Febrile Seizures, Ongoing Epileptiform Activity, and the Resulting Long-Term Consequences: Lessons From Animal Models

Abstract

Febrile seizures affect 2% to 14% of children. Prospective studies indicate that following a relatively prolonged febrile seizure there are long-term consequences. Although controlled experiments in children have ethical limitations, nonhuman animal models give us the ability to discover new phenomena, determine their mechanisms, and test treatments that can potentially translate to the human clinical population. Rat models of febrile seizures show two temporally distinct phases: (1); behavioral seizures and (2); ongoing epileptiform activity associated with hyperoxia. The behavioral seizures mimic those displayed by children including tonic-clonic convulsions and loss of postural control. Recordings show classic spiking discharges from cortical regions during the behavioral seizures. Following behavioral seizure termination electrical recordings in rodent models reveal that there is ongoing epileptiform activity that lasts longer than the duration of the behavioral seizures themselves. This ongoing epileptiform activity is also associated with hyperoxia—levels of brain tissue oxygen well above the normoxic zone (typical oxygen levels)—and can last more than an hour. When this hyperoxia, but not the epileptiform activity, is prevented in febrile rat pups the long-term learning impairments are also prevented. This leaves important questions unanswered, “Do children also have ongoing and long-lasting epileptiform activity and associated hyperoxia following termination of their febrile behavioral seizures and does this second phase have long-term consequences”? Here we discuss appropriate animal models of febrile seizures that replicate much of the human condition with special attention to the long-term effects of occult epileptiform activity following termination of a behavioral febrile seizure.