bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 135: Heart Failure and the Risk of Ischemic Stroke Recurrence: A Systematic Review and Meta-analysis
Authors: Tsivgoulis Georgios , Katsanos Aristeidis H , Parissis John , Frogoudaki Alexandra , Vrettou Agathi-Rosa , Ikonomidis Ignatios , Paraskevaidis Ioannis , Zompola Christina , Bhole Rohini , Goyal Nitin , Voumvourakis Konstantinos , Alexandrov Anne W , Alexandrov Andrei V
Published: July 2021

Background & Purpose:
Heart failure (HF) is a major risk factor for thromboembolism and first-ever stroke, and is associated with greater stroke severity and higher rates of early mortality and residual disability. There are limited data regarding the association of HF with stroke recurrence. We sought to evaluate the relationship between HF and recurrent IS stroke using a comprehensive meta-analytical approach.

Methods:
We performed a systematic literature review according to PRISMA guidelines to identify all prospective study protocols (randomized clinical trials or observational cohorts) that reported rates of IS recurrence in patients with concomitant HF. We pooled independently the reported corresponding risk ratios (RRs) and hazard ratios (HRs) from each study protocol using the random effects model.

Results:
Our literature search identified 7 eligible studies including 9,173 IS patients (18.2% with HF). The reported mean follow-up period in the included studies ranged from 7 days to 5 years. The pooled estimate of RRs and HRs for recurrent IS was 1.96 (95%CI: 1.49-2.60; p<0.0001; Figure, Caption A) and 1.93 (95%CI: 1.47-2.53; p<0.0001 Figure, Caption B). We found no evidence of heterogeneity within studies in both the RR (I2=13.5%, p for Cochran Q statistic: 0.325) and HR (I2=0%, p for Cochran Q statistic: 0.629) analyses.

Conclusions:
HF is associated with a continuous two-fold increase in the risk of IS recurrence in patients with prior history of cerebral ischemia. The benefit of anticoagulation in this high-risk group of patients may be studied along with additional risk factor modifications.
Abstract 151: The Stroke Oxygen Study - Subgroup Analyses of the Effect of Routine Oxygen Supplementation on Modified Rankin Scale Outcome at 90 Days
Authors: Roffe Christine ,   The Stroke Oxygen Study Collaborative Group
Published: July 2021

Introduction:
The Stroke Oxygen Study (SO2S) primary analysis revealed that routine oxygen supplementation, either continuous or only at night, for 72h post stroke did not improve patient outcome. A previous study suggested that the benefits of oxygen therapy may vary with stoke severity.

Objectives:
to establish whether routine oxygen supplementation early after acute stroke improves functional outcome for any predefined patient subgroups.

Methods:
patients within 24h of hospital admission, with no definite indications or contraindications to oxygen treatment were eligible for inclusion to the SO2S. Participants were randomised 1:1:1 to continuous oxygen, oxygen at night (between 21:00-06:00) only, or to control (room air) for 72h. Oxygen was given at a rate of 3L/min if the baseline oxygen saturation was ≤93% and at 2L/min if it was >93%. Follow-up at 3 months was by postal questionnaire with telephone follow-up for non-responders.

Results:
8003 participants were recruited from 136 hospitals in the UK (April 2008 to June 2013); Median age was 74 (range 19-100) y, 4398 (54.9%) were male, and the baseline NIHSS score was 5 (range 0-34). None of the predefined subgroups of oxygen treatment before enrolment (p=0.16), oxygen saturation on air at randomization (p=0.94), baseline NIHSS p=0.60), final diagnosis (p=0.97), time since stroke onset (p=0.94), aetiology (p=0.86), age (p=0.94), SSV prognostic index (p=0.17), level of consciousness (p=1.00), history of heart failure (p=0.73) or of chronic obstructive airways disease (p=0.13) showed any statistically significant interactions. All odds ratios were close to one with a range of 0.79-1.29).

Conclusion:
Routine oxygen therapy does not improve functional outcome at 90 days in any of the predefined subgroups including stroke type or severity.
Abstract 160: Association Between Time From Stroke Onset and Flair Lesion Intensity is Modified by Status of Collateral Circulation
Authors: Wouters Anke , Dupont Patrick , Christensen Sören , Norrving Bo , Laage Rico , Albers Gregory , Thijs Vincent , Lemmens Robin
Published: July 2021

Introduction and hypothesis:
In acute stroke patients the intensity of a FLAIR lesion in a region of diffusion restriction is associated with time from symptom onset. The DWI/FLAIR mismatch is currently used in trials for treatment of stroke patients with unknown onset time. However the accuracy of the DWI/FLAIR mismatch to predict symptom onset before 4.5h remains moderate. We hypothesized that collateral status, as assessed by the previously described hypoperfusion intensity ratio (HIR) could modify the association between time from stroke onset and FLAIR lesion intensity.

Methods:
From the ‘Ax200 for ischemic stroke trial’ 141 patients were included. Quantitative FLAIR maps were calculated in a voxel-based manner. For each voxel the relative signal intensity (rSI) was determined by the ratio of the signal intensity in that voxel and the median of the signal intensity in a sphere with radius 15mm positioned in the homologue voxel in the other hemisphere. Lesion volumes based on diffusion-weighted imaging and perfusion-weighted imaging were determined using RAPID software. The HIR was defined as the proportion of a Tmax >6 s lesion volume with a Tmax >10 s delay. A previously defined HIR-threshold of ≤ 0.4 dichotomized good versus poor collaterals. We studied the interaction between collateral circulation and the association between time from symptom onset and FLAIR intensity.

Results:
Time from symptom onset was associated with the mean FLAIR intensity in the region of non-reperfused core (b=1.05; 95%CI: 1.01-1.1). We identified an interaction between this association and collateral status (p=0.036). ROC analysis of FLAIR intensity to predict stroke onset before 4.5h showed an AUC of 0.66 (95% CI: 0. 49-0.83) for patients with good collaterals and 0.80 (95%CI: 0.71-0.90) for patients with poor collaterals.

