Outcome prediction in large vessel occlusion ischemic stroke with or without endovascular stroke treatment: THRIVE-EVT.

INTRODUCTION: The THRIVE score and the THRIVE-c calculation are validated ischemic stroke outcome prediction tools based on patient variables that are readily available at initial presentation. Randomized controlled trials (RCTs) have demonstrated the benefit of endovascular treatment (EVT) for many patients with large vessel occlusion (LVO), and pooled data from these trials allow for adaptation of the THRIVE-c calculation for use in shared clinical decision making regarding EVT. METHODS: To extend THRIVE-c for use in the context of EVT, we extracted data from the Virtual International Stroke Trials Archive (VISTA) from 7 RCTs of EVT. Models were built in a randomly selected development cohort using logistic regression that included the predictors from THRIVE-c: age, NIH Stroke Scale (NIHSS) score, presence of hypertension, diabetes mellitus, and/or atrial fibrillation, as well as randomization to EVT and, where available, the Alberta Stroke Program Early CT Score (ASPECTS). RESULTS: Good outcome was achieved in 366/787 (46.5%) of subjects randomized to EVT and in 236/795 (29.7%) of subjects randomized to control (P < 0.001), and the improvement in outcome with EVT was seen across age, NIHSS, and THRIVE-c good outcome prediction. Models to predict outcome using THRIVE elements (age, NIHSS, and comorbidities) together with EVT, with or without ASPECTS, had similar performance by ROC analysis in the development and validation cohorts (THRIVE-EVT ROC area under the curve (AUC) = 0.716 in development, 0.727 in validation, P = 0.30; THRIVE-EVT + ASPECTS ROC AUC = 0.718 in development, 0.735 in validation, P = 0.12). CONCLUSION: THRIVE-EVT may be used alongside the original THRIVE-c calculation to improve outcome probability estimation for patients with acute ischemic stroke, including patients with or without LVO, and to model the potential improvement in outcomes with EVT for an individual patient based on variables that are available at initial presentation. Online calculators for THRIVE-c estimation are available at www.thrivescore.org and www.mdcalc.com/thrive-score-for-stroke-outcome.

Underdiagnosis of Isolated Systolic and Isolated Diastolic Hypertension.

Systolic and diastolic hypertension independently predict the risk of adverse cardiovascular events. It remains unclear how systolic pressure, diastolic pressure, and other patient characteristics influence the initial diagnosis of hypertension. Here, we use a cohort of 146,816 adults in a large healthcare system to examine how elevated systolic and/or diastolic blood pressure measurements influence initial diagnosis of hypertension and how other patient characteristics influence the diagnosis. Thirty-four percent of the cohort were diagnosed with hypertension within 1 year. In multivariable logistic regression of the diagnosis of hypertension, controlling for covariates, isolated systolic hypertensive measures (odds ratio [OR] 0.42 [95% confidence interval {CI} 0.41 to 0.43]) and isolated diastolic hypertensive measures (OR 0.32 [95% CI 0.31 to 0.33]) were less likely to lead to hypertension diagnosis when compared with combined hypertensive measures. Higher levels of systolic blood pressure had a greater impact on hypertension diagnosis (OR 1.77 [95% CI 1.75 to 1.79] per Z-score) than did higher levels of diastolic blood pressure (OR 1.34 [95% CI 1.32 to 1.36] per Z-score). Older age, non-white race/ethnicity, and medical comorbidities all predicted the establishment of a diagnosis of hypertension. Isolated systolic and isolated diastolic hypertension are underdiagnosed in clinical practice, and several patient-centered factors also strongly influence whether a diagnosis is made. In conclusion, our findings uncover a care gap that can be closed with increased attention to the independent influence of systolic and diastolic hypertension and the various patient-centered factors that may impact hypertension diagnosis.

Risk of Distal Embolization From tPA (Tissue-Type Plasminogen Activator) Administration Prior to Endovascular Stroke Treatment.

