- Email: [email protected]
Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye
Accepted Manuscript 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. DaneshMeyer, Jennifer P. Craig PII:
S1542-0124(17)30311-7
DOI:
10.1016/j.jtos.2018.03.002
Reference:
JTOS 285
To appear in:
Ocular Surface
Received Date: 11 November 2017 Revised Date:
26 February 2018
Accepted Date: 2 March 2018
Please cite this article as: Wong ABC, Wang MTM, Liu K, Prime ZJ, Danesh-Meyer HV, Craig JP, Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye, Ocular Surface (2018), doi: 10.1016/j.jtos.2018.03.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Manuscript title: Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye Short title: Anti-glaucoma drops and the ocular surface
SC
Aaron B. C. Wong, MBChB 1 Michael T. M. Wang, MBChB 1 Kevin Liu, MBChB 1 Zak J. Prime, MBChB 1 Helen V. Danesh-Meyer, MBChB PhD FRANZCO 1 Jennifer P. Craig, PhD MCOptom FAAO FBCLA FCCLSA 1
RI PT
Authors:
M AN U
Corresponding author:
TE D
Associate Professor Jennifer P. Craig Department of Ophthalmology New Zealand National Eye Centre The University of Auckland, New Zealand Private Bag 92019 Auckland 1142 New Zealand
EP
Phone: +64 9 923 8173 Fax: +64 9 367 7173 Email: [email protected]
AC C
Author institutions: 1 Department of Ophthalmology, New Zealand National Eye Centre, The University of Auckland, New Zealand Disclosure statements: The authors have no commercial or proprietary interest in any concept or product described in this article. Sources of support: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT ABSTRACT
Purpose: To assess tear film parameters, ocular surface characteristics, and dry eye
RI PT
symptomology in patients receiving topical anti-glaucoma medications.
Methods: Thirty-three patients with a diagnosis of open angle glaucoma or ocular
hypertension, receiving unilateral topical anti-glaucoma medication for at least 6 months, were recruited in a cross-sectional, investigator-masked, paired-eye comparison study. Tear
M AN U
fellow eyes were evaluated and compared.
SC
film parameters, ocular surface characteristics, and dry eye symptomology of treated and
Results: The mean ± SD age of the participants was 67 ± 12 years, and the mean ± SD treatment duration was 5.3 ± 4.4 years. Treated eyes had poorer non-invasive tear film break-up time (p=0.03), tear film osmolarity (p=0.04), bulbar conjunctival hyperaemia
TE D
(p=0.04), eyelid margin abnormality grade (p=0.01), tear meniscus height (p=0.03), and anaesthetised Schirmer value (p=0.04) than fellow eyes. There were no significant differences in dry eye symptomology, meibomian gland assessments, and ocular surface
EP
staining between treated and fellow eyes (all p>0.05).
AC C
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.
KEYWORDS Glaucoma; prostaglandin analogue; tear film; ocular surface; dry eye; meibomian gland
ACCEPTED MANUSCRIPT 1. INTRODUCTION
Glaucoma and ocular surface disease are common chronic conditions, which frequently coexist in ophthalmic patients.[1-5] Over 60 million people are affected by glaucoma
RI PT
worldwide, and the global burden is expected to rise with the ageing population.[6] The prevalence of ocular surface disease is greater in glaucoma patients than in the normal adult population,[1, 3] and has been reported to be as high as 60%.[5] The associated tear film
comfort, vision and quality of life.[1-3, 7]
SC
dysfunction and dry eye symptoms can contribute towards further deterioration in ocular
M AN U
Although the propensity for dry eye development in glaucoma patients is not fully understood, it is thought to be multifactorial.[1-3] Clinical and laboratory studies have suggested that the long term use of topical anti-glaucoma medications may contribute.[1-4, 8] In particular, increased exposure to benzalkonium chloride, a common preservative in
TE D
ophthalmic preparations,[9] has been identified to be an independent risk factor for the development of ocular surface disease in glaucoma patients[4, 8] Benzalkonium chloride is recognised to destabilise the tear film lipid layer through its detergent-like tensioactive
EP
effects, which may promote excessive evaporation of the aqueous tear film. Furthermore, the pro-inflammatory and toxic effects of benzalkonium chloride can also lead to chronic
AC C
damage of the ocular surface, and disrupt tear film homeostasis.[1-4, 8, 9]
Recent studies have explored the potential association between topical anti-glaucoma medications and meibomian gland dysfunction.[10-13] Through its adverse effects on lipid layer integrity and tear film stability, meibomian gland dysfunction is a leading cause of evaporative dry eye disease.[7, 14-16] Poorer tear film quality and meibomian gland function have been observed with topical anti-glaucoma medication use in both paired-eye comparison and case control studies.[10-13]
ACCEPTED MANUSCRIPT This cross-sectional paired-eye comparison study sought to investigate the effect of topical anti-glaucoma medication use on ocular surface characteristics, tear film quality, aqueous
AC C
EP
TE D
M AN U
SC
RI PT
tear production, meibomian gland function, and dry eye symptomology.
ACCEPTED MANUSCRIPT 2. MATERIALS AND METHODS
2.1. Subjects
RI PT
This cross-sectional, investigator-masked, paired-eye comparison study adhered to the tenets of the Declaration of Helsinki, and was approved by the institutional ethics committee. Participants were required to be at least 18 years of age, with a diagnosis of open angle glaucoma or ocular hypertension, and topical anti-glaucoma medication use in only one eye.
SC
Furthermore, eligibility required participants to report no changes in anti-glaucoma
medications within the preceding 6 months, no contact lens wear, no use of other topical or
M AN U
systemic medications known to affect the eye, no history of Sjögren's syndrome, and no previous ocular surgery (other than phacoemulsification, childhood strabismus surgery, or epiretinal membrane surgery, more than 6 months before study enrolment).[17] Eligible
TE D
participants were enrolled after providing written informed consent.
A total of 33 eligible participants were recruited, exceeding sample size requirements. Nonparamateric adjusted power calculations were conducted using NCSS PASS 2002 (Utah,
EP
USA), with non-invasive tear film break-up time as the designated outcome (due to yielding the most stringent sample size requirements of all outcome measures), and the normal SD A minimum of 26 participants was required to detect a
AC C
estimated to be 6 seconds.[18]
clinically significant difference of 5 seconds, with 80% power (β= 0.2), at a two-sided statistical significance level of 5% (α = 0.05).
2.2. Measurements
Participants were instructed to refrain from taking the morning dose of topical anti-glaucoma medications before clinical assessment. Tear film parameters, ocular surface characteristics and dry eye symptomatology were evaluated in both treated and untreated eyes of each
ACCEPTED MANUSCRIPT participant, within a single clinical session. The investigators conducting measurements were masked to the treatment status of each eye. Assessments were conducted in ascending order of invasiveness to minimise the impact on tear film physiology for subsequent measurements: tear meniscus height, non-invasive tear film breakup time, tear
RI PT
film lipid layer grade, bulbar conjunctival hyperaemia, tear osmolarity, slit lamp examination, ocular surface staining, meibomian gland expression, infrared meibography, Schirmer I test. All participants were assessed in the same location, with a mean ± SD room temperature of
SC
21.5 ± 0.9°C, and a mean ± SD relative humidity of 57.0 ± 11.1%.
