Corneal nerve imaging in systemic neuropathy: A minireview of experimental and precision medicine applications

Small-fiber neuropathy is a common complication of metabolic, neurodegenerative, and treatment-related disorders. Early detection can be challenging because established diagnostic approaches may be invasive, resource-intensive, or relatively insensitive to early small-fiber injury. Corneal confocal microscopy (CCM) is a rapid, noninvasive imaging technique that enables quantitative assessment of the corneal subbasal nerve plexus and has been proposed as a biomarker of peripheral small-fiber damage. This minireview critically evaluates the role of CCM for early detection, diagnostic testing, prognostic stratification, longitudinal follow-up, and treatment response assessment in systemic neuropathies, particularly diabetic peripheral neuropathy (DPN). Evidence is strongest in DPN, in which CCM consistently demonstrates group-level corneal nerve loss; however, individual diagnostic performance is only moderate and varies according to patient spectrum, reference standard, sampling protocol, analysis method, and diagnostic threshold. Evidence in other neurologic diseases, including Parkinson's disease, multiple sclerosis, and chemotherapy-induced peripheral neuropathy, is less robust. Advancements in automated image analysis and artificial intelligence have improved reproducibility and efficiency of corneal nerve quantification in recent years. Nevertheless, widespread implementation in the clinics is still hampered by methodological heterogeneity, lack of full standardization, and absence of universally validated diagnostic and prognostic cut-off points. CCM is therefore a promising tool for translational research and precision medicine, but population-level differences in corneal nerve parameters should not be interpreted as establishing an individual diagnosis. At present, CCM should complement rather than replace established clinical, neurophysiological, functional, and pathological assessments, including quantitative sensory testing and skin biopsy when clinically indicated. Before integration into clinical practice can be recommended, multi-center prospective studies utilizing standardized acquisition and analysis protocols, validated thresholds, and clinically meaningful patient outcomes are required.