Clinical Characterization of the Lacrimal Functional Unit in Patients with Chronic Ocular Pain Associated with Dry Eye Disease

<b>Background/Objectives</b>: The purpose of this study was to clinically characterize the lacrimal functional unit (LFU) of patients with chronic ocular pain associated with dry eye disease (DED). <b>Methods</b>: Ninety-three participants were included in this cross-sectional study: 28 patients with chronic ocular pain associated with DED (pain-DED), 35 patients with DED but no pain (no pain-DED), and 30 subjects without DED or ocular pain (controls). The following examinations were performed: symptom questionnaires, visual function assessment, tear meniscus, ocular surface evaluation, meibography, corneal sensitivity, Schirmer test, and in vivo corneal confocal microscopy. <b>Results</b>: Both DED groups presented increased DED-related symptoms (<i>p</i> < 0.001), corneal staining (<i>p</i> < 0.001), Meibomian gland loss (<i>p</i> < 0.010), and dendritic cell density (<i>p</i> < 0.001) compared with controls. Comparing both DED groups, the pain-DED group showed higher DED-related symptoms (<i>p</i> < 0.002) and increased microneuroma density (<i>p</i> < 0.001). Additionally, significant positive correlations were observed between symptom questionnaires and corneal staining (vs. OSDI: r = 0.514, <i>p</i> < 0.001; vs. m-SIDEQ: r = 0.504, <i>p</i> < 0.001; vs. NRS: r = 0.361, <i>p</i> < 0.001; vs. WBFPRS: r = 0.317, <i>p</i> = 0.002), dendritic cell density (vs. OSDI: r = 0.429, <i>p</i> < 0.001; vs. m-SIDEQ: r = 0.440, <i>p</i> < 0.001), and microneuroma density (vs. NRS: r = 0.405, <i>p</i> < 0.001; vs. WBFPRS: r = 0.416, <i>p</i> < 0.001). <b>Conclusions</b>: Differences in the LFU, especially in the morphology of sub-basal corneal nerves, are related to the presence of DED and chronic ocular pain and, along with ocular clinical questionnaires, can help phenotype these patients.