bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 15: Trends in Performance and Outcomes of Carotid Endarterectomy Among Elderly Medicare Beneficiaries, 2003-2010
Authors: Lichtman Judith H , Jones Michael R , Sheffet Alice J , Howard George , Wang Yun , Leifheit-Limson Erica , Lal Brajesh K , Brott Thomas G
Published: July 2021

Background:
Carotid endarterectomy (CEA) is the leading procedure for carotid stenosis, yet national data on trends in rates and outcomes are limited. We determined CEA rates among Medicare beneficiaries and evaluated mortality and readmission over 8 years.

Methods:
We used Medicare fee-for-service data to identify beneficiaries aged ≥65y who had their first CEA (ICD-9 38.12) from 2003-2010 and calculated annual rates per 100,000 person-years (PY). We fit mixed models to assess trends in patient-level outcomes, adjusting for demographics, comorbidities, and symptomatic status. We also evaluated hospital-level trends by calculating risk-standardized mortality (RSMR) and readmission (RSRR) rates. A spatial mixed model adjusted for age, sex, and race was fit to calculate county-specific risk-standardized CEA rates in 2003-2004.

Results:
There were 505,966 unique CEA hospitalizations. The annual number of CEA discharges decreased from 81,604 in 2003 to 47,597 in 2010 (42% decrease), though the patient characteristics remained largely similar. The national CEA rate was 283 per 100,000 PY in 2003, and there was considerable geographic variability (Figure A). This rate decreased each year to a low of 172 per 100,000 PY in 2010. The rate of stroke or death within 30 days decreased from 3.2 to 2.7%, with a significant adjusted annual reduction of 3% (Figure B). Annual reductions in other short- and long-term outcomes were similar, ranging from 2-3%. The median hospital-level 30-day RSMR decreased over time from 0.99 to 0.57%, while the variation between hospitals increased (interquartile range of 0.7-1.67 percentage points). The 30-day RSRR decreased from 11.0 to 10.1%, but there was more homogeneity across hospitals and years.

Conclusions:
CEA use among Medicare patients decreased dramatically from 2003-2010, while mortality and readmission outcomes improved. The relative importance of biological and sociological mechanisms for these trends merits further study.
Abstract 154: Correlation Between Site of Venous Occlusion and Clinical Syndromes in Cerebral Venous Thrombosis
Authors: Barboza Miguel A , Chiquete Erwin , Cantú-Brito Carlos , Colín Jonathan , Quiroz-Compean Alejandro , Arauz Antonio
Published: July 2021

Introduction:
Cerebral venous thrombosis (CVT) is an uncommon cerebrovascular condition, which presents with a wide spectrum of symptoms' onset and clinical syndromes.

Hypothesis:
We assessed the hypothesis that there is a correlation among the main clinical syndromes in CVT and the sites of venous occlusion; also we analyzed functional outcome on each clinical syndrome in the acute setting (30-days).

Methods:
This is a retrospective analysis from a systematic database of hospitalized patients from January 1979 to December 2014. Univariate and adjusted multivariate models were used to evaluate in a first step, association between clinical syndromes and affected vessels, and in a second step functional outcome in the acute setting (30-day follow-up). Clinical syndromes were classified as: focal syndrome, encephalopathy, isolated intracranial hypertension, meningeal syndrome. Affected vessels were classified as isolated thrombosis or vessels combinations. Functional outcome was based on modified Rankin score (mRs) at 30- and 90-day (good functional outcome, mRs = 0-2).

Results:
467 confirmed CVT patients (81.6% women, median age: 29 years, IQR: 22-38 years). Isolated superior sagittal sinus (82.0%), lateral sinus (50.1%), and the combination of them (22.1%) were the most prevalent affected vessels. Good functional outcome was present in 359 (76.9%) and 394 (84.4%) of all patients, at 30- and 90-day respectively. Focal syndrome was associated with hemorrhagic (OR 11.8, 95% CI 5.59-25.0); encephalopathy with the combination of Vein of Galen + Straight sinus (OR 6.52, 95% CI 2.13-19.9); isolated intracranial hypertension was associated with the absence of parenchymal lesion (OR 71.8, 95% CI 25.1-205); meningeal syndrome was associated with the combination of deep and superficial venous thrombosis (OR 3.22, 95% CI 1.61-6.43). Good functional outcome at 30- and 90-day was mainly associated to absence of encephalopathy (HR 0.74) and absence of meningeal syndrome (HR 0.85).

Conclusions:
Focal syndrome depends on the type of parenchymal lesion; encephalopathy depends on the compromise of deep venous system; the strongest associations for 30-day mortality were found on the presence of meningeal and focal syndromes.
Abstract 156: Poor Correlation Between Non-contrast CT (NCCT) Aspects and CT Perfusion (CTP)-derived Ischemic Core Volumes
Authors: Haussen Diogo C , Dehkharghani Seena , Rangaraju Srikant , Anderson Aaron , Frankel Michael , Belagaje Samir , Rebello Leticia , Nogueira Raul
Published: July 2021

Introduction and Objectives:
The best imaging method for selecting patients for thrombectomy remains unknown. We aim to evaluate the correlation between ASPECTS and RAPID automated CT perfusion (CTP) ischemic core volumes.

Methods:
This was a retrospective review of a prospectively collected interventional database. We included patients from January 2011-February 2015 with MCA-M1, MCA-M2 or ICA-terminus occlusions that underwent good quality RAPID CTP. The correlation between ASPECTS and CTP-derived ischemic core volumes (CBF<30% contralateral hemisphere) was analyzed.

