Post-LASIK corneas show subclinical nerve deficits and altered immune cell behavior years after surgery

Subclinical differences in corneal nerve architecture, mechanosensitivity, and immune cell morphodynamics persist in eyes that have undergone myopic LASIK surgery up to two years prior, according to a prospective observational study published in The Ocular Surface. The findings, which include elevated tear levels of the pro-inflammatory cytokine interleukin-16 (IL-16) and accelerated T-cell motility in post-LASIK corneas, suggest that the neuroimmune consequences of laser refractive surgery extend well beyond the early postoperative period––and may not be fully captured by routine clinical examination.¹

The study is the first to apply functional in vivo confocal microscopy (Fun-IVCM), a time-lapsed imaging technique capable of quantifying the dynamic behaviors of distinct corneal immune cell subsets, to a post-LASIK population. The results offer a more granular view of corneal neuroimmune status than has been achievable with traditional static IVCM imaging, with implications for how clinicians counsel and monitor patients following laser refractive surgery.

Study Design and Population

The cross-sectional study enrolled 32 adults at the University of Melbourne between August 2023 and June 2024: 19 healthy controls and 13 individuals who had undergone myopic LASIK 6 to 24 months before enrollment (median: 9 months post-surgery). All post-LASIK participants had a preoperative spherical equivalent refractive error of at least −3.00 D. Groups were age- and sex-matched, and participants with systemic conditions affecting small nerve fibers, ocular surface pathology, or recent use of anti-inflammatory agents were excluded.¹

Participants underwent three structured study visits. Evaluations included comprehensive clinical ocular surface assessments, non-contact corneal esthesiometry (mechanical and osmotic sensitivity testing), static IVCM for nerve parameter quantification, Fun-IVCM for immune cell morphodynamic analysis at the corneal whorl and inferior cornea, and multiplex bead-based tear cytokine immunoassay. Primary endpoints encompassed corneal nerve architecture, sensory thresholds, and the distribution, morphology, and dynamics of epithelial T cells, dendritic cells (DCs), and stromal macrophages.¹

Primary Results

Corneal Nerve Architecture and Sensitivity
Post-LASIK participants demonstrated markedly reduced central corneal epithelial nerve parameters across all quantified metrics, including nerve fiber density (median 5.2 vs 45.4 nerves/mm² in controls), branch density, total branch density, fiber length, fiber area, and fractal dimension (P <.0001 for all comparisons).¹ Corneal mechanical sensitivity thresholds were significantly elevated in the post-LASIK group using both room-temperature (P = .02) and cooled-air (P = .002) stimuli. No statistically significant intergroup differences were found in responsivity to graded hyperosmotic saline stimuli, suggesting relative preservation of osmosensory function—or potential methodologic limitations of single-drop osmotic challenge paradigms—in this population.

Immune Cell Morphodynamics
At the corneal whorl, putative intraepithelial T cells in post-LASIK corneas exhibited significantly higher mean instantaneous speeds (P = .012) and displacement speeds compared to controls, without differences in cell density or meandering index. This pattern, suggestive of heightened tissue surveillance and immune activation, was not replicated in the inferior cornea, where T-cell dynamics were comparable between groups.¹

Putative DC density was lower in the inferior cornea of post-LASIK participants (P = .046), while central and whorl DC density did not differ significantly between groups. Morphologically, DCs in post-LASIK corneas were larger in the inferior region (P = .026) and showed greater circularity at both the whorl (P = .018) and inferior cornea (P = .030), as well as greater convexity at the whorl (P = .012)—changes that may reflect altered DC maturation states. DC dynamic behaviors (dSEARCH index, probing speed) did not differ between groups.

Stromal macrophage density, morphology, and dynamics at the corneal whorl were similar between groups.

Tear Cytokines
After Bonferroni correction for multiple comparisons, tear IL-16 concentration was the sole cytokine found to be significantly elevated in post-LASIK participants relative to controls (median 938.3 vs 562.8 pg/mL; P = .0004).¹ IL-16 is a lymphocyte chemoattractant with activity toward CD4+ T cells, produced largely by T cells and macrophages, and has been linked to neuroinflammatory processes in experimental models.

