The cornea is the most densely innervated part of the body.^1,2

Corneal innervation derives from the ophthalmic branch (V1) of the trigeminal nerve (CN V).³

Lesions may occur anywhere along the course of the corneal innervation pathway including the pons, the trigeminal (gasserian) ganglion, the ophthalmic branch, the nasociliary nerves, and the long ciliary nerves.

Despite corneal nerve density, the cornea is supplied by relatively few trigeminal neurons as a single neuron may support hundreds of individual nerve endings.^4,5,6

The corneal innervation is divided into three networks: stromal, sub-basal, and epithelial.^7,8

Corneal sensation is a necessary component of reflexive tearing and blinking, which prevent corneal injury.

Pain ordinarily would prompt patients to seek appropriate treatment after corneal injuries; however, an insensate cornea leaves patients unaware of their corneal injury.

Repetitive corneal epithelial injury and ulceration cause corneal scarring and vision loss.^9,10,11

Corneal nerves also contain neuromediators that promote corneal epithelial maintenance and repair.^3,11

Immediately following corneal denervation, animal models show decreases in epithelial cell vitality and mitosis, resulting in thinning, breakdown, and ulceration of the corneal epithelium.^12,13,14,15

Neurotrophic keratopathy is one of the most difficult ocular diseases to treat.¹

Prognosis is dependent on the severity of corneal hypoesthesia and the presence of other concomitant ocular disorders such as dry eye disease, exposure keratopathy, and corneal limbal stem cell deficiency.

Patients require lifelong treatment and even with optimal management many develop vision loss and blindness in the affected eye.

Inflammation and repeated corneal injury may also result in neovascularization of the cornea, further impeding vision.

Patients typically present with persistent asymptomatic corneal epithelial defects.

Neurotrophic keratopathy is classified into three stages depending on clinical findings based on the Mackie classification¹:

Diagnosis is based on clinical findings and a patient history of corneal hypoesthesia or anesthesia with delayed healing and persistence of corneal epithelial defects.^16,17

Slit lamp: identifies corneal epithelial abnormalities, including diffuse staining with fluorescein, epithelial sloughing, and stromal neovascularization.

Corneal esthesiometry: measures corneal sensation. This can be performed with a Cochet-Bonnet aesthesiometer (Luneau, France) by a skilled ophthalmologist.

Schirmer test: used to diagnose concomitant dry eye disease, when needed.

In vivo corneal confocal microscopy (IVCCM): documents the absence of corneal nerve fibers.

The goals of treatment are to prevent corneal ulceration and promote epithelial healing when ulcerations occur.^1,16,17

If a corneal perforation is suspected, then cyanoacrylate glue or keratoplasty (cornea transplant) may be indicated.

Exacerbating conditions, such as exposure keratopathy and limbal stem cell deficiency, should be treated.

Experimental treatments for persistent ulcerations include topical IGF-1, substance P, or nerve growth factor (NGF).^18,19,20,21