Coronavirus disease of 2019 (COVID-19) has currently reached pandemic levels and neurological manifestations, including stroke as the initial presentation, have been increasingly recognized.1–3 Majority of the reported ischemic strokes are large vessel occlusion or embolic appearing strokes and are frequently described in critically ill patients with severe COVID-19 disease2, but small ischemic strokes have also been reported.4 Recently, stroke as the presenting symptom in younger patients (< 50 years of age) with mild COVID-19 disease has gained increased attention.

Introduction: Given the time-critical nature of acute stroke, reducing door-in-door-out (DIDO) times at primary stroke centers (PSC) prior to transfer to comprehensive stroke centers (CSC) is a priority. We applied Failure Modes Effects and Criticality Analysis (FMECA) to the DIDO process at a PSC, an engineering methodology widely used in other industries, to understand the most critical areas negatively impacting DIDO time. Methods: We collected data during 2 in-person and 5 virtual Learning Collaborative (LC) meetings, enhanced by electronic surveys. The LC team consisted of 18 clinicians affiliated with 6 different healthcare systems including 3 PSCs and 3 CSCs, 2 participants from EMS agencies, and 5 patients and caregivers. The LC team created a DIDO process map with individual steps. For each step, we asked LC members to identify ways in which the process could be performed incorrectly, incompletely, skipped or delayed (failures) along with the clinical impact, their causes, frequency and existing safeguards. Each clinical impact, frequency and safeguard was scored from 1-10 (lowest to highest). Frequency, severity, and safeguards scores were multiplied to calculate a criticality score to rank the top DIDO process failures. Results: Among 61 DIDO process steps, the top 12 steps with the highest criticality score represented 40.4% of the sum of criticalities (Figure). Among these, the highest criticality scores were for: 1) Delay in the decision to obtain CTA; 2) Delay in stroke recognition by the EMS team; 3) Delay in stroke identification at triage. Conclusion: We identified opportunities to re-design the DIDO process for acute stroke. Existing safeguards for the identified “high” criticality failures rely on human factors (e.g., multiple visual inspections, provider’s experience). There is a need to develop better stroke identification tools and automatic triggers within the DIDO process to increase timely stroke transfers from PSC to CSCs.

Background: Patients who develop a stroke are at high risk for cognitive decline. The Montreal Cognitive Assessment (MOCA) is a validated tool for assessing cognitive function within this patient population prior to discharge. An important limitation of the MOCA is that often times there is no pre-morbid score for comparison. Despite this, consideration of occupational and cognitive therapy is important in this population because of the high risk for cognitive decline. Methods: A total of 231 patients were treated on the stroke unit from December 2015 to June 2016, of these 149 patients were excluded due to activity intolerance, severe communication barriers, patient refusal, or cognitive deficits exceeding the limit of the screening tool. A retrospective chart review was conducted on the 82 patients and data on demographics, stroke risk factors, stroke type (ischemic, subarachnoid hemorrhage, or intracerebral hemorrhage), MOCA scores, and discharge disposition (home or acute/subacute rehabilitation) was extracted. Results: Of the 82 patients in the study, 45 (55%) were male, with an average age of 54.9 years. Thirty-eight (46%) of these patients suffered hemorrhagic strokes. Average MOCA scores for hemorrhagic stroke patients who were either discharged home versus a rehab setting were similar when compared to the ischemic stroke population (20.1 and 18.2 versus 21.3 and 16.9, respectively). However, when subcategorized by stroke subtype, the subarachnoid hemorrhage population exhibited higher MOCA scores for those who were discharged home or to rehab versus the patients with ICH who were discharged home or to rehab (21.9 and 25.4 versus 19.1 and 13.6, respectively). Interestingly, the patients within the SAH cohort who were discharged to rehab had a higher MOCA average than those who were discharged home. Conclusion: Many patients who suffer hemorrhagic strokes in this population are discharged home despite having a MOCA score below normal (<26). This may demonstrate residual cognitive deficits as a result of their disease process. Despite a patient’s ability to be functionally and physically able to return home, there is an identified need for addressing cognitive deficits in order to improve quality of life.

