Pearls for the treatment of patients with neurotrophic keratitis

(image Credit: AdobeStock/rh2010)

Neurotrophic keratitis (NK) is a degenerative corneal disease caused by impairment of corneal sensory innervation. A reduction in corneal sensitivity or complete corneal anesthesia is the hallmark of this disease and is responsible for producing epithelial keratopathy, ulceration, and perforation.

It can be easily diagnosed, but management of the disease can be a challenge.

It leads to epithelial breakdown, impairment of healing, and ultimately the development of corneal ulceration, melting, and perforation.

Neurotrophic keratitis

Early NK may be asymptomatic, but patients with more advanced NK experience light sensitivity, ocular discomfort—despite reduced corneal sensitivity—epithelial breakdown, progressive scarring, and poor visual outcomes.^1-3

In healthy eyes, corneal nerves, which stem from the trigeminal nerve, help maintain corneal health and ocular surface homeostasis by relaying sensory information from the cornea and stimulating responses such as blinking and tear production.^2,3 Sensory information from corneal nerves also regulates the secretion of trophic factors, which promote healing and epithelial cell regeneration.

In NK, insufficient corneal innervation—whether from corneal nerve damage, congenital abnormalities, or other causes—leads to reduced sensitivity and corneal epithelial maintenance.² Eyes with NK are more susceptible to corneal microtrauma, epithelial breakdown, impaired healing, and vision-altering corneal ulceration and perforation.³

Trigeminal nerve injury due to herpes viral infection is the most common cause of NK, particularly herpes simplex virus or herpes zoster (shingles) keratoconjunctivitis.^3-5 NK can also be induced by a host of conditions including ocular trauma, abnormal or absent nerve development, diabetes, chronic dry eye syndrome, neurosurgery, and autoimmune disease.³

Diagnosing NK

Diagnosis of NK typically relies on a combination of patient history analysis and ocular examination.⁶ A careful review of a patient’s history may reveal events or comorbidities that could cause corneal nerve damage, such as prior herpes virus infection, corneal surgery, neurosurgery, or dry eye syndrome. At the slit lamp biomicroscope, NK appears as an abnormal or nonhealing corneal epithelium. Combining these morphological findings with reduced corneal sensitivity defines NK.

Corneal sensitivity can be assessed qualitatively or quantitatively. The most simple qualitative test is to gently touch the cornea with the tip of a cotton swab and look for a blink reflex or patient report on feeling the swab.

A more quantitative but still subjective assessment uses a Cochet-Bonnet aesthesiometer; while a small nylon wire’s tension is varied, the patient reports whether they can feel the wire touching their cornea. A patient with reduced corneal sensitivity can only feel the wire at shorter lengths when it is more rigid. Subjective diagnostic approaches, however, can sometimes be inaccurate, particularly when the cornea is heavily damaged by scar tissue, which can interfere with sensation despite normal corneal innervation.

A more objective approach is to image the cornea using in vivoconfocal microscopy, then count the number of corneal nerves in a given area. Reduced nerve density and a lack of nerves are hallmarks of NK.⁶

Treating NK

Because of the complicated biology of corneal nerves and the surrounding tissue, NK has been described as one of the most difficult ocular diseases to treat.¹ Traditionally, NK treatment has focused on supportive measures rather than disease-modifying treatment.³ Upon diagnosis, it is essential to first address the damaged corneal epithelium to initiate healing and prevent further tissue degeneration. Common methods for stabilizing the corneal epithelium include topical antibiotics for corneal ulcers, preservative-free artificial tears for lubrication, serum tears, and bandage contact lenses for protecting nonhealing epithelia. Tarsorrhaphy can also promote corneal healing, particularly in cases with persistent epithelial defects.¹

Stabilizing the corneal epithelium, however, only provides short-term relief; without proper innervation, the corneal epithelium will soon degenerate again. The next step focuses on treating corneal nerve damage.

The first line of treatment is a 2-month course of topical cenegermin (Oxervate). Cenegermin contains a recombinant human nerve growth factor that supports corneal epithelial cell growth and reinnervation.^7,8 In clinical trials, the majority of patients with NK experienced complete corneal healing after 2 months of cenegermin therapy, although data on changes in corneal sensitivity were mixed.^7,9 In practice, cenegermin is more effective in mild cases of NK; for patients with severe disease, the only rehabilitative treatment is corneal neurotization surgery. Corneal neurotization aims to correct the underlying problem by stimulating corneal nerve regeneration, providing long-term benefits for patients, and reducing recurrence rates.^3,10

Corneal neurotization

Corneal neurotization helps reinnervate the cornea in eyes with NK by transferring a healthy donor nerve segment to the affected eye, called coaptation. The exact technique used in corneal neurotization varies by patient, including direct transfer of ipsilateral sensory nerve and indirect transfer via an interpositional nerve graft.³ Often, the donor nerve is the ipsilateral or contralateral supraorbital, supratrochlear, infraorbital, or great auricular nerves.^3,11

Corneal neurotization has a high success rate, with the majority of patients showing reduced epithelial defects and improved corneal innervation beginning as early as within the first 6 months.^3,11,12 Significantly, some degree of corneal sensation often returns after surgery, which is not typically associated with topical nerve growth factor treatment.³

In cases with more severe corneal scarring, corneal neurotization also stabilizes the existing cornea so that follow-up procedures, such as penetrating keratoplasty, may be performed. Additionally, corneal reinnervation following corneal neurotization increases trophic factor levels in the tissue,¹³ which supports healing after corneal transplant and facilitates a higher rate of transplant success.^3,14

There are multiple ways to approach corneal neurotization,³ and it is important to carefully assess which technique best fits the patient to ensure successful outcomes. Factors to consider include donor nerve sensory function, size, and proximity to the recipient cornea.³ Typically, the easiest choice is an ipsilateral nerve, but a contralateral nerve can be used in some cases where the ipsilateral nerves are desensitized or underdeveloped.

