bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 2374: A New More Sensitive Method to Assess Balance Among Stroke Trial Populations
Authors: Mandava Pitchaiah , Brooks Michael E , Krumpelman Chase S , Kent Thoma A
Published: July 2021

Background:
Stroke outcome is dependent on baseline factors such as NIHSS and age. Relationships between these variables and outcomes are often non-linear and imbalances can influence outcomes, particularly in subgroup analysis with smaller number of subjects. Balance in baseline variables factors are typically compared by Wilcoxon rank sum, t-test or ANOVA. Because of non-linearity, these tests may be insensitive to important differences in the distribution of these factors and if multiple factors are considered simultaneously. We adapted a multi-dimensional extension of Kolmogorov-Smirnov (KS) test proposed by Fasano and Franceschini (FF) to compare population distributions. The FF algorithm provides a method to calculate KS Distance (KSD) between two distributions in multiple dimensions and a probability value can be obtained. We hypothesized that the FF algorithm would be more sensitive than traditional statistical tests to determine whether baseline factors differed among two trial arms. We further show that matching for baseline variables (nearest neighbor Euclidean matching, pPAIRS©; Mandava Kent Stroke 2010) improves the KSD, indicating closer matched populations.

Methods:
The NINDS database was used for this study (
ntis.gov
). The subgroup of rt-PA and placebo treated normoglycemic subjects with large artery stroke was analyzed. Median and mean NIHSS and age were compared and KSD and a p value were calculated using a custom program, pPOPULATION© written in Matlab®. rt-PA and placebo subjects were then matched using pPAIRS© and outliers eliminated. KSD and p value for the post-matched groups were calculated.

Results:
The left half of the
table
shows the pre-match comparisons. Baseline variables were not different using usual tests. A KSD value of 0.283, however yielded p=0.008, suggesting that the population distributions are indeed different when two variables are considered simultaneously. Right half of the
table
shows the post-match comparisons of baseline variables. The KSD value, 0.217, is lower and is associated with a p value = 0.175, indicating that the post-matched distributions are similar.
a
Wilcoxon Rank-Sum;
b
Student t-test;

Conclusion:
We demonstrate here a new application of a 2d version of the KS distance to verify the similarity of stroke populations and show that it is more sensitive than traditional difference testing. This finding is important because baseline imbalances are critical for accurate assessment of outcome. This algorithm can be further extended to additional dimensions (e.g.: glucose). Its relative advantages over other methods will be discussed.
Abstract 2395: Respiratory Muscle Weakness in Acute Stroke Patients
Authors: Pollock Ross , Rafferty Ged , Moxham John , Kalra Lalit
Published: July 2021

Background:
Increased frequency of chest infections in acute stroke patients may be the result of respiratory muscle weakness contributing to a weak cough and poor airway clearance. We undertook a systematic review of studies comparing respiratory muscle strength in acute stroke patients with age-matched controls.

Method:
A systematic review of literature was performed using the electronic databases Medline, EMBASE, ISI web of knowledge and the Scopus. The key words searched were
stroke
or
cerebrovascular accident
in combination with
cough,
inspiratory, expiratory
or
respiratory
and
strength
or
weakness.
Studies were included if they compared stroke patients with age matched controls and measured maximum inspiratory or expiratory mouth pressure (PImax and PEmax) for inspiratory and expiratory muscle strength respectively.

Results:
The initial search identified 136 articles, 14 of which remained after screening for pre-defined inclusion criteria and removal of duplicates. Eleven were excluded after reviewing abstracts (5 did not assess muscle strength, 5 did not include healthy control group, 1 absolute values could not be obtained). A further study was identified from the reference lists of screened articles. The 4 studies that met inclusion criteria included 121 subjects. Mean PImax ranged from 75-99 cmH
2
O in controls and 37-74 cmH
2
O in stroke patients. (mean difference 41 cmH
2
O, 95% CI 54 to 29 cm H
2
O; P<0.0001). Mean PEmax ranged from 52-89 cm H
2
O in stroke patients and was also reduced compared with age matched controls (mean difference 55 cmH
2
O, 95% CI 61 to 48 cmH
2
O; P<0.0001). (
Fig 1
).

Conclusion:
Individual studies and pooled data suggest that respiratory muscle strength is impaired in acute stroke patients. However, these studies are limited by small samples and design heterogeneity. Larger studies are needed to assess the relationship of respiratory muscle weakness with chest infections and clinical outcomes in the acute phase.
Abstract 2418: Reducing Door to Needle Time for Intravenous Alteplase in Community Hospital Based Primary Stroke Centers
Authors: Guisado Raul , de la Cuesta Karen , Catalli Linda
Published: July 2021

Intravenous alteplase (i.v. t-PA) for ischemic stroke is most effective when given early after stroke onset. The current national treatment initiative, Target:Stroke aims to administer i.v. t-PA within 60 minutes of patient’s arrival to the ED. This goal is challenging for community based primary stroke centers that do not have 24 hours in-house neurologists or radiologists and who are not able to mix alteplase in the ED. In 2010, we conducted a focused review of Stroke Alert Timelines in two community based Primary Stroke Centers in Santa Clara, California. This review led to the
hypothesis
that door-to-needle times for i.v. alteplase in ischemic stroke could be reduced by improving communication between key responders and by expediting the delivery of i.v. alteplase from pharmacy to the ED.

METHODS:
In January 2011 we implemented a new Emergency Room protocol for management of patients with acute ischemic stroke (
Fig
) and compared its performance with recent historical data in two community hospital based PSCs. This protocol emphasizes prompt communication between ED physician, on-call neurologist and radiology and expedites the delivery of i.v. alteplase to the ED.

