Shorter Door-to-Needle Times Are Associated With Better Outcomes After Intravenous Thrombolytic Therapy and Endovascular Thrombectomy for Acute Ischemic Stroke.

BACKGROUND: Existing data and clinical trials could not determine whether faster intravenous thrombolytic therapy (IVT) translates into better long-term functional outcomes after acute ischemic stroke among those treated with endovascular thrombectomy (EVT). Patient-level national data can provide the required large population to study the associations between earlier IVT, versus later, with longitudinal functional outcomes and mortality in patients receiving IVT+EVT combined treatment. METHODS: This cohort study included older US patients (age ≥65 years) who received IVT within 4.5 hours or EVT within 7 hours after acute ischemic stroke using the linked 2015 to 2018 Get With The Guidelines-Stroke and Medicare database (38 913 treated with IVT only and 3946 with IVT+EVT). Primary outcome was home time, a patient-prioritized functional outcome. Secondary outcomes included all-cause mortality in 1 year. Multivariate logistic regression and Cox proportional hazards models were used to evaluate the associations between door-to-needle (DTN) times and outcomes. RESULTS: Among patients treated with IVT+EVT, after adjusting for patient and hospital factors, including onset-to-EVT times, each 15-minute increase in DTN times for IVT was associated with significantly higher odds of zero home time in a year (never discharged to home) (adjusted odds ratio, 1.12 [95% CI, 1.06-1.19]), less home time among those discharged to home (adjusted odds ratio, 0.93 per 1% of 365 days [95% CI, 0.89-0.98]), and higher all-cause mortality (adjusted hazard ratio, 1.07 [95% CI, 1.02-1.11]). These associations were also statistically significant among patients treated with IVT but at a modest degree (adjusted odds ratio, 1.04 for zero home time, 0.96 per 1% home time for those discharged to home, and adjusted hazard ratio 1.03 for mortality). In the secondary analysis where the IVT+EVT group was compared with 3704 patients treated with EVT only, shorter DTN times (≤60, 45, and 30 minutes) achieved incrementally more home time in a year, and more modified Rankin Scale 0 to 2 at discharge (22.3%, 23.4%, and 25.0%, respectively) versus EVT only (16.4%, P<0.001 for each). The benefit dissipated with DTN>60 minutes. CONCLUSIONS: Among older patients with stroke treated with either IVT only or IVT+EVT, shorter DTN times are associated with better long-term functional outcomes and lower mortality. These findings support further efforts to accelerate thrombolytic administration in all eligible patients, including EVT candidates.

The Association of Socioeconomic Status and Discharge Destination with 30-Day Readmission after Ischemic Stroke.

OBJECTIVES: This study aimed to explore the association of socioeconomic status and discharge destination with 30-day readmission after ischemic stroke. MATERIALS AND METHODS: We examined 30-day all-cause readmission among patients hospitalized for ischemic stroke in states of Arkansas, Iowa, and Wisconsin in 2016 and 2017 and New York in 2016 using Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases. RESULTS: Among the 52301 patients included, 51.1% were female. The 30-day readmission rates were 10.2%, 8.2%, 9.3%, 10.4%, 11.6%, and 11.2% for age group 18-34, 35-44, 45-54, 55-64, 65-74, and ≥75 years, respectively (p<0.001). In Generalized Estimating Equation analysis, patients with Medicare and Medicaid insurance were more likely to be readmitted, compared with private insurance, (adjusted Odds Ratio [aOR] 1.37, 95% CI 1.23-1.53; and aOR 1.26, 95% CI 1.09-1.45, respectively). Patients in the bottom quartile of zip code level median household income had higher 30-day readmission rate (12.4%) than those in the 2nd, 3rd and 4th quartile (10.3%, 10.1%, and 10.7%, respectively, p<0.001). Compared with those discharged home with self-care which had the lowest readmission rate (8.4%), patients who left against medical advice had the highest readmission rate (18.6%; aOR 2.23, 95% CI 1.75-2.83), followed by rehabilitation and skilled nursing facilities (13.2%; aOR 1.33, 95% CI 1.22-1.46), and home with home health care (11.3%, aOR 1.18, 95% CI 1.08-1.28). CONCLUSIONS: Socioeconomic status and discharged destination affect readmission after stroke. These results provide evidence to inform vulnerable patient population as targets for readmission prevention.

Association Between Thrombolytic Door-to-Needle Time and 1-Year Mortality and Readmission in Patients With Acute Ischemic Stroke.

