Morphological alterations in corneal nerves of patients with dry eye and associated biomarkers

Exp Eye Res. 2023 May:230:109438. doi: 10.1016/j.exer.2023.109438. Epub 2023 Mar 16.


The purposes of the present study were to (1) identify the relationship between dry eye symptoms and morphological changes in corneal subbasal nerves/ocular surfaces, and (2) discover tear film biomarkers indicating morphological changes in the subbasal nerves. This was a prospective cross-sectional study conducted between October and November 2017. Adults with dry eye disease (DED, n = 43) and healthy eyes (n = 16) were evaluated based on their subjective symptoms and ophthalmological findings. Corneal subbasal nerves were observed using confocal laser scanning microscopy. Nerve lengths, densities, branch numbers, and nerve fiber tortuosity were analyzed using ACCMetrics and CCMetrics image analysis systems; tear proteins were quantified by mass spectroscopy. Compared with the control group, the DED group had significantly lower tear breakup times (TBUT) and pain tolerance capacity, and significantly higher corneal nerve branch density (CNBD) and corneal nerve total branch density (CTBD). CNBD and CTBD showed significant negative correlations with TBUT. Six biomarkers (cystatin-S, immunoglobulin kappa constant, neutrophil gelatinase-associated lipocalin, profilin-1, protein S100-A8, and protein S100-A9) showed significant positive correlations with CNBD and CTBD. The significantly higher CNBD and CTBD in the DED group suggests that DED is associated with morphological alterations in corneal nerves. The correlation of TBUT with CNBD and CTBD further supports this inference. Six candidate biomarkers that correlate with morphological changes were identified. Thus, morphological changes in corneal nerves are a hallmark of DED, and confocal microscopy may help in the diagnosis and treatment of dry eyes.

Keywords: Biomarker; Corneal nerve; Dry eye disease; In vivo corneal confocal microscopy; Nerve morphology; Proteome; Tear film breakup time.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cornea* / metabolism
  • Cross-Sectional Studies
  • Dry Eye Syndromes* / diagnosis
  • Dry Eye Syndromes* / metabolism
  • Humans
  • Microscopy, Confocal / methods
  • Nerve Fibers / metabolism
  • Prospective Studies
  • Tears / metabolism