Results:
A total of 188 were included. Mean age was 62.4±14.8, 51% were males, 71% had hypertension, 34% dyslipidemia, 33% atrial fibrillation, 21% diabetes, and 37% received IV-tPA. Mean baseline NIHSS was 17.1±5.4 and ASPECTS 7.7±1.5. Time from last-known-normal to groin puncture was 6.9±4.3 hours. Sixty-one percent had MCA-M1, 21% MCA-M2, and 18% ICA-terminus occlusions. Seventy-two percent were treated with stent-retrievers, leading to 82% mTICI 2b-3 reperfusion, 9% parenchymal hemorrhages, 54% mRS0-2 and 11% mortality at 90 days. The correlation between ASPECTS and CTP-derived ischemic core was weak (rho 0.27; p<0.01). The attached figure demonstrates the very wide variability of ischemic core volumes across specific ASPECTS.

Conclusion:
There is wide variability of CTP-derived ischemic core volumes within specific ASPECTS. Patient selection may significantly be affected by the imaging selection method.
Abstract 163: Frequency and Determinants of Hyperacute Stroke Progress Before Hospital Arrival and During Initial ED Course
Authors: Sanossian Nerses , Shkirkova Kristina , Starkman Sidney , Liebeskind David S , Hamilton Scott , Stratton Samuel , Eckstein Marc , Pratt Franklin D , Conwit Robin , Saver Jeffrey L ,   FAST-MAG Investigators and Coordinators
Published: July 2021

Background:
Many patients will experience progression of stroke symptoms and deteriorate on route prior to first assessment in the emergency department (ED); others may deteriorate early in the ED course prior to establishment of final diagnosis. We describe the early clinical course among hyperactue stroke patients evaluated by paramedics <2 hours from symptom onset.

Methods:
We analyzed patients in the NIH Phase 3 Field Administration of Stroke Therapy - Magnesium (FAST-MAG) multi-ambulance, multihospital trial enrolling prehospital acute stroke patients ≤2 hours from last known well. Three serial Glasgow Coma Scale (GCS) exams were performed: 1) in the field by at enrollment; 2) immediately upon ED arrival by ED staff; and 3)early post-arrival by trained study nurses. Clinical deterioration (CD) was defined as a 2-point deterioration in GCS from the prior exam.

Results:
Among the 962 patients, meeting study criteria, mean age was 69 (SD13) years, 42% female, 24% Hispanic ethnicity, 79% white, 12% Black, 8% Asian, with final diagnosis of cerebral ischemia in 713 (74%), intracranial hemorrhage in 213 (22%) and mimic in 40 (4%). Median time from last known well to initial paramedic GCS was 23 mins (IQR 14-42), to ED arrival GCS 45.5 mins (37-50) and to early post-arrival GCS 150 mins (120-180). Overall, neurologic deterioration in 166/962 (17.3%), including 60 (6.2%) with deterioration only in the prehospital period, 59 (5.1%) with deterioration only in the early post-arrival period, and 57 (5.9%) with deterioration in both.

Factors associated with prehospital CD were ICH diagnosis,23% vs. 9%, p<0.001,) and lower prehospital GCS, 14 (IQR 12-15) vs. 15( IQR 15-15), p<0.001. Factors associated with post-arrival CD included ICH diagnosis (24% vs. 7%, P<0.001and prehospital deterioration (20% vs. 10%, p=0.001). Age, gender, race and ethnicity were not associated with deterioration.

Conclusions:
Stroke progression is common in the hyperacute period, both prior to ED arrival and early after arrival. Intracranial hemorrhage causes neurologic deterioration 2-3 times as frequently as acute cerebral ischemia, both before and soon after ED arrival.
Abstract 165: Age Related Variations in Improvement in Door-to-Needle Times in Acute Ischemic Stroke: Findings From Target: Stroke Phase I
Authors: Fonarow Gregg C , Zhao Xin , Smith Eric , Saver Jeffrey , Reeves Mathew , Bhatt Deepak , Schulte Philip , Xian Ying , Hernandez Adrian , Peterson Eric , Schwamm Lee H
Published: July 2021

Background:
While shorter door-to-needle (DTN) times with intravenous tPA is associated with better outcomes, prior studies have demonstrated that older patients are less likely to be treated within 60 minutes. Whether stroke quality improvement programs can impact care to a similar degree for older and younger patients has not been well studied. This study aims to assess the improvements in DTN times before and after the launch of Target: Stroke Phase I in 2010 among different age groups.

Methods:
Target: Stroke identified and disseminated 10 best practice strategies, provided clinical decision support tools, and set hospital recognition goals. Rates of DTN times ≤60 minutes and cumulative improvements pre- 2003-2009 were compared to post-Target Stroke 2010-2013 for patients age <60, 60-69, 70-79, ≥80 years. Data were adjusted for patient and hospital characteristics, including stroke severity.

Results:
There were 71,169 intravenous tPA treated patients (27,303 pre-; 43,866 post-Target Stroke) from 1030 GWTG-Stroke participating hospitals. Patients were median age 72 (IRQ 60-82). Overall, patients with DTN times ≤ 60 minutes increased from 26.5% (95% CI 26.0-27.1%) pre-intervention to 41.3% (95% CI 40.8-41.7%) post-intervention (P<.0001), reaching 51.0% in 2013. Patients ≥80 years were less likely to have DTN times ≤ 60 minutes pre-TS. There were slightly greater cumulative improvements in DTN times among the older age groups after adjustment for other patient and hospital characteristics (Table). While the differences in DTN ≤ 60 minutes were narrowed, they were not eliminated.

