The FEBSTAT study examines the consequences of febrile status epilepticus (FSE) and is clarifying the relationship between FSE, hippocampal atrophy, hippocampal sclerosis (HS), and the development of subsequent temporal lobe epilepsy (TLE) and cognitive impairment. We prospectively recruited 199 children as part of the FEBSTAT cohort and 23 more as part of the pilot study at Duke. The FEBSTAT cohort had MRIs and EEGs within 72 hours as well as viral studies and baseline neuropsychological testing. Repeat studies have been performed at one year in the FEBSTAT cohort. A group of 96 children with first simple febrile convulsions (FC) recruited as part of Dr. Hesdorffer's NICHD funded study that had imaging studies at baseline and one year serve as controls. To date we have demonstrated abnormal hippocampal T2 signal in the FSE cases as well as subtle developmental hippocampal abnormalities that may predispose to FSE. At one year, those with abnormal T2 at baseline demonstrate loss of hippocampal volume and persistent T2 signal meeting radiologic criteria for HS. FSE cases with normal signal at baseline had less hippocampal growth than the simple FC control group. Acute EEG abnormalities were common, were associated with hippocampal T2 signal abnormality and often persisted on follow-up EEGs. The goals of this proposal are 1. Study the epileptogenic process leading to the development of clinical TLE utilizing serial MR imaging, EEG, and evaluation of cognitive function including memory and executive function, as well as evaluation of behavioral and psychiatric comorbidity. These evaluations occur at 5, 10 and 15 years and if epilepsy develops. In this phase we propose completing the FEBSTAT 5 year evaluations and doing the 10 year ones as well performing 10 and 15 year evaluations in the Duke cohort. DNA and genomic specimens are being collected. Hypotheses to be tested include that acute hippocampal imaging abnormalities and focal slowing/attenuation on the EEG will be associated with both subsequent HS and development of TLE and that children with hippocampal volume loss will demonstrate impairment of memory. 2. Ascertain and characterize the emergence of TLE and other forms of epilepsy in the FEBSTAT cohort and thereby determine the validity of putative clinical and laboratory biomarkers of HS and TLE following FSE. We predict that in addition to initial MRI and EEG abnormalities and their pattern of evolution, other parameters such as FSE duration and locality, genetic factors and HHV6,7 infection will predict hippocampal volume loss, HS and TLE after FSE. Given the estimated latency of 8-11 years from the time of FSE until development of clinical TLE, we expect the next 5 years to be critical to addressing the questions posed by the FEBSTAT study. The FEBSTAT study will likely identify surrogate markers for the development of hippocampal atrophy, HS and TLE following FSE and may also identify therapeutic targets such as prevention of hippocampal volume loss for future intervention trials.

Public Health Relevance

Seizures that occur with 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 recruited 222 children with an episode of prolonged febrile seizure lasting 30 minutes or more (febrile status epilepticus) and is using clinical, imaging, electrophysiological, and psychological data from serial examinations to determine the consequences of these prolonged seizures and provide the information necessary to design intervention studies to prevent brain damage and the subsequent development of temporal lobe epilepsy, a disabling, difficult to treat form of epilepsy. NOTE: The critiques and criterion scores from individual reviewers are provided below in an essentially unedited form. These were prepared prior to the review meeting and may not have been updated or revised subsequent to the discussion at the meeting. Therefore, they may not fully reflect the final opinions of the individual reviewers at the close of group discussion or th final majority opinion of the group. The Resume and Summary of Discussion above summarizes the final outcome of the group discussion.

Agency
National Institute of Health (NIH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS043209-12
Application #
8654363
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Fureman, Brandy E
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Bronx
State
NY
Country
United States
Zip Code
10461
Lewis, Darrell V; Shinnar, Shlomo; Hesdorffer, Dale C et al. (2014) Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study. Ann Neurol 75:178-85
Patterson, Katelin P; Baram, Tallie Z; Shinnar, Shlomo (2014) Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus. Neurotherapeutics 11:242-50
Callaghan, Brian; Choi, Hyunmi; Schlesinger, Malka et al. (2014) Increased mortality persists in an adult drug-resistant epilepsy prevalence cohort. J Neurol Neurosurg Psychiatry 85:1084-90
Hesdorffer, Dale C; Shinnar, Shlomo; Lewis, Darrell V et al. (2013) Risk factors for febrile status epilepticus: a case-control study. J Pediatr 163:1147-51.e1