Adjunct Thrombolysis Enhances Brain Reperfusion following Successful Thrombectomy.

OBJECTIVE: This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy. METHODS: This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity. RESULTS: The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001). INTERPRETATION: There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity. ANN NEUROL 2022;92:860-870.

Clinical and therapeutic variables may influence the association between infarct core predicted by CT perfusion and clinical outcome in acute stroke.

OBJECTIVES: After an acute ischemic stroke, patients with a large CT perfusion (CTP) predicted infarct core (pIC) have poor clinical outcome. However, previous research suggests that this relationship may be relevant for subgroups of patients determined by pretreatment and treatment-related variables while negligible for others. We aimed to identify these variables. METHODS: We included a cohort of 828 patients with acute proximal carotid arterial occlusions imaged with a whole-brain CTP within 8 h from stroke onset. pIC was computed on CTP Maps (cerebral blood flow < 30%), and poor clinical outcome was defined as a 90-day modified Rankin Scale score > 2. Potential mediators of the association between pIC and clinical outcome were evaluated through first-order and advanced interaction analyses in the derivation cohort (n = 654) for obtaining a prediction model. The derived model was further validated in an independent cohort (n = 174). RESULTS: The volume of pIC was significantly associated with poor clinical outcome (OR = 2.19, 95% CI = 1.73 - 2.78, p < 0.001). The strength of this association depended on baseline National Institute of Health Stroke Scale, glucose levels, the use of thrombectomy, and the interaction of age with thrombectomy. The model combining these variables showed good discrimination for predicting clinical outcome in both the derivation cohort and validation cohorts (area under the receiver operating characteristic curve 0.780 (95% CI = 0.746-0.815) and 0.782 (95% CI = 0.715-0.850), respectively). CONCLUSIONS: In patients imaged within 8 h from stroke onset, the association between pIC and clinical outcome is significantly modified by baseline and therapeutic variables. These variables deserve consideration when evaluating the prognostic relevance of pIC. KEY POINTS: •The volume of CT perfusion (CTP) predicted infarct core (pIC) is associated with poor clinical outcome in acute ischemic stroke imaged within 8 h of onset. •The relationship between pIC and clinical outcome may be modified by baseline clinical severity, glucose levels, thrombectomy use, and the interaction of age with thrombectomy. •CTP pIC should be evaluated in an individual basis for predicting clinical outcome in patients imaged within 8 h from stroke onset.

Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial.

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). Main Outcomes and Measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.

Susceptibility Vessel Sign in Deep Perforating Arteries in Patients with Recent Small Subcortical Infarcts.

OBJECTIVES: Recent small subcortical infarcts (RSSI) are considered an acute manifestation of cerebral small vessel disease. Paramagnetic signals in perforating arteries supplying RSSI may be detected on T2*-relaxation derived sequences on MRI and is defined as susceptibility vessel sign (SVS). We aimed to study the prevalence of SVS in patients with RSSI, and explore whether its identification is related to cerebral small vessel disease markers. MATERIALS AND METHODS: We selected patients with RSSI identified on MRI during admission from a single-center stroke registry. The main demographic and clinical features, including vascular risk factors, were collected. Radiological features of RSSI and cerebral small vessel disease [white matter hyperintensities in deep and periventricular regions, enlarged perivascular spaces, lacunae, microbleeds, and brain atrophy] were described using validated qualitative scores. The presence of SVS was assessed on T2*gradient-echo or other susceptibility-weighted imaging. We compared the clinical and radiological features of patients with or without SVS in uni- and multivariate models. RESULTS: Out of 210 patients with an RSSI on an MRI, 35 (17%) showed SVS. The proportion of SVS+ patients was similar in different susceptibility imaging modalities (p=.64). Risk factor profiles and clinical course were similar in SVS+ and SVS- patients. SVS+ patients had a higher grade of deep white matter hyperintensities and brain atrophy, more lacunae (p=.001, p=.034, p=.022, respectively), and a similar degree of the rest of radiological variables, compared to SVS- patients. In the multivariate analysis, the grade of deep white matter hyperintensities was the only independent factor associated with SVS [OR 3.1 (95% CI, 1.5-6.4)]. CONCLUSIONS: SVS in patients with RSSI is uncommon and related to a higher grade of deep white matter hyperintensities. Pathophysiological mechanisms underlying the deposition of hemosiderin in the path of occluded perforating arteries are uncertain and might include endothelial dysfunction or embolic mechanisms.