Conclusions:
The implementation of Target: Stroke was associated with significant improvements in DTN times across all age groups, but differences by age, while narrowed, still persisted post-Target: Stroke. Despite overall progress, additional efforts will be needed to address these age related differences in timely stroke care.
Abstract 169: Human Dose tPA Improves Functional Outcomes in Both Sexes in Embolic Model of Stroke: Differential Effect on Hemorrhagic Transformation
Authors: Li Weiguo , Valenzuela John Paul , El-Shafey Sally , Ward Rebecca , Guo Xinyue , Fagan Susan C , Ergul Adviye
Published: July 2021

Tissue plasminogen activator (tPA) is the only FDA-approved therapeutic agent for the treatment of acute ischemic stroke. The widespread use of tPA is still limited by the fear of hemorrhagic transformation (HT) and underlying mechanisms are actively being pursued in preclinical studies. However, experimental models use a 10 times higher dose of tPA than the clinical dose (10 mg/kg) and mostly employ only male animals. In this translational study, we hypothesized that low dose tPA would achieve clot lysis, decrease neurovascular injury and improve functional outcomes in both sexes. Aged-matched male and female Wistar rats (n=5-7) have been treated with or without tPA (1 mg/kg, i.v.) at 90 min after embolic middle cerebral artery occlusion with a fibrin-rich humanized clot. The neurological deficiency (Bederson score and adhesive removal test -ART), infarct size, HT index, and edema ratio were assessed 3 days after surgery (Table). Compared to male rats, female rats had smaller infarct size and better functional outcomes as previously reported in the literature. tPA decreased infarct size in both sexes. tPA reduced edema in males with no effect in females. While there was no difference in HT between males and females without tPA, HT was less in the female + tPA group. Functional outcomes, especially ART, were significantly improved with tPA in both sexes. These data suggest that 1) thrombolysis with a low dose tPA is effective in improving short term outcomes in both sexes, and 2) better functional outcomes in females are further enhanced with tPA. Additional studies are in progress to explore long term effects and the impact of therapeutic window, age and sex steroids on outcomes as well as the underlying mechanisms contributing to less HT in females.
Abstract 170: Arginase Contributes to Delayed Constriction of Large Cerebral Arteries in a Model of Subarachnoid Hemorrhage
Authors: Sun Weiyun , Kibler Kathleen K , Kwansa Herman , Kulikowicz Ewa , Tang Weizhu , Berkowitz Dan E , Santhanam Lakshmi , Koehler Raymond C
Published: July 2021

Introduction:
Increased arginase activity can limit nitric oxide synthase activity and contribute to age-related increase in aortic stiffness.

Hypothesis:
Subarachnoid hemorrhage (SAH) produces a delayed increase in arginase activity that contributes to delayed decreases in diameter of major cerebral arteries.

Methods:
Male rats underwent injection of blood into the cisterna magna on day 0 and again on day 2. Shams had double injection of artificial CSF. Measurements of arginase activity on vessels in the Circle of Willis and pia matter were made with an assay based on the conversion of radiolabeled arginine to urea. Measurements of diameter of basilar, posterior (PCA), middle (MCA), and anterior (ACA) cerebral arteries were made ex vivo after perfusion with paraformaldehyde and black latex casting.

Results:
Arginase activity (nmol of urea/min/mg of protein) increased from the control value of 13±3 (±SE; n=17) to 24±6 (n=6) at 3 days, 36±14 (n=4) at 5 days, and 48±16 (n=9) at 7 days after SAH and then recovered at 10 days (14±5; n=4) and 14 days (18±6; n=5) after SAH. Infusion of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) for 7 days after SAH with an ip osmotic pump blocked the increase in arginase activity (10±2; n=4). Assessment of arterial diameter at 3, 5, 7, 10, and 14 days after SAH revealed the smallest diameters occurring at 7 days (except for MCA which occurred at 5 days). Continuous ip infusion of 10 mg/kg/day ABH significantly attenuated the decrease in diameter (μm) 7 days after SAH in PCA (sham = 249±9, n=8; SAH = 209±12, n=10; SAH+ABH = 255±9, n=6) and ACA (sham = 178±11; SAH = 141±11; SAH+ABH = 198±10). Effects on basilar artery were of marginal significance (P=0.065).

Conclusion:
SAH produces an increase in vascular arginase activity that is temporally related to delayed decreases in diameter of cerebral arteries. Inhibition of arginase activity prevents the decrease in diameter at 7 days after SAH, thereby indicating a contribution of arginase to delayed arterial constriction/remodeling in post-fixed arteries.
Abstract 171: The Effect of Ischemia and Reperfusion and Tissue Plasminogen Activator on Cerebrovascular Function, Oxidative Stress and Polymorphonuclear Neutrophils in Ovariectomized Female Rats
Authors: Ahnstedt Hilda , Sweet Julie , Cruden Patrick , Bishop Nicole , McCullough Louise D , Cipolla Marilyn
Published: July 2021

Introduction:
Stroke is a growing health problem in women. We previously showed that ischemia/reperfusion (I/R) in male rats reduced tone in middle cerebral arteries (MCA) but enhanced tone in parenchymal arterioles (PA). Tissue plasminogen activator (tPA) may contribute to vascular dysfunction, oxidative stress and inflammation. However, vascular dysfunction and the effect of tPA have not been studied in females.

Hypothesis:
I/R in ovariectomized (OVX) female rats impairs MCA and PA function differentially, increases vascular oxidative stress and intravascular polymorphonuclear neutrophils (PMN). tPA has an additive effect on the vascular dysfunction after I/R.

Methods:
OVX female rats underwent 2 h MCA filament occlusion (n=16) or sham surgery (n=17) with 30 min reperfusion. tPA (1 mg/kg, i.v.) or vehicle (Vh) was given 10 min prior to reperfusion. Myogenic tone and reactivity to nitric oxide synthase (L-NNA, 10-4M) and Rho kinase (Y27632, 10-8 to 10-5M) inhibition were measured in pressurized MCA and PA. MCA were stained for F-actin and 3-nitrotyrosine (NT), a marker of oxidative stress. Brain intravascular PMN were identified with myeloperoxidase and collagen IV using immunohistochemistry, and counted blinded to group.

Results:
In MCA, I/R decreased tone at 75 mmHg (Sham Vh: 26±3%, Sham tPA: 27±3% vs. MCAO Vh: 21±2%, MCAO tPA: 21±3%, P<0.05) and reduced constriction to L-NNA (Sham Vh: 35±3%, Sham tPA: 34±2% vs. MCAO Vh: 20±3%, MCAO tPA: 25±3%, P<0.01) with no effect on dilation to Y27632. In PA, myogenic tone (at 40 mmHg) and reactivity to L-NNA and Y27632 was not affected by I/R. PA were less sensitive to Y27632 than MCA after I/R with tPA (EC50: 2.0±0.5 vs. 0.8±0.1 μM, P<0.05). F-actin and NT in the MCA were not affected by I/R or tPA. The number of PMN was small (<0.8±0.3/mm2) in all groups but there was a trend to increased ipsilateral intravascular PMN after I/R with tPA.