Dry eye symptomology for each eye was graded using the Ocular Surface Disease Index
M AN U
(OSDI). Tear meniscus height, bulbar conjunctival hyperaemia, non-invasive tear film breakup time (NIBUT), and tear film lipid layer grade were evaluated with the Oculus Keratograph 5M. Tear meniscus height was assessed using pre-calibrated digital imaging, and three measurements near the centre of the lower meniscus were averaged. Non-
TE D
invasive tear film break-up time was measured using automated detection of first break-up, and three readings were averaged.[19] Tear film lipid layer was graded according to the modified Guillon-Keeler system: grade 1, open meshwork; grade 2, closed meshwork; grade
EP
3, wave or flow; grade 4, amorphous; grade 5, colored fringes; grade 0, non-continuous layer (non-visible or abnormal colored fringes).[20, 21] Standardised JENVIS bulbar
AC C
conjunctival hyperaemia scores were quantified using automated objective evaluation of digital imaging.
Tear film osmolarity was assessed with a clinical osmometer (TearLab, California, USA), using 50nL tear samples collected from the lower tear meniscus. Two measurements were taken for each eye and the higher reading recorded. Lid margin abnormalities (lid margin irregularity, telangiectasia, plugged orifices of meibomian glands, and anterior or posterior replacement of the mucocutaneous junction) were assessed by slit lamp examination, and scored from 0 to 4, according to the number of abnormalities present in each eye.[10]
ACCEPTED MANUSCRIPT
Sodium fluorescein and lissamine green dyes were applied, in turn, to the bulbar conjunctiva in order to evaluate localised corneal and conjunctival areas of epithelial dessciation, and recorded using the Oxford grading scheme for ocular staining.[22] Lid wiper epitheliopathy
RI PT
(LWE) was also assessed following lissamine green application.[23]
Meibomian gland function assessment was conducted in accordance with the
recommendations of the International Workshop on Meibomian Gland Dysfunction and
SC
TFOS DEWS II.[19, 24] Expressibility of the inferior eyelid meibomian glands was assessed with the Korb Meibomian Gland Evaluator™ (TearScience®, North Carolina, USA). The
M AN U
number of meibomian orifices yielding lipid secretion was evaluated at each of the nasal, central and lateral aspects of the lower lid.[25] The meibum viscosity and expressibility was graded as: grade 0, clear fluid; grade 1, slightly turbid; grade 2, thick opaque; grade 3, toothpaste-like; grade 4, complete orifice blockage.[21] Infrared meibography was imaged
TE D
with the Oculus Keratograph 5M, with the superior and inferior eyelids everted in turn. From the captured image, the proportion of meibomian glands visible within the tarsal area were
EP
graded according to the Meiboscale.[26]
The Schirmer I test was then performed, as the final assessment, under topical anaesthesia
AC C
(0.4% oxbuprocaine).[27]
2.3. Statistics
Statistical analyses were performed using IBM SPSS Statistics version 22 (New York, USA) and Graph Pad Prism version 6.02 (California, USA). Comparisons of continuous variables were performed using paired t-tests, where normal distributions had been confirmed by Kolmogorov-Smirnov testing (p>0.05). Non-normally distributed continuous and ordinal data were analysed using Wilcoxon signed-rank test. All tests were two-tailed and p<0.05 was
ACCEPTED MANUSCRIPT considered significant. All normally distributed continuous data are presented as mean ± SD, non-normally distributed continuous data or ordinal data as median (IQR), and categorical
AC C
EP
TE D
M AN U
SC
RI PT
data as number of participants (% of participants), unless otherwise stated.
ACCEPTED MANUSCRIPT 3. RESULTS
The mean ± SD age of the 33 participants (24 male, 9 female) was 67 ± 12 years (range, 36 to 87 years), and the mean ± SD treatment duration was 5.3 ± 4.4 years (range, 0.5 to 13
RI PT
years). Thirty (91%) participants were of New Zealand European ethnicity, while the remaining three (10%) were Chinese.
The topical anti-glaucoma medications of study participants are listed in Table 1. Twenty-
M AN U
benzalkonium chloride-containing eye drops.
SC
nine (88%) participants received prostaglandin analogues, and all participants used
Clinical measurements are presented in Table 2. Treated eyes exhibited shorter noninvasive tear film break-up time (median 7.5s versus 10.1s, p=0.03, Figure 1), and poorer tear film osmolarity than untreated fellow eyes (313±12mOsmol/L versus 305±11mOsmol/L,
TE D
p=0.04, Figure 2). Higher automated objective bulbar conjunctival hyperaemia readings (p=0.04, Figure 3), and eyelid margin abnormality scores (p=0.01) were also observed in treated eyes. Overall, the inter-ocular difference in eyelid abnormality scores were
EP
accounted for by 9 participants exhibiting eyelid margin irregularity, 6 participants exhibiting plugged orifices of meibomian glands, and 2 participants exhibiting eyelid margin
AC C
telangiectasia in the treated eye but not the fellow eye.
Aqueous tear production evaluation showed that treated eyes had lower tear meniscus height (p=0.03) and anesthetised Schirmer values (p=0.04). Although there were trends towards higher levels of meibomian dropout and decreased numbers of glands yielding lipid secretions in treated eyes, the inter-ocular differences were not statistically significant (all p>0.05).
ACCEPTED MANUSCRIPT There were no differences in OSDI scores, lipid layer and expressed meibum quality, ocular surface staining, or lid wiper epitheliopathy between treated and fellow eyes (all p>0.05). Sub-group analysis of participants receiving prostaglandin analogue therapy revealed similar
AC C
EP
TE D
M AN U
SC
RI PT
trends.
ACCEPTED MANUSCRIPT 4. DISCUSSION
In agreement with trends reported in previous case control and paired-eye comparison studies,[5, 10-13, 17, 28-31] the findings of the current work demonstrated poorer tear film
RI PT
stability and osmolarity in eyes treated with topical anti-glaucoma medications than untreated fellow eyes. Moreover, both the median non-invasive tear film breakup time (7.2s) and mean tear osmolarity (313 mOsmol/L) of treated eyes met the TFOS DEWS II
diagnostic cut-off for dry eye disease,[19] while the two parameters remained within normal
SC
physiological limits in fellow eyes. The exact mechanisms underlying the association
between topical anti-glaucoma medication use and reduced tear film quality are not fully
M AN U
understood. However, the higher levels of automated objective bulbar conjunctival hyperaemia readings detected in treated eyes would suggest that inflammatory changes of the ocular surface are likely to be implicated.[19] This is further supported by the significantly increased eyelid margin abnormality scores in treated eyes. Consistent with the grading
TE D
system adopted by earlier studies,[10, 11] the eyelid margin abnormalities evaluated in the current work included signs of conjunctival inflammation associated with meibomian gland dysfunction, such as eyelid margin irregularity, telangiectasia, plugged orifices of meibomian
EP
glands, and anterior or posterior replacement of the mucocutaneous junction.
