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Background and Purpose Risk factors for formation and rupture of intracranial aneurysms (IAs) have been extensively investigated, and it is apparent that IAs and subarachnoid hemorrhage (SAH) are more common in females than males. Much is unknown about why IAs occur more frequently in females, but previous investigators have implicated hormonal and flow geometry variations in the development of compromised vessel wall integrity. The purpose of this study was to evaluate morphological characteristics of aneurysms within our population and differences in morphology and/or anatomic locations between males and females. Methods A retrospective review was performed of patients undergoing 3D angiograms for intracranial aneurysms at a comprehensive stroke center between January 1, 2012 and January 1, 2018. Data collected included patient demographic information, comorbidities and aneurysm characteristics evaluated by 3D angiogram. All statistical analyses were completed in SAS 9.4. Results 276 patients (203 female, 73 male) with 404 aneurysms were included. Of the 276 patients, 113 (81 female, 32 male) presented with ruptured IAs. On univariate analysis, female patients had significantly greater odds of having a posterior circulation aneurysm than males (p = 0.0073; OR, 4.30; 95% CI 1.48 to 12.48). For males and females, the most frequent locations were the anterior communicating artery and internal carotid artery, respectively. No statistically significant differences were observed in neck diameter, dome to neck ratio, or presence of secondary aneurysmal sacs. Conclusion The sex differences in aneurysm morphology and location require further investigation. Aneurysms found in male and female patients had different anatomic distributions; the most frequent location was the anterior communicating artery for men and the internal carotid artery for women. No statistically significant differences were discovered in the studied morphological parameters. Sex differences in IA characteristics may reveal unknown information about the pathophysiology of formation of IAs and possible disparities in treatment outcomes. In the future, these sex differences could impact management strategies. Disclosures E. Roney: None. D. Lukins: None. M. Nisiewicz: None. A. Alhajeri: None. S. Grupke: None. J. Fraser: None.

Introduction Cerebral Venous Sinus Thrombosis (CVST) has an estimated incidence of 1.32–1.57/100,000/yr, with death or severe disability in less than 10%. There is a reported elevated incidence in young -middle age females. The majority of reported epidemiologic and outcome data has been collected outside the United States (US). Available US data shows low representation of the Appalachian region, which has relatively a higher burden of disease and lower socioeconomic level. The objective of this study was to examine the gender characteristics of CVST patients in the United States, with greater representation of the Appalachian region. Methods Data were collected in a retrospective cohort using the Kentucky Appalachian Stroke Registry (KApSR), collected from admissions in a Comprehensive Stroke Center serving 554,300 from the central-eastern United States. All diagnosed CVST patients found in the database from 2010–2018 greater than 18 years of age were included in the data set. Descriptive data were computed using SPSS statistics. Results 101 patients diagnosed with CVST were included. 58 patients were female (57.4%). Median age was 44 years. The National Institutes of Health Stoke Scale (NIHSS) was reported for 32 female and 21 male patients. Median NIHSS was.5 in females and 0 in males at admission. Median length of stay was 7 days in females vs. 4 days in males. Discharge data were available for 51 female and 33 Male patients. Of female patients, 28 (55%) were discharged to home, 17(33%) were transferred to continued care, 4(8%) were transferred to hospice and 2(4%) died within 48 hours of admission. Of male patients, 25(76%) were discharged to home, 7 (21%) were transferred to continued care, and 1 (3%) was transferred to hospice. Female patients had a higher burden or comorbidities and multimorbidity compared to male patients. Conclusion The results of this study indicate a higher burden of comorbidity, more severe presentation, and worse prognosis in female patients. This is in contrast to the majority of CVST research, many of which have found the male sex to be an independent risk factor for worse outcomes. This may reflect a particular variant among the Appalachian population Disclosures S. Walsh-Blackmore: 1; C; University of Kentucky Center for Clnical and Translational Sciences Professional Student Mentored Research Fellowship. J. Fraser: None. P. Kitzman: None. M. Dobbs: None.

Background and purpose Mechanical thrombectomy (MT) is the standard of care for emergent large vessel occlusion (ELVO), one of the most severe subtypes of ischemic stroke, which accounts for 30–40% of all cases. Through MT, we can isolate distal blood within the artery immediately downstream from the clot and compare it to systemic arterial blood to provide insight into local intraluminal changes during ischemia. CXCL9 is in interferon gamma-inducible chemokine that binds CXCR3, degrading endothelial tight junctions, attracting T cells, and facilitating immune cell extravasation into brain parenchyma. We aimed to study local CXCL9 expression distal to the intracranial thrombus during large vessel occlusion in human patients. Methods Tissue samples of distal and proximal blood were collected as part of the BACTRAC tissue bank (www.clinicaltrials.gov NCT03153683). Adult subjects with ELVO were prospectively enrolled, and arterial blood distal (intracranial) and proximal (cervical) were collected and processed to optimize RNA quality. RNA were isolated and used to evaluate gene expression in both samples for each subject; proximal systemic blood was used as an internal control for each subject. Results 22 subjects were included in this preliminary analysis. 15 (68.2%) were female. 54.5% of subjects had a CTA collateral score of 1 (18.2% had a score of 0). 4.5% (1 subject) did not attain TICI 2B or 3 recanalization. Infarct time (last known normal to thrombectomy recanalization) was 491 ± 243 minutes. Mean change in NIHSS from admission to discharge was -8 ± 8. CXCL9 expression in distal blood was upregulated an average of 106-fold with a maximum upregulation of 805-fold in one subject. In plotting CXCL9 expression against infarct time, there was a clear negative correlation (Spearman coefficient -0.43, p=0.05). Conclusion For the first time, we evaluate chemokine alterations in human stroke patients in distal stagnant blood during ELVO. There is a significant variance in CXCL9 expression in distal blood in relationship to infarct time, which mirrors the known timing of blood-brain barrier disruption. Disclosures J. Fraser: None. S. Martha: None. L. Collier: None. S. Davis: None. A. Alhajeri: None. S. Grupke: None. K. Pennypacker: None.

Introduction Ischemic stroke is the one of the most severe and debilitating diseases, and despite animal models, there is much to learn about the neuropathology in humans in a way that could inform the development of therapies. We have developed a protocol to collect and evaluate arterial blood immediately distal and proximal from the removed intracranial thrombus during mechanical thrombectomy. These samples provide a unique resource in evaluating acute changes in acid/base and electrolyte concentrations at the time of ischemic stroke. The purpose of this study was to compare acid/base and electrolytes obtained proximal and distal to the occluded intracranial thrombi between male and female acute ischemic stroke subjects at the time of thrombectomy; and to determine whether arterial blood gas values predict outcomes in male and female subjects. Methods We analyzed the first 49 subjects (age = 67 ± 15.0, 21 males) in the BACTRAC registry. We compared arterial blood gas of blood distal versus proximal to the thrombus during thrombectomy which provided acid/base levels (pH, pCO2, pO2, BD, HCO3−) and electrolyte values (iCa2+, K+, and Na+). Comparisons were evaluated by one-way repeated measures ANOVA (p Results In general, distal intracranial luminal blood sample showed a compensated metabolic acidosis with an elevated oxygen concentration in both blood samples. Analysis indicated several significant differences in the proximal blood samples between sexes (pH, pCO2, and K+). Bicarbonate and base deficit were predictors of infarct time specifically in female subjects. Discussion and conclusion Acid/base and electrolyte response to ischemic conditions differ between men and women, and these early changes could be used to predict local acid/base changes and how they develop differently in men and women during ischemia. These findings provide a novel insight into the pathology of large vessel stroke in humans, particularly potential variations based on sex.

BACKGROUND: Early changes in acid/base and electrolyte concentrations could provide insights into the development of neuropathology at the onset of stroke. We evaluated associations between acid/base and electrolyte concentrations, and outcomes in permanent middle cerebral artery occlusion (pMCAO) model. METHODS: 18-month old male and female Sprague-Dawley rats underwent pMCAO. Pre-, post- (7 minutes after occlusion), and at 72 hours of pMCAO venous blood samples provided pH, carbon dioxide, oxygen, glucose, hematocrit, hemoglobin, and electrolyte values of ionized calcium, potassium and sodium. Multiple linear regression determined predictors of infarct and edema volumes from these values, Kaplan-Meier curve analyzed morality between males and females at 72 hours, and a Cox regression model was used to determine predictors for mortality. RESULTS: Analysis indicated significant differences in acid/base balance and electrolyte levels in aged rats not dependent on sex between the three time points in the pMCAO model. Changes in pH (from pre- to post and post- to 72 hours) and changes in sodium and ionized calcium (from post- to 72 hours) were predictors of infarct volume and edema volume, respectively. Cox Regression revealed there is a 3.25 times increased risk for mortality based on changes in bicarbonate (pre- to post-MCAO). CONCLUSIONS: These early venous blood changes in acid/base balance and electrolytes can be used to predict stroke outcomes in our rat model of stroke. This study provides potential biomarkers to be examined in the human condition that could provide profound prognostic tools for stroke patients.

