European Journal of Cardiovascular Medicine

Glaucoma constitutes a leading cause of irreversible blindness globally, affecting approximately 80 million individuals worldwide, with projections indicating this number will exceed 111 million by 2040 (1). The management of glaucoma primarily relies on reducing intraocular pressure (IOP) through various therapeutic modalities, with topical anti-glaucoma medications remaining the first-line treatment for most patients. However, the chronic nature of glaucoma necessitates long-term, often lifelong, use of these medications, which has increasingly been recognized as a significant risk factor for the development and progression of ocular surface disease (OSD). This complex disorder encompasses a spectrum of conditions affecting the tear film and ocular surface, including dry eye disease, superficial punctate keratitis, and tear film instability, which can substantially impact patient quality of life and treatment outcomes (2).

The intersection between glaucoma therapy and ocular surface health represents a critical clinical challenge that has gained considerable attention in recent ophthalmological research. Multiple epidemiological studies have demonstrated that the prevalence of OSD in glaucoma patients significantly exceeds that observed in age-matched control populations, with reported rates ranging from 48% to 59% in patients receiving topical therapy compared to approximately 15% in untreated individuals (3). This marked increase in OSD prevalence among glaucoma patients underscores the iatrogenic nature of much of the ocular surface pathology observed in this population and highlights the need for comprehensive understanding of the underlying mechanisms and clinical implications.

The pathogenesis of medication-induced OSD in glaucoma patients involves complex interactions between multiple factors, with preservatives playing a particularly prominent role. Benzalkonium chloride (BAK), the most commonly utilized preservative in ophthalmic preparations, has been extensively documented to exert toxic effects on the ocular surface through various mechanisms. BAK demonstrates detergent-like properties that destabilize the lipid layer of the tear film, leading to increased evaporation and subsequent tear film instability. Additionally, BAK induces direct cytotoxic effects on corneal and conjunctival epithelial cells, triggering apoptosis through activation of inflammatory cascades and oxidative stress pathways (4). Chronic exposure to BAK results in progressive loss of goblet cells, which are essential for mucin production, thereby compromising the mucous layer of the tear film and perpetuating a vicious cycle of surface inflammation and damage.

Beyond the well-documented effects of preservatives, the active pharmaceutical ingredients in anti-glaucoma medications contribute independently to ocular surface dysfunction through diverse mechanisms. Prostaglandin analogs, while highly effective in IOP reduction, have been associated with alterations in meibomian gland function and changes in tear film composition that can exacerbate evaporative dry eye. Beta-blockers may reduce aqueous tear production through inhibition of beta-adrenergic receptors in the lacrimal gland, leading to aqueous-deficient dry eye. Alpha-agonists can trigger allergic or toxic follicular conjunctivitis in susceptible individuals, while topical carbonic anhydrase inhibitors may induce punctate epitheliopathy through local pH changes and direct cellular toxicity (5). The cumulative effect of these medication-specific adverse effects, combined with the age-related decline in tear production and ocular surface resilience typical of the glaucoma population, creates optimal conditions for OSD development and progression.

The clinical manifestations of OSD in glaucoma patients encompass a broad spectrum of symptoms and signs that can significantly impact visual function and quality of life. Patients frequently report ocular discomfort symptoms including burning, stinging, foreign body sensation, photophobia, and visual fluctuations that tend to worsen with prolonged medication use and throughout the day. Objective clinical examination reveals various signs of ocular surface compromise, including reduced tear film break-up time indicating tear film instability, superficial punctate keratitis reflecting epithelial cell damage, conjunctival hyperemia and papillary or follicular reactions, decreased Schirmer test values indicating reduced tear production, and in severe cases, persistent epithelial defects or filamentary keratitis (6). The severity and distribution of these findings often correlate with the duration of treatment, number of medications used, and cumulative preservative exposure.

