Neurotrophic keratitis is a degeneration of the cornea or corneal superficial layers due to loss or decrease in sensation of the corneal nerves.

While neurotrophic keratitis is rare — its prevalence has been estimated to be less than five in 10,000 people, according to the U.S. Food and Drug Administration (FDA) — Sezen Karakus, M.D., a corneal specialist at Wilmer Eye Institute, Johns Hopkins Medicine says the condition in its earliest stages is under diagnosed and under recognized. Often, neurotrophic keratitis is diagnosed once patients start developing corneal ulcers, which is a more advanced stage of the disease.

“It’s not commonly seen, but when it’s seen, it might require urgent care and might lead to blindness,” Karakus says.

Early-stage neurotrophic keratitis can be misdiagnosed as severe dry eye, because the clinical findings are similar. However, patients with neurotrophic keratitis do not have usual dry eye symptoms such as burning, discomfort or irritation, and they may not respond to standard dry eye treatments. Patients with neurotrophic keratitis need treatment that repairs reduced corneal sensation, which is the hallmark of neurotrophic keratitis, Karakus says.

Corneal sensation is necessary for regular blinking and to maintain the homeostasis of the ocular surface. Also, if dryness or other abnormalities such as epithelial keratitis or defects are not felt, the body is unaware that the ocular surface needs repair.

Karakus, whose research interests include ocular surface disease, says she often sees patients with severe dry eye who do not respond well to conventional treatments.

“I noticed that some of these patients suffer from corneal nerve problems, and I found that these patients might have neurotrophic keratitis,” she says. “We need to address this problem before it progresses to more severe stages.”

Karakus wanted to try something new to help these patients. The FDA approved cenegermin, a nerve growth factor eyedrop, for treatment of neurotrophic keratitis in 2018. Karakus says the treatment was primarily studied in advanced stages of neurotrophic keratitis, but the FDA approved the medication to include treating patients with any stage of the condition.

As a result, Karakus began treating patients with cenegermin when she thought they may have been misdiagnosed with severe dry eye. This created a cohort of patients that she could follow and track to see how they reacted to the treatment.

Mentoring As Our Mission— Help from a Mentee

In 2019, as Karakus was starting this research, she was paired through the American Medical Women’s Association’s mentorship program with Daisy Dai, who was a second-year medical student at Johns Hopkins.

Karakus encouraged Dai to shadow her in the clinics and the operating rooms, and Dai became interested in a career in ophthalmology. This also led Dai to want to be more involved in research. As they brainstormed topic ideas, Karakus suggested that Dai assist her with the neurotrophic keratitis research.

As Dai shadowed Karakus, she noticed they saw many dry eye patients. She was excited to experience this convergence of research and patient care.

“When Dr. Karakus brought up the idea of this new drug that she was trying on some patients to treat neurotrophic keratitis and patients with refractory epithelial defects, that was something I thought sounded really interesting, and hopefully our results would be able to help ease patients further down the road,” she says.

Dai assisted with the research proposal and designing the protocols needed to gather data, and then helped collect data and analyze findings. She also won a grant from Fight for Sight last year that helped her dedicate more time to research and to present results from it at conferences.

Dai says Karakus has been an encouraging and supportive mentor, and that Karakus is a significant reason she decided to pursue a career in ophthalmology. Dai plans to continue her research in ophthalmology during the next year and hopes to get matched for a residency in 2023.

Karakus says it’s been rewarding to have someone to mentor and that Dai has played an important role in the study.

“It is really rewarding to see how your mentee understands the research question and then improves on that and makes the study better,” Karakus says. “It’s good to see how much progress she’s made since the beginning. I think that’s the most rewarding thing as a mentor, to see your mentee is succeeding and easily moving forward with the next steps in their career.”

Findings and the Path Forward

The work from Karakus, Dai and their team shows that patients who had tried other conventional treatments for neurotrophic keratitis showed improvements in their symptoms after an eight-week treatment course of cenegermin. This included restoration of corneal sensation through corneal nerve regeneration. Cenegermin is a recombinant human nerve growth factor.

The team followed the patients for three months after the treatment course, and although the effects were sustained for some, there was some relapse. Work will continue during the next year to gather more information, with the goal to gain a better understanding of who would benefit from this treatment and what regimen is necessary.

“We need to know what happens in the long term,” Karakus says.

The team also discovered that the medication increased tear production in some patients, such as those with controlled Sjögren’s syndrome or LASIK. This was not a primary outcome of the initial research, but the team has presented tear production research at several meetings this year.

Karakus says it’s important to raise awareness of a possible treatment for neurotrophic keratitis.

“We see patients are suffering from this problem for years without getting a real treatment, and they are always at risk if they haven’t developed serious complications already,” she says. “When I recognize the actual problem and am able to offer them a solution, I think it is very satisfying, especially when we see that the patient is finally improving.”