Exploring Topical Anti-Glaucoma Medication Effects on the Ocular Surface in the Context of the Current Understanding of Dry Eye

The Ocular Surface 16 (2018) 289e293

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Original Research Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye

Aaron B.C. Wong, Michael T.M. Wang, Kevin Liu, Zak J. Prime, Helen V. Danesh-Meyer, * Jennifer P. Craig

Department of Ophthalmology, New Zealand National Eye Centre, The University of Auckland, New Zealand article info abstract

Article history: Purpose: To assess tear film parameters, ocular surface characteristics, and dry eye symptomology in Received 11 November 2017 patients receiving topical anti-glaucoma medications. Received in revised form Methods: Thirty-three patients with a diagnosis of open angle glaucoma or ocular hypertension, 26 February 2018 receiving unilateral topical anti-glaucoma medication for at least 6 months, were recruited in a cross- Accepted 2 March 2018 sectional, investigator-masked, paired-eye comparison study. Tear film parameters, ocular surface characteristics, and dry eye symptomology of treated and fellow eyes were evaluated and compared. Keywords: Results: The mean ± SD age of the participants was 67 ± 12 years, and the mean ± SD treatment duration Glaucoma ± fi ¼ fi Prostaglandin analogue was 5.3 4.4 years. Treated eyes had poorer non-invasive tear lm breakup time (p 0.03), tear lm ¼ ¼ Tear film osmolarity (p 0.04), bulbar conjunctival hyperaemia (p 0.04), eyelid margin abnormality grade Ocular surface (p ¼ 0.01), tear meniscus height (p ¼ 0.03), and anaesthetised Schirmer value (p ¼ 0.04) than fellow eyes. Dry eye There were no significant differences in dry eye symptomology, meibomian gland assessments, and Meibomian gland ocular surface staining between treated and fellow eyes (all p > 0.05). Conclusions: Adverse changes in tear film stability, tear osmolarity, conjunctival hyperaemia, and eyelid margins were observed in treated eyes. This suggests that inflammatory mechanisms may be implicated in the development of dry eye in patients receiving long term topical anti-glaucoma therapy. © 2018 Elsevier Inc. All rights reserved.

