Pathological remodeling and functional evolution of the corneal nervous system in ocular surface dyshomeostasis

The corneal nerve plexus is essential to ocular surface homeostasis through sensory detection, trophic support, epithelial repair, blinking, and lacrimal reflexes. In dry eye disease (DED), chronic hyperosmolar, inflammatory, mechanical, and age-related stressors alter nerve morphology and function, contributing to reduced nerve density, aberrant regeneration, microneuroma formation, sensory loss, and peripheral or central sensitization. This review summarizes the ultrastructure of corneal innervation and the molecular basis of corneal sensory transduction, with emphasis on TRPM8, TRPV1, TRPA1, Piezo2, and acid-sensing ion channels. It then examines bidirectional neuroimmune signaling involving dendritic cells, cytokines, neuropeptides, and diminished neurotrophic support. We further discuss the relationship between age-related corneal hypoesthesia, local small-fiber degeneration, and systemic neurodegenerative disorders, while noting the limited disease specificity of currently proposed corneal biomarkers. Finally, we evaluate in vivo confocal microscopy (IVCM) and multimodal corneal esthesiometry for structural and functional phenotyping and review emerging nerve-directed interventions. Integrating morphology, sensory function, and neuroimmune biology may improve the mechanistic classification of DED and support more precise treatment of patients with symptom-sign discordance.