BACKGROUND AND PURPOSE: In large artery occlusion stroke, both intravenous (IV) tPA (tissue-type plasminogen activator) and endovascular stroke treatment (EST) are standard-of-care. It is unknown how often tPA causes distal embolization, in which a procedurally accessible large artery occlusion is converted to a more distal and potentially inaccessible occlusion. METHODS: We analyzed data from a decentralized stroke telemedicine program in an integrated healthcare delivery system covering 21 hospitals, with 2 high-volume EST centers. We captured all cases sent for EST and examined the relationship between IV tPA administration and the rate of distal embolization, the rate of target recanalization (modified Treatment in Cerebral Infarction scale 2b/3), clinical improvement before EST, and short-term and long-term clinical outcomes. RESULTS: Distal embolization before EST was quite common (63/314 [20.1%]) and occurred more often after IV tPA before EST (57/229 [24.9%]) than among those not receiving IV tPA (6/85 [7.1%]; P<0.001). Distal embolization was associated with an inability to attempt EST: after distal embolization, 26/63 (41.3%) could not have attempted EST because of the new clot location, while in cases without distal embolization, only 8/249 (3.2%) were unable to have attempted EST (P<0.001). Among patients who received IV tPA, 13/242 (5.4%) had sufficient symptom improvement that a catheter angiogram was not performed; 6/342 (2.5%) had improvement to within 2 points of their baseline NIHSS. At catheter angiogram, 2/229 (0.9%) of patients who had received tPA had complete recanalization without distal embolization. Both IV tPA and EST recanalization were associated with improved long-term outcome. CONCLUSIONS: IV tPA administration before EST for large artery occlusion is associated with distal embolization, which in turn may reduce the chance that EST can be attempted and recanalization achieved. At the same time, some IV tPA-treated patients show symptomatic improvement and complete recanalization. Because IV tPA is associated with both distal embolization and improved long-term clinical outcome, there is a need for prospective clinical trials testing the net benefit or harm of IV tPA before EST.

Sex-specific Association of Matrix Metalloproteinases with Secondary Injury and Outcomes after Intracerebral Hemorrhage.

OBJECTIVE: Intracerebral hemorrhage affects approximately 2 million individuals per year. While the incidence is roughly equal in men and women, few studies have examined the influence of sex on secondary injury and associated long-term functional outcomes. Matrix metalloproteinases (MMPs) promote vessel rupture and worsen outcomes by potentiating blood-brain barrier breakdown after injury. We hypothesized that different MMP isoform levels would be predictive of injury severity, secondary injury, and long-term functional outcomes in males and females, respectively. METHODS: We examined the levels of MMP isoforms in serum samples from a prospective patient biobank (n = 55). Baseline clinical, radiographic, and laboratory data were also analyzed. RESULTS: We found that MMP-1 (P = .036), MMP-2 (P = .014), MMP-3 (P < .001), and MMP-9 (P = .02) levels gradually increased over time in male patients until 10 DPI. In female patients, we found a different pattern of activation: MMP-8 (P = .02) was the only isoform that significantly changed with time, which reached a peak at 3-5 days postinjury. Several MMP isoforms correlated with markers of secondary injury in female patients (all P < .05). Additionally, serum levels of MMP-3 (P = .011) in males and MMP-10 (P = .044) in females were significantly associated with long-term functional outcomes in a sex-specific manner. CONCLUSIONS: This is the first sex-specific study to examine serum MMP levels and their correlation with clinicoradiologic measures after intracerebral hemorrhage, and identifies potential biomarkers of secondary injury and long-term outcomes in both sexes.

Serum Markers of Blood-Brain Barrier Remodeling and Fibrosis as Predictors of Etiology and Clinicoradiologic Outcome in Intracerebral Hemorrhage.

