Clinical Utility and Limitations of Sub-Basal Corneal Nerve Imaging Using Confocal Microscopy in Systemic Diseases

Corneal confocal microscopy (CCM), also referred to as in vivo confocal microscopy, is a non-invasive ophthalmic imaging technique that allows real-time visualization of the sub-basal nerve plexus and epithelial dendritic cells in the living cornea. Initially used for the diagnosis of anterior segment disorders, it has been increasingly applied to the evaluation of small-fiber involvement in systemic conditions, particularly diabetic peripheral neuropathy, in which CCM-derived parameters correlate with intraepidermal nerve fiber density (IENFD) on skin biopsy. This narrative review summarizes the technical principles of CCM, image-analysis approaches from manual tracing to deep learning, and the clinical evidence in peripheral neuropathies, central neurodegenerative diseases, autoimmune and inflammatory conditions, and long COVID. Outside diabetes, however, most data come from small, single-center, cross-sectional studies. Four barriers currently prevent CCM from becoming a routine clinical biomarker: (i) the absence of validated diagnostic thresholds and age-adjusted normative ranges outside diabetic neuropathy; (ii) the lack of disease specificity, as similar nerve loss occurs in many neurological, metabolic and ocular surface conditions; (iii) limited comparability across devices, acquisition protocols, image selection and analysis software, with automated and deep-learning tools still lacking multicenter external validation; and (iv) cost, contact-based acquisition and operator training. Overcoming these barriers will require standardized acquisition and reporting, open benchmark datasets, externally validated analysis pipelines, and large prospective longitudinal cohorts.