bluuebunny/crossref_metadata_2025 huggingface dataset:
Stroke education - success and limitations
Authors: Grond Martin , Schmuelling Susanne , Heiss Wolf-Dieter
Published: March 2022

P180

There is increasing evidence that success of acute stroke treatment is strongly influenced by the timepoint of intervention (“time is brain”). Therefore, intensive and costly educational campaigns are undertaken aiming to reduce the time delay between symptom onset and hospital presentation. Earlier studies have suggested that such efforts are impressively successful. However, most studies have major limitations because they were either center-based or excluded many patients from analysis because of various reasons.
Objective:
To study prospectively the impact of an educational campaign on acute stroke patients in a community-based approach.
Methods:
All consecutive patients who were admitted to all 16 Cologne hospitals (1 Mio. inhabitants) with the diagnosis of presumed stroke were documented within a first 3-month period before and a second 3-month period after an intense state-of-the-art campaign of 1 year duration.
Results:
1281 patients were documented, 618 met the final diagnosis of ischemic stroke. In 495 patients the time interval between symptom onset and hospital arrival could be obtained. In these patients, the median time interval only marginally decreased from 340 to 320 min. If only those patients were taken into consideration (as in most earlier studies) who were admitted within 24 hours of symptom onset and whose time of stroke onset could accurately be assigned (only 286 patients) the result would look much more impressive: median time interval decreased from 130 to 90 min.
Conclusion:
The potential effect of educational campaigns to encourage early hospital arrival in acute stroke patients should not be overestimated. Only in a small subgroup of stroke patients a substantial success could be demonstrated.
Safe rt-PA Administration for Ischemic Stroke During Telemedicine Consultation
Authors: LaMonte Marian P , Bates Vernice , Bahouth Mona N , Gunawardane Ruwani D , Yarbrough Karen L , Pathan Mohammed Y , Page C. Wesley , Mehlman Ira , Crarey Patrick E
Published: March 2022

P191

Background:
Telemedicine (TM) is emerging as a time-saving, efficient means for acute stroke evaluation. Absence of a local consulting stroke physician, and short therapeutic time window make TM an ideal alternative for providing patients at remote facilities optimal care. We describe our stroke treatment center (STC) experiences and report safety of rt-PA administration during TM consultation.
Methods:
The University of Maryland Medical Center (UMM) uses VTEL TC2000 units with triplexed ISDN line providing 30 fps video link to St. Mary’s Hospital, >100 miles distance. The Millard Fillmore Gates Circle Hospital (Gates) uses Sony TriniCom 3000 Plus Model 256 units with ISDN line at 256 Khz, linked to Millard Fillmore Suburban Hospital, 15 miles distance. An additional unit links to the stroke neurologist’s home. Both systems use pan, tilt and zoom camera with remote site control allowing two-way, realtime, audiovisual communication and CT transfer.
Results:
2/18 patients received rt-PA during TM consultation with the UMM Brain Attack Team and 3/12 by the Gates stroke specialist. Two were treated from the home link, and three via ED to ED transmission. Transport to the consulting STC occurred after completion of lytic therapy in 4 cases; in 1 case transport occurred during treatment. 4 out of 5 patients had excellent recovery defined as NIHSSS ≤1; 1 patient initially improved, but later had clinical symptoms of reocclusion. No patient experienced complications. Remote ED staff enthusiastically request TM consultation because of 1) ease of adaptability to clinical and technical procedures, and 2) immediate two-way audiovisual access to stroke specialist. Patients and family members rate the TM experience highly at post-consultation interview.
Conclusions:
TM consultation increased rt-PA administration from 0% to 6%, and provided treatment options not previously available at the remote hospitals. Administration of rt-PA during TM consultation was safe and effective and the system was well-received by clinicians and patients. Lack of reimbursement for TM services will hinder widespread adaptation of this exceptional technology for remote acute stroke treatment.
Preliminary Experience in Carotid Artery Angioplasty and Stenting with a New Cerebral Protection Device.
Authors: Lylyk Pedro , Ferrario Angel , Ceratto Rosana , Cohen Jose E , Miranda Carlos , Aguilar Marcos Vilca
Published: March 2022

P194

Purpose:
From the results of high-quality prospective randomized trials it has been apparent that symptomatic CA stenosis > 60–70% lead to a significant incidence of stroke if treated medically. Angioplasty and stenting is increasingly performed in the carotid artery and its most feared complication is distal emboli of dislodged plaque debris. We present, the partial results of CAFÉ protocol (Carotid Angioplasty-stenting Free of Emboli, a prospective multicentric study) of carotid angioplasty using a cerebral protection newly designed device in a single center. Clinical Material and
Methods:
The patient population was composed of 50 patients with 55 target lesions; 30 men and 20 women, with ages ranging from 51–84 (mean 60,6 years). All the patients presented at least 2 risk factors. 82.5 of the lesions were symptomatic. Before the procedure, cranial CT / MRI, cervical US and DSA of supraaortic vessels and cerebral parenchymography were performed. Stenosis were evaluated according to NASCET criteria. Mean stenosis: 79 %. Calcic plaque: 65%. Ulcerated plaque: 60 %. Associated lesions in supraaortic vessels: 45%. Mean lesion length: 21.1 mm.
Results:
The balloon-guidewire was able to successfully cross the lesion in all the cases. Mean balloon occlusion time was 10 min. The immediate angiographic result demonstrated residual stenosis of 0–20% in all the cases. Operative morbidity: bradychardia, 7 cases (12.7%); balloon intolerance, 2 cases (3.6%). 22 patients (44%) were followed clinically for more than 12 months. Postoperative morbidity: myocardial infarction, 1 case (2%); congestive heart failure, 1 case (2%). The mortality rate is 0%.
Conclusions:
Cerebral protection represents a major contrubution to carotid artery angioplasty and stenting technique reducing significantly the occurrence of procedural emboli.
Rationale for the selection of the dose regimen of ‘Zendra’ used in the CLASS-I study
Authors: Ekblom M , Cheng Y-F , Jerling M , Karlsson M O , Wahlgren N-G
Published: March 2022