Background: Intracerebral hemorrhage (ICH) is a stroke subtype associated with high disability and mortality. There is a clinical need for blood-based biomarkers that can aid in diagnosis, risk stratification, and prognostication. Given their role in the pathophysiology of ICH, we hypothesized markers of blood-brain barrier disruption and fibrosis would associate with neurologic deterioration and/or long-term functional outcomes. We also hypothesized these markers may be unique in patients with ICH due to cerebral amyloid angiopathy (CAA) vs. other etiologies. Methods: Seventy-nine patients enrolled in prospective ICH registries at two separate hospitals (the University of Texas Health Science Center at Houston and Hartford Hospital) were included in this study. We assessed initial injury severity and admission variables along with measures of inpatient deterioration (hematoma expansion, perihematomal edema (PHE), and early and delayed neurologic deterioration) and functional outcome [modified Rankin Scale (mRS) score at discharge and 90 days]. Serial biospecimens were obtained at 5 pre-specified timepoints (within 24 h, 1-2, 3-5, 6-8, and 10 days); serum samples were analyzed for fibronectin, all three TGF-ß isoforms, and 7 matrix metalloproteinases (MMPs). Results: In our initial correlation analysis, MMP 10 and 3 were associated with hematoma expansion and early neurologic deterioration, whereas MMP 8 and MMP 1 were associated with PHE and delayed neurologic deterioration (respectively). Subacute levels of MMP 8 (sampled from day 6-10) positively correlated with PHE even after adjusting for multiple comparisons (p = 0.02). Acute levels of MMP 1, TGF-ß1, and TGF-ß3 were predictive of functional outcome, with TGF-ß1 and TGF-ß3 associating with 90 day mRS independent of age, hematoma volume, hemorrhage location, GCS, and IVH [p = 0.02; OR 1.03 (95% CI 1.0-1.05); p = 0.03; OR 3.1 (95% CI 1.1-8.8)]. When evaluated together as a panel, the cytokines distinguished patients with ICH due to CAA vs. ICH due to hypertension (AUC 0.81). Conclusions: Serum levels of fibronectin, TGF-ß, and MMPs may be useful in refining ICH etiology and prognosis. Further large-scale studies are needed to confirm these findings, particularly regarding patients with CAA.

Thrombelastography Suggests Hypercoagulability in Patients with Renal Dysfunction and Intracerebral Hemorrhage.

BACKGROUND: The objective of this study was to quantify coagulopathy using thrombelastography (TEG) in patients with renal dysfunction and intracerebral hemorrhage (ICH). METHODS: We reviewed patients admitted with spontaneous ICH between November 2009 and May 2015. TEG was performed at the time of admission. Creatinine clearance (CCr) was calculated using the Cockroft-Gault equation. Patients were divided into 2 groups based on normal (CCr ≥ 90) or reduced renal function (CCr < 90). Multivariable regression models were conducted to compare the differences of TEG components. RESULTS: A total of 120 patients were included in the analysis. The normal CCr group was younger (56.1 versus 62.3 years, P < .01), was more often male (73.6% versus 53.7%, P = .03), and had higher mean admission hemoglobin (14.2 versus 13.2 mEq/L, P < .01) than the reduced renal function group. The 2 groups were similar with respect to antiplatelet or anticoagulant use, coagulation studies, and baseline ICH volume. Following multivariate analysis, the reduced renal function group was found to have shorter K (1.5 versus 2.2 min, P = 004), increased angle (66 versus 62.2 degrees, P = .04), increased MA (67.3 versus 62.3, P = .02), and increased G (11.3 versus 9.9 dynes/cm2, P = .04) compared with the normal group. Mortality, poor functional outcome (modified Rankin Scale score 4-6), hematoma enlargement, hospital length of stay, and surgical interventions were not different between the 2 groups. CONCLUSIONS: Patients with ICH and reduced CCr display faster clotting rate and increased clot strength, suggesting that patients with renal dysfunction present with a relatively hypercoagulable state based on TEG parameters thought to reflect platelet activity.

