bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract WMP97: Racial/Ethnic Disparities in the Risk of Intracerebral Hemorrhage Recurrence
Authors: King Zachary A , Leasure Audrey C , Torres-Lopez Victor , Woo Daniel , Hanley Daniel F , Ziai Wendy , Murthy Santosh B , Matouk Charles C , Sansing Lauren H , Falcone Guido J , Sheth Kevin N
Published: January 2019

Background:
Race/ethnicity is associated with risk of first-ever spontaneous intracerebral hemorrhage (ICH), but the influence of race/ethnicity on risk of ICH recurrence has not been well studied in a large, diverse population.

Methods:
We used claims data on all discharges from community hospital inpatient stays in California between January 1, 2005 and December 31, 2011 to identify patients who were hospitalized for ICH. California residents who survived to discharge were included. We used validated diagnosis codes to identify a primary outcome of recurrent ICH. We then used survival curves and log-rank tests for unadjusted analyses of survival across race/ethnic groups and multivariable Cox proportional-hazards regression to determine factors associated with risk of ICH recurrence after adjusting for potential confounders.

Results:
Between 2005-2011, we identified 31,554 first-ever ICH patients who survived to discharge, of which 15,828 (50%) were white, 6,254 (20%) Hispanic, 4,268 (14%) Asian, and 2,820 (9%) black. There were 1339 recurrences (4.2%) over a median follow-up time of 2.9 years (IQR 3.8). The 1-year recurrence rate was 3.0% (95% CI 2.8%-3.2%). In univariable and multivariable analysis, blacks (HR 1.22, 95% CI 1.01-1.48; p=0.035) and Asians (HR 1.29, 95% CI 1.10-1.50; p=0.001) had a higher risk of ICH recurrence than whites (reference categories). Private insurance was associated with a significant reduction in the risk of ICH recurrence compared to subjects with Medicare (HR 0.60, 95% CI 0.50-0.73, p<0.001), with consistent estimates across race/ethnic groups.

Conclusions:
Black and Asian subjects had a higher risk of ICH recurrence than white or Hispanic subjects. Further research is needed to determine drivers of these disparities.
Abstract WMP98: Apolipoprotein E Genotype Predicts Anticoagulation-associated Intracerebral Hemorrhage Recurrence
Authors: Urday Sebastian , Biffi Alessandro , Rodriguez-Torres Axana , Pasi Marco , Kourkoulis Christina , Schwab Kristin , Greenberg Steven M , Viswanathan Anand , Gurol M. Edip , Sheth Kevin N , Anderson Christopher , Rosand Jonathan
Published: January 2019

Introduction:
Oral Anticoagulation Therapy (OAT) resumption after ICH is a dilemma due to increased risk of recurrent ICH, particularly after lobar ICH caused by underlying Cerebral Amyloid Angiopathy (CAA). Apolipoprotein E (
APOE
) ε2/ε4 alleles are risk factors for recurrent CAA-related ICH.

Hypothesis:
APOE genotype predicts lobar ICH recurrence after OAT-ICH.

Methods:
We enrolled survivors of lobar OAT-ICH in a prospective single-center study to determine whether APOE ε2/ε4: 1) are associated with ICH recurrence following OAT-ICH, using time-to-event analyses; 2) improved prediction of ICH recurrence when added to MRI-based CAA markers (cerebral microbleeds [CMBs], white matter hyperintensities [WMH], expanded peri-vascular spaces [EPVS], and cortical superficial siderosis [CSS]), using Harrell’s C-statistic; 3) could be incorporated in a classification scheme to predict ICH recurrence, as defined by recursive partitioning analysis (RPA).

Results:
We followed 110 lobar OAT-ICH survivors for a median time of 52.2 months (IQR: 33.5-61.7). We observed 26 recurrent ICH events, corresponding to an annual recurrence rate of 5.7%.
APOE
ε2/ε4 variants were associated with ICH recurrence following OAT-ICH (ε2: HR 2.14, 95% CI 1.20-3.82; ε4: HR 1.50, 95% CI 1.21-3.47). These associations remained significant after adjusting for anticoagulation status, antiplatelet use, CMBs, WMH, EPVS, and CSS. Inclusion of
APOE
genotype alongside MRI data resulted in improved predictive ability for ICH recurrence (Harrell’s C: 0.76 vs. 0.68, p=0.034). RPA revealed that APOE ε2/ε4 stratified likelihood of ICH recurrence among otherwise low risk individuals based on MRI data alone (Figure).

Conclusions:
APOE
genotype predicts lCH recurrence following lobar OAT-ICH, and improves predictive performance when added to established neuroimaging markers. APOE-based lobar ICH recurrence prediction warrants further investigation and may affect clinical practice.
Abstract WMP99: In-Hospital Delirium and Long-Term Cognitive Outcomes Among Patients With Intracerebral Hemorrhage: A Population-Based Cohort Analysis
Authors: Meeks Jennifer R , Bambhroliya Arvind B , Tyson Jon E , Miller Charles C , Khan Babar , Sheth Sunil A , McCullough Louise D , Grotta James C , Aronowski Jaroslaw , Savitz Sean I , Vahidy Farhaan S
Published: January 2019

Introduction:
Little is known regarding the association between acute in-hospital exposures such as delirium and long-term cognitive outcomes in intracerebral hemorrhage (ICH) patients. We sought to explore the risk of mild cognitive impairment or dementia (MCID) among ICH patients who experienced in-hospital delirium.