P195

Clomethiazole (CMZ; ‘Zendra’) is a neuroprotective drug that enhances GABA-A receptor activity. Two clinical trials in stroke patients (pts) were performed: 92CM01 (n=17) and CLASS (CLomethiazole Acute Stroke Study; n=678 on CMZ). In CLASS, a post-hoc analysis showed that CMZ appeared to improve outcome in pts with clinical signs suggestive of a large stroke. Dosing for the pivotal trial, CLASS-I, was based on information from these previous studies. In 92CM01, a loading dose of 6 mg/kg given over 15 min followed by a maintenance dose of 69 mg/kg to 24 h was the maximum CMZ dose that could be given without excessive sedation. In this study, plasma sampling from each pt allowed for individual kinetic modelling. In CLASS, the same dose regimen was used. One sample for drug analysis was taken from each pt at the end of the 24-h infusion. In total, 619 CLASS pts were eligible for a population kinetic evaluation. The clearance estimates in both studies were in the same range. Therefore, the pharmacokinetic parameter estimates from study 92CM01 could be used to simulate the plasma concentrations according to a 2-compartment model for different dosing regimens. According to the protocols, CMZ infusion should be temporarily interrupted if pts become excessively sedated. In CLASS, there were 218 infusion interruptions in 158 pts. CMZ kinetics did not differ between pts who had interruptions and those who did not. There was a delay in the occurrence of excessive sedation, with the majority of interruptions seen between 10 and 24 h. Pts with clinical signs suggesting a large stroke were particularly susceptible to sedation in CLASS, a new dose regimen was needed to reduce excessive sedation in these pts. For CLASS-I the adjusted dosage regimen was calculated as a total CMZ dose of 68 mg/kg, given as a 15 min loading dose, followed by two maintenance doses over 7.75 and 16 h respectively. This should avoid high plasma concentrations during the second half of the infusion period. Taking into account treatment interruptions, CLASS-I pts are predicted to receive an average dose of 63 mg/kg, the same as was actually received by such pts in CLASS.
‘Zendra’ is a trademark, the property of the AstraZeneca group of companies
Carotid Endarterectomy in Women: Challenging the results from NASCET and ACAS.
Authors: Mattos Mark A , McLafferty Robert B , Karch Laura A , Ramsey Don E , Hodgson Kim J
Published: March 2022

P203

Purpose:
The randomized trials have clearly demonstrated the benefits of carotid endarterectomy in specific symptomatic and asymptomatic patients. However, the short and long-term benefits in women appear to be less clear, and the role of CEA among women remains uncertain. The purpose of our study was to evaluate and compare the outcomes in women and men after CEA.
Methods:
Over a recent 21 year period 1204 CEAs were performed, of which 465 (39%) were in women and 739 (61%)in men. Complete follow-up was available in 80% of patients.
Results:
Women were more likely to be hypertensive, and had a greater incidence of diabetes. The mean age at CEA was 68.5 ± 9.5 years for women and 68.0 ± 8.5 years for men. Operative mortality rates were nearly identical for symptomatic (women, 0.3% vs men, 0.8%) and asymmptomatic (women, 0.0% vs 0.8%)patients. Perioperative stroke rates were similar for symptomatic (women, 2.9% vs 4.5%) (p=0.27) and asymptomatic (women, 0.6% vs. men, 1.2%) (p=0.66) patients. Life-table stroke-free rates at 1, 5, and 8 years were similar for symptomatic women and men, 96% vs. 93%, 89% vs. 89%, and 83% vs. 85% (p>0.10), and asymptomatic women and men, 98% vs. 97%, 97% vs. 92%, and 97% vs. 86% (p>0.11). Long-term survival rates at 1, 5, and 8 years were higher for symptomatic women compared to men, 96% vs. 92%, 88% vs. 76%, and 67% vs. 58% (p=0.06), and for asymptomatic women as compared to men, 97% vs. 96%, 92% vs. 75%, 79% vs. 58% (p=0.01 > 5 years). As a result, stroke-free survival rates at these follow-up intervals were increased for symptomatic women compared to men, 93% vs. 89%, 76% vs. 73%, and 64% vs. 58% (p>0.11), and asymptomatic women as compared to men, 95% vs. 93%, 89% vs. 76%, and 77% vs. 64% (p>0.07).
Conclusion:
The results from our study challenge the conclusions from the NASCET and ACAS regarding the lack of benefit of CEA in women. Female gender did not adversely affect early or late survival, stroke-free, or stroke-free mortality rates following CEA. We conclude that CEA can be performed safely in women with symptomatic and asymptomatic carotid artery disease, and physicians should expect comparable benefits in women and men undergoing CEA.
Clinical Outcomes of Anticoagulation for Stroke Prevention in Atrial Fibrillation: A 10 year cohort study.
Authors: Weibert Robert T , Jackson Christy , Feld Gregory K
Published: March 2022