Importance: Earlier administration of intravenous tissue plasminogen activator (tPA) in acute ischemic stroke is associated with reduced mortality by the time of hospital discharge and better functional outcomes at 3 months. However, it remains unclear whether shorter door-to-needle times translate into better long-term outcomes. Objective: To examine whether shorter door-to-needle times with intravenous tPA for acute ischemic stroke are associated with improved long-term outcomes. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries aged 65 years or older who were treated for acute ischemic stroke with intravenous tPA within 4.5 hours from the time they were last known to be well at Get With The Guidelines-Stroke participating hospitals between January 1, 2006, and December 31, 2016, with 1-year follow-up through December 31, 2017. Exposures: Door-to-needle times for intravenous tPA. Main Outcomes and Measures: The primary outcomes were 1-year all-cause mortality, all-cause readmission, and the composite of all-cause mortality or readmission. Results: Among the 61 426 patients treated with tPA within 4.5 hours, the median age was 80 years and 43.5% were male. The median door-to-needle time was 65 minutes (interquartile range, 49-88 minutes). The 48 666 patients (79.2%) who were treated with tPA and had door-to-needle times of longer than 45 minutes, compared with those treated within 45 minutes, had significantly higher all-cause mortality (35.0% vs 30.8%, respectively; adjusted HR, 1.13 [95% CI, 1.09-1.18]), higher all-cause readmission (40.8% vs 38.4%; adjusted HR, 1.08 [95% CI, 1.05-1.12]), and higher all-cause mortality or readmission (56.0% vs 52.1%; adjusted HR, 1.09 [95% CI, 1.06-1.12]). The 34 367 patients (55.9%) who were treated with tPA and had door-to-needle times of longer than 60 minutes, compared with those treated within 60 minutes, had significantly higher all-cause mortality (35.8% vs 32.1%, respectively; adjusted hazard ratio [HR], 1.11 [95% CI, 1.07-1.14]), higher all-cause readmission (41.3% vs 39.1%; adjusted HR, 1.07 [95% CI, 1.04-1.10]), and higher all-cause mortality or readmission (56.8% vs 53.1%; adjusted HR, 1.08 [95% CI, 1.05-1.10]). Every 15-minute increase in door-to-needle times was significantly associated with higher all-cause mortality (adjusted HR, 1.04 [95% CI, 1.02-1.05]) within 90 minutes after hospital arrival, but not after 90 minutes (adjusted HR, 1.01 [95% CI, 0.99-1.03]), higher all-cause readmission (adjusted HR, 1.02; 95% CI, 1.01-1.03), and higher all-cause mortality or readmission (adjusted HR, 1.02 [95% CI, 1.01-1.03]). Conclusions and Relevance: Among patients aged 65 years or older with acute ischemic stroke who were treated with tissue plasminogen activator, shorter door-to-needle times were associated with lower all-cause mortality and lower all-cause readmission at 1 year. These findings support efforts to shorten time to thrombolytic therapy.

Case Fatality Decline from 2009 to 2013 among Medicare Beneficiaries with Ischemic Stroke.

OBJECTIVES: This study aimed to examine the temporal trend of 30-day and 1-year mortality among U.S. Medicare beneficiaries who were hospitalized for ischemic stroke, with special focus on the mortality among subgroup of patients in relation to acute reperfusion therapies including intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT). METHODS: We evaluated Medicare fee-for-service beneficiaries age 65 years or older who were hospitalized for ischemic stroke between 2009 and 2013. Multivariable Cox proportional hazards models were generated to analyze the trend of adjusted mortality. RESULTS: A total of 1,070,574 patients were included in the study. The 30-day mortality did not change among patients who were not treated with IVT or EVT. It decreased by 13% among patients treated with IVT but not EVT (HR = .87, 95% CI .82-.92), 25% among patients treated with EVT but not IVT (HR = .75, 95% CI .59-.95), and 37% among patients treated with both IVT and EVT (HR = .63, 95% CI .52-.77). One-year mortality decreased by 19% among patients who were not treated with IVT nor EVT (HR = .81, 95% CI .80-.83), 22% among those treated with IVT but not EVT (HR = .78, 95% CI .75-.81), 33% among those treated with EVT but not IVT (HR = .67, 95% CI .55-.81), and 38% among those treated with both IVT and EVT (HR = .62, 95% CI .53-.73). CONCLUSIONS: From 2009 to 2013, the 30-day stroke case fatality decreased only among the patients received reperfusion therapy. The 1-year mortality declined among all the stroke patients, with the greatest decline among those treated with both IVT and EVT.

The Patterns and Outcomes of Inter-Hospital Transfer Among Medicare Patients with Ischemic Stroke.