Higher Solar Irradiance Is Associated With a Lower Incidence of Coronavirus Disease 2019.

We studied the relationship between the incidence of coronavirus disease 2019 (COVID-19), demographical, and climatological measurements in different regions across the world. Lower solar irradiance and higher population density were independent predictors of greater COVID-19 outbreaks. Further studies on the potential protective effect of sunlight over COVID-19 are warranted.

Acute Stroke Care Is at Risk in the Era of COVID-19: Experience at a Comprehensive Stroke Center in Barcelona.

BACKGROUND AND PURPOSE: The purpose of the study is to analyze how the coronavirus disease 2019 (COVID-19) pandemic affected acute stroke care in a Comprehensive Stroke Center. METHODS: On February 28, 2020, contingency plans were implemented at Hospital Clinic of Barcelona to contain the COVID-19 pandemic. Among them, the decision to refrain from reallocating the Stroke Team and Stroke Unit to the care of patients with COVID-19. From March 1 to March 31, 2020, we measured the number of emergency calls to the Emergency Medical System in Catalonia (7.5 million inhabitants), and the Stroke Codes dispatched to Hospital Clinic of Barcelona. We recorded all stroke admissions, and the adequacy of acute care measures, including the number of thrombectomies, workflow metrics, angiographic results, and clinical outcomes. Data were compared with March 2019 using parametric or nonparametric methods as appropriate. RESULTS: At Hospital Clinic of Barcelona, 1232 patients with COVID-19 were admitted in March 2020, demanding 60% of the hospital bed capacity. Relative to March 2019, the Emergency Medical System had a 330% mean increment in the number of calls (158 005 versus 679 569), but fewer Stroke Code activations (517 versus 426). Stroke admissions (108 versus 83) and the number of thrombectomies (21 versus 16) declined at Hospital Clinic of Barcelona, particularly after lockdown of the population. Younger age was found in stroke admissions during the pandemic (median [interquartile range] 69 [64-73] versus 75 [73-80] years, P=0.009). In-hospital, there were no differences in workflow metrics, angiographic results, complications, or outcomes at discharge. CONCLUSIONS: The COVID-19 pandemic reduced by a quarter the stroke admissions and thrombectomies performed at a Comprehensive Stroke Center but did not affect the quality of care metrics. During the lockdown, there was an overload of emergency calls but fewer Stroke Code activations, particularly in elderly patients. Hospital contingency plans, patient transport systems, and population-targeted alerts must act concertedly to better protect the chain of stroke care in times of pandemic.

Deep Learning Based Software to Identify Large Vessel Occlusion on Noncontrast Computed Tomography.

BACKGROUND AND PURPOSE: Reliable recognition of large vessel occlusion (LVO) on noncontrast computed tomography (NCCT) may accelerate identification of endovascular treatment candidates. We aim to validate a machine learning algorithm (MethinksLVO) to identify LVO on NCCT. METHODS: Patients with suspected acute stroke who underwent NCCT and computed tomography angiography (CTA) were included. Software detection of LVO (MethinksLVO) on NCCT was tested against the CTA readings of 2 experienced radiologists (NR-CTA). We used a deep learning algorithm to identify clot signs on NCCT. The software image output trained a binary classifier to determine LVO on NCCT. We studied software accuracy when adding National Institutes of Health Stroke Scale and time from onset to the model (MethinksLVO+). RESULTS: From 1453 patients, 823 (57%) had LVO by NR-CTA. The area under the curve for the identification of LVO with MethinksLVO was 0.87 (sensitivity: 83%, specificity: 71%, positive predictive value: 79%, negative predictive value: 76%) and improved to 0.91 with MethinksLVO+ (sensitivity: 83%, specificity: 85%, positive predictive value: 88%, negative predictive value: 79%). CONCLUSIONS: In patients with suspected acute stroke, MethinksLVO software can rapidly and reliably predict LVO. MethinksLVO could reduce the need to perform CTA, generate alarms, and increase the efficiency of patient transfers in stroke networks.

Value of Vascular and Non-Vascular Pattern on Computed Tomography Perfusion in Patients With Acute Isolated Aphasia.