Conclusions:
Our findings suggest that the progression of FLAIR intensity with time varies depending on the quality of the collateral flow. Accordingly collateral circulation influences the accuracy of FLAIR lesion intensity to predict stroke onset before 4.5h. This could be of particular importance for clinical trials enrolling patients based on the DWI/FLAIR mismatch.
Abstract 173: A Novel Dual Function Molecule for the Treatment of Acute Ischemic Stroke
Authors: Kuo Tun-Hsun , Peng Hsiao-Yu , Fu Ru-Huei , Yeh Sheng-Wen , Huang Wendy
Published: July 2021

Rapid restoration of blood flow to ischemic brain is essential to prevent irreversible tissue injury and minimize neuronal function impairment after acute ischemic stroke. However, intracerebral hemorrhage, reperfusion injury and the oxidative stress provoked by returned blood supply remain the major concerns for the use of effective thrombolytic agent; such as, recombinant tissue plasminogen activator (rt-PA). DC009 is a novel small molecule designed to have both thrombolytic and free radical scavenging activities, which were characterized in various in vitro and in vivo models.

The thrombolytic effect of DC009 was demonstrated in vitro using whole blood clot lysis assay and euglobulin clot lysis assay. In comparison to rt-PA (1mg/ml), DC009 (11.11 mg/ml) exerts comparable (p value = 0.40) in vitro thrombolytic activity to rt-PA. Further investigation showed that DC009 induced endogenous t-PA protein secretion from endothelial vesicles, and it enhanced endothelial t-PA mRNA expression through cAMP pathway. Ability of DC009 in ABTS radical cation scavenging (2, 2-azinobis-(3-ethylbenzthiazoline-6-sulfonate) was measured and found to be dose dependent with an EC50 of 49 μM.

Using a focal cerebral ischemia induced by arterial thrombosis model in aged mice (12-15 months old), DC009 showed a steady thrombolytic action and superior safety profile compared to vessel recanalization induced by rt-PA.

We further investigated DC009’s effect on normal hemostasis and maximal tolerable dose (MTD) level in rodents in order to assess its therapeutic potential. At their comparable pharmacological dose, the tail amputation bleeding assay in mice showed that DC009 (up to 30mg/kg) did not cause bleeding prolongation; vs. rt-PA (10mg/kg) prolonged the bleeding to >10 folds of normal bleeding time. According to the MTD determined in preliminary toxicity dose range finding studies, greater 50 folds of safety margin was identified in both mouse and rat.

In conclusion, DC009 appears to both thrombolytic and free radical scavenging with minimal risk of bleeding. As a safe and dual functional small molecule, it is a drug candidate of great potential for the treatment of ischemic stroke.
Abstract 180: Stroke Mimics in Drip and Ship Thrombolytic Therapy
Authors: Dighe Gaurav P , Kumar Arooshi , Bilal Muhammad F , Abrol Tapan , Moore Kari , Wise Elizabeth , Jerde Ann , Bystrek Laura , Shah Jignesh , Wilder Michael , Remmel Kerri , Liu Wei
Published: July 2021

Introduction:
Drip and ship (DS) thrombolysis provides immediate acute ischemic stroke treatment and follow-up tertiary stroke care at a certified Comprehensive Stroke Center (CSC) for one quarter of the US population living in rural areas. Studies reveal that patients with stroke mimic (SM) inadvertently receive treatment due to lack of immediate access to specialists and the limited treatment time window.

Hypothesis:
We hypothesized that a higher percentage of SM would receive thrombolysis via the DS paradigm than those directly presenting to the CSC.

Methods:
We reviewed consecutive DS tPA cases transferred to the University of Louisville Hospital (ULH) and tPA cases originating at ULH from January, 2013 to June, 2015. ULH is a CSC that provides rural Kentucky and Southern Indiana hospitals with 24-hour telephone access to stroke specialists. We compared the percentage of SMs via a DS paradigm to those originating at ULH. SM data collected included demographics, medical history, NIHSS, complications, discharge diagnosis, discharge disposition, and the length of hospitalization. Etiology of SM was evaluated in the Old (≥ 65 years old) and the Young (<65 years old) group, respectively. Comparative analyses with t-tests and Fisher Exact tests were performed.

Results:
Total numbers of tPA cases were similar between the DS (201) and the ULH (200) groups, but the percentage of SM in the DS group was double the ULH group (27.4% vs 13.5%). Clinical features, NIHSS on admission, and percentage of SM patients who were 65 years or older were similar in both groups. None of SM had intracranial hemorrhage or severe adverse events. One patient in the DS had minor hematemesis without transfusion. All except one patient returned home or to an assisted living facility. One patient who was from home was discharged to a nursing home due to Parkinson’s disease. Psychiatric disease was more common in the Young SM than the old (45.3% vs 7.4%, p < 0.05). Encephalopathy for various reasons (25.9%) and seizures (22.2%) were the two most common causes in the Old SM.

Conclusions:
SMs are treated with tPA more often in the DS paradigm than when presenting to a CSC. Although the thrombolysis caused no harm, adequate access to specialists (i.e telestroke) may decrease unnecessary treatment with tPA.
Abstract 183: Trends in Hospitalizations and Cost Associated with Acute Ischemic Stroke by Age, United States 2003-2012
Authors: Tong Xin , George Mary G , Gillespie Cathleen , Merritt Robert K
Published: July 2021

Introduction:
Stroke mortality has decreased from 4
th
to 5
th
leading cause of death in the U.S. However, it is still a leading cause of disability and the disease burden associated with stroke by age is not well known.

Methods:
The study population consisted of 2003-2012 adult hospitalizations from the National Inpatient Sample of the Healthcare Cost and Utilization Project. Acute ischemic stroke (AIS) hospitalizations were identified by the principal diagnosis ICD-9-CM code. We estimated national acute ischemic stroke hospitalization rates and associated inflation-adjusted hospital costs across five consecutive 2-year time intervals (2003-04 through 2011-12), stratified by six age groups: 18-34 years, 35-44 years, 45-54 years, 55-64 years, 65-74 years, and ≥75 years.