BACKGROUND AND PURPOSE: Inter-hospital transfer for ischemic stroke is an essential part of stroke system of care. This study aimed to understand the national patterns and outcomes of ischemic stroke transfer. METHODS AND RESULTS: This retrospective study examined Medicare beneficiaries aged ≥65 years undergoing inter-hospital transfer for ischemic stroke in 2012. Cox proportional hazards model was used to compare 30-day and one-year mortality between transferred patients and direct admissions from the emergency department (ED admissions). Among 312,367 ischemic stroke admissions, 5.7% underwent inter-hospital transfer. Using this value as cut-off, the hospitals were classified into receiving (n = 411), sending (n = 559), and low-transfer (n = 1863) hospitals. Receiving hospitals were larger than low-transfer and sending hospitals as demonstrated by the median bed number (371, 189, and 88, respectively, p < 0.001); more frequently to be certified stroke centers (75%, 47%, and 16%, respectively, p < 0.001); and less commonly located in the rural area (2%, 7%, and 24%, respectively, p < 0.001). For receiving hospitals, transfer-in patients and ED admissions had comparable mortality at 30 days (10% vs 10%; adjusted HR [aHR]=1.07; 95% CI, 0.99-1.14) and 1 year (23% vs 24%; aHR=1.03; 95% CI, 0.99-1.08). For sending hospitals, transfer-out patients, compared to ED admissions, had higher mortality at 30 days (14% vs 11%; aHR=1.63; 95% CI, 1.39-1.91) and 1 year (30% vs 27%; aHR=1.33; 95% CI, 1.20-1.48). For low-transfer hospitals, overall transfer-in and transfer-out patients, compared to ED admissions, had higher mortality at 30 days (13% vs 10%; aHR=1.46; 95% CI, 1.33-1.60) and 1 year (28% vs 25%; aHR=1.27; 95% CI, 1.19-1.36). CONCLUSIONS: Hospitals in the US, based on their transfer patterns, could be classified into 3 groups that shared distinct characteristics including hospital size, rural vs urban location, and stroke certification. Transferred patients at sending and low-transfer hospitals had worse outcomes than their ED admission counterpart.

Impact of Stroke Center Certification on Mortality After Ischemic Stroke: The Medicare Cohort From 2009 to 2013.

BACKGROUND AND PURPOSE: An increasing number of hospitals have been certified as primary stroke centers (PSCs). It remains unknown whether the action toward PSC certification has improved the outcome of stroke care. This study aimed to understand whether PSC certification reduced stroke mortality. METHODS: We examined Medicare fee-for-service beneficiaries aged ≥65 years who were hospitalized between 2009 and 2013 for ischemic stroke. Hospitals were classified into 3 groups: new PSCs, the hospitals that received initial PSC certification between 2009 and 2013 (n=634); existing PSCs, the PSCs certified before 2009 (n=785); and non-SCs, the hospitals that have never been certified as PSCs (n=2640). Multivariate logistic regression and Cox proportional hazards model was used to compare the mortality among the 3 groups. RESULTS: Existing PSCs were significantly larger than new PSCs as reflected by total number of beds and annual stroke admission (P<0.0001). Compared with existing PSCs, new PSCs had lower in-hospital (odds ratio, 0.862; 95% confidence interval [CI], 0.817-0.910) and 30-day mortality (hazard ratio [HR], 0.981; 95% CI, 0.968-0.993), after adjusting for patient demographics and comorbidities. Compared with non-SCs, new PSCs had lower adjusted in-hospital (odds ratio, 0.894; 95% CI, 0.848-0.943), 30-day (HR, 0.904; 95% CI, 0.892-0.917), and 1-year mortality (HR, 0.907; 95% CI, 0.898-0.915). Existing PSCs had lower adjusted 30-day (HR, 0.922; 95% CI, 0.911-0.933) and 1-year mortality (HR, 0.900; 95% CI, 0.892-0.907) than non-SCs. CONCLUSIONS: Obtaining stroke certification may reduce stroke mortality and overcome the disadvantage of being smaller hospitals. Further study of other outcome measures will be useful to improve stroke system of care.

Differences in Acute Ischemic Stroke Quality of Care and Outcomes by Primary Stroke Center Certification Organization.