AC C
The greater severity of ocular surface inflammation observed in treated eyes may partially be attributed to medication side-effects of the topical prostaglandin analogues received by the overwhelming majority (88%) of participants.[2, 32] However, the natural course of prostaglandin analogue-related conjunctival hyperaemia is such that it typically falls following one month of use,[32] whereas participants in the current study had been on long term therapy for an average of 5.3 years. The pro-inflammatory and toxic effects of benzalkonium chloride may also potentially contribute.[1-4, 8, 9] Benazalkonium chloride is a quaternary ammonium, and one of the most frequently used preservatives in ophthalmic preparations.[9] All participants in the current study were using benzalkonium chloride-
ACCEPTED MANUSCRIPT containing eye drops. Ocular toxicity associated with benzalkonium chloride has been demonstrated consistently in laboratory, experimental and clinical studies, and includes ocular surface epithelial damage, goblet cell loss and superficial punctate keratitis.[1-3, 8, 9] Although the pathophysiological mechanisms underlying such effects have not yet been fully
RI PT
elucidated, it is thought to involve immunoinflammatory pathways mediated by the release of proinflammatory cytokines, oxidative stress, and apoptosis induction.[1-4, 8, 9]
Benzalkonium chloride is also recognised to compromise the integrity of the surface precorneal lipid layer through its tensioactive effects, increasing the susceptibility to excessive
SC
tear evaporation, ocular surface desiccation and inflammation.[1-3, 9] It is possible for such inflammatory pathways to predispose towards the vicious cycle which perpetuates dry eye
M AN U
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 mediator release, goblet cell loss, and disturbances in mucin expression. This can amplify tear film instability and evaporation which further exacerbates pre-existing tear film
TE D
hyperosmolarity.[33, 34]
Surprisingly, marginal trends towards reduced aqueous tear production were detected in
EP
treated eyes. Tear meniscus height, a non-invasive surrogate measure of basal tear production and volume,[19, 35] was lower in treated than fellow eyes. However, while
AC C
statistically significant, the inter-ocular difference was deemed to be of limited clinical significance, with mean measurements in both treated and fellow eyes remaining well above the TFOS DEWS II aqueous deficiency dry eye diagnostic cut-off of <0.2mm.[19] The anesthetised Schirmer test, another indirect measure of aqueous tear production, was also assessed.[19, 35] Consistent with the trends described in previous reports,[10-13] the Schirmer value was smaller in treated eyes than fellow eyes. However, the mean measurements of both eyes were above 10mm and within normal physiological limits,[19] and the inter-ocular differences were therefore likely to be of limited clinical significance.
ACCEPTED MANUSCRIPT Interestingly, no differences in tear film lipid layer, expressed meibum quality, and ocular surface staining were detected between treated and fellow eyes in the current study. Furthermore, no significant trends were detected in the dry eye symptomology, which is in contrast to the poorer levels of tear film stability and osmolarity observed in treated eyes.
RI PT
Although there were trends towards increased meibomian dropout and reduced numbers of glands yielding lipid secretions in treated eyes, the inter-ocular differences did not reach statistical significance. This contrasts with a similar paired-eye comparison study from
Japan, which reported higher meiboscores and poorer meibum quality in eyes receiving long
SC
term topical anti-glaucoma medications.[10] It is conceivable for differences in the ethnic distribution of participants in the two studies to play a role in the discordant findings
M AN U
observed. A higher degree of meibomian gland dropout has been observed in the Asian eye than the Caucasian eye, which may potentially predispose towards the greater prevalence and severity of dry eye reported in Asian populations.[21] In the current study, more than 90% of participants were Caucasian, which contrasted with the likely predominantly Asian
TE D
population in the Japanese study. It is possible for differences between treated and fellow eyes to be more marked with increasing underlying severity of meibomian gland dysfunction and dry eye. Similar discordant findings were also present between the current paired-eye
EP
comparison study and previous case control studies.[11-13] However, differences in methodological design may also potentially contribute. The development of dry eye and
AC C
meibomian gland dysfunction can be influenced by a variety of epidemiological factors including age, gender, ethnicity, disease duration, hormonal disturbances, medications, contact lens wear, and environmental exposure.[36, 37] Controlling for confounding factors can be difficult to achieve in case control studies, and the associated risks of selection bias cannot be discounted.
There are methodological limitations that need to be considered when interpreting the findings of this study. The cross-sectional design of the study precluded the measurement of pre-treatment signs and symptoms, and the detection of changes in ocular parameters over
ACCEPTED MANUSCRIPT a follow-up period. Nevertheless, the same limitations are acknowledged to exist in previous studies with similar designs. Future long term prospective paired eye comparison studies are therefore required to confirm the findings of the current study.
RI PT
5. Conclusions
Of note, decreased tear film stability and elevated tear osmolarity, both global indices of dry eye disease,[19] were observed in eyes treated with topical anti-glaucoma medications. This
SC
was associated with increased levels of bulbar conjunctival hyperaemia and eyelid margin changes. These findings suggest that inflammatory mechanisms may play a role in the
M AN U
propensity of dry eye development in patients receiving long term topical anti-glaucoma
AC C
EP
TE D
medications.
ACCEPTED MANUSCRIPT 6. ACKNOWLEDGEMENTS
RI PT
None.
7. FUNDING
This research did not receive any specific grant from funding agencies in the public,
AC C
EP
TE D
M AN U
SC
commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT REFERENCES
[1] Anwar Z, Wellik SR, Galor A. Glaucoma therapy and ocular surface disease: current literature and recommendations. Curr Opin Ophthalmol. 2013;24:136-43.
RI PT
[2] Kastelan S, Tomic M, Metez Soldo K, Salopek-Rabatic J. How ocular surface disease impacts the glaucoma treatment outcome. Biomed Res Int. 2013:696328.
[3] Stewart WC, Stewart JA, Nelson LA. Ocular surface disease in patients with ocular hypertension and glaucoma. Curr Eye Res. 2011;36:391-8.
SC
[4] Skalicky SE, Goldberg I, McCluskey P. Ocular Surface Disease and Quality of Life in Patients With Glaucoma. Am J Ophthalmol. 2012;153:1-9.
M AN U
[5] Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350-5.
[6] Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262-7.
TE D
[7] Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15:276-83. [8] Gomes JAP, Azar DT, Baudouin C, Efron N, Hirayama M, Horwath-Winter J, et al. TFOS
EP
DEWS II iatrogenic report. Ocul Surf. 2017;15:511-38. [9] Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops:
AC C
the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312-34. [10] Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Tomidokoro A, et al. Effects of long-term topical anti-glaucoma medications on meibomian glands. Graef Arch Clin Exp. 2012;250:1181-5.
[11] Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Tomidokoro A, et al. Comparison of the long-term effects of various topical antiglaucoma medications on meibomian glands. Cornea. 2012;31:1229-34.
ACCEPTED MANUSCRIPT [12] Mocan MC, Uzunosmanoglu E, Kocabeyoglu S, Karakaya J, Irkec M. The Association of Chronic Topical Prostaglandin Analog Use With Meibomian Gland Dysfunction. J Glaucoma. 2016;25:770-4. [13] Uzunosmanoglu E, Mocan MC, Kocabeyoglu S, Karakaya J, Irkec M. Meibomian Gland
RI PT
Dysfunction in Patients Receiving Long-Term Glaucoma Medications. Cornea. 2016;35:1112-6.
[14] Nichols KK, Foulks GN, Bron AJ, Glasgow BJ, Dogru M, Tsubota K, et al. The
Ophthalmol Vis Sci. 2011;52:1922-9.
SC
international workshop on meibomian gland dysfunction: executive summary. Invest
[15] McCulley JP, Shine WE. The lipid layer of tears: dependent on meibomian gland
M AN U
function. Exp Eye Res. 2004;78:361-5.
[16] Craig JP, Tomlinson A. Importance of the lipid layer in human tear film stability and evaporation. Optom Vis Sci. 1997;74:8-13.