BackgroundThe aim of this publication is to provide a detailed update on the diagnosis, treatment, and endovascular techniques for posterior circulation emergent large vessel occlusion (pc-ELVO).MethodsWe performed a review of the literature to specifically evaluate this disease and its treatments.ResultsData were analyzed, and recommendations were reported based on the strength of the published evidence and expert consensus.ConclusionWhile many questions about pc-ELVO remain to be studied, there is evidence to support particular practices in its evaluation and treatment.

Introduction: Moyamoya is a chronic cerebrovascular condition of unclear etiology characterized by progressive occlusion of one or both internal carotid arteries with neovascular collateral formation. With both a congenital juvenile form and a likely secondary adult form (moyamoya syndrome), it can cause ischemic and hemorrhagic stroke. Recent findings in the region have challenged traditional estimates of its incidence in US populations. Using the Kentucky Appalachian Stroke Registry (KApSR), our aim was to further characterize its incidence as a cause of stroke, and to understand the particular patient population in our region. Methods: A retrospective review was performed of patients identified with moyamoya within the KApSR database. Data collected included demographics, risk factors, comorbidities and healthcare encounters from January 1, 2012 to December 31, 2017. Statistical analyses were completed in SPSS 24 (IBM Corp., Armonk, NY, USA). Results: Sixty-seven patients were identified; 36 (53.7%) resided in Appalachian counties. The cohort accounted for 125 of 6305 stroke admissions, representing a prevalence of 1983 per 100000 stroke admissions. Most patients presented with ischemic strokes rather than hemorrhagic (OR 5.50, 95% CI:2.74-11.04, p Conclusion: The prevalence of moyamoya accounts for a significant portion of stroke admissions in Appalachia and these patients were more likely to develop an ischemic stroke than hemorrhagic. Autoimmune disorders were more prevalent in moyamoya patients compared to the general population. Finally, the reduced frequency of risk factors within the Appalachian group suggests an etiology distinct to the population.

Introduction: Moyamoya is an arteriopathy defined by the progressive stenosis of the intracranial internal carotid arteries accompanied by the formation of abnormal vascular networks. To address the paucity of research on the adult-onset Moyamoya Syndrome, which completely lacks any animal model for evaluation, our lab created a novel surgical technique, termed internal carotid artery stenosis (ICAS), that attempts to model the cerebrovascular changes seen in the human Moyamoya Syndrome. We hypothesized that the ICAS model would mimic the key proposed pathogenic features of Moyamoya Syndrome; namely, intimal hyperplasia of the major vessels of the cerebrovasculature leading to vessel stenosis and the formation of small, compensatory collateral arteries. Methods: ICAS (n=9) and sham (n=6) surgeries were performed in a randomized fashion on male C57Bl/6 mice (age=16 weeks). Brain tissue sections and RNA were collected 28-days post-surgery. Intimal hyperplasia was assessed with a modified Verhoeff-van Gieson stain. Expression of genes associated with human Moyamoya Syndrome (VEGF, SDF-1α, MMP-9, bFGF, VCAM-1, and MCP-1) was quantified by qPCR. MatLab and PRISM software were used for data analysis. Results: ICAS induces intimal hyperplasia of the cerebrovasculature ( p =0.033). ICAS increases genetic expression of VEGF in the whole brain (fold change=0.60, p =0.050) and SDF-1α in the striatum (fold change=0.59, p =0.016), and decreases genetic expression of MMP-9 in the ipsilateral cortex (fold change=0.39, p =0.044). Furthermore, a trend indicates that ICAS may increase genetic expression of VCAM-1 in the ipsilateral striatum (fold change=0.33, p =0.109). Conclusions: The present finding that ICAS induces intimal hyperplasia and alters genetic expression supports ICAS as a relevant model of the proposed pathology of Moyamoya Syndrome. The upregulation of VEGF, SDF-1α, and VCAM-1 is indicative of angiogenesis, hypoxia-induced vasculogenesis, and ischemia-induced inflammation, while the downregulation of MMP-9 may indicate decreased extracellular remodeling in the cortex. While investigation of the long-term effects of coil-placement is needed, ICAS may provide a crucial model for development of therapies for Moyamoya Syndrome.

Background and Purpose: The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) tissue bank collects blood proximal and distal to the intracranial thrombus during the process of mechanical thrombectomy in human stroke patients. These samples provide a unique resource in evaluating acute gene expression changes at the time of ischemic stroke. The purpose of this study was to evaluate gene expression changes occurring within the thrombus and across the occlusion in the intravascular space in acute ischemic stroke patients. Methods: We developed the BACTRAC protocol: an IRB-approved tissue banking approach for ELVO (clinicaltrials.gov NCT03153683). We evaluated relative concentrations of gene expression in 84 inflammatory molecules in thrombi removed from adults who received thrombectomy for ischemic stroke, in static blood distal to thrombus, and in peripheral circulation. Results: We analyzed the first 46 subjects (age = 67 ± 14.23, 20 males) in the BACTRAC registry. Results from qPCR gene expression analyses demonstrate that 21 genes (CCL1, CCL11, CCL13, CCL17, CCL26, CCL8, CSF3, CX3CL1, CXCL1, CXCL9, IFNA2, IL13, IL17C, IL17F, IL1A, IL27, IL3, IL33, LTA, TNFSF11, and TNFSF13) had at least 25 mean fold change in the distal blood compared to the peripheral blood. Fourteen genes (AIMP1, CCL11, CCL13, CCL15, CCL16, CCL23, CCR2, CCR4, CCR8, CD40LG, CXCL10, IL10RA, IL15, and TNFSF13B) had at least 10 mean fold change in the thrombus compared to the peripheral blood. Overall, these genes are associated with chemo-attraction and cell proliferation of monocytes, neutrophils, and T cells. Conclusions: These findings provide a novel insight into the initial pathology of large vessel stroke in humans, particularly in regard to identifying acute gene expression changes that occur during stroke.

Introduction: Vascular contributions to cognitive impairment and dementia (VCID) are a major factor in the overall clinical burden of dementia. Besides aging, metabolic disorders such as type 2 diabetes complicate understanding of underlying mechanisms. Despite the complexity, we hypothesize that pathological changes in cerebrovascular extracellular matrix (ECM) are an underlying component of VCID that can be therapeutically targeted to reduce neurodegeneration and improve outcomes . One such ECM component, the terminal domain V (DV) of perlecan, greatly reduces amyloid toxicity and enhances angiogenic cerebrovascular remodeling. Methods: DV’s mechanism and therapeutic potential in facilitating Aβ clearance were examined in an ex vivo model of isolated mouse brain capillaries in normal and high glucose environments. We also determined the cerebrovascular changes in a comorbidity mouse model of VCID (diabetic APP/PS1 knock in (db/AD)) that is associated with hemorrhages, aneurysms, Aβ deposition, cognitive decline and increased mortality. Results: DV (300 and 600 nM) doubled the transport of fluorescently tagged hAβ1-42 over 24 hours from the bath (abluminal) to luminal side of the brain capillaries. One of Aβ’s known transport proteins, P-glycoprotein (P-gp), also increased in total protein expression and in transport activity in the presence of DV. At 3-6 months in db/AD mice, we observed a decrease in BBB proteins (claudin-5) indicating an altered cerebrovascular function correlating with DV expression increase during the asymptomatic angiogenic stage. At 9-12 months, cognitive changes were associated with altered cerebrovascular protein expression in PECAM, Collagen IV, and DV correlating with the aberrant two-photon vascular imaging, increased saccular aneurysms, and microhemorrhages. Conclusion: These data show that DV increases cerebrovascular Aβ clearance through P-gp. Increased DV expression correlates with early cerebrovascular changes induced by angiogenic-remodeling in a diabetic co-morbid mouse model of VCID. Lower DV expression is associated with aberrant vasculature that contribute to increased mortality, suggesting that DV ‘replacement therapy’ could represent a novel therapeutic for VCID.

