Project Summary/Abstract Dr. Zafar is a neurointensivist and clinical neurophysiologist at the Massachusetts General Hospital, whose goal is to become an independent investigator with expertise in comparative effectiveness research and pragmatic clinical trials using neurophysiologic tools, to improve outcomes in patients with acute brain injuries and seizures. Epileptiform abnormalities (seizures and seizure-like rhythmic patterns) are seen on electroencephalography (EEG) in up to 40% of acute brain injury patients and are associated with worse outcomes. Due to lack of evidence-based guidance, patients with epileptiform abnormalities are often aggressively treated with anti-epileptic drugs (AEDs), exposing them to AED related adverse effects that may worsen outcomes. Dr. Zafar's preliminary data shows that increasing burden of epileptiform abnormalities in patients with hemorrhagic stroke is associated with worse outcomes. Up to half these patients receive AED treatment with no improvement in outcomes, and AED use itself is independently associated with worse outcomes. Dr. Zafar has built a comprehensive EEG database of 2000 patients to investigate AED effectiveness. In her career development plan, she will be using the rich neurophysiologic data in the EEG database, along with a nationwide dataset (Premier Healthcare Database) to study AED and EEG utilization patterns and AED effectiveness in a “real-clinical world” setting. Under the mentorship of Dr. M. Bradon Westover, and co-mentors (Dr. John Hsu, Dr. Elisabetta Patorno, and Dr. Hang Lee), Dr. Zafar proposes to: 1) Determine which specific epileptiform abnormalities show an acute response to AEDs by assessing neurological improvement within 24 hours of treatment (EEG database), 2) Assess the impact of AEDs on in- hospital clinical adverse outcomes and discharge functional outcomes in acute brain injury patients with epileptiform abnormalities (EEG database), 3) Investigate how AED-related adverse outcomes vary with practice patterns across hospitals with different resources and EEG utilization patterns (Premier Database). Dr. Zafar will perform a systematic exploration of the EEG database to determine EEG phenotypes associated with response to AED treatment, and determine the impact of AEDs on in-hospital adverse outcomes (e.g. mortality, hepatotoxicity, cardiac events). To account for national variation in AED prescription, hospital resources and EEG use, Dr. Zafar will examine adverse outcomes in the Premier Database. In addition to the proposed research, Dr. Zafar's career development plan includes a Masters of Science and coursework on analysis of large databases, pharmacoepidemiology and machine learning. Dr. Zafar will receive guidance from her mentors and advisors with diverse clinical and scientific expertise. The proposed training will allow Dr. Zafar to establish a niche in using neurophysiologic data in comparative effectiveness research and launch an independent research career aimed at improving neurologic outcomes in patients with acute brain injuries.

Project Narrative Although patients admitted with brain injuries such as stroke and traumatic brain injury are at high risk for developing seizures, physicians have very limited information to guide anti-epileptic drug management in such patients. This results in frequent overuse of anti-epileptic mediations that are also known to have harmful side effects. Dr. Zafar's proposed project will significantly advance our knowledge on which patients benefit the most from treatment and which patients are at highest risk for harmful side effects, providing guidance for physicians in making treatment decisions that will improve outcomes in the thousands of brain injury patients admitted to US hospitals each year.