BACKGROUND AND PURPOSE: Acute onset aphasia may be due to stroke but also to other causes, which are commonly referred to as stroke mimics. We hypothesized that, in patients with acute isolated aphasia, distinct brain perfusion patterns are related to the cause and the clinical outcome. Herein, we analyzed the prognostic yield and the diagnostic usefulness of computed tomography perfusion (CTP) in patients with acute isolated aphasia. METHODS: From a single-center registry, we selected a cohort of 154 patients presenting with acute isolated aphasia who had a whole-brain CTP study available. We collected the main clinical and radiological data. We categorized brain perfusion studies on CTP into vascular and nonvascular perfusion patterns and the cause of aphasia as ischemic stroke, transient ischemic attack, stroke mimic, and undetermined cause. The primary clinical outcome was the persistence of aphasia at discharge. We analyzed the sensitivity, specificity, positive and negative predictive values of perfusion patterns to predict complete clinical recovery and ischemic stroke on follow-up imaging. RESULTS: The cause of aphasia was an ischemic stroke in 58 patients (38%), transient ischemic attack in 3 (2%), stroke mimic in 68 (44%), and undetermined in 25 (16%). CTP showed vascular and nonvascular perfusion pattern in 62 (40%) and 92 (60%) patients, respectively. Overall, complete recovery occurred in 116 patients (75%). A nonvascular perfusion pattern predicted complete recovery (sensitivity 75.9%, specificity 89.5%, positive predictive value 95.7%, and negative predictive value 54.8%), and a vascular perfusion pattern was highly predictive of ischemic stroke (sensitivity 94.8%, specificity 92.7%, positive predictive value 88.7%, and negative predictive value 96.7%). The 3 patients with ischemic stroke without a vascular perfusion pattern fully recovered at discharge. CONCLUSIONS: CTP has prognostic value in the workup of patients with acute isolated aphasia. A nonvascular pattern is associated with higher odds of full recovery and may prompt the search for alternative causes of the symptoms.

Timing and Relevance of Clinical Improvement After Mechanical Thrombectomy in Patients With Acute Ischemic Stroke.

Background and Purpose- The clinical course in patients with ischemic stroke treated with mechanical thrombectomy (MT) is heterogeneous. We aimed to study the relevance of the timing of clinical improvement in the prediction of long-term outcome in patients treated with MT. Methods- We studied a cohort of 423 patients with anterior circulation stroke treated with MT, of whom 334 patients (79.0%) achieved good outcome (modified Rankin Scale score of 0-2 at 90-day follow-up). National Institutes of Health Stroke Scale scores were assessed before MT, at the end of MT (d0), at day 1 (d1), and at day 7 or discharge (d7). We explored the predictive value for good outcome of different cutoffs based on absolute and percentage changes in the National Institutes of Health Stroke Scale at each assessment (d0, d1, and d7) and selected the corresponding most informative cutoffs to define substantial clinical improvement (SCI) over time. Then, we classified patients in SCI subgroups according to the delay from MT to SCI (SCI-d0, SCI-d1, and SCI-d7) and analyzed their adjusted odds ratio for good outcome compared with patients not presenting SCI (no-SCI). Additionally, we identified the independent factors predicting SCI-d0 in multivariate models. Results- The most informative cutoffs were 30% at d0, 40% at d1, and 70% at d7. The adjusted odds ratios (95% CI) for good outcome were 47.4 (22.1-101.7, n=172) for SCI-d0, 27.7 (11.8-65.0, n=76) for SCI-d1, and 12.6 for SCI-d7 (95% CI, 3.8-41.4, n=17) compared with no-SCI (n=158). The independent factors predicting SCI-d0 were successful reperfusion (odds ratio, 25.79; 95% CI, 12.92-51.47) and shorter time to treatment (odds ratio per hour 0.90; 95% CI, 0.85-0.96). Conclusions- Shorter delay to clinical improvement is strongly related to better chances of a long-term good outcome, and an improvement >30% in National Institutes of Health Stroke Scale score at the end of MT represents a reliable prognostic marker for clinicians and also for clinical research.

Leukocytes, Collateral Circulation, and Reperfusion in Ischemic Stroke Patients Treated With Mechanical Thrombectomy.