FINDINGS:
The average door to needle time for patients treated between January 2009 and December 2010 was 89.5 ± 35.7 min (median 77 min). During this period, two patients (3.1%) received the drug within 60 minutes of arrival to the ED. The average door to needle time for patients treated between January 2011 and July 2011, was 70.7 ± 28.9 min, (median 60 min, p < 0.02). During this period, fourteen patients (58.3%) received i.v. t-PA within 60 minutes of arrival to the ED.

CONCLUSION:
an improved management protocol that optimizes communication between ED physician, neurologist, radiologist and pharmacy and makes alteplase promptly available at bedside, can significantly improve the door to needle time for i.v. alteplase in community hospital based primary stroke centers.
Abstract 2421: Neurologic Phenotype Associated With Hereditary Haemorrhagic Telangiectasia In A Monocentric Cohort Of 154 Patients
Authors: Drouet Thomas , Muresan Ioan Paul , Maro Betty , Carette MF , Alamowitch Sonia
Published: July 2021

Introduction
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that leads to the formation of vascular malformations in mucocutaneous tissues, visceral organs, and central nervous system. The most frequently reported neurologic injuries are cerebral vascular malformations (CVM), especially cerebral arteriovenous malformations (CAVM). Neurologic manifestations secondary to a right-to-left shunt through pulmonary arteriovenous malformations (PAVM) are less known.

Methods
All patients with HHT collected between 1991 and 2010 in a prospective registry in a tertiary teaching hospital were included in this study. Neurologic data and brain imaging were assessed by 2 neurologists and 1 neuroradiologist.

Results
In our cohort of 154 patients with HHT, 27 (17.5%) had a symptomatic neurologic injury, while symptomatic neurologic injury was present in 27 (29%) patients among the 93 patients with a PAVM. Prevalence of stroke or TIA was 14.2% in the overall group and 23.6% in the subgroup with PAVM. At 3 months, patients with stroke had good recovery (modified Rankin Score ≤ 2). Aetiological work-up for stroke or TIA revealed a right-to-left shunt through PAVM in 94.6% cases, including 13.6% of cases occurring during PAVM embolization. Ischemic events occurred in 4.5% of cases during cerebral AVM embolization. No cerebral ischemic recurrence occurred in patients with complete PAVM embolization. Four patients (0.03%) had cerebral abscesses. One patient had a symptomatic cerebral haemorrhage caused by a brain cavernoma. Various and asymptomatic CVMs were found on MRI in our study population: CAVM with small niduses (10 in 6 patients), capillary telangiectasias (8 in 6 patients), venous developpmental anomalies (7 in 4 patients), and cavernomas (3 patients).

Conclusion
Neurologic symptoms related to HHT affect more than 1 patient in 6. Our results underline the high prevalence of stroke or TIA in HHT, especially in those with a PAVM. Cerebral vascular anomalies are common and atypical in HHT patients.
Abstract 2466: Inter-observer Reliability and Validity of Pre-morbid Modified Rankin Scale
Authors: Dawson Jesse , McArthur Kate , Garrity Kevin , Graham Laura Jane , McGroarty Geraldine , Quinn Terry , Vincent Sarah
Published: July 2021

Background and Purpose:
The modified Rankin Scale (mRS) is the most prevalent outcome scale in stroke trials. Utility of standard mRS is limited by inter-observer variability. Pre-morbid function, described using mRS, is often used to determine eligibility for clinical trials or interventions. The clinimetric properties of pre-morbid mRS have not been described previously. We assessed the hypothesis that pre-morbid mRS would have acceptable reliability and validity for clinical use.

Methods:
Over a four week period (June 2011), four researchers assessed consenting, sequential stroke unit admissions across two University Hospitals. Paired interviewers (trained in mRS) were randomised to perform independent and blinded mRS assessment of patients. Clinical and demographic details were collated independent of interview. Inter-observer variability was calculated for pre-morbid and standard mRS using kappa (
k
) and weighted kappa (
kw
) with 95% confidence interval (95%CI) and percentage agreement. Validity was assessed by comparing pre-morbid mRS with other markers of function. Number of medications and comorbidity index were compared to pre-morbid mRS (average of paired scores) using rank correlation; proportions living alone with no external care were compared for those with pre-morbid mRS≤1 versus pre-morbid mRS>1 (chi-square test).

Results:
Seventy-four stroke survivors were assessed (four proxy assessments); including a variety of stroke types (TACS:13; PACS:27; POCS:9; LACS:15). Median age 72 years (IQR:62-79); median time since event 5 days (IQR:3-9). Median standard mRS was 4 (IQR:2-4). Median pre-morbid mRS was 1 (IQR:0-3; range:0-4); 27 (38%) patients had premorbid disability (mRS>1). Reliability for standard mRS interview was: 56% agreement;
k
=0.40 (95%CI:0.27-0.52);
kw
=0.55 (95%CI:0.39-0.71). Reliability of pre-morbid mRS was: 70% agreement;
k
=0.58 (95%CI:0.46-0.70);
kw
=0.70.(95%CI:0.53-0.87) Spearman’s Rho for pre-morbid mRS and comorbidity was 0.31 (95%CI:0.08-0.50); for pre-morbid mRS and number of medications was 0.33 (95%CI:0.11-0.52). There was no association between need for carers and pre-morbid mRS (p=0.10).

Conclusions:
Inter-observer reliability of pre-morbid mRS is limited but comparable to standard mRS. Poor correlation between markers of previous function and pre-morbid mRS suggest suboptimal validity. Based on these data premorbid mRS may not be a suitable trial entry criterion. There is scope for improvement, improved training and guidance specific to premorbid mRS is a potential solution.
Abstract 2533: Statewide System Approach has Positive Impact on Stroke Care
Authors: Cysyk Barbara , Aycock Anna , Groman Susan , Kahoe Lucinda , McHugh Megan , Norton Laura , Pazdalski Linda T ,   Maryland Stroke Cntr Consortium
Published: July 2021

Background and Issues:
Approximately 83% of acute-care hospitals in Maryland are designated as primary stroke centers. The Maryland Stroke Center Consortium (MSCC) is a network of representatives from all hospitals in the state of Maryland that have been designated as stroke centers. In collaboration with the Maryland Institute of Emergency Medicine Services Systems (MIEMSS)--the body that provides state oversight, the American Heart Association (AHA), and the Maryland Stroke Alliance (MSA), the MSCC works to improve stroke care outcomes statewide. Since 2007, the MSCC has met bi-monthly to network, review data, mentor, educate, and share best practices. Registry participation and data collection are standardized across the state.

