Neurotrophic Keratitis: Two Treatments in Practice

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Managing neurotrophic keratitis (NK) has long presented a thorny challenge for ophthal­mologists. If not treated effectively, said Albert Y. Cheung, MD, at Virginia Eye Consultants, it can have severe, poten­tially vision-threatening consequences, progressing from epithelial disruption to epithelial defects and even to stromal keratolysis.

In hope of avoiding such compli­cations, ophthalmologists have long employed a patchwork of modalities in treating NK, including serum tears, amniotic membrane transplant, con­junctival flap, bandage contact lens, and tarsorrhaphy. But, said Dr. Cheung, none of these therapies address the root cause of NK: inadequate corneal inner­vation and loss of sensation, which can result from a wide range of conditions, including herpesvirus infections, sur­gery, or trauma.

Today, however, ophthalmologists are having increasing success with two innovative approaches to corneal re-innervation: cenegermin (Oxervate), a drug approved in 2018, and corneal neurotization, a surgical procedure that has been refined over the last 10 years.¹

CENEGERMIN. Slit-lamp photographs of a patient with a history of LASIK and multiple herpes simplex virus infections with severe neurotrophic disease after cataract surgery. (1,2) Despite aggressive conservative management, stage 2 NK demonstrates a large epithelial defect at the start of cenegermin. (3,4) After cenegermin treatment, there was full healing of the epithelium and mild improvement in corneal sensitivity.

Cenegermin

The first FDA-approved treatment for NK, cenegermin is a recombinant form of human nerve growth factor that has demonstrated efficacy in healing the corneas of patients with moderate to severe NK.² Nerve growth factor kick-starts epithelial cell proliferation and stimulates corneal reinnervation.³ A typical dosing pro­tocol is one drop six times daily for eight weeks, and some patients require a second round of treat­ment, said Chirag K. Gupta, MD, at Beaumont Eye Institute, in Royal Oak, Michigan.

Promising out­comes. The goal of cenegermin use is to restore some corneal sensation and heal surface epithelial defects, said Dr. Gupta, adding that the medicine accomplishes that in a large majority of patients. Improvement can sometimes be seen as early as two to four weeks after starting treatment. Dr. Cheung said, “I have been able to discontinue chronic bandage contact lenses or partially open permanent tarsorrha­phies in some patients after cenegermin treatment.”

Data from the pivotal trial demon­strated positive results: at eight weeks, 62% of cenegermin-treated patients had corneal healing as indicated by absence of fluorescein staining, and 70% expe­rienced healing with <0.5 mm area of staining. By comparison, the results for the sham-treated group were 17% and 29%, respectively.⁴ 

When to use. “Although cenegermin can help in all stages of NK, I don’t typically jump to using it in stage 1 because of cost and coverage hurdles,” said Dr. Gupta. (Stage 1 is character­ized by epithelial irregularity most commonly in the form of punctate keratopathy without epithelial defect.) Roberto Pineda II, MD, at Massachu­setts Eye and Ear, added that there are “other treatment options for early-stage NK, including serum tears, amniotic membrane, and tarsorrhaphy.”

However, said Dr. Cheung, patients who have persistent stage 1 disease with significant superficial punctate keratitis—despite aggressive use of conservative treatments—may benefit from cenegermin. This is because “the chronically sick epithelium can lead to underlying visually significant stromal haze,” he said.

Patient selection. According to Jeanine A. Baqai, MD, at Northwest­ern University, in Chicago, many NK patients are good candidates for the drug. “I’ve taken all comers—everyone from patients with herpetic disease to those with skull base tumors—with the knowledge that some pathologies will respond better than others,” she said.

Dr. Cheung said, “I have found that traumatic injuries to the trigeminal nerve or central injuries [neurologic, surgical, compression] have a poorer response to cenegermin.” In addition, he said that patients with multiple pen­etrating or anterior lamellar keratoplas­ties may not respond as well, especially if limbal stem cell deficiency is present.

Similarly, in Dr. Gupta’s experience, cenegermin works better in patients whose trigeminal nerves aren’t severed or absent—those with low sensation rather than with anatomic abnormal­ity. Dr. Pineda concurred, adding that “when there is little-to-no innervation in the cornea, Oxervate can work, but the effect is not very long-lived.”

