Date of Award

January 2015

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Dr. Kevin N. Sheth

Second Advisor

Dr. Lauren A. Beslow

Subject Area(s)

Neurosciences

Abstract

TARGETING SECONDARY INJURY IN INTRACEREBRAL HEMORRHAGE -- PERI-HEMATOMAL EDEMA. Sebastian Urday, Lauren A. Beslow, W. Taylor Kimberly, Alexander O. Vortmeyer, David Goldstein, Feng Dai, Fan Zhang, Thomas WK Battey, Anastasia Vashkevich, Alison Ayres, Magdy Selim, Jonathan Rosand, J Marc Simard, and Kevin N Sheth. Yale University, School of Medicine, New Haven, CT

Intracerebral hemorrhage (ICH) is a devastating disease with no effective therapy. Our goal was to inform the development of novel therapies for ICH through a comprehensive analysis of peri-hematomal edema (PHE), a marker of secondary brain injury after hemorrhage.

The aim of the first study was to develop a novel method to conceptualize PHE formation within the framework of Starling's principle of movement of fluid across a capillary wall. We consider progression of PHE through three stages, characterized by ionic edema and progressive vasogenic edema. We highlight that combination treatment regimens that target different stages of PHE formation might be most effective to reduce swelling. Furthermore, we provide evidence that the sulfonylurea receptor 1-transient receptor potential M4 cation (SUR1-TRPM4) channel may contribute to early PHE formation and provide a new therapeutic target.

The aim of the second study was to develop a systematic approach for computed tomography (CT)-based measurement of PHE. Two independent raters measured PHE volumes on baseline and 24-hour post-ICH CT scans of twenty supratentorial ICH patients. CT-based PHE was also compared using magnetic resonance imaging (MRI)-based detection for eighteen subjects. There were no statistically significant differences in PHE measurements between raters. Furthermore, PHE volumes determined by CT and MRI were similar (24.5 ± 17.5 cc vs. 24.8 ± 16.9 cc, R2 = 0.98, p < 0.0001).

The aim of the third study was to determine the relationship between PHE and clinical outcome. Currently, whether PHE is an independent predictor of neurologic outcome is still controversial. This critical gap in knowledge severely impedes translation of novel therapies for ICH. We conducted a retrospective cohort study, designed to specifically answer this clinical question. We examined whether the rate of PHE expansion predicts 90-day mortality and functional outcome. We hypothesized that a faster PHE expansion rate predicts worse clinical outcome. For 139 spontaneous ICH patients, ICH, intraventricular hemorrhage, and PHE volumes were measured from CT scans obtained on presentation, at 24 hours and 72 hours post-ICH. Logistic regression was performed to evaluate the relationship between 1) PHE expansion rate and 90-day mortality and 2) PHE expansion rate and 90-day modified Rankin Scale score (mRS). The rate of PHE expansion between admission and 24-hours post-ICH was a strong predictor of 90-day mortality (OR 2.97, 95% CI 1.48-5.99, p = 0.002). This association persisted after adjusting for known predictors of outcome for ICH, including all components of the ICH score (OR 2.21, 95% CI 1.05-4.64, p = 0.04). Similarly, there was a strong association between the rate of PHE expansion from admission to 72 hours post-ICH scans and poor functional outcome at 90 days (mRS > 2) (OR 1.28, 95% CI 1.01-1.64, p = 0.04). This association persisted after adjusting for all components of the ICH score (OR 1.54, 95% CI 1.04-2.22, p = 0.03). Our findings suggest that PHE may represent an attractive translational target for ICH.

This Thesis lays the foundation for designing translational trials and understanding secondary injury in ICH.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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