Purpose:
To determine if a statewide consortium can have a positive impact on the quality of care for patients with stroke via the nursing-focused measures of Dysphagia Screening and Patient Education.

Methods:
All primary stroke centers in Maryland participate in AHA’s Get with the Guidelines (GWTG) Stroke Program. Data were collected using the internet-based Patient Management Tool
TM
(Outcome, Inc.). A 4-year retrospective review was performed of the Stroke Core Measures and Dysphagia Screening data in the Maryland Stroke Registry.

Results:
Although over time, improvement was seen in all Stroke Core Measures at both state and national levels, in 2010, Maryland stroke centers demonstrated a higher level of compliance in seven measures compared to all centers participating in the GWTG stroke registry. Moreover, statistically significant higher levels of compliance were found for Dysphagia Screening (82.1% versus 78.3%, p = <0.01) and Patient Education (85.4% versus 81.1%, p = <0.01).

Conclusions:
Participation in a statewide consortium, paired with oversight at the state level, results in a positive impact on the quality of stroke care and patient outcomes. The critical thinking, open communication, and sharing of information that occur at the consortium level translate into improved care consistent with evidence-based best practices at individual facilities.
Abstract 2591: Relationship Between Sunlight and Temperature Exposure to Stroke Incidence in the Reasons for Geographic and Racial Differences in Stroke (regards) Study
Authors: Kent Shia T , McClure Leslie A , Howard Virginia J , Crosson William L , Al-Hamdan Mohammad Z , Wadley Virginia G , Judd Suzanne E , Peace Fredrick , Kabagambe Edmond K
Published: July 2021

INTRODUCTION:
Stroke incidence is higher during the winter, indicating that long and short-term sunlight exposure may contribute to stroke incidence.

HYPOTHESIS:
Reduced sunlight exposure and extreme temperatures are associated with increased stroke incidence.

METHODS:
Data were obtained from the REGARDS study, a national population-based cohort of 30,239 enrolled from 2003-2007 consisting of black and white participants, aged 45+. A centralized phone interview was used for medical history, in-home evaluation for physical measures, and a self-administered questionnaire for complete residential histories (city/state) from birth. The risk of stroke and sunlight exposure was studied in the 16,529 participants that were free of stroke and coronary artery disease at baseline and had lifetime residential histories available. Fifteen-year residential history merged with satellite and ground monitor data were used to determine sunlight and temperature exposure. Since long-term sunlight and temperature measures have not been extensively used in health studies, we performed exploratory analyses to determine which measures carried the strongest relationships with stroke. Fifteen, ten, five, two and one-year exposures were used to predict stroke incidence using Cox proportional hazard models. Potential demographic, behavioral, and medical confounders and mediators were included during model-building.

RESULTS:
Over an average follow-up period of 5.0 years, 351 had an incident stroke. Monthly average sunlight and maximum temperature exposures at residence exhibited the strongest relationships with stroke. It was determined that the shortest period of sunlight exposure, one year, exhibited the strongest relationship. After adjustment for other covariates, the previous year’s monthly average sunlight exposure below the median predicted increased risk of stroke (HR=1.61 (95% CI: 1.15, 2.26)). Temperature exhibited a J-shaped relationship with stroke incidence.

CONCLUSION:
This is the first report showing a relationship between sunlight and stroke. In addition, we confirmed earlier studies that both hot and cold temperatures are related to increased stroke incidence. The biological pathway of this relationship is not clear. Future research will show whether this finding stands, the pathway for this relationship, and if it is due to short or long-term exposures.
Abstract 2601: Neurointerventional Practice Patterns in Acute Ischemic Stroke
Authors: Mehta Brijesh P , Leslie-Mazwi Thabele M , Chandra Ronil V , Hirsch Joshua A , Yoo Albert J
Published: July 2021

Background:
Intra-arterial therapy (IAT) is increasingly used to treat acute ischemic stroke patients with large vessel occlusions. However, there are minimal consensus guidelines for treatment indications and performance standards. Thus we aimed to gain a better understanding of IAT practice patterns among neurointerventionalists.

Methods:
An internet-based survey platform (
www.iasurvey.net
) was launched to address five specific areas of IAT in acute strokes: practice setting, operator background, quality and safety, decision-making and treatment strategies. The survey was distributed electronically to members of the major worldwide neurointerventional societies.

Results:
Of respondents to date, 67 neurointerventionalists based in North America are included in this analysis: 58% neurologists, 27% radiologists, 15% neurosurgeons. Approximately 81% work in academic setting. Across all institutions, the average yearly volume of IA stroke cases is 52 (median 50). Each neurointerventional radiology (NIR) group consists of an average of 3 attendings, with 94% performing IAT. For 43%, activation of the NIR team is on arrival of the patient to the ED, whereas 18 of the 37 with TeleStroke capabilities are alerted after remote evaluation. IAT decisions are made jointly according to 78%, by the NIR team alone for 13% and by the acute stroke service alone for 9%. The minimum NIHSS score for consideration of IAT ranges from 4-13 (median score 8). Imaging evaluation is with CT/CTA in 85%, and with MRI in 45%. Clinical and imaging selection criteria are used in lieu of time in 40% of anterior circulation strokes and 57% of posterior circulation strokes. Despite the emphasis on imaging selection, there is pronounced variability in the specific criteria always used: noncontrast CT (NCCT) hypodensity <1/3rd MCA territory in 55%; NCCT ASPECTS in 15%; CTA source images in 40%; CT perfusion in 33%; MRI mismatch in 12%; and DWI in 22%. For infarct volume determination, 66% use visual estimation alone. Approximately half of operators (54%) prefer conscious sedation if feasible. IAT following full dose IV tPA (ie, bridging therapy) is performed by 72%. For large vessel occlusions (LVO), the Penumbra and Merci devices are the first treatments of choice among 46% and 34%, respectively; for medium sized vessels, Penumbra is preferred by 61%. Local thrombolysis is utilized as first-line therapy in LVO by only 13%, as opposed to rescue therapy for 70%. Case termination is based on time from last seen normal for 75% (range 6-11 hours for anterior circulation).

