Abstract 2057 Perinatal Brain Injury: Patterns and Mechanisms Platform, Tuesday, 5/4

Introduction: Perinatal hypoxia-ischemia (HI) is the most common precipitant of seizures in the first 48-72 hrs of a newborns' life. Despite being treated as a medical emergency in neonatal intensive care units, whether or not neonatal seizures contribute to hypoxic-ischemic brain damage remains unknown. The current study was therefore undertaken to clarify whether or not seizures in the newborn contribute to the brain damaging effects of an asphyxial insult.

Methods: Ten day old rat pups were anesthetized with halothane, and underwent unilateral common carotid artery ligation followed by exposure to hypoxia in 8% oxygen for either 15 (Group I) or 30 (Group II) min. Separate groups of animals, having undergone the same procedure, and exposure to hypoxia in 8% oxygen for either 15 (Group III) or 30 (Group IV) min. were allowed to recover for 1/2 hr. afterwhich they were given a sc injection of 3 mg/kg of kainic acid (KA), followed by a 2mg/kg/hr sc infusion of KA for 3 hrs. Core temperatures and heart rate were monitored continuously throughout the experimental paradigm. Preliminary studies had indicated that all rat pups receiving KA injections, as described above, displayed clinical seizures characterized by head bobbing, circling, shaking, and tonic posturing. Electrographically, all rat pups had continuous high voltage polyspike and sharp wave activity lasting a mean of 4 hrs and 42 min. All animals were allowed to recover for 3 (early) or 20 (late) days following which they were sacrificed for neuropathologic assessment.

Results: Mortality rates for Groups III & IV (animals receiving KA) was significantly greater than those exposed to HI alone (Groups I & II) (p<0.05). Core temperatures were noted to also be significantly greater (p<0.0001) in KA animals (37.76°C) vs animals in the HI groups (36.29°C). In surviving animals there was no significant difference in heart rate between animals in the HI alone groups vs those recieving HI & KA. Neuropathologic assessment with H&E staining revealed no brain damage in either the cortical or hippocampal structures of animals exposed to 15 min. of HI alone (Group I) or in combination with KA (Group III). The mean brain damage score for animals in Group II (30 min. HI) was 2.34 at 3 days and 0.6 at 20 days of recovery. Group IV (30 min HI & KA) animals displayed a significantly greater mean brain damage of 12.14 (p<0.001) and 3.65 (p<0.05) at 3 and 20 days respectively compare to Group II. The increase in brain damage between Groups IV and II was accounted for entirely by an increase in damage to the hippocampus. Comparing the early (3 day) vs late (20 day) neuropathologic outcomes for Groups II vs IV revealed that the extent of injury was significantly worse during the early recovery period (p<0.05).

Conclusions: 1) Prolonged neonatal seizures as a consequence of perinatal asphyxia significantly exacerbates brain damage. 2) Topographically, the increase in neuronal injury occurs exclusively in the hippocampus. 3) Delayed neuronal injury appears not to play a role in the exacerbation of seizure induced damage to the HI neonatal brain. 4) Hyperthermia, as a consequence of prolonged seizure activity may play a role in the exacerbation of hippocampal brain damage under these circumstances. In humans, the prophylactic utilization of anticonvulsants following moderate to severe perinatal asphyxia may be warranted.

(This research was supported by a grant from the Health Services Utilization Commission of Saskatchewan).