Update on the Consequences of Prolonged Febrile Seizures (FEBSTAT) study (NINDS NS 43209)

May 30, 2008

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Science Editorials and Reviews—Edited by Sheryl Haut, MD

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
Author Disclosure

Background

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:

  1. A latency period of eight to eleven years, from the time of the febrile seizure to development of epilepsy
  2. Febrile seizures that present a marker for, rather than a cause of, the subsequent epilepsy
  3. Prolonged febrile seizures apparent in any given cohort

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.


Study Population

The study population included children aged one month to five years, with a febrile seizure lasting longer than 30 minutes; namely, febrile status epilepticus (febrile SE). Children with severe preexisting neurological abnormality were excluded from the study.

Study Hypothesis

  1. Hippocampal T2 signal abnormalities will be found in 30–40% of children with febrile SE on MRIs done within 72 hours of the SE.
  2. The severity of these T2 abnormalities will predict whether or not these children will demonstrate MTS on a one-year MRI.
  3. Children with febrile SE who develop TLE following febrile SE will have MTS detectable on the MRI, whereas the children developing other forms of epilepsy will not.

This study has been underway for almost five years. The recruiting sites for the study are:

  • Montefiore Medical Center and Jacobi Hospital at the Albert Einstein College of Medicine
  • Children's Memorial Hospital in Chicago
  • Duke University Medical Center, Durham NC
  • East Virginia Medical School
  • Virginia Commonwealth University

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:

  1. Prolonged febrile seizures tend to be very prolonged (mean duration less than 60 minutes) and in greater than 80% of the cases do not stop until benzodiazepine is administered.4 This is so, even though we set our screen at any seizure reported to be at least 15 minutes, in order to avoid missing cases.
  2. While treatment is generally appropriate, physicians routinely underestimate the duration of prolonged febrile seizures.
  3. Acute marked hippocampal T2 changes occur in a significant proportion (10–15%) of children with febrile SE in MRIs performed within 72 hours; milder T2 abnormalities also occur.
  4. Acute EEG abnormalities, primarily temporal slowing and attenuation are common, occurring in less than 30% of postictal EEGs performed within 72 hours of the febrile SE.
  5. Human herpesvirus 6 and 7 are the etiology of the febrile illness in less than 25% of cases, making them the most common identified cause of febrile SE.

    6. Current Status

    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:

    1. Is presence of acute hippocampal T2 a necessary and sufficient condition for development of subsequent MTS and TLE?
    2. How often does this occur and what are its risk factors?
    3. Are there cases where the initial imaging is normal but, subsequently, MTS and TLE develop?
    4. Is the initial EEG predictive of subsequent MTS and/or TLE?
    5. What is the role of herpes virus—and in particular herpesvirus 6B—which has recently been reported as present in temporal lobe tissue but not in extratemporal tissue from patients undergoing resections for intractable partial epilepsy?5 Are these children at higher risk for subsequent MTS and TLE?
    6. Are impairments of memory present in children with MTS even prior to the development of TLE or is this a late sequela?

    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.

    Conclusion

    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.

    Footnotes

    1. Shinnar S. Febrile seizures and mesial temporal sclerosis. Epilepsy Currents 2003;3:115-118.
    2. Vanlandingham KE, Heinz ER, Cavazos JE, Lewis DV. Magnetic resonance imaging evidence of hippocampal injury after prolonged focal febrile convulsions. Ann Neurol 1998;43:413-426.
    3. Lewis DV, Barboriak DP, MacFall JR, Provenzale JM, Mitchell TV, Vanlandingham KE. Do prolonged febrile seizures produce medial temporal sclerosis? Hypotheses, MRI evidence and unanswered questions. Prog Brain Res 2002;135:263-278.
    4. Shinnar S, Hesdorffer DC, Nordli DR Jr, Pellock JM, O’Dell C, Lewis DV, Frank LM, Moshe SL, Epstein LG, Marmarou A, Bagiella E and the FEBSTAT study team. Phenomenology of prolonged febrile seizures: Results of the FEBSTAT study Neurology, 2008 (in press).
    5. Donati D, Akhyani N, Fogdell-Hahn A, Cermelli C, Cassiani-Ingoni R, Vortmeyer A, Heiss JD, Cogen P, Gaillard WD, Sato S, Theodore WH, Jacobson S. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology 2003;61:1405-1411.

    Author Disclosure

    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.