P210

From January 1990 through July 2000 a cohort of 373 patients without prior thromboembolic events were treated with warfarin for nonvalvular or valvular atrial fibrillation. Patients were managed in an anticoagulation clinic using point-of-care prothrombin time monitoring. A computerized database was used to collect information on warfarin dose, INR results and clinical events. There were 6577 prothrombin time measurements with INR results as shown in the table and 52.1% of measured INRs were within the recommended range of 2.0–3.0. During 424 patient-years there was one stroke and three TIAs. The incidence of thromboembolism was 0.9% per year. Eleven patients sustained major bleeding events: gastrointestinal (8); retroperitoneal (1); subdural hematoma (1) and cebrebrospinal (1). The incidence of major bleeding was 2.6% per year. The lowest combined percentage of both major bleeding and thromboembolism occurred with INR values of 2.0–3.9. Long-term warfarin therapy with unselected outpatients in an anticoagulation clinic produced stroke and bleeding rates comparable to pooled data from controlled studies.
Smoking induces “nonresponse” under ASA and Ticlopidine treatment
Authors: Grotemeyer Karl-Heinz , Auge Burkhardt
Published: March 2022

P217

Smoking is assumed to be a risk factor in stroke-patients. Ticlopidine or ASA should prevent from stroke by inhibition of platelet function. Platelet function i.e. platelet reactivity (PR) (Grotemeyer, Thrombosis research 63;587) was determined before and after smoking without drugs, 2 hours after intake of ASA or ticlopidine and 5 days after loading with 2 x 250 mg ticlopidine/day . At each experiment 3 cigarettes (Marlboro ®) were smoked within 30 min. Blood was collected immediately before smoking and 30 min later. A washout period of 14 days was between each drug-experiment. Included were 23 healthy male smokers (age 25,2 ± 3,3 yr.) PR (before smoking) was 1.15 ± 0,15, after smoking 1,42 ± 0,18. Average difference (AD)(PR after - PR before smoking) was 0,28 ± 0,13. Pathological PR-values (>1.25) were seen in 95% of the smokers after the experiment. (Wilcoxon p<0,001) Two hours after intake of 500 mg ASA the AD was 0,13 ± 0,20. 60% of the values became pathological after smoking (p<0,01). Two hours after once 250 mg ticlopidine AD was 0,007 ± 0,16, 10% of the PR-values became pathological (n.s.). After 4 hours: AD =0,025 ± 0,04, after 6 hours: AD = 0,07 ± 0,04, after 8 hours: AD = 0,123 +/- 0,08 and 90% of the smokers showed pathological values (p<0,01). After the 5 day loading and 2 h after 250 mg ticlopidine AD was -0,01 ± 0,26, 5% PR-values became pathological (n.s.), after 4 h: AD = 0,05 ± 0,12, after 6 h: AD = 0,07 ± 0,07, after 8 h AD = 0,04 ± 0,05. 76% showed pathological values. AD after 10 h = 0,23 ± 0,27 Based on the percentage of smokers with pathological values the logrank-test showed with p<0,001 a significant difference in the ticlopidine experiments in favor to the testing after a loading time. Even if ticlopidine seems to be more effective as compared to ASA, it cannot be assumed that the drug - from the laboratory point of view - can compensate the negative activating effect of smoking on platelets completely.
Comparison of Patient and Proxy Responses to the Stroke Impact Scale
Authors: Dr. Pamela W Duncan , Dr. Dennis D Wallace , Dr. Sue-Min Lai , Ms. Denise A Tyler
Published: March 2022

P221

Purpose & Methods:
Our purpose was to compare patient and proxy responses to the Stroke Impact Scale ( SIS). We recruited 150 patients (mean age = 73±10) and their proxies (mean age = 59±15) from the Kansas City Stroke Registry at 90 to 120 days post stroke. Fifty-one percent of patients were male and 75% of proxies were female. The precision with which proxy responses replicated patient responses was estimated using intraclass correlation coefficient (ICC) obtained from random effects ANOVA model, while bias and precision of the proxy response as an estimate of patient response were assessed with linear models.
Results:
Two SIS subscales (ADL/IADL and hand function) and the aggregate physical function subscale showed no evidence of bias. Remaining subscales showed a consistent pattern of proxy overestimating patient scores at the low end of the scale and underestimating at the high end. However, with the exception of the emotion and communication scales (which are biased high over most of the range), the biases appear to be mathematical artifacts created by the bounds of the scales. Precision was reasonable for strength (.56), emotion (.50), communication (.42), and memory/ thinking (.43). ICC s were higher for social participation (.59), mobility (.66), ADL/IADL (.65), hand function (.81), and the aggregate physical domain (.78).
Conclusion:
In observable behavior (e.g. ADL/IADL, mobility, hand function, and combined physical functioning), our data indicate that proxies can be used as surrogates in clinical studies. Another important implication of this data is that clinical researchers must not develop one summary score of different health related domains.
Multicenter Evaluation of the Efficacy of Endovascular Treatment for Symptomatic Vasospasm unresponsive to Hypervolemic and Hypertensive Therapy in Patients with Subarachnoid Hemorrhage.
Authors: Kim Stanley H , Qureshi Adnan , Yahia Abutaher M , Suarez Jose , Zaidat Osama , Ali Zulfiqar , Suri M Fareed K , Tamargo Rafael J , Guterman Lee R , Hopkins L N
Published: March 2022

