Rationale:
Almost a third of epilepsy patients are refractory to conventional anti-seizure medications (ASMs), highlighting the urgent need for new treatments. Central to the development of novel treatments is testing of anticonvulsant activity in preclinical epilepsy and seizure models. While various models exist, the predictive validity of each model across the spectrum of epilepsies has been unclear. Here, we sought to establish the concordance between commonly used preclinical models and the clinical epilepsy spectrum spanning focal and generalized epilepsies to define the models with the highest clinical predictive validity.
Methods:
Preclinical seizure and epilepsy models were selected based on historical use and the Epilepsy Therapy Screening Program pipeline. Protective indices based on reported TD50 and ED50 values were calculated for each of 31 approved ASMs. A weighted scale representing corresponding relative anticonvulsant effect was then used to grade preclinical ASM response for each ASM in each seizure model. Established reports of ASM use in patients with focal and generalized epilepsies were similarly evaluated and a weighted scale representing prescribing patterns and associated relative anticonvulsant effect used to grade clinical ASM response for each ASM in each clinical indication.
In order to assess the predictive validity of the preclinical models, a unified translational scoring matrix was developed to assign a concordance score between preclinical and clinical ASM responses. For each preclinical model and clinical indication combination, individual ASM concordance scores were calculated and then combined to generate a global translational concordance score.
Results:
Across the focal epilepsy types, including focal onset aware, focal onset impaired awareness, temporal lobe epilepsy and focal bilateral tonic-clonic (secondarily generalized), preclinical models with the highest translational concordance were maximal electroshock seizure (MES, mouse or rat), mouse audiogenic seizure, mouse 6-Hz (32mA) and rat amygdala kindling.
Absence Epilepsy Rats from Strasbourg (GAERS) and inbred Wistar Albino Glaxo Rats from Rijswijk (WAG/Rij) models were in highest concordance with absence, myoclonic and atonic seizure types. Preclinical models with the highest concordance for
status epilepticus were MES, mouse 6-Hz (44mA), and rat amygdala kindling. Tonic-clonic seizures showed the greatest concordance with MES, mouse audiogenic, mouse 6-Hz (32mA) and rat amygdala kindling preclinical models.
Conclusions:
Using a newly developed scoring matrix to assess translational concordance and predictability, this study provides novel insights into the clinical validity of commonly used preclinical seizure models in focal and generalized epilepsies. Notably, we highlight MES (mouse or rat), mouse audiogenic and mouse 6-Hz (32mA) as three acute seizure models consistently demonstrating the highest predictive validity, irrespective of clinical indication. Based on these findings, we provide a pragmatic approach with decision tree to support efficient use of resources for novel ASM development.
Funding: Praxis Precision Medicines.