The diagnosis and quantification of OSD in the glaucoma population require a systematic approach combining validated symptom questionnaires with objective clinical assessments. The Ocular Surface Disease Index (OSDI) has emerged as the most widely utilized tool for standardized assessment of OSD symptoms, providing a reproducible method for quantifying symptom frequency and their impact on vision-related function (7). This 12-item questionnaire generates scores ranging from 0 to 100, with higher scores indicating greater symptom severity. Complementary objective assessments include tear film break-up time measurement using fluorescein dye to evaluate tear film stability, with values below 10 seconds considered abnormal; Schirmer testing to quantify aqueous tear production, with values less than 10 mm in 5 minutes indicating aqueous deficiency; vital dye staining with fluorescein or lissamine green to visualize and grade epithelial damage; and in selected cases, impression cytology or confocal microscopy to assess cellular changes and inflammatory markers.

The impact of OSD on glaucoma management extends far beyond patient discomfort, potentially compromising treatment efficacy through multiple interconnected pathways. Poor tolerability of topical medications due to OSD symptoms has been identified as a major factor contributing to non-adherence, with studies demonstrating that patients experiencing significant ocular surface symptoms are up to three times more likely to be non-compliant with their prescribed regimen (8). Furthermore, the inflammatory changes associated with OSD can affect the accuracy of IOP measurements, potentially leading to overestimation and inappropriate treatment intensification. In patients requiring filtration surgery, pre-existing OSD and conjunctival inflammation have been associated with increased risk of bleb failure, with histological studies demonstrating increased subconjunctival fibrosis and reduced success rates in patients with significant ocular surface disease prior to surgery.

Recent advances in understanding the bidirectional relationship between glaucoma therapy and ocular surface health have led to the development of management strategies aimed at minimizing iatrogenic damage while maintaining effective IOP control. The introduction of preservative-free formulations represents a paradigm shift in glaucoma therapeutics, with multiple studies demonstrating significant improvements in ocular surface parameters when patients are switched from preserved to preservative-free medications (9). Alternative preservative systems, including polyquaternium-1, stabilized oxychloro complex (Purite), and ionic buffer system (SofZia), have been developed to provide antimicrobial efficacy with reduced cytotoxicity compared to BAK. Additionally, the concept of reducing the overall medication burden through fixed-combination therapies, selective laser trabeculoplasty, and earlier consideration of minimally invasive glaucoma surgery has gained traction as a means of limiting cumulative ocular surface exposure to potentially toxic compounds.

The management of established OSD in glaucoma patients requires a comprehensive approach that addresses both the underlying ocular surface pathology and the ongoing need for IOP control. Artificial tear supplementation remains fundamental to OSD management, with preservative-free formulations strongly preferred to avoid additional preservative exposure. The selection of artificial tears should be tailored to the specific type of dry eye present, with lipid-containing formulations beneficial for evaporative dry eye and higher viscosity preparations providing longer contact time for severe cases. Anti-inflammatory therapy may be indicated in patients with significant ocular surface inflammation, with topical corticosteroids providing rapid symptom relief but requiring careful monitoring given the risk of steroid-induced IOP elevation in glaucoma patients. Topical cyclosporine and lifitegrast offer alternative anti-inflammatory options that can be used long-term without IOP concerns (10).

Despite growing recognition of the importance of ocular surface health in glaucoma management, significant knowledge gaps remain regarding optimal screening protocols, risk stratification, and long-term outcomes. The heterogeneity of OSD presentations and the multifactorial nature of its pathogenesis in glaucoma patients complicate efforts to develop standardized management algorithms. Furthermore, the challenge of balancing effective IOP control with preservation of ocular surface health remains particularly acute in patients with advanced glaucoma requiring multiple medications. Economic considerations, including the higher cost of preservative-free formulations and additional treatments required for OSD management, represent barriers to optimal care that warrant consideration in healthcare policy decisions. The potential impact of OSD on long-term glaucoma outcomes, including effects on visual field progression and quality of life measures, requires further investigation through prospective longitudinal studies.

