Neurotrophic keratitis more prevalent than previously thought

Neurotrophic keratitis is historically a rare disease, but now that more understanding has been gained of the underlying etiology and manifestations, its prevalence is starting to increase, and more cases are seen in clinics.

“We are diagnosing it a lot more commonly, and we are able to intervene a lot sooner. That really stems from our understanding of how it affects the nerves and how it can sometimes masquerade as dry eye disease,” Ashraf F. Ahmad, MD, a cornea specialist at Harvard Eye Associates in Laguna Hills, California, said.

Differentiating neurotrophic keratitis (NK) from dry eye disease (DED) and diagnosing it early are crucial and should become a common practice because the treatment horizon is expanding.

“If we are vigilant, we can potentially reduce the risk of it progressing to the more advanced vision-threatening stages,” he said.

Stain and no pain

The most common staging system for NK is the Mackie classification, which divides the disease in three stages.

“Stage 1 is the mild stage, where patients usually have punctate keratitis and minor epithelial irregularities. They might have symptoms of mild discomfort, maybe dryness, but more often they just complain of blurred vision,” Alfonso L. Sabater, MD, PhD, associate professor at Bascom Palmer Eye Institute in Miami, said.

At stage 2, patients present with persistent epithelial defects and might complain of foreign body sensation and discomfort but often no pain because corneal sensation is impaired, he said.

“At stage 3, we already see stromal melting and corneal ulceration, and there is a risk of corneal perforation. This is definitely rarer nowadays because we have better treatments to address stage 2. Usually, these patients don’t have any pain or even discomfort because the sensory nerves are heavily damaged,” Sabater said.

A new classification, more recently reported by the Neurotrophic Keratopathy Study Group, uses six stages instead of three.

“It includes, for example, a stage that we don’t have on the Mackie classification, which is the stage where patients have loss of corneal sensation but we don’t see any manifestations on the cornea,” Sabater said.

Due to the lack of specific symptoms, NK is often underdiagnosed or misdiagnosed as DED. If treated inappropriately, NK can progress to irreversible damage.

Differential diagnosis

Corneal sensitivity testing is the first step that helps differentiate between DED and NK and should be performed whenever there is a suspicion of something more than dry eye.

“Oftentimes, when you speak with the patient, there are clues there that cue you into the diagnosis. If they are not responding to traditional therapies and if they have a significant history of any ocular surgery, including LASIK, cataract or retinal surgery, then you absolutely need to check corneal sensation,” Ahmad said.

In his busy cornea practice, he sees quite a few cases of NK that masquerade as DED.

“I see them because I look for them, and my advice is to incorporate corneal sensitivity testing as one of the entry exams when you first see a new consult,” he said.

When the history, symptoms and clinical findings are suggestive of NK, corneal sensitivity testing should be performed, according to Fasika Woreta, MD, MPH, assistant professor at Johns Hopkins Wilmer Eye Institute in Baltimore.

“You should have a low threshold to check corneal sensation so that you don’t miss the diagnosis of neurotrophic keratopathy and just call it dry eye since the management is very different,” she said.

The patient’s history, the incongruence of signs and symptoms, such as a lack of pain with an epithelial defect that normally is painful, and the different pattern of corneal staining can help the diagnosis.

“For dry eye, staining is typically in the interpalpebral zone or inferior cornea, whereas with the neurotrophic cornea, it’s a more diffuse staining,” she said.

According to Sabater, blink rate can also be a good clue.

“In patients with dry eye, we see a higher blinking rate because of the discomfort, while in the early stages of NK, the blinking rate may be reduced,” he said.

Assessing corneal sensitivity

The basic qualitative method of corneal sensitivity testing is to use a cotton swab or dental floss in one or more quadrants of both eyes.

“If the patient feels it but doesn’t blink, then you know that there is a mild hypoesthesia. If they don’t blink and don’t feel anything, they have a moderate hypoesthesia. It is an easy, very approachable method, but its effectiveness in detecting corneal nerve function alterations in the early stages remains unclear,” Sabater said.