Detection of Anterior Circulation Large Artery Occlusion in Ischemic Stroke Using Noninvasive Cerebral Oximetry.

BACKGROUND AND PURPOSE: Large artery occlusion (LAO) in ischemic stroke requires recognition and triage to an endovascular stroke treatment center. Noninvasive LAO detection is needed to improve triage. METHODS: Prospective study to test whether noninvasive cerebral oximetry can detect anterior circulation LAO in acute stroke. Interhemispheric ΔBrSO2 in LAO was compared with controls. RESULTS: In LAO stroke, mean interhemispheric ΔBrSO2 was -8.3±5.8% (n=19), compared with 0.4±5.8% in small artery stroke (n=17), 0.4±6.0% in hemorrhagic stroke (n=14), and 0.2±7.5% in subjects without stroke (n=19) (P<0.001). Endovascular stroke treatment reduced the ΔBrSO2 in most LAO subjects (16/19). Discrimination of LAO at a -3% ΔBrSO2 cut had 84% sensitivity and 70% specificity. Addition of the G-FAST clinical score (gaze-face-arm-speech- time) to the BrSO2 measure had 84% sensitivity and 90% specificity. CONCLUSIONS: Noninvasive cerebral oximetry may help detect LAO in ischemic stroke, particularly when combined with a simple clinical scoring system.

Soluble CD163 in intracerebral hemorrhage: biomarker for perihematomal edema.

Objective: Patients with intracerebral hemorrhage (ICH) may elaborate varying degrees of perihematomal edema (PHE), requiring closer monitoring and a higher intensity of treatment. Here, we explore whether the soluble form of CD163, a scavenger receptor responsible for hemoglobin sequestration, can serve as a prognostic biomarker of PHE development and poor outcome after ICH. Methods: Our study cohort was comprised of 51 primary age- and sex-matched ICH patients with moderate-sized, hypertensive deep hemorrhages. Patients were part of a prospective ICH registry cataloguing admission data along with functional outcomes. We measured sCD163 levels in serial serum and cerebrospinal fluid (CSF) samples obtained at prespecified timepoints. Descriptive statistics, including a generalized estimating equation for longitudinal data, were used to analyze sCD163 in relation to ICH outcomes. Results: Acute serum sCD163 (<48 h postictus) was significantly elevated in ICH patients compared to both acute neurological event controls (P = <0.001) and healthy controls (P = 0.003). As predicted, acute serum sCD163 levels were significantly associated with both hematoma volume expansion (P = 0.009) and PHE expansion (P = 0.002). Further examination determined that patients with high PHE expansion had poorer modified Rankin Scale scores at discharge (P = 0.024), and circulating sCD163 levels were found to be significantly lower in patients with high-level PHE expansion. Interpretation: Acute sCD163 levels may be a useful biomarker for the acute identification of patients at risk for hematoma expansion, perihematomal edema expansion and poorer short-term outcomes.

Role of Interleukin-10 in Acute Brain Injuries.

Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation.

Antiplatelet therapy for the prevention of peri-coiling thromboembolism in high-risk patients with ruptured intracranial aneurysms.