Endothelial cell integrin receptors, specifically the β 1 subtype, play a direct role in inflammation and blood-brain barrier (BBB) dysfunction, both implicated in poor ischemic stroke outcomes. We hypothesize that inhibition of a particular β1 integrin subtype, α5β1, (a pro-angiogenic fibronectin receptor acutely expressed after ischemic stroke) could be therapeutic in ischemic stroke via BBB stabilization. Methods: 3-month-old male, C57BL/J6 wildtype mice underwent transient middle cerebral artery occlusion for 1 hour. Mice were treated intraperitoneally with the small peptide α5β1 integrin inhibitor ATN-161 (1 mg/kg) upon reperfusion, post stroke day (PSD) 1 and PSD2. On PSD3, infarct volume (TTC and T2-weighted MRI) and vasogenic edema (MRI) were assessed. Neuroscore, an 11-point functional assessment, was performed on PSD1-14. Expression of MMP-9, claudin-5 and IL-1β levels were determined by qPCR. On PSD3, immunohistochemical analyses of α5 integrin, collagen IV, claudin-5, CD45, and DAPI expression were performed. In vitro oxygen-glucose deprivation (OGD) experiments on brain endothelial (bEND3) cells were also performed, evaluating ATN-161 administration (10 μM) effects on BEND3 layer permeability via FITC-dextran migration, and on immunocytochemistry of α5 integrin and claudin-5 expression. Results: Acute post-stroke administration of ATN-161 significantly decreased infarct volume and vasogenic edema, and improved functional recovery. Additionally, ATN-161 appeared to stabilize the BBB by increasing expression of the tight junction protein claudin-5, while decreasing expression of the extracellular matrix proteinase, MMP-9, inflammatory cytokine (IL-1β), and infiltrating leukocytes (CD45). Additionally, permeability was conserved with ATN-161 administration following OGD. Conclusion: Administration of the α5β1 inhibitor ATN-161 stabilizes the BBB barrier, and reduces inflammatory infiltration, while reducing infarct volume, vasogenic edema, and behavioral dysfunction following experimental stroke. Collectively, these results suggest inhibition of α5β1 via ATN-161 could represent a promising novel therapeutic approach for ischemic stroke.

Background and Purpose: In the setting of mechanical thrombectomy for emergent large vessel occlusion (ELVO), we have developed a protocol to collect and evaluate blood immediately distal and proximal from the removed intracranial thrombus. These samples provide a unique resource in evaluating acute changes in acid/base and electrolyte concentrations at the time of ischemic stroke. The purpose of this study is to compare acid/base and electrolyte differences obtained proximal and distal to the occluded intracranial thrombus in acute ischemic stroke patients. Methods: We developed the Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol: an IRB-approved tissue banking strategy for ELVO (clinicaltrials.gov NCT03153683). We compared arterial blood gases (ABG) of blood distal versus proximal to the thrombus during thrombectomy. Comparisons were evaluated by Paired Samples T-Tests (p < 0.05). Results: We analyzed the first 46 subjects (age = 67 ± 14.23, 20 males) in the BACTRAC registry. Preliminary results demonstrate that, while pH is nonsignificant (p = 0.513), distal blood in relation to proximal blood showed significantly lower oxygen (p < 0.001), carbon dioxide (p < 0.001), bicarbonate (p < 0.001), ionized calcium (p < 0.001), and potassium (p < 0.001). Sodium concentration was significantly higher (p < 0.001) in distal blood. These results suggest alterations occurring intravascularly during ischemia. Conclusions: These preliminary findings provide a novel insight into the pathology of large vessel stroke in humans, particularly in regard to identifying acute changes in acid/base balance and electrolyte concentrations that occur during stroke.

Background and purposePlatelet function testing prior to flow diversion procedures, although initially heavily debated, has seen a substantial increase in its adoption to assess the risk of operative and perioperative thrombotic and hemorrhagic events. This meta-analysis was conducted to assess platelet function testing, particularly the VerifyNow Platelet Reactivity Unit (PRU) assay, for a relationship between the reported assay PRU value and thrombotic and hemorrhagic events.Materials and methodsThe currently available literature (2013–2018) was surveyed with PubMed and Google Scholar searches. Included studies were those for which there were at least 30 cases during the study period, for which VerifyNow platelet reactivity unit values were obtained prior to the procedures and for which intraoperative and perioperative adverse events were noted. PRU value cut-offs ranging from >200 to >240 comprised the hyporesponse group while values ranging from ResultsThe searches yielded 27 studies, of which 12 met the inclusion criteria for the meta-analysis. The meta-analysis included data from 1464 reported Pipeline cases. The study included 273 men and 1177 women with a mean age across the analyzed procedures of 58 years (range 25–85). After loading with antiplatelet medications, preprocedural platelet hyper-responsiveness was associated with a greater incidence of hemorrhagic events with an increased absolute risk of 12%, but showed no relationship with thrombotic events. Preprocedural platelet hyporesponsiveness was associated with a greater incidence of thrombotic events with an absolute risk of 15%, but showed no relationship with hemorrhagic events.ConclusionsVerifyNow PRU values that correspond to platelet hyporesponse or hyper-response to dual antiplatelet therapy are associated with a higher risk of thrombotic and hemorrhagic events, respectively. Thus, the PRU value may offer some predictive value for these events.

Background Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et al., J Cereb Blood Flow Metab 37:3531–3543, 2017; Hill et al., Lancet Neurol 11:942–950, 2012; Amaro et al., Stroke 47:2874–2876, 2016). Methods Transient stroke was induced in mice via one of two methods. One group of mice were subjected to tandem ipsilateral common carotid artery and middle cerebral artery occlusion, while another group underwent the filament-based middle cerebral artery occlusion. We have recently developed an animal model of intra-arterial (IA) drug administration after recanalization (Maniskas et al., J Neurosci Met 240:22–27, 2015). Sub groups of the mice were treated with either saline or Il-1α, wherein the drug was administered either acutely (immediately after surgery) or subacutely (on the third day after stroke). This was followed by behavioral and histological analyses. Results We now show in the above-mentioned mouse stroke models (transient tandem ipsilateral common carotid artery (CCA) and middle cerebral artery occlusion (MCA) occlusion, MCA suture occlusion) that IL-1α is neuroprotective when acutely given either intravenously (IV) or IA at low sub-pathologic doses. Furthermore, while IV administration induces transient hemodynamic side effects without affecting systemic markers of inflammation, IA delivery further improves overall outcomes while eliminating these side effects. Additionally, we show that delayed/subacute IV IL-1α administration ameliorates functional deficit and promotes neurorepair. Conclusions Taken together, our present study suggests for the first time that IL-1α could, unexpectedly, be an effective ischemic stroke therapy with a broad therapeutic window.

OBJECT Although the endonasal endoscopic approach has been applied to remove olfactory groove meningiomas, controversy exists regarding the efficacy and safety of this approach compared with more traditional transcranial approaches. The endonasal endoscopic approach was compared with the supraorbital (eyebrow) keyhole technique, as well as a combined “above-and-below” approach, to evaluate the relative merits of each approach in different situations. METHODS Nineteen cases were reviewed and divided according to operative technique into 3 different groups: purely endonasal (6 cases); supraorbital eyebrow (microscopic with endoscopic assistance; 7 cases); and combined endonasal endoscopic with either the bicoronal or eyebrow microscopic approach (6 cases). Resection was judged on postoperative MRI using volumetric analysis. Tumors were assessed based on the Mohr radiological classification and the presence of the lion’s mane sign. RESULTS The mean age at surgery was 61.4 years. The mean tumor volume was 19.6 cm3 in the endonasal group, 33.5 cm3 in the supraorbital group, and 37.8 cm3 in the combined group. Significant frontal lobe edema was identified in 10 cases (52.6%). The majority of tumors were either Mohr Grade II (moderate) (42.1%) or Grade III (large) (47.4%). Gross-total resection was achieved in 50% of the endonasal cases, 100% of the supraorbital eyebrow cases with endoscopic assistance, and 66.7% of the combined cases. The extent of resection was 87.8% for the endonasal cases, 100% for the supraorbital eyebrow cases, and 98.9% for the combined cases. Postoperative anosmia occurred in 100% of the endonasal and combined cases and only 57.1% of the supraorbital eyebrow cases. Excluding anosmia, permanent complications occurred in 83.3% of the cases in the endoscopic group, 0% of the cases in the supraorbital eyebrow group, and 16.7% of cases in the combined group (p = 0.017). There were 3 tumor recurrences: 2 in the endonasal group and 1 in the combined group. CONCLUSIONS The supraorbital eyebrow approach, with endoscopic assistance, leads to a higher extent of resection and lower rate of complications than the purely endonasal endoscopic approach. The endonasal endoscopic approach by itself may be suitable for a small percentage of cases. The combined above-and-below approaches are useful for large tumors with invasion of the ethmoid sinuses.

