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.

[Chronic degenerative conditions as risk factors for lethal COVID-19Doenças crônicas degenerativas como fator de risco para letalidade por COVID-19]. / Enfermedades crónicas degenerativas como factor de riesgo de letalidad por COVID-19 en México.

Objective: To determine the relative risk of a lethal outcome associated with chronic degenerative conditions in patients with COVID-19. Methods: A cohort study was conducted using electronic medical records belonging to patients who tested positive for COVID-19 on RT-PCR while receiving care as outpatients or inpatients in a social security system facility between March 2020 and March 2021. Two study groups were formed. The exposed group was divided into four subgroups, each of which was diagnosed with one and only one chronic condition (diabetes, hypertension, obesity, or chronic kidney disease); the unexposed group was obtained from the medical records of patients without comorbidities. A total of 1 114 medical records were examined using simple random sampling. Once the minimum sample size was reached, the relative risk was calculated for each chronic condition. Combinations of two, three, and four conditions were created, and each of them was included in the analysis. Results: In the absence of a chronic degenerative condition, the prevalence of a lethal outcome from COVID-19 is 3.8%; in the presence of type 2 diabetes mellitus, 15.8%; in the presence of arterial hypertension, 15.6%; and in the presence of obesity, 15.0%. For diabetes and hypertension combined, the prevalence of a lethal outcome is 54.1%; for diabetes and obesity combined, 36.8%, and for obesity and hypertension combined, 28.1%. Conclusion: In patients with COVID-19, the relative risk of a lethal outcome is 4.17 for those with diabetes, 4.13 for those with hypertension, and 3.96 for those with obesity. For two chronic conditions combined, the relative risk doubles or triples. The relative risk of a lethal outcome is 14.27 for diabetes plus hypertension; 9.73 for diabetes plus obesity, and 7.43 for obesity plus hypertension. Chronic conditions do not present alone; they generally occur together, hence the significance of the relative risks for lethal outcomes presented in this paper.

Objetivo: Determinar o risco de letalidade conferido por doenças crônicas degenerativas em pacientes com COVID-19. Métodos: Foi realizado um estudo de coorte em prontuários eletrônicos de pacientes com RT-PCR positivo para COVID-19 em atendimento ambulatorial ou hospitalar em uma instituição de previdência social, no período de março de 2020 a março de 2021. Foram constituídos dois grupos de estudo. O grupo exposto foi dividido em quatro subgrupos, cada um com diagnóstico único e exclusivo de uma doença crônica (diabetes, hipertensão, obesidade ou doença renal crônica). O grupo não exposto foi constituído por prontuários de pacientes sem comorbidades. Foram revisados 1.114 prontuários no total, utilizando técnica de amostragem aleatória simples. Uma vez obtido o tamanho mínimo da amostra, foi calculado o risco relativo para cada doença crônica. Foram realizadas combinações de 2, 3 e 4, tendo sido feita a análise com cada uma delas. Resultados: Na ausência de doença crônica degenerativa, a prevalência de letalidade na COVID-19 é de 3,8%; na presença de diabetes mellitus tipo 2, a letalidade é de 15,8%; na presença de hipertensão arterial, 15,6%; e na presença de obesidade, 15%. Quando tanto diabetes como hipertensão estão presentes, a letalidade é de 54,1%; com diabetes e obesidade, 36,8%; e obesidade com hipertensão, 28,1%. Conclusões: Em pacientes com COVID-19, o risco relativo de letalidade é de 4,17 naqueles com diabetes; 4,13 naqueles com hipertensão; e 3,96 naqueles com obesidade. Quando duas doenças crônicas são combinadas, o risco relativo dobra ou triplica. Para diabetes e hipertensão, o risco relativo de letalidade é 14,27; para diabetes e obesidade, 9,73; e para obesidade e hipertensão, 7,43. As doenças crônicas não ocorrem sozinhas (geralmente estão associadas), e nessa perspectiva os riscos relativos de letalidade apresentados neste artigo tornam-se relevantes.

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.

Linoleic Acid Status in Cell Membranes Inversely Relates to the Prevalence of Symptomatic Carotid Artery Disease.