Insurance challenges. “Insurance companies often ask what other treat­ments the patient has tried and failed, making approval cumbersome. Then, there is usually a wait to get the medi­cation,” said Dr. Gupta.

If denied, the cost of the drug is prohibitive for many, at $12,000 out of pocket, said Dr. Baqai.

Complex storage and adminis­tration. The drops need to stay re­frigerated, so “you can’t just carry a bottle around in your pocket,” said Dr. Pineda. Additionally, said Dr. Baqai, “Oxervate comes in vials and needs to be pipetted out, so the administration can be complex for some.” And these issues can be particularly challenging given the frequency of dosing.

May cause pain. The most frequently encountered adverse effect is ocular pain, Dr. Cheung said. Although pain may be a sign that the medication is promoting nerve regeneration, it can be severe in rare cases, he said. “Decreas­ing the frequency temporarily to three times daily has helped my patients tol­erate the discomfort. Chasing the drop with a chilled preservative-free tear after a couple of minutes can help the burning,” he added. However, in some cases, said Dr. Baqai, patients may need to stop using the medication because of severe pain.

Not a permanent fix. Supplemental treatments are often needed to main­tain the healing effects of cenegermin, according to Dr. Gupta. “Almost everyone will need punctal plugs or tears/ointment plus or minus bandage soft contact lenses, tarsorrhaphy, or some other coverage.” Moreover, many pa­tients will have a recurrence of neuro­trophic issues after one or two years, he said, adding, “It’s a good treatment to get you out of a hole, but not a cure for the disease.”

Corneal Neurotization

While cenegermin provides a nonin­vasive method for stimulating corneal healing and re-innervation, neuro­tization surgically reroutes part of a normal donor nerve to supply sensory function to a neurotrophic cornea. One important upside of successful reinner­vation is that it may allow patients with significant nerve damage to undergo a later corneal transplant, giving them a chance to achieve visual recovery, said Dr. Pineda, who partners with an oto­laryngologist to perform the procedure.

The neurotization approach pi­oneered by Terzis and colleagues in 2009 used a direct supraorbital and supratrochlear nerve transfer.¹ Current approaches vary based on the source of the donor nerve, need for other nerve grafts, and technique to secure the transferred fascicles.⁵

Preoperative evaluation. Dr. Pineda starts with a thorough preoperative evaluation. “This includes Cochet-Bon­net esthesiometry to assess each quad­rant and central portion of the cornea for innervation; corneal topography and confocal microscopy to measure corneal nerve density; and endothelial cell count,” he said. He also checks the proximity of the donor nerve to the cornea and its surgical accessibility. In addition, he assesses the patient’s eyelids because “many patients have lagophthalmos or exposure keratopa­thy, which may need to be addressed at time of surgery,” he said.

Dr. Baqai, who partners with an ophthalmic plastic surgeon, said that confocal microscopy in advance can help the surgeon follow the evolution of the subbasal nerve plexus after neuro­tization. Also, she said, “It’s helpful to map out where you think you’ll be able to place fascicles, taking prior surgery into consideration. A patient with con­junctival scarring will have areas that might be harder to dissect.”

Direct vs. indirect. If the length and anatomic configuration of the donor nerve are adequate, the donor nerve can be transferred directly to the cornea. If not, neurotization can be accomplished through the indirect method, which uses an interpositional nerve graft—a segment of a different nerve to bridge the distance between donor nerve and the cornea.¹ Dr. Baqai noted that “it doesn’t seem that we’ve demonstrated superiority of one approach over the other; it often comes down to surgeon preference.”

The interpositional nerve segment can be an autograft or a cadaveric allograft. Dr. Gupta has recently moved to using cadaveric nerves because he finds them easier to harvest.

Donor nerve and graft. If the pa­tient has a severed trigeminal nerve, Dr. Gupta usually uses a nerve from the opposite side of the forehead and tunnels it over. But if the patient has good sensation on their face, then “I go to the infraorbital nerve because it is likely well innervated and has a smaller distance to travel,” said Dr. Gupta who operates together with an ophthalmic plastic surgeon.