BackgroundBurnout takes a heavy toll on healthcare providers. We sought to assess the prevalence and risk factors for burnout among neurointerventional (NI) non-physician procedural staff (nurses and technologists) given increasing thrombectomy demands.MethodsA 41-question online survey containing questions including the Maslach Burnout Inventory-Human Services Survey for Medical Personnel was distributed to NI nurses and radiology technologists at 20 US endovascular capable stroke centers.Results244 responses were received (64% response rate). Median (IQR) composite scores for emotional exhaustion were 25 (15–35), depersonalization 6 (2–11), and personal accomplishment 39 (35–43). Fifty-one percent of respondents met established criteria for burnout. There was no significant relationship between hospital thrombectomy volume, call frequency, call cases covered, or length of commute. On multiple logistic regression analysis, feeling under-appreciated by hospital leadership (OR 4.1; PConclusionsThis survey of US NI non-physician procedural staff demonstrates a self-reported burnout prevalence of 51%. This was driven more by interaction with leadership and physician staff than by thrombectomy procedural volume and stroke call. Attrition among NI non-physician procedural staff is high.

Pediatric spinal vascular malformations are rare entities that typically present with symptoms from their effect on surrounding structures. Here we report a unique case of lumbar spinal dural/perimedullary arteriovenous fistula (AVF) that presented with intraventricular hemorrhage and hydrocephalus. The previously healthy child presented with lethargy and headache, and initial imaging revealed only ventriculomegaly with trace intraventricular blood. His mental status improved with CSF diversion via an external ventricular drain. Further workup revealed a spinal AVF that was treated via endovascular embolization. His course was complicated by vasospasm requiring endovascular treatment and he eventually required ventriculoperitoneal shunt placement. He made a full recovery and has returned to his normal activities. This is a unique case of spinal AVF presentation and highlights the importance of considering imaging of the entire neuroaxis during workup for hydrocephalus.

This document aims to provide an update on indications for mechanical thrombectomy in acute ischemic stroke (AIS) from emergent large vessel occlusion (ELVO) in the anterior circulation. This reflects new evidence building on the Society of NeuroInterventional Surgery (SNIS) recommendations published in 2015.1 Recommendations herein supersede those of previous SNIS guidelines where overlap exists. Previous publications included an overview of prehospital care, a summary of the role of intravenous (IV) and intra-arterial (IA) therapies, a review of technical aspects of thrombectomy, and initial hospital management.1–3 This guideline focuses on updated indications for thrombectomy of anterior circulation AIS. Evaluation and management of posterior circulation ELVO will be summarized in separate recommendations. The Standards and Guidelines Committee of the SNIS, a multidisciplinary society representing the leaders in the field of endovascular therapy for neurovascular disease, prepared this document based on a comprehensive review of the available English language literature relating to the topic. Recommendations follow the American College of Cardiology/American Heart Association (ACC/AHA) classification of recommendation/level of evidence and definition of classes and levels of evidence used in American Heart Association/American Stroke Association (AHA/ASA) recommendations.4 Throughout this document, we will refer to the specific selection criteria from the recent randomized trials and registries of modern thrombectomy approaches, which are summarized in table 1. View this table: Table 1 Randomized trials and registries of modern approaches to thrombectomy Defining the criteria to evaluate and select patients with ELVO for endovascular treatment is critically important, since between 3% and 22% of patients with AIS are potentially eligible for mechanical thrombectomy, depending on the specific selection criteria used.5–7 Time of symptom onset (or last known well, magnitude of early ischemic change on initial imaging, clinical severity of stroke symptoms, pre-stroke level of functioning and anatomic location of the ELVO are the most important determinants of …

Background Mechanical thrombectomy offers a unique opportunity to examine neurophysiological changes occurring during stroke. We developed a tissue banking protocol to capture intracranial thrombi as well as the blood immediately proximal and distal. These tissues provide a rare resource to correlate changes occurring at the time of stroke to patient outcomes. The purpose of this study is to develop a tissue banking protocol in order to provide high-quality yields of RNA for gene expression analysis and protein for proteomics. Methods We instituted an IRB-approved protocol for tissue processing during mechanical thrombectomy (www.clinicaltrials.gov NCT03153683). The protocol is a joint clinical/basic science effort among multiple laboratories and the NeuroInterventional Radiology service line. We developed a step-by-step process for specimen retrieval, initial processing, and storage, which begins in a designated workspace constructed for the study in the angiography suite. Further processing and analysis is performed in our basic science laboratories, and includes extraction of RNA from thrombi with distal and proximal blood samples to assess RNA integrity number (RIN) values. To demonstrate viability of the collected plasma, proteomics of distal and proximal blood was evaluated through an outside vendor (Olink Proteomics). Results We have enrolled 34 subjects (age=66±13.3, 14 males) in the BACTRAC registry thusfar. In our preliminary dataset, the process yielded adequate RNA for gene expression analysis and protein for proteomics. RNA integrity analysis reveal mean RIN values (±SD) for distal arterial blood (n=8) were 8.89±0.41 (range from 8.30 to 9.60) and mean RIN values (±SD) for proximal arterial blood (n=8) were 6.98±0.29 (range from 6.60 to 7.50), indicating moderate to high quality RNA with minimal degradation. Mean RIN values for the thrombi (n=7) were undetectable. The first subject samples of distal and proximal blood were analyzed for proteomics. Duplicates of these samples passed quality control, and were run on all 11 of their proteomic panels (92 proteins/panel) for a total of 1012 proteins. 100% of proteins were detected on cardiovascular 3 and neurology panels. The organ damage panel detected the fewest, with 61% of this panel. The cardiometabolic and cardiovascular 3 panels each showed the most proteins with the greatest differences in expression. Conclusion We have developed a novel tissue banking protocol utilizing mechanical thrombectomy to capture thrombus along with arterial blood distal and proximal to it. The protocol provides high-quality specimens facilitating analysis of the initial molecular response to ischemic stroke in the human condition for the first time. In addition, preliminary integrity analyses demonstrated high-quality yields for RNA and protein in distal and proximal blood samples. Disclosures S. Martha: None. L. Collier: None. A. Gorman: None. K. Salmeron: None. A. Trout: None. D. Edwards: None. S. Davis: None. A. Alhajeri: None. S. Grupke: None. J. Roberts: None. G. Bix: None. K. Pennypacker: None. J. Fraser: None.

Introduction Over 1.8 million Kentuckians live in rural areas,1 and timely access to acute stroke treatments, such as tPA and thrombectomy, is challenging. We evaluated transport patterns for thrombectomy patients, analyzing outcomes related to aspects of transport to our Comprehensive Stroke Center (CSC) from rural Kentucky. Our goal was to quantify the average amount of time our rural patients would actually save during transport. Methods Records of all patients who were evaluated for thrombectomy at our CSC between July, 2011 to March, 2017 were reviewed through an IRB-approved protocol. Demographics, comorbidities, time intervals, NIHSS scores, and inpatient outcome were collected retrospectively. These variables were analyzed against geographic maps of patient origins by county. Currently, our referral region has no Thrombectomy-capable Stroke Centers (TSC). To further understand resource capability, we mapped county of origin against Percutaneous Coronary Intervention (PCI) centers. Result Sixty-three percent of all patients included in our analysis originated from less than 65 miles away. The patients furthest from the CSC originated in counties 159 miles away. Patients less than or equal to 50 miles away (n=78) had LKN to recanalization times of 6.1 hours, while patients greater than 50 miles away had times of 7.7 hours (p=0.015). The number of patients originating from counties with a PCI ranged from 2 to 12. Conclusion From 2011 to early 2017, most thrombectomy patients at our CSC came from counties within 65 miles away. Most importantly, a significant number came from rural environments. This underscores the need for stroke systems of care that address rural needs. Certification of PCI centers for stroke is not a viable option in rural environments, as the average PCI facility in our region would only see 5 to 6 thrombectomy patients over 5.5 years. It is also important to note that a major hurdle in stroke care is recognition of symptoms and initiating contact with EMS. When timeline of stroke care was studied, the time interval between LKN and arrival to a hospital (CSC or regional) is significant for both patients brought directly to CSC and those taken to a regional hospital before being transferred to our CSC. Reference https://www.ruralhealthinfo.org/states/kentucky Disclosures S. Kamat: None. E. Abner: None. A. Kuhn: None. J. Fraser: 1; C; University of Kentucky Department of Neurology, University of Kentucky College of Medicine. 2; C; Stream Biomedical, Fawkes Biotechnology.