Conclusions:
We present a comprehensive study examining real-world practice patterns for IAT in acute ischemic stroke patients. While data collection continues, these early results illustrate the significant variation among neurointerventionalists in the use of this treatment modality. Our findings highlight the need for evidence based practice guidelines.
Abstract 2628: Remote Ischemic Conditioning Reduces Brain Edema in Experimental Ischemia/Reperfusion Injury
Authors: Ren Changhong , Gao Mingqing , Li Ning , Cao Jinqiang , Ding Yuchuan , Ji Xunming
Published: July 2021

Background and Purpose
_Remote ischemic conditioning (RIC) has been shown to provide neuroprotective effects, but the precise mechanisms underlying the therapeutic effects still remain unclear. In this study, we investigate changes in blood-brain barrier (BBB) permeability and edema formation, in association with expression of matrix metalloproteinases (MMP), tight junction proteins and aquaporins (AQP) in RIC treated rats following unilateral middle cerebral artery (MCA) occlusion and reperfusion.

Methods
_Ischemic stroke model was generated by occlusion of the right MCA for 1.5 hours in male Sprague-Dawley rats. Remote ischemic conditioning was conducted immediately after MCA occlusion in the bilateral lower limb by occluding and releasing the femoral artery for three cycles; each occlusion and release lasted for 10 minutes. Edema levels and BBB integrity were studied by quantification of brain water content and extravasations of Evans blue at 48 hours after reperfusion, respectively. Protein expression of occludin, claudin-5, ZO-1, MMP-2, MMP-9, as well as AQP-4 and AQP-9, were determined by Western blot analysis at 48 hours after reperfusion. The activity of MMP-2 and MMP-9 were determined by gelatin zymography at the same time points.

Results
_Treatment with RIC significantly (
P
<0.05) reduced brain edema (
P
<0.01) and BBB dysfunction when compared to the control ischemic groups. IPC treatment resulted in a significant (
P
<0.05) increase in the expression of tight junction protein occludin in comparison to the control non-treatment group. The expressions of claudin-5 and ZO-1were not different between RIC-treated group and control group. RIC treatment diminished ischemia-induced MMP-9 (
P
<0.01) but not MMP-2. The expressions of AQP-4 and AQP-9 were not different between RIC-treated group and control group.

Conclusions
_RIC ameliorates brain edema and BBB disruption after stroke, in association with a reduction of MMP-9 and increase in the expression of tight junction protein occludin. These results provide clues to neuroprotective properties of RIC.
Abstract 2634: A Prospective Study Of Asymptomatic Intracranial Arterial Stenosis In Japanese Healthy Subjects
Authors: Matsui Ryukichi , Oguro Hiroaki , Atsushi Nagai , Bokura Hirokazu , Onoda Keiichi , Kobayashi Shoutai , Yamaguchi Shuhei
Published: July 2021

Background and purpose:
Atherosclerotic stenosis of major intracranial arteries accounts for 5 to 10% of all causes of stroke. The Warfarin versus Aspirin Symptomatic Intracranial Disease (WASID) Study has demonstrated stroke onset in 5 among 100 patients with asymptomatic intracranial arterial stenosis (AIAS) during the follow-up period of 1.8 years. However, there are no prospective studies of intracranial stenosis in healthy subjects with a longer follow-up period. We conducted a 7-years longitudinal study in healthy subjects with AIAS to examine its risk factors and prognosis.

Methods:
We performed a prospective study on 3,155 neurologically normal subjects without history of stroke (1724 men, 1431 woman, mean age of 59). They were followed up with the mean interval of 83 months to obtain information about their stroke event with a questionnaire by mail or telephone interview and inquiry to the relevant medical facilities. AIAS were assessed on MRA at the time of first visit for all subjects.

Result:
AIAS was detected in 323 subjects (10.2%; AIAS group) at the initial examination. Significant risk factors for AIAS were older age, female, hypertension, high values of fasting blood glucose and HbA1c. During the follow-up stroke occurred in 77 subjects (2.7%) from the no-AIAS group and 14 subjects (4.3%) from the AIAS group (p = 0.07). Age and sex affected the stroke onset. The Cox's proportional-Hazards regression model after adjustment of age and sex revealed the significant contribution of AIAS on stroke onset (OR 1.9; 95% CI 1.03-3.4, p = 0.039). The stroke types were 11 ischemic and 3 hemorrhagic in the AIAS group.

Conclusions:
AIAS is a significant risk factor for future stroke even in healthy subjects. Intense management of blood pressure and glucose level might be crucial for preventing asymptomatic intracranial atherosclerotic disease.
Abstract 2662: Brain Natriuretic Peptide Levels Predict Stroke Outcomes in the Acute Rehabilitation Setting
Authors: Dohle Carolin I , Elashvili Mery , Reding Michael
Published: July 2021

Introduction:
Brain natriuretic peptide (BNP) is a known predictor of cardiovascular morbidity in patients with heart failure, and can predict cardiovascular complications in patients without known cardiovascular disease. Recent studies have focused on the relationship between elevated BNP levels and ischemic stroke. Increased BNP levels were correlated with increased for risk of stroke or transient ischemic attack. Plasma BNP levels are elevated in patients with acute ischemic stroke and predict death in acute ischemic stroke patients with atrial fibrillation. Hypothesis: Admission BNP (aBNP) levels predict outcomes in an acute rehabilitation setting.