Methods:
We utilized State Inpatient and Emergency Department Databases for NY (2006 - 2014), CA (2005 - 2011), and FL (2005 - 2014), and established a cohort by selecting MCID free patients with a primary diagnosis of ICH (ICD-9: 431) during a 2yr period. Patients with concurrent diagnoses of head trauma, arteriovenous malformation or missing linkage information were excluded. Delirium during the initial ICH event was tagged using a validated algorithm with high specificity for the confusion assessment method. The cohort was followed for MCID diagnoses. Patients that died within 90 days of ICH were excluded. We conducted time-to-event analyses and report cumulative incidence, 95% Confidence Interval (CI) and hazard ratios (HR) for risk of MCID among ICH patients with and without delirium.

Results:
A total of 18,083 ICH patients (age: 67.2, female: 47.6%, white: 59.1%) were included and were followed for up to 8yrs, resulting in 42,100 person-years. Patients who experienced delirium had a significantly higher comorbidity index and intensity of in-hospital treatment. Cumulative incidence (95% CI) for development of MCID was significantly higher among delirium patients (6.07, 5.05 - 7.30) as compared to non-delirium patients (4.07, 3.87 - 4.27). Likewise, the HR for MCID among delirium patients was statistically significant (1.42, 1.17 - 1.73) in the fully adjusted Cox proportional model (Figure).

Conclusion:
ICH patients with in-hospital delirium are at a significantly higher risk of developing MCID. Further investigation is warranted to understand the mechanism for cognitive decline among ICH patients who experience in-hospital delirium.
Abstract WP101: Comparative Effects of Thrombolysed Ischemic Patients With Low Platelet Count
Authors: Yang Jie
Published: January 2019

Introduction:
Platelet count (PC) < 100х10
9
/L is considered a relative contraindication to the use of intravenous alteplase in patients with acute ischemic stroke (AIS). However, this recommendation is based on expert opinion only. We aimed to assess whether low PC modified the comparative effects of low- versus standard-dose alteplase in patients who participated in the alteplase-dose arm of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED).

Methods:
Data from an international, multi-center, prospective, randomized, open-label, blinded-endpoint trial were used to assess the benefits and risks of low- (0.6mg/kg) versus standard-dose (0.9mg/kg) intravenous alteplase in thrombolysis-eligible AIS patients. A logistic regression model was used for analysis of patient subgroups defined by categorical PC (tertiles, with the lowest third as the reference group) on efficacy and safety outcomes, adjusted for confounding variables.

Results:
After adjusting for baseline characteristics in 3265 AIS patients, low PC was not associated with poor outcome: whether defined by ordinal modified Rankin scale (mRS) scores (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.69-1.37 [middle vs. low] vs. 1.17 (0.99-1.37) [high vs. low]; P=0.066 for trend) or symptomatic intracerebral hemorrhage (sICH) (1.36 (0.71-2.6) vs. 0.8 (0.38-1.69); P=0.630 for trend). There was no differential effect of low- versus standard-dose alteplase on ordinal shift in mRS scores, mortality, or sICH, by tertiles of PC.

Conclusions:
Low PC was not an independent predictor of poor outcome in thrombolysis-treated AIS patients and it does not modify the differences in effects of low- versus standard-dose alteplase.
Abstract WP103: Functional Outcome of Telestroke Patients Treated Under Drip-And-Stay Paradigm versus Drip-And-Ship Paradigm
Authors: Harvey Jillian , Al kasab Sami , Almallouhi Eyad , Girotra Tarun , Turner Nancy , Debenham Ellen , Holmstedt Christine
Published: January 2019

Introduction:
While more spokes are now capable of taking care of post-tPA patients, little is known, however, about long term functional outcome of those patients. In this study, we aim to compare long-term outcome for patients who received tPA at a telestroke spoke and remain at the spoke (drip-and-stay) to those patients who received tPA at a spoke and were transferred to the telestroke hub (drip-and-ship).

Methods:
This is a retrospective review of prospectively collected data on patients who received tPA through the Medical University of South Carolina (MUSC) telestroke program between January 2016 and March 2018. Collected data included age, sex, race, admission NIH stroke scale, door to needle time (DTN), and long-term outcomes measured by modified Rankin Scale (mRS) at 90 days. Patients who were transferred to the telestroke hub because of suspected large vessel occlusion were excluded from the study. Descriptive statistics were used to compare patient demographics and clinical outcomes across the two groups. Generalized linear regression model was used to assess the effect of the drip-and-ship paradigm on 90-day mRS controlling for baseline characteristics.

Results:
Total of 517 patients were identified (410 drip-and-stay and 107 drip-and-ship). Baseline characteristics are summarized in table 1. Drip-and-stay group had higher percentage of women (60%) as compared to the drip-and-ship group (46.7%) (P=0.013). mRS of 0-2 at 90 days was achieved in 323 patients (78.8%) in the drip-and-stay and in 80 patients (74.8%) in the drip-and-ship group (P=0.372). Regression analysis showed no difference in the adjusted relative risk of having 90-day mRS ≤2 between drip-and-stay and drip-and-ship patients (RR 0.95, p=0.365, 95% CI [0.05-1.1]).

Conclusion:
In our study, no difference was found in the long-term functional outcome for telestroke patients who were treated under drip-and-stay paradigm when compared to the drip-and-ship paradigm
Abstract WP105: Therapeutic Effects of D4F, an ApoA-I Mimetic Peptide, in Aged Mice Subjected to Ischemic Stroke
Authors: Shen Yi , Zacharek Alex , Venkat Poornima , Chopp Michael , Wang Fengjie , Landschoot-Ward Julie , Jiang Quan , Chen Jieli
Published: January 2019

Background:
D-4F, an ApoA-I mimetic peptide, improves the functional properties of high density lipoprotein cholesterol and has anti-inflammation effects. Ischemic stroke is a primary cause of mortality and disability in the aged population. In this study, we investigated the therapeutic effects and mechanisms underlying the beneficial effects of D4F in aged mice subjected to ischemic stroke.