Results:
The hospitalization rates per 100,000 persons with a principal diagnosis of AIS increased significantly among persons aged 18 to 54 years, but decreased significantly among those aged≥65 years. The largest increase was observed among ages 35-44 years. The average per-hospitalization cost increased 7%-19% across all 6 age groups after adjusting for inflation and the estimated total national cost increased 18% for AIS from 2003-04 to 2011-12. The estimated total cost for AIS hospitalization reached $12.55 billion in 2011-12.

Conclusions:
While AIS hospitalizations among ages ≥65 declined from 2003 to 2012, the hospitalization rates increased significantly among ages 18-54. The estimated hospital costs increased across all age groups during the study period, indicating the rising economic burden of stroke in the health care system.
Abstract 188: Differences in Quality of Life Across Modified Rankin Scale Categories in IMS-3
Authors: Rangaraju Srikant , Nogueira Raul , Haussen Diogo , Nahab Fadi , Frankel Michael
Published: July 2021

Background:
Modified Rankin Scale (mRS) score 0-2 is frequently used as a definition of good outcome in ischemic stroke trials. Patients with mRS 3 are frequently grouped with mRS 4-6 as having poor outcome yet there is limited data on health-related quality of life (QOL) across mRS scores.

Objective:
Determine QOL and levels of disability across mRS scores and to specifically compare mRS 2 and 3 outcome categories.

Methods:
A secondary analysis of the Interventional Management of Stroke 3 (IMS3) trial was performed. Patients with documented mRS, degree of disability assessed by Barthel Index (BI) and patient-completed EQ5D-3L quality of life questionnaires at 3 months after stroke were included. EQ5D index was calculated using utility weights published for the US population. Median and mean BI and EQ5D were compared across mRS categories. Multiple pairwise comparisons were performed and Bonferroni corrected p-values were used. No imputations were performed.

Results:
423 patients were included (mean age 64±13 years, median ASPECTS 8 [IQR 6-10], median baseline NIHSS 16 [IQR 12-19], mean BI 84.1±25.3 and mean EQ5D index 0.727±0.24. Overall, there were inverse correlations between mRS and BI (Rho=-0.78, p<0.001) and between mRS and EQ5D (Rho=-0.69, p<0.001). While significant differences in BI were observed across several mRS categories including 1 vs 2, 2 vs 3 and 3 vs 4 (Fig A), there was no difference in QOL between mRS 2 (N=82) and 3 (N=88) categories (Fig B). Based on BI and EQ5D indices, mRS 3 had greater similarity to mRS 2 than to mRS 4 (Fig C).

Conclusion:
Health-related QOL is similar in patients who achieve mRS of 2 and 3 despite differences in degree of disability. If preservation of quality of life is the ultimate goal of acute stroke therapies, our results question the commonly used mRS 0-2 cut point used to dichotomize stroke outcomes.
Abstract 201: Time is Brain: Results From the Escape Randomized Controlled Trial
Authors: Menon Bijoy K , Sajobi Tolulope T , Zhang Yukun , Rempel Jeremy L , Shuaib Ashfaq , Thornton John , Williams David , Roy Daniel , Poppe Alexandre Y , Jovin Tudor G , Sapkota Biggya , Baxter Blaise , Krings Timo , Silver Frank L , Frei Donald F , Fanale Christopher , Tampieri Donatella I , Teitelbaum Jeanne , Lum Cheemun , Dowlatshahi Dar D , Eesa Muneer , Lowerison Mark W , Kamal Noreen , Demchuk Andrew M , Hill Michael D , Goyal Mayank ,   ESCAPE Investigators
Published: July 2021

Introduction:
The ESCAPE trial used innovative imaging and aggressive target time metrics to demonstrate the benefit of additional endovascular treatment over standard care in patients with disabling acute ischemic stroke. We analyze the impact of time from onset to reperfusion and from imaging to reperfusion on clinical outcome.

Methods:
The trial enrolled 316 patients fulfilling eligibility criteria and presenting within 12 hours of stroke symptom onset from 22 sites across 3 continents between February 2013 and October 2014. Logistic regression models were used to estimate the probability of functionally independent outcome (modified Rankin Scale 0-2 at 90 days) based on time from stroke symptom onset to qualifying CT, stroke symptom onset to first reperfusion and qualifying CT to reperfusion after adjusting for age, sex, baseline NIHSS, occlusion site, baseline Alberta Stroke Program Early CT Score (ASPECTS), intravenous alteplase administration (and time from stroke symptom onset to qualifying CT when the predictor time variable was time from qualifying CT to reperfusion).

Results:
A 30-minute increase in time from qualifying CT to reperfusion decreases the probability of functionally independent outcome (mRS 0-2 at 90 days) by an absolute reduction of 8.5% (p=0.006). Similar trends in relationship between outcome and time from qualifying CT to reperfusion were noted for mRS cut-points 0-1 vs. 2-6 (p=0.08) and 0-3 vs. 4-6 (p=0.04). There was no relationship between clinical outcome and stroke symptom onset to qualifying CT for any mRS cut-point. A modest relationship was noted between stroke symptom onset to reperfusion time and the probability of achieving functionally independent outcome (mRS 0-2 vs. 3-6) (p = 0.04).

Conclusions and Relevance:
The ESCAPE trial data with imaging based selection reveals that imaging-to-reperfusion time is more important than onset-to-imaging time as a predictor of outcome.