Methods:
763 patients with ischemic stroke admitted to an acute inpatient rehabilitation unit were assessed. Admission BNP levels, admission and discharge Fugl-Meyer Motor Impairment (FMMI) scores and Functional Independence Measure (FIM) score were obtained for each patient. Odds ratios were calculated for aBNP quintile groups and need for transfer to acute care or death versus other discharge disposition (ACDvsO). Spearman Rank Order correlations were calculated for aBNP levels and cardiovascular comorbidities and complications, admission and discharge FMMI and FIM scores. Logistic Regression was used to assess interactions with age and the above co-variables.

Results:
aBNP quintile cut scores showed the following odds ratios and confidence intervals for ACDvsO discharge disposition: aBNP > 17.5 (O.R.=1.6; CI = 0.83-3.12 ; p=N.S); > 49.5 (1.83; 1.09-3.07; p= 0.02); > 104.9 (2.03; CI = 1.27-3.25; p=.003); >231.3 (2.03; CI = 1.22- 3.38; p= 0.006). aBNP was still a significant predictor of ACDvsO (X2 =6.84;p=.009) with age, admission FMMI and FIM scores entered as co-variables. aBNP was significantly correlated with admission FIM (r=-0.21; p=0.000); discharge FIM (r=-.245; p=0.000) but not with admission FMMI (0.001; p=0.98) or with discharge FMMI (0.019; p=0.70)

Conclusion:
Rehabilitation Hospital aBNP values can predict a two-fold increase in odds of death or need for transfer to acute care. They are also correlated with admission and discharge FIM scores perhaps indicating less cardiovascular reserve and poor endurance due to underlying cardiovascular disease. Previous studies have correlated BNP levels with stroke severity, however our analysis failed to find a correlation between BNP and FMMI as a measure of motor impairment. Patients with high aBNPs need to be closely monitored for adverse events and rehabilitation intensity needs to be tailored to their needs.
Abstract 2668: Lacunar Strokes In Patients With Symptomatic Intracranial Stenosis
Authors: Khan Amir , Kasner Scott E , Lynn Michael J , Chimowitz Marc I ,   The Warfarin Aspirin Symptomatic Intracranial Disease (WASID) Trial Investigators
Published: July 2021

Background and Purpose:
Lacunar strokes are conventionally attributed to a distinct microvascular pathophysiology, but the “lacunar hypothesis” has been challenged since some small deep infarcts are identified in patients with sources of cardioembolism or large vessel atherosclerotic disease. We hypothesized that patients with intracranial stenosis with a lacunar stroke presentation would have a lower risk of recurrent stroke than those with an index non-lacunar stroke, and that their recurrent strokes would predominantly be lacunar.

Methods:
We analyzed subjects enrolled with an index stroke into the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial. The index and endpoint strokes were classified as lacunar or non-lacunar by central adjudication. The primary endpoint was recurrent ischemic stroke. Cox proportional hazard models were generated with stratification for severity of stenosis.

Results:
347 subjects were enrolled after an index stroke, 38 were lacunar and 309 were non-lacunar. Over a mean follow-up of 1.8 years there was no significant difference in stroke recurrence between patients whose index stroke was lacunar (7/38; 18%) vs. non-lacunar (69/309; 22%) (HR 0.79, 95%CI: 0.36-1.71). Further, no significant differences were found when groups were stratified by 50-69% stenosis (HR 0.50, 95%CI:0.12-2.1) and ≥70% stenosis (HR 0.87, 95%CI: 0.34-2.2) but power was limited. Of the 7 recurrent strokes in patients whose index stroke was lacunar, all 7 were non-lacunar and 3 were in the territory of the stenotic artery. Of the 69 recurrent strokes in patients whose index stroke was non-lacunar, 6 (9%) were lacunar of which 4 were in the territory of the stenotic artery.

Conclusions:
The risk of recurrent stroke due to intracranial stenosis was similar in patients who presented with lacunar vs. non-lacunar strokes, and all recurrent strokes in patients presenting with lacunar stroke were non-lacunar. These findings suggest that the pathophysiology of index and recurrent strokes in patients presenting with a lacunar stroke and intracranial stenosis is related to the stenosis and not microvascular disease. Therefore, patients with intracranial stenosis who present with lacunar strokes should be included in future trials investigating secondary stroke prevention for symptomatic intracranial stenosis.
Abstract 2673: C-reactive Protein Increases The Severity Of Stroke Outcome In Mice
Authors: Atochin Dmitriy N , Swanson Helen , Mineo Chieko , Shaul Philip W , Huang Paul L
Published: July 2021

