Randomized, open-label, phase 1/2a study to determine the maximum tolerated dose of intraventricular sustained release nimodipine for subarachnoid hemorrhage (NEWTON [Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage])

BACKGROUND AND PURPOSE—: We conducted a randomized, open-label, phase 1/2a, dose-escalation study of intraventricular sustained-release nimodipine (EG-1962) to determine safety, tolerability, pharmacokinetics, and clinical effects in aneurysmal subarachnoid hemorrhage. METHODS—: Subjects with aneurysmal subarachnoid hemorrhage repaired by clipping or coiling were randomized to EG-1962 or enteral nimodipine. Subjects were World Federation of Neurological Surgeons grade 2 to 4 and had an external ventricular drain. Cohorts of 12 subjects received 100 to 1200 mg EG-1962 (9 per cohort) or enteral nimodipine (3 per cohort). The primary objective was to determine the maximum tolerated dose. RESULTS—: Fifty-four subjects in North America were randomized to EG-1962, and 18 subjects were randomized to enteral nimodipine. The maximum tolerated dose was 800 mg. One serious adverse event related to EG-1962 (400 mg) and 2 EG-1962 dose-limiting toxicities were without clinical sequelae. There was no EG-1962-related hypotension compared with 17% (3/18) with enteral nimodipine. Favorable outcome at 90 days on the extended Glasgow outcome scale occurred in 27/45 (60%, 95% confidence interval 46%–74%) EG-1962 subjects (5/9 with 100, 6/9 with 200, 7/9 with 400, 4/9 with 600, and 5/9 with 800 mg) and 5/18 (28%, 95% confidence interval 7%–48%, relative risk reduction of unfavorable outcome; 1.45, 95% confidence interval 1.04–2.03; P=0.027) enteral nimodipine subjects. EG-1962 reduced delayed cerebral ischemia (14/45 [31%] EG-1962 versus 11/18 [61%] enteral nimodipine) and rescue therapy (11/45 [24%] versus 10/18 [56%]). CONCLUSIONS—: EG-1962 was safe and tolerable to 800 mg, and in this, aneurysmal subarachnoid hemorrhage population was associated with reduced delayed cerebral ischemia and rescue therapy. Overall, the rate of favorable clinical outcome was greater in the EG-1962-treated group. CLINICAL TRIAL REGISTRATION—: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01893190

SDF1-A Facilitates Lin−/Sca1+ Cell Homing following Murine Experimental Cerebral Ischemia

Background Hematopoietic stem cells mobilize to the peripheral circulation in response to stroke. However, the mechanism by which the brain initiates this mobilization is uncharacterized. Methods Animals underwent a murine intraluminal filament model of focal cerebral ischemia and the SDF1-A pathway was evaluated in a blinded manner via serum and brain SDF1-A level assessment, Lin−/Sca1+ cell mobilization quantification, and exogenous cell migration confirmation; all with or without SDF1-A blockade. Results Bone marrow demonstrated a significant increase in Lin−/Sca1+ cell counts at 24 hrs (272±60%; P<0.05 vs sham). Mobilization of Lin−/Sca1+ cells to blood was significantly elevated at 24 hrs (607±159%; P<0.05). Serum SDF1-A levels were significant at 24 hrs (Sham (103±14), 4 hrs (94±20%, p = NS) and 24 hrs (130±17; p<0.05)). Brain SDF1-A levels were significantly elevated at both 4 hrs and 24 hrs (113±7 pg/ml and 112±10 pg/ml, respectively; p<0.05 versus sham 76±11 pg/ml). Following administration of an SDF1-A antibody, Lin−/Sca1+ cells failed to mobilize to peripheral blood following stroke, despite continued up regulation in bone marrow (stroke bone marrow cell count: 536±65, blood cell count: 127±24; p<0.05 versus placebo). Exogenously administered Lin−/Sca1+ cells resulted in a significant reduction in infarct volume: 42±5% (stroke alone), versus 21±15% (Stroke+Lin−/Sca1+ cells), and administration of an SDF1-A antibody concomitant to exogenous administration of the Lin−/Sca1+ cells prevented this reduction. Following stroke, exogenously administered Lin−/Sca1+ FISH positive cells were significantly reduced when administered concomitant to an SDF1-A antibody as compared to without SDF1-A antibody (10±4 vs 0.7±1, p<0.05). Conclusions SDF1-A appears to play a critical role in modulating Lin−/Sca1+ cell migration to ischemic brain

Endovascular Treatment for Acute Stroke Patients With a Pre-stroke Disability: An International Survey

