Medical hypothesis discovery and innovation in ophthalmology

Abstract

Background: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction predominantly mediated by antibodies that target the acetylcholine receptors in the skeletal muscles. Ocular involvement of the levator palpebrae superioris and extraocular muscles is common, resulting in ptosis and diplopia. Oral pyridostigmine, an acetylcholinesterase, is typically the first-line therapy, but its administration is frequently limited by systemic cholinergic adverse effects and inconsistent relief of ocular symptoms.
Hypothesis: We hypothesize that pyridostigmine can be reformulated as a topical ocular/periocular formulation to directly enhance the neuromuscular transmission of the levator palpebrae superioris and extraocular muscles, thereby improving ptosis and strabismus while minimizing systemic side effects. The levator palpebrae superioris and extraocular muscles underlie the conjunctiva. Pyridostigmine bromide is a small, hydrophilic quaternary ammonium compound with topical application properties that favor conjunctival permeability while limiting transcorneal penetration. Its formulation pH closely approximates that of conjunctival tissue. Clinical precedent from alpha-adrenergic eye drops (e.g., apraclonidine) that elevate the eyelid via Müller’s muscle support the plausibility of a topical approach. Although limited residence time on the ocular surface is a potential barrier, advances in delivery systems, including hydrogels, nanoparticles, and ionic liquids, may enhance retention and conjunctival penetration. Periocular transdermal delivery may further exploit the thin periocular skin to achieve localized vascular access. Based on the pharmacological mechanism of acetylcholinesterase inhibition, we propose that ex vivo animal model ocular permeability and tissue integrity be examined to determine the feasibility of topical pyridostigmine formulation providing effective localized neuromuscular transmission enhancement in patients with ocular MG.
Conclusions: If preliminary ex vivo animal model observations find that topical pyridostigmine formulations are stable with appropriate conjunctival penetration and preserved epithelial integrity, it would support progression to in vivo animal studies and translational modelling. The feasibility of topical or periocular pyridostigmine as a localized treatment strategy for ocular MG deserves further investigation. If validated, this approach could shift management toward targeted, better-tolerated topical therapies with reduced systemic risk.