Enhanced Detection Of Subclinical Keratoconus In Vernal Keratoconjunctivitis Using A Novel Biomarker Multimodal Epithelial–Stromal Dissociation Index (Esdi)

To investigate epithelial–stromal remodelling in vernal keratoconjunctivitis (VKC) and validate a novel composite structural biomarker (ESDI) for the early detection of subclinical keratoconus, addressing the "masking effect" of epithelial compensation in inflammatory eyes. This study hypothesizes that the early signatures of ectasia in VKC are defined not by a single layer’s measurements, but by the specific "dissociation" between the epithelium and the stroma where epithelial thinning occurs in direct spatial correlation with underlying stromal protrusion. We aimed to evaluate the diagnostic efficacy of a novel biomarker (ESDI) by integrating epithelial asymmetry and stromal thickness deviation into a single multimodal metric

Prospective cross-sectional study at a tertiary ophthalmic hospital

  Total of 184 eyes were enrolled, comprising a normal control group (n=72),VKC cohort (n=112). VKC eyes were classified into three groups:
VKC-only (n=77), subclinical KC (n=23), and definite KC (n=12) .Pentacam was used to map corneal topography and MS39 were used to map epithelial and stromal layers. A composite Epithelial–Stromal Dissociation Index (ESDI) was derived using multivariable logistic regression coefficients. Group comparisons were performed using one-way ANOVA with Bonferroni correction. Diagnostic performance was evaluated using ROC analysis, with AUC comparisons performed via the DeLong test (p < 0.05 considered significant).

One-way ANOVA showed significant differences (p < 0.001) across all groups. Minimum epithelial thickness was 53.4 ± 1.8 µm in normals (n=72), and progressively decreased in VKC-only (50.2 ± 2.1 µm), subclinical KC (44.6 ± 3.4 µm), and definite KC (39.8 ± 4.2 µm). The ESDI followed a similar progressive trend (0.12 ± 0.08 vs 0.48 ± 0.21 vs 1.18 ± 0.37 vs 2.31 ± 0.64; p < 0.001). For subclinical KC detection, the combined model achieved an AUC of 0.92 (95% CI: 0.83–0.99), statistically superior to tomography alone (AUC: 0.81, 95% CI: 0.67–0.94; p = 0.03). Independent predictors were epithelial asymmetry (OR: 3.6; 95% CI: 1.4–9.1) and stromal deviation (OR: 2.9; 95% CI: 1.2–7.0)

In vernal keratoconjunctivitis, measurable epithelial–stromal dissociation occurs significantly before overt tomographic progression. The novel ESDI, by integrating epithelial asymmetry and stromal deviation, effectively overcomes the biological "masking effect" that often obscures early ectasia signatures in inflammatory eyes. This study validates that a multimodal approach (combined AUC: 0.92) is statistically superior (p = 0.03) to standard tomography for subclinical detection. Given the high regional burden of keratoconus, implementing these biomarkers into routine screening protocols aligns with the 2025 Global Consensus and facilitates timely collagen cross-linking.