Understanding the Pathogenesis of Neurotrophic Keratitis: The Role of Corneal Nerves

Abstract

Neurotrophic keratitis (NK) is a rare degenerative disease of the cornea caused by trigeminal nerve damage, which leads to loss of corneal sensitivity, corneal epithelium breakdown, and poor healing. Though extremely uncommon, NK is increasingly recognized for its characteristics as a distinct and well-defined clinical entity rather than a rare complication of various diseases that can disrupt trigeminal innervation. Indeed, the defining feature of NK is loss of corneal sensitivity, and its clinical findings do not correlate with the wide range of systemic or ocular conditions that underlie trigeminal nerve damage. Despite increasing awareness of NK as a distinct condition, its management continues to be challenged by the lack of treatments that target nerve regeneration. This review focuses on the role of corneal nerves in maintaining ocular surface homeostasis, the consequences (such as alterations in neuromediators and corneal cell morphology/function) of impaired innervation, and advances in NK diagnosis and management. Novel therapeutic strategies should aim to improve corneal innervation in order support corneal renewal and healing. J. Cell. Physiol. 232: 717-724, 2017. © 2016 Wiley Periodicals, Inc.

Corneal myofibroblasts inhibit regenerating nerves during wound healing

“…Despite its clinical relevance, our knowledge about corneal nerve regeneration following injury and diseases such as neurotrophic keratitis remains sub-optimal 10 . Many studies have demonstrated interplay between immune cells and corneal nerves (e.g.…”

Neprilysin inhibition promotes corneal wound healing

“…When comparing corneal resurfacing in WT animals to those with constitutive loss of NEP activity, a potential confounding factor is the increased density of corneal innervation observed in NEP −/− mice. Because corneal nerves produce epitheliotrophic factors that promote physiological renewal as well as wound healing 43 – 45 , accelerated corneal wound healing in NEP −/− mice may be related to increased innervation at baseline. However, pharmacologic NEP inhibition with thiorphan also promoted epithelial recovery in WT mice within one week of corneal injury, an interval too brief for extensive reinnervation.…”

Drug Treatment of Corneal Neuropathies: Mini Review

“…Several excellent recent reviews [6][7][8][9] indicate that a large number of endogenous regulators are involved in regeneration of damaged corneal nerves ( Figure 3A). These corneal neurotrophins, guidance factors, inflammatory mediators, and hormones are important because they have been, or may be considered in the future, as the biochemical basis for drugs promoting nerve regeneration.…”

“…Since systemic treatments (subcutaneous injection, intracerebro-ventricular infusion) were associated with hyperalgesia and back pain, current efforts have been directed towards gene therapy or topical application of NGF. Possibly one of the best studied has been the use of topical NGF against neurotrophic keratitis (NK) [8].…”