Epilepsy Benchmark IC2

 

Epilepsy Benchmark IC2 Benchmark Area I: Understanding basic mechanisms of epileptogenesis Section C: Validate and apply models of epileptogenesis and epilepsy as biological test systems for novel therapy Specific Benchmark 2: Characterize and develop new models for epileptogenesis and epilepsy in the developing brain, and therapy resistant epilepsy.

2005 Report submitted by Benchmark Steward(s):
Solomon L. Moshé, M.D. (Albert Einstein College of Medicine)
Philip A. Schwartzkroin, Ph.D. (University of California – Davis)

Background of the benchmark goal: 
Epilepsy is relatively common in infants and babies.  Some of the most catastrophic epilepsy syndromes occur in the immature.  Unfortunately, there are few animal models of these early epilepsies.  Models are needed to carry out basic investigations of underlying mechanisms, for the development of age-appropriate therapies, and for testing strategies to prevent the development of an epileptic encephalopathy (static or progressive).

Current status of field:
There is currently much interest and concern in pediatric seizure issues.  A significant focus of recent research has been on genetic predisposition, and on events/trauma in early development that may lead to an epileptic state - both during the first few years of life and also much later on.  But there have been few publications that describe models within which we can study a specific form of pediatric epilepsy - seizure or syndrome. Further, for the vast majority of the pediatric epilepsies, there is no specific treatment (and no model within which to develop a specific treatment).             

Activities update: 
An NIH-sponsored workshop was held in the spring of 2004.  Investigators actively involved in pediatric epilepsy research, as well as those focused on pediatric research in related fields, attended and contributed.  A follow-up workshop was held at the 2004 American Epilepsy Society Annual Meeting (Investigators' Workshop session), to solicit input from a larger audience.  We are in the process of generating a "white paper," summarizing the discussion and recommendations of those workshops.  The "white paper" will be submitted to an epilepsy journal.

Top priorities for next 5-10 years:

• Develop appropriate models (especially for at least one form of catastrophic epilepsy)
• Generate data bases for relevant clinical information regarding pediatric epilepsies, and for basic research investigations and available models
• Develop age specific therapies/treatments (again, for at least one form of catastrophic epilepsy)
• Encourage the development of experimental technologies that will facilitate studies on pediatric models (i.e., micro-techniques appropriate for studying baby rats and mice)

Roadblocks to progress:

• There is a need for research focused specifically on pediatric epilepsy issues
• Absence of effective inter-institutional networks for sharing clinical data (especially on rare forms of catastrophic epilepsies)
• Need for collaborative cross-laboratory, multi-disciplinary approaches
• Poorly-developed technologies/hardware applicable to immature animals (e.g., micro-imaging, EEG monitoring)

References:

Chan KF, Jia Z, Murphy PA, Burnham WM, Cortez MA, Snead OC 3rd (2004) Learning and memory impairment in rats with chronic atypical absence seizures. Exp. Neurol., 190:328-336.

Schwartzkroin PA, Roper SN, Wenzel HJ (2004) Cortical dysplasia and epilepsy: animal models.  Adv Exp Med Biol. 548:145-174.

Stables JP, Bertram EH, White HS, Coulter DA, Dichter MA, Jacobs MP, Loscher W, Lowenstein DH, Moshe SL, Noebels JL, Davis M (2002) Models for epilepsy and epileptogenesis: report from the NIH workshop, Bethesda, Maryland. Epilepsia 43:1410-1420.

Jensen FE, Baram TZ (2000) Developmental seizures induced by common early-life insults: short- and long-term effects on seizure susceptibility.  Ment Retard Dev Disabil Res Rev. 6:253-257.

Dube C, Marescaux C, Nehlig A (2000) A metabolic and neuropathological approach to the understanding of plastic changes that occur in the immature and adult rat brain during lithium-pilocarpine-induced epileptogenesis. Epilepsia 41 (Suppl 6):S36-S43.

Anderson AE, Hrachovy RA, Antalffy BA, Armstrong DL, Swann JW (1999) A chronic focal epilepsy with mossy fiber sprouting follows recurrent seizures induced by intrahippocampal tetanus toxin injection in infant rats. Neuroscience  92:73-82.

Kubova H, Moshe SL (1994) Experimental models of epilepsy in young animals.

J Child Neurol. 9 (Suppl 1):S3-S11.

Pitkänen, A., Schwartzkroin, P., Moshé, S.L. (Eds), Models of Seizures and Epilepsy, Elsevier (2005).