Introduction With the current prominent usage of endovascular methods in managing intracranial aneurysms, understanding the value and role of these techniques to specifically address Infectious Intracranial Aneurysms (IIAs) is important. IIAs are often a complication of intravenous (IV) drug use. While these aneurysms carry high risk of rupture, there is some lack of consensus for optimal management. Furthermore, with the growing opioid epidemic, these lesions are likely to become more commonplace. To better understand current practice patterns and the role endovascular techniques occupy, we performed a systematic review. Methods Pubmed search terms included: ‘Infectious Intracranial Aneurysm’, ‘mycotic cerebral aneurysm’, ‘cerebral mycotic aneurysm, and ‘intracranial infectious aneurysm’. We included retrospective and prospective publications 1/1980 to 5/2017. Manual search of references was also performed. We evaluated total publication number, patient and aneurysm number, ruptured status, mention of infective endocarditis, pathogen reported, treatment categories, failure, death, and rupture rates of conservative management and cardiac surgery timing. Single case reports were included. Results 131 publications with a total of 499 patients and 665 aneurysms were included. Of the 499 patients, 83 were single case reports, and 20.5% of the total had multiple aneurysms. 35.8% of all aneurysms were ruptured. Chronologically, publication of IIAs has increased. Of those aneurysms where treatment options were reported 31.8% were managed endovascularly. Methods varied from parent artery occlusion using glue agents to coiling with or without stent assistance. Furthermore, usage of endovascular therapies has grown, while conservative (30.0% overall) and surgical management (31.1%) have declined in the literature. Of those managed endovascularly, only 5 unsuccessful attempts and 3 additional patient deaths were reported. By comparison, 56.2% of aneurysms for which conservative therapy was initiated eventually either underwent intervention, or death of the patient occurred. Of 51 patients who underwent cardiac valve surgery after aneurysm management, and for whom corresponding aneurysm treatment modality could be determined, 30 (51.7%) had undergone endovascular management. Discussion Increasing trend of endovascular management of IIAs is evident. Strong consideration of endovascular methods as a predominant form of management for IIAs is warranted as the literature demonstrates both small rates of unsuccessful attempts/patient deaths. The literature also reflects the additional benefit of sooner subsequent cardiac surgery when aneurysms are treated via endovascular methods. Disclosures R. Ragulojan: None. S. Grupke: None. J. Fraser: 1; C; University of Kentucky Department of Neurosurgery, University of Kentucky Department of Neurology, NIH CTSA UL1TR001998. 4; C; Fawkes Biotechnology, Stream Biomedical.

Introduction In the setting of mechanical thrombectomy for emergent large vessel occlusion (ELVO), we have for the first time developed a protocol to collect and evaluate blood immediately distal and proximal from the removed intracranial thrombus. These samples provide a unique resource in evaluating acute changes in acid/base and electrolyte concentrations at the time of ischemic stroke. The purpose of this study is to compare acid/base and electrolyte differences obtained proximal and distal to the occluded intracranial thrombus in acute ischemic stroke patients. Methods We developed the BACTRAC protocol: an IRB-approved tissue banking strategy for ELVO (clinicaltrials.gov NCT03153683). We compared arterial blood gases (ABG) of blood distal versus proximal to the thrombus during thrombectomy. Comparisons were evaluated by Paired Samples T-Tests (p Results We analyzed the first 24 subjects (age=65±0.54, 11 males) in the BACTRAC registry. Preliminary results demonstrate that, while pH is nonsignificant, distal blood in relation to proximal blood showed significantly lower oxygen (p=0.010), carbon dioxide (p=0.001), bicarbonate (p=0.002), ionized calcium (p=0.001), and potassium (p=0.001). Sodium concentration was significantly higher (p=0.002) in distal blood. These results suggest alterations occurring intravascularly during ischemia. Conclusion These findings provide a novel insight into the pathology of large vessel stroke in humans, particularly in regard to identifying acute changes in acid/base balance and electrolyte concentrations that occur during stroke. Disclosures J. Fraser: None. S. Martha: None. L. Collier: None. S. Davis: None. A. Abdulnasser: None. S. Grupke: None. K. Pennypacker: None.

BackgroundIschemic stroke research faces difficulties in translating pathology between animal models and human patients to develop treatments. Mechanical thrombectomy, for the first time, offers a momentary window into the changes occurring in ischemia. We developed a tissue banking protocol to capture intracranial thrombi and the blood immediately proximal and distal to it.ObjectiveTo develop and share a reproducible protocol to bank these specimens for future analysis.MethodsWe established a protocol approved by the institutional review board for tissue processing during thrombectomy (www.clinicaltrials.govNCT03153683). The protocol was a joint clinical/basic science effort among multiple laboratories and the NeuroInterventional Radiology service line. We constructed a workspace in the angiography suite, and developed a step-by-step process for specimen retrieval and processing.ResultsOur protocol successfully yielded samples for analysis in all but one case. In our preliminary dataset, the process produced adequate amounts of tissue from distal blood, proximal blood, and thrombi for gene expression and proteomics analyses. We describe the tissue banking protocol, and highlight training protocols and mechanics of on-call research staffing. In addition, preliminary integrity analyses demonstrated high-quality yields for RNA and protein.ConclusionsWe have developed a novel tissue banking protocol using mechanical thrombectomy to capture thrombus along with arterial blood proximal and distal to it. The protocol provides high-quality specimens, facilitating analysis of the initial molecular response to ischemic stroke in the human condition for the first time. This approach will permit reverse translation to animal models for treatment development.

At the International Stroke Conference (ISC) in Los Angeles in January 2018, the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke were released by the American Heart Association/American Stroke Association (AHA/ASA).1 These guidelines replaced the previous 2013 guidelines and their subsequent updates.2 3 They became an immediate focal point of discussion, with a range of questions raised. One example was the robust discussion regarding how these Guidelines should address patient selection for thrombectomy between 6 and 24 hours given differences in inclusion criteria for DAWN and DEFUSE 3.4 5 How should the new evidence be interpreted and incorporated into routine clinical practice? To understand these new guidelines, it is necessary to remember their function and helpful to review the process involved in creating them. Their purpose is to provide clinicians a comprehensive, evidence-based summary of treatment recommendations. They inform a broad audience involved in the early management of adults with acute ischemic stroke: pre-hospital providers, physicians, allied health professionals, and hospital administrators. The creation of this document required a broad-based writing group with multidisciplinary backgrounds, appointed by the AHA/ASA Stroke Council’s Scientific Statements Oversight Committee. The writing group reviewed the stroke literature and drafted recommendations with supporting evidence. For limited clinical questions, an independent evidence review committee performed systematic reviews, the results of which were incorporated. The full writing group then evaluated the complete guidelines, which had to be unanimously approved. The draft guideline was then reviewed by four expert peer reviewers, members of the Stroke Council’s Scientific Statements Oversight and Leadership Committees. It was approved by the American Heart Association Science Advisory and Coordinating and Executive Committees. Prior to publication, it was reviewed for evidence-based integrity and endorsed by the American Association of Neurological Surgeons and Congress of Neurological Surgeons, as well as …

As the role of advanced practice providers (APPs) expands to include increasingly complex patient care within the intensive care unit, the educational needs of these providers must also be expanded. An onboarding process was designed for APPs in the neurocritical care service line.Onboarding for new APPs revolved around 5 specific areas: candidate selection, proctor assignment, 3-phased orientation process, remediation, and mentorship. To ensure effective training for APPs, using the most time-conscious approach, the backbone of the process is a structured curriculum. This was developed and integrated within the standard orientation and onboarding process. The curriculum design incorporated measurable learning goals, objective assessments of phased goal achievements, and opportunities for remediation.The neurocritical care service implemented an onboarding process in 2014. Four APPs (3 nurse practitioners and 1 physician assistant) were employed by the department before the implementation of the orientation program. The length of employment ranged from 1 to 4 years. Lack of clinical knowledge and/or sufficient training was cited as reasons for departure from the position in 2 of the 4 APPs, as either self-expression or peer evaluation. Since implementation of this program, 12 APPs have completed the program, of which 10 remain within the division, creating an 83% retention rate.The onboarding process, including a 3-phased, structured orientation plan for neurocritical care, has increased APP retention since its implementation. The educational model, along with proctoring and mentorship, has improved clinical knowledge and increased nurse practitioner retention. A larger-scale study would help to support the validity of this onboarding process.

Background and importance Intracerebral abscess is a very serious condition associated with significant morbidity and mortality. This article describes a novel treatment for a cerebral abscess, using the Penumbra Apollo suction/vibration aspiration system (Penumbra, Almeda, CA, USA). This article represents the first reported case of the device’s use for treatment of an intracerebral abscess. Clinical presentation The patient discussed presented to the emergency department in critical condition, and was found to be suffering from a right thalamic cerebral abscess. She underwent treatment with both medical management and surgical intervention with the use of the Apollo system. Conclusion This report details a novel technique for surgical abscess drainage with an excellent clinical outcome. The aim is to provide insight into the treatment of intracerebral abscesses, the utility of the Apollo system, and the device’s application beyond intracerebral and intraventricular hemorrhage.