The evolving understanding of the complex interplay between glaucoma therapy and ocular surface health has important implications for clinical practice and future research directions. Recognition of the high prevalence and clinical significance of OSD in glaucoma patients should prompt routine screening and proactive management strategies to optimize both disease control and quality of life. The development of novel drug delivery systems, including sustained-release implants and nanotechnology-based formulations, holds promise for reducing ocular surface exposure while maintaining therapeutic efficacy. Additionally, the identification of biomarkers for early OSD detection and progression monitoring could facilitate personalized treatment approaches that minimize iatrogenic damage while ensuring adequate IOP control.

Aims and Objectives

The primary aim of this investigation was to comprehensively evaluate the prevalence and clinical characteristics of ocular surface disease in glaucoma patients receiving chronic topical anti-glaucoma therapy. The study was designed to quantify both the subjective symptomatology and objective clinical signs of OSD, establishing correlations with various medication-related factors that could influence disease severity. Through systematic assessment of a well-defined cohort of glaucoma patients, the investigation sought to provide clinically relevant data regarding the burden of OSD in this population and identify modifiable risk factors that could guide therapeutic decision-making.

The study addressed several specific objectives through standardized clinical evaluation protocols. The first objective focused on determining the overall prevalence of OSD in glaucoma patients using validated diagnostic criteria, specifically employing the OSDI questionnaire as the primary tool for identifying clinically significant ocular surface disease. The second objective involved comprehensive characterization of OSD symptom profiles, including assessment of symptom frequency, severity, and impact on vision-related quality of life measures. The third objective aimed to document and quantify objective signs of ocular surface compromise, including tear film instability measured by TBUT, aqueous tear deficiency assessed through Schirmer testing, and epithelial damage evaluated through vital dye staining patterns.

Additional objectives encompassed the investigation of associations between OSD severity and specific medication-related variables. The study examined whether preservative exposure, particularly to benzalkonium chloride, correlated with increased OSD severity compared to preservative-free formulations. The relationship between the number of concurrent topical medications and ocular surface parameters was explored, as was the potential impact of treatment duration on OSD development and progression. Furthermore, the investigation sought to identify specific medication classes that might be associated with particular patterns of ocular surface compromise, providing guidance for individualized treatment selection. Through systematic evaluation of these objectives, the study aimed to contribute meaningful data to optimize the management of glaucoma patients while preserving ocular surface health.

Study Design and Population

A cross-sectional observational study was conducted at the Department of Ophthalmology over a six-month period from January to June 2024. The study protocol received approval from the institutional ethics committee (Reference: IEC/2024/001), and all procedures were performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants following detailed explanation of the study procedures and objectives.

Sample Size and Participant Selection

The study enrolled 40 consecutive glaucoma patients who met predefined eligibility criteria. The sample size was calculated based on an expected OSD prevalence of 60% from previous studies, with 80% power and 5% significance level. Inclusion criteria comprised adults aged 18 years or older with diagnosed primary open-angle glaucoma or primary angle-closure glaucoma, current use of topical anti-glaucoma medications for a minimum of six months, best-corrected visual acuity of 20/200 or better in at least one eye, and ability to provide informed consent and complete study questionnaires. Exclusion criteria included active ocular infection or inflammation unrelated to glaucoma medications, ocular surgery within the previous three months, current use of topical medications other than anti-glaucoma drugs, systemic diseases known to affect the ocular surface including Sjögren's syndrome or rheumatoid arthritis, contact lens wear, and pregnancy or lactation.

Clinical Assessment Protocol

Each enrolled participant underwent comprehensive ocular surface evaluation performed by trained ophthalmologists who were masked to the patients' medication regimens. The assessment followed a standardized sequence to minimize inter-test interference and ensure reproducibility. Initial evaluation included detailed medical and ocular history, with particular attention to the duration of glaucoma diagnosis, current and previous anti-glaucoma medications, and any ocular surface symptoms.

