The present study has found that patients with glaucoma had a significant improvement in OSD after NPDS. New non-invasive technologies such as K5M and FD-OCT could be useful tools to objectively study different parameters of the ocular surface that could help us to evaluate the OSD in glaucomatous eyes.
In this prospective study, all POAG patients were already in a combined hypotensive drug treatment with preservatives. Corneal neurotoxicity and tear film disorder are examples of side effects that have been already described in patients with glaucoma (26–28) due to the chronic use of IOP–lowering therapies. Therefore, the main idea of this study was to investigate the ocular surface changes after NPDS once anti-glaucoma eye drops were removed.
Portela et al.(29) and Ling et al.(30) have already described worst scores in OSDI and NEI-VQF25 questionnaires in glaucoma patients with hypotensive treatment. Similarly, before surgery, our study showed significant differences in the median OSDI and NEI-VFQ25 scores between POAG group and healthy controls. However, to our knowledge, there is no previous information about these questionnaires after NPDS. In the current study, we have observed a significant improvement in both tests during the sixth month after NPDS. Nevertheless, after surgery, we also found significant differences between groups. This may be due to the fact that 51.52% of patients have anti-glaucomatous treatment in the contralateral eye (bilateral POAG).
Our findings support literature evidence (11, 29, 31–33), and the present study found that POAG eyes had a higher prevalence of OSD criteria than the healthy controls. Before NPDS, treated eyes, showed worse objective data regarding OH, LTMH,NIBUT and meibography evaluated by the Keratography 5M, worse FD-OCT LTMH and higher Oxford scores on ophthalmologic examination than the healthy controls. However, we document a significant improvement in most of these parameters throughout the follow-up period. No significant differences were observed between the groups in the following parameters: FD-OCT LTMH, K5M LTMH, NIBUT (f and av values), corneal-conjunctival staining grades and in most OH sectors values six months after surgery. These findings could demonstrate an improvement in OSD after NPDS due to anti-glaucomatous drops withdrawn.
LTMH can be measured with both modern devices (FD-OCT and K5M) reducing the interpretation bias of subjective assessments. FD-OCT LTMH measurements have been proposed as a good diagnostic method for OSD; showing low variability (34) good repeatability (35, 36) and a better reproducibility than the K5M (24). This could explain the difference in LTMH measurements when using the different devices. Therefore, these methods are not considered to be interchangeable.
Conjunctival hyperaemia is a common side effect described after the use of most topical anti-glaucoma medications (12, 31). Besides being a cosmetic problem, ocular hyperaemia may lead to poor treatment adherence. In recent studies, the Keratography 5M emerged as a reliable method to consistently score bulbar redness (12, 31, 37). Previous studies (12, 31) have already described the relationship between conjunctival hyperaemia and anti-glaucoma medication using K5M. Our results are consistent with previous studies, we observed higher K5M OH in the glaucoma group. In our prospective study, a significant increase of OH was observed in the first week after surgery. It could be due to the surgical procedure itself and/or to the postoperative treatment with anti-inflammatory drops. The OH-sector scores were gradually restored to the baseline level, observing a significant improvement in most of OH-sectors values during the sixth month. Significant group differences, disappeared by the sixth month in all the sectors except for the nasal bulbar one. Pérez-Bartolomé et al. (31) detected a greater impact of treatment burden on nasal hyperaemia scores than on the temporal quadrant ones. It could be explained by a longer contact time of the tear film in the nasal area, due to the normal spreading of the tear film across the ocular surface until it reaches the lacrimal punctum.
Previous studies have suggested that goblet cell secreting mucin 5AC, plays an important role in tear film stability (38) and several studies have reported toxic side effects for anti-glaucoma drugs on the conjunctiva, especially if preservatives are used (12, 39, 40). Moreover, the reduction in goblet cell density and mucin 5AC could also be due to several glaucoma surgery factors such as: toxicity of MMC used during the surgery, damage of the conjunctival nerves and the limbus stem cells, inflammation or mechanical trauma produced by the surgery and post-operative topical medication (41–43). Zhong et al. (35) have recently investigated the influence of trabeculectomy and phacotrabeculectomy on the ocular surface in a 3-month retrospective study using Oculus Keratograph. They observed that both, NIBUTf and NIBUTav values, tended to improve in the first and third month after surgery; recovering baseline in the third month postoperatively. According to previous reports, goblet cell density did not return to preoperative level after three months cataract surgery (44), the same happened with mucin 5AC after phacotrabeculectomy (41). They propose that the improvement of the NI-BUT is related to the recovery of the levels of goblet cell density and mucin 5AC. In line with these findings, we also found NIBUTf and average values improvement in the third month after NPDS; additionally, not significant differences were observed in the sixth month compared to healthy eyes. Taking into account these results, parameters of ocular surface could not return to preoperative levels until three months post-NPDS.
Recent studies have suggested that trabeculectomy filtering bleb is a determining factor in the state of the ocular surface for at least half a year. It could cause dry eye by inducing meibomian gland loss, particularly when the bleb is avascular or contains numerous intraepithelial microcysts (45, 46). According to previous research, trabeculectomy filtering bleb morphology also affects tear film (46, 47) indicating that the higher filtering bleb would decrease TBUT and increase the corneal staining.
In the present study, no significant changes were observed in meibomian gland six months after NPDS. Furthermore, we documented a significant reduction in the percentage of glaucoma eyes with Oxford ≥ 1 in the third month postoperatively, and no differences were recorded in corneal and conjunctival staining between groups in the last follow up visit. The different bleb morphology in NPDS and trabeculectomy could explain our results. (48, 49). Oh and colleagues found that eyes that underwent trabeculectomy had significantly higher, broader and lesser vascular blebs than eyes treated with deep sclerectomy. Also, eyes treated with trabeculectomy were more likely to show microcysts. Longer-term follow-up studies will be necessary to determine if deep sclerectomy bleb could cause more meibomian gland loss degrees.
Despite the significant findings, our study is subject to a number of limitations. First of all, the small sample size; which however has been enough to find significant differences, being the first study that uses non-invasive technologies (Keratograph and FD-OCT) to investigate OSD in glaucoma patients after NPDS. Second, the clinical ophthalmology examinations (corneal and conjunctival staining) are subjective, however, they were performed by just one ophthalmologist to avoid possible bias, and the comparison of keratitis was done using the Oxford scale, already published, obtaining therefore more reliable values. Finally, post-surgical steroids could improve ocular surface masking our results, nonetheless, the measurements of the third and sixth month should not be influenced by the treatment since it had already been completed.
In conclusion, although the association between anti-glaucoma eye drops and OSD has been extensively explored, to the best of our knowledge, this is the first study to compare different ocular surface parameters before and after NPDS. In addition, based on the objective parameters measured by Keratographs 5M and FD-OCT, we have reported a significant improvement of different variables such as OH-sectors, NI-BUT and LHTM after NPDS; as well as, lower corneal-conjunctival fluorescein staining and better total scores on the OSDI and NEI-VFQ25 questionnaires than before surgery.
The current study demonstrates that the withdrawn of anti-glaucomatous topical treatment could improve the ocular surface six months after NPDS. In addition, NPDS may be considered as a good as surgical technique to restore the ocular surface, however further studies should be performed to corroborate our results.