Corneal Nerve Fiber Structure, Its Role in Corneal Function, and Its Changes in Corneal Diseases

Abstract

Recently, in vivo confocal microscopy is used to examine the human corneal nerve fibers morphology. Corneal nerve fiber architecture and its role are studied in healthy and pathological conditions. Corneal nerves of rats were studied by nonspecific acetylcholinesterase (NsAchE) staining. NsAchE-positive subepithelial (stromal) nerve fiber has been found to be insensitive to capsaicin. Besides, NsAchE-negative but capsaicin-sensitive subbasal nerve (leash) fibers formed thick mesh-like structure showing close interconnections and exhibit both isolectin B4- and transient receptor potential vanilloid channel 1- (TRPV1-) positive. TRPV1, TRPV3, TRPA (ankyrin) 1, and TRPM (melastatin) 8 are expressed in corneal nerve fibers. Besides the corneal nerve fibers, the expressions of TRPV (1, 3, and 4), TRPC (canonical) 4, and TRPM8 are demonstrated in the corneal epithelial cell membrane. The realization of the importance of TRP channels acting as polymodal sensors of environmental stresses has identified potential drug targets for corneal disease. The pathophysiological conditions of corneal diseases are associated with disruption of normal tissue innervation, especially capsaicin-sensitive small sensory nerve fibers. The relationships between subbasal corneal nerve fiber morphology and neurotrophic keratopathy in corneal diseases are well studied. The recommended treatment for neurotrophic keratopathy is administration of preservative free eye drops.

Figure 1

A putative architecture and distribution pattern of corneal nerve fibers of rats in normal (a) and their alterations after neonatal capsaicin treatment (b). Thick stromal subepithelial nerve fiber plexus are reactive to NsAchE. The NsAchE-positive (+) nerve plexus (indicated in blue) are resistant to capsaicin. On the other hand, NsAchE-negative (−) nerve fiber bundles showing dense interconnections (meshwork structure) reactive to neuropeptides and IB4 or TRPV1 seem to be subbasal leash fibers in rats cornea (indicated in orange). They are assumed to be destroyed (especially in the central portion) after neonatal capsaicin treatment (b), but NsAchE (+) nerves are never influenced by capsaicin. Probably, capsaicin-sensitive neurotrophic peptidergic nerve fibers are destroyed by neonatal capsaicin treatment resulting in the defect of epithelial cells (neuroparalytic keratitis) and desensitization to chemical or thermal stimuli. BEP: basal epithelial plexus of leash fibers, BL: Bowman's layer, DEC: defect of epithelial cells, and SEP: subepithelial (stromal) plexus.

Figure 2

Stage 1 neurotrophic keratopathy (NK). Slit lamp microscope image stained by fluorescein. Superficial punctate keratitis (indicated by white arrows) occurred in a diabetic patient.

Figure 3

Stage 2 persistent epithelial defect (PED). Slit lamp microscope image (a). PED is located in the center of the cornea with cloudy stroma. Fluorescein staining image (b). The rolled edge of the PED can be seen.

Figure 4

PED due to brain surgery and diabetes followed by infectious keratitis. The corneal epithelial disorder by NK led to methicillin-resistant Staphylococcus aureus keratitis (this picture is presented under the permission of Medical View Co., Ltd.).