A narrative review of ocular surface disease considerations in the management of glaucoma

Introduction

Glaucoma is a leading cause of preventable blindness in the world, affecting more than 2 million people in the United State alone. One of the few proven ways of preventing glaucoma progression is by decreasing intraocular pressure (IOP), typically with the use of topical ocular hypotensive medications (1-3). However, the use of these IOP-lowering drops has been shown to worsen objective findings of ocular surface disease (OSD), initiate or exacerbate existing OSD-related symptoms, and consequently decrease long-term compliance with medications (4-8).

The correlation between OSD and glaucoma has been well-documented, with both diseases increasing in prevalence with advancing age. OSD prevalence has also been shown to correlate with glaucoma severity; Ocular Surface Disease Index (OSDI) scores tend to worsen in patients with higher drop requirements (9). This relationship appears to be reciprocal, with severe OSD likewise correlating with higher rates of glaucoma (10). Clinicians must have a low threshold in the diagnosis and treatment of co-existing, symptomatic OSD in glaucoma patients, particularly those that are initiating or escalating medical therapy.

One of the newer options in the management of glaucoma is the development of minimally invasive glaucoma surgery (MIGS), typically performed in combination with cataract surgery. There are currently a wide range of Food and Drug Administration (FDA)-approved MIGS procedures with varying mechanisms of action and efficacy. Several studies on various MIGS procedures have demonstrated a post-operative reduction in IOP as well as a reduction in the number of medications required for IOP control.

The goal of this review article is to summarize the current literature regarding the varying treatment options of glaucoma and its relation to OSD, with emphasis on surgical considerations and complications related to OSD. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-22-59/rc).

Methods

PubMed, Google Scholar, and Cochrane Review searches were performed using the following search terms: ocular surface, dry eye, MIGS, trabeculectomy, glaucoma medications. The titles and abstracts from those searches were screened for relevance to our review topics. Publications were included if the subjects included glaucoma patients, and if ocular surface outcomes were described. Non-English papers were excluded (Table 1).

The adverse effects of glaucoma medications on the ocular surface

The Collaborative Initial Glaucoma Treatment Study (CIGTS) showed that initial management with medicine or surgery resulted in similar visual field outcomes after 5 years of follow-up (11). Given its relative safety and ease of use, medical therapy remains the preferred first choice of treatment for most forms of glaucoma in the United States. The side effects of the numerous topical hypotensive medications that are in common use have been well-explored to date. Broadly, these medications can worsen OSD either due to toxicity from the active medications themselves or from the preservative.

Prostaglandin analogs are widely considered as a first line option for the treatment of glaucoma due to their efficacy, favorable side effect profile, and simple once nightly dosing. Although they are generally well-tolerated, they have been found to increase prevalence and severity of meibomian gland disease and worsen subjective symptoms of OSD as measured through the OSDI (5,12-14).

Beta-blockers are another widespread ocular hypotensive medication utilized in the management of glaucoma. As one of the older agents, their efficacy and side effect profile have been well-established in the literature, including their potential negative effect on the ocular surface (8,15). Beta-blockers lower IOP through the proposed mechanism of inhibition of aqueous humor production in the ciliary epithelium. However, since their inhibitory effect on beta receptors is non-specific, they are also thought to act on the beta receptors within the lacrimal gland, resulting in decreased tear production. In addition, timolol specifically has been demonstrated to alter the composition of the tear film, leading to increasing toxicity to the ocular surface (16-18).

Brimonidine, an alpha-agonist, is also a proven topical IOP-lowering medication. However, it has also been shown to have elevated allergenicity, at a significantly higher rate than other topical preparations. Long-term intolerance to brimonidine is common due to this local adverse reaction. The allergic response associated with brimonidine use triggers an IgE cascade, which can also increase the likelihood of allergic reactions to other future topical medications (19).

In addition to the medications themselves, the preservatives used in ophthalmic preparations are also well-known to adversely affect the ocular surface. Preservatives are a necessity in inhibiting contamination and bacterial growth in liquid medications; however, the same mechanism by which they prevent bacterial growth also causes toxicity to the ocular surface (20). Of note, most of the studies exploring these harmful side effects of topical glaucoma medications focus on a limited time window of approximately 1 to 5 years. However, when applied to a population level, it must be acknowledged that many of these patients will require lifelong use of topical hypotensive medication, likely amplifying the cumulative, chronic effects of these medications.