C-reactive protein (CRP) is an acute-phase reactant that is elevated in a variety of chronic inflammatory conditions including obesity and autoimmune disorders. Elevated CRP is associated with greater incidence and severity of stroke. However, it is unknown whether CRP directly impacts the severity of stroke outcome. We previously demonstrated that CRP antagonizes endothelial NO synthase (eNOS) by attenuating eNOS serine 1176 phosphorylation via the activation of SHIP-1 in endothelium, which blunts signaling downstream of PI3 kinase. Furthermore, we have shown that modulation of the eNOS serine 1176 phosphorylation site affects vascular reactivity and determines stroke size in vivo. We therefore hypothesize that CRP increases stroke vulnerability in vivo by altering the phosphorylation state of eNOS. To test our hypothesis, we subjected wild-type (WT) and CRP transgenic mice (TG-CRP), which have modest elevations in CRP, to a stroke model of temporal focal ischemia with subsequent reperfusion. Mean blood pressure measured acutely from the common carotid artery under aerrane anesthesia (30 % oxygen, 70% nitrous oxide and 1.5% aerrane) was similar in TG-CRP mice (96 ± 8 mmHg, Mean ± SD, n=6) and WT mice (93 ± 9 mmHg, n=14). Using Laser Doppler flowmetry, we monitored cerebral blood flow (CBF) above the middle cerebral artery (MCA) during 30 minutes of MCA occlusion (MCAO) provoked by a filament and during the first 30 minutes of subsequent reperfusion. Although there was a directional trend, in TG-CRP mice CBF reperfusion after 30 minutes (55 ± 34 %, n=5) was not different from WT mice (80 ± 16 %, n=5, P=0.28). However, the TG-CRP mice demonstrated markedly larger infarct volumes as compared with WT mice after 30 minutes of MCAO and 48 hours of reperfusion (100 ± 26 mm3 in TG-CRP vs. 51 ± 21 mm3 in WT, n=5/group, p< 0.03). Neurological deficit after 48 hours of reperfusion was also worse in TG-CRP mice (3.0 points) as compared with WT mice (1.8 point). These findings indicate that CRP increases the severity of stroke outcome in a mouse model of cerebral reperfusion. As such, future therapies aimed at CRP or its mechanism of action in stroke may potentially prevent or improve the stroke outcomes in patients with chronic inflammatory conditions such as obesity.
Abstract 2674: DWI Reversal is associated with Small Infarct Volume and Early Reperfusion in Patients with TIA and Minor Stroke. Data from VISION and CATCH study groups
Authors: Asdaghi Negar , Coulter Jonathan I , Modi Jayish , Qazi Abdul , Goyal Mayank , Butcher ken S , Hill Michael D , Demchuk Andrew M , Coutts Shelagh B
Published: July 2021

Introduction:
One-third of patients with TIA and minor ischemic stroke (MIS) have evidence of ischemic penumbra, defined as hypoperfused regions that have not been irreversibly damaged. Diffusion weighted Imaging (DWI) lesions are thought to represent irreversibly damaged tissue. DWI reversal therefore has implications in accurate estimation of penumbra. We aimed to determine the rate of DWI reversal in this population.

Methods:
Patients with TIA/MIS (NIH Stroke Scale ≤ 3) were prospectively enrolled and imaged within 24 hours of symptom onset as part of two prospective imaging cohorts. Patients were included if their baseline modified Rankin scale (mRS) score was ≤1. All patients were followed clinically for 3 months and had a repeat MRI either at day 30 or 90. Baseline diffusion and perfusion lesions and follow-up FLAIR final infarct volumes were measured.

Results:
418 patients were included; 55.5% had DWI lesions and 37% had PWI (Tmax+2s delay) deficits at baseline. A total of 337 (81%) patients had follow-up imaging. DWI reversal occurred in 22/192 (11.5%) of patients who had a diffusion lesion at baseline. The median time from symptom onset to follow-up imaging was not significantly different between those with or without DWI reversal (78.6 days, IQR=33.3 vs. 79.7 days, IQR= 59.4, p=0.65). The median DWI lesion volume was significantly smaller in those with reversal (0.27ml, IQR=0.75 ml) compared to those who did not reverse (1.45 ml, IQR=3.8 ml, p<0.001). Patients with concurrent perfusion deficits (Tmax+2s) were significantly less likely to have DWI reversal (6%) compared to those without evidence of tissue hypoperfusion (20%; p=0.003). DWI reversal occurred in 4% of patients with penumbral patterns ((Tmax+2s)-DWI) and 18% of those without penumbra (p=0.003).Severity of hypoperfusion defined as greater prolongation of Tmax (+2,+4, +6, +8s) did not affect the likelihood of DWI reversal (linear trend p=0.147). No patient with DWI reversal had a mRS of ≥2 at 90 day, compared to 19% of those with evidence of infarction on follow-up imaging (p= 0.02).

Conclusion:
DWI reversal is common in patients with TIA/MIS and is more likely to occur in those with smaller baseline lesions without concurrent tissue hypoperfusion. DWI reversal therefore should not have a significant effect on the accuracy of penumbra definition. These data suggest early reperfusion is correlated with DWI reversal and better clinical outcome as measured by mRS.
Abstract 2676: Lipoprotein associated-phospholipase A2 Activity Level is Increased in Acute Cerebral Ischemic Events
Authors: Tai Waimei A , Chen Charlene , Mlynash Michael , Thai Demi , Schwartz Neil , Kemp Stephanie , Lansberg Maarten G , Singh Inder P , Albers Gregory W , Olivot Jean Marc
Published: July 2021

Introduction:
Lipoprotein associated -phospholipase A2 (Lpa-A2) mass and activity can help identify high risk TIA patients. We evaluate the yield of Lpa-A2 mass and activity to differentiate acute cerebral ischemic events from non-ischemic events.

Methods:
From July 2007 to March 2009, 48 patients presenting to the Stanford Unversity Medical Center Emergency room with stroke or TIA symptoms were prospectively enrolled and blood samples were obtained at time of presentation, 24 hours, and 72 hours after presentation. Blood samples were analyzed for Lpa-A2 mass and activity using commercially available assays (diaDexus, Inc). Patients with final diagnosis of stroke or TIA were classified as ischemic and others as non-ischemic. The size of the ischemic lesion was measured among stroke patients on diffusion weighted imaging (DWI).