Trial Registration at clinicaltrials.gov NCT01778335
Abstract 202: Endovascular Therapy for Acute Ischemic Stroke With Distal Large Vessel Occlusion in the Anterior Circulation
Authors: Sarraj Amrou , Sangha Navdeep , Hussain Muhammad Shazam , Wisco Dolora , Vora Nirav , Elijovich Lucas , Goyal Nitin , Abraham Michael , Mittal Manoj , Feng Lei , Wu Abel , Janrdan Vallabh , Nalluri Suman , Yoo Albert , George Megan , Edgell Randall , Shah Rutvij J , Sitton Clark , Supsupin Emilio , Bajgur Suhas , Denny M. Carter , Chen Peng R , Dannenbaum Mark , Martin-Schild Sheryl , Savitz Sean I , Gupta Rishi
Published: July 2021

Introduction:
Five RCTs demonstrated the superiority of endovascular therapy (EVT) over best medical management (MM) for acute ischemic strokes (AIS) with large vessel occlusion (LVO) in the anterior circulation. Patients with M2 occlusions, however, were underrepresented (95 randomized; 51 EVT treated). Evidence from RCTs of the benefit of EVT for M2 occlusions is lacking, as reflected in the recent AHA guidelines.

Methods:
A retrospective cohort was pooled from 10 academic centers from 1/12 to 4/15 of AIS patients with LVO isolated to M2 presenting within 8 hours from last known normal (LKN). Patients were divided into EVT and MM groups. Primary outcome was 90 day mRS (good outcome 0-2); secondary outcome was sICH. Logistic regression compared the 2 groups. Univariate and multivariate analyses evaluated predictors of good outcome in the EVT group.

Results:
Figure 1 shows participating centers, 522 patients (288 EVT and 234 MM) were identified. Table (1) shows baseline characteristics. MM treated patients were older and had higher IV tPA treatment rates, otherwise the 2 groups were balanced. 62.7 % EVT patients had mRS 0-2 at 90 days compared to 35.4 % MM (figure 2). EVT patients had 3 times the odds of good outcome as compared to MM patients (OR: 3.1, 95% CI:2.1-4.4, P <0.001) even after adjustment for age, NIHSS, ASPECTS, IV tPA and LKN to door time (OR: 3.2, 95%CI: 2-5.2, P<0.001). sICH rate was 5.6 %, which was not statistically different than the MM group (table 1, P=0.1). Age, NIHSS, good ASPECTS, LKN to reperfusion time and successful reperfusion mTICI ≥ 2b were independent predictors of good outcome in EVT patients. There was a linear relationship between good outcome and time LKN to reperfusion (Figure 3).

Conclusion:
Despite inherent limitations of its retrospective design, our study suggests that EVT may be effective and safe for distal LVO (M2) relative to best MM. A trial randomizing M2 occlusions to EVT vs. MM is warranted to confirm these findings.
Abstract 214: Corticospinal Tract Integrity is Acutely Maintained Within Perihematoma Edema
Authors: McCourt Rebecca , Misaghi Ehsan , Guinand Taurian , Kate Mahesh , Gioia Laura , Treit Sarah , Beaulieu Christian , Butcher Ken
Published: July 2021

Background:
Perihematoma edema in intracerebral hemorrhage (ICH) is thought to be associated with tissue injury. Fractional Anisotropy (FA), as measured with Diffusion Tensor Imaging (DTI), can be used to assess white matter integrity. We tested the hypotheses that sections of the Corticospinal Tract (CST) passing directly through edema would 1) have low FA relative to the entire tract and 2) predict motor score in ICH patients.

Methods:
Patients were prospectively imaged with DTI within 14 days of symptom onset. Hematoma volume was measured on CT using planimetric techniques. Edema volume was assessed on CT using a 5-23 Hounsfield Unit threshold. Mean FA was measured in the edematous region (‘perihematoma edema'), the entire ipsilateral CST, and in the portion of CST passing through the perihematoma edema ('edematous CST'). Motor function was evaluated with a composite of the upper and lower extremity NIHSS motor score (0=normal, 8=hemiplegia).

Results:
Patients (n=27, mean age 67±13) were scanned with DTI at a median of 2 (3) days. Hematoma distribution was: lobar 5 (18%), basal ganglia 21 (78%), and brainstem 1 (4%). Median acute ICH volume was 8.2 (22) ml at 2 (2)h. Acute edema volume was 0.9 (1.8) ml and grew to 1.9 (3.9) ml at 26h (26). NIHSS motor score was 3 (6) at 72h and 3 (7) at day 7.

FA in the edema was significantly lower (0.23±0.06) than in contralateral mirror regions (0.37 ±0.07, p<0.0001). Mean FA in the edematous CST was lower (0.34±0.08) than FA in the entire ipsilateral CST (0.44±0.04, p<0.0001), but higher than FA in the perihematoma edema (0.25±0.06, p<0.0001).

There was a weak correlation between FA in the edematous CST and 72h motor score (r= -0.40, p=0.050,) which disappeared at day 7 (r= -0.34, p=0.131). FA in the edematous CST was not related to time to scan (r=-0.027, p=0.892).

Hematoma volume predicted FA in the edematous CST (ß=-0.46, 95% CI:[-0.05- -0.01]; p=0.015). Perihematoma edema volume did not predict FA in the edematous CST independently of the ICH (ß=-0.29, [-0.1-0.04]; p=0.475).

Conclusion:
FA is decreased in the CST where it passes through the edema, though not to the extent of the surrounding edema. The transient relationship between decreased FA and motor function suggests that edema temporarily impairs tract function but not integrity.
Abstract 215: Evaluation of Intracranial Pressure and Cerebral Perfusion Pressure in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Trial (CLEAR III)
Authors: Ziai Wendy , Mayo Steven , Freeman William D , McBee Nichol , Dlugash Rachel , Ram Malathi , Thompson Richard , Lane Karen , Awad Issam , Hanley Daniel F
Published: July 2021

Background:
Elevated intracranial pressure (ICP) and inadequate cerebral perfusion pressure (CPP) are mechanisms causing poor outcomes in spontaneous intraventricular hemorrhage (IVH). We characterized intracranial hypertension in severe IVH requiring extraventricular drainage (EVD).