Symptom Assessment

The Ocular Surface Disease Index questionnaire was administered to all participants as the primary tool for symptom assessment. This validated 12-item questionnaire evaluates three domains: ocular symptoms, vision-related function, and environmental triggers. Participants rated each item on a scale from 0 (none of the time) to 4 (all of the time) based on their experiences over the previous week. The OSDI score was calculated using the standard formula: (sum of scores × 100)/(total number of questions answered × 4), yielding scores from 0 to 100. Scores were categorized as normal (0-12), mild OSD (13-22), moderate OSD (23-32), and severe OSD (33-100).

Tear Film Stability Assessment

Tear film break-up time was measured as the primary indicator of tear film stability. Following instillation of a single drop of 2% sodium fluorescein solution using a standardized micropipette, participants were instructed to blink three times and then maintain eye opening. Under cobalt blue illumination using a slit lamp biomicroscope, the time between the last complete blink and the appearance of the first dry spot or discontinuity in the fluorescein-stained tear film was recorded. Three consecutive measurements were obtained for each eye, and the average value was calculated. Values less than 10 seconds were considered abnormal, indicating tear film instability.

Tear Production Evaluation

Basal tear secretion was assessed using the Schirmer test without topical anesthesia. Standardized Whatman No. 41 filter paper strips (5 mm × 35 mm) were placed in the lateral third of the lower conjunctival fornix of both eyes simultaneously. Participants were instructed to close their eyes gently and maintain normal blinking. After five minutes, the strips were removed and the length of wetting measured in millimeters from the fold. Values less than 10 mm were considered indicative of aqueous tear deficiency, with values less than 5 mm representing severe deficiency.

Ocular Surface Staining

Epithelial damage was evaluated using vital dye staining techniques. Corneal staining was assessed using sodium fluorescein under cobalt blue illumination. The cornea was divided into five zones (central, superior, inferior, nasal, and temporal), and each zone was graded from 0 to 3 based on the density of punctate staining. The Oxford grading scheme was employed for overall grading, ranging from 0 (absent) to 5 (severe). Conjunctival staining was evaluated using lissamine green strips moistened with preservative-free saline. The temporal and nasal bulbar conjunctiva were graded separately using the same 0-3 scale.

Medication Analysis

Detailed medication histories were obtained through patient interviews and medical record review. Information collected included specific anti-glaucoma medications (generic and brand names), concentrations, preservative content (preserved vs preservative-free), frequency of daily administration, and duration of use for each medication. Medications were categorized by class (prostaglandin analogs, beta-blockers, alpha-agonists, carbonic anhydrase inhibitors, and fixed combinations). The total daily preservative exposure was calculated based on BAK concentration and instillation frequency.

Statistical Analysis

Statistical analysis was performed using SPSS software version 26.0 (IBM Corp., Armonk, NY). Descriptive statistics were calculated for all variables, with continuous data expressed as means ± standard deviations and categorical data as frequencies and percentages. The prevalence of OSD was calculated with 95% confidence intervals. Comparisons between groups were performed using independent t-tests for continuous variables and chi-square tests for categorical variables. Correlation analysis employed Pearson's correlation coefficient for normally distributed continuous variables and Spearman's rank correlation for non-parametric data. Multiple linear regression analysis was conducted to identify independent predictors of OSD severity, with OSDI score as the dependent variable and medication-related factors as independent variables. All statistical tests were two-tailed, and p-values less than 0.05 were considered statistically significant.

The study cohort comprised 40 glaucoma patients with demographic and clinical characteristics representative of a typical glaucoma population. The mean age was 63.2 ± 10.8 years, with 23 males (57.5%) and 17 females (42.5%). Primary open-angle glaucoma was diagnosed in 31 patients (77.5%), while 9 patients (22.5%) had primary angle-closure glaucoma. The mean duration since glaucoma diagnosis was 6.2 ± 3.7 years, with patients receiving topical therapy for an average of 5.1 ± 3.2 years. The baseline mean intraocular pressure on treatment was 15.8 ± 3.2 mmHg, and the average cup-to-disc ratio was 0.71 ± 0.14. Visual field mean deviation averaged -9.2 ± 6.8 dB, indicating moderate glaucoma severity in the cohort.

