Proposed rodent models for Onchocerciasis-associated epilepsy: Integrating Infection, microfilarial load, and...

Onchocerciasis-associated epilepsy (OAE) clusters where transmission of Onchocerca volvulus is intense, yet the causal steps to epileptogenesis remain unresolved. Rodent models can close this gap by enabling standardized, brain-anchored readouts that are impossible in humans. Here we synthesize current platforms and outline a pragmatic path to high construct validity. Implantation models using Onchocerca ochengi establish feasibility and reveal longitudinal physiological and behavioral effects, but lack natural infection routes and rarely generate sustained skin microfilariae. Gerbil models are informative for systemic physiology and macrofilaricidal stress-tests, whereas humanized NOD scid gamma mouse (NSG) infection introduces bona fide parasite development and a coherent context for anti-Wolbachia and anti-microfilarial probes, even without reliable patency. We propose a hybrid program integrating: (i) an Infection Core (humanized NSG with trickle L3 and doxycycline/ivermectin perturbations; (ii) an mf-centric arm that reconstructs controllable skin microfilaridermia; (iii) a standardized excretory/secretory product (ESP) program under tight biochemical quality control to test mechanistic sufficiency; and (iv) a refined implantation arm using gravid O. ochengi masses at low load with longer follow-up to generate measurable microfilariae in skin. Across all arms, a Core Outcome Set comprising wireless EEG, quantitative neuropathology, a minimal behavior battery, and paired brain-serum cytokine profiling enables cross-study comparability under ARRIVE-aligned bias control. This integrated approach transforms diffuse hypotheses into testable predictions linking infection context, microfilarial density, and parasite products to seizure propensity, advancing OAE toward actionable prevention and therapy.