MD/PhD Candidate University of Illinois College of Medicine Chicago, Illinois
This abstract has been invited to present during the Investigators Workshop Platform poster session
Rationale: Subarachnoid hemorrhage (SAH) commonly occurs after aneurysm rupture or head injury and results in severe long-term impairment. With increased utilization of electroencephalography (EEG) in the ICU setting, studies have shown high rates of electrographic abnormalities acutely after SAH. Between 2-25% of SAH patients may go on to develop epilepsy. Studies combining imaging, electrographic, and cellular changes after SAH in rodent models could aid in understanding the relationship between EEG changes and pathogenic mechanisms of brain injury to help develop new therapeutics. Because inflammation has been strongly implicated in many forms of epileptogenesis, we examined the spatial relationships between brain imaging, EEG changes, microglial, and synaptic alterations that could underlie epileptogenesis and compared these to changes in SAH patient EEG. Methods: Following endovascular perforation in rats to model SAH, we performed long-term video EEG to study electrographic abnormalities in the acute and chronic setting and how these changes relate to inflammatory and synaptic alterations. We compared three groups – SAH, sham (no vessel perforation), and naïve (EEG implant only). T2-weighted MRI imaging was performed at 24 hours to quantify and localize the location, volume, and extension of blood. Neurological scoring via the Modified Garcia score and EEG recordings covering the cortex with six epidural screws were conducted weekly for three months after SAH. Brains in different experimental groups were harvested at two days, seven days, and three months and stained for inflammatory markers including microglia. 3D modeling was used to evaluate the relationship between blood location, microglial activation, and EEG changes. EEG changes were compared to those seen in SAH patients. Results: SAH animals (n=9), similar to SAH patients, developed diffuse, sharp paroxysmal activity (spikes and sharp waves) in the acute setting (within days of SAH) along with increased slow-wave activity compared to sham and naïve controls (n=6). EEG changes were often more pronounced on the side ipsilateral to the site of hemorrhage. Spontaneous recurrent seizures developed in two out of nine SAH animals (22.2%), and none of the control animals, were clinically associated with behavioral arrest. Acute upregulation of activated microglia throughout the brain together with EEG changes were linked to the site of bleeding. Conclusions: The combined analysis of blood location, EEG, and neuroinflammatory markers in an animal model of SAH offers a new approach to study post-SAH epileptogenesis. A similar spatial pattern of electrographic excitability and disorganization occurs between an animal and human EEG after SAH. Future preclinical studies will investigate the role of microglial-mediated synaptic alterations in driving post-SAH EEG changes in addition to exploring the therapeutic immunomodulatory and antiepileptic drugs to prevent these changes. Funding: Please list any funding that was received in support of this abstract.: Joseph R. Geraghty receives grant support from the National Institute of Neurological Disorders and Stroke (Grant No. 1F31NS105525-01A1). This work was supported by Citizens United for Research in Epilepsy (CURE) based on a grant received from the United States Army Medical Research and Material Command, Department of Defense, through the Psychological Health and Traumatic Brain Injury Research Program (Award No. W81WWH-15-2-0069) awarded to Jeffrey A. Loeb.