Conclusions:
The differential effect of I/R on MCA vs. PA in OVX females on tone suggest parenchymal blood flow may be restricted during reperfusion that could increase perfusion deficits. tPA had no effect on tone in MCA and PA but might enhance intravascular PMN, implicated in no-reflow after I/R. Therapies to alleviate parenchymal vasoconstriction may improve stroke outcome in females.
Abstract 178: Cerebral Microbleeds and Risk of Intracerebral Hemorrhage Post Intravenous Thrombolysis (IVT)
Authors: Singh Mantinderpreet , McCormack Michael , Goyal Nitin , Tsivgoulis Georgios , Nearing Katherine , Elijovich Lucas , Alexandrov Anne W , Liebeskind David S , Alexandrov Andrei V , Zand Ramin
Published: July 2021

Background:
Symptomatic intracranial hemorrhage (sICH) is the most feared complication of IVT for ischemic stroke, and patients who have cerebral microbleeds (CMBs) can potentially be at greater risk. This study aims to assess the association between the number and location of CMBs on MRI and the incidence of sICH post IVT.

Subjects & Methods:
We analyzed consecutive IVT-treated patients during a 5-year period (2010-2014) at a tertiary care stroke center. Patients without pre or within 24-hour post-treatment MRI were excluded from the study. All neuroimaging studies were examined by two independent readers and a third reader as a tie-breaker. CMBs were defined according to recent consensus recommendations for MRI studies as round or oval, hypointense lesions with associated blooming on T2*-weighted MRI and can be up to 10 mm in diameter. Outcome measures in our study were occurrences of sICH and were defined according to European Cooperative Acute Stroke Study (ECASS)-III criteria combined with clinical deterioration of ≥4 points on NIHSS, or death.

Results:
Of 589 IVT patients (mean age 61±15 years, 51% men, median admission NIHSS: 6 points [IQR 3-11]), 97 patients had CMBs on T2*-MRI. Ten patients had more than 10, while the remaining 87 patients had 1-10 CMBs on T2*-MRI. The rates of sICH did not differ between patients with and without CMBs (4.1% vs. 3.5%; p=0.75). However, sICH occurred more frequently (p=0.0031) in patients with >10MBs (30 %, 95%CI by the adjusted Wald method: 10%-61%) than in patients with 1-10 CMBs (1 %, 95%CI: 0%-7%). After adjusting for potential confounders, the presence of >10 CMBs on T2*-MRI was independently (p=0.0004) associated with a higher likelihood for sICH [OR: 13.4, 95% CI: 3.2-55.9] in multivariate logistic regression analyses. Among patients with sICH in >10 CMBs group, one patient developed multiple ICHs in different regions and one developed a large thalamic ICH remote from the infarcted area. In both these patients the location of ICHs corresponded to the location of CMBs on T2*-MRI. The third patient developed sub-arachnoid hemorrhage.

Conclusions:
Our findings indicate a higher risk of sICH after IVT when more than 10 CMBs are present. However, it does not demonstrate an increased risk of sICH among patients who have ≤ 10 CMBs.
Abstract 19: Multicenter Prospective Trial of Intracranial Stent Placement in Patients With Symptomatic High-grade Intracranial Stenosis
Authors: Gao Peng , Jiao Liqun , Zhao Zhenwei , Cai Yiling , Li Tianxiao , Shi Huaizhang , Wu Wei , He Weiwen , Yin Long , Huang Shengping , Zhu Fengshui , Wang Daming , Qureshi Adnan I , Ji Xunming , Ling Feng
Published: July 2021

Purpose:
Based on the results of SAMMPRIS trial, modifications in patient selection and procedural aspects for intracranial stent placement have been recommended. We performed a multicenter prospective single arm trial to determine if such modifications will result in lower rates of peri-procedural stroke and/or death.

Materials and Methods:
The study enrolled patients with recent transient ischemic attack or ischemic stroke (excluding lacunar ischemic events) related to high-grade (70-99% in severity) stenosis of a major intracranial artery. Patients were treated using angioplasty and self-expanding stent after 3 weeks of index ischemic event at one of the 10 high volume centers in China. An independent neurologist ascertained the occurrence of any stroke and/or death within one month after the procedure.

Results:
A total of 100 consecutive patients were recruited. The target lesions were located in middle cerebral artery [M1] (n=38, 38%), intracranial internal carotid artery (n=17, 17%), intradural vertebral artery (n=18, 18%), and basilar artery (n=27, 27%). The technical success rate of stent deployment with residual stenosis <50% was 100%. The overall one-month stroke and/or death rate was 2% (95% confidence interval 0.7% - 4.7%). Two ischemic strokes occurred in pontine region (perforator distribution) in patients following angioplasty and stent placement for basilar artery stenosis.