[17] Lee SY, Wong TT, Chua J, Boo C, Soh YF, Tong L. Effect of chronic anti-glaucoma
TE D
medications and trabeculectomy on tear osmolarity. Eye. 2013;27:1142-50. [18] Wang MT, Jaitley Z, Lord SM, Craig JP. Comparison of Self-applied Heat Therapy for Meibomian Gland Dysfunction. Optom Vis Sci. 2015;92:e321-6.
EP
[19] Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II Diagnostic Methodology report. Ocul Surf. 2017;15:539-74.
AC C
[20] Guillon JP. Use of the Tearscope Plus and attachments in the routine examination of the marginal dry eye contact lens patient. Adv Exp Med Biol. 1998;438:859-67. [21] Craig JP, Wang MT, Kim D, Lee JM. Exploring the Predisposition of the Asian Eye to Development of Dry Eye. Ocul Surf. 2016;14:385-92. [22] Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 2003;22:640-50. [23] Korb DR, Herman JP, Greiner JV, Scaffidi RC, Finnemore VM, Exford JM, et al. Lid wiper epitheliopathy and dry eye symptoms. Eye Contact Lens. 2005;31:2-8.
ACCEPTED MANUSCRIPT [24] Tomlinson A, Bron Aj Fau - Korb DR, Korb Dr Fau - Amano S, Amano S Fau - Paugh JR, Paugh Jr Fau - Pearce EI, Pearce Ei Fau - Yee R, et al. The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee. Invest Ophthalmol Vis Sci. 2011;52:2006-49.
eye symptoms and gland location. Cornea. 2008;27:1142-7.
RI PT
[25] Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry
[26] Pult H, Riede-Pult B. Comparison of subjective grading and objective assessment in meibography. Cont Lens Anterior Eye. 2013;36:22-7.
SC
[27] Li N, Deng XG, He MF. Comparison of the Schirmer I test with and without topical anesthesia for diagnosing dry eye. Int J Opthalmol. 2012;5:478-81.
M AN U
[28] Labbe A, Terry O, Brasnu E, Van Went C, Baudouin C. Tear film osmolarity in patients treated for glaucoma or ocular hypertension. Cornea. 2012;31:994-9. [29] Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after longterm treatment with an antiglaucomatous drug. Ophthalmol. 1992;99:1082-8.
TE D
[30] Arici MK, Arici DS, Topalkara A, Guler C. Adverse effects of topical antiglaucoma drugs on the ocular surface. Clin Exp Opthalmol. 2000;28:113-7. [31] Inoue K, Okugawa K, Kato S, Inoue Y, Tomita G, Oshika T, et al. Ocular factors relevant
EP
to anti-glaucomatous eyedrop-related keratoepitheliopathy. J Glaucoma. 2003;12:480-5. [32] Sakata R, Sakisaka T, Matsuo H, Miyata K, Aihara M. Time Course of Prostaglandin
AC C
Analog-related Conjunctival Hyperemia and the Effect of a Nonsteroidal Antiinflammatory Ophthalmic Solution. J Glaucoma. 2016;25:e204-8. [33] Baudouin C, Messmer EM, Aragona P. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol. 2016;100:300-6. [34] Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15:438-510. [35] Foulks GN, Pflugfelder SC. New testing options for diagnosing and grading dry eye disease. Am J Ophthalmol. 2014;157:1122-9.
ACCEPTED MANUSCRIPT [36] Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II Epidemiology Report. Ocul Surf. 2017;15:334-65. [37] Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK. The international workshop on meibomian gland dysfunction: report of the subcommittee on
RI PT
the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci.
AC C
EP
TE D
M AN U
SC
2011;52:1994-2005.
ACCEPTED MANUSCRIPT TABLES
Table 1: Topical anti-glaucoma medications of study participants. Data are presented as number of participants (% of participants).
RI PT
No. (%)
8 (24%) 8 (24%) 6 (18%)
SC
1 (3%)
1 (3%) 1 (3%) 1 (3%) 3 (9%) 2 (6%) 1 (3%) 1 (3%)
AC C
EP
TE D
M AN U
Medication Prostaglandin analogue monotherapy Bimatoprost Latanoprost Travoprost β-blocker monotherapy Timolol Combination therapy Betaxolol and Latanoprost Bimatoprost and Timolol Bimatoprost, Brimonidine and Timolol Bimatoprost, Dorzolamide and Timolol Brimonidine and Timolol Dorzolamide and Timolol Timolol and Travoprost
ACCEPTED MANUSCRIPT 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).
p
0.11
5.0 (2.3-14.6)
7.5 (5.2-13.0) 10.1 (6.8-14.5)
0.03* 7.2 (5.2-13.0)
SC
5.0 (2.3-14.6) 6.3 (2.1-11.4)
6.3 (2.2-11.4)
0.14
10.1 (6.8-14.6)
0.03*
305±11
0.04*
314±14
304±12
0.03*
0.41±0.19 14±7
0.47±0.17 16±8
0.03* 0.04*
0.40±0.22 14±8
0.46±0.19 16±8
0.04* 0.04*
3 (3-4) 2 (1-3)
3 (3-4) 1 (1-3)
0.65 0.49
3 (3-4) 2 (1-3)
3 (3-4) 1 (1-3)
0.53 0.46
2 (1-3)
1 (1-2)
0.38
2 (1-3)
1 (1-2)
0.36
5 (2-7)
5 (3-7)
0.41
5 (2-7)
5 (3-7)
0.35
TE D
M AN U
313±12
1 (1-2)
1 (1-2)
0.63
1 (1-2)
1 (1-2)
0.57
2 (1-3)
1 (1-2)
0.01*
2 (1-3)
1 (1-2)
0.008*
1.5±0.3
1.3±0.3
0.04*
1.6±0.4
1.4±0.4
0.04*
0 (0-2)
0 (0-2)
0.54
0 (0-2)
0 (0-2)
0.58
0 (0-1)
0 (0-0)
0.14
0 (0-1)
0 (0-0)
0.20
1 (0-3)
1 (0-3)
0.80
1 (0-3)
1 (0-3)
0.56
AC C
EP
Dry eye symptomology OSDI score Tear film function Non-invasive tear film breakup time (s) Tear film osmolarity (mOsmol/L) Aqueous tear production Tear meniscus height (mm) Schirmer value (mm) Meibomian gland function Tear film lipid layer grade Superior eyelid meibography grade Inferior eyelid meibography grade Number of meibomian glands yielding lipid secretions Expressed meibum grade Ocular surface characteristics Eyelid margin abnormality score JENVIS bulbar conjunctival hyperaemia score Conjunctival lissamine green staining score (out of 30) Corneal sodium fluorescein staining score (out of 25) Lid wiper epitheliopathy grade
Participants on prostaglandin analogue therapy Treated eye Fellow Eye p (n=29) (n=29)
RI PT
All participants Treated eye Fellow Eye (n=33) (n=33)
ACCEPTED MANUSCRIPT FIGURE LEGENDS
Figure 1: Non-invasive tear film breakup time of the eyes of participants treated with antiglaucoma medications and untreated fellow eyes. Each point represents the tear film
RI PT
breakup time of an individual eye. Bars represent the median tear film breakup time. Error bars represent the interquartile range. Asterisks denote statistically significant differences
SC
(p<0.05).
Figure 2: Tear film osmolarity of the eyes of participants treated with anti-glaucoma
M AN U
medications and untreated fellow eyes. Each point represents the tear film osmolarity of an individual eye. Bars represent the mean tear film osmolarity. Error bars represent the
TE D
standard deviation. Asterisks denote statistically significant differences (p<0.05).