Methods:
A total of 24 aged (~24 months) C57BL/6J male mice were subjected to photochemical distal middle cerebral artery occlusion (dMCAo). Treatment was initiated at 24 hours after dMCAo with: 1) PBS; 2) D4F (16mg/kg/day, intraperitoneal injection) daily for 4 weeks until sacrifice at 28 days post stroke (n=12/group). Immunostaining, Luxol fast blue staining, PCR and Western blot measurements were performed. One-way Analysis of Variance was employed for statistical analysis.

Results:
Compared to PBS-control stroke mice, D4F treatment in aged stroke mice significantly (p<0.05): 1) reduced the mortality post dMCAo (50% vs 12.5%) and decreased ischemic lesion volume ratio (13% vs 9%); 2) improved the neurological functional outcome identified by the mNSS (Modified Neurological Severity Score) and foot-fault test as well as improved cognitive functions evaluated by Novel object cognitive test, Odor test and Three-chamber sociability test;
3)
decreased white matter/axonal damage tested by Luxol fast blue and Bielschowsky silver staining; 4) increased oligodendrogenesis and synaptic plasticity measured by NG2 and NF200 expression in the ischemic brain; 5) increased vascular density in the ischemic border of ischemic brain measured by von Willebrand staining; 6
)
decreased glial scar formation identified by reducing GFAP positive cells as well as decreased IBA-1 expression in the IBZ; 7) as well as decreased inflammatory factor TLR4 and thrombin, but increased IL-10 gene expression in the ischemic brain.

Conclusions:
D4F treatment decreases ischemic lesion, glial scar formation and neuroinflammation, and promotes WM/axonal and neurovascular remodeling as well as improves neurological and cognitive function in aged ischemic stroke mice. D4F not only induces neuroprotective effect, but also promotes neurorestorative effects in aged ischemic stroke mice.
Abstract WP106: Timing of Tissue-plasminogen-activator Induced Recanalization and Functional Recovery in Acute Ischemic Stroke
Authors: Tsivgoulis Georgios , Saqqur Maher , Sharma Vijay K , Brunser Alejandro , Eggers Jürgen , Mikulik Robert , Katsanos Aristeidis H , Sergentanis Theodore N , Vadikolias Konstantinos , Perren Fabienne , Rubiera Marta , Shahripour Reza Bavarsad , Nguyen Huy Thang , Martínez-Sánchez Patricia , Safouris Apostolos , Heliopoulos Ioannis , Shuaib Ashfaq , Derksen Carol , Voumvourakis Konstantinos , Psaltopoulou Theodora , Alexandrov Anne W , Alexandrov Andrei V
Published: January 2019

Introduction:
Although onset-to-treatment time is associated with early clinical recovery in acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (tPA), the effect of the timing of tPA-induced recanalization on functional outcomes in AIS remains debatable.

Methods:
We sought to determine whether early (within 1-hour from tPA-bolus) complete or partial recanalization assessed during 2-hour real-time transcranial Doppler (TCD) monitoring is independently associated with improved 3-month outcomes in tPA-eligible patients with proximal intracranial arterial occlusions. Outcome events included dramatic clinical recovery (DCR) within 2 and 24-hours from tPA-bolus, 3-month mortality, favorable functional outcome (FFO) and functional independence (FI) defined as modified Rankin Scale scores of 0-1 and 0-2 respectively.

Results:
We prospectively enrolled 480 AIS patients (mean age 66±15 years, 60% men, baseline NIHSS score 15) during a 7-year period from 12 participating centers. Complete or partial early recanalization was detected in 53% of patients. Patients with early recanalization had (p<0.001) higher rates of 2-hour DCR (54% vs. 10%), 3-month FFO (67% vs. 28%), FI (81% vs. 39%) and lower mortality rates (6% vs. 17%) compared to patients with persisting occlusions. In multivariable analyses, recanalization during tPA infusion was independently (p<0.05) associated with higher probability of three-month FFO and lower likelihood of three-month mortality. Onset to treatment time correlated to the elapsed time between tPA-bolus and recanalization (Spearman’s rho= +0.151, p=0.009).

Conclusions:
Earlier tPA treatment after stroke onset is associated with faster tPA-induced recanalization. Earlier onset-to-recanalization time results in improved functional recovery and survival in AIS patients with proximal intracranial occlusions.
Abstract WP110: Does Paradoxical Embolism Impart Different Outcomes After IVT Treatment?
Authors: Bavarsad Shahripour Reza , Goyal Nitin , Tsivgoulis Georgios , Pandhi Abhi , Singh Savdeep , Malhotra Konark , Bryndziar Tomas , Sukhdeo Rena , Aboud Talal , Krishnaiah Balaji , Nearing Katherine , Alexandrov Anne W , Alexandrov Andrei V
Published: January 2019

Introduction:
There are pilot data indicating that patients with acute ischemic stroke (AIS) due to paradoxical embolism (PxE) via patent foramen ovale (PFO) may respond better to intravenous thrombolysis compared to other stroke subtypes. We sought to compare the safety and efficacy of IVT in AIS patients with and without PxE as their stroke etiopathogenic mechanism in a high-volume tertiary care stroke center.

Methods:
Consecutive AIS patients treated with IVT during a five-year period were evaluated. Baseline stroke severity and early hypodensity on baseline CT were assessed by NIHSS-score and ASPECTS by certified physicians. Presence of PFO was diagnosed by echocardiography, while PxE was determined using the TOAST criteria. Safety of IVT was evaluated using SITS-MOST sICH definition. Three-month functional status was assessed using modified Rankin Scale (mRS) scores.