Background and Purpose- Peripheral immune cells are activated after stroke and may in turn influence the fate of ischemic brain tissue, thus exerting a dual role in ischemic stroke. We evaluated the contribution of neutrophil and lymphocyte counts to hemorrhagic complications and functional outcome in stroke patients treated with mechanical thrombectomy (MT) with varying degrees of collateral circulation and reperfusion. Methods- We retrospectively analyzed 433 consecutive ischemic stroke patients treated with MT. Neutrophil and lymphocyte counts and the neutrophil-to-lymphocyte ratio (NLR) were collected before MT and 1 day after symptom onset. Outcome measures included categories of hemorrhagic transformation, symptomatic intracerebral hemorrhage, 3-month functional dependence (modified Rankin Scale, 3-6), and mortality. Patients were categorized according to their baseline collateral status and the degree of reperfusion after MT. Results- Neutrophil counts and NLR increased, whereas lymphocyte counts decreased after MT (P<0.001), and changes in neutrophils and NLR at day 1 were significantly greater in patients with poor reperfusion. Neutrophil counts and NLR were significantly higher already at admission in patients with poor 3-month outcome. In adjusted analysis, the impact of neutrophilia on poor functional outcome was more substantial in patients with good collaterals achieving successful reperfusion (aOR, 3.09 per quartile; 95% CI, 1.95-4.90), whereas admission lymphopenia (aOR, 4.08 per decreasing quartile; 95% CI, 1.56-10.64) and higher NLR (aOR, 3.76 per quartile; 95% CI, 1.44-9.79) predicted subsequent symptomatic intracerebral hemorrhage in patients with poor collaterals and successful reperfusion. Conclusions- In patients treated with MT, neutrophil and lymphocyte counts are dynamic parameters associated with hemorrhagic complications and long-term outcome. The extent of collateral circulation and the success of brain reperfusion influence the strength of these associations and highlight the dual role of leukocytes in acute stroke.

Relevance of Collaterals for the Success of Neuroprotective Therapies in Acute Ischemic Stroke: Insights from the Randomized URICO-ICTUS Trial.

BACKGROUND: Collateral circulation may modify the effect of neuroprotective therapies. We report a post hoc analysis of the URICO-ICTUS trial (NCT00860366) assessing the modifying treatment effect of pretreatment collaterals on clinical and radiological outcomes in patients with large-vessel acute ischemic stroke receiving uric acid therapy or placebo. METHODS: URICO-ICTUS was a randomized clinical trial where 411 alteplase-treated patients also received uric acid 1,000 mg (n = 211) or placebo (n = 200) before the end of alteplase infusion. Herein, we included a nested study of 84 patients (placebo = 40, uric acid = 44) who had a pretreatment CT-angiography (CTA) showing a proximal arterial occlusion in the carotid territory. Excellent collaterals were defined as 100% collateral supply on pretreatment CTA. Regression models assessed the interaction between therapy (uric acid/placebo) and collaterals on the main outcome (ordinal modified Rankin Scale [mRS] shift at 90 days). RESULTS: Overall, excellent collaterals were associated with improved outcome. There was a significant interaction between therapy and pretreatment collaterals (p interaction = 0.02) for the prediction of improved mRS shift. The largest treatment contrast in favor of uric acid was found in patients with excellent collaterals (adjusted OR 9.2; 95% CI 1.23-68.6; p = 0.03). CONCLUSIONS: Collectively, the study found that collaterals were associated with the neuroprotective effect of uric acid therapy highlighting the importance of assessing collateral status in neuroprotection trials.

T Cells Prevent Hemorrhagic Transformation in Ischemic Stroke by P-Selectin Binding.

Objective- Hemorrhagic transformation is a serious complication of ischemic stroke after recanalization therapies. This study aims to identify mechanisms underlying hemorrhagic transformation after cerebral ischemia/reperfusion. Approach and Results- We used wild-type mice and Selplg-/- and Fut7-/- mice defective in P-selectin binding and lymphopenic Rag2-/- mice. We induced 30-minute or 45-minute ischemia by intraluminal occlusion of the middle cerebral artery and assessed hemorrhagic transformation at 48 hours with a hemorrhage grading score, histological means, brain hemoglobin content, or magnetic resonance imaging. We depleted platelets and adoptively transferred T cells of the different genotypes to lymphopenic mice. Interactions of T cells with platelets in blood were studied by flow cytometry and image stream technology. We show that platelet depletion increased the bleeding risk only after large infarcts. Lymphopenia predisposed to hemorrhagic transformation after severe stroke, and adoptive transfer of T cells prevented hemorrhagic transformation in lymphopenic mice. CD4+ memory T cells were the subset of T cells binding P-selectin and platelets through functional P-selectin glycoprotein ligand-1. Mice defective in P-selectin binding had a higher hemorrhagic score than wild-type mice. Adoptive transfer of T cells defective in P-selectin binding into lymphopenic mice did not prevent hemorrhagic transformation. Conclusions- The study identifies lymphopenia as a previously unrecognized risk factor for secondary hemorrhagic transformation in mice after severe ischemic stroke. T cells prevent hemorrhagic transformation by their capacity to bind platelets through P-selectin. The results highlight the role of T cells in bridging immunity and hemostasis in ischemic stroke.