The most common preservative on the market is benzalkonium chloride (BAK), a quaternary ammonia compound used in approximately 70% of preserved ophthalmic solutions. Its biocidal properties prevent microbial contamination, and it can also enhance corneal penetration of some drugs by acting as a detergent and disrupting corneal epithelial tight junctions, thereby increasing permeability to water-soluble substances. However, it can also cause significant toxicity to various ocular tissues, including the corneal and conjunctival epithelium. The most significant known side effect of BAK is impaired corneal sensitivity. This impairment follows a dose-response curve, with studies showing a correlation between cumulative drop burden, duration of treatment, and severity of corneal sensation loss (21,22). Overall, BAK has been correlated with more severe OSD and worsened quality of life, which also contributes to decreased medication compliance.

Several studies have shown that OSD-related symptoms from topical glaucoma therapy interfere with patient compliance rates (4,5,23,24). One study found 27% of patients endorse side effects related to the drops affect adherence to glaucoma regimens (24). Another reported that 2% of patients cited medication side effects as the main reason for non-adherence (24,25). Lee et al. found an inverse relationship between meibomian gland function and rates of compliance of prostaglandin analogs (5). Alternative options exist for patients with severe BAK-related OSD, including preservative-free formulations or those that utilize gentler oxidizing preservatives. Preservative-free agents have been shown to decrease disturbances to the ocular surface and reduce OSD symptoms, leading to improved patient compliance (8,15,20,26). Although these preservative-free medications are better tolerated, they also are poorly covered by health insurance due to the lack of available generic formulations on the market, and therefore less economically viable for many patients.

The effect of MIGS on OSD

MIGS are one of the newer developments in the treatment of mild-to-moderate glaucoma and have steadily gained prominence as an alternative to traditional glaucoma surgeries such as trabeculectomy or glaucoma drainage device implantation. The term MIGS refers to a group of glaucoma procedures typically performed via ab interno approach and characterized by minimal disruption of normal anatomy, high safety profile, and rapid patient recovery. Studies have shown varying degrees of success among these procedures in achieving statistically significant decreases in medication burden, or complete independence from drops for a percentage of patients (27-32). Given the known correlation between the topical medication burden and OSD, MIGS should be given significant consideration as a means of controlling IOP while simultaneously relieving or minimizing OSD symptoms.

iStent was the first MIGS device to receive FDA approval, and subsequently has the most published evidence regarding efficacy and safety amongst the MIGS procedures. iStent has been demonstrated to provide consistent short-term and long-term reduction in IOP, as well as a reduction in medication burden (28-30,33-38). To date, there has been one study assessing changes to the ocular surface in patients before and after cataract surgery with iStent (27). This study found significant improvement in OSDI, tear break-up time, and corneal and conjunctival staining up to 3 months post-operatively, as well as a notable decrease in medication burden and a 17% reduction in mean IOP. The improvement to the ocular surface, both in patient symptoms and objective data, was attributed to the overall decreased medication burden. This study was the first to directly assess the relationship between OSD and MIGS; however, given its relatively short-term 3-month follow-up period, further studies are needed to validate and reinforce these findings.

Other MIGS procedures, such as Trabectome, Hydrus, Xen Gel Stent, Kahook Dual Blade, Cypass, and Gonioscopy-Assisted Transluminal Trabeculotomy (GATT), have been proven to decrease mean IOP and have varying degrees of success in reducing the medication burden in patients with mild-to-moderate glaucoma (32). However, there is a lack of data directly assessing the effect of these MIGS procedures on OSD-related subjective symptoms or objective findings. As there is ample literature describing the correlation between decreased medication burden and improvement in OSD, it would be reasonable to presume that the aforementioned procedures would similarly improve the overall health of the ocular surface. Further research is needed on the long-term effect of MIGS procedures on the ocular surface, to better elucidate their role in the treatment of glaucoma patients with OSD.