Figure 3: Standardised JENVIS bulbar conjunctival hyperaemia scores of the eyes of participants treated with anti-glaucoma medications and untreated fellow eyes. Each point
EP
represents the conjunctival hyperaemia score of an individual eye. Bars represent the mean conjunctival hyperaemia score. Error bars represent the standard deviation. Asterisks
AC C
denote statistically significant differences (p<0.05).
ACCEPTED MANUSCRIPT
p=0.03*
RI PT M AN U
SC
20
EP
10
TE D
15
5
0
AC C
Non-invasive breakup time (s)
25
Treated eye
Fellow eye
ACCEPTED MANUSCRIPT
p=0.04*
RI PT M AN U
SC 300
EP
TE D
320
AC C
Tear film osmolarity (mOsmol/L)
340
280
Treated eye
Fellow eye
AC C
1
0
EP TE D
2
M AN U
SC
RI PT
JENVIS conjunctival hyperaemia score
ACCEPTED MANUSCRIPT
p=0.04*
3
Treated eye Fellow eye
S1542-0124(17)30311-7
DOI:
10.1016/j.jtos.2018.03.002
Reference:
JTOS 285
To appear in:
Ocular Surface
Received Date: 11 November 2017 Revised Date:
26 February 2018
Accepted Date: 2 March 2018
Please cite this article as: Wong ABC, Wang MTM, Liu K, Prime ZJ, Danesh-Meyer HV, Craig JP, Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye, Ocular Surface (2018), doi: 10.1016/j.jtos.2018.03.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Manuscript title: Exploring topical anti-glaucoma medication effects on the ocular surface in the context of the current understanding of dry eye Short title: Anti-glaucoma drops and the ocular surface
SC
Aaron B. C. Wong, MBChB 1 Michael T. M. Wang, MBChB 1 Kevin Liu, MBChB 1 Zak J. Prime, MBChB 1 Helen V. Danesh-Meyer, MBChB PhD FRANZCO 1 Jennifer P. Craig, PhD MCOptom FAAO FBCLA FCCLSA 1
RI PT
Authors:
M AN U
Corresponding author:
TE D
Associate Professor Jennifer P. Craig Department of Ophthalmology New Zealand National Eye Centre The University of Auckland, New Zealand Private Bag 92019 Auckland 1142 New Zealand
EP
Phone: +64 9 923 8173 Fax: +64 9 367 7173 Email: [email protected]
AC C
Author institutions: 1 Department of Ophthalmology, New Zealand National Eye Centre, The University of Auckland, New Zealand Disclosure statements: The authors have no commercial or proprietary interest in any concept or product described in this article. Sources of support: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT ABSTRACT
Purpose: To assess tear film parameters, ocular surface characteristics, and dry eye
RI PT
symptomology in patients receiving topical anti-glaucoma medications.
Methods: Thirty-three patients with a diagnosis of open angle glaucoma or ocular
hypertension, receiving unilateral topical anti-glaucoma medication for at least 6 months, were recruited in a cross-sectional, investigator-masked, paired-eye comparison study. Tear
M AN U
fellow eyes were evaluated and compared.
SC
film parameters, ocular surface characteristics, and dry eye symptomology of treated and
Results: The mean ± SD age of the participants was 67 ± 12 years, and the mean ± SD treatment duration was 5.3 ± 4.4 years. Treated eyes had poorer non-invasive tear film break-up time (p=0.03), tear film osmolarity (p=0.04), bulbar conjunctival hyperaemia
TE D
(p=0.04), eyelid margin abnormality grade (p=0.01), tear meniscus height (p=0.03), and anaesthetised Schirmer value (p=0.04) than fellow eyes. There were no significant differences in dry eye symptomology, meibomian gland assessments, and ocular surface
EP
staining between treated and fellow eyes (all p>0.05).
AC C
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.
KEYWORDS Glaucoma; prostaglandin analogue; tear film; ocular surface; dry eye; meibomian gland
ACCEPTED MANUSCRIPT 1. INTRODUCTION
Glaucoma and ocular surface disease are common chronic conditions, which frequently coexist in ophthalmic patients.[1-5] Over 60 million people are affected by glaucoma
RI PT
worldwide, and the global burden is expected to rise with the ageing population.[6] The prevalence of ocular surface disease is greater in glaucoma patients than in the normal adult population,[1, 3] and has been reported to be as high as 60%.[5] The associated tear film
comfort, vision and quality of life.[1-3, 7]
SC
dysfunction and dry eye symptoms can contribute towards further deterioration in ocular
M AN U
Although the propensity for dry eye development in glaucoma patients is not fully understood, it is thought to be multifactorial.[1-3] Clinical and laboratory studies have suggested that the long term use of topical anti-glaucoma medications may contribute.[1-4, 8] In particular, increased exposure to benzalkonium chloride, a common preservative in
TE D
ophthalmic preparations,[9] has been identified to be an independent risk factor for the development of ocular surface disease in glaucoma patients[4, 8] Benzalkonium chloride is recognised to destabilise the tear film lipid layer through its detergent-like tensioactive
EP
effects, which may promote excessive evaporation of the aqueous tear film. Furthermore, the pro-inflammatory and toxic effects of benzalkonium chloride can also lead to chronic
AC C
damage of the ocular surface, and disrupt tear film homeostasis.[1-4, 8, 9]
Recent studies have explored the potential association between topical anti-glaucoma medications and meibomian gland dysfunction.[10-13] Through its adverse effects on lipid layer integrity and tear film stability, meibomian gland dysfunction is a leading cause of evaporative dry eye disease.[7, 14-16] Poorer tear film quality and meibomian gland function have been observed with topical anti-glaucoma medication use in both paired-eye comparison and case control studies.[10-13]
ACCEPTED MANUSCRIPT This cross-sectional paired-eye comparison study sought to investigate the effect of topical anti-glaucoma medication use on ocular surface characteristics, tear film quality, aqueous
AC C
EP
TE D
M AN U
SC
RI PT
tear production, meibomian gland function, and dry eye symptomology.
ACCEPTED MANUSCRIPT 2. MATERIALS AND METHODS
2.1. Subjects
RI PT
This cross-sectional, investigator-masked, paired-eye comparison study adhered to the tenets of the Declaration of Helsinki, and was approved by the institutional ethics committee. Participants were required to be at least 18 years of age, with a diagnosis of open angle glaucoma or ocular hypertension, and topical anti-glaucoma medication use in only one eye.
SC
Furthermore, eligibility required participants to report no changes in anti-glaucoma
medications within the preceding 6 months, no contact lens wear, no use of other topical or
M AN U
systemic medications known to affect the eye, no history of Sjögren's syndrome, and no previous ocular surgery (other than phacoemulsification, childhood strabismus surgery, or epiretinal membrane surgery, more than 6 months before study enrolment).[17] Eligible
TE D
participants were enrolled after providing written informed consent.
A total of 33 eligible participants were recruited, exceeding sample size requirements. Nonparamateric adjusted power calculations were conducted using NCSS PASS 2002 (Utah,
EP
USA), with non-invasive tear film break-up time as the designated outcome (due to yielding the most stringent sample size requirements of all outcome measures), and the normal SD A minimum of 26 participants was required to detect a
AC C
estimated to be 6 seconds.[18]
clinically significant difference of 5 seconds, with 80% power (β= 0.2), at a two-sided statistical significance level of 5% (α = 0.05).
