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Models II: Identification and Characterization of Animal Models of Human Therapy Resistance and Epileptogenesis

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Models II: Identification and Characterization of Animal Models of Human Therapy Resistance and Epileptogenesis
September 26 - 27, 2002
Bethesda Marriott Hotel
Bethesda, MD

This meeting was in follow-up to the White House sponsored "Curing Epilepsy" Conference held in March 2000 and the subsequent NINDS workshop "Models for Epilepsy and Epileptogenesis" held in March 2001. One of the recommendations of these earlier conferences was new models be identified to enhance the process of therapy discovery, specifically for therapy resistant epilepsy and for the prevention of epilepsy.

At this two day workshop there were representatives from the medical community, the basic science community, the pharmaceutical industry, government and patient advocacy groups. They were given the task to review available epilepsy and seizure models (in vivo, in vitro, genetic or induced) and to recommend which among the models might be most appropriate for the therapy identification process. Initially, current processes of therapy development from the earliest screening steps through clinical trials were reviewed. Presentations from both academic and industrial perspectives delineated the many difficulties encountered in discovery and development processes. Also discussed were characteristics comprising the "ideal model" such as ease of use and the desirability of the model to predict clinical success. In the course of these early discussions it was emphasized that the identification of models for use in therapy screening should not be viewed as a models approval or ranking system. There are many epilepsy and seizure models that have scientifically valid and important features for understanding these conditions, but it is likely that not all of them will be highly predictive of clinical success for a particular experimental therapy.

The workshop panel was divided into two groups. Participants in the first group were tasked with examining models for pharmacoresistance while the other focused on antiepileptogenesis. Group discussions centered on current research areas including in vitro, genetic, acutely induced seizures and models of chronic epilepsy. At the end of the conference, the two groups reported their findings. Both groups recommended the use of the post status epilepticus limbic epilepsy models. These models were chosen because of their many similarities to human temporal lobe epilepsy including pathology and seizure morphology on EEG. A feature of these models that is important for antiepileptogenesis research is the latent period between the initial insult and the eventual development of spontaneous seizures. In addition to model identification, the panel recommended that the initial stages of the development of these models into full screening tools must include a period of validation with the standard antiepileptic drugs as well as a focus on assuring that the use of these models is efficient as possible. Another recommendation included adopting a mechanistic approach to the therapy screening process. The results of these validation studies along with the development of mechanism-oriented screens should be made publicly available to assist the epilepsy research community in ongoing basic and clinical research.

The panel recognized that the selection and focus on these particular models could temporarily slow the identification of therapies for some epilepsy syndromes due to resource allocation issues. Clearly, there is a lack of models for some of the most difficult to treat epilepsies such as the Lennox-Gastaut Syndrome or infantile spasms. Therefore, an additional strong recommendation was made that the NINDS support model development through novel funding mechanisms. Key characteristics of some of the common refractory epilepsy syndromes were also reviewed. These characteristics were identified as important features required in any syndrome specific model.

The recommendations of this workshop will take a number of years to realize. But when completed it is expected that the efforts will have provided new and more effective therapies for untreated or poorly treated conditions. In addition, the scientific community will possess a better understanding of the mechanisms involved in epileptogenesis and the phenomena of pharmacoresistance. Past experience in the epilepsy therapy discovery program suggests that advances made in this area may add to our understanding and treatment of other neurological diseases including stroke, anxiety and pain.

Last updated February 09, 2005