To determine whether the intraventricular hemorrhage (IVH) score is associated with outcome after intracerebral hemorrhage (ICH).

Background: The use of oral anticoagulants (OAC) is associated with poor outcome in intracerebral hemorrhage (ICH). In this study we investigated the effect of delayed INR reversal and the factors influencing it in patients with OAC-associated ICH (OAC-ICH). Methods: Data were obtained from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study which is a prospective, multi-ethnic multicenter study of ICH. Exclusion criteria included missing initial hematoma volume, INR or ED arrival time and being on heparin. Baseline characteristics, INR at baseline and 12h, hematoma location and volume, treatment received, hematoma expansion at 24h, and mortality at 3 months were recorded. INR reversal was defined as INR<1.4 at 12h post admission. Variables associated with INR reversal and case fatality at 3 months in non-OAC users and OAC users with and without INR <1.4 were compared. Results: A total of 1,746 of 2,276 subjects were included in the analysis. A higher proportion of OAC users (n=185) were white and had hypertension, diabetes, hypercholesterolemia, and lobar ICH than non-users (P<0.05). Baseline INRs for the OAC group were 3.1 (28.7%). Subjects on OAC received fresh frozen plasma (FFP, 44%) monotherapy, either recombinant factor VII or prothrombin complex (FVII/PCC, 7%), or a combination of FFP/FVII/PCC (11%). Increasing age (OR=0.96, 95% CI 0.94-0.98), elevated baseline INR (OR=0.34, 95% CI 0.26-0.43), and use of FFP only (OR=0.07, 95% CI 0.04-0.13) was associated with lack of INR reversal at 12h. Median INR at 12h (IQR) were 1.4 (1.3-1.6), 1.1 (0.9-1.1), and 1.0 (1.0-1.3) for the FFP, PCC/FVII, and FFP/FVII/PCC groups, respectively (p1.4 did not influence the rate of hematoma expansion at 24h. Case fatality at 3 months was 22% for non-OAC-ICH, 34% for OAC-ICH with INR<1.4, and 44% for OAC-ICH with INR>1.4 (p=.0005). Conclusion: In the ERICH study, patients treated with FFP monotherapy were less likely to have a normalized INR at 12h and this was associated with increased case fatality at 3 months. The use of FVII/PCC may shorten time to INR correction and improve outcome in OAC-ICH.

Objectives: To determine whether vascular and demographic factors predict worsening disability up to 8 years after lacunar stroke. Methods: SPS3 (Secondary Prevention of Small Subcortical Strokes) was a clinical trial in lacunar stroke patients with annual assessment of disability using the Older Americans Resources and Survey instrumental activities of daily living (IADL) scale (range 0–14). Generalized estimating equations modeled the likelihood of disability (IADL <14) over time, adjusting for demographics, medical risk factors, cognition, mood, stroke location, and geographic region in univariate and multivariable models. IADL assessments after recurrent stroke were censored. We stratified by study region and age quartile. Results: Among 2,820 participants, mean age was 63.4 years (SD 10.8), 63% were male, 36% had diabetes, 90% hypertension, and 10% prior stroke. Mean follow-up was 3.7 years. In multivariable models, female sex, education, diabetes, nonregular alcohol use, prior stroke, Cognitive Abilities Screening Instrument score, depression, mild cognitive impairment, and stroke location were associated with disability. The youngest age quartile had decreased odds of disability over time (odds ratio 0.90 per year, 95% confidence interval 0.85–0.95), whereas the oldest age quartile had increased odds (2.20, 95% confidence interval 1.75–2.75). Americans and Latin Americans had >2-fold greater odds of disability per year compared with Spaniards (p < 0.0001). Conclusions: In lacunar stroke patients, older age was associated with worsening long-term disability, even without recurrence. Worse long-term function was associated with diabetes, cognitive status, and prior stroke, and regional differences may be attributable to variations in health care delivery or scale interpretation.