Results:
Twenty eight patients (58%) had a diagnosis of brain infarction [median NIHSS=7 (IQR=4-12)], 9 (19%) had a diagnosis of TIA [median ABCD2=4, (IQR=3-6)] and 11(23%) had a non ischemic event (1 peripheral vertigo, 2 infections, 3 seizures, 4 peripheral neuropathy/myopathy, 1 multiple sclerosis relapse). Among the 37 ischemic patients, stroke mechanisms were according to TOAST criteria: 6 (16%) large artery atherosclerosis, 21 (57%) cardioembolic, 1 (3%) small artery, 4 (11%) other determined and 5 (13%) undetermined. At admission, Lpa-A2 activity level was higher among patients experiencing an ischemic event (stroke or TIA) compared to non ischemic event (p=0.007). Among ischemic patients, Lpa-A2 activity measured at admission was lower than the activity measured at day 1 (p=0.006) and day 3 (p=0.002) and was stable among non ischemic patients. Among the 24 ischemic patients who underwent acute MRI and were found to have an ischemic lesion on DWI, there was no relation between Lpa-A2 activity level and infarct volume. Lipoprotein associated -phospholipase A2 mass level was not different between ischemic and non ischemic patients. The mass levels remained stable over time in each group and were not related to infarct volume.

Conclusions:
Lpa-A2 activity levels were higher among ischemic patients compared with non ischemic etiologies. Lpa-A2 activity levels rose during the first days after brain ischemia. This exploratory data suggests Lpa-A2 activity level could possibly help physicians discriminate cerebral ischemic from non ischemic events. Further research is warranted and ongoing.
Abstract 2697: Fully-automated Identification of Acute Stroke Lesion Volumes with CT Perfusion
Authors: Straka Matus , Albers Gregory W , Lansberg Maarten G , Kemp Stephanie M , Marks Michael P , Wilder Michael J , Wechsler Lawrence R , Bammer Roland
Published: July 2021

Purpose:
Mismatch between volumes of infarct core and critically hypoperfused tissue (CHT) may be used to identify acute stroke patients who could benefit from reperfusion therapies. We present a fully-automated, operator-free approach for identifying the core and CHT lesion volumes with CT perfusion (CTP).

Methods:
31 scans of 25 acute stroke patients who underwent CTP followed by MRI (range: 23-120 min) were analyzed. CTP was obtained as a one or two 2cm slabs. MRI included DWI and PWI. Reference stroke lesion metrics were MRI-based: core via DWI (ADC<615x10
-6

mm
2
/s), and CHT via PWI (Tmax>6s). CTP and PWI scans were processed with an automated image analysis program (RAPID) with delay-independent deconvolution. MRI maps were coregistered to CTP. Contralaterally-relative CBV
CT
and CBF
CT
(
cr
CBF
CT
,
cr
CBF
CT
) maps were computed by putting into ratio the original and corresponding laterally-mirrored and smoothed rCBV
CT
and rCBF
CT
maps (obtained by vertical flip and coregistration of the anatomic images, see Fig). Stroke core in CTP was delineated by thresholding
cr
CBV
CT
and
cr
CBF
CT
, and CHT by thresholding Tmax
CT
. Optimal thresholds were obtained by ROC analysis and minimization of lesion volume differences between CT and MRI.

Results:
For identification of stroke core in CTP,
cr
CBF
CT
performed better than
cr
CBV
CT
. Optimal threshold was
cr
CBF
CT
< 0.30 with sensitivity 60% (CI
95%
57-63%) and specificity 88%, (CI
95%
87-89%); median volume difference between CBF
CT
and DWI lesions was 0 ml (IQR: -6ml to 6 ml); correlation of volumes was

r
2

=0.72 (
p
<0.0001). For identification of CHT, reference MRI lesions (Tmax
MR
>6s) were most accurately identified by Tmax
CT
>6s with sensitivity 72% (CI
95%
70-74%), specificity 97% (CI
95%
96-97%); median volume difference between Tmax
CT
and Tmax
MR
was -3ml (IQR: -10ml to 0ml); correlation of CHT volumes

r
2

=0.89 (p<0.0001).

Conclusions:
The processing methods and CTP thresholds presented in this study show a great promise for fully-automated outlining of stroke lesions using CTP. Such a technique could be of great value for CTP-based patient selection in clinical trials and clinical practice.
Abstract 2701: Multicenter Study For Prediction And Validation Of Intracranial Hemorrhage Risk In The Natural History Of Brain Arteriovenous Malformation Patients
Authors: Kim Helen , Pourmohamad Tony , McCulloch Charles E , Lawton Michael T , Mohr Jay P , Stapf Christian , Young William L , Al-Shahi Salman Rustam ,   for the Multicenter AVM Rsch Study (MARS)
Published: July 2021

Background:
BAVM is an important cause of intracranial hemorrhage (ICH) in younger persons. Accurate and reliable prediction models for determining ICH risk in the natural history course of BAVM patients are needed to help guide management. The purpose of this study was to develop a prediction model of ICH risk, and validate the performance independently using the Multicenter AVM Research Study (MARS).

Methods:
We used 3 BAVM cohorts from MARS: the UCSF Brain AVM Study Project (n=726), Columbia AVM Study (COL, n=640), and Scottish Intracranial Vascular Malformation Study (SIVMS, n=218). Cox proportional hazards analysis of time-to-ICH in the natural course after diagnosis was performed, censoring patients at first treatment, death, or last visit, up to 10 years. UCSF served as the model development cohort. We chose a simple model, including known risk factors that are reliably measured across cohorts (age at diagnosis, gender, initial hemorrhagic presentation, and deep venous drainage); variables were included without regard to statistical significance. Tertiles of predicted probabilities corresponding to low, medium, and high risk were obtained from UCSF and risk thresholds were validated in COL and SIVMS using Kaplan-Meier survival curves and log-rank tests (to assess whether the model discriminated between risk categories).