Results:
Out of total 1301 IVT-treated AIS patients, we identified 51 cases (4%) with PxE due to PFO. Patients with PxE were younger (mean age 52±15 vs. 63±15 years; p<0.001), but had similar baseline and 24-hour NIHSS-scores compared to the others. The rates of sICH (4% vs. 5%), 3-month functional independence (mRS-scores 0-2; 77% vs. 68%) and 3-month favourable functional outcome (mRS-scores 0-1; 64% vs. 53%) did not differ (p>0.1) between the two groups. Three-month mortality was lower in the PxE group (0% vs. 9% by Fisher exact test). PxE due to PFO (OR computed using Firth’s penalized likelihood method for rare events: 0.11; 95%CI: 0.01-1.74) was not independently associated with 3-month mortality on multivariable logistic regression models adjusting for potential confounders.

Conclusions:
Our study indicates that AIS patients with PxE due to PFO have similar response to IVT compared to AIS patients with other underlying mechanisms.
Abstract WP112: Trends of Hospitalization for Intravascular Thrombolysis and Acute Ischemic Stroke Among Patients With Multiple Sclerosis and United States: A 10 Year National Estimate
Authors: Kumar Varun , Savani Chirag , Singh Tejinder , Yi Xiyan , Pathak Ambarish , Chib Anjula , Renati Swetha
Published: January 2019

Background:
Several studies reported increased incidence of acute ischemic stroke (AIS) among patients with multiple sclerosis (MS) but there is paucity of data for utilization of intravascular thrombolysis (IVT) and its outcomes in this population. This study aimed to evaluate trends in utilization of IVT and its outcomes among MS patients.

Methods:
Nationwide Inpatient Sample (NIS) from 2005 to 2014 was utilized to identify patients with MS using ICD CM code 340 in any diagnostic field and AIS with appropriate diagnostic codes in primary field. IVT utilization was identified by ICD9 procedure code 99.10 in any procedural field. Differences between categorical variables were tested using the chi-square test and continuous variables using the Student t-test.

Results:
We identified 11,881 patients with ischemic stroke among MS patients, of which 638 (5.4%) received IVT during our study period (86.4% with age≥ 50years; 68.4% Female). IVT study compared to non-IVT group associated with more comorbid conditions (CCI ≥2 in 70.1 % vs 41.4%). Hospitals in the Southern states constitute the highest percentage of IVT hospitalizations in patients with MS (33.7%), followed by West (27%), Midwest (23.1%), and Northeast (16.3%). MS patients that received thrombolysis were more likely to be at a teaching hospital (59.4%) (p <0.0001). Overall in-hospital mortality associated with IVT hospitalizations was 4.7% vs 2.8% in non IVT group and was associated with longer mean length of stay (6 days vs 5 days, p=0.01). Hospitalizations for AIS among MS patients increased from 0.7% in 2005 to 1.1% in 2014. A similar upward trend was seen in IVT use in this population (from 0.4% in 2005 to 9.3% in 2014, ptrend <0.0001).

Conclusion:
1 out of 20 MS patients with AIS received thrombolysis. IVT was more likely to be administered at a teaching hospital during our study period. There were significant upward trend in number of MS patients receiving thrombolysis. Patients with MS that received thrombolysis for AIS had higher mortality. It is important to note however that this group was older and had more comorbid conditions.
Abstract WP113: Racial Disparities in Patient Selection for Drip and Ship Thrombolytic Therapy for Acute Ischemic Stroke
Authors: Sukhdeo Rena D , Goyal Nitin , Tsivgoulis Georgios , Nearing Katherine , Krishnaiah Balaji , Aboud Talal , Pandhi Abhi , Bavasard Shahripour Reza , Bryndziar Tomas , Quitasol Peter , Dusenbury Wendy , Swatzell Victoria , Fiornarelli Ashley , Rhudy James P , Deep Aman , Ansari Saeed , Ishfaq Muhammad , Alexandrov Anne W , Alexandrov Andrei V
Published: January 2019

Introduction:
There is preliminary data indicating potential racial disparities in use of intravenous thrombolysis (IVT) for acute ischemic stroke (AIS). We sought to compare “drip and ship” (DNS) tPA use between African-Americans (AA) and Caucasians (CS) in a high-volume tertiary care stroke center.

Methods:
AIS patients treated with IVT during a seven-year period were evaluated. Baseline stroke severity and early hypodensity on baseline CT were assessed by NIHSS-score and ASPECTS by certified physicians. All patients who received IVT at an outside facility with subsequent transfer to our center were included in the DNS group. Safety of IVT was evaluated SITS-MOST symptomatic intracranial hemorrhage (sICH) definition. Three-month functional status was assessed using modified Rankin Scale (mRS) scores.

Results:
Out of total 1339 IVT-treated AIS patients [51% men, 63% AA, mean age 63±15years, median baseline NIHSS-score: 7 pts (IQR: 3-13)], 521 (39%) were treated using the DNS approach. DNS tPA use was less common in AA compared to CS (33% vs. 51%; p < 0.001). AA race was independently associated with lower likelihood of DNS tPA use (OR: 0.46; 95%CI: 0.35-0.62; p<0.001) on multivariable logistic regression models adjusting for multiple potential confounders including demographics, vascular risk factors, onset-to-treatment time, door-to-needle time, baseline stroke severity, serum glucose, BP parameters and ASPECTS. Among DNS patients, the rates of sICH, three-month favorable functional outcome (mRS-scores of 0-1) and mortality did not differ between AA and CS. Using geospatial software, the observed treatment disparity could not be explained by racial zipcode. distribution.