BACKGROUND AND PURPOSE: Primary stroke center (PSC) certification was established to identify hospitals providing evidence-based care for stroke patients. The numbers of PSCs certified by Joint Commission (JC), Healthcare Facilities Accreditation Program, Det Norske Veritas, and State-based agencies have significantly increased in the past decade. This study aimed to evaluate whether PSCs certified by different organizations have similar quality of care and in-hospital outcomes. METHODS: The study population consisted of acute ischemic stroke patients who were admitted to PSCs participating in Get With The Guidelines-Stroke between January 1, 2010, and December 31, 2012. Measures of care quality and outcomes were compared among the 4 different PSC certifications. RESULTS: A total of 477 297 acute ischemic stroke admissions were identified from 977 certified PSCs (73.8% JC, 3.7% Det Norske Veritas, 1.2% Healthcare Facilities Accreditation Program, and 21.3% State-based). Composite care quality was generally similar among the 4 groups of hospitals, although State-based PSCs underperformed JC PSCs in a few key measures, including intravenous tissue-type plasminogen activator use. The rates of tissue-type plasminogen activator use were higher in JC and Det Norske Veritas (9.0% and 9.8%) and lower in State and Healthcare Facilities Accreditation Program certified hospitals (7.1% and 5.9%) (P<0.0001). Door-to-needle times were significantly longer in Healthcare Facilities Accreditation Program hospitals. State PSCs had higher in-hospital risk-adjusted mortality (odds ratio 1.23, 95% confidence intervals 1.07-1.41) compared with JC PSCs. CONCLUSIONS: Among Get With The Guidelines-Stroke hospitals with PSC certification, acute ischemic stroke quality of care and outcomes may differ according to which organization provided certification. These findings may have important implications for further improving systems of care.

Stroke Legislation Impacts Distribution of Certified Stroke Centers in the United States.

BACKGROUND AND PURPOSE: The number of certified primary stroke centers (PSCs) have increased dramatically during the past decade in the United States We aimed to understand the factors affecting PSC distribution in the United States, including the impact of state stroke legislation. METHODS: PSCs certified by national organization or state until December 2013 were searched from available databases. The proportion of PSC among short-term general hospitals in each state was calculated and factors affecting its distribution were analyzed. RESULTS: By the end of 2013, the proportion of PSC varied from 4% to 100% among the 50 states and District of Columbia. The 18 states that had legislation in designating stroke centers and regulating stroke triage had higher PSC percentages (median, 43%; range, 13%-100%) than the remaining states (median, 13%; range, 4%-75%; P<0.001). State stroke legislation, urbanization, state economic output, and larger hospital size independently increased the likelihood of a hospital to be stroke certified. From 2009 to 2013, states with stroke legislation had greater increase of PSC percentages when compared with the states without legislation (median increase, 16% versus 6%; P=0.0067). Among the 1505 stroke centers, 74% were certified by the Joint Commission, 20% by state, and 6% by other organizations. Stroke centers certified only by state were smaller in size by hospital bed count compared with those certified by the Joint Commission (P<0.001). CONCLUSIONS: State stroke legislation, a generalizable intervention, increased the number of certified stroke centers in the United States, potentially improving accessibility of standardized care for patients with acute ischemic stroke.

Predictors of infarct growth after endovascular therapy for acute ischemic stroke.

BACKGROUND: Intra-arterial (IA) thrombectomy for acute ischemic stroke has an excellent recanalization rate but variable outcomes. The core infarct also grows at a variable rate despite recanalization. We aim to study the factors that are associated with infarct growth after IA therapy. METHODS: We reviewed the hyperacute ischemic stroke imaging database at Cleveland Clinic for those undergoing endovascular thrombectomy of anterior circulation from 2009 to 2012. Patients with both pretreatment and follow-up magnetic resonance imaging were included. Seventy-six patients were stratified into quartiles by infarct volume growth from initial to follow-up diffusion-weighted imaging (DWI) measure by a region of interest demarcation. RESULTS: The median infarct growth of each quartile was .6 cm(3) (no-growth group), 13.8, 37, and 160.2 cm(3) (large-growth group). Pretreatment stroke severity was comparable among groups. Compared with the no-growth group, the large-growth group had larger initial infarct defined by computed tomography (CT) Alberta Stroke Program Early CT score (median 10 versus 8, P = .032) and DWI volume (mean 13.8 versus 29.2 cm(3), P = .034), lack of full collateral vessels on CT angiography (36.8% versus 0%, P = .003), and a lower recanalization rate (thrombolysis in cerebral infarction ≥2b, P = .044). The increase in infarct growth is associated with decrease in favorable outcomes defined by a modified Rankin Scale score of 0-2 at 30 days: 57.9%, 42.1%, 21.1%, and 5.3%, respectively (P < .001). DWI reversal was observed in 11 of 76 patients, translating to 82% favorable outcome. CONCLUSIONS: Infarct evolution after endovascular thrombectomy is associated with an outcome. DWI reversal or no growth translated to a favorable outcome. Small initial ischemic core, good collateral support, and better recanalization grades predict the smaller infarct growth and favorable outcome after endovascular thrombectomy.

Addition of hyperacute MRI AIDS in patient selection, decreasing the use of endovascular stroke therapy.