2.2. Measurements
Participants were instructed to refrain from taking the morning dose of topical anti-glaucoma medications before clinical assessment. Tear film parameters, ocular surface characteristics and dry eye symptomatology were evaluated in both treated and untreated eyes of each
ACCEPTED MANUSCRIPT participant, within a single clinical session. The investigators conducting measurements were masked to the treatment status of each eye. Assessments were conducted in ascending order of invasiveness to minimise the impact on tear film physiology for subsequent measurements: tear meniscus height, non-invasive tear film breakup time, tear
RI PT
film lipid layer grade, bulbar conjunctival hyperaemia, tear osmolarity, slit lamp examination, ocular surface staining, meibomian gland expression, infrared meibography, Schirmer I test. All participants were assessed in the same location, with a mean ± SD room temperature of
SC
21.5 ± 0.9°C, and a mean ± SD relative humidity of 57.0 ± 11.1%.
Dry eye symptomology for each eye was graded using the Ocular Surface Disease Index
M AN U
(OSDI). Tear meniscus height, bulbar conjunctival hyperaemia, non-invasive tear film breakup time (NIBUT), and tear film lipid layer grade were evaluated with the Oculus Keratograph 5M. Tear meniscus height was assessed using pre-calibrated digital imaging, and three measurements near the centre of the lower meniscus were averaged. Non-
TE D
invasive tear film break-up time was measured using automated detection of first break-up, and three readings were averaged.[19] Tear film lipid layer was graded according to the modified Guillon-Keeler system: grade 1, open meshwork; grade 2, closed meshwork; grade
EP
3, wave or flow; grade 4, amorphous; grade 5, colored fringes; grade 0, non-continuous layer (non-visible or abnormal colored fringes).[20, 21] Standardised JENVIS bulbar
AC C
conjunctival hyperaemia scores were quantified using automated objective evaluation of digital imaging.
Tear film osmolarity was assessed with a clinical osmometer (TearLab, California, USA), using 50nL tear samples collected from the lower tear meniscus. Two measurements were taken for each eye and the higher reading recorded. Lid margin abnormalities (lid margin irregularity, telangiectasia, plugged orifices of meibomian glands, and anterior or posterior replacement of the mucocutaneous junction) were assessed by slit lamp examination, and scored from 0 to 4, according to the number of abnormalities present in each eye.[10]
ACCEPTED MANUSCRIPT
Sodium fluorescein and lissamine green dyes were applied, in turn, to the bulbar conjunctiva in order to evaluate localised corneal and conjunctival areas of epithelial dessciation, and recorded using the Oxford grading scheme for ocular staining.[22] Lid wiper epitheliopathy
RI PT
(LWE) was also assessed following lissamine green application.[23]
Meibomian gland function assessment was conducted in accordance with the
recommendations of the International Workshop on Meibomian Gland Dysfunction and
SC
TFOS DEWS II.[19, 24] Expressibility of the inferior eyelid meibomian glands was assessed with the Korb Meibomian Gland Evaluator™ (TearScience®, North Carolina, USA). The
M AN U
number of meibomian orifices yielding lipid secretion was evaluated at each of the nasal, central and lateral aspects of the lower lid.[25] The meibum viscosity and expressibility was graded as: grade 0, clear fluid; grade 1, slightly turbid; grade 2, thick opaque; grade 3, toothpaste-like; grade 4, complete orifice blockage.[21] Infrared meibography was imaged
TE D
with the Oculus Keratograph 5M, with the superior and inferior eyelids everted in turn. From the captured image, the proportion of meibomian glands visible within the tarsal area were
EP
graded according to the Meiboscale.[26]
The Schirmer I test was then performed, as the final assessment, under topical anaesthesia
AC C
(0.4% oxbuprocaine).[27]
2.3. Statistics
Statistical analyses were performed using IBM SPSS Statistics version 22 (New York, USA) and Graph Pad Prism version 6.02 (California, USA). Comparisons of continuous variables were performed using paired t-tests, where normal distributions had been confirmed by Kolmogorov-Smirnov testing (p>0.05). Non-normally distributed continuous and ordinal data were analysed using Wilcoxon signed-rank test. All tests were two-tailed and p<0.05 was
ACCEPTED MANUSCRIPT considered significant. All normally distributed continuous data are presented as mean ± SD, non-normally distributed continuous data or ordinal data as median (IQR), and categorical
AC C
EP
TE D
M AN U
SC
RI PT
data as number of participants (% of participants), unless otherwise stated.
ACCEPTED MANUSCRIPT 3. RESULTS
The mean ± SD age of the 33 participants (24 male, 9 female) was 67 ± 12 years (range, 36 to 87 years), and the mean ± SD treatment duration was 5.3 ± 4.4 years (range, 0.5 to 13
RI PT
years). Thirty (91%) participants were of New Zealand European ethnicity, while the remaining three (10%) were Chinese.
The topical anti-glaucoma medications of study participants are listed in Table 1. Twenty-
M AN U
benzalkonium chloride-containing eye drops.
SC
nine (88%) participants received prostaglandin analogues, and all participants used
Clinical measurements are presented in Table 2. Treated eyes exhibited shorter noninvasive tear film break-up time (median 7.5s versus 10.1s, p=0.03, Figure 1), and poorer tear film osmolarity than untreated fellow eyes (313±12mOsmol/L versus 305±11mOsmol/L,
TE D
p=0.04, Figure 2). Higher automated objective bulbar conjunctival hyperaemia readings (p=0.04, Figure 3), and eyelid margin abnormality scores (p=0.01) were also observed in treated eyes. Overall, the inter-ocular difference in eyelid abnormality scores were
EP
accounted for by 9 participants exhibiting eyelid margin irregularity, 6 participants exhibiting plugged orifices of meibomian glands, and 2 participants exhibiting eyelid margin
AC C
telangiectasia in the treated eye but not the fellow eye.
Aqueous tear production evaluation showed that treated eyes had lower tear meniscus height (p=0.03) and anesthetised Schirmer values (p=0.04). Although there were trends towards higher levels of meibomian dropout and decreased numbers of glands yielding lipid secretions in treated eyes, the inter-ocular differences were not statistically significant (all p>0.05).
ACCEPTED MANUSCRIPT There were no differences in OSDI scores, lipid layer and expressed meibum quality, ocular surface staining, or lid wiper epitheliopathy between treated and fellow eyes (all p>0.05). Sub-group analysis of participants receiving prostaglandin analogue therapy revealed similar
AC C
EP
TE D
M AN U
SC
RI PT
trends.
ACCEPTED MANUSCRIPT 4. DISCUSSION
In agreement with trends reported in previous case control and paired-eye comparison studies,[5, 10-13, 17, 28-31] the findings of the current work demonstrated poorer tear film
RI PT
stability and osmolarity in eyes treated with topical anti-glaucoma medications than untreated fellow eyes. Moreover, both the median non-invasive tear film breakup time (7.2s) and mean tear osmolarity (313 mOsmol/L) of treated eyes met the TFOS DEWS II
diagnostic cut-off for dry eye disease,[19] while the two parameters remained within normal
SC
physiological limits in fellow eyes. The exact mechanisms underlying the association
between topical anti-glaucoma medication use and reduced tear film quality are not fully
M AN U
understood. However, the higher levels of automated objective bulbar conjunctival hyperaemia readings detected in treated eyes would suggest that inflammatory changes of the ocular surface are likely to be implicated.[19] This is further supported by the significantly increased eyelid margin abnormality scores in treated eyes. Consistent with the grading
TE D
system adopted by earlier studies,[10, 11] the eyelid margin abnormalities evaluated in the current work included signs of conjunctival inflammation associated with meibomian gland dysfunction, such as eyelid margin irregularity, telangiectasia, plugged orifices of meibomian
EP
glands, and anterior or posterior replacement of the mucocutaneous junction.