Conclusions:
Our study uncovers substantial racial disparities in the selection of AIS patients for DNS thrombolytic therapy that cannot be explained by racial geographic proximity to the primary stroke center.
Abstract WP115: Association of HDAC9, TWIST1, and FERD3L Expression With the Risk of Intracranial Aneurysm
Authors: Lansdell Theresa , Fisher Courtney , Dorrance Anne , Demel Stacie L
Published: January 2019

Background and Purpose:
Subarachnoid hemorrhage is a devastating consequence of ruptured IA, therefore early identification is important. Identification of biomarkers may improve the understanding of IA pathogenesis and can be used to improve patient management. A risk allele (rs10230207) has been associated with IA incidence and is located nearby the HDAC9, TWIST1 and FERD3L genes. Changes in the expression of one or both of these genes is believed to be related to the increased risk of IA. We test the hypothesis that patients harboring this risk allele have changes in the expression of these genes, which can be measured in their blood.

Methods:
Immortalized B-lymphocytes from patients with unruptured IA and population controls were obtained from the NINDS repository. Subject genomic DNA was isolated and genotyped for the presence of the risk allele using assays directed toward either rs10230207, or rs11767221, a SNP in high linkage disequilibrium with rs10230207. HDAC9, TWIST1, and FERD3L mRNA and protein were analyzed in each cell line. HDAC9 and TWIST1 protein and mRNA levels were confirmed in peripheral blood mononuclear cells (PBMCs) from the whole blood of subjects with and without IA.

Results:
IA cases expressed more HDAC9 (p=0.005) and less TWIST1 and FERD3L (p=0.0200 and 0.0320 respectively) compared to the population controls. The GWAS association of IA with rs10230207 in the Finnish and Dutch population was replicated in the NINDS sample population. Within the sample population, the odds of IA was 7.25 higher given the presence of the risk allele compared to no risk allele (95% CI 2.023-24.96). While changes in HDAC9 expression was not associated with the presence of the risk allele, decreased expression of TWIST1 and FERD3L were associated with the risk allele. Changes in TWIST1 and FERD3L were confirmed in genotyped case and control PBMCs

Conclusions:
The presence of the rs10230207 risk allele was not associated with changes in HDAC9 but was associated with decreased TWIST1 and FERD3L expression in case and control immortalized lymphoblasts, which was confirmed in patient PBMCs. Our studies demonstrate a potential marker associated with IA risk. Future studies are aimed at looking at the positive and negative predictive values of TWIST1 levels and IA.
Abstract WP117: Quantitative Susceptibility Mapping (QSM) and Vessel Wall Imaging (VWI) MRI Sequences in Identifying Subjects With Intracranial Aneurysms Who Have Microbleeds
Authors: Samaniego Edgar A , Nakagawa Daichi , Zanaty Mario , Jabbour Pascal , Hasan David M
Published: January 2019

Background and Purpose:
Sentinel symptoms of aneurysm’s micro - hemorrhage such as sentinel headache or cranial nerve (CN) neuropathies are associated with an increased risk of subarachnoid hemorrhage (SAH). We tested a new MRI protocol that may aid the identification of microbleeds associated with sentinel symptoms in patients with negative head CTs and lumbar punctures.

Methods:
Twenty-eight consecutive subjects with a total of 35 aneurysms were enrolled in this pilot study between March/2018 to July/2018. All subjects presented with sentinel symptoms, no evidence of SAH on head CT or spinal puncture. The MRI protocol included: MRA with gadolinium, high-resolution MR vessel wall imaging (MRI-VWI) and MR imaging quantitative susceptibility mapping (MRI-QSM). Two blinded neuroimaging experts reviewed every image to determine evidence of vessel-wall enhancement or positive MRI-QSM signal. A third adjudicator intervened in case of disagreement. Statistical differences were determined by Student t-test, as well as Mann-Whitney U test for non-parametric variables.

Results:
35 CAs (100%) were analyzed with MR-VWI, whereas only 24 CAs (77.1%) on MRI-QSM due artifact form the skull base bone (
P
=0.005). Fifty percent (50%) of anterior communicating artery aneurysm were not visualized on MRI-QSM. Four subjects presented with typical sentinel headache and twenty four with some cranial neuropathy. Interobserver agreement was 100% for MRI-QSM, while 83.9% in MRI-VWI (P=0.06). Disagreements derived from the differentiation between mild and no contrast enhancement in MR-VWI. MRI-QSM had a sensitivity of 100% and a specificity of 100% in micro-hemorrhage identification. Whereas, MRI-VWI had sensitivity of 100% and specificity of 51.9%.

Conclusions:
MRI-QSM is a valuable tool in identifying micro-hemorrhage in patients who present with sentinel symptoms. However, its main limitation is bone artifact in aneurysms close to bone structures.
Abstract WP118: Roles of Vitamin D Deficiency in the Development of Intracranial Aneurysm Rupture
Authors: Kimura Tetsuro , Kudo Daisuke , Miyamoto Takeshi , Sato Hiroki , Ikedo Taichi , Lawton Michael , Hashimoto Tomoki
Published: January 2019

Introduction:
Beyond its essential roles in bone and mineral homeostasis, vitamin D has been implicated in a wide range of chronic pathology. Clinical studies have shown the increased incidence of subarachnoid hemorrhage during winter to spring months when vitamins D levels are decreased because of the less sunlight exposure. Therefore, we hypothesized that vitamin D contributes to the rupture of intracranial aneurysm. Using a mouse model of intracranial aneurysm, we examined whether vitamin D deficiency promotes intracranial aneurysm rupture.

Methods and Materials:
We used 15-week old C57BL/6 male and female mice. To induce aneurysm, we combined induced systemic hypertension (deoxycorticosterone acetate-salt hypertension) and a single injection of elastase (17.5 mU) into the cerebrospinal fluid at the right basal cistern. Mice were assigned to either (1) control (vitamin D 2000 IU/kg) or (2) vitamin D deficient diet (VDD) (vitamin D 0 IU/kg) group. The diet treatment was started seven weeks prior to aneurysm induction and continued until 21 days after aneurysm induction. In female mice, bilateral ovariectomy was also performed one week before aneurysm induction to avoid estrogen-dependent changes in vitamin D levels.

