In line with previous studies, our study showed that NK patients showed significant abnormalities in tear film stability, corneal fluorescein staining scores, corneal perception, and corneal nerve parameters compared to the control group [16, 17]. In addition, we found that patients with NK 2 stage showed not only a significant difference in slit lamp examination compared to NK 1 stage but also a worse performance in terms of IVCM and tear film stability, suggesting that IVCM can be used as an important indicator of the severity of the disease. The decline in the morphology and function of corneal nerves often leads to varying degrees of corneal epithelial injury, probably due to the trophic effect of the corneal nerve on the corneal epithelium, while corneal epithelial and corneal cells affect nerve fiber survival, differentiation, and maturation through the release of neuropeptides, neurotrophins, and growth factors such as nerve growth factor (NGF), neurotrophic factor 3 (NT-3), nerve growth factor 4/5 (NT-4), epidermal growth factor (EGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor and glial cell-derived neurotrophic factor (GDNF) [7, 10, 18, 19]. Corneal epithelial injury leads to the exposure of subepithelial neural plexus, infiltration and recruitment of inflammatory cells, release of inflammatory factors, oxidative stress, and so on. These, in turn, can affect the normal function of corneal nerves. Therefore, the course of NK should be a complex process in which the corneal nerve and corneal epithelium interact.
Innate and adaptive immunity are sentinels of dendritic cells, which are bone marrow-derived antigen-presenting cells. Infectious and inflammatory mediators activate antigen-specific DCs which migrate to secondary lymphoid organs via a chemokine gradient to initiate cell-mediated immunity by activating naive T cells (CD4 + and CD8+) and B cells [20, 21]. The cornea is an immune privileged tissue in vivo, Streilein et al. reported that ocular immune privilege is under neural control. The anterior chamber of the eye contains immunosuppressive neuropeptides. When the corneal nerve is damaged, the tissue surrounding the anterior chamber stops secreting these immunosuppressive factors, anterior chamber-associated immune deviation (ACAID) fails, and corneal immune cells increase [22]. In addition, we found an increased density of dendritic cells in the contralateral eye of NK patients compared to controls by IVCM, suggesting an inflammatory response in the contralateral eye, but the exact mechanism of this is unclear.
Tear secretion is mainly dependent on nerve stimulation. In NK patients, nerve damage reduces tear secretion and tear film stability, which in turn causes abnormal epithelial cell metabolism and epithelial damage, which may be one of the mechanisms of NK pathogenesis [7]. In this study, we observed a significant reduction in tear river height and tear film break-up time in NK-affected eyes, and interestingly, the contralateral eye also showed a shortened tear film break-up time, probably due to corneal nerve damage in NK-affected eyes, reduced blink frequency, increased incomplete blink rate and impaired tear film renewal [23]. Jordan A et al. found that local anesthetic drops in rabbit eyes reduced tearing by 75% and bilateral blinking by about 30%, and that tear film renewal was largely dependent on blinking action [24]. Whether the increased DC density in the contralateral eye is a bilateral immune response to monocular nerve damage or a decrease in tear film stability in the contralateral eye, with signs of dry eye and consequent inflammatory response, needs further study to confirm.
Unlike previous studies, this study did not find significant differences in contralateral corneal nerve parameters, such as CNFD, CNBD, CNFL, CTBD, CNFA, CNFW, and CNFrD, compared to the control group. Possible reasons for this include the fact that the software used for corneal nerve analysis in previous studies was mostly semi-automatic, and although there was a high level of agreement between the fully automatic and semi-automatic analysis software in terms of analyzing SNPs, there were still differences in some indicators such as CNFrD [25–27]. Moreover, some studies have included patients with NK who have either herpes simplex keratitis or herpes zoster keratitis. Since viral infections can latently affect the trigeminal ganglion or corneal nerves, these patients may exhibit potential pathological changes in the corneal nerves. Such patients are challenging to categorize as "unilateral" NK patients. In this study, we included subjects with NK who underwent unilateral trigeminal nerve surgery. The trigeminal nerve in the contralateral eye was not affected, making the experimental results appear more reliable. The age of the patients included in this study was higher than before, and previous studies have confirmed that corneal nerve parameters may also change with age [17, 28, 29].
The present study has the following limitations: Firstly, we conducted only a cross-sectional study, lacking a time-series analysis to evaluate the changes in the ocular surface condition and neural function of NK patients over time. Secondly, the sample size included in this study is limited, necessitating multi-center or larger sample studies to further validate the reliability of the experimental results. Thirdly, while the study observed the presence of DC recruitment and changes in the tear film in the contralateral eye of NK patients, the causal relationship between the two remains to be further analyzed.
In summary, this study evaluated the ocular surface condition and changes in corneal nerves of both eyes in patients with unilateral NK. It was found that compared to the control group, NK patients exhibited lower tear film stability and nerve function. The tear film abnormalities in the contralateral eye of patients with unilateral NK should be of particular concern. Clinicians should take measures to improve the quality of life and ocular surface health of NK patients.