1. Introduction a common preservative in ophthalmic preparations [9], has been identified to be an independent risk factor for the development of Glaucoma and ocular surface disease are common chronic ocular surface disease in glaucoma patients [4,8] Benzalkonium conditions, which frequently coexist in ophthalmic patients [1e5]. chloride is recognised to destabilise the tear film lipid layer through Over 60 million people are affected by glaucoma worldwide, and its detergent-like tensioactive effects, which may promote excessive the global burden is expected to rise with the ageing population [6]. evaporation of the aqueous tear film. Furthermore, the pro- The prevalence of ocular surface disease is greater in glaucoma inflammatory and toxic effects of benzalkonium chloride can also patients than in the normal adult population [1,3], and has been lead to chronic damage of the ocular surface, and disrupt tear film reported to be as high as 60% [5]. The associated tear film homeostasis [1e4,8,9]. dysfunction and dry eye symptoms can contribute towards further Recent studies have explored the potential association between deterioration in ocular comfort, vision and quality of life [1e3,7]. topical anti-glaucoma medications and meibomian gland Although the propensity for dry eye development in glaucoma dysfunction [10e13]. Through its adverse effects on lipid layer patients is not fully understood, it is thought to be multifactorial integrity and tear film stability, meibomian gland dysfunction is a [1e3]. Clinical and laboratory studies have suggested that the long leading cause of evaporative dry eye disease [7,14e16]. Poorer tear term use of topical anti-glaucoma medications may contribute film quality and meibomian gland function have been observed [1e4,8]. In particular, increased exposure to benzalkonium chloride, with topical anti-glaucoma medication use in both paired-eye comparison and case control studies [10e13]. * Corresponding author. Department of Ophthalmology, New Zealand National This cross-sectional paired-eye comparison study sought to Eye Centre, The University of Auckland, New Zealand, Private Bag 92019, Auckland, investigate the effect of topical anti-glaucoma medication use on 1142, New Zealand. ocular surface characteristics, tear film quality, aqueous tear E-mail address: [email protected] (J.P. Craig). https://doi.org/10.1016/j.jtos.2018.03.002 1542-0124/© 2018 Elsevier Inc. All rights reserved. 290 A.B.C. Wong et al. / The Ocular Surface 16 (2018) 289e293 production, meibomian gland function, and dry eye symptomology. eye and the higher reading recorded. Lid margin abnormalities (lid margin irregularity, telangiectasia, plugged orifices of meibomian 2. Materials and methods glands, and anterior or posterior replacement of the mucocutaneous junction) were assessed by slit lamp examination, and scored 2.1. Subjects from 0 to 4, according to the number of abnormalities present in each eye [10]. This cross-sectional, investigator-masked, paired-eye compari- Sodium fluorescein and lissamine green dyes were applied, in son study adhered to the tenets of the Declaration of Helsinki, and turn, to the bulbar conjunctiva in order to evaluate localised corneal was approved by the institutional ethics committee. Participants and conjunctival areas of epithelial dessciation, and recorded using were required to be at least 18 years of age, with a diagnosis of open the Oxford grading scheme for ocular staining [22]. Lid wiper epi- angle glaucoma or ocular hypertension, and topical anti-glaucoma theliopathy (LWE) was also assessed following lissamine green medication use in only one eye. Furthermore, eligibility required application [23]. participants to report no changes in anti-glaucoma medications Meibomian gland function assessment was conducted in within the preceding 6 months, no contact lens wear, no use of accordance with the recommendations of the International Work- other topical or systemic medications known to affect the eye, no shop on Meibomian Gland Dysfunction and TFOS DEWS II [19,24]. history of Sjogren's€ syndrome, and no previous ocular surgery Expressibility of the inferior eyelid meibomian glands was assessed ® (other than phacoemulsification, childhood strabismus surgery, or with the Korb Meibomian Gland Evaluator™ (TearScience , North epiretinal membrane surgery, more than 6 months before study Carolina, USA). The number of meibomian orifices yielding lipid enrolment) [17]. Eligible participants were enrolled after providing secretion was evaluated at each of the nasal, central and temporal written informed consent. aspects of the lower lid [25]. The meibum viscosity and expressi- A total of 33 eligible participants were recruited, exceeding bility was graded as: grade 0, clear fluid; grade 1, slightly turbid; sample size requirements. Non-paramateric adjusted power cal- grade 2, thick opaque; grade 3, toothpaste-like; grade 4, complete culations were conducted using NCSS PASS 2002 (Utah, USA), with orifice blockage [21]. Infrared meibography was imaged with the non-invasive tear film breakup time as the designated outcome Oculus Keratograph 5 M, with the superior and inferior eyelids (due to yielding the most stringent sample size requirements of all everted in turn. From the captured image, the proportion of mei- outcome measures), and the normal SD estimated to be 6 s [18]. A bomian glands visible within the tarsal area were graded according minimum of 26 participants was required to detect a clinically to the Meiboscale [26]. significant difference of 5 s, with 80% power (b ¼ 0.2), at a two- The Schirmer I test was then performed, as the final assessment, sided statistical significance level of 5% (a ¼ 0.05). under topical anaesthesia (0.4% oxbuprocaine) [27].