Background: It is unclear what factors clinicians consider when deciding about endovascular thrombectomy (EVT) in acute ischemic stroke patients with a pre-existing disability. We aimed to explore international practice patterns and preferences for EVT in patients with a pre-stroke disability, defined as a modified Rankin score (mRS) ≥ 2. Methods: Electronic survey link was sent to principal investigators of five major EVT trials and members of a professional interventional neurology society. Results: Of the 81 survey-responding clinicians, 57% were neuro-interventionalists and 33% were non-interventional stroke clinicians. Overall, 64.2% would never or almost never consider EVT for a patient with pre-stroke mRS of 4-5, and 49.3% would always or almost always offer EVT for a patient with pre-stroke mRS 2-3. Perceived benefit of EVT (89%) and severity of baseline disability (83.5%) were identified as the most important clinician-level and patient-level factors that influence EVT decisions in these patients. Conclusion: In this survey of 80 respondents, we found that EVT practice for patients with pre-stroke disability across the world is heterogenous and depends upon patient characteristics. Individual clinician opinions substantially alter EVT decisions in pre-stroke disabled patients

Temporal pattern of C1q deposition after transient focal cerebral ischemia

Recent studies have focused on elucidating the contribution of individual complement proteins to post-ischemic cellular injury. As the timing of complement activation and deposition after cerebral ischemia is not well understood, our study investigates the temporal pattern of C1q accumulation after experimental murine stroke. Brains were harvested from mice subjected to transient focal cerebral ischemia at 3, 6, 12, and 24 hr post reperfusion. Western blotting and light microscopy were employed to determine the temporal course of C1q protein accumulation and correlate this sequence with infarct evolution observed with TTC staining. Confocal microscopy was utilized to further characterize the cellular localization and characteristics of C1q deposition. Western Blot analysis showed that C1q protein begins to accumulate in the ischemic hemisphere between 3 and 6 hr post-ischemia. Light microscopy confirmed these findings, showing concurrent C1q protein staining of neurons. Confocal microscopy demonstrated co-localization of C1q protein with neuronal cell bodies as well as necrotic cellular debris. These experiments demonstrate the accumulation of C1q protein on neurons during the period of greatest infarct evolution. This data provides information regarding the optimal time window during which a potentially neuroprotective anti-C1q strategy is most likely to achieve therapeutic success. © 2006 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50651/1/20775_ftp.pd

Endovascular Therapy vs Medical Management for Patients With Acute Stroke With Medium Vessel Occlusion in the Anterior Circulation

Importance Randomized clinical trials have shown the efficacy of endovascular therapy (EVT) for acute large vessel occlusion strokes. The benefit of EVT in acute stroke with distal, medium vessel occlusion (DMVO) remains unclear. Objective To examine the efficacy and safety outcomes associated with EVT in patients with primary DMVO stroke when compared with a control cohort treated with medical management (MM) alone. Design, Setting, and Participants This multicenter, retrospective cohort study pooled data from patients who had an acute stroke and a primary anterior circulation emergency DMVO, defined as any segment of the anterior cerebral artery (ACA) or distal middle cerebral artery, between January 1, 2015, and December 31, 2019. Those with a concomitant proximal occlusion were excluded. Outcomes were compared between the 2 treatment groups using propensity score methods. Data analysis was performed from March to June 2021. Exposures Patients were divided into EVT and MM groups. Main Outcomes and Measures Main efficacy outcomes included 3-month functional independence (modified Rankin Scale [mRS] scores, 0-2) and 3-month excellent outcome (mRS scores, 0-1). Safety outcomes included 3-month mortality and symptomatic intracranial hemorrhage. Results A total of 286 patients with DMVO were evaluated, including 156 treated with EVT (mean [SD] age, 66.7 [13.7] years; 90 men [57.6%]; median National Institute of Health Stroke Scale [NIHSS] score, 13.5 [IQR, 8.5-18.5]; intravenous tissue plasminogen activator [IV tPA] use, 75 [49.7%]; ACA involvement, 49 [31.4%]) and 130 treated with medical management (mean [SD] age, 69.8 [14.9] years; 62 men [47.7%]; median NIHSS score, 7.0 [IQR, 4.0-14.0], IV tPA use, 58 [44.6%]; ACA involvement, 31 [24.0%]). There was no difference in the unadjusted rate of 3-month functional independence in the EVT vs MM groups (151 [51.7%] vs 124 [50.0%]; P = .78), excellent outcome (151 [38.4%] vs 123 [31.7%]; P = .25), or mortality (139 [18.7%] vs 106 [11.3%]; P = .15). The rate of symptomatic intracranial hemorrhage was similar in the EVT vs MM groups (weighted: 4.0% vs 3.1%; P = .90). In inverse probability of treatment weighting propensity analyses, there was no significant difference between groups for functional independence (adjusted odds ratio [aOR], 1.36; 95% CI, 0.84-2.19; P = .20) or mortality (aOR, 1.24; 95% CI, 0.63-2.43; P = .53), whereas the EVT group had higher odds of an excellent outcome (mRS scores, 0-1) at 3 months (aOR, 1.71; 95% CI, 1.02-2.87; P = .04). Conclusions and Relevance The findings of this multicenter cohort study suggest that EVT may be considered for selected patients with ACA or distal middle cerebral artery strokes. Further larger randomized investigation regarding the risk-benefit ratio for DMVO treatment is indicated