Conclusion:
The results of this prospective multi-center study demonstrated that modifications in patient selection and procedural aspects can substantially reduce the one-month stroke and/or death rate following intracranial stent placement.
Abstract 190: Safety, Tolerability, Pharmacokinetics and Efficacy of Intraventricular Sustained Release Nimodipine (EG-1962) for Subarachnoid Hemorrhage
Authors: Hanggi Daniel , Etminan Nima , Steiger Hans-Jakob , Macdonald R. Loch , Mayer Stephan , Mocco J. , Aldrich Francois , Diringer Michael N , Hoh Brian L , Strange Poul , Miller Michael , Faleck Herbert J
Published: July 2021

Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. EG-1962 is a sustained release formulation of nimodipine for intraventricular delivery into the subarachnoid space while avoiding dose-limiting hypotension common with systemic administration. We conducted a phase 1/2a multicenter, controlled, randomized, open label, dose escalation study to determine the maximum tolerated dose (MTD) and assess safety, tolerability, pharmacokinetics and clinical outcome at 90 days on the extended Glasgow outcome scale (GOSE) of a single intraventricular dose of EG-1962 (www.clinicaltrials.gov Identifier: NCT01893190). Subjects with aSAH repaired by clipping or coiling were randomized within 60 hours of aSAH to EG-1962 or oral nimodipine if they were World Federation of Neurological Surgeons grade 2 to 4 and had a ventricular catheter. Cohorts of 12 subjects received 100, 200, 400, 600, 800 or 1200 mg EG-1962 (9 per cohort) or oral nimodipine (3 per cohort). The MTD was 800 mg EG-1962. Plasma nimodipine concentrations after administration of EG-1962 were sustained for 21 days and increased in a dose-dependent fashion. Cerebrospinal fluid nimodipine concentrations with EG-1962 were orders of magnitude higher than in plasma and with oral nimodipine. There was one serious adverse event (possible allergic reaction) related to EG-1962 (400 mg) and two EG-1962 dose limiting toxicities (increased intracranial pressure, 400 and 800 mg); all were without clinical sequelae. There was no EG-1962-related hypotension as compared to hypotension in 17% (3/18) with oral nimodipine. Favorable outcome (GOSE 6-8) was achieved in 27 of 45 (60%) EG-1962 subjects (5 of 9 with 100, 6 of 9 with 200, 7 of 9 with 400, 4 of 9 with 600 and 5 of 9 with 800 mg) and 5 of 18 (28%) oral nimodipine subjects. Improved efficacy was supported by reduction in delayed cerebral ischemia (15/45 [33%] EG-1962 versus 11/18 [61%] oral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]) in EG-1962 subjects. Intraventricular EG-1962 was safe and tolerable to 800 mg, associated with sustained and dose-dependent nimodipine plasma concentrations,improved clinical outcome and reduced delayed cerebral ischemia and use of rescue therapy after aSAH.
Abstract 194: Cognitive Outcome in Acute Simvastatin Treatment for Aneurysmal Subarachnoid Hemorrhage
Authors: Wong George ,   HDS-SAH Study Group
Published: July 2021

Objectives:
Experimental evidence has indicated the benefit of simvastatin in the treatment of subarachnoid haemorrhage (SAH). Recently, acute simvastatin treatment was not shown to be beneficial in neurological outcome using modified Rankin Scale. Cognitive function is another important dimension of outcome assessment and yet had not been investigated in statin studies for aneurysmal subarachnoid hemorrhage. We therefore explored whether acute simvastatin treatment would improve cognitive outcomes.

Methods:
The study recruited SAH patients with acute simvastatin treatment enrolled in a randomized controlled double-blinded clinical trial (ClinicalTrials.gov Identifier: NCT01038193). A control cohort of SAH patients without simvastatin treatment was identified with propensity score matching of age and admission grade. Primary outcome measure was Montreal Cognitive Assessment (MoCA). Secondary outcome measures were delayed ischaemic deficit (DID), delayed cerebral infarction, modified Rankin Scale (mRS), and Mini-Mental State Examination( MMSE).

Results:
Fifty-one SAH patients with acute simvastatin treatment and 51 SAH patients without simvastatin treatment were recruited for analysis. At 3 months, there were no differences in MoCA scores (MoCA: 21+/-6 vs. 21+/-5, p=0.772). MoCA-assessed cognitive impairment (MoCA<26) was not different (75% vs. 80%, OR 0.7, 95%CI 0.3 to 1.8, p=0.477). There were also no differences in DID, delayed cerebral infarction, favorable mRS outcome, and MMSE scores, and MMSE-assessed cognitive impairment between both groups.

Conclusions:
The current study does not support that acute simvastatin treatment improves cognitive outcome after aneurysmal subarachnoid hemorrhage.
Abstract 20: Higher Stroke Risk With Lower Blood Pressure in Hemodynamic Vertebrobasilar Disease: Analysis From the Prospective Multicenter VERiTAS Study
Authors: Amin-Hanjani Sepideh , Turan Tanya , Du Xinjian , Rose-Finnell Linda , Pandey Dilip K , Richardson DeJuran , Elkind Mitchell S , Zipfel Gregory J , Liebeskind David S , Silver Frank L , Kasner Scott E , Derdeyn Colin P , Gorelick Philip B , Charbel for the VERiTAS Study Group Fady T
Published: July 2021

Introduction:
Despite theoretical concerns regarding hypoperfusion in patients with large artery occlusive disease, strict blood pressure (BP) control has become adopted as a safe strategy for stroke risk reduction. We examined the relationship between BP control, flow, and risk of subsequent stroke in the prospective Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke (VERiTAS) Study.

Hypothesis:
Strict BP control may be less efficacious and safe in flow compromised patients with symptomatic vertebrobasilar (VB) disease.

Methods:
VERiTAS enrolled patients with recent VB TIA or stroke and ≥50% atherosclerotic stenosis or occlusion of vertebral or basilar arteries. Hemodynamic status using large vessel flow in the VB territory was designated as low or normal flow using quantitative MRA. Patients underwent standard medical management and follow-up for primary outcome event of VB territory stroke. Mean SBP during follow-up (<140 vs. ≥140 mm Hg) and flow status were examined relative to subsequent stroke risk using Cox proportional hazards analysis.

Results:
The 72 enrolled subjects had an average of 3.8±1.2 BP recordings over the 20 ±8 months of follow-up; 40 (56%) had mean SBP of <140 mm Hg. The BP groups were largely comparable for baseline demographics, risk factors, and stenosis severity. There was a trend to a higher risk of subsequent stroke in patients with SBP <140 mm Hg (20% vs. 6.2%, p=0.17). As shown in the Figure, comparing subgroups stratified by SBP and hemodynamic status revealed that patients with both low flow and SBP <140 mm Hg (n=10) had a higher risk of subsequent stroke with HR 4.5 (CI 1.3-16.0, p=0.02) compared to the other subgroups combined.