BACKGROUND AND PURPOSE: The failure of recent trials to show the effectiveness of acute endovascular stroke therapy (EST) may be because of inadequate patient selection. We implemented a protocol to perform pretreatment MRI on patients with large-vessel occlusion eligible for EST to aid in patient selection. METHODS: We retrospectively identified patients with large-vessel occlusion considered for EST from January 2008 to August 2012. Patients before April 30, 2010, were selected based on computed tomography/computed tomography angiography (prehyperacute protocol), whereas patients on or after April 30, 2010, were selected based on computed tomography/computed tomography angiography and MRI (hyperacute MRI protocol). Demographic, clinical features, and outcomes were collected. Univariate and multivariate analyses were performed. RESULTS: We identified 267 patients: 88 patients in prehyperacute MRI period and 179 in hyperacute MRI period. Fewer patients evaluated in the hyperacute MRI period received EST (85 of 88, 96.6% versus 92 of 179, 51.7%; P<0.05). The hyperacute-MRI group had a more favorable outcome of a modified Rankin scale 0 to 2 at 30 days as a group (6 of 66, 9.1% versus 33 of 140, 23.6%; P=0.01), and when taken for EST (6 of 63, 9.5% versus 17 of 71, 23.9%; P=0.03). On adjusted multivariate analysis, the EST in the hyperacute MRI period was associated with a more favorable outcome (odds ratio, 3.4; 95% confidence interval, 1.1-10.6; P=0.03) and reduced mortality rate (odds ratio, 0.16; 95% confidence interval, 0.03-0.37; P<0.001). CONCLUSIONS: Implementation of hyperacute MRI protocol decreases the number of endovascular stroke interventions by half. Further investigation of MRI use for patient selection is warranted.

Trends in Stroke Thrombolysis Care Metrics and Outcomes by Race and Ethnicity, 2003-2021.

Importance: Understanding is needed of racial and ethnic-specific trends in care quality and outcomes associated with the US nationwide quality initiative Target: Stroke (TS) in targeting thrombolysis treatment for acute ischemic stroke. Objective: To examine whether the TS quality initiative was associated with improvement in thrombolysis metrics and outcomes across racial and ethnic groups. Design, Setting, and Participants: This retrospective cohort study included patients who presented within 4.5 hours of ischemic stroke onset at hospitals participating in the Get With The Guidelines-Stroke initiative from January 1, 2003, to December 31, 2021. The data analysis was performed between December 15, 2022, and November 27, 2023. Exposures: TS phases I (2010-2013), II (2014-2018), and III (2019-2021). Main Outcomes and Measures: The primary outcomes were thrombolysis rates and time metrics. Patient function and mortality were secondary outcomes. Results: Analyses included 1 189 234 patients, of whom 1 053 539 arrived to the hospital within 4.5 hours. The cohort included 50.4% female and 49.6% male patients and 2.8% Asian [median (IQR) age, 72 (61-82) years], 15.2% Black [median (IQR) age, 64 (54-75) years], 7.3% Hispanic [median (IQR) age, 68 (56-79) years], and 74.1% White [median (IQR) age, 75 (63-84) years] patients). Unadjusted thrombolysis rates increased in both the pre-TS (2003-2009) and TS periods in all racial and ethnic groups from 10% to 15% in 2003 to 43% to 46% in 2021, but disparities were observed in adjusted analyses and persisted in TS phase III, with Asian, Black, and Hispanic patients having significantly lower odds of receiving thrombolysis than White patients (adjusted odds ratio, 0.85 [95% CI, 0.81-0.90], 0.76 [95% CI, 0.74-0.78], and 0.86 [95% CI, 0.83-0.89], respectively). Door-to-needle (DTN) times improved in all racial and ethnic groups during TS, with DTN times of 60 minutes or less increasing from 26% to 28% in 2009 to 66% to 72% in 2021. However, in adjusted analyses, racial and ethnic disparities emerged. During TS phase III, compared with White patients, Asian, Black, and Hispanic patients had significantly lower odds of receiving thrombolysis with a DTN time of 60 minutes or less compared with White patients (risk-adjusted odds ratios, 0.91 [95% CI, 0.84-0.98], 0.78 [95% CI, 0.75-0.81], and 0.87 [95% CI, 0.83-0.92], respectively). During TS, clinical outcomes improved for all racial and ethnic groups from pre-TS, with TS phase III showing higher odds of ambulation at discharge among Asian, Black, Hispanic, and White patients. Asian, Black, and Hispanic patients were less likely to present within 4.5 hours. Conclusions and Relevance: In this cohort study of patients with ischemic stroke, the TS quality initiative was associated with improvement in thrombolysis frequency, timeliness, and outcomes for all racial and ethnic groups. However, disparities persisted, indicating a need for further interventions.

