Healing Treatment— Refractory Neurotrophic Keratopathy

Retrospective study highlights utility of topical insulin. Cheryl Guttman Krader reports from the 39th Congress of the ESCRS in Amsterdam. Topical insulin, an old treatment to enhance wound healing, appears promising in a new indication as a treatment for refractory neurotrophic keratopathy (NK), according to Ricardo Machado Soares MD. Dr Soares presented the findings of a recent clinical study looking at the potential role of insulin for this indication. The study included 21 eyes of 20 patients with NK stage 2 (epithelial defect without stromal ulceration, n = 11) or NK stage 3 (corneal ulceration and/or stromal lysis, n = 10) that were refractory to multiple standard medical and/or surgical treatments. Complete re-epithelialisation of the persistent epithelial defect or ulcer was the primary endpoint. Ninety percent of the eyes achieved the endpoint within 7 to 45 days of starting treatment. There were no reported side effects associated with the topical insulin. “We recognise that our study, which is an uncontrolled and nonrandomised case series of patients, has some limitations. However, our results suggest topical insulin could be an effective therapeutic in refractory NK. Furthermore, it may prove extremely useful due to its low cost, high accessibility, and low morbidity compared to surgical alternatives. However, more clinical studies are needed to evaluate the efficacy, posology, duration, and side effects of this treatment,” Dr Soares told delegates. The insulin drops were prepared by mixing 1 unit of fast-acting insulin per 1 mL of an artificial tear with a propylene glycol base and kept refrigerated. The drops were applied four times daily. Treatment also included placement of a therapeutic contact lens with a topical fluoroquinolone drop, used to prevent complications related to the contact lens. The treatment continued until the NK epithelial defect or ulcer resolved, and then the regimen was tapered. Mean follow-up for the group was 20 months. ADDITIONAL DATA Fitting problems prohibited placement of the therapeutic contact lens in the two eyes that did not achieve complete re-epithelialisation. However, one eye went on to heal with the addition of a lateral temporal tarsorrhaphy. Two eyes experienced recurrence of the epithelial defect after stopping topical insulin. After patients restarted insulin, both eyes went on to complete re-epithelialisation. Thereafter, the patients maintained a low dose of the topical insulin. Analyses of outcomes with eyes stratified by NK stage showed that eyes with stage 2 disease benefited from faster re-epithelialisation than eyes with stage 3 NK (mean 18 days vs 29 days). The difference between subgroups was statistically significant. Analyses of BCVA showed a statistically significant improvement from baseline in the NK stage 2 and NK stage 3 subgroups. However, the magnitude of improvement and final BCVA was better in the stage 2 subgroup than in eyes with stage 3 NK. “The faster re-epithelialisation time and differences in BCVA outcomes between eyes with stage 2 NK were to be expected,” Dr Soares said. HISTORICAL PERSPECTIVE Dr Soares noted that insulin’s role in wound healing is well-known and was first described as a treatment for corneal ulcers in 1945. “But its use was lost over time,” he said. Recently, there have been a few published papers describing success using topical insulin for corneal wound healing. Dr Soares discussed two of those articles. One was a randomised placebo-controlled trial investigating three topical insulin concentrations to treat corneal epithelial defects that developed in patients with diabetes who underwent corneal debridement during vitreoretinal surgery. The results showed topical insulin 0.5 units/mL was more effective than higher concentrations and placebo for promoting healing. “Importantly, the study also proved that topical insulin is safe for human ocular usage,” Dr Soares said. The second report described a case series of six patients with treatment-refractory NK ulcers. All eyes in the cohort achieved complete corneal re-epithelialisation within 7 to 25 days of treatment. “This series is similar to ours. Although some of our cases required a higher number of treatment days, we believe the difference is mostly due to the larger size of our study population and its more diverse aetiologies for NK,” Dr Soares said. He added, “Our study also has a longer duration of follow-up, which attests to the long-term efficacy and safety of topical insulin.” MECHANISM OF ACTION Dr Soares suggested dual activities might explain the benefit of topical insulin for promoting corneal epithelial cell wound healing. First, through binding to insulin receptors present in the eye, insulin promotes the mitosis and migration of corneal epithelial cells. In addition, by activating insulin and insulin-like growth factor 1 receptors, insulin can induce the PI3k/ Akt/mTOR pathway that results in a total block in autophagy, including mitophagy, in corneal epithelial cells. The study was published recently and is available online. [Soares RJDSM, Arêde C, Sousa Neves F, et al. Cornea. 2021 Sep 4. doi: 10.1097/ICO.0000000000002858.]