AC C
The greater severity of ocular surface inflammation observed in treated eyes may partially be attributed to medication side-effects of the topical prostaglandin analogues received by the overwhelming majority (88%) of participants.[2, 32] However, the natural course of prostaglandin analogue-related conjunctival hyperaemia is such that it typically falls following one month of use,[32] whereas participants in the current study had been on long term therapy for an average of 5.3 years. The pro-inflammatory and toxic effects of benzalkonium chloride may also potentially contribute.[1-4, 8, 9] Benazalkonium chloride is a quaternary ammonium, and one of the most frequently used preservatives in ophthalmic preparations.[9] All participants in the current study were using benzalkonium chloride-
ACCEPTED MANUSCRIPT containing eye drops. Ocular toxicity associated with benzalkonium chloride has been demonstrated consistently in laboratory, experimental and clinical studies, and includes ocular surface epithelial damage, goblet cell loss and superficial punctate keratitis.[1-3, 8, 9] Although the pathophysiological mechanisms underlying such effects have not yet been fully
RI PT
elucidated, it is thought to involve immunoinflammatory pathways mediated by the release of proinflammatory cytokines, oxidative stress, and apoptosis induction.[1-4, 8, 9]
Benzalkonium chloride is also recognised to compromise the integrity of the surface precorneal lipid layer through its tensioactive effects, increasing the susceptibility to excessive
SC
tear evaporation, ocular surface desiccation and inflammation.[1-3, 9] It is possible for such inflammatory pathways to predispose towards the vicious cycle which perpetuates dry eye
M AN U
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 mediator release, goblet cell loss, and disturbances in mucin expression. This can amplify tear film instability and evaporation which further exacerbates pre-existing tear film
TE D
hyperosmolarity.[33, 34]
Surprisingly, marginal trends towards reduced aqueous tear production were detected in
EP
treated eyes. Tear meniscus height, a non-invasive surrogate measure of basal tear production and volume,[19, 35] was lower in treated than fellow eyes. However, while
AC C
statistically significant, the inter-ocular difference was deemed to be of limited clinical significance, with mean measurements in both treated and fellow eyes remaining well above the TFOS DEWS II aqueous deficiency dry eye diagnostic cut-off of <0.2mm.[19] The anesthetised Schirmer test, another indirect measure of aqueous tear production, was also assessed.[19, 35] Consistent with the trends described in previous reports,[10-13] the Schirmer value was smaller in treated eyes than fellow eyes. However, the mean measurements of both eyes were above 10mm and within normal physiological limits,[19] and the inter-ocular differences were therefore likely to be of limited clinical significance.
ACCEPTED MANUSCRIPT Interestingly, no differences in tear film lipid layer, expressed meibum quality, and ocular surface staining were detected between treated and fellow eyes in the current study. Furthermore, no significant trends were detected in the dry eye symptomology, which is in contrast to the poorer levels of tear film stability and osmolarity observed in treated eyes.
RI PT
Although there were trends towards increased meibomian dropout and reduced numbers of glands yielding lipid secretions in treated eyes, the inter-ocular differences did not reach statistical significance. This contrasts with a similar paired-eye comparison study from
Japan, which reported higher meiboscores and poorer meibum quality in eyes receiving long
SC
term topical anti-glaucoma medications.[10] It is conceivable for differences in the ethnic distribution of participants in the two studies to play a role in the discordant findings
M AN U
observed. A higher degree of meibomian gland dropout has been observed in the Asian eye than the Caucasian eye, which may potentially predispose towards the greater prevalence and severity of dry eye reported in Asian populations.[21] In the current study, more than 90% of participants were Caucasian, which contrasted with the likely predominantly Asian
TE D
population in the Japanese study. It is possible for differences between treated and fellow eyes to be more marked with increasing underlying severity of meibomian gland dysfunction and dry eye. Similar discordant findings were also present between the current paired-eye
EP
comparison study and previous case control studies.[11-13] However, differences in methodological design may also potentially contribute. The development of dry eye and
AC C
meibomian gland dysfunction can be influenced by a variety of epidemiological factors including age, gender, ethnicity, disease duration, hormonal disturbances, medications, contact lens wear, and environmental exposure.[36, 37] Controlling for confounding factors can be difficult to achieve in case control studies, and the associated risks of selection bias cannot be discounted.
There are methodological limitations that need to be considered when interpreting the findings of this study. The cross-sectional design of the study precluded the measurement of pre-treatment signs and symptoms, and the detection of changes in ocular parameters over
ACCEPTED MANUSCRIPT a follow-up period. Nevertheless, the same limitations are acknowledged to exist in previous studies with similar designs. Future long term prospective paired eye comparison studies are therefore required to confirm the findings of the current study.
RI PT
5. Conclusions
Of note, decreased tear film stability and elevated tear osmolarity, both global indices of dry eye disease,[19] were observed in eyes treated with topical anti-glaucoma medications. This
SC
was associated with increased levels of bulbar conjunctival hyperaemia and eyelid margin changes. These findings suggest that inflammatory mechanisms may play a role in the
M AN U
propensity of dry eye development in patients receiving long term topical anti-glaucoma
AC C
EP
TE D
medications.
ACCEPTED MANUSCRIPT 6. ACKNOWLEDGEMENTS
RI PT
None.
7. FUNDING
This research did not receive any specific grant from funding agencies in the public,
AC C
EP
TE D
M AN U
SC
commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT REFERENCES
[1] Anwar Z, Wellik SR, Galor A. Glaucoma therapy and ocular surface disease: current literature and recommendations. Curr Opin Ophthalmol. 2013;24:136-43.
RI PT
[2] Kastelan S, Tomic M, Metez Soldo K, Salopek-Rabatic J. How ocular surface disease impacts the glaucoma treatment outcome. Biomed Res Int. 2013:696328.
[3] Stewart WC, Stewart JA, Nelson LA. Ocular surface disease in patients with ocular hypertension and glaucoma. Curr Eye Res. 2011;36:391-8.
SC
[4] Skalicky SE, Goldberg I, McCluskey P. Ocular Surface Disease and Quality of Life in Patients With Glaucoma. Am J Ophthalmol. 2012;153:1-9.
M AN U
[5] Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350-5.
[6] Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol. 2006;90:262-7.
TE D
[7] Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15:276-83. [8] Gomes JAP, Azar DT, Baudouin C, Efron N, Hirayama M, Horwath-Winter J, et al. TFOS
EP
DEWS II iatrogenic report. Ocul Surf. 2017;15:511-38. [9] Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops:
AC C
the good, the bad and the ugly. Prog Retin Eye Res. 2010;29:312-34. [10] Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Tomidokoro A, et al. Effects of long-term topical anti-glaucoma medications on meibomian glands. Graef Arch Clin Exp. 2012;250:1181-5.
[11] Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Tomidokoro A, et al. Comparison of the long-term effects of various topical antiglaucoma medications on meibomian glands. Cornea. 2012;31:1229-34.