P231

BACKGROUND AND PURPOSE:
Symptomatic vasospasm remains an important cause of morbidity and mortality in patients with subarachnoid hemorrhage (SAH). Endovascular techniques have recently been introduced for treatment of vasospasm resistant to medical treatment. We performed this study to determine the safety and efficacy of these techniques in a large series of patients with SAH.
METHODS:
We reviewed the medical records, angiograms, and computed tomographic (CT) scans for patients who underwent endovascular treatment for symptomatic vasospasm at 3 university-affiliated centers. The following outcomes were analyzed; angiographic improvement, neurological improvement, ability to prevent cerebral infarction as demonstrated by serial CT scans, and outcome at 3 months using Glasgow Outcome Scale (GOS).
RESULTS:
Forty-five patients (mean age 51 ±10 years; 13 were men) were treated for symptomatic vasospasm. The vasospasm was graded as severe (n=27), moderate (n=16), and mild (n=2) by angiographic criteria. Angioplasty was performed in 26 patients; intra-arterial papaverine was administered as adjunctive therapy in 11 procedures. Nineteen patients were treated with intra-arterial papaverine alone. Angiographic improvement was documented in all patients. Cerebral infarction was observed in 29 (64%) of 45 patients on follow-up CT scan. Good outcome (minimal or no disability by GOS) was seen in 12 (27%) patients.
CONCLUSIONS:
Although endovascular treatment of symptomatic vasospasm results in good angiographic response, a high proportion of cerebral infarction and poor outcomes is still observed in patients who failed medical treatment. New strategies need to be developed to improve outcome in this subset of patients with SAH.
Focal Neurologic Deficits in Adults After Global Hypoxia-Ischemia and Extracorporeal Membrane Oxygenation
Authors: Kleindorfer Dawn O , Posner Steven , Schmidt Shelley , Hickenbottom Susan L , Bartlett Robert H , Selwa Linda
Published: March 2022

P243

Introduction:
Extracorporeal Membrane Oxygenation, or ECMO, provides cardiopulmonary support in critically ill patients with reversible cardiac or respiratory disease processes. Neurologic sequelae after ECMO have been well-studied in infants, but have not been evaluated in adults. We investigated the incidence of focal neurologic deficits in adults after global hypoxia-ischemia and ECMO as reported by the survivors or as seen on physical examination of the survivors.
Methods:
We performed a retrospective analysis of all adult patients who received ECMO urgently between 12/95 and 1/99. Fifty-nine percent of the survivors were contacted to participate in a telephone survey regarding neurologic symptoms and quality of life measures, including a Barthel Index. One survivor declined to participate.
Results:
During the time period of 12/95 to 1/99, 86 adult patients received ECMO urgently at the University of Michigan, 42 patients survived the hospitalization, and 44 patients died. Of the 42 survivors, 7 were lost to followup, and 8 died at a later date, with a mean length of survival after the ECMO hospitalization of 17 months. The mean age of the ECMO survivors was 38 (18–72), racial distribution was 66% white, 27% black, and 7% unknown or other. The survivors were 58% male and 42% female. Underlying diagnoses requiring ECMO support were 85% respiratory, and 15% cardiac. Average length of followup was 36.5 months. Of those contacted, 39% reported at least one neurologic symptom, moderately to severely disabling, that was new since the hospitalization during which ECMO occurred. Those symptoms are as follows: 13% unilateral weakness in face and/or body, 13% difficulty with language, 17% difficulty walking, and 9% blurred or double vision. All patients reported a completely independent Barthel Index score.
Conclusions:
A significant proportion of adult survivors of global hypoxia-ischemia and ECMO report neurologic deficits that are at least moderately disabling which are new since receiving ECMO. Of these deficits, problems with ambulation were the most common. Physical examinations are planned to further investigate these findings.
Abstract 1: Did Carotid Stenting and Endarterectomy Outcomes Change Over Time in the Carotid Revascularization Endarterectomy versus Stenting Trial?
Authors: Howard George , Roubin Gary S , Hopkins L. Nelson , Moore Wesley S , Gray William A , Rosenfield Kenneth , Katzen Barry T , Chakhtoura Elie , Morrish William F , Ferguson Robert D , Hye Robert J , Shawl Fayaz A , Harrigan Mark R , Voeks Jenifer H , Lal Brajesh K , Meschia James F , Brott Thomas G
Published: March 2022

Background
The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) enrolled 2502 patients between December of 2000 and mid-July of 2008. We analyzed temporal changes in outcomes for both CEA and CAS over the course of this study. Methods Enrollment was divided into 3 consecutive epochs (5 years, 14 months, and 16 months), each with approximately 834 patients (
Table
). Rates for the primary outcome of death, stroke, and myocardial infarction (DSMI) and for death and stroke (DS) during the periprocedural period were calculated. Poisson regression was used to adjust rates for age, sex, dyslipidemia, and symptomatic status, all of which were found to influence outcomes.

Results
For CAS, there was a 26% decline in DSMI (6.2% → 4.6%) and a 35% decline in DS (5.5% → 3.6%). For both composite endpoints in CEA there was no consistent pattern (
Table
). As CREST progressed, it enrolled younger patients, more men, patients more likely to be dyslipidemic and enrolled more asymptomatic patients (all p < 0.05). Adjustment for these changes mediated the improvement in event rates for the CAS patients, and had no consistent effect on CEA event rates (
Table
).

Conclusion
Periprocedural safety for CAS improved over time in CREST. Changes were inconsistent for CEA. Improvements for CAS in part appear to reflect changes in patient selection related to age, sex, and risk factors, as adjustment for those variables attenuated the decline in rates. Linking rates to operator experience was not feasible because of the large number of new interventionalists and surgeons entering CREST over time.
Abstract 100: Small Intracerebral Hematomas Have A Low Spot Sign Prevalence And Are Unlikely To Expand
Authors: Dowlatshahi Dar , Aviv Richard , Luna Rodriguez David , Molina Carlos , Silva Blas Yolanda , Dzialowski Imanuel , Czlonkowska A , Boulanger Jean-Martin , Lum Cheemun , Gubitz Gord , Padma Vasantha , Roy Jayanta , Kase Carlos , Stewart Teri , Bhatia Rohit , Boyko Matthew , Kosior Jayme , Gladstone David , Hill Michael D , Demchuk Andrew
Published: March 2022

Background:
Early intracerebral hemorrhage (ICH) expansion is a major determinant of poor clinical outcome. We previously reported baseline hematoma volume was a predictor of hematoma expansion (HE), and that hematomas <3mL may represent a subgroup with good prognosis. Our objective was to validate our previous findings in a multi-centre prospective observational cohort, and to assess the relationship between baseline hematoma size and the CTA spot-sign. We hypothesized that small hematomas are less likely to expand, and have low spot-sign prevalence.