Clinical Ocular Surface Parameters
Despite greater dry eye symptom burden in post-LASIK participants (OSDI median 11.4 vs 2.5; P = .001), most objective clinical markers—including tear osmolarity, non-invasive tear break-up time, and Schirmer test values—did not differ significantly between groups. Statistically significant but clinically modest differences were observed in tear meniscus height, limbal hyperemia, anterior blepharitis, ocular surface staining, and lid wiper epitheliopathy scores.

Clinical Context

LASIK is among the most common elective surgical procedures worldwide. During flap creation, corneal sensory nerve fibers are severed, precipitating acute neurogenic inflammation, impaired lacrimal gland feedback, and a high incidence of dry eye in the early postoperative period.^2,3 Prior static IVCM studies have established that corneal subbasal nerve fiber density remains reduced relative to preoperative levels at six months and two years following surgery, and structural nerve recovery may require more than a decade.¹

A lower density of corneal intraepithelial immune cells has been reported up to 16 months post-LASIK using conventional IVCM, but those methods aggregate immune cell subsets and cannot capture cellular dynamics.⁵ The current study is notable for its application of Fun-IVCM, which enables real-time characterization of distinct immune cell populations and provides a more informative picture of the post-LASIK corneal milieu.

Interpretation and Limitations

The convergence of elevated tear IL-16, accelerated intraepithelial T-cell motility, and altered DC density and morphology—in the absence of overt clinical inflammation—supports the presence of ongoing subclinical neuroimmune activity in post-LASIK corneas well beyond the acute recovery phase. These data add biological texture to the known symptom-sign discordance that clinicians frequently encounter in post-LASIK dry eye: patients may report persistent discomfort even when slit-lamp and tear function findings appear unremarkable.

The finding that immune cell morphodynamics did not differ significantly between post-LASIK participants with and without concurrent dry eye disease, defined per TFOS DEWS II criteria, suggests that these immune alterations may be a consequence of LASIK itself, rather than secondarily driven by dry eye disease severity. However, this interpretation is limited by the mild-to-moderate nature of dry eye in the affected subgroup.

The study sample is small (n = 32), which constrains statistical power and generalizability. The cross-sectional design precludes causal inference or longitudinal tracking of neuroimmune changes. Preoperative data were unavailable for post-LASIK participants, preventing within-subject comparisons. Specific surgical variables (ablation depth, flap parameters, laser platform) were not available for all participants, limiting analysis of procedure-related predictors. The study enrolled only participants with myopic LASIK and moderate-to-high baseline refractive error, so findings may not extend to hyperopic corrections or lower myopes. Finally, stromal macrophage analysis was possible in only a subset of post-LASIK participants due to challenges in identifying anatomical landmarks in nerve-depleted corneas.

Looking Ahead

Longitudinal studies with preoperative baseline imaging and extended follow-up are needed to characterize the trajectory of corneal neuroimmune recovery following LASIK. Head-to-head comparisons with other refractive procedures—including LASIK-alternative approaches such as small incision lenticule extraction or photorefractive keratectomy—could clarify whether specific surgical variables modulate the observed neuroimmune changes. Whether elevated tear IL-16 or accelerated T-cell motility are associated with patient-reported outcomes or long-term clinical sequelae warrants prospective investigation.

References

1. Rajan R, Wu M, Bedggood P, et al. Post-LASIK corneas show sub-clinical differences in sensory nerves and immune cell morphodynamics. Ocul Surf. 2026;41:26–36. doi:10.1016/j.jtos.2026.04.002
2. Chao C, Golebiowski B, Stapleton F. The role of corneal innervation in LASIK-induced neuropathic dry eye. Ocul Surf. 2014;12:32–45. doi:10.1016/j.jtos.2013.09.001
3. Toda I. Dry eye after LASIK. Invest Ophthalmol Vis Sci. 2018;59:DES109-DES115. doi:10.1167/iovs.17-23538
4. Erie JC, McLaren JW, Hodge DO, Bourne WM. Recovery of corneal subbasal nerve density after PRK and LASIK. Am J Ophthalmol. 2005;140:1059–1064. doi:10.1016/j.ajo.2005.06.026
5. Chao C, Tajbakhsh Z, Stapleton F, et al. Corneal epithelial dendritic cells, tear neuropeptides and corneal nerves continue to be affected more than 12 months after LASIK. Acta Ophthalmol. 2023;101:e302–e314. doi:10.1111/aos.15290