Background: Oral anticoagulant (OAC) use is associated with poor outcome in intracerebral hemorrhage (ICH). The aim of this study was to determine if race/ethnic differences exist in this condition. Methods: Data were obtained from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study which is a prospective multicenter study of ICH. Exclusion criteria included missing initial hematoma volume or being on heparin or LMWH. Baseline and clinical characteristics, laboratory and imaging data at presentation and 24h, and mortality at 3 months were compared by OAC use and race/ethnicity. ANOVA was used to identify factors affecting initial hematoma volume by location and OAC use. Logistic regression was performed to evaluate risk of hemorrhage based on race/ethnicity. Results: A total of 2,020 of 2,276 cases met the inclusion criteria and were included in the analysis (627 whites, 739 blacks, and 654 Hispanics) of which 214 (10.5%) were on OAC (54% white, 22% black, and 23% Hispanic). History of hypertension, diabetes, hypercholesterolemia, previous stroke, and atrial fibrillation, elevated INR at admission, infratentorial location, and dementia were associated with OAC use (p Conclusion: In the largest prospective study in ICH we found that location and outcome in OAC-associated ICH differ among subjects of different racial/ethnic background. Our findings indicate that OAC-associated ICH is a heterogeneous condition and identifies blacks as a group with increased case fatality rate.

Background: Intracerebral hemorrhage (ICH) is associated with early neurological deterioration and death. Prior studies showed that delays in seeking medical attention may occur among minorities. In this study we investigated the factors affecting time from symptom onset to ER arrival (TOA) in a race/ethnic enriched population. Methods: Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) is a prospective study of spontaneous ICH. Baseline characteristics, presenting symptoms, first contact (911 vs. ER vs. primary physician), ICH volume, location and intraventricular extension, insurance status, GCS at presentation, and TOA were collected. Data was analyzed using generalized linear models and Spearman’s rank correlations. TOA was natural log transformed and a multivariate model was developed using backward elimination (P-value=0.05). Results: A total of 1158 subjects were enrolled; 28 were excluded due to lack of TOA. Of the 1,030 included 59% were men with 24% whites, 41% blacks, and 35% Hispanics. Mean age was 61±15 years, mean Glasgow Coma Scale (GCS) at presentation was 12.4±3.7 (median=15), and median TOA was 431 min (interquartile range 106-820). Location of ICH was 56% deep, 28% lobar, 8% cerebellum, and 5% brainstem. Approximately 29% of subjects had no medical insurance, 36% had medicare, 18% medicaid, 36% private insurance, and 1% VA insurance. In univariate analysis women, use of 911, EMS run, different presenting symptoms, lobar and deep location, and low GCS were associated with shorter TOA. In multivariate model only women (p=0.05), GCS (p=0.04), use of 911 (p<0.001), EMS run (p<0.001), and weakness and dysarthria as presenting symptoms remained significant. Ethnicity was not a significant predictor (p=0.79). These variables explain 23.3% of the variation in TOA. Conclusion: Ethnicity and insurance status did not affect time to presentation. Women, use of 911, EMS run, weakness and lower GCS were associated with shorter TOA in ICH. Increased education in target populations with higher incidence of ICH such as minorities on stroke signs/symptoms and use of 911 may expedite access to medical care. Further studies are needed to determine the impact of TOA on outcome.