Methods:
The PREDICT study is a prospective, observational cohort study of consecutive patients with acute ICH. Inclusion criteria are age>18, symptom onset <6 hours, and baseline CT and CTA; exclusions are baseline ICH >100ml, planned ICH surgery within 24 hours, known secondary cause of ICH, known renal impairment, GCS<6, or premorbid disability or terminal illness. Scans were reviewed for spot sign presence/absence by a neuroradiologist blinded to outcomes and follow-up imaging. Volumes were measured by planimetry by a neurologist blinded to CTA images and outcomes. The predictor of interest was baseline hematoma volume which was stratified as <3mL, 3-9mL, 10-19mL, 20-29mL and >30mL based on our prior study. Primary outcome was significant HE defined as ≥6mL. We used multivariable models to calculate adjusted odds ratios (aOR) for HE.

Findings:
Two-hundred and sixty-eight patients were enrolled from 11 centers in 6 countries: HE analysis was limited to 228 patients with follow-up CT before rFVIIa or surgical intervention. Median baseline hematoma volume was 12.4ml, spot-sign was present in 26.8% of patients, and 25% of patients had HE of ≥6ml. HE and spot sign prevalence increased with increasing baseline hematoma volume

(see
table
)

. Only one patient with volume <3ml had HE; the patient was on warfarin (INR 2.2) but spot negative. Two patients with volumes <3ml were spot positive, but neither had HE. When compared to hematomas >30ml, the aOR for HE was 0.09 for <3ml hematomas, 0.14 for 3-9ml, 0.49 for 10-20ml, and 1.83 for 20-30ml (p<0.001). Associations between baseline hematoma volume and clinical outcomes will be presented.

Discussion:
Our results validate baseline hematoma volume as a predictor of HE. Furthermore, spot sign prevalence is associated with baseline hematoma volume. These results can inform ICH trial design and clinical prognostication at the bedside: small hematomas have a low spot sign prevalence and are unlikely to expand ≥6 ml, even when spot positive. Conversely, half of hematomas >30ml are spot positive and will expand.
Abstract 102: High Rate of Silent Ischemic Lesions at 1 Year in Patients with Primary Intracerebral Hemorrhage
Authors: Kidwell Chelsea S , Menon Ravi S , Sobotka Ian , German Laura , Fernandez Stephen , Gibbons M. C , Wing Jeffrey J , Burgess Richard E , Shara Nawar M , Jayam-Trouth Annapurni , Edwards Dorothy F
Published: March 2022

Background:
We have previously reported that approximately one-third of patients with primary intracerebral hemorrhage (ICH) have acute ischemic lesions remote from the hematoma on baseline and day 30 MR imaging. The objective of the current analysis was to determine the prevalence, characteristics, and associated risk factors for concurrent silent ischemic lesions at 1 year in a predominantly black, hypertensive ICH population. The analysis was undertaken as part of a prospective, multicenter, MRI-based, longitudinal natural history study of racial differences in patients with primary ICH.

Methods:
Inclusion criteria were: primary ICH, age ≥ 18, baseline and 1 year MRI scan obtained. Clinical and demographic data were collected on all subjects. A standardized MRI protocol was employed and included DWI (with apparent diffusion coefficient [ADC] maps), T2*-weighted image sequences (GRE), and FLAIR sequences. Images were evaluated for: location and volume of the primary hematoma, frequency and location of ischemic lesions, frequency and location of microbleeds, and white matter disease severity. DWI lesions were categorized as acute or subacute based on ADC maps.

Results:
Of the 104 patients with 1 year MRIs, mean age was 58 years, 55% were male, 76% black, and 87% had a history of hypertension. Primary hematoma location was deep in 77% of subjects and lobar in 23%. Mean baseline NIHSS was 8 (median 5). Mean baseline ICH volume was 20 cc (median 13 cc). DWI ischemic lesions were found in 18 (17%) subjects. Fifteen subjects had 1 lesion and 3 had 2 lesions. Of the total 21 lesions, 12 (57%) were acute (low ADC), and 9 (43%) were subacute. Nine (43%) lesions were located in lobar locations, and 12 (57%) were in deep structures. On univariate analysis, age, hypertension, prior stroke, microbleed burden, leukoaraiosis, antiplatelet use at 1 year, and mean arterial pressure at 1 year were not significantly associated with presence of DWI lesions.

Conclusions:
In this longitudinal MR imaging study of ICH, we found that 17% of subjects had evidence of ongoing silent ischemia on diffusion-weighted imaging at 1 year. This finding further supports the active nature of the underlying vasculopathy. A larger cohort is needed to identify risk factors for and/or imaging characteristics predictive of ischemic lesions. These lesions may be an important biomarker for future risk factor control.
Abstract 11: The Utility of Causative Classification System: Correlation between Causative and Phenotypic Stroke Subtypes
Authors: Arsava Ethem Murat , Barrett Kevin , Biffi Alessandro , Brenner David , Brown Robert , Gamble Dale , Grazer Anja , Gschwendtner Andreas , Helenius Johanna , Huq Mohammed , Katschnig Petra , Katsnelson Michael , Kittner Steven , Li Linxin , Labovitz Daniel L , Malik Shaneela , Meschia James , Ossi Raid , Peddareddygari Leema , Pucek Mateusz , Rannikmae Kristiina , Rhodes David , Saraf Neha , Sheikh Huma , Stoegerer Eva , Southerland Andrew , Weissman Darren , Woo Daniel , Worrall Bradford , Ay Hakan
Published: March 2022

Background:
Causative Classification of Stroke (CCS) system is a novel, web-based, and fully-computerized algorithm that integrates clinical, diagnostic, and etiologic stroke characteristics in an evidence-based manner (available at
http://ccs.mgh.harvard.edu
) and provides in a given patient both phenotypic subtypes where abnormal evaluation findings are simply organized in major etiologic categories and causative subtypes where abnormal evaluation findings are filtered through a decision making process to identify the most likely cause of stroke. In this study, we sought to identify the concordance between phenotypic and causative CCS subtypes in the NINDS Stroke Genetics Network (SiGN).

