Major reviewCorneal nerves in health and disease
Introduction
The cornea is the most densely innervated structure in the human body. In 1831, Schlemm discovered nerves in the cornea. Prior to this discovery, the cornea was thought to be entirely without nerves. Several years after Schlemm's original observation, Bochdalek dissected the ciliary nerves within the cornea and found that they divided into corneal and iris branches and that the corneal nerves entered at the anterior thickness.27, 196 Corneal nerves are responsible for sensations of touch, pain, and temperature and play an important role in blink reflex, wound healing,26 and tear production and secretion.86, 169 Numerous studies have established that corneal nerve dysfunction is a frequent pathobiological feature of corneal diseases that cause opacities and result in blindness. Approximately 285 million people worldwide suffer from impaired vision; of these, 2.85 million have corneal opacities.176 Likewise, of the 39.3 million people worldwide who are blind, in 1.57 million this is the result of corneal opacities.176 In conditions that cause corneal blindness, sensation is frequently diminished or absent because of nerve dysfunction or degeneration. Several infectious and noninfectious inflammatory corneal diseases can lead to lost or compromised innervation and result in neurotrophic keratopathy and blindness.50, 214 Although the sub-basal nerve density is variably reduced in these inflammatory corneal diseases,22, 50, 214, 217 the number of antigen-presenting dendritic cells is increased,50, 214 suggesting that the immune and nervous system pathways in the cornea are intertwined.
Despite the high prevalence of corneal blindness and nerve dysfunction and the clinical need to promote corneal nerve regeneration in neurotrophic corneas, there are relatively few specific therapeutic interventions. Therefore, it is not surprising that the National Eye Institute (NEI) Cornea Disease Panel in its July, 2012, Vision Research: Needs, Gaps and Opportunities document highlights the need to develop novel agents capable of stimulating appropriate corneal nerve regeneration. Additionally, this panel has emphasized the importance of correlating the molecular and structural composition of corneal nerves with their function. These recommendations build upon those of the NEI Workshop on Ocular Pain and Sensitivity. This panel concluded that the role of neurons in the health, healing, scarring, and immunology of the cornea, as well as the responsible molecular and cellular mechanisms, has yet to be determined. Therefore, further understanding the molecular and cellular changes that occur in primary sensory neurons as a result of disease or trauma, including their regenerative mechanisms, constitute a high priority.
Section snippets
Corneal nerve anatomy
In the cornea, 50–450 sensory trigeminal neurons transmit nerve fibers via the ophthalmic division of the trigeminal nerve (cranial nerve V) and terminate in free nerve endings in the corneal epithelium.154 From trigeminal ganglion cells, nerve fibers travel suprachoroidally and branch to form nerve bundles that come to rest uniformly around the corneoscleral limbus to form the limbal plexus.5 Autonomic innervation may travel along with these nerve fibers, though it is believed to be scarce
Corneal diseases causing nerve dysfunction
Neurotrophic keratopathy can be caused by a variety of infectious agents–as well as congenital, ocular, and systemic diseases, pharmaceutical agents, trauma, and corneal dystrophies.A Sensory nerves in the cornea deploy afferent stimulation signals to the brain, which then returns an efferent signal; for example, to the lacrimal gland via autonomic nerves to drive tear production and secretion. When the cornea is damaged, these neural circuits are disrupted. Corneal nerve damage leads to
The link between inflammation and nerve regeneration pathways
Inflammation plays a key role in peripheral nerve regeneration.24 Corneal nerve regeneration and inflammation pathways appear to be intertwined (Table 4). Corneal nerve regeneration is enhanced by a γδ T cell–dependent inflammatory cascade that involves IL-17, neutrophils, platelets, and VEGF-A.125 A strong and significant correlation has been reported between increased numbers of dendritic-shaped cells of the central cornea and decreased sub-basal corneal nerves, suggesting a potential
Evidence-based treatment of neurotrophic corneal disease
Corneal nerves have complex interactions with resident cells (limbal stem cells, epithelium, and antigen-presenting cells) as well as bone marrow–derived inflammatory cells that migrate into the cornea. Corneal nerve dysfunction from injury or disease perturbs these interactions and leads to neurotrophic keratitis, characterized by reduced corneal sensation, epithelial defects, and corneal scarring. The pathways controlling corneal nerve regeneration molecularly link with pathways that control
Evidence-based treatment of corneal neuropathic pain
Neuropathic pain arises from damaged or dysfunctional sensory nerves. Patients with corneal neuropathic pain report dysesthesias perceived as ocular dryness or phantom pain.18 Receptors on free nerve endings in the corneal epithelium are implicated in neuropathic pain. Neuropathic pain may be triggered by damage, inflammatory cells, or extracellular chemicals such as glutamate that, through signaling cascades, increase receptor excitability and/or receptor expression.197 Corneal nerve injury or
Future directions
The role of neurons in the health, healing, scarring, and immunology of the cornea, as well as the responsible molecular and cellular mechanisms, have yet to be fully determined. Therefore, the molecular and cellular changes that occur in primary sensory neurons as a result of disease or trauma, including their regenerative mechanisms, constitute high priority needs, gaps, and opportunities in the field and require further study. Recent laboratory investigations have revealed additional corneal
Method of literature search
In preparing this review, we conducted a Medline and PubMed search of medical literature for the period between 1960 and 2013 using the following key words in various combinations: cornea, corneal nerves, nerve regeneration, neurotrophic keratitis, neurotrophic factors, platelet-rich plasma, autologous serum, umbilical cord serum, Alphagan, contact lens, corticosteroids, and minocycline. Individual molecules, disease processes, and surgical procedures as discussed in the review were also used
Disclosure
The authors have no disclosures to report.
Acknowledgments
We thank James Kubilus, PhD (Tufts University) for contributing to the section on corneal nerve development and Nitin K. Garg (University of Illinois at Chicago) for contributing to the literature search in the section on corneal surgeries causing nerve dysfunction.
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Supported by National Eye Institute (NEI) grants K08EY018874 and R01EY023656 (SJ), NEI core grant EY001792, and Research to Prevent Blindness.