Seizures are a common symptom of neurologic dysfunction in the neonatal period, affecting more than 16,000 newborns in the United States per year. Over 25% of neonates with acute symptomatic seizures develop post- neonatal epilepsy (PNE), which is often resistant to medical therapies. There is a critical need to identify those patients most at risk for PNE and understand the mechanisms by which early seizures increase the propensity for recurrent seizures, in hopes of identifying novel therapeutic targets in this population. There is increasing evidence for the role of neuro-inflammation in the development of epilepsy. Levels of cytokines and micro-RNA (miRNA) may serve as markers of disease severity and have been implicated in epileptogenesis in animal models. Studies examining the relationship between plasma cytokine or miRNA levels with acquired epilepsy in pediatric populations however, have not been performed. Our long-term goal is to identify those at highest risk of developing PNE and explore novel therapeutics that may ultimately prevent epilepsy after acute brain injury in this population. Our objective here is to evaluate plasma cytokine and miRNA levels after neonatal- onset acute symptomatic seizures and determine their association with acute seizure severity and PNE. The central hypothesis is that increases in specific pro-inflammatory molecules will be associated with acute symptomatic seizure severity and subsequent development of PNE. This investigation will leverage an existing national consortium, entitled the Neonatal Seizure Registry II (NSR II) which aims to understand the effect of anti-seizure drug therapy after neonatal seizures on the risk of neurodevelopment and PNE. Within NSRII, we will create a prospective cohort study with a nested case-control component, enrolling 72 neonates with acute symptomatic seizures as well as 15 `control' subjects. Blood will be collected prior to discharge and at 2-4 months of age, then analyzed for levels of cytokines and miRNA. The diagnosis of PNE assessed at 24 months of age. Expression patterns of cytokines will be correlated with presence and severity of acute symptomatic seizures (Aim 1), and prediction analyses performed for development of PNE (Aim 2). We will conduct similar analyses with miRNA levels (Aim 3). As a pediatric epileptologist, my career goal is to prevent the development of epilepsy in at-risk populations and optimize treatment regiments in those patients who do develop epilepsy. During this award period, I will acquire expertise in registry development, advanced immunologic methods, gene expression profiling, and bioinformatics for management of large data sets ? all necessary as I transition towards an independent investigator. This skill-set, in combination with expert mentoring and the data I acquire here will inform a future R01 evaluating these molecular pathways in a larger population of neonates with acute symptomatic seizures, as well as in similar pediatric cohorts at-risk for epilepsy including those with traumatic brain injury and stroke.

Public Health Relevance

Neonatal seizures affect more than 16,000 newborns in the United Stats per year and are a risk factor for the development post-neonatal epilepsy (PNE), which can be severe and resistant to medical therapies. While injury severity may predict onset of PNE, additional risk factors stratifying those infants at highest risk are lacking. This study aims to evaluate the relationship between inflammation and epilepsy in neonates with seizures, with our results having the potential to 1) identify inflammatory molecules predictive of the development of PNE, thereby immediately informing providers and families of a patient's individual risk, and 2) reveal new insights in the processes that cause epilepsy in the injured and developing brain, providing evidence for anti-inflammatory therapeutic strategies that can modify neurologic sequelae after brain injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Neurological Sciences Training Initial Review Group (NST)
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Whittemore, Vicky R
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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