Published in Ocular Surface

The Ultimate Guide to Neurotrophic Keratitis

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Gain a thorough understanding of the etiology of neurotrophic keratitis and what options are available to optometrists to treat the condition.
The Ultimate Guide to Neurotrophic Keratitis
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

Overview of neurotrophic keratitis

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.2 NK is relatively rare, affecting only approximately 65,000 people in the US.3 This number, however, is likely an underestimate as the signs and symptoms in the early stages of NK can be subtle and easily overlooked—or even misattributed to other conditions.
Until recently, there were no treatments specifically for NK, which made managing the condition challenging even when diagnosed. However, Oxervate (cenegermin-bkbj ophthalmic solution 0.002% (20 mcg/mL)) received FDA approval in 2018 as the first medication indicated for the treatment of NK.4 This development has changed the treatment landscape for NK and placed even greater importance on early recognition, diagnosis, and treatment of the disease.
Figure 1 is a clinical image of a patient with neurotrophic keratitis.
Neurotrophic Keratitis
Figure 1: Courtesy of Cory Lappin, OD, MS, FAAO

What role do corneal nerves play?

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 per 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 corneal nerves are damaged?

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 and even cause damage to 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, altered blinking, and lacrimation.11,12 Ultimately, these changes compromise the integrity of the corneal surface and lead to non-healing epithelial defects and ulcers and potentially more serious corneal scarring and perforation.2

What causes neurotrophic keratitis?

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 ganglion,14,15 where their presence and reactivation can damage sensory nerves resulting in NK.

Chronic ocular surface diseases, 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 NK.22

Understanding systemic causes of neurotrophic keratitis

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 the 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, including diabetes and multiple sclerosis.2,26 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 neurotrophic keratitis?

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 stages.1,16
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.
Figure 2 highlights Stage 1, mild NK, which consists of epithelial disruption, and 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.
Stage 1 Neurotrophic Keratitis
Figure 2: Courtesy of Cory Lappin, OD, MS, FAAO.
Figure 3 depicts stage 2, moderate NK, which involves the presence of nonhealing, persistent epithelial defects (PEDs).28
Stage 2 Neurotrophic Keratitis
Figure 3: Courtesy of Cory Lappin, OD, MS, FAAO.
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
Figure 4 highlights a patient with Stage 3 neurotrophic keratitis.
Stage 3 Neurotrophic Keratitis
Figure 4: Courtesy of Cory Lappin, OD, MS, FAAO.
At Stages 2 or 3, vision may be significantly impacted if an epithelial defect or ulcer occurs centrally. Corneal edema can be present as well.28 The PEDs and ulcers present in NK tend to exhibit smooth, rolled edges, which are characteristic of NK.28
Due to reduced or absent corneal sensation, any corneal defect present will often be painless, even significant PEDs and ulcers; this serves as another defining feature of NK. This phenomenon lends itself to the phrase “stain without pain,” as these lesions will stain with vital dyes, sometimes dramatically, but the patient will exhibit little or no pain in proportion to their clinical signs. This is the reason some NK patients are completely asymptomatic.

Screening for and diagnosing NK

As stated previously, the ultimate diagnosis of NK is based upon a reduction or absence of corneal sensitivity, which is pathognomonic for the disease.1,16 Therefore, the key to diagnosing NK is sensitivity testing, especially as the signs and symptoms of NK in its early stage can be subtle and nonspecific and mirror other conditions, like dry eye. While corneal sensitivity testing is essential for diagnosing NK, there are several ways this testing can be performed.
The Cochet–Bonnet aesthesiometer is the gold standard for measuring corneal sensitivity; however, several items commonly found in any clinic can be used to quickly and easily assess nerve function. Some of the most frequently used items include the tip of a tissue, a wisp made from the tip of a cotton tip applicator, or dental floss. Sensitivity is tested by touching the implement to the corneal surface and assessing the patient’s response. If the patient noticeably blinks or recoils, that indicates normal sensation. If the patient barely feels the touch or feels nothing, even with greater applied pressure, this indicates reduced or absent sensation.
As this is a qualitative test, it is recommended that eyecare providers (ECPs) practice sensitivity testing on patients with normal corneal sensitivity to establish a baseline for a normal testing response. Sensitivity can be classified as normal, reduced, or absent, and sensation can be assessed at one location or in multiple areas of the cornea, based on practitioner preference.

Sensitivity testing must be performed prior to the instillation of any topical anesthetic and, ideally, prior to the instillation of any topical drop. If topical anesthetic has been applied before testing could be performed, it is recommended that the patient return at another time for testing.

Figure 5 shows a patient being screened for neurotrophic keratitis by assessing with a cotton-tipped applicator the presence of reduced or absent corneal sensitivity.
Screening for Neurotrophic Keratitis
Figure 5: Courtesy of Cory Lappin, OD, MS, FAAO.

What are the treatments for neurotrophic keratitis?

