# Stress convulsions in rodents: within a weight-of-evidence framework for human seizure risk

## TL;DR

This paper discusses how stress in rodents can cause convulsions that may be mistaken for drug-induced seizures, and proposes a framework to better distinguish between the two.

## Contribution

The paper introduces a Weight-of-Evidence framework to differentiate stress-induced convulsions from true drug-induced seizures in preclinical studies.

## Key findings

- Stress-induced convulsions in rodents can lead to false-positive seizure liability assessments.
- A Weight-of-Evidence approach is proposed to improve the accuracy of seizure risk evaluation in drug safety studies.
- Context-specific criteria are recommended to address inconsistencies and artifacts in seizure assessments.

## Abstract

In research settings, rodents exhibit a well-documented sensitivity to stress-induced behavioral alterations ranging from stereotypy to convulsions. These events complicate preclinical drug safety assessments where establishing a No-Observed-Effect Level (NOEL) requires distinguishing true pharmacologic seizures from stress-related convulsions, including a type lacking electrographic cortical correlates, referred to as psychogenic nonepileptic seizures (PNES). Stress triggers in preclinical settings include environmental factors and systemic conditioning effects of investigational drugs unrelated to seizure risk. Stress-induced behaviors can bias safety assessments by creating false-positive findings of seizure liability incorrectly attributed to the test compound. This paper highlights situations when stress conditioning is present during rodent seizure liability studies and proposes a Weight-of-Evidence (WoE) approach to differentiate between drug-induced ES and stress-conditioned PNES. It supports applying context-specific criteria for regulatory considerations especially when convulsions are absent in higher species, when there are inconsistent findings across facilities, and when rodents present stereotypy and lack of neuropathological evidence of drug-induced seizures. This approach aims to minimize the misinterpretation of stress-related artifacts as true pharmacologic seizures, providing a framework for more reliable and translatable seizure liability assessments.