The effect of trabeculectomy on OSD

Trabeculectomy is a standard, proven glaucoma surgery typically utilized in patients that have otherwise failed medical therapy (11). In this operation, an ostium into the anterior chamber is created through a partial-thickness scleral flap, which drains into the subconjunctival space resulting in a localized elevation of the conjunctiva, also known as a filtering bleb. An antimetabolite is typically used intraoperatively to prevent post-operative scarring and limit unintended closure of the ostium. Although the indications and complications associated with trabeculectomy have been well-established to date, there is a relative paucity of literature evaluating the effect of trabeculectomy on the ocular surface.

Anatomic disruption to the normal ocular surface anatomy can cause OSD or worsen pre-existing disease. The creation of an elevated conjunctival bleb may inadvertently cause mechanical friction of the bleb against the meibomian glands, leading to chronic irritation when blinking. This disruption can cause long-term meibomian gland loss over a median time span of 7 years, resulting in tear film instability and worsened OSD (39).

The net overall effect of trabeculectomy on the ocular surface health appears to vary depending on the time after surgery. Ono et al. found that patients can develop corneal epithelial defects at a median onset of 1.5 days, corneal dellen at a median onset of 5.5 days, and filamentary keratitis at median onset of 28.0 days (40). Another study found that trabeculectomy patients had more OSD symptoms than the phacoemulsification control group in the immediate and sub-acute post-operative period; however, by 3 months these objective measures had equalized between the two groups (41). In the subacute post-operative period, clinicians should remain vigilant for signs of ocular surface complications, as these typically occur within the first 60 days after surgery.

In contrast, trabeculectomy may confer an overall long-term benefit to objective measures of ocular surface health over 6 months to 1 year (42-44). The mechanism for this is not clear, but similar to MIGS, is thought to be a result of de-escalation of topical glaucoma drops leading to reduced pro-inflammatory gene expression on the ocular surface (45). Of note, however, Agnifili et al. reported a lack of correlation between these objective findings and patients’ subjective symptoms (44).

Mitomycin-C and 5-fluorouracil (5-FU) are common anti-metabolites used as adjuvants during trabeculectomy, intended to inhibit closure of the partial-thickness scleral flap. As these anti-metabolites have non-specific activity, they also have adverse effects on the active replication of limbal stem cells, which can in turn prevent adequate replacement and healing of the corneal epithelium and subsequently cause or exacerbate OSD (46). Traverso et al. noted a dose-dependent corneal toxicity from 5-FU, specifically an absence of corneal epithelial defects and a significant reduction of punctate epitheliopathy 15 months post-trabeculectomy using lower doses of 5-FU (47).

Overall, trabeculectomy can contribute to OSD due to disruption in normal anatomy and corneal sensation, adjuvant anti-metabolites administered during surgery, and post-operative complications. However, from the current literature, it appears there may be a net long-term benefit of trabeculectomy due to the decreased medication requirement in patients that undergo this surgery. Further research is needed to more directly assess this relationship.

The effect of OSD on trabeculectomy outcomes

In patients with comorbid glaucoma and OSD, the presence and severity of OSD can also significantly influence the outcomes of potential glaucoma treatments, particularly trabeculectomy. As mentioned, the chronic administration of topical glaucoma medications and their associated preservatives often have cytotoxic effects on the ocular surface. The effect of underlying OSD on glaucoma filtration surgery outcomes should always be considered prior to proceeding with trabeculectomy.

Boimer et al. performed a retrospective study evaluating the effect of BAK exposure on trabeculectomy outcomes and found a dose-dependent response between pre-operative BAK use and early surgical failure (48). In addition to the BAK preservative, topical medications themselves may also predispose to increased risk of surgical failure. The subclinical histologic inflammation induced by topical medications has been theorized to increase the risk of conjunctival bleb scarring, and thus surgical failure (49,50). However, the clinical correlation of this histological inflammation is controversial. Lavin et al. and Broadway et al. found that long-term topical combination therapy was a significant risk factor for trabeculectomy failure, with differences in histological inflammation seen on conjunctival biopsy (51,52). However, these findings may have been influenced by possible selection bias, due to poor randomization and lack of blinding in the study protocols. Johnson et al. also evaluated the effect of medical therapy on trabeculectomy outcomes, and found no significant correlation between long-term medication use and trabeculectomy failure rates (53).

