Corneal nerve status as a biomarker for neurodegenerative and neurological diseases: a narrative review

Corneal nerve status has gained prominence as a potential adjunctive biomarker for neurodegenerative and neurological diseases, as corneal small-fibre abnormalities can be detected in peripheral neuropathy and may precede conventional manifestations in certain conditions. Advances in in vivo confocal microscopy (IVCM) allow non-invasive, cellular-level assessments of corneal nerve alterations in real-time. Corneal nerve metrics have been associated with disease progression and severity. This review explores the role of corneal nerve status in the evaluation and monitoring of neurodegenerative and neurological diseases or conditions, including diabetic peripheral neuropathy (DPN), Parkinson’s disease (PD), mild cognitive impairment (MCI) and dementia, multiple sclerosis (MS), schizophrenia, amyotrophic lateral sclerosis (ALS), migraine, tauopathies, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The strength and maturity of evidence vary substantially between conditions. DPN has the most established evidence base, with replicated cross-sectional and longitudinal studies showing reductions in corneal nerve fibre density, branch density and length, and evidence that corneal nerve loss may precede conventional manifestations of neuropathy. In MS, longitudinal studies demonstrate progressive corneal nerve loss associated with worsening disability. In PD, the extent of corneal nerve fibre loss correlates with severity of motor deterioration, cognitive impairment and development of autonomic dysfunction, although proposed applications in prodromal detection, disease phenotyping, and prognostication remain largely dependent on small, single-centre studies. Studies in MCI and dementia suggest potential diagnostic and prognostic utility, including comparisons with neuroimaging, but are largely derived from overlapping single-centre cohorts. Evidence in CIDP, migraine, ALS, and schizophrenia remains limited or conflicting, while evidence in tauopathies is predominantly pre-clinical. Overall, current literature supports corneal nerve parameters primarily as promising adjunctive rather than established diagnostic, prognostic, treatment-response biomarkers. Direct evidence that IVCM provides incremental diagnostic or prognostic value over established biomarkers remains limited. Furthermore, heterogeneity in confocal platforms, image acquisition, image sampling, and analytical methods must be considered in the interpretation across studies. Standardised acquisition and analysis protocols, prospective multicentre longitudinal studies, appropriate adjustment for confounders, and direct comparison with established biomarkers are necessary before broader clinical translation.