Adrenal hormones and circulating leukocyte subtypes in stroke patients treated with reperfusion therapy.

Ischemic stroke sets in motion a dialogue between the central nervous and the immune systems that includes the sympathetic/adrenal system. We investigated the course of immune cells and adrenocortical and adrenomedullary effectors in a cohort of 51 patients with acute stroke receiving reperfusion therapy (intravenous alteplase or mechanical thrombectomy) and its correlation with stroke outcomes and infarct growth. Cortisol increased rapidly and fleetingly after stroke, but 39% of patients who had larger infarctions on admission showed a positive delta cortisol at day 1. It was associated with enhanced infarct growth (p = 0.002) and poor outcome [OR (95% CI) 5.30 (1.30-21.69)], and correlated with less lymphocytes and T cells at follow up. Likewise, fewer circulating lymphocytes, T cells, and Tregs were associated with infarct growth. By contrast, metanephrines did not increase at clinical onset, and decreased over time. Higher levels of NMN correlated with more Treg and B cells. Eventually, complete reperfusion at the end of therapy headed the identification of more circulating Tregs at day 1. Then activation of cortical or medullar compartments of the adrenal gland result in specific signatures on leukocyte subpopulations. Manipulation of the adrenal gland hormone levels warrants further investigation.

Vessel Wall Enhancement and Blood-Cerebrospinal Fluid Barrier Disruption After Mechanical Thrombectomy in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Less than half of acute ischemic stroke patients treated with mechanical thrombectomy obtain permanent clinical benefits. Consequently, there is an urgent need to identify mechanisms implicated in the limited efficacy of early reperfusion. We evaluated the predictors and prognostic significance of vessel wall permeability impairment and its association with blood-cerebrospinal fluid barrier (BCSFB) disruption after acute stroke treated with thrombectomy. METHODS: A prospective cohort of acute stroke patients treated with stent retrievers was analyzed. Vessel wall permeability impairment was identified as gadolinium vessel wall enhancement (GVE) in a 24- to 48-hour follow-up contrast-enhanced magnetic resonance imaging, and severe BCSFB disruption was defined as subarachnoid hemorrhage or gadolinium sulcal enhancement (present across >10 slices). Infarct volume was evaluated in follow-up magnetic resonance imaging, and clinical outcome was evaluated with the modified Rankin Scale at day 90. RESULTS: A total of 60 patients (median National Institutes of Health Stroke Scale score, 18) were analyzed, of whom 28 (47%) received intravenous alteplase before mechanical thrombectomy. Overall, 34 (57%) patients had GVE and 27 (45%) had severe BCSFB disruption. GVE was significantly associated with alteplase use before thrombectomy and with more stent retriever passes, along with the presence of severe BCSFB disruption. GVE was associated with poor clinical outcome, and both GVE and severe BCSFB disruption were associated with increased final infarct volume. CONCLUSIONS: These findings may support the clinical relevance of direct vessel damage and BCSFB disruption after acute stroke and reinforce the need for further improvements in reperfusion strategies. Further validation in larger cohorts of patients is warranted.

Neuroanatomical correlates of stroke-associated infection and stroke-induced immunodepression.