Nonetheless, optimization of the ocular surface is an important step that should be taken into consideration prior to proceeding with glaucoma surgery, as successful outcomes may be facilitated by reducing inflammation and improving overall ocular surface health (54,55). Treatment of underlying OSD should include frequent administration of topical lubricants, appropriate lid hygiene, and avoiding the use of preservatives when appropriate.

In addition to optimizing the ocular surface pre-operatively, the continued management of OSD may be beneficial in minimizing risk of post-operative complications. Infection is a risk inherent to any surgery, and certain ocular surface findings can predispose to the development of post-operative infections. Chronic blepharitis has been found to be a significant risk factor for developing a bleb-related infection (56,57). The exact mechanism is unclear, but it is posited that alterations to the tear film composition may interfere with the ability of the ocular surface to eliminate bacteria. Rai et al. advocated for pre-operative screening of blepharitis, to properly assess and discuss the risk of infection with the patient prior to surgery.

Discussion

OSD is a prevalent, yet often undertreated condition in the management of glaucoma both medically and surgically. Given the well-known adverse effects of glaucoma medications on the ocular surface, patients on medical therapy for glaucoma should be regularly assessed for OSD, especially if escalation of medical therapy is being considered. Incisional glaucoma surgery, such as trabeculectomy, may cause an acute worsening of OSD due to anatomic alteration of the conjunctiva and subsequent mechanical disruption of the tear film. It is therefore important for clinicians to perform a thorough pre-operative evaluation of the ocular surface, and to maintain a high clinical suspicion for OSD exacerbations during the first 6 post-operative months. However, there may be an overall long-term net benefit of trabeculectomy on OSD, likely related to decreased medication burden. Similarly, numerous MIGS procedures have been shown in pilot studies to effectively reduce IOP as well as post-operative medication burden. Given their relatively minimal disruption of the ocular surface, the expanding role of MIGS in the surgical management of glaucoma may represent a promising development for the treatment of comorbid OSD. However, further studies are needed to assess the long-term impact of MIGS on the ocular surface.

This review has some limitations. First, there was a paucity of dedicated studies assessing the effect of MIGS procedures on the ocular surface. At this time, the study by Schweitzer et al. on the iStent’s effects on the ocular surface remains the only study on this topic (27). However, it is limited by its small sample size, single-arm design, and limited follow-up of only 3 months. Mathew et al. (32) provided a thorough review of MIGS to date; however, their Cochrane review was more focused on the efficacy of iStent relative to other proven therapies, rather than directly addressing the ocular surface. There remains a lack of dedicated randomized controlled trials assessing the effect of each glaucoma intervention on the ocular surface. The majority of the aforementioned studies were cross-sectional, observational studies, which are more susceptible to bias and confounding. Additionally, heterogeneity in study design on a given subject made it difficult to directly compare outcomes. For example, the studies assessing the effects of trabeculectomy on the ocular surface included an observational cross-sectional study, a retrospective case-control study, a case series, and a single-arm prospective cohort study. Conclusions drawn from these studies are in need of further support. Areas for further study include the effect of pre-operative OSD on trabeculectomy outcomes, the quantitative effect of MIGS on ocular surface health, and the long-term effects of trabeculectomy on the ocular surface beyond 1 year.

Conclusions

When managing glaucoma patients, clinicians must continually assess the ocular surface and maintain a low threshold to treat coexisting OSD. A comprehensive understanding of the importance of OSD in both the medical and surgical management of glaucoma is essential in optimizing patient care and improving outcomes.

Acknowledgments

The authors would like to thank Dr. Kang (Department of Ophthalmology & Visual Sciences, Albert Einstein College of Medicine, Montefiore Medical Center, Greene Medical Arts PavilionHenkind Institute, Bronx, NY, USA) for guidance throughout this project.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Joann Kang and Roy S. Chuck) for the series “Ocular Surface Reconstruction/Transplantation” published in Annals of Eye Science. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-22-59/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-22-59/coif). The series “Ocular Surface Reconstruction/Transplantation” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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