Results:
In male mice, the vitamin D deficient diet significantly increased aneurysmal rupture compared to the control diet (control vs. VDD: 54% vs. 93%;
P
< 0.01). In ovariectomized female mice, there was no significant difference in the rupture rate between two diet treatment groups (control vs. VDD: 88% vs. 86%;
P
= 1.0). There was no significant difference in the incidence of aneurysmal formation between two groups in both sexes. Experiments using sham-ovariectomized female mice are currently ongoing.

Conclusion:
Our preliminary data suggest that vitamin D deficiency promotes intracranial aneurysmal rupture in male mice, but not in ovariectomized female mice. There may be sex-dependent or sex steroids dependent effects of vitamin D on the development of intracranial aneurysm rupture. Our ongoing experiments will elucidate the underlying mechanisms for the potential sex differences in the contributions of vitamin D to the pathophysiology of intracranial aneurysm.
Abstract WP125: Small Aneurysm Size is a Predisposing Factor for Intraprocedural Rupture During Coil Embolization of Unruptured Intracranial Aneurysms
Authors: Yamagami Keitaro , Hatano Taketo , Ando Mitsushige , Chihara Hideo , Ogura Takenori , Suzuki Keita , Kondo Daisuke , Kamata Takahiko , Sakai Shota , Higashi Eiji , Sakamoto Hiroki , Nagata Izumi
Published: January 2019

Introduction:
Intraprocedural rupture(IPR) is one of the most severe complications during coil embolization of intracranial aneurysms. The incidence of IPR during endovascular coiling has been estimated to be 1-8.7%; however, few studies have focused exclusively on unruptured aneurysms. The aim of the present study is to evaluate the predisposing factors for IPR during coil embolization of unruptured intracranial aneurysms.

Methods:
This study included 254 consecutive patients with 281 unruptured intracranial aneurysms treated with endovascular coiling between April 2013 to March 2018 at our institution (mean age 61.7, range 26-88). Dissecting aneurysms and repeated endovascular procedures in recurrent aneurysms were excluded. The medical records were reviewed retrospectively and the following data were collected: age; gender; medical history; smoking habit; family history of intracranial aneurysm; presence or absence of multiple aneurysms; history of earlier subarachnoid hemorrhage from another aneurysm; aneurysm location, size and morphology; and procedural details. The mechanisms of IPR were also investigated. Univariate and multivariate analyses were conducted to determine independent predictors of IPR.

Results:
The incidence of IPR was 4.2%(12 of 281 endovascular procedures). The most common mechanism of IPR was perforation by coils. In the univariate analysis, IPR was associated with aneurysm size(less than 5mm)[odds ratio(OR) 4.8, 95% confidence interval(CI) 1.44-15.88, p=0.005], aneurysms of the anterior communicating artery(OR 4.6, CI 1.39-15.35, p=0.007), aneurysms of the basilar artery(OR 4.4, CI 1.10-17.56, p=0.024) and history of earlier subarachnoid hemorrhage from another aneurysm(OR 5.8, CI 1.10-30.30, p=0.020). There was no significant association between IPR and treatment modality. Multivariate logistic regression analysis proved that the size of aneurysm(less than 5mm) was an independent factor associated with IPR(OR 6.9, CI 1.24-38.52, p=0.027).

Conclusion:
This study suggests the association of the size of aneurysm with incidence of IPR during coil embolization for unruptured intracranial aneurysms. Small aneurysms less than 5mm are associated with increased risk of IPR during coil embolization.
Abstract WP128: Preoperative Prediction of the Necessity for Anterior Clinoidectomy during Microsurgical Clipping of Posterior Communicating Artery Aneurysms
Authors: Kamide Tomoya , Burkhardt Jan K , Tabani Halima , Lawton Michael T
Published: January 2019

Background:
Although most posterior communicating artery (PCoA) aneurysms can be clipped easily with excellent results, some require anterior clinoidectomy for safe and complete clipping.

Objectives:
To review our microsurgical series of ruptured PCoA aneurysms and identify the preoperative predictors for anterior clinoidectomy during microsurgical clipping for PCoA aneurysms

Methods:
Results from microsurgical clipping of 104 patients with ruptured PCoA aneurysms were retrospectively reviewed. Distances and angles were obtained from computed tomographic angiography and compared between the anterior and non-anterior clinoidectomy groups.

Result:
Anterior clinoidectomy was required in 19 of the 104 cases (18%). None developed surgical complications due to anterior clinoid process (ACP) resection, including postoperative visual deficit. Univariate and multivariate analyses revealed that the distances from the ACP tip to the aneurysmal proximal neck and from the ACP line to the aneurysmal proximal neck were statistically significant predictive factors for the need of anterior clinoidectomy. Based on a receiver operating characteristic (ROC) analysis, the distances from the ACP tip to the aneurysmal proximal neck < 4.0 mm and from the ACP line to the aneurysmal proximal neck
<
2.0 mm were selected as optimal cut-off values for predicting the necessity of anterior clinoidectomy, and the area under the ROC curve values were 0.991 and 0.955, respectively.

Conclusion:
In case of ruptured PCoA aneurysm surgery, the distances from the ACP tip to the aneurysmal proximal neck and from the ACP line to the aneurysmal proximal neck were both found to be useful predictors of whether anterior clinoidectomy was required.
Abstract WP13: Time to Treatment With Endovascular Reperfusion Therapy and Outcome From Acute Ischemic Stroke in the National US GWTG-Stroke Population
Authors: Jahan Reza , Saver Jeffrey L , Schwamm Lee H , Fonarow Gregg C , Liang Li , Matsouaka Roland A , Xian Ying , Peterson Eric D , Yavagal Dileep , Smith Eric E
Published: January 2019

Background:
Randomized trials have shown the benefit of endovascular reperfusion therapy (ERT) in acute ischemic stroke (AIS) is time dependent. However, generalizability to routine practice is uncertain; and modest sample sizes have limited characterization of the degree to which onset to treatment time influences outcome from ERT.

