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December 2, 2025Open Access

Quantitative assessment of the corneal subbasal nerve plexus in children with neurofibromatosis type 1 and optic pathway glioma using in vivo confocal microscopy

Key Points

Children with neurofibromatosis type 1 exhibit increased corneal nerve fiber length, suggesting nerve proliferation.
Significant differences in nerve fiber density were observed using automated analysis methods between diagnostic groups.
Assessment utilized in vivo confocal microscopy with NeuronJ and ACCMetrics software for image analysis.
Findings highlight the necessity for standardizing automated methods in corneal nerve assessments to improve diagnostic accuracy.

Abstract

To quantitatively evaluate corneal subbasal nerve plexus (SNP) in children with neurofibromatosis type 1 (NF1) and optic pathway glioma using in vivo confocal microscopy (IVCM), comparing semi-automated and automated image analysis methods. In this prospective observational case series, 13 eyes of 7 children with NF1 and optic pathway glioma and 10 eyes of 6 age-matched healthy controls underwent IVCM imaging. Three high-quality central corneal images per eye were analyzed using NeuronJ (semi-automated) and ACCMetrics (automated) software. Corneal nerve fiber length (CNFL), nerve fiber density (CNFD), branch density, fiber area, fiber width, and fractal dimension were quantified. Group comparisons used t-tests and linear mixed modeling, accounting for inter-eye correlation. Agreement between methods was assessed with Bland-Altman analysis. NF1 eyes showed significantly greater CNFL on NeuronJ (27.13 ± 5.17 vs. 22.70 ± 4.98 mm/mm²; P = 0.042) and higher CNFD on ACCMetrics (27.32 ± 10.64 vs. 20.83 ± 7.98 fibers/mm²; P = 0.038) compared with controls. Other ACCMetrics parameters (CNFL, CNBD, CTBD, CNFA, CNFW, CNFrD) were not significantly different. Bland-Altman analysis demonstrated poor agreement between methods, with ACCMetrics systematically underestimating CNFL relative to NeuronJ (bias = 8.85 mm/mm²; limits of agreement 2.20 to 15.50 mm/mm²) and increasing underestimation at higher CNFL values (r = 0.43, P < 0.001). Children with NF1 and optic pathway glioma exhibit increased corneal nerve fiber length and density, suggesting enhanced nerve proliferation or branching rather than hypertrophy. However, automated ACCMetrics underestimated CNFL relative to semi-automated NeuronJ, emphasizing the need for analytic standardization. Larger, longitudinal studies are required to confirm these findings and explore their potential as noninvasive biomarkers of NF1-associated neuropathy.

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