Cochet-Bonnet esthesiometry is a quantitative measuring tool for corneal sensation.

“In studies or when you want to monitor the effects of a therapy and be precise, then you want to quantify the sensitivity rather than just checking if sensation is present or not,” Woreta said.

However, Cochet-Bonnet esthesiometry is not commonly available for routine clinical practice. The filament cannot be properly sterilized and can scratch the eye, and stimulus reproducibility is problematic, according to Sabater.

“We have now a newer noncontact esthesiometer manufactured by Brill Engines that is commercially available. You can deliver an air puff at varying pressure ranges with five distinct levels of stimuli, and if the required pressure exceeds a specific stimulus level, it indicates a reduction or loss of corneal sensitivity,” he said.

Sabater has been using this device in reproducibility studies that have shown good results.

“In the last study, we used it also in patients with dry eye, and that’s the device that allowed us to discover that there were more cases with early-stage neurotrophic keratitis than what we had expected,” he said.

On the research side, the noncontact CRCERT-Belmonte esthesiometer has also been used.

Functional tests can then be integrated with structural analysis, primarily confocal microscopy, which highlights specific characteristics in the corneal nerve structure.

“The problem with confocal microscopy is that it is not really good as a screening tool because it’s a contact device, it’s time-consuming and it requires some expertise. But it’s good when you suspect that a patient has NK to confirm the diagnosis,” Sabater said.

Multiple etiologies

Neurotrophic keratitis has multiple potential etiologies.

“At the heart of it, it’s anything that can cause damage to the trigeminal nerve, which leads to loss of corneal healing power, epithelial defects and, in worst-case scenarios, ulceration,” Ahmad said.

The more common causes are infections, such as herpes zoster ophthalmicus and herpes simplex keratitis. Systemic causes include diabetes, multiple sclerosis and sometimes even vitamin A deficiency.

Another frequent cause is trauma from surgical procedures, including LASIK, corneal transplant, vitreoretinal surgery, particularly scleral buckling, and glaucoma surgery.

Neurosurgical procedures such as surgery for acoustic neuroma may indirectly affect the trigeminal nerve, leading to NK. The long-term use of contact lenses can also lead to loss of sensation in some cases.

“Another group would be those patients who have been on glaucoma medications containing preservatives for a long time,” Sabater said.

“Long-term use of glaucoma drops containing benzalkonium chloride can cause diminished sensation in the cornea. There are now minimally invasive glaucoma surgeries that can allow glaucoma patients to reduce topical medications. You have to weigh the benefits of continuing the medication and work closely with the glaucoma specialist,” Woreta said.

Stephen C. Pflugfelder, MD, professor at Baylor College of Medicine in Houston, said that DED itself can also cause the cornea to become neurotrophic.

“With long-standing moderate to severe dry eye, virtually everyone develops some neurotrophic component where there’s alterations of the basal corneal nerve plexus. We routinely check sensitivity using two methods, and it’s not unusual in the chronic and moderate to severe aqueous-deficient patients that they have evidence of NK,” he said.

Cenegermin, a breakthrough treatment

Pflugfelder was the first author of the randomized multicenter pivotal trial that evaluated the efficacy and safety of topical Oxervate (cenegermin-bkbj, Dompé) at 11 sites in the United States.

“Epithelial healing was about 75% in the cenegermin group vs. 35% to 40% in the vehicle group. The effect of healing was sustained in about 80% of the patients up to 1 year after the treatment course. Interestingly, the findings in the U.S. clinical trial were very similar to the European trial. The percentage differences between the active cenegermin group and the placebo were virtually the same,” he said.

Oxervate is a recombinant human nerve growth factor (NGF), first investigated in Europe and approved by the European Medicines Agency with orphan drug designation in 2017. In the U.S., it is approved for neurotrophic keratitis at any stage, but most physicians likely use more conventional treatments for stage 1 disease, according to Pflugfelder.