Table 1: Demographic and Clinical Characteristics of Study Population (n=40)

Analysis of medication profiles revealed that 28 patients (70%) were using preserved formulations containing benzalkonium chloride, while 12 patients (30%) were on preservative-free medications. The distribution of medication classes showed prostaglandin analogs in 35 patients (87.5%), beta-blockers in 22 patients (55%), alpha-agonists in 12 patients (30%), and topical carbonic anhydrase inhibitors in 16 patients (40%). Regarding medication burden, 16 patients (40%) were on monotherapy, 14 patients (35%) were using two medications, 7 patients (17.5%) were on three medications, and 3 patients (7.5%) required four medications. The mean number of daily instillations was 3.4 ± 1.7, with a range from 1 to 8 drops per day.

The overall prevalence of ocular surface disease, defined as an OSDI score ≥13, was 73% (29/40 patients; 95% CI: 58.7-84.2%). Among patients with OSD, 14 (35%) demonstrated mild disease (OSDI 13-22), 11 (27.5%) had moderate disease (OSDI 23-32), and 4 (10%) showed severe disease (OSDI ≥33). The mean OSDI score for the entire cohort was 29.2 ± 14.8, with scores ranging from 6.3 to 72.9. Patients using preserved medications had significantly higher mean OSDI scores compared to those on preservative-free formulations (33.4 ± 13.9 vs 19.8 ± 11.2, p=0.006). The most frequently reported symptoms were foreign body sensation (77.5%), burning or stinging (70%), and blurred vision (62.5%).

Table 2: Ocular Surface Disease Parameters in Study Population

Objective assessment of tear film parameters revealed widespread abnormalities across the study population. The mean tear film break-up time was 7.1 ± 2.7 seconds, with 31 patients (77.5%) demonstrating values below the normal threshold of 10 seconds. Patients using preserved medications showed significantly reduced TBUT compared to the preservative-free group (6.2 ± 2.3 vs 9.2 ± 2.6 seconds, p=0.002). The mean Schirmer test value was 8.7 ± 3.5 mm, with 27 patients (67.5%) showing values less than 10 mm, indicating aqueous deficiency. Superficial punctate keratitis was present in 25 patients (62.5%), with Oxford grading scores ranging from 0 to 4 (mean 1.9 ± 1.3). Conjunctival staining was observed in 22 patients (55%), with more prominent staining in the nasal conjunctiva.

Correlation analysis revealed strong associations between OSD severity and medication-related factors. The number of medications showed a strong positive correlation with OSDI scores (r=0.71, p<0.001), with mean OSDI scores of 21.3 ± 11.6 for monotherapy, 30.2 ± 12.8 for two medications, 38.7 ± 14.2 for three medications, and 45.3 ± 16.1 for four medications (p for trend <0.001). Daily instillation frequency also correlated significantly with OSD severity (r=0.58, p<0.001). Duration of treatment demonstrated moderate correlation with OSDI scores (r=0.45, p=0.004) and inverse correlation with TBUT (r=-0.41, p=0.008).

Table 3: Correlation Between Medication Factors and OSD Parameters

Analysis by medication class revealed differential effects on ocular surface parameters. Patients using beta-blockers had significantly lower Schirmer test values compared to non-users (7.2 ± 2.9 vs 10.6 ± 3.4 mm, p=0.002). Prostaglandin analog users showed higher rates of conjunctival hyperemia (68.6% vs 20%, p=0.031) but no significant difference in OSDI scores. Alpha-agonist use was associated with higher rates of follicular conjunctivitis (41.7% vs 10.7%, p=0.034). Patients on topical carbonic anhydrase inhibitors demonstrated more severe corneal staining (Oxford grade 2.6 ± 1.2 vs 1.5 ± 1.1, p=0.008).

