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

Table 3 Strengths, current limitations, and future priorities in corneal nerve imaging

Domain	Strengths	Current limitations	Future priorities
Imaging technique[18,39,40]	Rapid, noninvasive, and repeatable visualization of the corneal subbasal nerve plexus	Requires dedicated equipment and trained operators; image quality may be affected by focus, illumination, motion, tissue compression, and limited sampling area	Wider access to the technique; standardized operator training, acquisition protocols, image-quality criteria, and anatomical sampling strategies
Biological significance[24,25,29,30]	Direct quantitative evaluation of small sensory nerve fibers in an easily accessible tissue	Corneal nerve abnormalities are not disease-specific and similar morphometric changes may occur across different systemic, neurological, and ocular conditions	Interpretation of CCM findings within the appropriate systemic, neurological, and ocular clinical context
Quantitative analysis[15,21,22,39,45]	Objective morphometric assessment of CNFL, CNFD, CNBD, CTBD, IWL, and other structural nerve parameters	Considerable heterogeneity in devices, sampling strategies, image-selection procedures, parameter definitions, and manual, semiautomated, or automated analysis methods	Harmonization of acquisition, sampling, parameter definitions, image selection, analysis software, and reporting standards
Clinical utility[5,47,48,51]	Potential role in detecting subclinical small-fiber abnormalities, longitudinal follow-up, patient phenotyping, and assessment of nerve regeneration	Group-level differences do not necessarily translate into accurate classification of individual patients; correlations with neuropathy severity and established reference tests are variable	Prospective multicenter diagnostic-accuracy and longitudinal studies using prespecified thresholds, representative populations, and clinically meaningful patient-level outcomes
Relationship with established tests[47,50,51]	May provide complementary structural information alongside clinical examination, quantitative sensory testing, neurophysiological assessment, and skin biopsy	Agreement with skin biopsy and functional small-fiber assessments is incomplete; CCM may capture partially overlapping but distinct aspects of nerve injury and cannot currently replace established diagnostic tests	Define the incremental clinical value of CCM and its optimal position within multimodal and multidisciplinary diagnostic pathways
Ocular confounding factors[24,25,52-55]	Ocular history, slit-lamp examination, and ocular-surface assessment allow many local modifiers of corneal nerve morphology to be identified	Dry eye disease, primary corneal disease, contact lens-related changes, previous ocular surgery, corneal trauma or infection, and topical treatments may independently alter CCM measurements and confound attribution to systemic neuropathy	Prespecified ocular eligibility criteria; standardized ocular-surface assessment; documentation of contact lens use and previous ocular procedures; exclusion of major active corneal disease when appropriate; and stratified, adjusted, or sensitivity analyses for relevant ocular confounders
Automation and artificial intelligence[16,17,41,46,56,57]	Faster image analysis, reduced dependence on manual quantification, improved repeatability, and encouraging diagnostic-classification performance	Current evidence is derived largely from selected datasets; limited cross-device and multicenter validation, potential patient-level data leakage, class imbalance, domain shift, insufficient calibration, and limited model interpretability restrict clinical generalizability	Participant-level data separation; multicenter and cross-device external validation; diverse populations; transparent reporting; calibration and uncertainty estimation; interpretable outputs; and demonstration of incremental clinical value beyond conventional CCM morphometry
Reference standards and diagnostic thresholds[20,47,48,51]	Growing availability of normative datasets and quantitative reference values for major CCM parameters	Diagnostic thresholds remain insufficiently validated for broad patient-level clinical use and may vary according to population, device, anatomical region, analytical method, and reference standard	Expansion of representative normative datasets and prospective validation of clinically meaningful, device- and population-appropriate thresholds

CCM: Corneal confocal microscopy; CNBD: Corneal nerve branch density; CNFD: Corneal nerve fiber density; CNFL: Corneal nerve fiber length; CTBD: Corneal total branch density; IWL: Inferior whorl length.