Consequences of Prolonged Febrile Seizures in Childhood

Temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS) is often associated with a history of febrile seizures (FC). However, the proposed causal relationship between FCs and MTS remains controversial. Identification of children at high risk to develop MTS or TLE is necessary before designing interventions aimed at prevention. The FEBSTAT study examines the consequences of febrile status epilepticus (FSE) and will clarify the relationship between FSE, hippocampal atrophy, MTS, and subsequent epilepsy and cognitive impairment. We have prospectively recruited 144 children with FSE (165 are expected by end of year 5) and performed MRIs and EEGs within 72 hours as well as viral studies and baseline neuropsychological testing. Repeat studies have been performed at one year. To date we have demonstrated acute hippocampal imaging changes in 27% and acute EEG abnormalities in 38%. We have also demonstrated that human herpes virus 6 and 7 (HHV6,7) account for 35% of all FSE. Moreover >80% of subjects have returned for one year studies including MRI and EEG demonstrating our ability to retain the cohort. In this application we propose long term follow-up of the FEBSTAT cohort with 5-year reevaluations consisting of imaging, EEG and neuropsychological testing. Identical assessments will also be done if epilepsy develops. The goals of this proposal are to 1. Study the evolution of the epileptogenic process in terms of imaging, EEG, neuropsychological function and development of clinical TLE 2. Assess the importance of predictive factors such as HHV 6,7 infection, FSE duration and focality on the risk of hippocampal atrophy, MTS and TLE. Hypotheses to be tested include: I-II: The presence of acute hippocampal imaging or EEG abnormalities will be associated with later development of hippocampal atrophy, MTS and TLE. We will explore whether the extent of injury extends beyond the hippocampus. III: Children with FSE who develop hippocampal atrophy, regardless of whether they have developed clinical TLE, will have specific impairments on tasks associated with hippocampal function such as memory. IV: Acute HHV 6,7 infection at the episode of FSE and focal FSE are associated with an increased risk of developing hippocampal atrophy, MTS and TLE following FSE . We expect that the evolution of hippocampal changes on MRI and of chronic EEG abnormalities will substantially precede the development of clinical TLE and therefore can serve as surrogate biomarkers as well as potential therapeutic endpoints in future clinical trials. The research is responsive to Benchmark 1A2 from The Cure Epilepsy 2000 conference Additional human collaborative imaging studies such as consequences of prolonged febrile seizures and to the benchmark on identifying and characterizing potential surrogate markers of epileptogenesis and epilepsy. It is also responsive to Senate Report 109-287 that urges NINDS to engage in research into the possible role of HHV-6 in SE and MTS. Our results to date suggest that the FEBSTAT study will likely identify surrogate markers for the development of hippocampal atrophy, MTS and TLE following FSE. Seizures that occur in the context of a febrile illness are the most common type of seizure in childhood, occurring in 2-5% of all children. These febrile seizures are generally brief and benign, but when prolonged, they have been associated with brain injury and temporal lobe epilepsy. This prospective study is recruiting 200 children with an episode of prolonged, longer than 30 min, febrile seizures (febrile status epilepticus) and using clinical, imaging, electrophysiological, and psychological data from serial examinations to examine the consequences of these prolonged seizures and provide the information necessary to design intervention studies to prevent brain damage and the subsequent development of a disabling, difficult to treat form of epilepsy.