We read the correspondence by Mocan and associates with great interest and appreciate the opportunity to further expand on our study and clarify their concerns. In order to avoid redundancy to our previously published paper, focusing on subbasal nerve changes, we opted to not repeat these results, and to instead focus on epithelial changes, and their correlation to corneal sensation that is of greater clinical value. Our previous data suggest that the cornea possesses a significant neural reserve. Both loss of corneal sensation and epithelial cell changes are not observed unless close to two-thirds of subbasal nerves have diminished. This is corroborated by the fact that contralateral eyes in our herpetic patients demonstrate no changes in epithelial cells, despite modest corneal nerve loss. Further, epithelial cell changes appear with functional, and not early morphological, loss of nerves, as measured by corneal sensation. In fact, the main outcome measures in our recent abstract do not include nerve analysis, as erroneously stated by Mocan and associates.
We thank the authors for bringing the issue of reproducibility of superficial epithelial cell density and the effect of fluorescein dye to our attention. While these cells are more difficult to visualize in normal eyes, they can be easily visualized in patients with ocular surface disease, such as in our patient cohort. In order to address this issue further, we had modified our standard imaging approach and performed a second scan that is obtained for the epithelium, using sections of 3 μm, instead of the standard 7 μm, as already stated in our methods section. Furthermore, the analysis for all our studies is routinely performed by 2 masked observers to ensure reproducible image analysis. Regarding the fluorescein dye, we completely agree with the authors that adding dye may change image characteristics of epithelial cells, and we routinely perform in vivo confocal microscopy (IVCM) prior to vital dye application.
Changes in keratocytes and nerve density have been demonstrated in several previous reports, including in patients after corneal transplantation and refractive surgery, as well as in patients with Fuchs’ endothelial corneal dystrophy, keratoconus, and neurotrophic keratopathy. Given the lack of abnormal keratocyte density in our cohort, there was no relationship to corneal nerve density, and thus the role of keratocytes in patients with herpes zoster, if any, remains to be elucidated. Regarding endothelial cell changes in our cohort, we currently have a manuscript under review and hope to report these interesting findings soon.
As the authors correctly state, neurotrophic keratitis can result in persistent epithelial defects. Identification of patients at risk is of great importance, as the therapy of these patients can be extremely difficult. Our study clearly demonstrates that despite the lack of epithelial defects, IVCM allows for quantitative assessment of epithelial cell alterations that correlate with functional nerve changes. We agree that correlating the biomicroscopic findings with IVCM results at different stages of neurotrophic keratopathy may assist in understanding the progression of this debilitating disease. In fact, longitudinal studies are currently underway assessing the utility of IVCM findings as potential prognosticators to identify patients at risk for neurotrophic ulcers and other diseases of the ocular surface.