Sathish Srinivasan and Douglas A.M. Lyall

Introduction

The cornea is one of the most richly innervated organs. Corneal innervation not only provides sensation but is integral in the maintenance of the structure and function of the cornea. Normal innervation helps the cornea to regulate epithelial integrity, proliferation and wound healing. Neurotrophic keratopathy (NK) is a degenerative condition of the cornea, characterized by lack of or decreased corneal sensation. This results in increased susceptibility of the corneal surface to injury and compromised healing. In severe cases this can lead to corneal ulceration, stromal melt and perforation. The cornea is supplied by the long ciliary nerve, derived via the nasociliary nerve from the ophthalmic branch of the trigeminal nerve. Any ocular, localized or systemic condition affecting the nerve function along this course can create corneal anesthesia, resulting in NK (Box 27.1).¹ Management of NK can be formidable, with the aim of therapy being prevention of disease progression, preservation of globe integrity and promotion of ocular surface repair.

Pathogenesis

Most of the corneal nerves are derived from the ophthalmic division of the trigeminal nerve, via the anterior ciliary nerves and to a lesser degree from the maxillary nerve. The limbus and the peripheral cornea also receive autonomic sympathetic innervation from the superior cervical ganglion.²

Nerves enter the cornea in the middle third of the stroma and run forward anteriorly in a radial fashion towards the center where they lose their myelin sheath approximately 1 mm from the corneal limbus, giving rise to branches that innervate the anterior and mid-stromal layers. In the interface between Bowman’s layer and the anterior stroma, the stromal nerves form the subepithelial nerve plexus. They perforate Bowman’s layer and form the sub-basal epithelial nerve plexus, providing innervation to the basal epithelial cell layer, to terminate finally within the superficial epithelial layers (Fig. 27.1).³ Thin branches of the subepithelial plexus ascend and penetrate Bowman’s layer, bending almost at a right angle to form the sub-basal nerve plexus at the basal epithelial cell layer (Fig. 27.2).⁴

In vivo confocal microscopy has emerged as a powerful tool to image the corneal cellular structure, including the corneal nerves (Fig. 27.3). The density of the sub-basal plexus varies depending on the method of examination and method of analysis. However, when compared to normal controls, the density of the plexus is reduced in NK and several predisposing disease states, including diabetes mellitus and viral keratitis (Fig. 27.4 and Fig. 27.5).⁵

Alteration in the density of sub-basal nerves has been shown to alter the concentration of several neuromediators and growth factors on the ocular surface.6,7 These neuromediators contribute to the homeostatic cycle that maintains a healthy ocular epithelial surface, in addition to altering tear production rate. These include substance P, calcitronin gene-related peptide, neuropeptide Y, vasoactive intestinal peptide, galanin, methionine-enkephalin and acetylcholamine.^6–8

Deficiencies in such mediators have been shown to reduce mitosis rates in epithelial cells, leading to epithelial thinning and surface breakdown. Limbal stem cells fail to replace central epithelium, leading to a persistent epithelial defect. There is also a reduction in microvilli on the epithelial surface, resulting in poor tear adherence to the cornea.¹ Tear composition is also altered by a reduction in goblet cell density within the conjunctival epithelium.⁹

Nerve growth factors (NGF) are a family of circulating mediators that are known to be essential for development and maintenance of both sympathetic and sensory nerves. NGF has also been shown to play a role in the production of acetylcholine and substance P.¹⁰ The cornea and conjunctiva are known to possess specific NGF receptors and it is likely that it plays a multifactorial role in maintaining normal corneal nerve density and preservation of the epithelium.¹¹ NGF and neuromediators have been the target for several therapeutic agents for neurotrophic keratopathy.

Clinical Presentation

Neurotrophic keratopathy (NK) can present with varied clinical signs. Groos divided the clinical sings into three stages (Box 27.2).¹² Stage 1, the least severe, is characterized by punctate keratopathy, altered tear viscosity with shorter tear break time, peripheral corneal vascularization and punctate staining of the palpebral conjunctiva. Stage 2 is characterized by a compromised corneal epithelial surface, with the defect often bordered by edematous and loose epithelium that forms a smooth edge. Compromise of the epithelium can also lead to stromal edema and visible folds in Descemet’s membrane (Fig. 27.6 – Fig. 27.8