Results:
Overall, 82 ICH events occurred during the natural course: 28 in UCSF, 41 in COL, and 13 in SIVMS. Effects in the prediction model (estimated from UCSF data) were: age in decades (HR=1.1, 95% CI=0.9-1.4, P=0.41), initial hemorrhagic presentation (HR=3.6, 95% CI=1.5-8.6, P=0.01), male gender (HR=1.1, 95% CI=0.48-2.6; P=0.81), and deep venous drainage (HR=0.8, 95% CI=0.2-2.8 P=0.72). Tertiles of ICH risk are shown in the
Figure
, demonstrating good separation of curves into low, medium and high risk after 3 years in UCSF (left, log-rank P=0.05). The model validated well in the COL referral cohort with better discrimination of curves (middle, P<0.001). In SIMVS, a population-based study, the model separated curves in the earlier years but a consistent pattern was not observed (right, P=0.51), possibly due to the small number of ICH events.

Conclusion:
Our current prediction model for predicting ICH risk in the natural history course validates well in another referral population, but not as well in a population cohort. Inclusion of additional cohorts and risk factors after data harmonization may improve overall prediction and discrimination of ICH risk, and provide a generalizable model for clinical application.
Abstract 2726: The Mir-17-92 Microrna Cluster Enhances Axonal Outgrowth In A Rat Cortical Neurons After Oxygen-glucose Deprivation
Authors: Ueno Yuji , Chopp Michael , Buller Benjamin , Liu Xian Shuang , Wang Xinli , Roberts Cynthia , Zhang Zheng Gang
Published: July 2021

Background:
There is a paucity of studies on the biological function of MicroRNAs (miRNAs) in axons. We investigated the role of the miR-17-92 cluster, one of the first oncogenic miRNAs, on axonal outgrowth in cortical neurons subjected to oxygen-glucose deprivation (OGD).

Methods:
Cortical neurons harvested from embryonic day-17 Wistar rats were cultured in a Standard Neuron Device, and were subjected to OGD for 3h. Quantitative real-time RT-PCR (qRT-PCR) was used to selectively analyze the abundance of individual members of the miR-17-29 cluster in axons and somas. Cortical neurons were transfected with a pCAG-vector carrying a rat miR-17-92 cluster, or miRNA hairpin inhibitors against rat miR-18a and miR-19a. Axonal outgrowth was monitored with time-lapse microscopy. Western blot was performed to analyze phosphatase tensin homolog deleted on chromosome 10 (PTEN) and the mammalian target of rapamycin (mTOR).

Results:
qRT-PCR revealed that compared to somas, axons had relatively abundant levels of six individual members of the miR-17-92 cluster: miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92. The presence of miR-18a and miR-19a in axons was confirmed by in situ hybridization. OGD challenge (n=5) upregulated axonal levels of the six individual members of the miR-17-92 cluster by approximately two fold compared to axonal levels without OGD (n=5, p<0.05). Concurrently, OGD increased the number of axons (213 ± 27, n=5) compared to the number of axons without OGD (175 ± 22, n=5, P<0.05). Overexpression of the miR-17-92 cluster further increased the number of OGD-augmented axons (222 ± 16 vs 179 ± 9 in the empty vector, n=4, P<0.05). Overexpression of the miR-17-92 cluster in OGD challenged neurons significantly increased the length of axons (1.0 ± 0.1 vs 0.4 ± 0.1, μ m/5min in the empty vector, n=3/group, P<0.01), whereas attenuation of the endogenous miR-19a suppressed OGD-induced axonal elongation (0.7 ± 0.1, μ m/5min, n= 3, P<0.05) compared with the length of axons in neurons transfected with cel-miR-67 (1.2 ± 0.2, n=3). Western blot analysis revealed that overexpression of the miR-17-92 cluster reduced miR-19 targeting protein PTEN by 87% and activated mTOR by 194% (n= 5, P<0.05).

Conclusion:
The present study provides the first evidence that cortical neurons contain the miR-17-92 cluster in axons and that the miR-17-92 cluster mediates axonal outgrowth in neurons subjected to OGD likely through targeting PTEN. These data suggest that the miR-17-92 cluster may play a role in axonal remodeling after stroke.
Abstract 2816: Relation Between Neurologic Deficit Severity and Final Functional Outcome Shifts and Strengthens During First Hours after Onset
Authors: Saver Jeffrey L , Altman Hernan
Published: July 2021

Background:
Early neurologic deficit severity is the most important determinant of final functional outcome in acute ischemic stroke. Accordingly, in hospital quality performance measures and in clinical trials, deficit severity as assessed by an early NIH Stroke Scale (NIHSS) score is increasingly used to adjust outcomes for baseline prognosis/case mix. However, deficit severity frequently changes during the first hours and days post-onset.

Methods:
Analysis was performed of control group patients enrolled in the two NINDS TPA trials. Neurologic deficit severity was measured serially using the NIH Stroke Scale (NIHSS) at 1-3 hours post onset, 3-5 hours, 24 hours, 7-10 days, and 90 days. Final global disability outcome was assessed at 90 days using the modified Rankin Scale (mRS).

Results:
Among the 312 patients, median neurologic deficit severity on the NIHSS improved throughout the 90d observation period, from 15 (9.5-20) at 1-3h through 12 (6-19) at 24h to 7 (2-19) at 90d. Between 1-3h to 24h, more patients spontaneously improved than worsened, 39.1% vs 17.6% (p<0.001). NIHSS scores associated with individual final mRS global disability ranks shifted to lower values over time, e.g. patients with a final day 90 mRS of 2 had the following median NIHSS scores: 12 at 1-3h, 9 at 24h, and 3 at 90d (
Figure
). The correlation coefficient between NIHSS and the final mRS increased over time, from 0.51 at 1-3h through 0.72 at 24h to 0.87 at 90d.

Conclusion:
During the first 24 hours after onset, spontaneous improvement occurs in 2 of 5 acute ischemic stroke patients. The NIHSS scores associated with individual global disability ranks shift lower over time. Neurologic deficit severity increasingly predicts final disability outcome, accounting for one quarter of the variance at 1-3h, one half at 24h, and three quarters at 90d. It is desirable to consider timing of NIHSS assessment, in addition to the NIHSS score, when performing severity adjustment for performance measure reporting and clinical trials.