OBJECTIVE The most frequent procedural complication of the endovascular treatment of intracranial aneurysms is a thromboembolic event (TEE); in a subset of patients, such events will cause permanent neurological disability. In patients with unruptured aneurysms, increasing evidence supports the use of periprocedural antiplatelet therapy to prevent TEEs. The object of this study was to evaluate whether patients with ruptured aneurysms and subarachnoid hemorrhage would also benefit from periprocedural antiplatelet therapy. METHODS The authors reviewed a prospective registry of 169 patients with endovascularly treated intracranial aneurysms to delineate angiographic features associated with periprocedural TEEs. They then performed a controlled before-and-after study in 79 patients with ruptured aneurysms who were deemed to be at high risk for TEEs (for example, patients with at least 1 angiographic feature associated with TEEs) to evaluate whether selective aspirin administration would reduce the rate of periprocedural thromboembolism without increasing major hemorrhagic complications. RESULTS Six angiographic features were associated with periprocedural TEEs in the study cohort: wide aneurysm neck, coil or loop protrusion, small parent artery diameter, an incorporated branch, intraprocedural thrombus formation, and intracranial parent vessel atherosclerosis. Aspirin administration to high-risk patients significantly decreased the rate of periprocedural TEEs, from 53.8% in the control group to 10.6% in the aspirin-treated group (p = 0.001). The reduction in TEEs in the aspirin-treated group continued to be statistically significant even when adjusted for age, sex, cardiovascular risk factors (smoking, diabetes, hypertension, dyslipidemia, coronary artery disease), and factors associated with TEEs in other large studies (wide aneurysm neck, aneurysm size ≥ 10 mm), with an adjusted OR of 0.16 (95% CI 0.03-0.8). There were no major systemic hemorrhagic complications, and aspirin did not increase the risk of aneurysm rebleeding, symptomatic intracranial hemorrhage, or major external ventricular drain (EVD)-associated hemorrhage (p = 0.3), though there was an increase in asymptomatic, minor (< 1 cm) EVD-associated hemorrhage in the aspirin-treated group (p = 0.02). CONCLUSIONS The study findings suggest that for ruptured aneurysm patients with high-risk features, antiplatelet therapy can significantly reduce the rate of periprocedural TEE without increasing major systemic or intracranial hemorrhages.

Treatment Strategies to Attenuate Perihematomal Edema in Patients With Intracerebral Hemorrhage.

Spontaneous intracerebral hemorrhage (SICH) continues to be a significant cause of neurologic morbidity and mortality throughout the world. Although recent advances in the treatment of SICH have significantly decreased mortality rates, functional recovery has not been dramatically improved by any intervention to date. There are 2 predominant mechanisms of brain injury from intracerebral hemorrhage: mechanical injury from the primary hematoma (including growth of that hematoma), and secondary injury from perihematomal inflammation. For instance, in the hours to weeks after SICH as the hematoma is being degraded, thrombin and iron are released and can result in neurotoxicity, free radical damage, dysregulated coagulation, and harmful inflammatory cascades; this can clinically and radiologically manifest as perihematomal edema (PHE). PHE can contribute to mass effect, cause acute neurologic deterioration in patients, and has even been associated with poor long-term functional outcomes. PHE therefore lends itself to being a potential therapeutic target. In this article, we will review 1) the pathogenesis and time course of the development of PHE, and 2) the clinical series and trials exploring various methods, with a focus on minimally invasive surgical techniques, to reduce PHE and minimize secondary brain injury. Promising areas of continued research also will be discussed.

Efficacy of a Self-Expandable Porous Stent as the Sole Curative Treatment for Extracranial Carotid Pseudoaneurysms.

OBJECTIVE: Extracranial carotid pseudoaneurysms are uncommon vascular lesions. Even with conservative management complications can happen, such as delayed cerebral embolization or symptoms due to flow limitation. Although endovascular therapy can be curative, literature demonstrating a preferred technique is scant. Our goal was to evaluate the use of 1 technique only-the deployment of overlapping self-expandable porous stents-to treat a series of extracranial carotid pseudoaneurysms. METHODS: From 2008 to 2014, 14 consecutive cases of symptomatic extracranial carotid pseudoaneurysms were managed with single or multilayer porous stents at our institution. Each patient underwent a standardized angiographic follow-up at 6 months. Twelve patients also received a follow-up computed tomography angiogram at 12 months, and yearly thereafter (median radiographic follow-up, 38 months). The total clinical follow-up period ranged between 6 and 69 months (median, 46 months). RESULTS: In our series, each of the extracranial carotid pseudoaneurysms appeared to be the result of carotid artery dissection with associated carotid stenosis at the origin of every pseudoaneurysm. Endovascular treatment consisted of 1-3 layers of self-expandable porous stents placed without balloon angioplasty. Immediately after stenting angiographic images were notable for stagnant opacification of the pseudoaneurysm through the stent(s). All pseudoaneurysms were completely obliterated by the 6-month follow-up angiogram and remained so throughout the radiographic follow-up period. Complications were minimal, consisting of 1 patient developing a mild Horner's syndrome after treatment that resolved during clinical follow-up. CONCLUSIONS: Extracranial carotid pseudoaneurysms can be successfully obliterated with the use of porous, self-expandable stents.