Methods:
Prospective analysis of ICP in all 500 patients enrolled in the CLEAR III trial, a multicenter, double-blind, randomized study comparing EVD + intraventricular recombinant tissue plasminogen activator (rtPA) vs. EVD + placebo for treatment of obstructive IVH and intracerebral hemorrhage (ICH) volume <30cc. Maximum and minimum ICP/CPP were recorded every 4 hours until 7 days post randomization (rand), analyzed at pre-defined thresholds and compared by clinical and radiological variables.

Results:
of 23,406 ICP readings, maximum ICP ranged from 0-97 mmHg (median, IQR; 11,8); 90.7% (21,223) were ≤20mmHg, 1.8% >30, 0.5% >40, and 0.2% > 50mm Hg. Proportion of threshold events >20mmHg were more frequent with persistent closure of the lower ventricular system after day 3 (p=0.02), and was correlated with initial and end of treatment (72 hours post rand) ICH volumes (p=0.01, p=0.04, respectively). ICP elevation >20mmHg occurred during a required 1 hr EVD closure interval after 566/3712 (15.3%) study agent injections. Early re-opening of the EVD occurred in 3.9%. Shunting for hydrocephalus occurred in 18.6% over 1 year follow-up and was associated with % of high ICP events >20 and 30 mmHg (p=0.01 for both). After adjustment for ICH severity factors and IVH volume, % of ICP readings>20 mmHg was significantly associated with 30 and 180 day mortality (p=0.01; p=0.03 respectively), and borderline with modified Rankin Scale (mRS4-6) (p=0.09; p=0.11 respectively). Proportion of CPP readings <70mmHg was associated with day 30 poor mRS (p=0.02), with a weaker association for day 180 mRS (p=0.07).

Conclusions:
Elevated ICP and inadequate CPP are not infrequent during monitoring and EVD drainage in severe IVH and predict higher short and long-term mortality. Early opening of the lower ventricular system may reduce high ICP events. These results permit future correlation of ICP and CPP with treatment rendered (thrombolysis vs placebo), with upcoming unblinding of the trial.
Abstract 40: Mortality Due to Hemorrhagic and Ischemic Stroke Following Left Ventricular Assist Device
Authors: Frontera Jennifer A , Cho Sung-Min , Mountis Maria , Starling Randall , Moazami Nader
Published: July 2021

Introduction:
The time course and risk of hemorrhagic and ischemic stroke following left ventricular assist device (LVAD) placement is not well described.

Hypothesis:
Ischemic and hemorrhagic stroke are major causes of mortality following LVAD placement.

Methods:
Prospectively collected data of Heartmate II (N=335) and Heartware (N=70) LVAD patients from a single center were reviewed from 10/21/2004-5/19/2015. Patients were followed until transplant or death. Predictors of ischemic and hemorrhagic stroke (ICH, SAH, SDH) occurring during hospitalization for LVAD placement (early stroke) or in follow-up (late stroke) were assessed using Chi-squared or Mann-Whitney U tests. The association of stroke and mortality was assessed using multivariable logistic regression analysis.

Results:
Of 405 patients, stroke occurred in 69 (17%). Early ischemic and hemorrhagic stroke occurred in 18 (4.4%) and 11 (2.7%) patients, respectively. Late ischemic and hemorrhagic stroke occurred in 25 (6.2%) and 29 (7.2%) patients, respectively and 11 (3%) had more than one stroke. ICH was the most common type of hemorrhagic stroke (N=23). History of implanted cardioverter defibrillator, tobacco use, poor NYHA class and hypertension post-LVAD significantly predicted ischemic stroke, while history of hypertension and arrhythmia predicted hemorrhagic stroke (all P<0.05). Stroke was the leading primary cause of death in 17% of LVAD patients (second only to multi-system organ failure [21%]). Most deaths were related to late ischemic stroke (N=9/150, 6%), or late hemorrhagic stroke (N=15/150, 10%), while only 2 (1%) died from early stroke. After adjusting for age, NYHA class, and LVAD type, late ischemic stroke (adjusted odds ratio [aOR] 8.8, 95% CI 3.3-23.5, P<0.0001) and late hemorrhagic stroke (aOR 9.7, 95% CI 4.0-23.4, P<0.0001) predicted death, while early ischemic or hemorrhagic stroke did not.

Conclusions:
Stroke is a leading cause of death in LVAD patients. Late ischemic and hemorrhagic stroke have a greater impact on mortality than early stroke. Management of risk factors, such as hypertension post LVAD, may reduce stroke and mortality rates.
Abstract 44: Enlarged Perivascular Spaces Correlate With CSF Biomarkers for Abnormal Blood-brain Barrier Permeability and Neuroinflammation in Patients With Vascular Cognitive Impairment
Authors: Maali Laith , Huisa Branko , Prestopnik Jillian , Qualls Clifford , Thompson Jeffrey , Rosenberg Gary A
Published: July 2021

Background:
Enlarged perivascular spaces (PVS) in the brain are common but their etiology and specificity are unclear. Multiple studies have shown a correlation between enlarged PVS and white matter hyperintensities (WMHs), but the relationship with vascular disease is uncertain. We used albumin CSF to blood ratio as a method to measure permeability of the blood-brain barrier (BBB) in patients with vascular cognitive impairment (VCI). It is possible that the enlarged PVS are associated with an increase in BBB permeability, which could interfere with perivascular fluid flow. Therefore, we hypothesized that enlarged PVS correlate with CSF markers of increased BBB permeability and neuroinflammation.

Methods:
We prospectively recruited 107 VCI patients with white matter disease. At entry, they had brain MRIs with standardized ranking for enlarged PVS. Sixty-one had lumbar puncture to obtain CSF for analysis of albumin ratio, matrix metalloproteinases-2 (MMP-2) index, and amyloid-beta1-42

(Abeta42). The data was analyzed statistically with nonparametric correlation methods.