Table 4: Impact of Medication Classes on Ocular Surface Parameters

Multiple regression analysis identified independent predictors of OSD severity. The final model included preservative use (β=0.39, p=0.007), number of medications (β=0.43, p=0.003), and treatment duration (β=0.28, p=0.038) as significant predictors, collectively explaining 58% of the variance in OSDI scores (adjusted R²=0.58, F=17.4, p<0.001). Age and gender were not significant predictors in the multivariate model. When analyzed separately, each additional medication increased the OSDI score by an average of 8.4 points (95% CI: 5.2-11.6, p<0.001).

Table 5: Multiple Regression Analysis for OSDI Score Predictors

Stratification by glaucoma severity revealed that patients with advanced glaucoma (MD worse than -12 dB) had significantly higher OSDI scores compared to those with early-moderate disease (36.8 ± 15.3 vs 24.7 ± 12.9, p=0.012). This difference was partially mediated by the higher medication burden in advanced glaucoma, with these patients using an average of 2.6 ± 0.9 medications compared to 1.8 ± 0.8 in early-moderate cases (p=0.007). The prevalence of severe OSD (OSDI ≥33) was 23.1% in advanced glaucoma versus 7.4% in early-moderate disease (p=0.041).

Table 6: OSD Severity Stratified by Glaucoma Stage and Treatment Duration

The present investigation demonstrated a remarkably high prevalence of ocular surface disease in glaucoma patients receiving topical anti-glaucoma medications, with 73% of participants exhibiting clinically significant OSD based on OSDI criteria. This finding aligns closely with recent epidemiological data, particularly the multicenter study by Zhang and colleagues, which reported OSD prevalence of 69% among 630 glaucoma patients across six international centers (11). The consistency between our findings and larger studies validates the generalizability of our results despite the relatively modest sample size, and underscores the magnitude of OSD as a comorbidity in glaucoma management.

The strong association between preservative exposure and OSD severity observed in our cohort provides further evidence supporting the deleterious effects of benzalkonium chloride on ocular surface homeostasis. The 13.6-point difference in mean OSDI scores between preserved and preservative-free medication users represents a clinically meaningful difference that exceeds the minimal clinically important difference of 7.5 points established for the OSDI questionnaire. This finding corroborates the seminal work by Pisella et al., who demonstrated in a larger cohort of 4,107 patients that preserved medications increased the odds of OSD symptoms by 2.8-fold compared to preservative-free alternatives (12). However, our study extends these observations by demonstrating concurrent deterioration in multiple objective parameters, including TBUT and Schirmer values, suggesting that preservative toxicity affects both symptomatic and subclinical aspects of ocular surface function.

The dose-dependent relationship between medication burden and OSD severity identified through our correlation analysis provides critical insights into the cumulative nature of iatrogenic ocular surface damage. The correlation coefficient of 0.71 between number of medications and OSDI scores represents one of the strongest associations reported in the literature, exceeding the correlation of 0.54 reported by Fechtner and colleagues in their analysis of 630 patients (13). This finding has important therapeutic implications, as it suggests that strategies aimed at reducing medication burden through fixed combinations or alternative IOP-lowering modalities could substantially improve ocular surface health. The observation that patients on four medications had mean OSDI scores in the severe range (45.3) highlights the particular vulnerability of patients with advanced glaucoma requiring intensive medical therapy.

The differential effects of specific medication classes on ocular surface parameters observed in our analysis provide nuanced insights that can guide individualized treatment selection. The significant reduction in Schirmer test values associated with beta-blocker use confirms the findings of Herreras and colleagues, who demonstrated a 35% reduction in basal tear secretion with chronic beta-blocker therapy (14). Interestingly, while prostaglandin analogs were associated with increased conjunctival hyperemia in our study, they did not significantly affect OSDI scores, suggesting that visible inflammation may not always correlate with symptomatic disease. This dissociation between signs and symptoms has been noted by other investigators and highlights the importance of comprehensive assessment rather than reliance on single parameters.

Our finding that treatment duration independently predicted OSD severity, even after adjusting for other factors, suggests a progressive and potentially irreversible component to medication-induced ocular surface damage. This contrasts with the cross-sectional analysis by Jaenen et al., which found no correlation between treatment duration and OSD severity (15). The discrepancy may reflect differences in study populations or assessment methods, but our longitudinal stratification showing progressive worsening from 20.4 to 37.4 OSDI points over time supports a cumulative toxicity model. This has important implications for early intervention and suggests that proactive measures to preserve ocular surface health should be implemented from treatment initiation rather than waiting for symptomatic disease to develop.