Intracellular and circulating neuronal antinuclear antibodies in human epilepsy.

There are overwhelming data supporting the inflammatory origin of some epilepsies (e.g., Rasmussen's encephalitis and limbic encephalitis). Inflammatory epilepsies with an autoimmune component are characterized by autoantibodies against membrane-bound, intracellular or secreted proteins (e.g., voltage gated potassium channels). Comparably, little is known regarding autoantibodies targeting nuclear antigen. We tested the hypothesis that in addition to known epilepsy-related autoantigens, the human brain tissue and serum from patients with epilepsy contain autoantibodies recognizing nuclear targets. We also determined the specific nuclear proteins acting as autoantigen in patients with epilepsy. Brain tissue samples were obtained from patients undergoing brain resections to treat refractory seizures, from the brain with arteriovenous malformations or from post-mortem multiple sclerosis brain. Patients with epilepsy had no known history of autoimmune disease and were not diagnosed with autoimmune epilepsy. Tissue was processed for immunohistochemical staining. We also obtained subcellular fractions to extract intracellular IgGs. After separating nuclear antibody-antigen complexes, the purified autoantigen was analyzed by mass spectrometry. Western blots using autoantigen or total histones were probed to detect the presence of antinuclear antibodies in the serum of patients with epilepsy. Additionally, HEp-2 assays and antinuclear antibody ELISA were used to detect the staining pattern and specific presence of antinuclear antibodies in the serum of patients with epilepsy. Brain regions from patients with epilepsy characterized by blood-brain barrier disruption (visualized by extravasated albumin) contained extravasated IgGs. Intracellular antibodies were found in epilepsy (n=13/13) but not in multiple sclerosis brain (n=4/4). In the brain from patients with epilepsy, neurons displayed higher levels of nuclear IgGs compared to glia. IgG colocalized with extravasated albumin. All subcellular fractions from brain resections of patients with epilepsy contained extravasated IgGs (n=10/10), but epileptogenic cortex, where seizures originated from, displayed the highest levels of chromatin-bound IgGs. In the nuclear IgG pool, anti-histone autoantibodies were identified by two independent immunodetection methods. HEp-2 assay and ELISA confirmed the presence of anti-histone (n=5/8) and anti-chromatin antibodies in the serum from patients with epilepsy. We developed a multi-step approach to unmask autoantigens in the brain and sera of patients with epilepsy. This approach revealed antigen-bound antinuclear antibodies in neurons and free antinuclear IgGs in the serum of patients with epilepsy. Conditions with blood-brain barrier disruption but not seizures, were characterized by extravasated but not chromatin-bound IgGs. Our results show that the pool of intracellular IgG in the brain of patients with epilepsy consists of nucleus-specific autoantibodies targeting chromatin and histones. Seizures may be the trigger of neuronal uptake of antinuclear antibodies.

Quantitative CTA vascular calcification, atherosclerosis burden, and stroke mechanism in patients with ischemic stroke.

BACKGROUND: Vascular calcification is recognized as the advanced stage of atherosclerosis burden. We hypothesized that vascular calcium quantification in CT angiography (CTA) would be helpful to differentiate large artery atherosclerosis (LAA) from other stroke etiology in patients with ischemic stroke. METHODS: We studied 375 acute ischemic stroke patients (200 males, mean age 69.9 years) who underwent complete CTA images of the aortic arch, neck, and head. The automatic artery and calcification segmentation method measured calcification volumes in the intracranial internal carotid artery (ICA), cervical carotid artery, and aortic arch using deep-learning U-net model and region-grow algorithms. We investigated the correlations and patterns of vascular calcification in the different vessel beds among stroke etiology by age category (young: <65 years, intermediate: 65-74 years, older ≥75 years). RESULTS: Ninety-five (25.3%) were diagnosed with LAA according to TOAST criteria. Median calcification volumes were higher by increasing the age category in each vessel bed. One-way ANOVA with Bonferroni correction showed calcification volumes in all vessel beds were significantly higher in LAA compared with other stroke subtypes in the younger subgroup. Calcification volumes were independently associated with LAA in intracranial ICA (OR; 2.89, 95% CI 1.56-5.34, P = .001), cervical carotid artery (OR; 3.40, 95% CI 1.94-5.94, P < .001) and aorta (OR; 1.69, 95%CI 1.01-2.80, P = .044) in younger subsets. By contrast, the intermediate and older subsets did not show a significant relationship between calcification volumes and stroke subtypes. CONCLUSION: Atherosclerosis calcium volumes in major vessels were significantly higher in LAA compared to non-LAA stroke in younger age.

