March 2020


Examining effect of anti-VEGF on corneal nerves

by Maxine Lipner Senior Contributing Writer

Intravitreal injection
Source: Steve Charles, MD


Patients who receive anti-VEGF injections have a lower corneal nerve density compared to those who have not received these injections, study results indicate.1
The impetus for the study came from some earlier work conducted by Mark Rosenblatt, MD, who had researched VEGF A and VEGF B on animal corneas, said Anat Galor, MD. “He was the one who gave us the idea when he talked about VEGF as a neurotrophic agent along with being an angiogenic agent,” Dr. Galor said, explaining that investigators in this recent research wanted to make sure that there was not an adverse effect on corneal nerves that was being missed.
Investigators looked at three groups of patients: those who received anti-VEGF injections in one eye only, those who received anti-VEGF injections in both eyes, and controls with no history of anti-VEGF injections. In individuals who received injections in one eye only, the researchers compared corneal nerve density in the injected case eye to the non-injected control eye. They also compared corneal nerve density in individuals who received injections in one or both eyes to those who had no history of anti-VEGF injections.
With both comparisons, investigators found the same thing. “It didn’t matter if it was one injection or 100 injections, eyes that were injected with an anti-VEGF agent had lower nerve densities than eyes that had not,” Dr. Galor said.
Raquel Goldhardt, MD, pointed out that almost all the nerve parameters were decreased. “It was not just corneal nerve density,” Dr. Goldhardt said, adding that investigators looked at branching, length, and number of nerves.
Dr. Galor noted that the measurement software employed quantified nine different facets of the nerves and found that most of them were decreased. “Those that received the anti-VEGF had very different nerve parameters,” Dr. Galor said.
Investigators interpreted this as showing that VEGF in humans probably has a role in keeping corneal nerves healthy, Dr. Galor said. However, she added that blocking VEGF is needed in several retinal diseases.
Still, there were limitations in considering the clinical effects. “We didn’t measure things like corneal sensation, and we didn’t see any clinical issues like epithelial defects or scarring associated with the change in nerve density,” Dr. Galor said. “We’re not saying that our findings are clinically significant.” Rather, she views this as indicating that more study is needed.
Drs. Galor and Goldhardt hope that practitioners come away from the study with the understanding that VEGF has an effect on corneal nerves. “We saw a change in the anatomy and the morphology of the nerves,” they said, adding that while they didn’t see a clinical effect, if one is identified, there are a lot of patients with unhealthy nerves who could benefit. These include patients with zoster, trigeminal nerve injuries, or diabetes. “Right now, we don’t have many specific treatments for those patients,” Dr. Galor said. “This opens up the possibility of a new pathway that may be applied therapeutically.”
Based on animal data, VEGF B appears to have particular therapeutic potential. Dr. Galor views it as a target for patients who have neurotrophic keratitis, a difficult condition to treat. “Our study suggests that anti-VEGF agents may have an effect on corneal nerves, suggesting that VEGF is a neurotrophic factor,” she said.
As for concerns about anti-VEGF usage, clinically these were not seen in the study, Dr. Galor noted. “But if that patient had trauma, would they be slower to heal because of their repeated anti-VEGF injections?” she wondered. “We don’t know, but we hypothesize that this may be the case.” Dr. Goldhardt agreed with the concern over a possible connection with delayed healing.
Going forward, Dr. Galor hopes to continue research in this area, specifically studying subclinical parameters and looking for clinical manifestations of anti-VEGF injections.

About the doctors

Anat Galor, MD

Associate professor of ophthalmology
Bascom Palmer Eye Institute
Miami, Florida

Raquel Goldhardt, MD
Associate professor of clinical ophthalmology
Bascom Palmer Eye Institute
Miami, Florida


1. Goldhardt R, et al. Effect of anti-vascular endothelial growth factor therapy on corneal nerves. Cornea. 2019;38:559–564.

Relevant disclosures

: None
Goldhardt: None



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