Results:
Enlarged PVS had a positive correlation with CSF albumin ratio, which is a biomarker for increased BBB permeability (
p
<0.01), and a negative correlation with the neuroinflammatory biomarker, MMP2 index (
p
<0.02), and with Abeta42 (
p
<0.02), which is cleared by the PVS.

Conclusion:
Our results suggest an association between PVS, MMP-mediated increased BBB permeability, and clearance of Abeta42. The role of perivascular fluid movement and its relationship with CSF biomarkers will require further investigation.
Abstract 54: Soluble FLT1 Gene Therapy Through Systemic Viral Delivery Reduces the Severity of Mouse Brain Arteriovenous Malformation
Authors: Zhu Wan , Shen Fanxia , Kang Shuai , Mao Lei , Sun Zhengda , Zou Dingquan , Zhang Rui , Zhan Lei , Forsayeth John , Su Hua
Published: July 2021

Background & Purpose:
Brain arteriovenous malformation (bAVM) is a risk factor for intracranial hemorrhage. Current therapies are associated with high morbidities. We tested a minimally invasive gene therapy using an adeno-associated viral vector (AAV9) to intravenously (IV) deliver an anti-angiogenic agent, soluble FLT1 (sFLT1), to two bAVM mouse models.

Method:
Model 1 consists of
SM22α
Cre;
Endoglin (Eng,
a bAVM causative gene)-floxed mice, which have a 90% occurrence of spontaneous bAVM after 5 weeks and 50% mortality after 6 weeks. In Model 2, bAVM is induced in RosaCreER;
Eng
-floxed mice through tamoxifen-mediated
Eng
-deletion and AAV1-VEGF-induced brain angiogenesis. AAV9-sFLT1 or AAV9-GFP was IV injected to 4-week-old Model 1 mice, or Model 2 mice 8 weeks after model induction. Brain vasculature was analyzed 4 weeks later through vessel-casting and brain section staining with CD31 antibody. Potential toxicities were assessed by analyzing brain and liver histology, and measuring serum alkaline phosphatase (ALP) and alanine transaminase (ALT) activities as well as creatinine (CR) levels.

Results:
sFLT1-treatment increased Model 1 mice survival. BAVMs were detected in all GFP-treated, but only in 25% of sFLT1-treated mice. In Model 2, sFLT1 treatment reduced abnormal vessels. No neuronal death or lymphocyte was detected in the brain of sFLT1-treated mice. AAV9 treatment did not cause weight loss, or alter CR levels or ALP and ALT activities. Small clusters of inflammatory cells were detected in the liver of 58% of GFP- and 56% of sFLT1-treated mice.

Conclusion:
Systemic sFLT1 gene therapy reduces bAVM severity with minimal adverse effect. Future studies should consider restricting sFLT1 expression in the brain to reduce liver inflammation.
Abstract 68: Exosomes from Rhesus Monkey MSCs Promote Neuronal Growth and Myelination
Authors: Buller Benjamin , Moore Tara , Zhang Yi , Pikula Elizabeth , Martin Christopher , Mortazavi Farzad , Rosene Douglas , Chopp Michael , Zhang Zhenggang
Published: July 2021

Introduction:
Treatment of rodents with bone marrow mesenchymal stromal cells (MSCs) enhances functional recovery after stroke. We have shown in a series of studies that much or all of this effect is mediated through release of exosomes--small, membrane bound vesicles that contain many biomolecules--by the MSCs, and that functional benefit is dependent on white matter remodeling.

Hypothesis:
We hypothesize that exosomes derived from monkey MSCs enhance axonal growth and myelination.

Methods:
We isolated MSCs from the bone marrow of a young adult rhesus monkey, and harvested their exosomes from MSC culture medium.

Results:
We first investigated the effect of exosomes on cultured organotypic brain slices from the cerebrum of rat pups. Treatment of brain slices with exosomes markedly increased myelination in cortex and corpus callosum compared to control. Image analysis of 3D reconstructions showed that exosomes increased connections of oligodendrocyte processes with axons by 48%, suggesting enhancement of initiation of myelination. To examine the effect of exosomes directly on neurons and oligodendrocyte progenitor cells (OPCs), exosomes were applied to either cortical neurons cultured in a microfluidic chamber or OPCs. We found that exosomes significantly (p<0.05) increased axonal length (526±22μm vs. 320±15μm for control, n=75/group) and increased the number of NG2+ OPCs by twofold compared to control (P < 0.01). However, exosomes had no significant effect on mature, MBP expressing oligodendrocytes.

Conclusion:
Our data suggest that exosomes enhance myelination by a two-pronged effect. First, they promote axonal growth, and second, they increase the number of available OPCs. Increased axonal growth may trigger OPCs to myelinate axons. This work is the first to demonstrate the therapeutic potential of monkey exosomes for axonal growth and myelination.
Abstract 75: Effects of Physical Exercise Following Ischemic Stroke: Too Early is not a Good Thing
Authors: Khan Hajra M , Geng Xiaokun , Rafols Jose A , Ding Yuchuan
Published: July 2021

Introduction:
Accumulating evidence has shown that physical rehabilitation after stroke may reduce morbidity. The extents of these rehabilitative benefits, however, appear to be contingent upon the initiation time of exercise. The specific role of initiation time and the corresponding underlying mechanisms that influence the brain repair processes have yet to be thoroughly investigated. In this study, we assessed the
hypothesis
that very early exercise increases the risk of cell injury by stimulating lactic acidosis and ROS activation.

Methods:
Using an intraluminal filament, adult male Sprague-Dawley rats were subjected to middle cerebral artery (MCA) occlusion for 2 hours and were randomly assigned to 4 different training groups: 1) non-exercise, 2) Rota-rod exercise, initiated very early (at 6 h of reperfusion) for 30 min, 3) early (at 24 h), and 4) relatively late (at day 3) after stroke. The extent of brain injury was determined by apoptotic cell death 24 hours after exercise. Brain oxidative metabolism was determined by levels of NADH, ATP and reactive oxygen species (ROS) immediately after exercise, while lactic acidosis was also obtained at the same time point.

