Bridging the Gaps: Complexities and Challenges in Studying SUDEP Using Animal Models

Sudden unexpected death in epilepsy (SUDEP) is the most catastrophic complication associated with epileptic seizures. Despite its devastating impact, the mechanistic underpinnings of SUDEP remain poorly understood, limiting the development of effective preventive strategies. Animal models have proven indispensable in understanding the complex pathophysiology of SUDEP, offering controlled systems to dissect potential causes of these fatal events. This review provides a comprehensive overview of the current landscape of SUDEP animal models, with an emphasis on key experimental variables that impact SUDEP outcome in animal studies. In particular, this review focuses on how the animals' genetic background, age, sex, vigilance state, and time of day influence their phenotypic variability. We also report the major discrepancies in terminal seizure characteristics between mice and humans and highlight the necessity to segregate "anti-SUDEP" effects from potential "antiseizure" effects. From a regulatory and animal welfare perspective, we discuss the challenges of studying SUDEP as an endpoint and outline the critical steps to implement the preclinical SUDEP common data element, thereby promoting consistency, reproducibility, and interoperability across preclinical studies. By synthesizing insights across critical experimental variables and remaining challenges in SUDEP preclinical studies, this review aims to promote rigorous experimental design in animal SUDEP studies, with the long-term goal of facilitating translational insights into human SUDEP prevention.