2.2. Measurements 2.3. Statistics

Participants were instructed to refrain from taking the morning Statistical analyses were performed using IBM SPSS Statistics dose of topical anti-glaucoma medications before clinical assess- version 22 (New York, USA) and Graph Pad Prism version 6.02 ment. Tear film parameters, ocular surface characteristics and dry (California, USA). Comparisons of continuous variables were per- eye symptomatology were evaluated in both treated and untreated formed using paired t-tests, where normal distributions had been eyes of each participant, within a single clinical session. The in- confirmed by Kolmogorov-Smirnov testing (p > 0.05). Non- vestigators conducting measurements were masked to the treat- normally distributed continuous and ordinal data were analysed ment status of each eye. Assessments were conducted in ascending using Wilcoxon signed-rank test. All tests were two-tailed and order of invasiveness to minimise the impact on tear film physi- p < 0.05 was considered significant. All normally distributed ology for subsequent measurements: tear meniscus height, non- continuous data are presented as mean ± SD, non-normally invasive tear film breakup time, tear film lipid layer grade, bulbar distributed continuous data or ordinal data as median (IQR), and conjunctival hyperaemia, tear osmolarity, slit lamp examination, categorical data as number of participants (% of participants), un- ocular surface staining, meibomian gland expression, infrared less otherwise stated. meibography, Schirmer I test. All participants were assessed in the same location, with a mean ± SD room temperature of 21.5 ± 0.9 C, 3. Results and a mean ± SD relative humidity of 57.0 ± 11.1%. Dry eye symptomology for each eye was graded using the Ocular The mean ± SD age of the 33 participants (24 male, 9 female) Surface Disease Index (OSDI). Tear meniscus height, bulbar conjunctival hyperaemia, non-invasive tear film breakup time Table 1 fi Topical anti-glaucoma medications of study participants. Data are presented as (NIBUT), and tear lm lipid layer grade were evaluated with the number of participants (% of participants). Oculus Keratograph 5 M. Tear meniscus height was assessed using pre-calibrated digital imaging, and three measurements near the Medication No. (%) centre of the lower meniscus were averaged. Non-invasive tear film Prostaglandin analogue monotherapy breakup time was measured using automated detection of first Bimatoprost 8 (24%) Latanoprost 8 (24%) breakup, and three readings were averaged [19]. Tear film lipid Travoprost 6 (18%) fi layer was graded according to the modi ed Guillon-Keeler system: b-blocker monotherapy grade 1, open meshwork; grade 2, closed meshwork; grade 3, wave Timolol 1 (3%) or flow; grade 4, amorphous; grade 5, colored fringes; grade 0, non- Combination therapy continuous layer (non-visible or abnormal colored fringes) [20,21]. Betaxolol and Latanoprost 1 (3%) Bimatoprost and Timolol 1 (3%) Standardised JENVIS bulbar conjunctival hyperaemia scores were Bimatoprost, Brimonidine and Timolol 1 (3%) quantified using automated objective evaluation of digital imaging. Bimatoprost, Dorzolamide and Timolol 3 (9%) Tear film osmolarity was assessed with a clinical osmometer Brimonidine and Timolol 2 (6%) (TearLab, California, USA), using 50 nL tear samples collected from Dorzolamide and Timolol 1 (3%) Timolol and Travoprost 1 (3%) the inferior tear meniscus. Two measurements were taken for each A.B.C. Wong et al. / The Ocular Surface 16 (2018) 289e293 291

Table 2 Measurements of the eyes of participants treated with anti-glaucoma medications and untreated fellow eyes. Data are presented as mean ± SD or median (IQR). Asterisks denote statistically signiﬁcant differences (p < 0.05).

All participants Participants on prostaglandin analogue therapy

Treated eye (n ¼ 33) Fellow Eye (n ¼ 33) p Treated eye (n ¼ 29) Fellow Eye (n ¼ 29) p