Methods:
We analyzed data of 6756 AIS patients treated with ERT at 231 hospitals between January 2015 to December 2016. Multivariable logistic regression modeling was conducted to evaluate the independent impact of onset to puncture (OTP) and door to puncture (DTP) time on efficacy and safety outcomes.

Results:
Among the 6756 patients, median age was 71, 51.2% were female, and NIHSS was 17 (IQR 12-22). Median OTP was 230m (IQR 170-305) and DTP 87m (IQR 62-116). Substantial reperfusion (TICI 2b-3) was in 85.9%. At discharge, 36.9% had independent ambulation, 27.8% were discharged to home, and 23.0% were functionally independent (mRS 0-2). Symptomatic intracranial hemorrhage (sICH) occurred in 6.7% and in-hospital mortality/hospice in 19.6%. For OTP, time-outcome relationships were nonlinear, with steeper slope in 0-270m than 271-480m (see Table and Figure). DTP showed a similar nonlinear time-outcome relationship, with steeper benefit decline in the 30-120m than 121-180m period.

Conclusions:
In this national registry, faster endovascular therapy start, after onset and after arrival, was associated with better ambulation and functional independence at discharge, and reduced sICH and mortality/hospice. These findings support intensive efforts to accelerate hospital presentation and endovascular treatment in patients with stroke.
Abstract WP130: Unruptured Intracranial Aneurysm Treatment Score Fails for at Risk Patients Over 58 Years Old
Authors: Janjua Nazli A , Moradiya Yogesh , Tse-Chang Karen , Jones Kimberly , Woolfolk Katrina , Keasler Debbie , Popalzai Adeel , Desai Bhupat
Published: January 2019

Introduction:
The Unruptured Intracranial Aneurysm Treatment Score (UIATS) weighs treatment versus observation risk, while the PHASES score estimates rupture risk. Certain clinical and radiographic features overlap between them whereas other features diverge. Thus management decisions may rely on conflicting information.

Objective:
We sought to determine the UIATS for known aneurysmal subarachnoid hemorrhage (aSAH) patients, as if the aneurysms been detected prior to rupture, and to correlate this with their PHASES scores.

Methods:
UIATS and PHASES scores were calculated for consecutive aSAH patients admitted to a regional stroke center between 1/2014 and 8/2018. A UIAT differential score was derived by subtracting the ‘observation’ from the ‘treatment’ score (a higher score favors treatment). Pro-treatment UIATS rates were calculated for the whole group and after excluding patients with non definitive scores of -3 to 3. These rates were also calculated for age-quartiles (<44, 45-58, 59-66, and >/=67 years). The relationship of age and PHASES scores with UIATS was assessed using logistic regression.

Results:
Of 130 total patients, 121 (mean age 55 +/-15 years) had complete data, with median PHASES score of 5, concordant with their ultimate aSAH. Conversely, their median UIATS score was -1, and only in 54 (45%) did the score show balance (0) or favor treatment. Excluding those with UIATS -3 to 3, the number dropped to 18 (15%). Each unit increase in PHASES score was associated with 23% higher likelihood of pro-treatment UIATS (OR: 1.23, 95% CI: 1.05-1.44, p=0.009) indicating a degree of harmony. In contrast, although age>/=70 increases PHASES score, the odds of UIATS favoring treatment decreased by 5% with each year increase [OR: 0.95, 95% CI: 0.92-0.98, p=0.002]. When the four quartiles were analyzed, as age rose >58 years, the likelihood of pro-treatment UIATS fell (45-58 years, 63%; 59-66 years, 32%; >/=67 years, 0%). Results were comparable when analysis was repeated after excluding cases with UIATS - 3 -to 3.

Discussion:
UIATS and PHASES scores help guide management discussions, but clinicians should assume caution with those>58 years, as UIATS is more likely to fail these patients, who may still be at greater natural history risk of aneurysmal rupture.
Abstract WP132: Korean Red Ginseng Attenuates Reactive Gliosis and Confers Sustained Neuroprotection against Cerebral Hypoxic-Ischemic Damage in an Nrf2-Dependent Manner
Authors: Liu Lei , Vollmer Mary K. , Fernandez Victoria M. , Kim Hocheol , Dore Sylvain
Published: January 2019

Introduction:
The transcriptional factor Nrf2, a master regulator of oxidative stress and inflammation that contribute to cerebral ischemia pathogenesis, plays a vital role in inducing the endogenous neuroprotective process. The standardized Korean red ginseng (Ginseng) extracts, derived from the root of Panax ginseng C.A. Meyer, have exhibited an encouraging protective efficacy with antioxidant and anti-inflammatory properties.

Hypothesis:
We hypothesized that the putative protection of Ginseng, a potent Nrf2 inducer, was through an Nrf2-dependent mechanism involving the attenuation of reactive gliosis in the hypoxic-ischemic (HI) stroke.

Methods:
Adult Nrf2 knockout and wildtype mice were orally pretreated with Ginseng for 7 days prior to HI surgery. The histological and neurobehavioral outcomes, as well as the structural and functional alternation of reactive gliosis were examined before and at 6h, 24h, 7d after HI. The Nr2 and its downstream markers were also monitored.