Results:
Apoptotic cell death was significantly (p<0.05) increased in the 6 h but not 24 h exercise group compared to the stroke group without exercise. There was a decrease in apoptosis in the 3 day exercise group compared to the non-exercise stroke group (p<0.05). This exacerbated injury at the very early stage (6 h) was associated with increased lactate levels (p<0.05), although decreased levels (p<0.05) of NADH and ATP were observed in all exercise groups. ROS production was significantly enhanced by early but not late (3 days) exercise.

Conclusion:
Lactic acidosis and ROS generation were enhanced by post-stroke exercise, if conducted too early. The early exercise may lose its benefits and diminish long-term functional recovery after stroke. Our results provide a basis for future investigation to reveal a more comprehensive understanding of the time-sensitive exercise effects in post-stroke rehabilitation, and aid clinicians in determining how best to administer exercise therapy post-stroke.
Abstract 88: Social Inequalities in Stroke Mortality, Incidence and Case-fatality in Europe.
Authors: Ferrario Marco M , Veronesi Giovanni , Kuulasmaa Kari , Bobak Martin , Chambless Lloyd E , Salomaa Veikko , Soderberg Stefan , Pajak Andrzej , Jørgensen Torben , Amouyel Philippe , Arveiler Dominique , Drygas Wojciech , Ferrieres Jean , Giampaoli Simona , Kee Frank , Malyutina Sofia , Peters Annette , Tamosiunas Abdonas , Tunstall-Pedoe Hugh , Cesana Giancarlo ,   for the MORGAM Project
Published: July 2021

Introduction and aim:
There are limited comparative data on social inequalities in stroke morbidity across Europe. We aimed to assess the magnitude of educational class inequalities in stroke mortality, incidence and 1-year case-fatality in European populations.

Methods:
The MORGAM study comprised 45 cohorts from Finland, Denmark, Sweden, Northern Ireland, Scotland, France, Germany, Italy, Lithuania, Poland and Russia, mostly recruited in mid 1980s-early 90s. Baseline data collection and follow-up (median 12 years) for fatal and non-fatal strokes adhered to MONICA-like procedures. Stroke mortality was defined according to the underlying cause of death (ICD-IX codes 430-438 or ICD-X I60-I69). We derived 3 educational classes from population-, sex- and birth year-specific tertiles of years of schooling. We estimated the age-adjusted difference in event rates, and the age- and risk factor-adjusted hazard ratios (HRs), between the bottom and the top of the educational class distribution from sex- and population-specific Poisson and Cox regression models, respectively. The association between 1-year case-fatality and education was estimated through logistic models adjusted for risk factors.

Results:
Among the 91,563 CVD-free participants aged 35-74 at baseline, 1037 stroke deaths and 3902 incident strokes occurred during follow-up. Low education accounted for 26 additional stroke deaths per 100,000 person-years in men (95%CI: 9 to 42), and 19 (7 to 32) in women. In both genders, inequalities in fatal stroke rates were larger in the East EU and in the Nordic Countries populations. The age-adjusted pooled HRs of first stroke, fatal or non-fatal, for the least educated men and women were 1.52 (95%CI: 1.29-1.78) and 1.51 (1.25-1.81), respectively, consistently across populations. Adjustment for smoking, blood pressure, HDL-cholesterol and diabetes attenuated the pooled HRs to 1.34 (95%CI: 1.14-1.57) in men and 1.29 (1.07-1.55) in women. A significant association between low education and increased 1-year case-fatality was observed in Northern Sweden only.

Conclusions:
Social inequalities in stroke incidence are widespread in most European populations, and less than half of the gap is explained by major risk factors.
Abstract NS11: Using a Template in the Electronic Medical Record to Improve Communication Between Emergency Medical Services and the Emergency Department for Acute Stroke
Authors: Richardson Melissa , Rankin Christopher
Published: July 2021

Background:
In the advent of electronic medical records (EMR), emergency departments (ED) are challenged to include communication with inbound Emergency Medical Services (EMS) within the medical record. Using standardized documentation to guide and capture this critical communication may impact early activation of the stroke team and improve ‘Door to CT’ times. Starting with the “Pre-Notification” measure in Get With the Guidelines (GWTG), our team set out to improve this measure, then evaluate its impact on early stroke team activation and imaging timelines.

Purpose:
To utilize a standardized template in the EMR to improve the GWTG Pre-Notification measure by 30% and evaluate its impact on early stroke team activation and imaging.

Methods:
Initially, the team agreed that clear criteria for stroke team activation were needed. Once established, a standardized template was designed within the EMR. This included point of care glucose, neurological symptoms, cardiac rhythm, time ‘last known well’, and establishment of IV access/labs drawn. The communication nurses, designated to receive incoming EMS calls, were instructed on the use of this standardized template to guide and record communication for incoming stroke patients. Education and feedback were also provided to EMS providers so that they could anticipate required information and ensure that appropriate care occurred in the pre-hospital setting.

Results:
The “Pre-Notification Measure” improved from 29%-77%, early stroke team activation improved from 45% - 73%, and median ‘Door to CT’ time improved from 25 minutes - 18 minutes. (Figure).

Conclusions:
Using a standardized template in the EMR improves expectations of care for the ED and EMS providers. This translates into better scores for the GWTG “Pre-Notification” measure, as well early stroke team activation and imaging timelines.
Abstract NS3: The Influence of Chinese Culture on Caregiving Role Perceptions Among Stroke Caregivers
Authors: Qiu Xichenhui , SIT Janet W , Feng Haixia
Published: July 2021

Introduction:
Among the estimated 22.5 million stroke survivors in China, 78% of them require home care. Previous research has indicated that culture can have a significant impact on caregivers’ perceptions of the caregiving role. There is a dearth of research on stroke caregivers’ perceptions within the Chinese culture.

