Neurotrophic Keratitis: A Comprehensive Guide

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May 10, 2022
22 min read
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Neurotrophic Keratitis: A Comprehensive Guide

Neurotrophic keratitis (NK) is a degenerative disease caused by damage to the nerves responsible for trigeminal sensory innervation of the cornea, leading to reduced or absent corneal sensation and a spontaneous breakdown of the corneal surface.1 Loss of nerve function results in reduced epithelial cell turnover, compromised wound healing, disrupted blinking and tearing, and painless, persistent corneal defects that can lead to permanent scarring and vision loss when left untreated.2 NK is relatively rare, affecting nearly 65,000 people in the U.S.,3 however this is likely an underestimate as the signs and symptoms in the early stages of NK can be subtle and easily overlooked or misattributed to other conditions.

Until recently, there were no treatments specifically for NK, which made managing the condition challenging even when diagnosed. However, in 2018, after receiving Priority Review, Breakthrough Therapy Designation, Fast Track Status, and classification as an orphan drug, Oxervate® (cenegermin-bkbj ophthalmic solution 0.002% (20 mcg/mL), Dompe U.S. Inc.) received FDA-approval as the first medication indicated for the treatment of NK.4 Additionally, Oxervate® is the first topical biological medication approved for ophthalmic use, as well as the first application of human nerve growth factor as a therapeutic treatment,5 making it an incredible innovation in eye care. This development has fundamentally changed the treatment landscape for NK and placed an even greater importance on early recognition, diagnosis, and treatment of the disease.

Neurotrophic keratitis is a degenerative disease of the cornea caused by damage to the sensory nerves that results in a loss of sensation and a subsequent breakdown of the corneal surface.

Figure 1. Neurotrophic keratitis is a degenerative disease of the cornea caused by damage to the sensory nerves that results in a loss of sensation and a subsequent breakdown of the corneal surface.

What are the roles of the corneal nerves?

The cornea is a highly organized tissue that requires precise homeostatic balance to provide visual function and protection for the eye. The cornea is avascular by necessity to allow for optical clarity, which means it relies heavily on the corneal nerves for nourishment and metabolic support.6,7 This is likely one of the reasons the cornea is the most densely innervated structure in the body with nearly 7,000 nerve endings for square millimeter.6,8,9 This innervation is directly and indirectly responsible for several critical functions of the cornea including sensation,6 routine epithelial cell turnover,10 wound healing,6 blinking,2 lacrimation,11,12 and maintenance of ocular surface homeostasis.6 Therefore, healthy nerve function is critical to maintaining corneal integrity and an environment conducive to optimal ocular surface health.

What happens if the nerves are damaged?

However, if the corneal nerves are damaged there is a breakdown of corneal surface integrity and function. The majority of corneal nerves originate from the ophthalmic branch of the trigeminal nerve,9 so injury to the nerve fibers at any point along this pathway can disrupt nerve function, even damage at the sensory trigeminal nuclei located in the midbrain. Corneal nerve damage diminishes corneal sensation and interrupts trophic support to the rest of the tissue causing epithelial irregularity, disrupted cell turnover, impaired healing, and altered blinking and lacrimation.11,12 Ultimately, these changes compromise the integrity of the corneal surface and lead to nonhealing epithelial defects and ulcers, and even corneal scarring and perforation.2

What causes NK?

There are many potential sources of damage to the corneal nerves and trigeminal pathway including infection, ocular surface disease, injury, systemic disease, medication use, and surgical trauma. Likely the most common source of NK is herpetic infections involving Herpes Simplex and Herpes Zoster.13 Both viruses remain dormant in sensory nerve ganglia, including the trigeminal ganglion14,15 where their presence and reactivation can damage sensory nerves resulting in NK. Chronic ocular surface disease, such as dry eye and exposure keratitis, can also lead to nerve impairment,2 as can injury, especially chemical exposure directly to the ocular surface.16 Damage related to contact lens wear and misuse is another common cause, as chronic hypoxia and microtrauma can induce NK.16

Ocular surgeries are another source of nerve damage. In LASIK and other refractive surgeries, the corneal nerves are directly severed or damaged, either through flap creation or the ablation process.17 Likewise, the corneal nerves are severed during corneal transplantation procedures including penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK).18,19 The corneal nerves can also be injured in other ocular surgeries, including retinal procedures like retinal detachment repair.20,21 Non-ocular surgeries, such as ablative procedures to treat trigeminal neuralgia and tumor removal, may also cause NK22. Iatrogenic nerve damage can be seen in conditions like glaucoma, in which chronic exposure to preservatives like benzalkonium chloride (BAK) occurs with long-term topical drop use.23 The use of timolol and betaxolol, specifically, have been associated with the development of NK, as has use of topical NSAIDs like diclofenac.16,24,25 Similarly, the abuse of topical anesthetics can result in NK.16,24,25

Other causes of NK include systemic diseases that affect the nerves, such as diabetes and multiple sclerosis,2,26 while genetic and congenital conditions like Riley-Day syndrome, Goldenhar-Gorlin syndrome, Moebius syndrome, and familial corneal hypoesthesia may cause NK as well.1 Diabetes is especially a concern, as it is reaching epidemic levels,27 and its propensity to cause peripheral neuropathy confers a risk for NK development, creating a large population at risk for the disease. Additionally, a tumor or aneurysm can lead to compressive injury of the nerves of the trigeminal pathway, while a stroke can cause ischemic damage, which can also result in NK.2,28

What are the signs and symptoms of NK?

The signs and symptoms of NK are directly related to disrupted nerve function and the associated breakdown of the corneal surface. Depending on the signs present, the condition is categorized into one of three stages based on the Mackie Classification System.28 However, the finding that is diagnostic of NK is reduced or absent corneal sensation, which occurs at all stages1,16. Patients may also exhibit conjunctival injection, photophobia, epiphora, tear film dysfunction, and neovascularization at any stage.28-30 Furthermore, NK is degenerative, so if left untreated it will likely progress from a mild to severe stage, making early detection and treatment critical.

Stage 1, mild NK, consists of epithelial disruption which can exist as epithelial irregularity or superficial punctate epithelial keratopathy.28 Symptomatically, these patients may have complaints similar to dry eye including difficulty with prolonged computer use or light sensitivity.

Figure 2.  Stage 1 – Mild NK

Figure 2. Stage 1; mild NK.

Stage 2, moderate NK, involves the presence of nonhealing, persistent epithelial defects (PEDs).28

Stage 2, moderate NK, involves the presence of nonhealing, persistent epithelial defects (PEDs).

Figure 3. Stage 2, moderate NK.

Stage 3, severe NK, includes corneal ulceration with stromal involvement.28 At this stage the patient is at risk for stromal melting, perforation, and scarring that may permanently impact vision.28 In some cases, an anterior chamber reaction with hypopyon formation can occur.28