Conclusion:
Among a subgroup of patients with VB disease and low flow, strict BP control (SBP <140) appears to increase the risk of recurrent stroke. This finding within a modest sized cohort supports the strategy of hemodynamic assessment to inform decision making regarding BP management.
Abstract 21: Hypo-intensity of MRI Vessel Wall Imaging Indicates Advanced Intracranial Atherosclerosis With Lipid Core
Authors: Yang Wenjie , Chen Xiangyan , Zhao Hailu , Niu Chunbo , Wong Kasing , Ng HoKeung
Published: July 2021

Objective:
Although Magnetic Resonance Imaging (MRI) vessel wall imaging could visualize the pathology of intracranial arterial disease, signal changes are poorly interpreted due to lacking of cerebral artery specimens. Based on a MRI-histology comparison study on a series of post-mortem cerebral arteries, we aimed to examine the occurrence of hyper-, iso- and hypo-intensity on T1-weighted fat-suppressed images of MCA plaques, which might be suggestive of different plaque components.

Methods:
Fifty-eight pairs of MCAs were imaged at 1.5T MRI with T1-weighted

Table 1:
The distribution of different atherosclerotic phenotypes among MCA plaques with iso-, hyper- and hypo-intensity on T1-weighted fat-suppressed images fat-suppressed- and T2-weighted sequence. MRI was performed in the postmortem brains to scan the cross-sections of MCAs with barium expanding the artery lumen. The MCAs were then removed for histopathologic processing and atherosclerotic plaque classification, which was used as a reference standard to interpret the signal changes on MRI pictures.

Results:
A total of 76 MRI vessel wall images were adequate for signal changes interpretation. On T1-weighted fat-suppressed images of MCA plaques, hyper-intensity was revealed on 34 vessels (44.7%), iso-intensity on 24 vessels (31.6%) and hypo-intensity was revealed on 18 samples (23.7%). There was a trend that iso-intensity indicated lower grade atherosclerosis and hypo-intensity represented advanced atherosclerosis, while hyper-intensity was suggestive of median grade atherosclerotic plaques. Further analysis demonstrated that nearly all hypo-intensity was found to be histology-verified advanced atherosclerosis with lipid core formation.

Interpretation:
Signals of hypo-intensity on T1-weighted fat-suppressed images of MCA plaques may be useful in stratification of stroke patients with intracranial atherosclerosis.
Abstract 217: Venous Thromboembolism in Patients With Spontaneous Intraventricular Hemorrhage- Results From the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR) III Trial
Authors: Shah Jharna N , Murthy Santosh B , McBee Nichol , Dlugash Rachel , Ram Malathi , Lane Karen , Awad Issam , Hanley Daniel F , Ziai Wendy
Published: July 2021

Introduction:
Intraventricular hemorrhage (IVH) occurs in about 40% of patients with intracerebral hemorrhage (ICH) and is associated with higher mortality and worse outcomes than ICH patients without IVH. Venous thromboembolism (VTE) is common in ICH patients but data in IVH patients are limited.

Methods:
Prospective analysis of adjudicated adverse event reporting of VTE (deep venous thrombosis (DVT) and pulmonary embolism (PE)) during first 180 days in 500 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing external ventricular drain (EVD) + intraventricular recombinant tissue plasminogen activator (rtPA) vs EVD + placebo for treatment of obstructive IVH and intracerebral hemorrhage (ICH) volume <30cc. Outcome measures were 90-day and 180-day mortality, ICU and hospital length of stay (LOS), catheter tract hemorrhage as well as predictors of VTE.

Results:
VTE was reported in 63 patients (13%); 46 (9%), 11 (2%) and 6 (1%) patients had DVT, PE or both, respectively. VTE occurred between 4 and 209 days from ICH onset. VTE pharmacologic prophylaxis was initiated in 404 (81%) patients, at median of 4 days [range:1-48] from ICH onset. Unfractionated and low molecular weight heparin were used in 71% and 29% patients, respectively. These patients had similar rates of VTE but showed a trend towards higher catheter tract hemorrhages (25 vs 15%, p=0.056) as compared to those who did not receive VTE prophylaxis. Patients who developed VTE had similar 90-d and 180-d mortality and ICU LOS but had prolonged hospital LOS (p=0.012) as compared to those who did not develop VTE. On multivariable analysis, ICH volume was a significant predictor of development of VTE (OR 1.04, 95% CI: 1.01-1.07, p=0.024).

Conclusions:
The association of IVH with VTE is important but complex, in spite of consideration of early VTE prophylaxis. There was trend towards higher catheter tract hemorrhages in patients receiving VTE prophylaxis. ICH volume was a significant predictor of VTE development. However, mortality and ICU LOS were not affected by VTE development. These results form a basis for future correlation of VTE complications with treatment rendered (thrombolysis versus placebo), with upcoming unblinding of the trial.
Abstract 219: Tumor Necrosis Factor Receptor 1 and Subclinical Cerebrovascular Disease: the Levels of Inflammatory Markers in Treatment of Stroke Study
Authors: Elkind Mitchell S , McClure Leslie A , Luna Jorge M , Del Brutto Oscar H , Pikula Aleksandra , Benavente Oscar R
Published: July 2021

Background:
The role of inflammation in cerebral small vessel disease remains uncertain. Tumor necrosis factor-alpha receptor 1 (TNFR1) has been associated with atherosclerosis and risk of stroke. We hypothesized that TNFR1 concentrations would be associated with cerebral white matter disease (WMD) and subclinical infarcts in patients with recent lacunar stroke.