Dry eye symptomology OSDI score 5.0 (2.3e14.6) 6.3 (2.1e11.4) 0.11 5.0 (2.3e14.6) 6.3 (2.2e11.4) 0.14 Tear film function Non-invasive tear film breakup time (s) 7.5 (5.2e13.0) 10.1 (6.8e14.5) 0.03* 7.2 (5.2e13.0) 10.1 (6.8e14.6) 0.03* Tear film osmolarity (mOsmol/L) 313 ± 12 305 ± 11 0.04* 314 ± 14 304 ± 12 0.03* Aqueous tear production Tear meniscus height (mm) 0.41 ± 0.19 0.47 ± 0.17 0.03* 0.40 ± 0.22 0.46 ± 0.19 0.04* Schirmer value (mm) 14 ± 716± 8 0.04* 14 ± 816± 8 0.04* Meibomian gland function Tear film lipid layer grade 3 (3e4) 3 (3e4) 0.65 3 (3e4) 3 (3e4) 0.53 Superior eyelid meibography grade 2 (1e3) 1 (1e3) 0.49 2 (1e3) 1 (1e3) 0.46 Inferior eyelid meibography grade 2 (1e3) 1 (1e2) 0.38 2 (1e3) 1 (1e2) 0.36 Number of meibomian glands yielding lipid secretions 5 (2e7) 5 (3e7) 0.41 5 (2e7) 5 (3e7) 0.35 Expressed meibum grade 1 (1e2) 1 (1e2) 0.63 1 (1e2) 1 (1e2) 0.57 Ocular surface characteristics Eyelid margin abnormality score 2 (1e3) 1 (1e2) 0.01* 2 (1e3) 1 (1e2) 0.008* JENVIS bulbar conjunctival hyperaemia score 1.5 ± 0.3 1.3 ± 0.3 0.04* 1.6 ± 0.4 1.4 ± 0.4 0.04* Conjunctival lissamine green staining score (out of 30) 0 (0e2) 0 (0e2) 0.54 0 (0e2) 0 (0e2) 0.58 Corneal sodium fluorescein staining score (out of 25) 0 (0e1) 0 (0e0) 0.14 0 (0e1) 0 (0e0) 0.20 Lid wiper epitheliopathy grade 1 (0e3) 1 (0e3) 0.80 1 (0e3) 1 (0e3) 0.56

p=0.03* p=0.04*

25 340

320 15

10 300

5 Tear film osmolarity (mOsmol/L) osmolarity film Tear Non-invasive breakup time (s) time breakup Non-invasive

0 280 Treated eye Fellow eye Treated eye Fellow eye

Fig. 2. Tear film osmolarity of the eyes of participants treated with anti-glaucoma Fig. 1. Non-invasive tear film breakup time of the eyes of participants treated with medications and untreated fellow eyes. Each point represents the tear film osmolar- anti-glaucoma medications and untreated fellow eyes. Each point represents the tear ity of an individual eye. Bars represent the mean tear film osmolarity. Error bars film breakup time of an individual eye. Bars represent the median tear film breakup represent the standard deviation. Asterisks denote statistically significant differences time. Error bars represent the interquartile range. Asterisks denote statistically sig- (p < 0.05). nificant differences (p < 0.05).

abnormality scores (p ¼ 0.01) were also observed in treated eyes. ± e ± was 67 12 years (range, 36 87 years), and the mean SD treat- Overall, the interocular difference in eyelid abnormality scores ± e ment duration was 5.3 4.4 years (range, 0.5 13 years). Thirty were accounted for by 9 participants exhibiting eyelid margin ir- (91%) participants were of New Zealand European ethnicity, while regularity, 6 participants exhibiting plugged orifices of meibomian the remaining three (9%) were Chinese. glands, and 2 participants exhibiting eyelid margin telangiectasia in The topical anti-glaucoma medications of study participants are the treated eye but not the fellow eye. listed in Table 1. Twenty-nine (88%) participants received prosta- Aqueous tear production evaluation showed that treated eyes glandin analogues, and all participants had been prescribed ben- had lower tear meniscus height (p ¼ 0.03) and anesthetised zalkonium chloride-containing eye drops. Schirmer values (p ¼ 0.04). Although there were trends towards Clinical measurements are presented in Table 2. Treated eyes higher levels of meibomian dropout and decreased numbers of fi exhibited shorter non-invasive tear lm breakup time (median 7.5s glands yielding lipid secretions in treated eyes, the interocular ¼ fi versus 10.1s, p 0.03, Fig. 1), and poorer tear lm osmolarity than differences were not statistically significant (all p > 0.05). ± ± untreated fellow eyes (313 12mOsmol/L versus 305 11mOsmol/ There were no differences in OSDI scores, lipid layer and ¼ L, p 0.04, Fig. 2). Higher automated objective bulbar conjunctival expressed meibum quality, ocular surface staining, or lid wiper ¼ hyperaemia readings (p 0.04, Fig. 3), and eyelid margin epitheliopathy between treated and fellow eyes (all p > 0.05). Sub- 292 A.B.C. Wong et al. / The Ocular Surface 16 (2018) 289e293