Background: Research in ischemic stroke struggles from failures to translate stroke conditions between animal models and human patients. With mechanical thrombectomy, we have for the first time developed a protocol to facilitate tissue banking of intracranial thrombi as well as the blood immediately proximal and distal to it. These tissues provide a unique resource to correlate changes in the human condition to animal models. Our aim was to develop a reproducible protocol to bank these specimens for future gene expression and proteomic analysis. Methods: We developed an IRB-approved protocol for tissue processing during thrombectomy (www.clinicaltrials.gov NCT03153683). The protocol was a joint clinical/basic science effort among multiple laboratories and the Neurointerventional Radiology Service Line. We placed laboratory supplies in the angio suite, and developed a step-by-step protocol for specimen retrieval and processing. Results: Our protocol successfully yielded samples for analysis in all but one case. In our preliminary dataset, the protocol yielded adequate amounts of tissue for distal blood, proximal blood, and thrombus. We present the tissue banking protocol for dissemination, and highlight the training protocol and mechanics of on-call research staffing for 24/7 tissue processing. In addition, preliminary integrity analyses demonstrated high quality yields for RNA and protein. Conclusion: We have developed a novel tissue banking protocol to capture thrombus, and both proximal and distal blood to the intracranial thrombus in human stroke patients. The specimens are captured during the thrombectomy procedure, and allow us to study the initial molecular response to ischemic stroke in the human condition in ways previously unavailable.

Introduction: Moyamoya is characterized by progressive stenosis and occlusion of the intracranial internal carotid arteries (ICA) and their major branches. Vascular stenosis is accompanied by formation of abnormal vascular networks, with major symptoms including ischemia and hemorrhage. Current treatments are limited to antiplatelet therapy and surgical bypass. While research has recently discovered a susceptibility gene (RNF213) for idiopathic moyamoya disease, there is still no animal model which mimics the acquired vasculopathy of moyamoya syndrome, which is often associated with autoimmune diseases. We report here a novel surgical model of moyamoya that employs microcoils placed on the ICA of mice. Methods: Male C57Bl/6 mice (4 months old) underwent surgery for the unilateral placement of a microcoil (0.16 mm) onto the proximal ICA, referred to as internal carotid artery stenosis (ICAS). After 28 days, the blood vessels were examined for changes in diameter and number of anastomoses using a fluorescent dye called Di I. Cresyl violet and Prussian blue were used to assess ischemia and hemorrhage, while PCR was used to examine biomarkers typically altered in moyamoya patients. Results: We observed a significant narrowing of the distal ICA and anterior cerebral artery (ACA) in the Circle of Willis, as well as a decreased number of anastomoses between the middle cerebral artery (MCA) and the ACA in the watershed region of the cortex in ICAS-treated mice. Histological examination also showed changes in brain cellular morphology and alterations in VEGF and MMP9 gene expression. Conclusions: We report for the first time the development of an animal model with moyamoya-like vasculopathies as observed in humans. While further characterization is needed, it may provide a crucial model for development of therapies for moyamoya syndrome.

Background: Mechanical thrombectomy has become standard of care for emergent large vessel occlusive (ELVO) stroke. Estimates of incidence for thrombectomy eligibility vary significantly. NIH Stroke Scale (NIHSS) of 9 or greater is highly predictive of large vessel occlusion. Using our Kentucky Appalachian Stroke Registry (KApSR), we evaluated regional trends in stroke admissions with NIHSS of 10 or more to determine effects and needs in thrombectomy utilization. Methods: Using the KApSR database that captures patients throughout the Appalachian region in our stroke network, we evaluated patients admitted with ischemic stroke with NIHSS > 9 anytime during admission. We recorded demographics, comorbidities, treatment (thrombectomy, decompressive craniectomy), and county of origin. Change in NIHSS from admission to discharge was measured as an indicator of inpatient outcome. Summary statistics and analyses were performed on SPSS; p Results: From 2010 to 2016, 2250 patients were included; 132 (5.9%) underwent thrombectomy. 66.8% were admitted with NIHSS > 9. Annual utilization of thrombectomy increased over time from 0.8% in 2010 to 10.6% in 2016. When thrombectomy was considered, median change in NIHSS was -2 (IQR 8) in patients without thrombectomy versus -5 (IQR 12) in patients who underwent thrombectomy; the difference was significant (p Conclusion: Among patients with significant inpatient ischemic stroke, a majority present with NIHSS greater than 9. While thrombectomy has become more common, it was only utilized in 10.6% of patients in 2016. Furthermore, patients who underwent thrombectomy has significant inpatient clinical improvement compared to those that did not. Thus, further efforts are necessary to maximize the use of thrombectomy when appropriate.

Reperfusion-induced injury after recanalization is exacerbated by blood-brain barrier (BBB) dysfunction after ischemic stroke. Endothelial cell integrin receptors, specifically the β 1 subtype, play a direct role in BBB dysfunction through regulation of barrier-forming tight junction (TJ) proteins. We hypothesize that inhibition of an endothelial specific β 1 integrin, α 5 β 1 , after oxygen-glucose deprivation (OGD) in vitro and also after experimental stroke in vivo will stabilize the BBB through the TJ claudin-5, reducing infarct volumes and improving functional recovery. First, stroke was simulated in vitro by OGD or TNF- α treatment of brain endothelial cell monolayers. Treatment with the small peptide α 5 β 1 inhibitor ATN-161 (10 μM) resulted in decreased barrier permeability as measured by trans-endothelial cell electrical resistance and FITC-dextran permeability. Immunocytochemistry showed extracellular localization and upregulation of claudin-5 with ATN-161 treatment. Next, transient tandem middle cerebral artery occlusion was performed on 12-week-old male mice for 1 hour. On confocal and SEM imaging, post-stroke α 5 β 1 expression was upregulated primarily in the luminal vascular surface by post-stroke day (PSD) 2 rather than at the basement membrane (next to its extracellular matrix ligands). IP injection of ATN-161 (1 mg/kg) immediately after reperfusion and on PSD 1, and PSD2 caused a significant, but transient and acute (after the initial dose only) change in animal pulse distension, but no change in body temperature or heart rate. Infarct volumes, measured by TTC stain, were significantly reduced in ATN-161 treated animals. Furthermore, BBB integrity was improved by ATN-161 as determined by IgG staining and FITC-Dextran injection. Functional recovery, assessed by a 5-item Neuroscore, was also significantly improved. In conclusion, inhibition of α 5 β 1 by ATN-161 was well tolerated, reduced infarct volume, and improved behavioral recovery. Additional studies showed this result was likely due to reduced BBB permeability through the TJ claudin-5. Therefore, inhibition of α 5 β 1 with ATN-161 could represent a novel therapeutic approach for stroke worthy of further investigation.

Background and Purpose: Mechanical thrombectomy is now a standard of care therapy for large vessel stroke; however, patients often demonstrate variable outcomes, and do not return to independent function. Physical Therapy (PT) and Occupational Therapy (OT) after thrombectomy may play a vital role in maximizing patient recovery. The goal of this study was to examine the relationships between PT/OT and patient characteristics on mobility outcome in patients who have undergone thrombectomy after a stroke. The primary hypothesis was that earlier PT/OT evaluation would be associated with higher scores on the Kansas University Hospital Physical Therapy Acute Care Functional Outcomes Tool. Methods: A retrospective review was performed of 127 patients diagnosed with stroke who underwent mechanical thrombectomy at a Comprehensive Stroke Center 07/2011-02/2017. Collected data included demographics, National Institute of Health Stroke Scale (NIHSS), ICU/hospital length of stay, functional status (Kansas score), timing of PT/OT evaluation, and number of PT/OT sessions. To account for the collinearity of the covariates, the least absolute shrinkage and selection operator (LASSO) method was used to identify the best subset of predictors of change in Kansas score. Results: Median length of stay was four days in the ICU and eight days overall. Mean NIHSS at discharge was higher among those not receiving a PT/OT evaluation than among those who did (22.1 vs 8.8, respective, p Conclusion: The data demonstrated that early recanalization time correlated to improved Kansas score. However, this study also demonstrated a significant relationship between earlier PT/OT evaluations and higher Kansas scores. Therefore, for patients who have undergone thrombectomy, earlier PT/OT evaluations could have significant impact on clinical outcomes.