Methods:
A total of 24 adjudicators from 15 US and European sites certified in CCS retrospectively determined CCS subtypes through chart review in 7134 patients. The CCS software provided causative subtypes in 3 confidence levels as “evident”, “probable” or “possible” based on the weight of causal evidence. We estimated how often CCS classified a given major abnormal evaluation finding as the causative stroke mechanism.

Results:
CCS assigned 55% of patients with the phenotype of moderate-to-severe atherosclerotic stenosis into the causative category of “evident large artery atherosclerosis”. Likewise, 50% of patients with a major cardiac source (such as atrial fibrillation) were classified into “evident cardio-aortic embolism”, and 74% of those with imaging evidence of a typical lacunar infarct into “evident small artery occlusion”. In 20% to 30% of patients, phenotypic and causative categories were the same but the causative subtype was assigned with a lower level of confidence. Six to 20% of patients with a given phenotypic feature were classified into a different causative category. Failure to investigate for other subtypes in the presence of a positive test finding and the presence of multiple competing etiologies were key contributors to the observed disconcordance between phenotypic and causative subtypes.

Conclusions:
Our findings show that the presence of a major abnormality in stroke evaluation does not necessarily mean that it is always the cause. The ability of CCS system to discriminate between phenotypic and causative characteristics of stroke etiology provides the opportunity to refine stroke phenotypes for use in research studies.
Abstract 110: Tumor Necrosis Factor-alpha Induces Phenotypic Modulation in Cerebral Vascular Smooth Muscle Cells via KLF4: Implications for Cerebral Aneurysm Pathology
Authors: Ali Muhammad S , Yu Zaifang , Jabbour Pascal M , Tjoumakaris Stavropoula I , Gonzalez L. Fernando , Rosenwasser Robert H , Koch Walter J , Koch Walter J , Dumont Aaron S
Published: March 2022

Inflammation and vascular smooth muscle cell (VSMC) phenotypic modulation appears to be important in cerebral aneurysm formation/progression yet molecular pathological mechanisms remain unknown. We investigated a potential direct role of Tumor Necrosis Factor-alpha (TNF-alpha) mediated via the transcription factor, KLF4, in inducing VSMC phenotypic modulation and inflammation in vitro and in vivo, which may be critical in the pathogenesis of cerebral aneurysms.

Methods:
Rat cerebral VSMCs were treated with TNF-alpha (5 and 50 ng/ml) for 24 hours. The expression of KLF4, VSMCs marker genes (SM-alpha-Actin, SM-22alpha and SM-MHC), the SRF co-activator, Myocardin, and inflammatory/ matrix remodeling genes (MMP-3, VCAM-1, iNOS, and MCP-1) was measured using qPCR. Cells were transfected with siRNA against KLF4 to examine the role of KLF4 as a direct mediator of phenotypic modulation. To investigate in vivo effects, pluronic gel (40% w/v) containing TNF-alpha (30-60 ug/ml) was applied to carotid vessels in 7-week-old rats for 6 and 24 hours. Carotid vessels were harvested and qPCR performed. In another experiment, aneurysm induction surgery was performed in rats using a standard model (unilateral carotid ligation/induction of hypertension). The circle of Willis cerebral vessels were harvested and qPCR performed comparing treated and control animals.

Results:
TNF-alpha treatment produced a dose-dependent decrease in SMC marker gene and myocardin expression while potently inducing expression of KLF4 and the aforementioned inflammatory/matrix remodeling genes (p<0.05 vs. baseline) demonstrating a profound direct role of TNF-alpha in inducing cerebral VSMC phenotypic modulation in vitro. This phenotypic modulation was markedly abrograted using siKLF4. In vivo, TNF-alpha applied to carotid vessels produced a marked increase in KLF4 expression at 6 hours and a subsequent decrease in SMC marker gene expression and increase in expression of inflammatory/matrix remodeling genes at 24 hours (p<0.05 treated vs. control). Similarly, increased expression of KLF4 and TNF-alpha was noted in the Circle of Willis in vivo two weeks after aneurysm induction surgery. Decreased marker gene expression along with increased inflammatory/matrix remodeling marker gene expression was also seen (all p<0.05 vs. control).

Conclusion:
TNF-alpha appears to potently induce phenotypic modulation of cerebral VSMCs producing a pro-inflammatory phenotype with elevation of matrix remodeling genes both in vitro and in vivo. KLF4 appears to be a critical mediator of this process. As inflammation (and specifically TNF-alpha) and matrix remodeling have been implicated in the pathogenesis of human cerebral aneurysms, the molecular mechanisms outlined herein may represent a novel target for future therapy.
Abstract 115: Aspirin-triggered Neuroprotectin D1 Protects The Penumbra In Focal Cerebral Ischemia In Rats
Authors: Bazan Nicolas G , Serhan Charles N , Petasis Nicos A , Khoutorova Larissa , Atkins Kristal D , Eady Tiffany N , Hong Song , Jun Bok Kyoo , Obenaus Andre , Belayev Ludmila
Published: March 2022

Background and Purpose:
Acute ischemic stroke triggers complex neurovascular, neuroinflammatory and synaptic alterations. Aspirin and the omega-3 essential fatty acid, docosahexaenoic acid (DHA), have beneficial effects on cerebrovascular diseases. Unlike most anti-inflammatory agents, aspirin jumpstarts resolution mainly due to acetylation of cyclooxygenase enzymes. Both neuroprotectin D1 (NPD1) and its precursor, DHA, participate in neuroprotection. Here we have tested the effect of aspirin plus DHA administration and discovered the synthesis of aspirin-triggered NPD1 (AT-NPD1) in the penumbra. Then we performed the total chemical synthesis of this molecule and, upon systemic administration 1h after 2h of middle cerebral artery occlusion (MCAo), uncovered remarkable protection.

