Effect of recombinant human nerve growth factor treatment on corneal nerve regeneration in patients with neurotrophic keratopathy

Abstract

Introduction: Neurotrophic Keratopathy (NK) is a neurodegenerative corneal disease that results in diminished corneal sensation. Previous studies have found that Cenegermin 0.002%, a recombinant human nerve growth factor (rhNGF), improves corneal epithelial healing in stage 2 and 3 NK patients. However, rhNGF effect on corneal sensation and nerve regeneration has not been well established. Thus, this study aims to analyze the effect of rhNGF on corneal nerve regeneration using in vivo confocal microscopy (IVCM) and on corneal sensitivity in NK patients.

Methods: This is a retrospective, longitudinal, case-control study that included patients with NK, treated with rhNGF for at least 4 weeks, with pre- and post-treatment IVCM images available for analysis. Chart reviews were conducted documenting prior medical and surgical history, clinical signs and symptoms, and corneal sensation using Cochet-Bonnet esthesiometry. Corneal nerve parameters were assessed by IVCM. Sex- and age-matched reference controls were selected from a database of healthy subjects for comparison.

Results: The study included 25 patients, with 22 (88%) stage 1, two (8%) stage 2, and 1 (4%) stage 3 NK patients, with a median age of 64 years (range: 30-93 years). Total, main, and branch nerve densities [median (range) in mm/mm²] were lower in the NK group pre-treatment [2.3 (0.0-21.1); 1.7 (0.0-13.0); 0.5 (0.0-10.2); respectively] vs. controls [22.3 (14.9-29.0); 10.1 (3.2-15.4); and 12.1 (6.2-18.4), (p < 0.0001 for all), respectively]. Post-treatment nerve densities increased compared to pre-treatment to 5.3 (0.0-19.4, p = 0.0083) for total, 3.5 (0.0-13.2, p = 0.0059) for main, and 2.0 (0.0-10.4, p = 0.0251) for branch nerves, but remained lower than controls (p < 0.0001 for all). Corneal sensation increased from 2.3 ± 1.1 cm pre-treatment to 4.1 ± 1.4 cm post-treatment (p = 0.001). Median best corrected visual acuity significantly increased following rhNGF treatment from 0.4 (0.0-1.6) to 0.12 (-0.1 to 1.6) (p = 0.007).

Conclusion: Patients with NK treated with at least 4 weeks of rhNGF, showed a significant increase in corneal nerve densities after treatment. A significant increase in corneal sensation, as well as best corrected visual acuity, was observed following treatment.

Keywords: cenegermin; corneal nerves; neurotrophic keratitis; neurotrophic keratopathy; recombinant human nerve growth factor.

Figure 1

Breakdown of patient exclusion.

Figure 2

Examples of IVCM images from a healthy control (A), and a patient with neurotrophic keratopathy pre- (B) and post-rhNGF treatment (C).

Figure 3

Median nerve density comparisons between pre- and post-rhNGF treatment and control groups for (A) total nerve density, (B) main nerve density, and (C) branch nerve density. Values presented in Tukey boxplot (****p < 0.0001, **p < 0.01, *p < 0.05).

Figure 4

Median nerve number comparisons between pre- and post-rhNGF treatment and control groups for (A) total nerve number, (B) main nerve number, and (C) branch nerve number. Values presented in Tukey boxplot (***p < 0.001, **p < 0.01, *p < 0.05).

Figure 5

Box and whisker plot showing distribution BCVA pre- and post-rhNGF values (**p < 0.01).

Figure 6

ROC curve using nerve densities in mm/mm² for restoration of corneal sensation with (A) total nerve density, (B) main nerve density, and (C) branch nerve density.

Figure 7

ROC curve using nerve densities in mm/mm² for improvement in corneal fluorescein staining with (A) total nerve density, (B) main nerve density, and (C) branch nerve density.

Figure 8

Correlations between pre-rhNGF treatment and control groups total nerve density with (A) corneal sensation, (B) corneal fluorescein staining, and (C) visual acuity. Visual acuity measurements were not available for control groups. Both ρ and p values are presented.