Are we there yet? A critical evaluation of sudden and unexpected death in epilepsy models

Abstract

Although animal models have helped to elaborate meaningful hypotheses about the pathophysiology of Sudden Unexpected Death in Epilepsy (SUDEP), specific prevention strategies are still lacking, potentially reflecting the limitations of these models and the intrinsic difficulties of investigating SUDEP. The interpretation of pre‐clinical data and their translation to diagnostic and therapeutic developments in patients thus require a high level of confidence in their relevance to model the human situation.Preclinical models of SUDEP models are heterogeneous and range from rodent and non‐rodent species. A critical aspect is whether the animals have isolated seizures exclusively induced by a specific trigger, such models where seizures are elicited by electrical stimulation or pharmacological intervention or DBA mouse strains, or whether they suffer from epilepsy with spontaneous seizures, with or without spontaneous SUDEP, either of non‐genetic epilepsy etiology or of genetically‐based developmental and epileptic encephalopathies. All these models have advantages and potential disadvantages, but it is important to be aware of these limitations to interpret data appropriately in a translational perspective. The majority of models with spontaneous seizures are of a genetic basis whereas SUDEP cases with a genetic basis represent only a small proportion of the total number. In almost all models, cardio‐respiratory arrest occurs during the course of the seizure, contrary to that in patients observed at the time of death, potentially raising the issue of whether we are studying models of SUDEP or models of peri‐seizure death. However, some of these limitations are impossible to avoid and can in part be dependent on specific features of SUDEP, which may be difficult to model. Several preclinical tools are available to address certain gaps in SUDEP pathophysiology, which can be used to further validate current preclinical models.