p=0.04* chloride-containing eye drops. Ocular toxicity associated with benzalkonium chloride has been demonstrated consistently in 3 laboratory, experimental and clinical studies, and its effects include ocular surface epithelial damage, goblet cell loss and superficial punctate keratitis [1e3,8,9]. Although the pathophysiological mechanisms underlying such effects have not yet been fully eluci- dated, it is thought to involve immunoinflammatory pathways 2 mediated by the release of proinflammatory cytokines, oxidative stress, and apoptosis induction [1e4,8,9]. Benzalkonium chloride is also recognised to compromise the integrity of the surface pre- corneal lipid layer through its tensioactive effects, increasing the susceptibility to excessive tear evaporation, ocular surface desic- 1 cation and inflammation [1e3,9]. It is possible for such inflammatory pathways to predispose towards the vicious cycle which perpetuates dry eye disease, through its adverse impact on tear film osmolarity and stability [8,33,34]. Tear film hyperosmolarity can induce further ocular surface epithelial damage, inflammatory JENVIS conjunctival hyperaemia score hyperaemia conjunctival JENVIS 0 mediator release, goblet cell loss, and disturbances in mucin Treated eye Fellow eye expression. This can amplify tear film instability and evaporation which further exacerbates pre-existing tear film hyperosmolarity Fig. 3. Standardised JENVIS bulbar conjunctival hyperaemia scores of the eyes of participants treated with anti-glaucoma medications and untreated fellow eyes. Each [33,34]. point represents the conjunctival hyperaemia score of an individual eye. Bars represent Surprisingly, marginal trends towards reduced aqueous tear the mean conjunctival hyperaemia score. Error bars represent the standard deviation. production were detected in treated eyes. Tear meniscus height, a fi < Asterisks denote statistically signi cant differences (p 0.05). non-invasive surrogate measure of basal tear production and vol- ume [19,35], was lower in treated than fellow eyes. However, while fi group analysis of participants receiving prostaglandin analogue statistically signi cant, the interocular difference was deemed to be of limited clinical significance, with mean measurements in both therapy revealed similar trends. treated and fellow eyes remaining well above the TFOS DEWS II aqueous deficiency dry eye diagnostic cut-off of <0.2 mm [19]. The 4. Discussion anesthetised Schirmer test, another indirect measure of aqueous tear production, was also assessed [19,35]. Consistent with the In agreement with trends reported in previous case control and trends described in previous reports [10e13], the Schirmer value paired-eye comparison studies [5,10e13,17,28e31], the findings of was smaller in treated eyes than fellow eyes. However, the mean the current work demonstrated poorer tear film stability and os- measurements of both eyes were above 10 mm and within normal molarity in eyes treated with topical anti-glaucoma medications physiological limits [19], and the interocular differences were than untreated fellow eyes. Moreover, both the median non- therefore likely to be of limited clinical significance. invasive tear film breakup time (7.2s) and mean tear osmolarity Interestingly, no differences in tear film lipid layer, expressed (313 mOsmol/L) of treated eyes met the TFOS DEWS II diagnostic meibum quality, and ocular surface staining were detected be- cut-off for dry eye disease [19], while the two parameters remained tween treated and fellow eyes in the current study. Furthermore, no within normal physiological limits in fellow eyes. The exact significant trends were detected in the dry eye symptomology, mechanisms underlying the association between topical anti- which is in contrast to the poorer levels of tear film stability and glaucoma medication use and reduced tear film quality are not osmolarity observed in treated eyes. Although there were trends fully understood. However, the higher levels of automated objec- towards increased meibomian dropout and reduced numbers of tive bulbar