Methods:
Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, ancillary biomarker study nested within the Secondary Prevention of Small Subcortical Strokes trial (SPS3; www.clinicaltrials.gov unique identifier: NCT00059306), a Phase III trial in patients with recent lacunar stroke. Patients had blood samples collected at enrollment, and concentrations of inflammatory biomarkers, including TNFR1, were measured using ELISA at a central laboratory. Enrollment MRI scans were read centrally and interpreted for silent infarcts and burden of WMD using semi-quantitative scales. We compared proportions of patients with prior infarcts and WMD scores across quartiles of TNFR1, and used logistic regression to estimate odds ratios and 95% confidence intervals (OR, 95%CI) to examine the relationship between TNFR1 and subclinical disease after adjusting for demographics and comorbidities.

Results:
Among 1004 lacunar stroke patients with TNFR1 data (mean age 63.3 ± 10.8 years), 407 (40%) had infarcts besides the qualifying infarct; half the cohort had 0-4 white matter lesions, 27% had 5-8 lesions, and 23% had >=9 lesions. TNFR1 levels were associated with WMD score >=9 (OR per standard deviation (SD) TNFR1=1.2, 95%CI 1.0-1.4). Larger proportions of those in the top quartile of TNFR1, compared to those in the lowest, had ≥9 white matter lesions (29% versus 19%, p=0.026) and additional infarcts (45% versus 37%, p=0.28). After adjusting for demographics and comorbidities, the effect of TNFR1 on WMD score >=9 (adjusted OR per SD=1.1, 95%CI 1.0-1.3) and additional infarcts (adjusted OR 1.2, 95%CI 1.0-1.3) attenuated.

Conclusions:
Among recent lacunar stroke patients, TNFR1 concentrations were associated with prior or subclinical cerebrovascular disease. Future studies of TNF and TNF inhibitors in cerebral ischemic disease may be warranted.
Abstract 221: Tlr-4 Activation Decreases Brain Endothelial Cell Survival in Hypoxia/reoxygenation in Diabetes: Role of Necroptosis and Ferroptosis
Authors: Abdul Yasir , Hussen Nebat , Ergul Adviye
Published: July 2021

Introduction:
Diabetes increases bleeding into the brain and mediates vasoregression leading to poor stroke recovery. The iron released from the bleeding is neurotoxic but how it affects the repair of damaged blood vessels is not known. Ferroptosis and necroptosis are recently identified forms of regulated cell death. While ferroptosis is an iron-dependent process, activation of toll like receptor (TLR) mediate necroptosis. We hypothesized that 1) iron activates TLR4 signaling through oxidative stress and reduces viability and migration of brain microvascular endothelial cells (BMVECs), and 2) necroptosis and ferroptosis contribute to BMVEC death after hypoxia/reoxygenation in diabetes.

Methods:
To mimic increased HT (free iron) in diabetes, BMVECs isolated from diabetic rats were subjected to oxygen glucose deprivation (OGD) and iron (III) sulfate (0.1mM) with and without TLR4 neutralizing antibody (10ug/ml) or antioxidant N-acetyl cysteine (NAC; 1mM) for 6 hours, followed by 12 hours of reoxygenation. TLR4 and markers of necroptosis (RIPK3) and ferroptosis (citrate synthase; CS) were assessed by immunohistochemistry in brain sections of diabetic rats subjected to middle cerebral artery occlusion. In pilot experiments, BMVECS were treated with inhibitors of necroptosis (necrostatin; 100μM) or ferroptosis (ferrostatin-1(2μM)/TAK-242(10μM) during hypoxia and apoptosis (caspase-3)/necrosis (7AAD) were measured by flow cytometry.

Results:
Presence of iron in OGD reduced viability (% of normoxia, 76.9±3.1 vs 97.4±4.0 OGD alone) and both TLR4 inhibition (114±8.0) and NAC (112±5.0) prevented this effect (n=3, p<0.05). OGD reduced migration (in %, 31.7±3.1 vs 42.7±3.4) and iron did not have an additive effect (29.1±3.5). Both TLR4 inhibition (47.0±3.1) and NAC (54.4±4.8) prevented this effect (n=3, p<0.05). CS, TLR4 and RIPK3 colocalized to the vasculature after stroke. Inhibition of necroptosis and ferroptosis reduced the number of apoptotic and necrotic cells while increasing the number of viable cells.

Conclusions:
Necroptosis and ferroptosis contribute to endothelial cell death after hypoxia/reoxygenation via TLR4 activation. Inhibiting TLR4 signaling may prevent vasoregression and improve recovery after stroke in diabetes.
Abstract 41: Stroke Unit Evaluation of Sleep Apnea: Validity of Screening Tools and Use of a Portable Sleep Study
Authors: Aparicio Hugo J , Sturzoiu Tudor , Lau Helena W , Clark Judith , Grimes Julie , Masoud Hesham E , Nguyen Thanh N , Auerbach Sanford H , Pyatkevich Yelena G
Published: July 2021

Background:
Despite high prevalence in the stroke population, sleep apnea is underdiagnosed. Obstructive sleep apnea is associated with poor cardiovascular outcomes and treatment with continuous positive airway pressure has been shown to lower blood pressure. No standard exists for screening patients who present to the hospital with acute stroke. We assessed three screening tools, the Epworth Sleepiness Scale (ESS), Berlin Questionnaire (BQ), and STOP-BANG Questionnaire (STOP-BANG), along with the use of a portable sleep study device for evaluation of sleep apnea. Overnight polysomnography (PSG) was performed on a subset of patients on outpatient follow up.

Methods:
Patients admitted to the stroke unit at our hospital, over nine months, were screened for sleep apnea using the three instruments, ESS, BQ, and STOP-BANG. The patients were evaluated with a portable sleep study device, ApneaLink Air (ResMed, USA), prior to discharge. Respiratory effort, respiratory flow, pulse oximetry, and oxygen saturation were recorded and sleep apnea was determined by apnea-hypopnea index (AHI) ≥ 5. Predictions from the screening tools were compared to the portable sleep study and overnight PSG results. Sensitivity and specificity testing were used to assess the validity and reliability of the tools.

