Corneal nerves in health and disease

Abstract

Corneal nerves are responsible for the sensations of touch, pain, and temperature and play an important role in the blink reflex, wound healing, and tear production and secretion. Corneal nerve dysfunction is a frequent feature of diseases that cause opacities and result in corneal blindness. Corneal opacities rank as the second most frequent cause of blindness. Technological advances in in vivo corneal nerve imaging, such as optical coherence tomography and confocal scanning, have generated new knowledge regarding the phenomenological events that occur during reinnervation of the cornea following disease, injury, or surgery. The recent availability of transgenic neurofluorescent murine models has stimulated the search for molecular modulators of corneal nerve regeneration. New evidence suggests that neuroregenerative and inflammatory pathways in the cornea are intertwined. Evidence-based treatment of neurotrophic corneal diseases includes using neuroregenerative (blood component-based and neurotrophic factors), neuroprotective, and ensconcing (bandage contact lens and amniotic membrane) strategies and avoiding anti-inflammatory therapies, such as cyclosporine and corticosteroids.

Keywords: corneal nerves; inflammation; nerve regeneration; neuropathic pain; neurotrophic keratitis.

Figure 1

Three-dimensional schematic of human corneal nerves. Stromal nerve bundles traverse Bowman’s membrane to form the subbasal nerve plexus and innervate the epithelium. Unmyelinated nerve fibers (blue) bifurcate, and are composed of several straight (red) and beaded (green) nerve fibers. Beaded fibers branch orthogonally to terminate in free nerve endings in the anterior epithelium. Adapted from Müller et al. Copyright Association for Research in Vision and Ophthalmology.

Figure 2

Corneal nerves during development. A) Formation of the chick pericorneal nerve ring at embryonic day 6 (E6). Fluorescence image with brightfield overlay. B) Completion of the chick pericorneal nerve ring and subsequent penetration of corneal nerves into the stroma at E8. Fluorescence image only. Scale bar for A and B: 1 mm. Courtesy of Dr. James K. Kubilus, Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, MA.

Figure 3

In vivo imaging of corneal nerves. A) Heidelberg Retina Tomograph II with Rostock Corneal Module optical coherence tomography showing corneal nerves traversing Bowman’s membrane (BM) to innervate the epithelium (Epi). Arrows point to nerves in the BM area. B and C) Nidek ConfoScan 4 slit-scanning confocal microscopy showing parallel nerves of the subbasal nerve plexus (B) and branching thick nerves of stroma (C). Courtesy of Heidelberg Engineering, Inc. and Nidek, Inc.

Figure 4

In vivo maximum intensity projection image of fluorescent nerves in the normal thy1-YFP mouse cornea. A stromal network is formed by thick nerve trunks that traverse the cornea, branching frequently (white arrowheads) and anastomosing with adjacent nerve trunks. A second network is formed by thinner subbasal hairpin-like nerves that project centripetally and run roughly parallel to one another. The subbasal nerves arise from the stromal nerve trunks at variable distances from the periphery (black arrows indicate more peripheral origins and white arrows more central origins) and terminate as free nerve endings. In some corneas, the subbasal nerves show swirling at the corneal apex (black arrowhead). Intraepithelial nerves are not resolved with the stereo fluorescence microscope at the magnification used. Scale bar A, 500 μm; B, 250 μm.

Figure 5

Clinical photograph of a patient with neurotrophic keratitis. A) A central epithelial defect is surrounded by corneal haze. B) Fluorescein stains the central epithelial defect and reveals extensive superficial punctate keratitis.

Figure 6

Subbasal nerves before and after LASIK. Heidelberg Retina Tomograph II with Rostock Corneal Module optical coherence tomography showing subbasal corneal nerves A) before LASIK, and B) regenerated nerve loops in the flap area 4 years postoperatively. Courtesy of Heidelberg Engineering, Inc. and Dr. E.M. Messmer, Munich, Germany.

Figure 7

Clinical photograph of a patient with LASIK-induced neurotrophic epitheliopathy (LINE). Superficial punctate keratitis stained with fluorescein is limited to the flap area of the cornea.