Objective:
To explore how Chinese culture influences the perceptions of the caregiving role among stroke caregivers.

Methods:
In this qualitative descriptive study, 14 stroke caregivers were recruited from a 1800-bed regional hospital in China. Caregivers were on average 58 years old (range 46-74), 78% female, 50% spouse-caregivers and 50% children-caregivers. Caregivers spent on average 14 hours per day (range 5-24) providing care. All were 1st time caregivers who had provided stroke caregiving < 12 months. Individual, semi-structured interviews were conducted. Qualitative content analysis was performed. Strategies to achieve trustworthiness include triangulation of the data in the analysis process, member checking and peer debriefing.

Results:
Three themes emerged from the interviews. (1) Caregiving is a natural expected part of life. All caregivers accepted caregiving for the sick family member as an expected part of life. This perception is deeply rooted in Chinese culture. (2) Caregiving is a culturally prescribed obligation. Spouse caregivers believe that it is their moral obligation to take care of their sick life partner. Female caregivers emphasized their position and role in the family to take up caregiving for sick relative. (3) Caregiving is an expression of reciprocal love within the immediate family. Tangible caregiving and support during adversity are viewed as expression of reciprocal love among family members. Particularly, the children-caregivers believed in the virtue of filial piety and perceived stroke caregiving as a means of repaying their parents.

Conclusions:
Our findings highlight an underlying acceptance and devotion of undertaking stroke caregiving within the Chinese culture. Researchers and clinicians that plan to develop an intervention to support Chinese stroke caregivers need to consider integrating these findings.
Abstract TMP34: OnabotulinumtoxinA Treatment in Post-stroke Lower Limb Spasticity: Long-term Results From a Phase 3 Study
Authors: Wein Theodore , Esquenazi Alberto , Jost Wolfgang H , Ward Anthony , Kwan Tinna , Pan Grace , Dimitrova Rozalina
Published: July 2021

Introduction:
Long-term efficacy of onabotulinumtoxinA (onabotA) in post-stroke lower limb spasticity (PSLLS) is not clearly established.

Hypothesis:
OnabotA provides sustained efficacy in PSLLS.

Methods:
A multicenter, phase 3, 12-week, double-blind (DB), placebo-controlled study of patients with ankle PSLLS (Modified Ashworth Scale [MAS] ≥3) was followed by an open-label (OL) extension, during which all patients received 1-3 treatment cycles (∼12-week intervals) of onabotA (≤400U). Endpoints: change from baseline in MAS and Clinical Global Impression of Change (CGI) physician rating, and percent of patients achieving passive and active goals (Goal Attainment Scale [GAS]) by physician and patient.

Results:
468 patients enrolled (onabotA, n=233; placebo, n=235); 447 (95.5%) completed the DB and 249 (53.2%) completed the OL phase at DB database lock. Significant improvement in MAS achieved with onabotA in DB was sustained in OL phase (Table). Significant improvements in CGI in DB continued to improve in OL phase. During OL phase, MAS ankle change from baseline and CGI by physician raw scores and proportions of responders were largest at week 6 and generally increased over 3 OL treatment cycles. With onabotA, GAS by patient improved (
P
=0.036), as did the proportion that progressed toward active (
P
=0.009) and passive (
P
=0.044) goal attainment by physician. The percentage of patients who met passive and active goals (GAS by physician≥0) after 1 onabotA treatment increased from 40% to 64% and 27% to 65%, respectively, after 4 treatments. Common DB treatment-related AEs (onabotA vs placebo): injection-site pain (1.7% vs 0.9%) and pain in extremity (0.4% vs 2.1%).

Conclusions:
OnabotA was well-tolerated and produced improvements in MAS, CGI, and GAS during the DB phase that continued into the OL phase, demonstrating long-term benefits in patients with PSLLS.
Abstract TMP58: Post Stroke Activation of Angiotensin II Type 2 Receptors Shows Sustained Neuroprotective Effects in Aged Rats
Authors: Isenberg Jacob D , Bennion Douglas M , Irwin Alexander J , Harmel Allison T , Candelario-Jalil Eduardo , Sumners Colin
Published: July 2021

Background:
The renin angiotensin system is a promising target for stroke neuroprotection and therapy through activation of angiotensin type II receptors (AT2Rs). Compound 21 (C21), a selective non-peptide AT2R agonist, has been shown to exhibit neuroprotection and improve stroke outcomes in preclinical studies. Stimulation of AT2Rs is believed to counteract the negative effects of angiotensin type 1 receptor and provide distinctive beneficial anti-inflammatory and neurotropic effects. We hypothesized that C21 given after stroke through peripheral injections would have sustained neuroprotective effects in aged rats.

Methods:
Aged adult male SD rats (18-20 months) underwent ischemic stroke by monofilament middle cerebral artery occlusion (MCAO) and were randomly divided into two groups that received intraperitoneal (IP) injections of either 0.9% NaCl or 0.03mg/kg C21 at reperfusion (90 min), 24h, and 48h after stroke. All animals received blinded neurological exams at 4h, 24h, 72h, 7d, 14d, and 21d post-stroke. Infarct size was assessed by magnetic resonance imaging at 21 days.

Results:
Post-stroke treatment with C21 significantly improved neurological function, as evidenced by neurological testing using Rotarod and somatosensory dysfunction exams. At 7d and 14d after stroke, C21-treated rats had significantly increased Rotarod times versus saline-treated rats, and at 21d, the somatosensory function was significantly improved as measured by time to removal of paw adhesive. Infarct volume tended to be non-significantly decreased by C21 treatment at 21d post-stroke.

Conclusions:
Our findings indicate that targeting the renin-angiotensin system, specifically by stimulation of AT2Rs with C21, improves neurological function in aged rats with stroke over a sustained period of 21 days. These findings encourage further research into the renin-angiotensin system and specifically AT2Rs, and offers hope for effective alternatives for treating stroke.