Frequency and Risk Factors for Cerebral Arterial Disease in a HIV/AIDS Neuroimaging Cohort.

BACKGROUND: Infection with HIV predisposes patients to a myriad of neurologic disorders, including cerebrovascular disease. The pathophysiology is likely multifactorial, with proposed mechanisms including infectious vasculitis, HIV-induced endothelial dysfunction and adverse effects of combination antiretroviral therapy (cART). Epidemiologic data on clinically evident cerebral vasculopathy in HIV-infected adults is scarce, even though stroke hospitalizations are rising in this patient population. METHODS: A total of 6,298 HIV-infected adults (San Francisco General Hospital, 2000-2013) were screened to generate a cohort of patients with dedicated neuroimaging of the intra- and extracranial cerebral vasculature. We extracted information regarding the extent of HIV disease (including serial viral load and CD4 counts), cardiovascular disease risk factors and exposure to cART (cross-referenced with pharmacy records) and performed multivariate logistic regression analysis to identify predictors of vasculopathy. RESULTS: Of 144 patients, 55 patients (38.2%) had radiographic evidence of cerebral vasculopathy. Twenty (13.9%) had a vasculopathy characterized by vessel dolichoectasia and intracranial aneurysm formation. Thirty-five patients (24.3%) had intra- and or extracranial stenosis/occlusion. cART use (OR 2.27, 95% CI 1.03-5) and tobacco abuse (OR 2.35, 95% CI 1.04-5.25) were independently associated with the development of any vasculopathy, whereas cART use was also an independent risk factor for the stenosis/occlusion subtype specifically (OR 2.87, 95% CI 1.11-7.45). CONCLUSIONS: There was a high frequency of cerebral arterial disease in this neuroimaging cohort of HIV/AIDS patients. A history of cART use and a history of tobacco abuse were independent risk factors for vasculopathy, though these findings should be confirmed with large-scale prospective studies.

Quantification of Cerebral Edema After Subarachnoid Hemorrhage.

BACKGROUND: Global cerebral edema (GCE) is a manifestation of early brain injury (EBI) after subarachnoid hemorrhage (SAH) and is an independent risk factor for poor outcome. The lack of a quantitative method to measure GCE limits the study of its pathophysiology. The goal of this study is to develop a quantitative surrogate marker that represents GCE after SAH. METHODS: Patients with spontaneous SAH were enrolled into a prospective observational database. Initial CT scans were graded for GCE using established qualitative criteria. Selective sulcal volume (SSV) was defined as total mL of sulcal volumes on axial CT slices above the most cranial section of the lateral ventricles to the last visible section. Using a semiautomatic threshold approach, sulcal regions were traced out with manual adjustments when necessary. The volume of sulci in each slice was calculated and multiplied by the slice thickness and number of slices to calculate the SSV. All volumetric analysis was performed using Medical Image Processing, Analysis and Visualization Version 7.0.1 (MIPAV). RESULTS: A total of 109 subjects were included in our analysis. Mean selective sulcal volumes (SSV) differed between subjects with and without GCE 4.5 and 21.2 mL (P < 0.001). When separated into quartiles, the odds of qualitative GCE increases as SSV decreases. Compared to the highest SSV quartile, smaller SSV was associated with worse clinical outcomes. CONCLUSION: GCE can be quantified using volumetric analysis of SSV measurements on routine CT scans. Smaller SSV on admission is predictive of worse clinical outcomes. SSV may be an important marker of EBI after SAH.