BACKGROUND AND PURPOSE: The red blood cell fatty acid composition objectively reflects the long-term dietary intake of several fatty acids. In patients undergoing carotid endarterectomy, we explored whether red blood cell status of selected fatty acids related to symptomatic carotid artery disease. METHODS: We included patients with symptomatic (n=22) and asymptomatic (n=23) carotid artery disease. We determined all-C18:1 trans, linoleic acid (LA, C18:2n6), alpha-linolenic acid (C18:3n3), and the omega-3 index (sum of eicosapentaenoic [C20:5n3] and docosahexaenoic [C22:6n3] acids) in both red blood cells and carotid plaque phospholipids by gas-chromatography. RESULTS: In a multivariate logistic regression analysis, we only observed a significant association for LA, whose red blood cell status was inversely related to symptomatic carotid artery disease (odds ratio, 0.116 [95% CI, 0.022-0.607], P=0.011, for each 1-SD increase). A similar result was observed for LA in carotid plaque phospholipids. CONCLUSIONS: Cell membrane enrichment in LA, which reflects its intake, was inversely related to symptomatic carotid disease. This increases evidence supporting a favorable role of dietary LA in vascular health.

Impact of COVID-19 Infection on the Outcome of Patients With Ischemic Stroke.

BACKGROUND AND PURPOSE: We evaluated whether stroke severity, functional outcome, and mortality are different in patients with ischemic stroke with or without coronavirus disease 2019 (COVID-19) infection. METHODS: A prospective, observational, multicentre cohort study in Catalonia, Spain. Recruitment was consecutive from mid-March to mid-May 2020. Patients had an acute ischemic stroke within 48 hours and a previous modified Rankin Scale (mRS) score of 0 to 3. We collected demographic data, vascular risk factors, prior mRS score, National Institutes of Health Stroke Scale score, rate of reperfusion therapies, logistics, and metrics. Primary end point was functional outcome at 3 months. Favourable outcome was defined depending on the previous mRS score. Secondary outcome was mortality at 3 months. We performed mRS shift and multivariable analyses. RESULTS: We evaluated 701 patients (mean age 72.3±13.3 years, 60.5% men) and 91 (13%) had COVID-19 infection. Median baseline National Institutes of Health Stroke Scale score was higher in patients with COVID-19 compared with patients without COVID-19 (8 [3-18] versus 6 [2-14], P=0.049). Proportion of patients with a favourable functional outcome was 33.7% in the COVID-19 and 47% in the non-COVID-19 group. However, after a multivariable logistic regression analysis, COVID-19 infection did not increase the probability of unfavourable functional outcome. Mortality rate was 39.3% among patients with COVID-19 and 16.1% in the non-COVID-19 group. In the multivariable logistic regression analysis, COVID-19 infection was a risk factor for mortality (hazard ratio, 3.14 [95% CI, 2.10-4.71]; P<0.001). CONCLUSIONS: Patients with ischemic stroke and COVID-19 infection have more severe strokes and a higher mortality than patients with stroke without COVID-19 infection. However, functional outcome is comparable in both groups.

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.

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.

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.

Glucose Modifies the Effect of Endovascular Thrombectomy in Patients With Acute Stroke.

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

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.

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.

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.

Administration of Uric Acid in the Emergency Treatment of Acute Ischemic Stroke.

Oxidative stress is one of the main mechanisms implicated in the pathophysiology of inflammatory and neurodegenerative diseases of the central nervous system (CNS). Uric acid (UA) is the end product of purine catabolism in humans, and it is the main endogenous antioxidant in blood. Low circulating UA levels have been associated with an increased prevalence and worse clinical course of several neurodegenerative and inflammatory diseases of the CNS, including Parkinson's disease and multiple sclerosis. Moreover, the exogenous administration of UA exerts robust neuroprotective properties in experimental models of CNS disease, including brain ischemia, spinal cord injury, meningitis, and experimental allergic encephalitis. In experimental brain ischemia, exogenous UA and the thrombolytic agent alteplase exert additive neuroprotective effects when administered in combination. UA is rapidly consumed following acute ischemic stroke, and higher UA levels at stroke admission are associated with a better outcome and reduced infarct growth at follow-up. A recent phase II trial demonstrated that the combined intravenous administration of UA and alteplase is safe and prevents an early decrease of circulating UA levels in acute ischemic stroke patients. Moreover, UA prevents the increase in the circulating levels of the lipid peroxidation marker malondialdehyde and of active matrix metalloproteinase (MMP) 9, a marker of blood-brain barrier disruption. The moderately sized URICOICTUS phase 2b trial showed that the addition of UA to thrombolytic therapy resulted in a 6% absolute increase in the rate of excellent outcome at 90 days compared to placebo. The trial also showed that UA administration resulted in a significant increment of excellent outcome in patients with pretreatment hyperglycemia, in females and in patients with moderate strokes. Overall, the encouraging neuroprotective effects of UA therapy in acute ischemic stroke warrants further investigation in adequately powered clinical trials.

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.