BACKGROUND: Infections represent the most frequent medical complications in stroke patients. Their main determinants are dysphagia and a transient state of immunodepression. We analyzed whether distinct anatomical brain regions were associated with the occurrence of stroke-associated infections or immunodepression. MATERIALS AND METHODS: In 106 patients with acute ischemic stroke, we evaluated the incidence of pneumonia, urinary tract infection, or other infections together with the characterization of biomarkers of immunodepression. Twenty control subjects served to provide reference values. Using voxel-based lesion-symptom mapping, the involvement of gray and white matter structures was correlated with clinical and laboratory findings in crude analyses and in volume adjusted models to rule out associations reflecting differences in the size of the infarction. RESULTS: Stroke-associated infection occurred in 22 (21%) patients and prevailed in patients with larger infarcts. Volume adjusted voxel-based lesion-symptom mapping revealed the involvement of the superior and middle temporal gyri, the orbitofrontal cortex, the superior longitudinal fasciculus and the inferior fronto-occipital fasciculus amongst infected patients. These associations were similar for pneumonia but not for urinary tract infections. Lymphopenia was associated with lesions of the superior and middle temporal gyri. Laterality did not influence stroke-associated infections or the presence of immunodepressive traits after volume control. The greatest overlap in the neuroanatomical correlates occurred between pneumonia and dysphagia. CONCLUSION: Infarct volume plays a relevant role in the occurrence of stroke-associated infections, but lesions in specific brain locations such as the superior and lateral temporal lobe and the orbitofrontal cortex are also associated with increased infectious risk, especially pneumonia.

Different Perfusion Patterns in a Patient with Acute Ischemic Stroke.

A 29-year-old male patient with aphasia and mild weakness of the right arm arrived at the emergency room 4 hours after symptom onset. The computed tomography perfusion showed a typical delay in the time-based maps in the left occipital lobe and another hyperperfused area in the left frontal lobe. The follow-up magnetic resonance imaging confirmed cortical ischemic lesions in both areas. This case shows that besides hypoperfusion, hyperperfusion can also be found in the first stages of acute stroke, and it is highly suggestive of established ischemic lesions.

Uric Acid Therapy Prevents Early Ischemic Stroke Progression: A Tertiary Analysis of the URICO-ICTUS Trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke).

BACKGROUND AND PURPOSE: Identification of neuroprotective therapies in acute ischemic stroke is imperative. We report a predefined analysis of the URICO-ICTUS trial (Efficacy Study of Combined Treatment With Uric Acid and r-tPA in Acute Ischemic Stroke) assessing the efficacy of uric acid (UA) compared with placebo to prevent early ischemic worsening (EIW) and the relevance of collateral circulation. METHODS: URICO-ICTUS was a double-blind, placebo-controlled, phase 2b trial where a total of 411 patients treated with alteplase within 4.5 hours of stroke onset were randomized (1:1) to receive UA 1000 mg (n=211) or placebo (n=200) before the end of alteplase infusion. EIW defined an increment ≥4 points in the National Institutes of Health Stroke Scale score within 72 hours of treatment in the absence of hemorrhage or recurrent stroke. Logistic regression models assessed the interaction between therapy and the collateral circulation in 112 patients who had a pretreatment computed tomographic angiography. RESULTS: EIW occurred in 2 of 149 (1%) patients with good outcome and 23 of 262 (9%) patients with poor outcome (χ2; P=0.002). EIW occurred in 7 of 204 (3%) patients treated with UA and in 18 of 200 (9%) patients treated with placebo (χ2; P=0.01). There was a significant interaction between the efficacy of UA to prevent EIW and collaterals (P=0.029), with lower incidence in patients with good collaterals treated with UA compared with placebo (2% versus 15%, respectively; P=0.048). CONCLUSIONS: UA therapy may prevent EIW after acute stroke in thrombolysed patients. Optimal access of UA to its molecular targets through appropriate collaterals may modify the magnitude of the neuroprotective effect. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00860366.

Uric acid improves glucose-driven oxidative stress in human ischemic stroke.

OBJECTIVE: A study was undertaken to test in a subgroup reanalysis of the URICO-ICTUS trial whether uric acid is superior to placebo in improving the functional outcome in patients with acute stroke and hyperglycemia. METHODS: Patients were part of the URICO-ICTUS trial, a double-blind study that compared the administration of uric acid versus placebo in stroke patients treated with alteplase within 4.5 hours of onset. The effect of therapy on the rate of excellent outcome at 90 days (modified Rankin Scale ≤ 2) in each tertile of admission glucose was assessed with multivariate adjusted models in 409 of the 421 randomized patients who had available pretreatment glucose levels. The effect of therapy on infarct growth was assessed in 72 patients who had longitudinal multimodal brain imaging. RESULTS: Uric acid was associated with an increased rate of excellent outcome in patients with glucose levels in the upper tertile range (odds ratio [OR] = 2.9, 95% confidence interval [CI] = 1.0-8.3). However, the effect was not apparent for patients in the middle tertile (OR = 1.6, 95% CI = 0.8-3.6) or lower tertile of glucose (OR = 1.1, 95% CI = 0.5-2.6). Uric acid therapy was more effective than placebo in limiting infarct growth in the upper tertile range (Mann-Whitney U test, p = 0.04) but not in the middle tertile (p = 0.95) or lower tertile of glucose (p = 0.30). Uric acid also proved superior to placebo in reducing infarct growth in patients with early recanalization. INTERPRETATION: Uric acid therapy was associated with reduced infarct growth and improved outcome in patients with hyperglycemia during acute stroke.