Preoperative sensation testing can be done by systemically probing (eg, with a cotton swab tip) the regions on the face to identify feasible donor nerves. In cases that require nerve grafts, surgery should be carefully planned to ensure the harvested nerve is of sufficient length for the procedure, sometimes up to 10 to 15 cm.³ An alternative approach is to daisy-chain cadaveric nerve grafts to achieve the needed length.

Eyes with extensive ocular surface damage pose additional challenges during surgery. In some cases, the tissue is more difficult to dissect if it has already undergone multiple prior surgeries to manage conditions such as conjunctivitis or corneal scarring. Other challenges to corneal neurotization surgery include gaining approval for anesthesia and adequate patient adherence to postoperative care regimens. For the latter, it may be necessary to use temporary postsurgical tarsorrhaphy for a few weeks to protect the ocular surface and minimize any movement that may lead to complications.

Role of cryopreserved amniotic membrane

Since the introduction of corneal neurotization surgery, the surgical technique has been revised substantially. One of the revisions is the addition of cryopreserved amniotic membrane (CAM) to enhance the healing process. Derived from the placenta, CAM has natural anti-inflammatory, antiscarring, and proregenerative properties that promote tissue healing, and it serves as a protective film against mechanical damage.^15,16

The amniotic membrane contains a heavy-chain hyaluronic acid and the protein pentraxin 3, forming a complex (HC-HA/PTX3) that promotes neuronal survival and enhances neurogenesis.^17,18 Amniotic membranes can be preserved via dehydration, but dehydrated membranes do not retain the same degree of bioactive molecules as CAMs and have fewer anti-inflammatory and proregenerative properties.¹⁵ In the management of NK, I routinely use CAM before and during corneal neurotization.

The first use case is at the initial stage of treatment, when the cornea needs to be stabilized before surgery can proceed; I usually work with a cornea specialist to help optimize corneal and conjunctival health. In many cases, I will use a contact lens containing CAM (Prokera; BioTissue) to promote corneal healing and prevent further tissue degeneration. Other corneal stabilization methods include lubrication, bandage contact lenses, serum tears, cenegermin drops, or temporary tarsorrhaphy.

During surgery, I prefer to use umbilical cord CAM (UCAM) (AmnioGraft; BioTissue) because it is the thickest form of CAM, persists for several weeks, and has the highest content of HC-HA/PTX3 complex. To perform corneal neurotization, a donor nerve is coapted to a nerve graft (usually supraorbital or infraorbital nerve), and the other end of the graft is divided into fascicles, tunneled through the fornix under the bulbar conjunctiva, and secured around the corneal limbus. Here, it is critical that the nerve endings are covered by conjunctiva.

When the donor nerve and graft fascicles are sutured together during coaptation, I wrap UCAM around the nerve coaptation to reduce inflammation and promote nerve regeneration. UCAM also physically protects the coaptation from the surrounding tissue (eg, connective tissue and fat), which can interfere in the healing of the nerve.

Next, I layer the ocular surface with UCAM, covering the cornea, conjunctiva, and grafted nerve fascicles. By directly applying UCAM to the surgical site, bioactive molecules found in UCAM promote healing of the corneal surface, conjunctiva, and the axons coming through the nerve graft fascicles to innervate the cornea.^3,15 PTX3, in particular, has known neuro-regenerative properties.^19,20

After covering the ocular surface with UCAM, I place a temporary tarsorrhaphy and keep the eyelids sutured shut for 3 to 4 weeks, which is how long UCAM typically will last under these conditions. Following corneal neurotization, corneal reinnervation takes approximately 6 to 12 months, although corneal healing may occur more rapidly due to the UCAM treatment. In my experience, patching the ocular surface with UCAM is a major factor contributing to the success of corneal neurotization surgery by directly supporting corneal reinnervation
and healing.

Case study

A patient with NK caused by shingles viral infection initially presented with a severe opaque cornea and, essentially, total loss of functional vision in the eye (Figure, left). Prior attempts to improve the cornea failed, including an ineffective corneal transplant surgery. A successful corneal neurotization surgery was performed in the eye, and the corneal epithelium improved substantially within 6 months. At 18 months post surgery, the patient underwent a repeat penetrating corneal transplant, which resulted in favorable final vision in an eye that was previously blind (Figure, right).

The future of corneal neurotization surgery

Among the various therapeutic options for NK, corneal neurotization surgery may be the only curative treatment available.¹⁰ Since the first corneal neurotization surgeries in 2009, surgical tools and techniques have matured, turning the procedure into a predictable surgery with good outcomes.¹¹ Corneal neurotization with adjunct CAM coaptation wrap and ocular surface covering has been safe and effective for the vast majority of my patients, with vision- and eye-saving outcomes. The greatest challenge now is to inform referring doctors about the availability of this procedure for patients with vision-threatening NK. Although it is a long and delicate procedure, I am very optimistic that corneal neurotization surgery will become a standard part of the ophthalmic armamentarium, with future advances making the procedure shorter and simpler to perform.

Alon Kahana, MD, PhD

P: 248-800-1177

Kahana is the owner of Kahana Oculoplastic & Orbital Surgery in Livonia and Ann Arbor, Michigan, and is a professor of oculoplastic surgery and vice chair for academic affairs in the Department of Ophthalmology at Oakland University William Beaumont School of Medicine in Rochester, Michigan.

References:

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