Hypoxic-ischemic encephalopathy (HIE) is the most common cause of neonatal seizures. However, considerable controversy exists over the treatment of seizures in encephalopathic neonates. A major problem is the electroclinical dissociation or uncoupling observed in the neonatal population with infants displaying behaviors that mimic seizures without EEG documentation, or electro-encephalographic seizure activity without clear clinical manifestations (subclinical seizures), in addition to clinical seizures (reviewed in Silverstein and Jensen(1)). The impact of either of these seizure subtypes on longterm outcome, as well as whether and how to treat neonatal seizures, remain vital questions. To address questions such as these it is important to turn to our well-described animal models of hypoxic-ischemic injury to the immature brain. However, most studies to date have used chemicals to induce seizures in conjunction with hypoxia-ischemia (HI), potentially making them less relevant to the clinical situation. We have recently expanded our model of unilateral cerebral hypoxia-ischemia in the immature rat to include simultaneous video monitoring and EEG (VEEG) and EMG recording before, during, and following HI. We are able to record behavioral, EEG, and EMG changes induced by HI in the absence of any chemical seizure induction. Our preliminary studies suggest that HI induces seizure-like behaviors without corresponding EEG changes, subclinical seizures of EEG activity without activity, as well as clinical seizures, similar to that observed in both term and preterm infants. We have begun to correlate seizure pattern during and after HI with brain damage. However, it is clear that unbiased, quantitative methods are needed to detect and characterize the different seizure types accurately. We propose two Specific Aims: 1) To analyze and expand existing data from the term-equivalent P12 rat pup to characterize and reliably detect seizure types;and 2) To apply the methods of Aim 1 to the more immature, near-term equivalent, P7, rat pup to test the hypothesis that the younger animals will have a greater number of subclinical seizures during and after HI. For both aims we propose that the accurate detection of all of these events will allow for correlation of seizure burden with outcome in individual animals. The experiments proposed here are appropriate to the R03 mechanism in that they will firmly establish this new methodology so that we can specifically address the important clinical/translational questions related to neonatal seizures in the context of hypoxic-ischemic encephalopathy.

Public Health Relevance

Perinatal asphyxial brain damage, or hypoxic-ischemic encephalopathy (HIE), is a major cause of acute mortality and chronic neurologic morbidity in infants and children. HIE is the most common cause of seizures in the neonatal period, yet there continues to be major clinical questions regarding accurate diagnosis of these seizures, especially in the absence of behavioral changes, and whether, and how, to treat them. Seizures in preterm infants due to hypoxia-ischemia (HI) may be different from those in term infants with HIE. Many animal studies addressing these questions employ chemical induction of seizures in addition to experimental hypoxia-ischemia. We have developed a model to study HI-induced neonatal seizures in the rat (both term- and preterm-equivalent) without chemical intervention. This research proposal will develop the quantitative methods necessary to detect and characterize the different seizure types accurately and objectively so that we will then be able to address the important translational/clinical questions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1-BDCN-Y (02))
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Stewart, Randall R
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Patel, Shyama D; Pierce, Leslie; Ciardiello, Amber J et al. (2014) Neonatal encephalopathy: pre-clinical studies in neuroprotection. Biochem Soc Trans 42:564-8