Neuronal Interleukin-4 as a Modulator of Microglial Pathways and Ischemic Brain Damage.

After ischemic stroke, various damage-associated molecules are released from the ischemic core and diffuse to the ischemic penumbra, activating microglia and promoting proinflammatory responses that may cause damage to the local tissue. Here we demonstrate using in vivo and in vitro models that, during sublethal ischemia, local neurons rapidly produce interleukin-4 (IL-4), a cytokine with potent anti-inflammatory properties. One such anti-inflammatory property includes its ability to polarize macrophages away from a proinflammatory M1 phenotype to a "healing" M2 phenotype. Using an IL-4 reporter mouse, we demonstrated that IL-4 expression was induced preferentially in neurons in the ischemic penumbra but not in the ischemic core or in brain regions that were spared from ischemia. When added to cultured microglia, IL-4 was able to induce expression of genes typifying the M2 phenotype and peroxisome proliferator activated receptor γ (PPARγ) activation. IL-4 also enhanced expression of the IL-4 receptor on microglia, facilitating a "feedforward" increase in (1) their expression of trophic factors and (2) PPARγ-dependent phagocytosis of apoptotic neurons. Parenteral administration of IL-4 resulted in augmented brain expression of M2- and PPARγ-related genes. Furthermore, IL-4 and PPARγ agonist administration improved functional recovery in a clinically relevant mouse stroke model, even if administered 24 h after the onset of ischemia. We propose that IL-4 is secreted by ischemic neurons as an endogenous defense mechanism, playing a vital role in the regulation of brain cleanup and repair after stroke. Modulation of IL-4 and its associated pathways could represent a potential target for ischemic stroke treatment. SIGNIFICANCE STATEMENT: Depending on the activation signal, microglia/macrophages (MΦ) can behave as "healing" (M2) or "harmful" (M1). In response to ischemia, damaged/necrotic brain cells discharge factors that polarize MΦ to a M1-like phenotype. This polarization emerges early after stroke and persists for days to weeks, driving secondary brain injury via proinflammatory mediators and oxidative damage. Our study demonstrates that, to offset this M1-like polarization process, sublethally ischemic neurons may instead secrete a potent M2 polarizing cytokine, interleukin-4 (IL-4). In the presence of IL-4 (including when IL-4 is administered exogenously), MΦ become more effective in the cleanup of ischemic debris and produce trophic factors that may promote brain repair. We propose that IL-4 could represent a potential target for ischemic stroke treatment/recovery.

Cleaning up after ICH: the role of Nrf2 in modulating microglia function and hematoma clearance.

As a consequence of intracerebral hemorrhage (ICH), blood components enter brain parenchyma causing progressive damage to the surrounding brain. Unless hematoma is cleared, the reservoirs of blood continue to inflict injury to neurovascular structures and blunt the brain repair processes. Microglia/macrophages (MMΦ) represent the primary phagocytic system that mediates the cleanup of hematoma. Thus, the efficacy of phagocytic function by MMΦ is an essential step in limiting ICH-mediated damage. Using primary microglia to model red blood cell (main component of hematoma) clearance, we studied the role of transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), a master-regulator of antioxidative defense, in the hematoma clearance process. We showed that in cultured microglia, activators of Nrf2 (i) induce antioxidative defense components, (ii) reduce peroxide formation, (iii) up-regulate phagocytosis-mediating scavenger receptor CD36, and (iv) enhance red blood cells (RBC) phagocytosis. Through inhibiting Nrf2 or CD36 in microglia, by DNA decoy or neutralizing antibody, we documented the important role of Nrf2 and CD36 in RBC phagocytosis. Using autologous blood injection ICH model to measure hematoma resolution, we showed that Nrf2 activator, sulforaphane, injected to animals after the onset of ICH, induced CD36 expression in ICH-affected brain and improved hematoma clearance in rats and wild-type mice, but expectedly not in Nrf2 knockout (KO) mice. Normal hematoma clearance was impaired in Nrf2-KO mice. Our experiments suggest that Nrf2 in microglia play an important role in augmenting the antioxidative capacity, phagocytosis, and hematoma clearance after ICH.