Uric Acid Therapy Improves Clinical Outcome in Women With Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: It is unknown whether women and men with acute ischemic stroke respond similar to an antioxidant regimen administered in combination with thrombolysis. Here, we investigated the independent effect of sex on the response to uric acid (UA) therapy in patients with acute stroke treated with alteplase. METHODS: In the Efficacy Study of Combined Treatment With Uric Acid and rtPA in Acute Ischemic Stroke (URICO-ICTUS) trial, 206 women and 205 men were randomized to UA 1000 mg or placebo. In this reanalysis of the trial, the primary outcome was the rate of excellent outcome at 90 days (modified Rankin Scale, 0-1, or 2, if premorbid score of 2) in women and men using regression models adjusted for confounders associated with sex. The interaction of UA levels by treatment on infarct growth was assessed in selected patients. RESULTS: Excellent outcome occurred in 47 of 111 (42%) women treated with UA, and 28 of 95 (29%) treated with placebo, and in 36 of 100 (36%) men treated with UA and 38 of 105 (34%) treated with placebo. Treatment and sex interacted significantly with excellent outcome (P=0.045). Thus, UA therapy doubled the effect of placebo to attain an excellent outcome in women (odd ratio [95% confidence interval], 2.088 [1.050-4.150]; P=0.036), but not in men (odd ratio [95% confidence interval], 0.999 [0.516-1.934]; P=0.997). The interactions between treatment and serum UA levels (P<0.001) or allantoin/UA ratio (P<0.001) on infarct growth were significant only in women. CONCLUSIONS: In women with acute ischemic stroke treated with alteplase, the administration of UA reduced infarct growth in selected patients and was better than placebo to reach excellent outcome. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00860366.

Relevance of blood-brain barrier disruption after endovascular treatment of ischemic stroke: dual-energy computed tomographic study.

BACKGROUND AND PURPOSE: Computed tomographic (CT) high attenuation (HA) areas after endovascular therapy for acute ischemic stroke are a common finding indicative of blood-brain barrier disruption. Dual-energy CT allows an accurate differentiation between HA areas related to contrast staining (CS) or to brain hemorrhage (BH). We sought to evaluate the prognostic significance of the presence of CS and BH after endovascular therapy. METHODS: A prospective cohort of 132 patients treated with endovascular therapy was analyzed. According to dual-energy CT findings, patients were classified into 3 groups: no HA areas (n=53), CS (n=32), and BH (n=47). The rate of new hemorrhagic transformations was recorded at follow-up neuroimaging. Clinical outcome was evaluated at 90 days with the modified Rankin Scale (poor outcome, 3-6). RESULTS: Poor outcome was associated with the presence of CS (odds ratio [OR], 11.3; 95% confidence interval, 3.34-38.95) and BH (OR, 10.4; 95% confidence interval, 3.42-31.68). The rate of poor outcome despite complete recanalization was also significantly higher in CS (OR, 9.7; 95% confidence interval, 2.55-37.18) and BH (OR, 15.1; 95% confidence interval, 3.85-59.35) groups, compared with the no-HA group. Patients with CS disclosed a higher incidence of delayed hemorrhagic transformation at follow-up (OR, 4.5; 95% confidence interval, 1.22-16.37) compared with no-HA patients. CONCLUSIONS: Blood-brain barrier disruption, defined as CS and BH on dual-energy CT, was associated with poor clinical outcomes in patients with stroke treated with endovascular therapies. Moreover, isolated CS was associated with delayed hemorrhagic transformation. These results support the clinical relevance of blood-brain barrier disruption in acute stroke.