middle cerebral artery (M1) were retrospectively analyzed. Thrombi were segmented on coregistered noncontrast computed tomography and CT angiography to determine the thrombus attenuation increase and void fraction (attenuation increase relative to contralateral side). RESULTS: TP measures were significantly higher in patients with cardioembolic stroke compared to patients with stroke attributed to large artery atherosclerosis (median thrombus attenuation increase [interquartile range], 2.79 [-3.54 to 8.85] versus -5.11 [-11.23 to -1.47]; P=0.001). In linear regression analysis for TP including age, time to scan, prior medication with antiplatelets or anticoagulants, and selected laboratory parameters, only stroke cause was significantly associated with TP. In multivariable binary logistic regression analysis for dichotomized stroke cause (ie, cardioembolic versus noncardioembolic stroke), only thrombus attenuation increase was independently associated with cardioembolic stroke (odds ratio of 1.12 [95% CI, 1.04-1.22]; P=0.004). Receiver operating characteristic analysis indicated that TP can identify cardioembolic stroke with an area under the curve of 0.75 (95% CI, 0.63-0.87) for thrombus attenuation increase. With a cutoff value of 6.23 Hounsfield units, cardioembolic strokes were identified with 100% specificity. Results for void fraction were similar. CONCLUSIONS: The assessment of TP on baseline noncontrast computed tomography/CT angiography in patients with M1 occlusion may aid in determining cardioembolic stroke cause and guide secondary prevention. Selected clinical and laboratory parameters other than stroke cause did not affect TP measures.

Two simple and rapid methods based on maximum diameter accurately estimate large lesion volumes in acute stroke.

BACKGROUND: We compared two simple and rapid diameter-based methods (ABC/2, od-value) in terms of their accuracy in predicting lesion volume >70 ml and >100 ml. METHODS: In 238 DWI images of ischemic stroke patients from the AXIS2 trial, maximum lesion diameter and corresponding maximum orthogonal diameter were measured. Estimation of infarct volume based on od-value and ABC/2 calculation was compared to volumetric assessments. RESULTS: Accuracy of od-value and ABC/2 was similar for >70 ml (92.0 vs. 87.4) and >100 ml (92.9 vs. 93.3). ABC/2 overestimated lesion volume by 29.9%, resulting in a lower specificity. CONCLUSIONS: Od-value is a robust tool for patient selection in trials.

Smoking Does Not Alter Treatment Effect of Intravenous Thrombolysis in Mild to Moderate Acute Ischemic Stroke-A Dutch String-of-Pearls Institute (PSI) Stroke Study.

Background: The smoking-thrombolysis paradox refers to a better outcome in smokers who suffer from acute ischemic stroke (AIS) following treatment with thrombolysis. However, studies on this subject have yielded contradictory results and an interaction analysis of exposure to smoking and thrombolysis in a large, multicenter database is lacking. Methods: Consecutive AIS patients admitted within 12 h of symptom onset between 2009 and 2014 from the prospective, multicenter stroke registry (Dutch String-of-Pearls Stroke Study) were included for this analysis. We performed a generalized linear model for functional outcome 3 months post-stroke depending on risk of the exposure variables (smoking yes/no, thrombolysis yes/no). The following confounders were adjusted for: age, smoking, hypertension, atrial fibrillation, diabetes mellitus, stroke severity, and stroke etiology. Results: Out of 468 patients, 30.6% (N = 143) were smokers and median baseline NIHSS was 3 (interquartile range 1-6). Smoking alone had a crude and adjusted relative risk (RR) of 0.99 (95% CI 0.89-1.10) and 0.96 (95% CI 0.86-1.01) for good outcome (modified Rankin Score ≤ 2), respectively. A combination of exposure variables (smoking and thrombolysis) did not change the results significantly [crude RR 0.87 (95% CI 0.74-1.03], adjusted RR 1.1 (95%CI 0.90-1.30)]. Smoking alone had an adjusted RR of 1.2 (95% CI 0.6-2.7) for recanalization following thrombolysis (N = 88). Conclusions: In patients with mild to moderate AIS admitted within 12 h of symptom onset, smoking did not modify treatment effect of thrombolysis.

Extent of FLAIR Hyperintense Vessels May Modify Treatment Effect of Thrombolysis: A Post hoc Analysis of the WAKE-UP Trial.

Background and Aims: Fluid-attenuated inversion recovery (FLAIR) hyperintense vessels (FHVs) on MRI are a radiological marker of vessel occlusion and indirect sign of collateral circulation. However, the clinical relevance is uncertain. We explored whether the extent of FHVs is associated with outcome and how FHVs modify treatment effect of thrombolysis in a subgroup of patients with confirmed unilateral vessel occlusion from the randomized controlled WAKE-UP trial. Methods: One hundred sixty-five patients were analyzed. Two blinded raters independently assessed the presence and extent of FHVs (defined as the number of slices with visible FHV multiplied by FLAIR slice thickness). Patients were then separated into two groups to distinguish between few and extensive FHVs (dichotomization at the median <30 or ≥30). Results: Here, 85% of all patients (n = 140) and 95% of middle cerebral artery (MCA) occlusion patients (n = 127) showed FHVs at baseline. Between MCA occlusion patients with few and extensive FHVs, no differences were identified in relative lesion growth (p = 0.971) and short-term [follow-up National Institutes of Health Stroke Scale (NIHSS) score; p = 0.342] or long-term functional recovery [modified Rankin Scale (mRS) <2 at 90 days poststroke; p = 0.607]. In linear regression analysis, baseline extent of FHV (defined as a continuous variable) was highly associated with volume of hypoperfused tissue (ß = 2.161; 95% CI 0.96-3.36; p = 0.001). In multivariable regression analysis adjusted for treatment group, stroke severity, lesion volume, occlusion site, and recanalization, FHV did not modify functional recovery. However, in patients with few FHVs, the odds for good functional outcome (mRS) were increased in recombinant tissue plasminogen activator (rtPA) patients compared to those who received placebo [odds ratio (OR) = 5.3; 95% CI 1.2-24.0], whereas no apparent benefit was observed in patients with extensive FHVs (OR = 1.1; 95% CI 0.3-3.8), p-value for interaction was 0.11. Conclusion: While the extent of FHVs on baseline did not alter the evolution of stroke in terms of lesion progression or functional recovery, it may modify treatment effect and should therefore be considered relevant additional information in those patients who are eligible for intravenous thrombolysis. Clinical Trial Registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered February 2, 2012.

Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial.

Background: The "smoking paradox" indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce. Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status. Results: Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; p < 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; p = 0.02) or atrial fibrillation (3.8% vs. 15.3%; p < 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; p = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score>10 in 27.1% vs. 19.5%; p = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (p-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451-0.978], p = 0.04). Conclusions: In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase. Clinical Trial registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012.

Hyperintense Vessels, Collateralization, and Functional Outcome in Patients With Stroke Receiving Endovascular Treatment.

BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery hyperintense vessels (FHV) are frequently observed on magnetic resonance imaging in acute stroke patients with proximal vessel occlusion. Whether FHV can serve as a surrogate for the collateral status and predict functional outcome of patients is still a matter of debate. METHODS: Acute ischemic stroke patients with M1-middle cerebral artery occlusion who received magnetic resonance imaging before endovascular treatment in 3 hospitals in Germany between January 2007 and June 2016 were eligible. Quantification of FHV was performed using an FHV-Alberta Stroke Program Early CT Score (ASPECTS) rating system. Functional outcome was evaluated with the modified Rankin Scale 3 months after stroke. Collateral status of patients was graded on baseline angiography using the American Society of Interventional and Therapeutic Neuroradiology grading system. Odds for good outcome (modified Rankin Scale score, 0-2) were determined using logistic regression analyses. RESULTS: Overall, 116 patients were analyzed (median age, 74; interquartile range [IQR], 64-79; median National Institutes of Health Stroke Scale, 14; IQR, 10-19). The median FHV-ASPECTS was 2 (IQR, 1-3). Good collateral status (American Society of Interventional and Therapeutic Neuroradiology grade 3-4) on angiography was more frequently observed in patients with FHV-ASPECTS ≤2 (83% versus 57%; P=0.025). Patients with an FHV-ASPECTS ≤2 had a better functional outcome after 3 months (median modified Rankin Scale score, 2; IQR, 0-5), compared with patients with an FHV-ASPECTS >2 (median modified Rankin Scale score, 4; IQR, 3-6; P=0.015). In multiple regression analyses, FHV-ASPECTS ≤2 was independently associated with good functional outcome (adjusted odds ratio, 5.3; 95% confidence interval, 1.5-18.2). CONCLUSIONS: Low FHV-ASPECTS is associated with both better collateral status and better 3-month functional outcome in acute stroke patients with M1 vessel occlusion.

Infarct volume-based subgroup selection in acute ischemic stroke trials.

BACKGROUND AND PURPOSE: We investigated whether hyperintensities with a diameter of at least 3, 3.5, and 4 cm and visible on at least 3 slices on diffusion-weighted imaging enables patient selection with an infarct volume of ≥15 mL. METHODS: Consecutive acute stroke patients were screened for the AXIS2 trial and examined according to a standardized magnetic resonance imaging protocol in 65 sites. Diffusion-weighted lesion diameters were measured and compared with volumetric assessments. RESULTS: Out of 238 patients, 86.2% (N=206) had infarct diameter of at least 3 cm. Volumetric assessments showed infarct volume of ≥15 mL in 157 patients. A cut-off value of 3 cm led to 96.8% sensitivity and 33.3% specificity for predicting lesion volume of ≥15 mL. Analogously, a 3.5 cm cut-off led to 96.8% sensitivity and 50.6% specificity and a 4 cm cut-off led to 91.7% sensitivity and 61.7% specificity. CONCLUSIONS: Lesion diameter measures may enable multicentric patient recruitment with a prespecified minimal infarct volume. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.

Validity of negative high-resolution diffusion-weighted imaging in transient acute cerebrovascular events.

BACKGROUND AND PURPOSE: A significant amount of strokes are reported to be diffusion-weighted imaging (DWI) negative in acute imaging. We attempted to quantify the rate of false-negative high-resolution (hr) DWI and to identify a valid screening tool to guide follow-up MRI to diagnose infarction initially not visible on hrDWI. METHODS: An a priori-defined post hoc analysis of a prospective 3T MRI cohort of acute cerebrovascular events imaged within 24 hours of ictus. Basic demographics, risk factors, National Institute of Health Stroke Scale, and imaging parameters were recorded. RESULTS: Of 151 patients with negative acute hrDWI, 63 received follow-up scans depicting infarction in 7 cases (11.1%). Persistence of clinical symptoms as established by National Institute of Health Stroke Scale on the following day was strongly associated with infarction on follow-up MRI (odds ratios, 17.5; 95% confidence interval, 2.83-108.12). Negative predictive value of follow-up National Institute of Health Stroke Scale was 0.96. CONCLUSIONS: Infarcts are frequently invisible on initial hrDWI, but we may well trust in negative hrDWI in completely transient cerebrovascular events.