OBJECTIVE: To validate GRASPS score in an independent cohort. BACKGROUND: The recently developed GRASPS score predicts risk for symptomatic intracerebral hemorrhage (sICH) within 36 hours post intravenous tissue plasminogen activator (iv-tPA) infusion. In the original study, sICH adjudication was based on documentation but neuroimaging was not centrally available. DESIGN/METHODS: Consecutive acute ischemic stroke (AIS) patients admitted to our institutions between January 2011 and July 2012, and treated with iv-tPA were identified. Age, race/ethnicity, sex, NIHSS, blood pressure, and glycemia at presentation were obtained, and GRASPS scores calculated. Charts were reviewed looking for neurological deterioration and sICH at 36h post iv-tPA infusion. Neuroimaging was used to confirm the diagnosis of sICH. Scores were analyzed for sensitivity and specificity and the C-statistic calculated based on the receiver operating characteristic (ROC) curve. RESULTS: A total of 41 cases treated with iv-tPA within 3 hours of symptom onset were identified and analyzed. Our study population was predominantly white (73.2%), male (54%), with a median age of 79±13 years, and median NIHSS of 14±8 at baseline. Symptomatic ICH occurred in 6 cases. GRASPS scores ranged between 49 and 87, and the ROC area under the curve was 0.73 (95% CI = 0.48-0.98). A score of ≥86 had a positive likelihood ratio of 8.8 and correctly classified 87.8% of the population. Using this cut-off, the specificity was 94.3% and the sensitivity was 50.0%. CONCLUSIONS: The GRASPS score may be a useful prediction tool for the risk of sICH in AIS patients receiving iv-tPA within 3 hours of symptom onset. A higher GRASPS score, specifically 86 and higher, predicts the occurrence of sICH; however, the score had a low sensitivity. Our findings underscore the need for prospective validation of the GRASPS score in different clinical settings with diverse study population. Disclosure: Dr. Ong has nothing to disclose. Dr. Nouh has nothing to disclose. Dr. Pandey has nothing to disclose. Dr. Grysiewicz has nothing to disclose. Dr. Khaja has nothing to disclose. Dr. Shafi has nothing to disclose. Dr. Ruland has received personal compensation for activities with AstraZeneca Pharmaceuticals and Boehringer Ingelheim Pharmaceuticals, Inc. Dr. Hillmann has nothing to disclose. Dr. Hoelzel has nothing to disclose. Dr. Castillo has nothing to disclose. Dr. Testai has nothing to disclose.

Background: The pathogenesis of brain injury after subarachnoid hemorrhage (SAH) is multifactorial and not completely understood. We recently described that profound changes in the ceramide (Cer) profile occur after SAH. Cer is an endogenous sphingolipid associated with brain-cell death. Dihydroceramide (DH-Cer) is an inactive sphingolipid that is metabolized into Cer by desaturases. In this study we sought to investigate if a differential metabolism of Cer into DH-Cer occurs in SAH and if this is related to vasospasm (VS) and outcome. Methods: Cerebrospinal fluid (CSF) Cer and DH-Cer levels were determined by mass spectrometry in control subjects and patients with Fisher 3 grade SAH within 48 hours of the bleed. Patients were prospectively followed and subcategorized based on the presence or absence of symptomatic VS (sVS versus no-sVS) and modified Rankin Scale (mRS) at discharge. Results: A total of 8 controls and 23 SAH patients were enrolled in the study. Compared to controls, patients with SAH had higher CSF levels of total Cer (12.41±8.84 versus 54.65±49.30 pmol/mL, p=0.001) and DH-Cer (1.44±1.05 versus 4.73±3.43 pmol/mL, p<0.0001). Cer/DH-Cer ratios in both groups were comparable (p>0.05). Within the SAH group, sVS had higher Cer and DH-Cer levels than no-sVS (104.23±56.97 versus 28.60±16.91 pmol/mL, p=0.001 for Cer; 7.87±4.03 versus 3.12±1.88 pmol/mL, p=0.005 for DH-Cer). In addition, the sVS group had lower Cer/DH-Cer ratios than no-sVS (0.11±0.03 versus 0.08±0.02; p=0.009). Compared to individuals with good outcome (mRS≤3), SAH patients with poor outcome (mRS≥4) had lower Cer/DH-Cer ratios (0.12±0.04 versus 0.09±0.02; p=0.04) Conclusions: CSF levels of Cer and DH-Cer increase after SAH, particularly in individuals with sVS and poor neurological outcome at discharge. The distinctive Cer/DH-Cer ratios observed in sVS and no-sVS groups suggest that differences in sphingolipid metabolism exist in these subgroups.

