The Effects of Age on the Presence of Atypical Corneal Nerve Formations

PURPOSE: The aim of this study was to describe the presence of atypical nerve formations (ANFs, previously termed microneuromas) and their relation to standardized ocular surface parameters and changes in the sub-basal nerve plexus in a group of patients with suspected small fiber neuropathy or type 1 diabetes referred for in vivo confocal microscopy (IVCM). METHODS: This retrospective single-center study enrolled 143 patients (286 eyes) referred for corneal nerve morphology evaluation between 2019 and 2024. Patients with severe dry eye disease, a history of ocular surgery, or recent eye drop use were excluded. All participants underwent comprehensive ocular surface assessment, including OSDI, Cochet-Bonnet esthesiometry, tear break-up time (TBUT), Oxford grading, tear osmolarity, and tear metalloproteinase-9 (MMP-9) concentration. IVCM was performed to obtain corneal nerve fiber metrics (corneal nerve fiber length, corneal nerve fiber density, corneal nerve branch density) and to manually identify ANFs. Generalized estimating equations were used to account for intereye correlation. RESULTS: Corneal ANFs were identified in 25.5% of the 286 eyes. Age demonstrated a statistically significant association with ANF presence, with the odds increasing by approximately 5% for each additional year of age (odds ratio 1.05; P < 0.001). A statistically significant inverse association was observed with corneal sensitivity (P = 0.040). No statistically significant correlations were found between ANFs and TBUT, tear osmolarity, MMP-9 concentrations, OSDI scores, or standard IVCM metrics. CONCLUSIONS: Corneal ANFs seem to be strongly associated with aging, suggesting that they may represent age-related degenerative remodeling rather than specific biomarkers for ocular neuropathic pain or inflammation in this population and, as such, should be interpreted with caution and within the broader clinical context.