Methods:
Sprague-Dawley rats were anesthetized with isoflurane and received 2h MCAo. Neurological status was evaluated at 24h, 48h, 72h, and 7 days. Treatment with 333µg/kg of AT-NPD1 sodium salt (AT-NPD1-SS) or AT-NPD1 methyl-ester (AT-NPD1-ME) or vehicle (saline) (n=7-8 per group) was administered i.v. at 3h after stroke. On day 7,
ex vivo
magnetic resonance imaging (MRI) of the brains was conducted on 11.7T MRI. T2WI, 3D volumes, and apparent diffusion coefficient (ADC) maps were generated. In addition, infarct volumes and number of GFAP (reactive astrocytes), ED-1 (activated microglia/microphages) and NeuN (neurons)-positive cells were counted in the cortex and striatum at the level of the central lesion.

Results:
All animals showed similar values for rectal and cranial temperatures, arterial blood gases, and plasma glucose during and after MCAo. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly improved neurological scores compared to saline treatment at 24h, 48h, 72h and 7 days. Total lesion volumes computed from T2WI images were significantly reduced by both AT-NPD1-SS and AT-NPD1-ME treatment in the cortex (by 44% and 81%, respectively), striatum (by 61% and 77%) and total infarct (by 48% and 78%, respectively). Brain edema, computed from T2WI in the cortex (penumbra) and striatum (core), was elevated in the saline group. In contrast, both AT-NPD1-SS and AT-NPD1-ME decreased water content in the striatum on day 7. 3D volumes, computed from T2WI,
were dramatically reduced
with AT-NPD1-SS and AT-NPD1-ME, and the lesion was mostly localized in the subcortical areas. Treatment with both AT-NPD1-SS and AT-NPD1-ME significantly reduced cortical (by 76% and 96%), subcortical (by 61% and 70%) and total (69% and 84%) infarct volumes as defined by histopathology.

Conclusions:
Ex vivo
MRI, histopathology, and behavioral testing shows neuroprotective efficacy of novel AT-NPD1 therapy in focal cerebral ischemia and uncover a novel approach for pharmaceutical intervention and clinical translation.
Abstract 119: Bone Marrow Stromal Cell Transplantation Enhances Recovery of Local Glucose Metabolism after Cerebral Infarct in Rats: A
18
F-FDG PET Study
Authors: Miyamoto Michiyuki , Kuroda Satoshi , Zhao Songji , Magota Keiichi , Kuge Yuji , Ito Masaki , Kawabori Masahito , Shichinohe Hideo , Houkin Kiyohiro , Tamaki Nagara
Published: March 2022

Background:
Recent studies have indicated that bone marrow stromal cells (BMSC) have the potential to improve neurologic function when transplanted into animal models of central nervous system disorders. However, no methods have been established to objectively evaluate the beneficial effect of BMSC transplantation on the host brain in clinical situation. Therefore, this study was aimed to assess whether the BMSC significantly improve local glucose metabolism in the peri-infarct area on
18
F-fluorodeoxyglucose (FDG) PET, when transplanted into the infarct brain of rats.

Methods:
The BMSC were harvested from green fluorescent protein (GFP)-transgenic rats and were cultured. The rats were subjected to permanent middle cerebral artery (MCA) occlusion. The BMSC or vehicle was transplanted into the ipsilateral striatum at 7 days after the onset of MCA occlusion. Using
18
F-FDG PET, local glucose metabolism was semi-quantitatively and serially measured at 6 days post-ischemia and at 4 weeks after BMSC transplantation. Motor function was serially evaluated throughout the experiments. The distribution and fate of engrafted cells were examined, using fluorescence immunohistochemistry at 4 weeks after BMSC transplantation. Simultaneously, the expression of brain-type glucose transporter (GLUT1 and GLUT3) was also evaluated.

Results:
Local glucose metabolism was significantly lower in the dorsal peri-infarct neocortex at 6 days post-ischemia. However, BMSC transplantation significantly accelerated the recovery of local glucose metabolism in that area at 4 weeks after transplantation. Thus, the ratio of glucose metabolism in the ipsilateral to contralateral dorsal neocortex significantly increased from 72.5 ± 4.2% to 78.7 ± 4.0% in the vehicle group (P<0.01). On the other hands, the values more pronouncedly increased from 72.7 ± 4.4% to 87.7 ± 5.3% in the BMSC group (P<0.01). The BMSC were engrafted in the boundary zone of cerebral infarct and also expressed the phenotypes of neural cells. BMSC transplantation significantly prevented the overexpression of GLUT1 in the endothelium and of GLUT3 in the neurons in that area.