The treatment options for NK range from surface lubrication to surgical intervention, depending on severity. Artificial tears, autologous serum, soft bandage contact lenses with antibiotic coverage, and amniotic membranes can all be used in the management of NK.2,29 Topical steroids and NSAIDs should be avoided as they impede healing and increase the chance of corneal melting.1,31-33
The goal of these treatments is to stabilize the ocular surface and prevent progression. Likewise, surgical procedures, such as tarsorrhaphy or a conjunctival flap, are used in advanced cases with significant corneal degeneration to protect the corneal surface and prevent further breakdown.2,29 Any existing comorbidities, such as dry eye, should also be addressed, especially if they were a causative factor in the initial development of NK.
However, none of these treatments address the underlying cause of NK. There is currently only one treatment on the market that targets the underlying cause of NK by repairing damaged nerves and restoring their function, which in turn restores corneal surface integrity.34

Using Oxervate to treat neurotrophic keratitis

Cenegermin-bkbj, the active ingredient in Oxervate, is a recombinant form of human nerve growth factor (rhNGF), which is structurally identical to endogenous NGF found in ocular tissue.35 Oxervate is the first topical biological medication approved for ophthalmic use, as well as the first application of hNGF as a therapeutic treatment.5
NGF is naturally produced by the corneal epithelium, keratocytes, and the lacrimal gland,36,37 and is a critical component to the maturation and maintenance of the corneal nerves and the overall health of the cornea.2,6,10 NGF is also capable of repairing and regenerating damaged nerves and enhancing corneal epithelium proliferation and wound healing,10,36 through binding to high-affinity TrkA, and low-affinity p75NTR NGF receptors.34
Additionally, NGF helps maintain a healthy ocular surface environment by stimulating tear production through the lacrimal gland and ensuring proper blinking through the maintenance of corneal innervation and sensation, both of which are critical components of tear film stability.2,10

Results of the REPARO study

The REPARO study was a large combined population study of patients with NK, and included a diverse subject pool, with subject ages ranging from 2 years old to over 65 and with varying etiologies of NK.38,39
The study specifically looked at Stages 2 and 3 of NK, meaning all subjects enrolled had PEDs or ulceration. The patients in the study received Oxervate six times per day for 8 weeks, and at the end of this period, 72% of subjects demonstrated complete healing, which was defined as no staining, meaning their epithelial lesions were completely resolved.39 And at a 48-week follow-up, nearly 80% of these patients displayed sustained healing, demonstrating that Oxervate provides robust, lasting recovery for patients affected by NK.39
Although the trial only looked at Stages 2 and 3, Oxervate is approved for the treatment of all stages of NK,40,41 so ideally, NK patients will be identified at Stage 1 when the condition is mild, and treatment initiated before it progresses. Because Oxervate is an orphan drug with a very specific indication, the prescribing process is slightly different than for the typical medication. Oxervate is prescribed through the Dompé CONNECT to Care program, which works with several organizations and foundations that help provide financial assistance.

Oxervate is dosed six times per day (every 2 hours) for 8 weeks. If the patient is a contact lens wearer, contact lenses should be removed prior to drop instillation. Patients using Oxervate are often seen at 4-week intervals corresponding to the halfway point of treatment, the end of treatment, and 1-month post-treatment, with further follow-ups determined by their presentation at that time.

What are the side effects of Oxervate?

There are no contraindications to the use of Oxervate.44 The most common side effect is eye pain, which occurs in about 16% of cases.34 This discomfort can be mild to moderate, and it is helpful to discuss this potential side effect ahead of time and to reassure patients that it is normal and a sign the medication is working, as they are regaining sensation in their nerves.
Other less common side effects include hyperemia, inflammation, epiphora, foreign body sensation, and corneal deposits (1 to 10% of patients).34 These side effects, along with ocular pain, are usually mild and transient.39,45 Oxervate is safe to use in patients as young as 2 years of age. There are no safety data for Oxervate when used during pregnancy or nursing, but animal models showed no adverse effects when used during these periods.44


Neurotrophic keratitis is frequently underdiagnosed, and there exist few treatment options compared to other ocular surface diseases. However, there are options for patients, especially when diagnosed early.
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Cory J. Lappin, OD, MS, FAAO
About Cory J. Lappin, OD, MS, FAAO

Dr. Cory J. Lappin is a native of New Philadelphia, Ohio and received his Bachelor of Science degree from Miami University, graduating Phi Beta Kappa with Honors with Distinction. He earned his Doctor of Optometry degree from The Ohio State University College of Optometry, where he concurrently completed his Master of Science degree in Vision Science. At the college he served as Class President and was a member of Beta Sigma Kappa Honor Society. Following graduation, Dr. Lappin continued his training by completing a residency in Ocular Disease at the renowned Cincinnati Eye Institute in Cincinnati, Ohio.

Dr. Lappin has been recognized for his clinical achievements, receiving the American Academy of Optometry Foundation Practice Excellence award. He has also been actively engaged in research, being selected to take part in the NIH/NEI T35 research training program and receiving the Vincent J. Ellerbrock Memorial Award in recognition of accomplishments in vision science research.

Dr. Lappin practices at Phoenix Eye Care and the Dry Eye Center of Arizona in Phoenix, Arizona, where he treats a wide variety of ocular diseases, with a particular interest in dry eye and ocular surface disease. He is a Fellow of the American Academy of Optometry, a member of the American Optometric Association, and serves on the Board of Directors for the Arizona Optometric Association. He is also a member of the Tear Film and Ocular Surface Society (TFOS) and volunteers with the Special Olympics Opening Eyes program.

Cory J. Lappin, OD, MS, FAAO
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