Advances in the critical care management of ischemic stroke.

Given recent advances in diagnostic modalities and revascularization capabilities, clinicians are not only able to rapidly and accurately identify acute ischemic stroke, but may also be able to aggressively intervene to minimize the extent of infarction. In those cases where revascularization cannot occur and/or the extent of infarction is large, there are multiple strategies to prevent secondary decompensation as the stroke evolves, for instance, if malignant cerebral edema should develop. In this paper, we will review the indications for specialized ICU care for an ischemic stroke patient, the treatment principles, and strategies employed by neurointensivists to minimize secondary neuronal injury, the literature in support of such strategies (and the questions to be addressed by future studies), all with the ultimate goal of increasing the likelihood of favorable neurologic outcomes in our ischemic stroke population.

The safety of intravenous thrombolysis for ischemic stroke in patients with pre-existing cerebral aneurysms: a case series and review of the literature.

BACKGROUND AND PURPOSE: Unruptured cerebral aneurysms are currently considered a contraindication to intravenous tissue-type plasminogen activator for acute ischemic stroke. This is due to a theoretical increase in the risk of hemorrhage from aneurysm rupture, although it is unknown whether this risk is a significant one. We sought to determine the safety of intravenous tissue-type plasminogen activator administration in a cohort of patients with pre-existing aneurysms. METHODS: We reviewed the medical records of patients treated for acute ischemic stroke with intravenous tissue-type plasminogen activator during an 11-year period at 2 academic medical centers. We identified a subset of patients with unruptured cerebral aneurysms present on prethrombolysis vascular imaging. Our outcomes of interest were any intracranial hemorrhage, symptomatic intracranial hemorrhage, and subarachnoid hemorrhage. Fisher exact test was used to compare the rates of hemorrhage among patients with and without aneurysms. RESULTS: We identified 236 eligible patients, of whom 22 had unruptured cerebral aneurysms. The rate of intracranial hemorrhage among patients with aneurysms (14%; 95% CI, 3%-35%) did not significantly differ from the rate among patients without aneurysms (19%; 95% CI, 14%-25%). None of the patients with aneurysms developed symptomatic intracranial hemorrhage (0%; 95% CI, 0%-15%) compared with 10 of 214 patients without aneurysms (5%; 95% CI, 2%-8%). Similar proportions of patients developed subarachnoid hemorrhage (5%; 95% CI, 0%-23% versus 6%; 95% CI, 3%-10%). CONCLUSIONS: Our findings suggest that intravenous tissue-type plasminogen activator for acute ischemic stroke is safe to administer in patients with pre-existing cerebral aneurysms because the risk of aneurysm rupture and symptomatic intracranial hemorrhage is low.

Isofagomine increases lysosomal delivery of exogenous glucocerebrosidase.

Intravenous enzyme replacement therapy (ERT) with purified glucocerebrosidase (GLA) leads to significant improvement of the clinical manifestations in patients with Type 1 Gaucher disease. However, the high doses required, slow response and inability to recover most of the infused enzyme in the target tissues may be attributed to losses occurring during transit en route to the lysosome. Preincubation of GLA with isofagomine (IFG), a slow-binding inhibitor, significantly increased stability of the enzyme to heat, neutral pH and denaturing agents in vitro. Preincubation of GLA with isofagomine prior to uptake by cultured cells results in increased intracellular enzyme activity accompanied by an increase in enzyme protein suggesting that reduced denaturation of GLA in the presence of isofagomine leads to a decrease in the degradation of the enzyme after internalization. Preincubation of GLA with slow-binding inhibitors before infusion may improve the effectiveness of ERT for Gaucher disease.