Conclusion:
These findings strongly suggest that BMSC may enhance the recovery of local glucose metabolism in the peri-infarct area when directly transplanted into the infarct brain at clinically relevant timing. The recovery of local glucose metabolism may inhibit pathological upregulation of GLUT1 and GLUT3.
18
F-FDG PET may be the candidate of valuable modalities to scientifically prove the beneficial effects of BMSC transplantation on the host brain in clinical situation.
Abstract 121: Symptomatic Intracranial Atherosclerotic Disease in Acute Cerebral Ischemia: Frequency, Clinical Course and Short-Term Outcome in a Tertiary Care Hospital in the Southeastern United States
Authors: Barlinn Kristian , Kepplinger Jessica , Kolieskova Stanislava , Kesani Maruthi , Samal Andrey A , Chaudhary Asad A , Harrigan Mark R , Albright Karen C , Alexandrov Andrei V
Published: March 2022

Background:
In the recently stopped SAMMPRIS trial, enrolled patients had to be stable for at least 3 days since the index event. Following that, the early results suggest a benefit with aggressive medical therapy and risk factor modification. We sought to explore the frequency, risk of early neuroworsening (NW), stroke recurrence and short-term prognosis in patients with symptomatic intracranial atherosclerotic disease (IAD).

Methods:
We retrospectively reviewed our consecutive stroke database for patients with acute cerebral ischemia admitted in 2010 to our tertiary hospital. Demographics, vascular risk factors, clinical and imaging data were collected. The extent of IAD (mild <50%, moderate 50-69%, severe 70-99%) was identified by MRA, CTA and DSA. Early stroke-related NW was defined as in-hospital increase in the NIHSS score (>2 points) without any systemic cause. Functional outcome (mRS), stroke recurrence rate and death were also determined at discharge and follow-up.

Results:
A total of 438 patients with acute cerebral ischemia were reviewed (18% TIA; median age 65, range 21-99; 51% men, 61% Caucasians; median NIHSS 5, range 0-40), of which 408 (93%) had vascular imaging. IAD was present in 98/408 (24%) patients with 40 (9.8%) symptomatic 50-99% IAD. Baseline characteristics, clinical data and outcomes are summarized in the
Table
. The median follow-up time was 31 (0-507) days. After adjusting for known confounders, neither moderate nor severe IAD alone predicted early NW, functional outcome, stroke recurrence or death (at discharge or follow-up). However, when the 15 cases of 50-69% were combined with the 25 cases of 70-99% IAD (50-99%), symptomatic IAD was a significant independent predictor of early NW (OR 4.2, 95%CI 1.2-14.8, p=0.025), but not of stroke recurrence, outcome or death (at discharge or follow-up). In addition, NW had a strong positive correlation to poor modified Rankin and death (at discharge and follow-up, p<0.001).

Conclusions:
Symptomatic 50-99% IAD is common in our patient population and it predicts early neuroworsening. The strong correlation between neuroworsening and poor functional outcome and death underscores the importance of prompt diagnostic work-up for IAD. Despite the initial results of SAMMPRIS it is unclear if stenting has no role in acute and subacute management of these patients. This could be a subject of a randomized controlled trial.
Abstract 124: Collaterals Determine Risk of Early Territorial Stroke and Hemorrhage in the SAMMPRIS Trial
Authors: Liebeskind David S , Cotsonis George A , Lynn Michael J , Cloft Harry J , Fiorella David J , Derdeyn Colin P , Chimowitz Marc I ,   on behalf of the SAMMPRIS Investigators
Published: March 2022

Background:
The degree of collateral circulation is a powerful risk factor for recurrent stroke in the setting of medical therapy for symptomatic intracranial atherosclerosis. The impact of collaterals on the short-term risk for stroke in patients treated by stenting or intensive medical therapies is not known. We systematically evaluated baseline angiographic features of collateral circulation and antegrade flow across intracranial stenoses in randomized subjects of the multicenter SAMMPRIS trial and correlated these to their 30-day risk of ischemic stroke.

Methods:
Digital review of baseline angiograms in SAMMPRIS was conducted to score ASITN/SIR collateral grade and TICI antegrade flow, blind to other data. Dichotomized collateral and TICI scores (none/partial versus complete) were analyzed independently and in combinations with trial endpoints of territorial ischemic stroke or stroke in territory (SIT) and intracranial hemorrhage (ICH) within 30 days in the intensive medical and stenting arms of the study. Log-rank tests with follow-up time censored at 30 days were used in the analysis.

Results:
Collaterals could be assessed on 376/424 baseline angiography studies available for digital imaging review for the 451 randomized subjects in SAMMPRIS (186 medical, 190 stenting). Early territorial stroke (SIT) occurred in 6/186 (3.2%) subjects in the medical arm and 20/190 (10.5%) after stenting. SIT was not associated with TICI in either arm, whereas collaterals exerted a potent protective influence in medical (p=0.067) and stented (p=0.004) cases, with 0/66 (0%) SIT in the medical arm and 0/51 (0%) SIT in the stented arm when collaterals were complete. SIT in medical cases was associated with partial TICI/partial collaterals (5/25 (20.0%)) versus complete TICI/partial collaterals (1/95 (1.1%)) and partial TICI/complete collaterals (0/66 (0%)), p<0.001. SIT in stented cases was associated with partial TICI/partial collaterals (11/46 (23.9%)) versus complete TICI/partial collaterals (9/93 (9.7%)) and partial TICI/complete collaterals (0/51 (0%)), p<0.001. ICH within 30 days occurred in 0/186 (0%) subjects randomized to medical therapy. In the stenting arm, early ICH occurred in 8/190 (4.2%) and was associated with TICI (p=0.036) and collaterals (p=0.077). Overall, early ICH after stenting was associated with partial TICI/partial collaterals (7/46 (15.2%)) versus complete TICI/partial collaterals (1/93 (1.1%)) and partial TICI/complete collaterals (0/51 (0%)), p<0.001.

Conclusions:
Patients with impaired collateral flow associated with severe intracranial stenosis had the highest risk for stroke within 30 days, both with intensive medical therapy and as a complication of angioplasty and stenting.