“At the earlier stages, I think the insurers would prefer that the patients receive conventional therapy. If those aren’t effective and there is a marked reduction in corneal sensitivity, then cenegermin could be considered,” he said.

“In my experience, it works very well, particularly in patients with stage 2 NK. When it’s really a neurotrophic corneal problem, then the treatment has a remarkable effect and is well tolerated,” Sabater said.

Again, in Sabater’s experience, tolerability is not as great in patients with stage 1 disease.

“They start having discomfort after a few weeks using the drops, and many times they cannot complete the treatment. So, I don’t use it in the early stages,” he said.

According to Pflugfelder, pain can occur at any stage after some weeks of treatment, as the nerves start to regenerate.

“Usually, it’s transient pain occurring several weeks to a month after initiation of the therapy. It is probably because the nerves are regenerating or becoming more sensitive again, and it seems to peak and then come back down. In my experience and in the clinical trial, the pain wasn’t sustained over the full 8-week course,” he said.

Accessibility, cost and compliance

Prescribing Oxervate is a fairly lengthy procedure that requires a documented diagnosis of neurotrophic keratitis with the ICD-9 or ICD-10 code.

“The prescriptions are done through a centralized pharmacy where a form is submitted. They do the preauthorization for the patient, and if it is approved by the insurer, then they’ll take care of sending the medication out,” Pflugfelder said.

Once the form is submitted, it usually takes at least 2 to 4 weeks before the medication is delivered. This can be a significant problem for patients who urgently need to be treated.

“You often have to wait and do nothing. Sometimes the patient is switched over to a different therapy, either awaiting the cenegermin treatment or continuing with that therapy if it shows effective enough,” Pflugfelder said.

Accessibility, however, has improved significantly. The approval for stage 1 might be more problematic, but most insurances cover the entire cost for NK stage 2 and 3, where it becomes more of a sight-threatening condition, Pflugfelder said.

There are patient assistance plans to help cover the cost of treatment almost entirely, Ahmad said.

“The cost of cenegermin is high, around $80,000 for the course of the treatment, but patients don’t pay anywhere near that. The most I have seen them pay is around $100 for the course of the 8 weeks,” he said.

Oxervate requires six times daily dosing for 8 weeks and must be kept refrigerated. This can be challenging for patients.

“They need to be able to maintain the frequent dosing schedule, and also they need to have a little bit of dexterity because it’s a different administration than your typical eye drop. It comes in a little syringe, and there’s a learning curve in the beginning,” Ahmad said.

However, Dompé has been active in providing resources for patient education, and adherence is usually not a problem, Woreta said.

“Problems may arise with very elderly patients or with children who are at school. Then you need the cooperation of family members, caregivers or teachers. However, Oxervate is an 8-week treatment. It may be repeated twice or three times maximum — it is not indefinite. Explaining the benefits and the costs usually helps motivate patients and those who take care of them,” she said.

Cenegermin is a breakthrough in the treatment of NK, Woreta said, but more studies on cost-effectiveness of the drug are needed. A study she did with her group in the Medicare population showed that the total gross drug cost of cenegermin therapy for 2,410 Medicare beneficiaries in 2019-2020 was $287 million.

“Not surprisingly, the cost is enormous. However, we need to measure the impact on the patient’s quality of life and other intangible benefits that are hard to quantify in terms of cost,” she said.

Surgery and procedures as an alternative

Corneal neurotization is a surgical alternative for NK stage 2 and 3, in which a small nerve graft from the leg (sural nerve) or a synthetic nerve graft (Axogen) is tunneled around the cornea to serve as a conduit for nerve growth from a nearby normal sensory nerve. It takes several months for the nerve growth to reach the cornea and restore sensation, so it is important to continue lubrication in the meantime.

While some specialists perform it as a first-line option, Woreta uses this technique in patients who do not respond to Oxervate. It has also been reported to be effective in combination with neurotization.