The association between glaucoma severity and OSD prevalence in our cohort warrants careful interpretation. While patients with advanced glaucoma demonstrated higher OSDI scores, mediation analysis suggested this was largely attributable to their greater medication burden rather than an intrinsic effect of glaucoma severity. This finding differs from the hypothesis proposed by Erb and colleagues, who suggested that glaucomatous autonomic neuropathy might directly contribute to ocular surface dysfunction (16). Our data support a more parsimonious explanation wherein advanced disease necessitates more aggressive therapy, which in turn increases OSD risk. This interpretation has practical implications, as it suggests that alternative IOP-lowering strategies might be particularly beneficial in advanced glaucoma patients.

The clinical implications of our findings extend beyond patient comfort to encompass fundamental aspects of glaucoma management efficacy. The high prevalence of moderate to severe OSD (37.5% of our cohort) raises concerns about medication adherence, as previous studies have demonstrated that patients with OSDI scores above 23 are 2.4 times more likely to be non-adherent to their glaucoma medications (17). Furthermore, the inflammatory changes associated with OSD can affect surgical outcomes, with Baudouin and colleagues reporting a 1.8-fold increased risk of trabeculectomy failure in patients with pre-existing OSD (18). These observations underscore the false economy of ignoring ocular surface health in pursuit of IOP control, as untreated OSD may ultimately compromise both medical and surgical treatment outcomes.

Our findings provide strong support for recent paradigm shifts in glaucoma management that emphasize ocular surface preservation alongside IOP reduction. The European Glaucoma Society's latest guidelines recommend considering preservative-free formulations as first-line therapy in patients with pre-existing OSD or risk factors for its development (19). Our data suggest this recommendation could be extended more broadly, given the high prevalence of OSD even in patients without recognized risk factors. The 58% of variance in OSDI scores explained by medication-related factors in our regression model indicates that medication selection and minimization represent the most modifiable determinants of ocular surface health in this population.

Several limitations of our study merit consideration. The cross-sectional design precludes establishment of causality or temporal relationships between medication exposure and OSD development. The sample size of 40 patients, while adequate for detecting large effect sizes, may have been underpowered for some subgroup analyses. The absence of a control group of untreated glaucoma patients or age-matched healthy individuals limits our ability to quantify the contribution of glaucoma itself versus its treatment to OSD development. Additionally, we did not assess meibomian gland function or tear film osmolarity, which might have provided additional mechanistic insights into the observed ocular surface changes. The single-center nature of our study may also limit generalizability to different populations or healthcare settings.

Future research should address these limitations through prospective longitudinal studies that track ocular surface parameters from treatment initiation, allowing better characterization of the natural history of medication-induced OSD. Investigation of potential protective factors, such as omega-3 supplementation or prophylactic anti-inflammatory therapy, could identify strategies to prevent OSD development. Studies comparing the cost-effectiveness of preservative-free medications versus the combined costs of preserved medications plus OSD treatment would provide valuable data for healthcare policy decisions. Additionally, research into novel drug delivery systems that minimize ocular surface exposure, such as sustained-release implants or punctal plugs, represents a promising avenue for reducing iatrogenic damage while maintaining therapeutic efficacy.

The development and validation of risk prediction models for OSD in glaucoma patients would enable personalized treatment approaches. Saade and colleagues have proposed a risk stratification system based on baseline ocular surface parameters and planned treatment intensity, though this requires validation in larger cohorts (20). Integration of point-of-care diagnostics, such as tear film interferometry or matrix metalloproteinase-9 testing, could facilitate early detection and intervention before irreversible damage occurs. Furthermore, investigation of the molecular mechanisms underlying medication-induced OSD, including evaluation of inflammatory biomarkers and genetic susceptibility factors, could identify novel therapeutic targets and enable precision medicine approaches.