Post-carotid endarterectomy neurocognitive decline is associated with cerebral blood flow asymmetry on post-operative magnetic resonance perfusion brain scans

Objective: Up to 25% of patients experience subtle declines in post-operative neurocognitive function following, otherwise uncomplicated, carotid endarterectomy (CEA). We sought to determine if post-CEA neurocognitive deficits are associated with cerebral blood flow (CBF) abnormalities on post-operative MR perfusion brain scans. Methods: We enrolled 22 CEA patients to undergo a battery of neuropsychometric tests pre-operatively and on post-operative day 1 (POD 1). Neurocognitive dysfunction was defined as a two standard deviation decline in performance in comparison to a similarly aged control group of lumbar laminectomy patients. All patients received MR perfusion brain scans on POD 1 that were analysed for asymmetries in CBF distribution. One patient experienced a transient ischemic attack within 24 hours before the procedure and was excluded from our analysis. Results: Twenty-nine percent of CEA patients demonstrated neurocognitive dysfunction on POD 1. One hundred percent of those patients with cognitive deficits demonstrated CBF asymmetry, in contrast to only 27% of those patients without cognitive impairment. Post-CEA cognitive dysfunction was significantly associated with CBF abnormalities (RR=3.75, 95% CI: 1.62-8.67, p=0.004). Conclusion: Post-CEA neurocognitive dysfunction is significantly associated with post-operative CBF asymmetry. These results support the hypothesis that post-CEA cognitive impairment is caused by cerebral hemodynamic changes. Further work exploring the relationship between CBF and post-CEA cognitive dysfunction is needed

Toward Objective Quantification of Perfusion-weighted Computed Tomography in Subarachnoid Hemorrhage: Quantification of Symmetry and Automated Delineation of Vascular Territories

Rationale and Objectives: Perfusion-weighted computed tomography (CTP) is a relatively recent innovation that estimates a value for cerebral blood flow (CBF) using a series of axial head CT images tracking the time course of a signal from an intravenous contrast bolus. Materials and Methods: CTP images were obtained using a standard imaging protocol and were analyzed using commercially available software. A novel computer-based method was used for objective quantification of side-to-side asymmetries of CBF values calculated from CTP images. Results: Our method corrects for the inherent variability of the CTP methodology seen in the subarachnoid hemorrhage (SAH) patient population to potentially aid in the diagnosis of cerebral vasospasm (CVS). This method analyzes and quantifies side-to-side asymmetry of CBF and presents relative differences in a construct termed a Relative Difference Map (RDM). To further automate this process, we have developed a unique methodology that enables a computer to delineate vascular territories within a brain image, regardless of the size and shape of the brain. Conclusions: While both the quantification of image symmetry using RDMs and the automated assignment of vascular territories were initially designed for the analysis of CTP images, it is likely that they will be useful in a variety of applications

Morphology parameters for intracranial aneurysm rupture risk assessment

OBJECTIVE—The aim of this study is to identify image-based morphological parameters that correlate with human intracranial aneurysm (IA) rupture. METHODS—For 45 patients with terminal or sidewall saccular IAs (25 unruptured, 20 ruptured), three-dimensional geometries were evaluated for a range of morphological parameters. In addition to five previously studied parameters (aspect ratio, aneurysm size, ellipticity index, nonsphericity index, and undulation index), we defined three novel parameters incorporating the parent vessel geometry (vessel angle, aneurysm [inclination] angle, and [aneurysm-to-vessel] size ratio) and explored their correlation with aneurysm rupture. Parameters were analyzed with a two-tailed independent Student's t test for significance; significant parameters (P < 0.05) were further examined by multivariate logistic regression analysis. Additionally, receiver operating characteristic analyses were performed on each parameter. RESULTS—Statistically significant differences were found between mean values in ruptured and unruptured groups for size ratio, undulation index, nonsphericity index, ellipticity index, aneurysm angle, and aspect ratio. Logistic regression analysis further revealed that size ratio (odds ratio, 1.41; 95% confidence interval, 1.03−1.92) and undulation index (odds ratio, 1.51; 95% confidence interval, 1.08−2.11) had the strongest independent correlation with ruptured IA. From the receiver operating characteristic analysis, size ratio and aneurysm angle had the highest area under the curve values of 0.83 and 0.85, respectively. CONCLUSION—Size ratio and aneurysm angle are promising new morphological metrics for IA rupture risk assessment. Because these parameters account for vessel geometry, they may bridge the gap between morphological studies and more qualitative location-based studies