Background and Purpose— The purpose of this study was to investigate changes in the cerebrospinal fluid sphingolipid profile in patients with subarachnoid hemorrhage in relation to the occurrence of symptomatic vasospasm and outcome at hospital discharge. Methods— The ceramide profile in the cerebrospinal fluid was determined by mass spectrometry in control subjects and patients with Fisher 3 grade subarachnoid hemorrhage within 48 hours of the bleed. Patients were prospectively followed and subcategorized based on the occurrence of symptomatic vasospasm and modified Rankin Scale at discharge. Results— Compared to control subjects, patients with subarachnoid hemorrhage had higher cerebrospinal fluid levels of total ceramide (12.4±8.8 versus 54.6±49.3 pmol/mL; P <0.001). In the subgroup analysis, total ceramide levels in individuals with symptomatic vasospasm (104.2±57.0 pmol/mL) were higher than in those with asymptomatic vasospasm (32.4±25.7 pmol/mL; P =0.006) and no vasospasm (30.9±15.7 pmol/mL; P =0.003). In addition, compared to patients with a good outcome (modified Rankin Scale ≤3), individuals with poor outcome (modified Rankin Scale ≥4) had higher cerebrospinal fluid levels of total ceramide (79±25 versus 23±6 pmol/mL; P =0.008). When the relative contributions of the different ceramide species were calculated, a higher relative concentration of C 18:0 ceramide was observed in individuals with symptomatic vasospasm ( P =0.018) and poor outcome ( P =0.028). Conclusions— Ceramide profile changes occur in subarachnoid hemorrhage. In this small case-based series elevation of levels of this sphingolipid, particularly C 18:0 , was associated with the occurrence of symptomatic vasospasm and poor neurological outcome after subarachnoid hemorrhage.

Cerebral vasospasm (VS) after subarachnoid hemorrhage (SAH) is associated with delayed cerebral ischemia and poor neurological outcome. We have recently reported that shortly after SAH, there is a dramatic elevation in the levels of the endogenous VEGF-antagonist soluble fms- like tyrosine kinase-1 (sFlt1), particularly among individuals that will later develop symptomatic VS (sVS). Based on this observation we have proposed that an imbalance in the levels of endogenous angiogenic and anti-angiogenic factors occurs in SAH. In this study we examined the association of cerebrospinal fluid (CSF) levels of VEGF, sFlt1, and VEGF/sFlt1 ratio with vasospasm in SAH patients. We studied seventeen patients with Fisher Grade 3 aneurysmal SAH and five controls with no prior history of neurological disorders who underwent lumbar puncture for headache and had normal CSF studies. Demographics and medical history were documented. Patients were followed prospectively and samples of CSF were obtained within 48-hours of symptoms onset. VEGF and sFlt1 levels were determined using commercially available ELISA tests (R&D Systems). SAH subjects were subcategorized into those with sVS and those who did not develop symptomatic VS (noVS). sVS was defined as the occurrence of neurological deterioration in the setting of angiographically proven VS and in the absence of other conditions that could explain the neurological decline. Ratios and levels of the compounds of interest in the different groups were compared using the nonparametric Mann-Whitney U test. Age, history of hypertension, exposure to elicit drugs, RBC count in the CSF and proteinorrachia were not statistically different between sVS and noVS groups. Similar to what has been described by others, compared to controls, SAH patients showed a trend towards having higher VEGF levels in the CSF (106±53 vs. 180±172 pg/mL); this, however, did not reach statistical significance (p>0.05). The CSF levels of sFlt1 were 46±23 pg/mL in the control group and 598±423 pg/mL in the SAH group (p=0.01). Among patients with SAH, sFlt1 levels were 1018±797 pg/mL in the sVS group and 304±184 pg/mL in the noVS group (p=0.01). The mean VEGF/sFlt1 ratios were 2.27±0.25 in controls, 0.39±0.25 in SAH patients, 0.23±0.10 in the sVs group, and 0.61±26 in the noVS group (p=0.02). An early elevation in sFlt1 levels and a relative deficiency of VEGF occur in the CSF of SAH patients, particularly in those with sVS. These results suggest that an imbalance in the production of angiogenic and anti-angiogenic factors may be part of the pathogenesis of VS and that analysis of these molecules might potentially have a role in predicting sVS in SAH patients.

The pathogenesis of vasospasm (VS) post aneurysmal subarachnoid hemorrhage (SAH) is multifactorial and not completely understood. The authors hypothesize that circulating antiangiogenic factors play an important role in brain injury post SAH and that elevated levels predict the occurrence of symptomatic vasospasm.

Whited, Karen; Aiyagari, Venkatesh; Calderon-Arnulphi, Mateo; Cursio, John; Pandey, Dilip; Hillmann, Maureen; Ruland, Sean Author Information