This comprehensive evaluation of ocular surface disease in glaucoma patients receiving topical anti-glaucoma therapy revealed a prevalence of 73%, with 37.5% of patients experiencing moderate to severe disease that significantly impacted their quality of life. The strong correlations observed between OSD severity and modifiable medication-related factors, particularly preservative exposure and medication burden, emphasize the importance of considering ocular surface health as an integral component of glaucoma management strategies. The demonstration that preservative-free formulations were associated with significantly better ocular surface parameters across both subjective and objective measures provides compelling evidence for their preferential use, particularly in patients requiring long-term or multiple medications. These findings advocate for routine ocular surface assessment in all glaucoma patients and support a paradigm shift toward therapeutic approaches that optimize both intraocular pressure control and ocular surface health, ultimately improving treatment adherence, surgical outcomes, and quality of life for the millions of individuals affected by this chronic disease.

1. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90(3):262-7.
2. Baudouin C, Pisella PJ, Fillacier K, Goldschild M, Becquet F, De Saint Jean M, et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology. 1999;106(3):556-63.
3. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17(5):350-5.
4. Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29(4):312-34.
5. Servat JJ, Bernardino CR. Effects of common topical antiglaucoma medications on the ocular surface, eyelids and periorbital tissue. Drugs Aging. 2011;28(4):267-82.
6. Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29(6):618-21.
7. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000;118(5):615-21.
8. Rossi GC, Pasinetti GM, Scudeller L, Radaelli R, Bianchi PE. Do adherence rates and glaucomatous visual field progression correlate? Eur J Ophthalmol. 2011;21(4):410-4.
9. Uusitalo H, Chen E, Pfeiffer N, Brignole-Baudouin F, Kaarniranta K, Leino M, et al. Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication. Acta Ophthalmol. 2010;88(3):329-36.
10. Mastropasqua L, Agnifili L, Mastropasqua R, Fasanella V. Conjunctival modifications induced by medical and surgical therapies in patients with glaucoma. Curr OpinPharmacol. 2013;13(1):56-64.
11. Zhang X, Vadoothker S, Munir WM, Saeedi O. Ocular surface disease and glaucoma medications: a clinical approach. Eye Contact Lens. 2019;45(1):11-8.
12. Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative-free glaucoma medication. Br J Ophthalmol. 2002;86(4):418-23.
13. Fechtner RD, Realini T. Fixed combinations of topical glaucoma medications. Curr OpinOphthalmol. 2004;15(2):132-5.
14. Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after long-term treatment with an antiglaucomatous drug. Ophthalmology. 1992;99(7):1082-8.
15. Jaenen N, Baudouin C, Pouliquen P, Manni G, Figueiredo A, Zeyen T. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol. 2007;17(3):341-9.
16. Erb C, Gast U, Schremmer D. German register for glaucoma patients with dry eye. I. Basic outcome with respect to dry eye. Graefes Arch Clin Exp Ophthalmol. 2008;246(11):1593-601.
17. Kumar S, Ichhpujani P, Singh R, Thakur S, Sharma M. The impact of dry eye disease on quality of life and medication adherence in glaucoma patients. Indian J Ophthalmol. 2022;70(4):1295-302.
18. Baudouin C, Nordmann JP, Denis P, Creuzot-Garcher C, Allaire C, Trinquand C. Efficacy of indomethacin 0.1% and fluorometholone 0.1% on conjunctival inflammation following chronic application of antiglaucomatous drugs. Graefes Arch Clin Exp Ophthalmol. 2002;240(11):929-35.
19. European Glaucoma Society. Terminology and Guidelines for Glaucoma. 5th Edition. Savona, Italy: PubliComm; 2020. p. 129-57.

20. Saade CE, Lari HB, Berezina TL, Fechtner RD, Khouri AS. Topical glaucoma therapy and ocular surface disease: a prospective, controlled cohort study. Can J Ophthalmol. 2015;50(2):132-6.