Amyloid beta interaction with receptor for advanced glycation end products up-regulates brain endothelial CCR5 expression and promotes T cells crossing the blood-brain barrier.

How circulating T cells infiltrate into the brain in Alzheimer disease (AD) remains unclear. We previously reported that amyloid beta (Abeta)-dependent CCR5 expression in brain endothelial cells is involved in T cell transendothelial migration. In this study, we explored the signaling pathway of CCR5 up-regulation by Abeta. We showed that inhibitors of JNK, ERK, and PI3K significantly decreased Abeta-induced CCR5 expression in human brain microvascular endothelial cells (HBMECs). Chromatin immunoprecipitation assay revealed that Abeta-activated JNK, ERK, and PI3K promoted brain endothelial CCR5 expression via transcription factor Egr-1. Furthermore, neutralization Ab of receptor for advanced glycation end products (RAGE; an Abeta receptor) effectively blocked Abeta-induced JNK, ERK, and PI3K activation, contributing to CCR5 expression in HBMECs. Abeta fails to induce CCR5 expression when truncated RAGE was overexpressed in HBMECs. Transendothelial migration assay showed that the migration of MIP-1alpha (a CCR5 ligand)-expressing AD patients' T cells through in vitro blood-brain barrier model was effectively blocked by anti-RAGE Ab, overexpression of truncated RAGE, and dominant-negative PI3K, JNK/ERK, or Egr-1 RNA interference in HBMECs, respectively. Importantly, blockage of intracerebral RAGE abolished the up-regulation of CCR5 on brain endothelial cells and the increased T cell infiltration in the brain induced by Abeta injection in rat hippocampus. Our results suggest that intracerebral Abeta interaction with RAGE at BBB up-regulates endothelial CCR5 expression and causes circulating T cell infiltration in the brain in AD. This study may provide a new insight into the understanding of inflammation in the progress of AD.

Target: Stroke Was Associated With Faster Intravenous Thrombolysis and Improved One-Year Outcomes for Acute Ischemic Stroke in Medicare Beneficiaries.

BACKGROUND: The benefit of intravenous thrombolytic therapy for acute ischemic stroke is time dependent. To assist hospitals in providing faster thrombolytic treatment, the American Heart Association launched target: stroke quality initiative in January 2010 which disseminated feasible strategies to shorten door-to-needle times for thrombolytic therapy. This study aimed to examine whether target: stroke was associated with improved door-to-needle times and 1-year outcomes. METHODS: We analyzed Medicare beneficiaries aged ≥65 years receiving intravenous thrombolytic treatment for acute ischemic stroke at 1490 Get With The Guidelines-Stroke hospitals during January 2006 and December 2009 (preintervention, n=10 804) and January 2010 and December 2014 (postintervention, n=31 249). The median age was 80 years and 42.7% were male. RESULTS: The median door-to-needle times decreased from 80 minutes for the preintervention to 68 minutes for the postintervention (P<0.001). The proportion of patients receiving intravenous thrombolysis with door-to-needle times 45 minutes and 60 minutes increased from 9.6% and 24.8% for preintervention to 17.1% and 40.6% for postintervention, respectively (P<0.001). The annual rate of increase in the door-to-needle times of 60 minutes or less accelerated from 0.20% (95% CI, -0.43% to 0.83%) per each 4 quarters for preintervention to 5.68% (95% CI, 5.23%-6.13%) for postintervention (P<0.001) which was further confirmed in piecewise multivariable generalized estimating analysis (adjusted odds ratio, 1.27 [95% CI, 1.19-1.35]). Cox proportional hazards analysis, after adjusting for patient and hospital characteristics and within-hospital clustering, showed that target: stroke was associated with lower all-cause readmission (40.4% versus 44.1%; hazard ratio, 0.91 [95% CI, 0.88-0.95]), cardiovascular readmission (19.7% versus 22.9%; hazard ratio, 0.85 [95% CI, 0.80-0.89]), and composite of all-cause mortality or readmission (56.0% versus 58.4%; hazard ratio, 0.96 [95% CI, 0.93-1.00]). The risk decline in all-cause mortality dissipated after risk adjustment (adjusted hazard ratio, 0.98 [95% CI, 0.94-1.02]). CONCLUSIONS: Target: stroke quality initiative was associated with faster thrombolytic treatment times for acute ischemic stroke and modestly lower 1-year all-cause and cardiovascular readmissions.

Human brain microvascular endothelial cells and umbilical vein endothelial cells differentially facilitate leukocyte recruitment and utilize chemokines for T cell migration.