“I prefer to try the medical therapy first and wait several months to see an effect. If medical therapy fails, then I offer the option of neurotization,” Woreta said.

Although cenegermin is an expensive drug, the overall cost of having surgery is also high.

“There have been no trials comparing them head to head, but certainly a major surgery that requires hospitalization and multiple follow-up visits is expensive, too,” Woreta said.

Another procedure she often recommends in the severe stages and always in cases of exposure keratitis accompanied by NK is tarsorrhaphy.

“It is inexpensive and can be effective in helping persistent epithelial defects to heal,” she said.

For NK stage 2, a self-retained amniotic membrane such as Prokera (BioTissue) can be an effective, readily available option to be used while waiting for cenegermin to become available, according to Ahmad.

“You also want to cover those patients with topical antibiotics to minimize the risk of an infection,” he said.

Scleral contact lenses, although not widely utilized, also work well, according to Pflugfelder.

“If the practice has someone who can fit scleral lenses expertly, then that’s certainly an option. They provide protection and help to heal the ulcer or the keratitis,” he said.

Other options

In the early stages of NK, plasma rich in growth factors (PRGF) has shown efficacy in studies.

“We reported the results in NK stage 1 cases. In 2 months, we found a significant recovery in corneal sensation and tear film parameters,” Sabater said.

Another multicenter study, a collaboration among Bascom Palmer, Duke University and Baylor College of Medicine, reported positive results in a larger population of patients with DED and NK.

“I use it more often on the NK stage 1 cases, but sometimes I start with this treatment in NK stage 2 until we’re able to get approval to use cenegermin,” Sabater said. “PRGF needs to be manufactured on site, but I am also working on making this treatment more accessible to patients.”

“Autologous serum tears are also very effective because they have a lot of natural growth factors to help the epithelium regain its footing,” Ahmad said.

Local companies can provide home service to patients to draw blood and then deliver the serum tears in a preservative-free vial, he said.

Novel therapies using growth factors other than NGF are under investigation, including BRM424 (Brim Biotechnology), a pigment epithelium-derived factor peptide, and CSB-001 (Claris Bio), a human recombinant variant of hepatocyte growth factor. REC 0/0559 (Recordati) is an NGF mimetic currently in a phase 2 trial. Tyrvaya (Viatris), a varenicline solution nasal spray for dry eye, is under study in an NK population.

“Another potential treatment is topical insulin. It is used for persistent epithelial defects with good outcomes, and there are clinical studies evaluating the role in neurotrophic keratitis. Insulin is basically a growth factor because it stimulates some receptors that promote corneal epithelial regeneration and potentially nerve regeneration, but further studies are needed to better understand its role in neurotrophic keratitis,” Sabater said.

RGN-259 ophthalmic solution (RegeneRx Biopharmaceuticals), containing the regenerative protein thymosin beta 4, has shown efficacy in phase 3 trials as a way to promote epithelial regeneration in patients with stage 2 and 3 NK.

“Mesenchymal stem cell secretome (MSC-S, Kala Pharmaceuticals) is also being evaluated for persistent corneal epithelial defects, quite a few of which have a neurotrophic component,” Pflugfelder said.

“These are exciting times because now we’re going even further and moving into the early stages of neurotrophic keratitis. I hope new treatments will become available soon for patients in the earlier stages of the condition,” Sabater said.

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• For more information:
• Ashraf F. Ahmad, MD, of Harvard Eye Associates, Laguna Hills, California, can be reached at aahmad@harvardeye.com.
• Stephen C. Pflugfelder, MD, of Baylor College of Medicine, Cullen Eye Institute, can be reached at stevenp@bcm.edu.
• Alfonso L. Sabater, MD, PhD, of Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, can be reached at asabater@med.miami.edu.
• Fasika Woreta, MD, MPH, of Johns Hopkins Wilmer Eye Institute, can be reached at fworeta1@jhmi.edu.

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