Results:
The expression levels of Nrf2 and its target markers were distinctly elevated in the ischemic brain region. Ginseng pretreatment elicited robust neuroprotection against the deterioration of acute cerebral ischemia damage in an Nrf2-dependent manner over 7 days, revealed by the reductions of neurological deficits score (P≤0.05, n=7-10), infarct volume and brain edema (P≤0.05, n=5-7), as well as the enhanced expression levels of Nrf2 target antioxidant proteins and anti-inflammation mediators (P≤0.05, n=4) compared to WT controls. In both ischemic striatum and cortex, the dynamic pattern of attenuated reactive gliosis in astrocytes and microglia, including affected astrocytic dysfunction in glutamate metabolism and cell osmotic water permeability, correlated well with the Nrf2-dependent neuroprotection by Ginseng. Furthermore, such neuroprotective benefits extended to the late phase of ischemic brain damage after HI, as evidenced by the improvements in neurobehavioral outcomes, infarct volume and brain edema.

Conclusion:
Overall, pretreatment with Ginseng attenuates reactive gliosis and confers long-lasting neuroprotective efficacy against ischemic brain damage through an Nrf2-dependent mechanism.
Abstract WP136: Grafted Human Neural Stem Cell-Secreted Matrilin-2 Improves Functional Recovery in Ischemic-Stroke Rats
Authors: Azevedo-Pereira Ricardo L , Vu Jennifer , Du Fang , Bliss Tonya , Steinberg Gary K
Published: January 2019

Identifying the secretome of grafted stem cells is an important first step to elucidate how the graft communicates with the host brain, at the
molecular level
, to enhance post-stroke recovery. Here we use Translating Ribosome Affinity Purification (TRAP) to uncover the secretome of grafted human neural stem cells (hNSCs) and identify potential efficacious stem cell factors. Nude rats were subjected to permanent distal cerebral artery occlusion; 7d later hNSCs expressing GFP under a ribosomal-specific promoter were transplanted into the cortex of stroke (S) and naive (N) rats. The graft site was dissected 7d later and processed using TRAP to isolate ribosome-bound RNA from the grafted hNSCs. TRAP-isolated RNA was subjected to RNA sequencing and 479 differentially expressed genes were found between hNSC grafts in S and N brains. Of these, 21 genes encode secreted proteins, 14 of which were upregulated in hNSCs grafts in the stroke-injured brain. Pearson Correlation analysis revealed that the expression level of 9 of the 14 genes positively correlated with functional recovery. Gene Ontology (GO) analysis of the 14 genes identified the top enriched biological process as Response to Wounding which is related (i.e. a direct ancestor in the GO tree) to inflammatory response and axon injury. Three genes were present in this GO term: NOG, MATN2 and WNT1. MATN2 encodes matrilin-2, a protein known to be involved in axon regeneration and inflammation.
In situ
hybridization and immunohistochemistry showed high expression of matrilin-2 in grafted hNSCs. To test if matrilin-2 could affect post-stroke recovery we infused human recombinant matrilin-2 or vehicle into the cortex of stroke-injured rats. Seven days post-infusion, rats receiving matrilin-2 showed greater behavior recovery than the vehicle group. As matrilin-2 promotes axon outgrowth we investigated if it activated Rac-1 GTPase, which is associated with axon sprouting. Recombinant matrilin-2 increased activation of Rac-1 in primary mouse neural cultures, compared to the control. Our data show that grafted hNSCs in the stroke-injured brain express MATN2 and that secreted matrilin-2 may be involved in hNSC-induced stroke recovery potentially via activation of Rac-1 GTPase and axon sprouting.
Abstract WP141: Neuroprotection by Mesenchymal Stem Cells (MSC) Administration Was Enhanced by Local Cooling Infusion (LCI) in Ischemic Rats
Authors: Wei Wenjing , Stone Christopher , Guan Longfei , Wu Di , Ji Xunming , Ding Yuchuan
Published: January 2019

Introduction:
Although mitochondrial transfer from MSCs to neurons has been found to be a promising strategy for the treatment of ischemic stroke, uncertainty regarding the appropriate quantity of MSCs and inefficient delivery to affected tissue have limited the applicability of this emerging therapy. In this study we sought, using LCI-mediated hypothermia, to provide a micro-environment conducive to mitochondrial homing and function, and thus to improve the neuroprotective efficacy of MSC mitochondrial transfer.

Methods:
Sprague-Dawley rats were subjected to 90min middle cerebral artery occlusion followed by 24h reperfusion. Rats were treated with either MSCs (1х10
5
), LCI (cold saline, 0.6 ml/min, 5min) or both. After 24h reperfusion, infarct volume and neurological deficits were examined. After 28d, long-term functional outcomes were evaluated using foot-fault and rota-rod testing. In parallel, human neural SH-SY5Y cells were investigated
in vitro
using 2h oxygen-glucose deprivation (OGD), followed by MSC co-culture, with or without hypothermia (34°C, 4h). Mitochondrial transfer was assessed by O
2
consumption, extracellular ATP levels, mitochondrial membrane potential (MMP) in co-culture supernatant, and quantity (Western blot) of mitochondrial transfer related protein Rho GTPase Miro 1. Neural cell viability and intracellular ATP were measured at 6 h and 24 h after OGD.

Results:
After 24h reperfusion, MSC and LCI groups showed significant decreases in infarct volume and neuronal deficit. After 28d, the combination therapy group showed significantly greater long-term recovery than either of the monotherapy groups. With hypothermia, cell culture showed increased extracellular ATP, MMP and O
2
consumption in supernatant, cell viability, and neuronal intracellular ATP, indicating that MSC mitochondrial transfer to neurons was enhanced by hypothermia. Miro 1 was observed to be upregulated in the combination group, indicating its involvement in the transfer mechanism.

Conclusion:
Therapeutic hypothermia, by upregulating Miro 1 and thus improving transfer, greatly enhanced MSC mitochondrial transfer-mediated neuroprotection in ischemic stroke. This combined approach may facilitate the clinical translation of this therapy.