Imaging and Proteomics: Differentiating Neuropathic Corneal Pain from Dry Eye

Neuropathic corneal pain (NCP) and dry eye disease (DED) can present with similar symptoms—ocular discomfort, visual disturbance, and tear film instability—but differ significantly in pathophysiology and treatment response. For clinicians, distinguishing between these two conditions remains a diagnostic challenge.

New findings presented by Yu-Chi Liu, MD, PhD, and colleagues at the 2025 American Academy of Ophthalmology Annual Meeting offer a multimodal approach that integrates in-vivo imaging and tear proteomics, with potential to reshape how these conditions are clinically parsed.

Here’s a brief overview of what they found.

Identifying Actionable Biomarkers
In this cross-sectional analysis, the team evaluated 104 eyes with NCP, 106 with DED, and 106 healthy controls. Patients underwent comprehensive ocular surface evaluation, the Ocular Pain Assessment Survey (OPAS), and in-vivo confocal microscopy (IVCM). Tear fluid from all participants was subjected to high-resolution quantitative proteomic analysis.

Microneuromas (MNs)—focal nerve enlargements that may reflect nerve injury or aberrant regeneration—were the primary imaging focus. IVCM data revealed that MNs were not only more prevalent in NCP patients, but also more prominent by several measures: number, total area, perimeter, and average size. Corneal nerve fiber width was also significantly increased in the NCP group.

These metrics were significantly correlated with OPAS pain scores, particularly in peripheral forms of NCP, suggesting alignment between symptom severity and structural nerve changes.

Deepening the Differential with Proteomics
The tear proteome added a molecular dimension to this differentiation. Across the cohorts, 129 proteins were differentially expressed. In NCP, proteins associated with neuronal injury and inflammation—such as vinculin (upregulated) and DLG-associated protein 4 (downregulated)—were distinct from those observed in DED, where upregulation of S100A12 and matrix metallopeptidase 9 indicated a more prominent epithelial and inflammatory profile.

These proteomic shifts align with known pathomechanisms: in NCP, neuropathic signaling and synaptic dysregulation dominate, whereas DED involves tear film instability and ocular surface inflammation. Importantly, the combination of MN imaging parameters and OPAS scores yielded a robust area under the receiver operating curve (AUC 0.916) for distinguishing NCP from DED—supporting the potential for these tools to serve as diagnostic adjuncts.

Moving Toward Precision in Ocular Surface Pain
These findings may recalibrate the clinical approach to patients presenting with eye pain or discomfort. In cases where conventional dry eye therapies underperform, the presence of MNs and a high OPAS score could prompt reconsideration of the underlying diagnosis and a shift toward neuropathic pain management strategies.

The tear proteome, while not yet practical for widespread clinical use, underscores the molecular divergence of these entities and may guide future therapeutic targeting.

Assessing Limitations and Next Steps
As a cross-sectional study, this investigation does not capture temporal changes or treatment response. The population was well-powered for imaging and proteomic comparisons but may not reflect all phenotypes, particularly mixed NCP-DED presentations.

Further validation in prospective and longitudinal cohorts will be necessary, and clinical accessibility of tear proteomics remains a key hurdle.

Applying These Findings in Clinical Practice
Differentiating NCP from DED is critical for targeting treatment effectively. This study highlights the value of combining objective nerve imaging with patient-reported pain scores—and adds molecular evidence to support NCP as a distinct clinical entity.

As diagnostic pathways evolve, multimodal assessments may help clinicians better align treatment with pathophysiology in ocular surface disease.

Reference:
Liu YC, Mehta JS, Tong LMG. Exploration of imaging and molecular biomarkers for differentiation of neuropathic corneal pain from dry eye syndrome. Poster PO239 presented at: American Academy of Ophthalmology Annual Meeting; October 18-20, 2025; Orlando, Florida.