Epilepsy Benchmark IIIA

2005 Report submitted by Benchmark Steward(s):
Tallie Z. Baram, M.D., Ph.D. (University of California, Irvine)

Background of the benchmark goal: 
Age and individual ‘environmental’ differences: stress, gender, and the hormonal underpinnings of both.  These two factors affect the likelihood of seizures and the response to seizure medications. Therefore, to provide therapies that will be tailor-made to a given individual, we need to consider all of these factors. 

Current status of the field:
It is now recognized that effective therapies need to take into account the age-specific processes described above. In other words, to be effective, therapies for epilepsies during development will need to be designed to account for the different underlying mechanisms of the disease, as well as the age-specific handling and reactions to the therapeutic agents.

 It is recognized that sex, sex hormones and stress hormones all influence the process by which epilepsy arises, the type of the epilepsy and the way the individual responds to medication. To be effective, therapies need to take these facts into consideration.

Activities update: 
“Assess the potential efficacy of therapies in individual patients by examining effects on markers of epileptogenicity”

A. The human study of Van-Landingham (Ann Neurol, 1998), suggesting that Magnetic Resonance Imaging (MRI) changes might provide a marker for Epileptogenicity has been corroborated in a larger British study (Scott et al., Brain, 2002,3)

B. Significant progress has been achieved in defining MRI as marker of Epileptogenicity in a developmental epilepsy model, that leads to TLE: MRI changes have been identified in prospective analysis of limbic structures including hippocampus. In the animal model, pre-existing malformations, lesions or other factors that might lead to MRI changes can be excluded, by imaging all subjects also before the inciting epileptogenic event. (Dube et al., Ann Neurol, 2004)

C. Several proposals for anti-epileptogenesis model validation have recently been funded.  

D. A major human study fully launched: a prospective evaluation of MRI as marker for epileptogenesis (Shinnar).

E. Meetings and Education (partial):

• NIH sponsored workshop on Models in Pediatric Epilepsy (May 2004)
• NIH endorsed, AES supported meetings on Epilepsy and Autism (Davis, CA, 2004)
• NIH endorsed, AES supported meeting on Hot topics in Epilepsy- (UC Irvine, CA 2004). 
• NIH supported meeting on Neuropeptides in Epilepsy (Miami Fla, July 2004)

“Aim at developing highly individualized treatments that take into account the maturational state of the brain and other factors proven to be relevant such as hormonal status”.

A. Use of functional MRI as marker of gender-dependent and individual outcome to surgical treatment of Epilepsy (Rabin et al., Brain 2004)

B. Identification of gender specific side-effects of currently available AEDs (Human: Herzog et al., Epilepsia, 2004; Animal: Tauball et al., Epilepsia 2003).

C. An ongoing, prospective assessment of the role of individual and genetic factors in the response to specific anti-epilepsy drugs (Glauser)

D. CRISP search suggests 26 new grants (R21, K08, RO1 etc), pertaining to this benchmark.

Top priorities for next 5-10 years:

• Low risk: Validate MRI or related surrogate markers for the epileptogenic process in the developing brain
• Medium/ High risk: Define a 4-dimensional gene-expression brain atlas, that will highlight the temporal aspects of gene expression and function, as a basis for understanding age-related epileptogenic processes and issue of response to therapy.
• High risk: translate the use of surrogate markers as endpoint into clinical trials of novel therapies based on finding from laboratory research.

Roadblocks to progress:

• Need for better consensus within the field regarding the broad variance within the spectrum of “”the developing brain”“: need to define ages and age-specific processes within this paradigm (e.g., in the human, the premature, 32 week brain is not similar to that of a 10 year old child....).
• Need for better definition of hormonal cycle and stage-of life variance within the population of women with epilepsy
• True understanding the epileptogenic processes in infants and children requires concerted efforts of laboratories and groups (teams) focused on this issue
• Roadblocks to Translation: The current procedures of drug development prohibit (by law or by via financial disincentive) testing of antiepileptic compounds that are explicitly designed for infants and children. ALL compounds and agents are ‘hand me downs’ from those developed for the mature epileptic CNS. A mechanism to permit rapid, focused targeting of mechanism- derived novel pediatric therapies directly to children should be implemented.