Stroke remains the fifth leading cause of death in the U.S, highlighting a pressing need to improve the translatability of experimental stroke studies. To more reproducibly mimic clinical assessments in animal stroke models, we developed and tested a novel behavioral Neuroscore assessment designed to serve as an experimental analog to the National Institutes of Health Stroke Scale. Our Neuroscore measured discrepancies in visual, sensorimotor, and fatigue-related performances over five tasks while generating a numerical score ranging from zero to eleven (zero representing normal). Once administered, the resulting score was used as a predictor for determining the severity of stroke. The Neuroscore was designed and administered on C57Bl/6 mice. To mimic the NIH Stroke Scale, the Neuroscore used similar, but mouse-appropriate components over five-minute administrations: Level of Consciousness, Gaze and Visual Field, Sensory-Limb testing in response to stimuli, and a motor component assessed with Paralysis-Paw Hang tasks. Inter-rater reliability assessments were also performed. For this initial experiment, the MCAo model (tandem common carotid/middle cerebral artery occlusion model) was tested. Neuroscore effectively and significantly increased on post-stroke day (PSD) 1 after MCAo (N=36) compared to shams (N=25, p

Background and Purpose: Monitoring for hypotension, hyperglycemia, hypoxia, and dehydration is key to reducing early death in stroke patients. Evaluation of physiological predictors of infarct volume and mortality may provide opportunities for effective interventions to improve outcomes. The purpose of this study is: 1) to describe and compare the predictive effects of venous blood gas (VBG) on infarct volume and mortality in acute stroke in rats; 2) and we have begun to collect arterial blood gas (ABG) to compare differences obtained proximal and distal to the occluded intracranial thrombi in acute ischemic stroke patients. Methods: 3-month old Sprague-Dawey rats (n = 9) underwent permanent or transient middle cerebral artery occlusion (MCAO). Pre- and post-MCAO venous samples provided pH, pCO 2 , pO 2 , and electrolyte values (iCa 2+ , K + , and Na + ). Linear regression determined predictors of infarct volume from these values, and Cox regression analyzed VBG changes between tMCAO (n = 28) and pMCAO (n = 29) to determine predictors of mortality. We compared mean proximal and distal pH, pCO 2 , pO 2 , and electrolytes (iCa 2+ , K + , and Na + ) in stroke patients (n = 7) arterial samples using Wilcoxon Signed Ranks test. Results: Animal studies demonstrated pH and iCa 2+ are predictors of infarct volume, but not mortality. After pMCAO (n = 9), change in pH or iCa 2+ significantly predicted infarct volume [F(1,7) = 7.351, β = -0.716, p = 0.03] and [F(1, 7) = 6.782, β = -0.701, p = 0.035]; as pH and calcium decreased, infarct volume increased. These variables explained 44% and 42% of the total variance in these models. In human patients (n = 7), there were significant differences in blood samples proximal and distal to the intracranial thrombus for pCO 2 (p = 0.018), HCO 3- (p = 0.028), iCa 2+ (p = 0.043), K + (p = 0.028), and Na + (p = 0.044). Conclusions: In conclusion, there are acute changes in acid/base balance and electrolytes during stroke in rodent models and humans. In cross-species comparison ionized calcium changes were significant in both, with iCa 2+ changes predicting stroke volume in the rat model. These preliminary findings are novel, and warrant further exploration in human patients.

Endovascular thrombectomy combined with t-PA is the current standard of care for emergent large vessel occlusion (ELVO) stroke. Unfortunately, despite rising recanalization rates, stroke remains the leading cause of long-term disability worldwide suggesting that additional therapies are needed. Severe stroke morbidity may be due, partially, to the acute and sustained inflammatory stroke response. Preclinical research has shown some promise with anti-inflammatory agents in limiting brain injury and improving functional outcome; however, the post-stroke inflammatory cascade appears to have both beneficial and deleterious effects making the translation of such anti-inflammatory approaches perilous. We aim to show that the inflammatory cytokine interleukin-1alpha (IL-1α) is well-tolerated, neuroprotective, and conveys functional benefit after ischemic stroke. 3-month-old C57/BL6 mice were subjected to MCAo and given IL-1α via IV injection or IA infusion upon recanalization. Mice were allowed to recover for 7 days before sacrifice. Brains were flash frozen for IHC and serum for high sensitivity ELISA. We noted that IV IL-1α (1 ng) is neuroprotective (as measured by cresyl violet stained infarct volumes) and significantly improved functional recovery in open field behavioral tests. When given IV, IL-1α showed transient hemodynamic side effects that are typical of IL-1α’s known physiologic functions (fever, sterile inflammation, etc.) These effects are short lived with systemic (IV) administration and IA IL-1α (0.1 ng) administration showed neuroprotection without the side effects seen with IV treatment. Additionally, we noted that IL-1α is directly neuroprotective of primary mouse cortical neurons exposed to oxygen and glucose deprivation conditions in vitro . IL-1α’s profound, direct neuroprotective effects and its functional benefit, make IL-1α an attractive target for future study in ischemic stroke.

Background and Purpose Acid/base and electrolytes could provide clinically valuable information about cerebral infarct core and penumbra. We evaluated associations between acid/base and electrolyte changes and outcomes in 2 rat models of stroke, permanent, and transient middle cerebral artery occlusion. Methods Three-month old Sprague-Dawley rats underwent permanent or transient middle cerebral artery occlusion. Pre- and post-middle cerebral artery occlusion venous samples for permanent and transient models provided pH, carbon dioxide, oxygen, glucose, and electrolyte values of ionized calcium, potassium, and sodium. Multiple regression determined predictors of infarct volume from these values, and Kaplan-Meier curve analyzed morality between permanent and transient middle cerebral artery occlusion models. Results Analysis indicated significant differences in the blood gas and electrolytes between pre- to post-middle cerebral artery occlusion. A decrease in pH and sodium with increases in carbon dioxide, potassium, ionized calcium, and glucose changes were found in both middle cerebral artery occlusion models; while hematocrit and hemoglobin were significant in the transient model. pH and ionized calcium were predictors of infarct volume in the permanent model, as changes in pH and ionized calcium decreased, infarct volume increased. Conclusions There are acute changes in acid/base balance and electrolytes during stroke in transient and permanent rodent models. Additionally, we found pH and ionized calcium changes predicted stroke volume in the permanent middle cerebral artery occlusion model. These preliminary findings are novel, and warrant further exploration in human conditions.

Moyamoya is a cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries. There are two forms: Disease and Syndrome, with each characterized by the sub-population it affects. Moyamoya syndrome (MMS) is more prominent in adults in their 20's-40's, and is often associated with autoimmune diseases. Currently, there are no surgical models for inducing moyamoya syndrome, so our aim was to develop a new animal model to study this relatively unknown cerebrovascular disease. Here, we demonstrate a new surgical technique termed internal carotid artery stenosis (ICAS), to mimic MMS using micro-coils on the proximal ICA. We tested for Moyamoya-like vasculopathies by fluorescently labelling the mouse cerebrovasculature with Di I for visualization and analysis of vessel diameter at the distal ICA and anastomoses on the cortical surface. Results show a significant narrowing of the distal ICA and anterior cerebral artery (ACA) in the Circle of Willis, as observed in humans. There is also a significant decrease in the number of anastomoses between the middle cerebral artery (MCA) and the ACA in the watershed region of the cortex. While further characterization is needed, this ICAS model can be applied to transgenic mice displaying co-morbidities as observed within the Moyamoya syndrome population, allowing a better understanding of the disease and development of novel treatments.

Patients with subarachnoid hemorrhage (SAH) typically exhibit hyperdynamic cardiovascular hemodynamics, which may lead to increased medication clearance. The aims of this study were to evaluate the actual creatinine clearance (CrClA) in an aneurysmal SAH population and the effect of the development of cerebral vasospasm (CV) along with its treatment to better understand if this population exhibits augmented renal clearance (ARC).This was a prospective, single-center study in a neurosciences ICU at a university hospital. A total of 20 patients were consented and provided a 24-h urine sample to measure the CrClA. If patients experienced CV, a 24-h urine collection was repeated during vasospasm treatment. CrClA was measured using a modified Jaffe assay.Among the 20 patients enrolled, the mean SAH CrClA was 325.93 ± 135.20 ml/min 1.73 m(2) and this differed significantly from the SAH estimated creatinine clearance (CrClE) 144.93 ± 42.82 ml/min 1.73 m(2) (p 0.001). Four patients developed CV; the mean CV CrClA was 558.43 ± 356.12 ml/min 1.73 m(2) and there was no significant difference when compared to those patients' mean SAH CrClA (246.91 ± 84.14 ml/min 1.73 m(2), p = 0.16).ARC was present in 100 % of the patients with recent SAH enrolled. Although ARC remained present in the patients who experienced CV, their creatinine clearance was not significantly further augmented. Further work is needed to clarify the impact of such clearances on renally excreted medications and how the development and treatment of CV further augment these findings.

