This editorial was developed for AAN.com, which is publishing expert opinions on a variety of hot topics in neurology.
By Shlomo Shinnar, MD, PhD, FAAN
Professor of Neurology, Pediatrics and Epidemiology and Population Health
Hyman Climenko Professor of Neuroscience Research
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx NY
One of the most controversial issues in epilepsy research is whether prolonged febrile seizures cause mesial temporal sclerosis (MTS) and mesial temporal lobe epilepsy (TLE).1 Retrospective studies of patients undergoing surgical evaluation for medically refractory epilepsy have consistently found that approximately 30–40% report prior febrile seizures in childhood. However, prospective studies of febrile seizures have failed to confirm this finding.
The difficulties in establishing the association between prolonged febrile seizures and TLE include:
With the availability of better technology, magnetic resonance imaging (MRIs) of children with prolonged febrile seizures performed within 72 hours of the event can show increased T2 signal in the hippocampus, which in some cases is associated with subsequent MTS.1-3 This finding led to the FEBSTAT study, a prospective study designed to determine the association between prolonged febrile seizures and subsequent MTS and TLE.
This study has been underway for almost five years. The recruiting sites for the study are:
In addition, Columbia University serves as the epidemiology biostatistics center and provides controls from a study of the first febrile seizures, using similar imaging techniques (HD 36867. Principal Investigator Dale Hesdorffer PhD). The Epilepsy Consortium at Virginia Commonwealth University serves as the study's data coordinating center.
In the first five years, we have recruited approximately 165 children (with an ultimate goal of 200). We have found the following:
At this point we have nearly completed the baseline studies. In the next five years we intend to conclude the one-year MRIs, EEGs, and cognitive testing, and also perform five-year studies in a significant proportion of our population. We have retained the cohort and are in the process of performing outcome studies. Although it is premature to discuss the outcomes, as reported in meetings, some of these children have gone on to develop MTS.
In the long run the FEBSTAT study will likely define, in a prospective manner, the association between prolonged febrile seizures and subsequent MTS and TLE. In particular, the long-term studies will try to address the following questions:
In addition, we have banked tissue at the Coriel National Institute on Neurological Disorders and Stroke (NINDS) epilepsy repository for future planned genetic studies. Finally, if the study hypotheses are confirmed, can the baseline studies (MRI, EEG, virology) identify those who are at high risk for future MTS and TLE? If so they can serve as surrogate biomarkers, allowing us to design intervention studies whose outcome does not take 8–11 years to determine. If successful, for the first time we will be able to prospectively study epileptogenesis, or the development of epilepsy and its markers.
A study of this nature requires significant resources and many dedicated collaborators. It is clear that the combined efforts of many dedicated colleagues have made it a success so far. It will be some time before final results from this study are available. However, the results to date show that we are able to successfully recruit and retain this cohort, and that these studies are feasible. Hopefully, we will be able to provide definitive answers for the controversy still surrounding prolonged febrile seizures.
Within the past 24 months, Dr. Shinnar has received personal compensation as a consultant on the advisory boards of Jazz Pharmaceuticals, Marinus Pharmaceuticals, Questcor Pharmaceuticals, Schwartz Bioscience, and Valeant Pharmaceuticals. In addition, he has served on the Data Safety Monitoring Board (DSMB) of King Pharmaceuticals. Dr. Shinnar has also received honoraria from ID&A, UCB Pharma, Questcor Pharmaceuticals, and Valeant Pharmaceuticals. He has also served on the editorial boards of Neurology® and Pediatric Neurology, as well as providing expert witness in both medical malpractice and personal injury cases. He has received research support from NINDS, Glaxo Smith Kline, and Marinus.