conjunctival hyperaemia readings detected in treated glands yielding lipid secretions in treated eyes, the interocular eyes would suggest that inflammatory changes of the ocular surface differences did not reach statistical significance. This contrasts with are likely to be implicated [19]. This is further supported by the a similar paired-eye comparison study from Japan, which reported significantly increased eyelid margin abnormality scores in treated higher meiboscores and poorer meibum quality in eyes receiving eyes. Consistent with the grading system adopted by earlier studies long term topical anti-glaucoma medications [10]. It is conceivable [10,11], the eyelid margin abnormalities evaluated in the current for differences in the ethnic distribution of participants in the two work included signs of conjunctival inflammation associated with studies to play a role in the discordant findings observed. A higher meibomian gland dysfunction, such as eyelid margin irregularity, degree of meibomian gland dropout has been observed in the Asian telangiectasia, plugged orifices of meibomian glands, and anterior eye than the Caucasian eye, which may potentially predispose to- or retroplacement of the mucocutaneous junction. wards the greater prevalence and severity of dry eye reported in The greater severity of ocular surface inflammation observed in Asian populations [21]. In the current study, more than 90% of treated eyes may be attributed, in part, to medication side-effects of participants were Caucasian, which contrasted with the likely the topical prostaglandin analogues received by the overwhelming predominantly Asian population in the Japanese study. It is possible majority (88%) of participants [2,32]. However, the natural course of for differences between treated and fellow eyes to be more marked prostaglandin analogue-related conjunctival hyperaemia is such with increasing underlying severity of meibomian gland dysfunc- that it typically falls following one month of use [32], whereas tion and dry eye. Similar discordant findings were also present participants in the current study had been on long term therapy for between the current paired-eye comparison study and previous an average of 5.3 years. The pro-inflammatory and toxic effects of case control studies [11e13]. However, differences in methodo- benzalkonium chloride may also potentially contribute [1e4,8,9]. logical design may also potentially contribute. The development of Benazalkonium chloride is a quaternary ammonium, and one of the dry eye and meibomian gland dysfunction can be influenced by a most frequently used preservatives in ophthalmic preparations [9]. variety of epidemiological factors including age, gender, ethnicity, All participants in the current study were using benzalkonium disease duration, hormonal disturbances, medications, contact lens A.B.C. Wong et al. / The Ocular Surface 16 (2018) 289e293 293 wear, and environmental exposure [36,37]. Controlling for con- et al. TFOS DEWS II iatrogenic report. Ocul Surf 2017;15:511e38. founding factors can be difficult to achieve in case control studies, [9] Baudouin C, Labbe A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 2010;29: and the associated risks of selection bias cannot be discounted. 312e34. There are methodological limitations that need to be considered [10] Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Tomidokoro A, et al. Effects of when interpreting the findings of this study. The cross-sectional long-term topical anti-glaucoma medications on meibomian glands. Graefes Arch Clin Exp 2012;250:1181e5. design of the study precluded the measurement of pre-treatment [11] Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Tomidokoro A, et al. Comparison signs and symptoms, and the detection of changes in ocular pa- of the long-term effects of various topical antiglaucoma medications on rameters over a follow-up period. Nevertheless, the same limita- meibomian glands. Cornea 2012;31:1229e34. [12] Mocan MC, Uzunosmanoglu E, Kocabeyoglu S, Karakaya J, Irkec M. 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