Endothelial cells that functionally express blood brain barrier (BBB) properties are useful surrogates for studying leukocyte-endothelial cell interactions at the BBB. In this study, we compared two different endothelial cellular models: transfected human brain microvascular endothelial cells (THBMECs) and human umbilical vein endothelial cells (HUVECs). With each grow under optimal conditions, confluent THBMEC cultures showed continuous occludin and ZO-1 immunoreactivity, while HUVEC cultures exhibited punctate ZO-1 expression at sites of cell-cell contact only. Confluent THBMEC cultures on 24-well collagen-coated transwell inserts had significantly higher transendothelial electrical resistance (TEER) and lower solute permeability than HUVECs. Confluent THBMECs were more restrictive for mononuclear cell migration than HUVECs. Only THBMECs utilized abluminal CCL5 to facilitate T-lymphocyte migration in vitro although both THBMECs and HUVECs employed CCL3 to facilitate T cell migration. These data establish baseline conditions for using THBMECs to develop in vitro BBB models for studying leukocyte-endothelial interactions during neuroinflammation.

Comparison of Acute Ischemic Stroke Care and Outcomes Between Comprehensive Stroke Centers and Primary Stroke Centers in the United States.

BACKGROUND: To improve stroke care, the Brain Attack Coalition recommended establishing primary stroke center (PSC) and comprehensive stroke center (CSC) certification. This study aimed to compare ischemic stroke care and in-hospital outcomes between CSCs and PSCs. METHODS AND RESULTS: We analyzed patients with acute ischemic stroke who were hospitalized at stroke centers participating in Get With The Guidelines-Stroke from 2013 to 2015. Multivariable logistic regression models were generated to examine the association between stroke center certification (CSC versus PSC) and performances and outcomes. This study included 722 941 patients who were admitted to 134 CSCs and 1047 PSCs. Both CSCs and PSCs had good conformity to 7 performance measures and the summary defect-free care measure. Among emergency department admissions, CSCs had higher intravenous tPA (tissue-type plasminogen activator) and endovascular thrombectomy rates than PSCs (14.3% versus 10.3%, 4.1% versus 1.0%, respectively). Door to intravenous tPA time was shorter at CSCs (median, 52 versus 61 minutes; adjusted risk ratio, 0.92; 95% confidence interval, 0.89-0.95). More patients at CSCs had door to intravenous tPA time ≤60 minutes (79.7% versus 65.1%; adjusted odds ratio, 1.48; 95% confidence interval, 1.25-1.75). For transferred patients, CSCs and PSCs had comparable overall performance in defect-free care, except higher endovascular thrombectomy therapy rates. The overall in-hospital mortality was higher at CSCs in both emergency department admissions (4.6% versus 3.8%; adjusted odds ratio, 1.14; 95% confidence interval, 1.01-1.29) and transferred patients (7.7% versus 6.8%; adjusted odds ratio, 1.17; 95% confidence interval, 1.05-1.32). In-hospital outcomes were comparable between CSCs and PSCs in patients who received intravenous tPA or endovascular thrombectomy. CONCLUSIONS: CSCs and PSCs achieved similar overall care quality for patients with acute ischemic stroke. CSCs exceeded PSCs in timely acute reperfusion therapy for emergency department admissions, whereas PSCs had lower risk-adjusted in-hospital mortality. This information may be important for acute stroke triage and targeted quality improvement.

Inflammatory cell migration into the central nervous system: a few new twists on an old tale.

Understanding the mechanisms of leukocyte trafficking into the brain might provide insights into how to modulate pathologic immune responses or enhance host protective mechanisms in neuroinflammatory diseases such as multiple sclerosis. This review summarized our knowledge about the sites for leukocyte entry into the central nervous system, highlighting the routes from blood into the perivascular space and brain parenchyma through the blood-brain barrier. We further discussed the multistep paradigm of leukocyte-endothelial interactions at the blood-brain barrier, focusing on the adhesion molecules and chemokines involved in leukocyte transmigration. Luminal chemokines, which are immobilized on endothelial surfaces, initiate leukocyte integrin clustering and conformational change, leading to leukocyte arrest. Some leukocytes undergo post-arrest locomotion across the endothelial surface until interendothelial junctions are identified. Leukocytes then extend protrusions through the interendothelial junctions, in search of abluminal chemokines, which will serve as guidance cues for transmigration. Extravasating cells first accumulate in the perivascular space between the endothelial basement membrane and the basement membrane of the glia limitans. Matrix metalloproteases may be involved in leukocyte transverse across glia limitans into the brain parenchyma. The adhesion molecules and chemokine receptors provide attractive targets for neuroinflammatory diseases because of their important role in mediating central nervous system inflammation.