Results:
Sleep questionnaires were administered on 37 patients who underwent an overnight sleep study. Portable studies were used to evaluate 33 patients, and 13 PSGs were performed. Obstructive sleep apnea was diagnosed in 20 (69%) and central sleep apnea in 9 (31%). Cheyne-Stokes pattern breathing was observed in 2 (5%). Mean AHI was 18.3 + 21.8/hr and maximum AHI was 105.8/hr. Sensitivity for the ESS, BQ, and STOP-BANG were 0.39, 0.66, and 0.83 and specificity for these tools were 0.26, 0.33, and 0.29, respectively. In patients who underwent the portable sleep study and overnight PSG, 9/10 (90%) of the studies were concordant.

Conclusions:
The STOP-BANG questionnaire, administered to hospitalized stroke patients, had high sensitivity and low-moderate specificity in our study, compared to two other commonly used screening tools. Further, the feasibility of using an unattended inpatient portable sleep study on stroke inpatients is demonstrated.
Abstract 52: Clinical Impairment in Patients Followed With or Without Interventional Therapy in a Randomized Trial of Unruptured Brain Avms (aruba)
Authors: Mohr JP ,   The International ARUBA Investigators (21 co-authors), Overbey J R , Stapf Christian , Hartmann Andreas , Stefani Marco Antonio , Parides Michael K , Moquete Ellen , Moy Claudia S , Moskowitz Alan J , Cordonnier Charlotte , von Kummer Ruediger , Biondi Alessandra , Harkness Kirsty , Libman Richard , Kim Helen , Pile-Spellman John , Klijn CJM (Karin) ,   The Investigators at the 39 International ARUBA Cntrs
Published: July 2021

Background and Purpose:
A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA) compared outcome after interventional treatment of unbled brain AVMs with medical management. Follow-up data to assess pre-specified functional impairment after primary outcome events by treatment group and exploratory analyses by Spetzler-Martin grade are presented.

Methods:
We examined functional impairment using the modified Rankin scale score (mRS ≥2) at the time of primary outcome (death or stroke) by treatment group, and an exploratory analysis with these outcomes by Spetzler-Martin Grade. Analyses were performed both by intention to treat (as randomized) and as treated.

Results:
After a median of 42 months of follow-up, the median post-primary outcome event mRS for those ‘
as randomized
’ to medical management (MM) was 2 (IQR: 1,4) versus 3 (IQR: 1,5) in the interventional therapy (IT) arm. Values for those ‘
as treated’
, were 1 (IQR: 1,5) versus 4 (IQR: 2,5). The risk of functional impairment, as measured by an mRS ≥2 after a primary outcome event, was significantly lower for patients ‘
as randomized’
to MM (8/110, 7%) compared to IT (27/116, 23%) (HR 0.26, 95%CI 0.12, 0.57), and even lower for those
‘as treated’
(4/122, 3% vs 31/104, 30%; HR 0.09, 95% CI 0.03,0.27). Spetzler-Martin Grade and primary outcome events were not associated in the medical arm (p=0.80) but were so with increasing grades in the interventional arm (p=0.0002).

Conclusion:
In ARUBA, a death or stroke with a significant increase in functional impairment was more common for patients undergoing preventive intervention compared to those randomized to medical management.
Abstract 59: Extending the Time for Thombolysis in Emergency Neurological Deficits (EXTEND) - High Prevalence of Intracranial Vessel Occlusion in Wake-up-stroke Patients
Authors: Ma Henry , Campbell Bruce C , Parsons Mark W , Levi Christopher , Meretoja Atte , Churilov Leonid , Christensen Soren , Yassi Nawaf , Yan Bernard , Mitchell Peter , Sharma Gagan , Connelly Alan , Carey Leeane , Howells David , Chandra Ronil , Hsu Chung Y , Davis Stephen M , Donnan Geoffrey A ,   EXTEND Investigators
Published: July 2021

Background:
EXTEND is an investigator-initiated, randomised, double-blind and placebo-controlled Phase III trial of intravenous alteplase vs placebo in patients with ischemic stroke 4.5-9 hours from stroke onset or wake-up-stroke (WUS). The prevalence of intra-cranial vessel occlusion in WUS patients remains to be determined and can guide the development of optimal therapy for this unique group of stroke patients.

Objective:
To study the prevalence and characteristics of intra-cranial vessel occlusion in this WUS cohort.

Methods:
Ischemic stroke patients within 4.5-9 hours from stroke onset or with WUS (time of WUS onset defined as the midpoint between time to sleep and awakening with the stroke symptoms) are eligible for enrollment. Criteria for entry into the trial include perfusion-diffusion mismatch using a perfusion threshold of Tmax>6sec and a perfusion:diffusion lesion volume ratio of >1.2. Diffusion lesion volume must be <70mL based on assessment by automated RAPID software. Intra-cranial vessel occlusion was assessed on MR or CT angiogram performed at randomisation and 24 later. Two expert readers assessed these images independently.

Results:
97 patients had images with adequate quality, including 63 (65%) in the WUS group with median age of 77.0 yrs (IQR 67.0, 81.0) and NIHSS of 14.0 (9.0, 19.0). 62 of 63 patients (98%) had vessel occlusion with 44.4% involving M1 of the middle cerebral artery, 17.5% M2, 4.8% M3, 25.4% both internal carotid artery (ICA) and M1, 4.8% ICA alone and 3.1% the posterior cerebral artery. The median ischemic core volume was 15.0 ml (6.5, 31.5), Tmax>6 volume 88.5ml (58.0, 122.0), mismatch volume 65.5ml (42.8, 92.0), and ratio of 4.8 (2.5, 8.7). 19 patients (30%) demonstrated recanalization on follow-up imaging.

Conclusion:
In WUS patients there is a very high rate of intracranial vessel occlusion with relatively large volumes of salvageable penumbral tissue. Intravenous thrombolytic therapy followed by thrombectomy in selected cases may be an appropriate therapeutic option with safety and efficacy remaining to be established in randomized controlled trials.