Stroke is the leading cause of adult disability in North America and is the fifth most common cause of death.1 ,2 The natural history of patients with acute ischemic stroke and occlusion of a major intracranial vessel such as the internal carotid artery (ICA), middle cerebral artery (MCA), or basilar artery is dismal, with high rates of mortality and low rates of disability-free survival.3 ,4 We introduce the term ‘Emergent Large Vessel Occlusion (ELVO)’ to describe this clinical scenario. Among acute ischemic stroke, ELVO accounts for the greatest proportion of patients with long-term disability. For the past two decades the use of endovascular therapy has been performed in many centers across the world. The therapies have spanned from infusion of thrombolytic agents5 ,6 to mechanical embolectomy with the introduction of first-generation devices,7 ,8 aspiration-based embolectomy techniques,9 ,10 and the use of stent-retriever based procedures.11 ,12 However, these embolectomy trials were single-arm trials demonstrating safety of the procedure and technique or superiority over another, without direct comparison with standard medical therapy alone. In the past 3 years, several major trials have been published comparing endovascular therapy with standard medical therapy alone. The purpose of this document is to summarize the results of these trials and synthesize the level of evidence supporting the use of embolectomy in patients with ELVO. This document was prepared by the Standards and Guidelines Committee of the Society of NeuroInterventional Surgery, a multidisciplinary society representing the leaders in the field of endovascular therapy for neurovascular disease. The strength of the evidence supporting each recommendation was summarized using a scale previously described by the American Heart Association. ### Role of intravenous thrombolysis In 1996 the FDA approved the use of recombinant tissue plasminogen activator (tPA) for the treatment of acute ischemic stroke …

Background Neuroprotection for ischemic stroke is a growing field, built upon the elucidation of the biochemical pathways of ischemia first studied in the 1970s. Beginning in the early 1990s, means by which to pharmacologically intervene and counteract these pathways have been sought, though with little clinical success. Through a comprehensive review of translations from laboratory to clinic, we aim to evaluate individual mechanisms of action, while highlighting potential barriers to success that will guide future research. Methods The MEDLINE database and The Internet Stroke Center clinical trials registry were queried for trials involving the use of neuroprotective agents in acute ischemic stroke in human subjects. For the purpose of the review, neuroprotective agents refer to medications used to preserve or protect the potentially ischemic tissue after an acute stroke, excluding treatments designed to re-establish perfusion. This excludes mechanical or pharmacological thrombolytics, anti-thrombic medications, or anti-platelet therapies. Results This review summarizes previously trialed neuroprotective agents, including but not limited to glutamate neurotransmission blockers, anti-oxidants, GABA agonists, leukocyte migration blockers, various small cation channel modulators, narcotic antagonists, and phospholipid membrane stabilizers. We outline key biochemical steps in ischemic injury that are the proposed areas of intervention. The agents, time to administration of therapeutic agent, follow-up, and trial results are reported. Discussion Stroke trials in humans are burdened with a marked heterogeneity of the patient population that is not seen in animal studies. Also, trials to date have included patients that are likely treated at a time outside of the window of efficacy for neuroprotective drugs, and have not effectively combined thrombolysis with neuroprotection. Through an evaluation of the accomplishments and failures in neuroprotection research, we propose new methodologies, agents, and techniques that may provide new routes for success.

Purpose A case of probable nimodipine-induced hypoxemia in a patient undergoing treatment for aneurysmal subarachnoid hemorrhage (SAH) is reported. Summary A 62-year-old man hospitalized for SAH developed symptoms of respiratory distress on several occasions within days of initiation of nimodipine therapy (60 mg every four hours, with three doses withheld during intubation for intracranial surgery). Several hours after extubation (on hospital day 5), the patient had rapidly worsening tachypnea and declining arterial oxygen saturation (SPO2) despite increased oxygen delivery by mask, necessitating reintubation. When a nurse noted that the declines in SPO2 occurred soon after nimodipine administration, the patient’s respiratory and hemodynamic functions were closely monitored after a single dose of nimodipine via nasogastic tube; the monitoring results supported the suspicion that nimodipine’s vascular effects were a causal or contributory factor in the hypoxemia episodes. With subsequent fractionated dosing (30 mg every two hours), the patient completed the prescribed 21-day course of nimodipine therapy. Using the rating scale of Naranjo et al., this case was assigned a score of 7, indicating a probable pulmonary adverse reaction to nimodipine. As nimodipine is commonly used in cases of SAH to reduce delayed neurologic deficits due to persistent cerebral vasospasm, clinicians should be mindful of its potential hypoxemic effects in vulnerable patients. Conclusion A patient with aneurysmal SAH developed hypoxemia associated with the administration of nimodipine. Hypoxemia is a known complication of treatment with other vasodilatory agents, particularly in patients who have concomitant pulmonary disease.

With continuing disconnect between laboratory stroke treatment models and clinical stroke therapy, we propose a novel experimental model to study stroke and vessel recanalization that mirrors acute management of large vessel stroke, with concomitant directed pharmacotherapy. Using the tandem transient ipsilateral common carotid/middle cerebral artery occlusion (MCAO) model to induce stroke in mice we then added selective intra-arterial (IA) drug administration for directed pharmacotherapy. The IA model uses micro-angio tubing placed at the bifurcation of the CCA to selectively administer the drug to the internal carotid distribution. We have shown that delivery of pharmacotherapy agents selectively through an IA injection is feasible in a mouse model, which will permit studies involving pharmacotherapy, transgenic modification, and/or a combination. Our IA model has similarities to previously published models of IA injection but differs in that we do not leave an indwelling micro-port or catheter in our animals, which is not clinically relevant as it does not reflect the human condition or current clinical management. Furthermore, we optimized our model to selectively direct therapy to the ipsilateral, stroke affected hemisphere. By developing an IA drug delivery model that mirrors clinical conditions, we are bridging the gap between basic stroke research and what is standard practice in acute ischemic stroke intervention. The IA model of drug delivery can target agents directly to the site of injury while blunting systemic effects, dose penetration issues, and administration delay that have plagued the intraperitoneal and oral drug administration models.

Acute ischemic stroke (AIS) is the fifth leading cause of death, and remains the leading cause of disability in the USA.1 There are an estimated 680 000 new strokes per year in the USA, with a mortality rate of 53–94%, and with an even greater morbidity.2 It is estimated that 3–22% of these patients are candidates for endovascular therapy.3–6 In addition to baseline stroke severity, emergent large vessel occlusion (ELVO) has been shown to be an independent predictor of poor outcome at 6 months.3 4 While intravenous recombinant tissue plasminogen activator (IV r-tPA) has proven efficacious predominantly for small cerebral vessel occlusions, endovascular therapies, including stent retriever based, aspiration based mechanical thrombectomy techniques, and intra-arterial administration of thrombolytic agents, have been shown to achieve higher rates of recanalization in patients with ELVO.7–10 The purpose of this document is to provide an update and critical assessment of technical aspects of the mechanical thrombectomy procedure. This document was prepared by the Standards and Guidelines Committee of the Society of NeuroInterventional Surgery (SNIS), a multidisciplinary society representing the leaders in the field of endovascular therapy for cerebrovascular disease. A review of the English language literature published between January 1998 and March 2016 was conducted using search terms that included: ‘stroke,’ ‘ischemic stroke,’ ‘large vessel occlusion,’ ‘thrombectomy,’ ‘mechanical thrombectomy,’ ‘neurointerventional,’ ‘tPA,’ and ‘technique.’ Additionally, we incorporated already existing guidelines published by the American Heart Association (AHA) and the SNIS.11–15 The strength of the evidence supporting each recommendation was summarized using a scale previously described by the AHA guideline panels, and by the University of Oxford, Centre for Evidence Based Medicine.13 15–18 Much of our current practice in mechanical thrombectomy derives from recent randomized controlled trials (RCTs) which provide a foundation for treatment goals. The online supplementary tables 1-3 provide details of these thrombectomy trials, and …

Background The population of rural Kentucky and West Virginia has a disproportionately high incidence of stroke and stroke risk factors. The Kentucky Appalachian Stroke Registry (KApSR) is a novel registry of stroke patients developed to collect demographic and clinical data in real time from these patients' electronic health records. Objective We describe the development of this novel registry and test it for ability to provide the information necessary to identify care gaps and direct clinical management. Methods The KApSR was developed as described in this article. To assess utility in patient care, we developed a “Diabetes Quality Assurance Dashboard” by cross-referencing patients in the registry with a diagnosis of ischemic cerebrovascular disease with patients that were tested for hemoglobin A1c (HbA1c) levels, patients with HbA1c levels diagnostic for diabetes mellitus (DM), and patients with an elevated HbA1c that were formally diagnosed with DM. Results For the 1008 patients treated for ischemic cerebrovascular disease in the year studied, 859 (85%) had their HbA1c tested. Of those, 281 had levels of 6.5 or greater, although only 261 (93%) were discharged with a formal diagnosis of DM. Conclusions The KApSR has practical value as a tool to assess a large population of patients quickly for care quality and for research purposes.