Patients with trigeminal neuralgia or exposure keratopathy from herpes zoster may be candidates for contralateral supraorbital and supratrochlear nerve neurotization, using an interpositional nerve graft, said Dr. Pineda. For cases that involve facial reanimation, he said, “I sometimes use the sural nerve as the autograft because it has a low morbidity rate, although a nerve allograft can also be used to provide innervation.

“For people with combined fifth and seventh nerve palsy and also lagoph­thalmos,” he added, “I use the great auricular nerve and typically place it onto the ocular surface through the inferior fornix.”

Intraoperative techniques. Supra­orbital and supratrochlear nerves are accessed through an upper lid crease or subbrow incision, while infraorbital nerve use requires an inferior orbitot­omy.¹

“Once I get down to the donor nerve and the fascicles, from there I attach the cadaveric graft, tunnel it under subcon­junctiva, tether it medially and laterally to the cornea, and glue it in place with fibrin glue,” said Dr. Gupta. Although Dr. Baqai also uses glue, she said that suturing is an option that may result in less movement.

Dr. Pineda has helped develop a technique using clear corneal lamellar pockets for placement of the nerve fascicles, “to essentially plug the nerves directly into the cornea,” he said.

Dr. Gupta said it doesn’t make a big difference whether you tunnel the nerve, tack it to the cornea, or leave it near the sclera. “Standardize your tech­nique because the better you get at it, the more time you’ll save,” he advised.

Postop. All three surgeons place a tarsorrhaphy to protect the eye while the nerve heals. Supplementing that with amniotic membrane can provide additional support, according to Dr. Gupta. Dr. Pineda added that most patients are prescribed low-dose steroid drops for several months after surgery.

Outcomes. “The procedure has worked in everyone to varying degrees,” said Dr. Pineda, who has done more than 15 neurotizations since 2017.

Short term. Dr. Gupta has completed a comparable number of surgeries and reported that “all of my patients have made gains; some have gone from zero to 50% sensation.” Noticeable progress typically takes six months, he said.

“One way to test innervation is when patients place drops in their eyes, they will typically have referred sensa­tion. For example, if the great auricular nerve was used, the patient will feel the drop on the same side as the earlobe,” said Dr. Pineda.

Longer term. The improvements hold up over time, said Dr. Gupta. “Two years out from neurotization you can treat these eyes like a relatively nor­mal eye and do procedures to get vision improvements,” he said. Dr. Gupta has been able to provide corneal transplants to five of his neurotization patients.

Downsides. Neurotization is not an immediate fix, said Dr. Gupta, adding that if there is a defect in the cornea, it must heal first before corneal neu­rotization. In addition, patients will experience a loss of sensation in the location of the donor nerve, but usually it’s a very small area, said Dr. Pineda. He also cautioned that there is a possi­bility that the connection between the nerve graft and the nerve may need to be revised.

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1 Liu C et al. Ocul Surf. 2021;20:163-172.

2 Sacchetti M et al. Graefes Arch Clin Exp Oph­thalmol. 2022;260(3):917-925.

3 Deeks ED, Lam YN. Drugs. 2020;80:489-494.

4 Pflugfelder SC et al. Ophthalmology. 2020;127(1):14-26.

5 Jowett N et al. Curr Opin Otolaryngol Head Neck Surg. 2021;29(4):252-258.

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Dr. Baqai is Associate Professor of Ophthalmolo­gy at the Feinberg School of Medicine, North­western University, Chicago. Relevant financial disclosures: None.

Dr. Cheung is a cornea specialist at Virginia Eye Consultants in Norfolk. Relevant financial disclosures: None.

Dr. Gupta is a cornea specialist at Beaumont Eye Institute, Royal Oak, Mich. Relevant financial disclosures: None.

Dr. Pineda is Thomas Y. and Clara W. Butler Chair in Ophthalmology at Massachusetts Eye and Ear and Associate Professor of Ophthalmol­ogy at Harvard Medical School, both in Boston. Relevant financial disclosures: None.

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