ACCEPTED MANUSCRIPT [12] Mocan MC, Uzunosmanoglu E, Kocabeyoglu S, Karakaya J, Irkec M. The Association of Chronic Topical Prostaglandin Analog Use With Meibomian Gland Dysfunction. J Glaucoma. 2016;25:770-4. [13] Uzunosmanoglu E, Mocan MC, Kocabeyoglu S, Karakaya J, Irkec M. Meibomian Gland
RI PT
Dysfunction in Patients Receiving Long-Term Glaucoma Medications. Cornea. 2016;35:1112-6.
[14] Nichols KK, Foulks GN, Bron AJ, Glasgow BJ, Dogru M, Tsubota K, et al. The
Ophthalmol Vis Sci. 2011;52:1922-9.
SC
international workshop on meibomian gland dysfunction: executive summary. Invest
[15] McCulley JP, Shine WE. The lipid layer of tears: dependent on meibomian gland
M AN U
function. Exp Eye Res. 2004;78:361-5.
[16] Craig JP, Tomlinson A. Importance of the lipid layer in human tear film stability and evaporation. Optom Vis Sci. 1997;74:8-13.
[17] Lee SY, Wong TT, Chua J, Boo C, Soh YF, Tong L. Effect of chronic anti-glaucoma
TE D
medications and trabeculectomy on tear osmolarity. Eye. 2013;27:1142-50. [18] Wang MT, Jaitley Z, Lord SM, Craig JP. Comparison of Self-applied Heat Therapy for Meibomian Gland Dysfunction. Optom Vis Sci. 2015;92:e321-6.
EP
[19] Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II Diagnostic Methodology report. Ocul Surf. 2017;15:539-74.
AC C
[20] Guillon JP. Use of the Tearscope Plus and attachments in the routine examination of the marginal dry eye contact lens patient. Adv Exp Med Biol. 1998;438:859-67. [21] Craig JP, Wang MT, Kim D, Lee JM. Exploring the Predisposition of the Asian Eye to Development of Dry Eye. Ocul Surf. 2016;14:385-92. [22] Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 2003;22:640-50. [23] Korb DR, Herman JP, Greiner JV, Scaffidi RC, Finnemore VM, Exford JM, et al. Lid wiper epitheliopathy and dry eye symptoms. Eye Contact Lens. 2005;31:2-8.
ACCEPTED MANUSCRIPT [24] Tomlinson A, Bron Aj Fau - Korb DR, Korb Dr Fau - Amano S, Amano S Fau - Paugh JR, Paugh Jr Fau - Pearce EI, Pearce Ei Fau - Yee R, et al. The international workshop on meibomian gland dysfunction: report of the diagnosis subcommittee. Invest Ophthalmol Vis Sci. 2011;52:2006-49.
eye symptoms and gland location. Cornea. 2008;27:1142-7.
RI PT
[25] Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry
[26] Pult H, Riede-Pult B. Comparison of subjective grading and objective assessment in meibography. Cont Lens Anterior Eye. 2013;36:22-7.
SC
[27] Li N, Deng XG, He MF. Comparison of the Schirmer I test with and without topical anesthesia for diagnosing dry eye. Int J Opthalmol. 2012;5:478-81.
M AN U
[28] Labbe A, Terry O, Brasnu E, Van Went C, Baudouin C. Tear film osmolarity in patients treated for glaucoma or ocular hypertension. Cornea. 2012;31:994-9. [29] Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after longterm treatment with an antiglaucomatous drug. Ophthalmol. 1992;99:1082-8.
TE D
[30] Arici MK, Arici DS, Topalkara A, Guler C. Adverse effects of topical antiglaucoma drugs on the ocular surface. Clin Exp Opthalmol. 2000;28:113-7. [31] Inoue K, Okugawa K, Kato S, Inoue Y, Tomita G, Oshika T, et al. Ocular factors relevant
EP
to anti-glaucomatous eyedrop-related keratoepitheliopathy. J Glaucoma. 2003;12:480-5. [32] Sakata R, Sakisaka T, Matsuo H, Miyata K, Aihara M. Time Course of Prostaglandin
AC C
Analog-related Conjunctival Hyperemia and the Effect of a Nonsteroidal Antiinflammatory Ophthalmic Solution. J Glaucoma. 2016;25:e204-8. [33] Baudouin C, Messmer EM, Aragona P. Revisiting the vicious circle of dry eye disease: a focus on the pathophysiology of meibomian gland dysfunction. Br J Ophthalmol. 2016;100:300-6. [34] Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al. TFOS DEWS II pathophysiology report. Ocul Surf. 2017;15:438-510. [35] Foulks GN, Pflugfelder SC. New testing options for diagnosing and grading dry eye disease. Am J Ophthalmol. 2014;157:1122-9.
ACCEPTED MANUSCRIPT [36] Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II Epidemiology Report. Ocul Surf. 2017;15:334-65. [37] Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK. The international workshop on meibomian gland dysfunction: report of the subcommittee on
RI PT
the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci.
AC C
EP
TE D
M AN U
SC
2011;52:1994-2005.
ACCEPTED MANUSCRIPT TABLES
Table 1: Topical anti-glaucoma medications of study participants. Data are presented as number of participants (% of participants).
RI PT
No. (%)
8 (24%) 8 (24%) 6 (18%)
SC
1 (3%)
1 (3%) 1 (3%) 1 (3%) 3 (9%) 2 (6%) 1 (3%) 1 (3%)
AC C
EP
TE D
M AN U
Medication Prostaglandin analogue monotherapy Bimatoprost Latanoprost Travoprost β-blocker monotherapy Timolol Combination therapy Betaxolol and Latanoprost Bimatoprost and Timolol Bimatoprost, Brimonidine and Timolol Bimatoprost, Dorzolamide and Timolol Brimonidine and Timolol Dorzolamide and Timolol Timolol and Travoprost
ACCEPTED MANUSCRIPT 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).
p
0.11
5.0 (2.3-14.6)
7.5 (5.2-13.0) 10.1 (6.8-14.5)
0.03* 7.2 (5.2-13.0)
SC
5.0 (2.3-14.6) 6.3 (2.1-11.4)
6.3 (2.2-11.4)
0.14
10.1 (6.8-14.6)
0.03*
305±11
0.04*
314±14
304±12
0.03*
0.41±0.19 14±7
0.47±0.17 16±8
0.03* 0.04*
0.40±0.22 14±8
0.46±0.19 16±8
0.04* 0.04*
3 (3-4) 2 (1-3)
3 (3-4) 1 (1-3)
0.65 0.49
3 (3-4) 2 (1-3)
3 (3-4) 1 (1-3)
0.53 0.46
2 (1-3)
1 (1-2)
0.38
2 (1-3)
1 (1-2)
0.36
5 (2-7)
5 (3-7)
0.41
5 (2-7)
5 (3-7)
0.35
TE D
M AN U
313±12
1 (1-2)
1 (1-2)
0.63
1 (1-2)
1 (1-2)
0.57
2 (1-3)
1 (1-2)
0.01*
2 (1-3)
1 (1-2)
0.008*
1.5±0.3
1.3±0.3
0.04*
1.6±0.4
1.4±0.4
0.04*
0 (0-2)
0 (0-2)
0.54
0 (0-2)
0 (0-2)
0.58
0 (0-1)
0 (0-0)
0.14
0 (0-1)
0 (0-0)
0.20
1 (0-3)
1 (0-3)
0.80
1 (0-3)
1 (0-3)
0.56
AC C
EP
Dry eye symptomology OSDI score Tear film function Non-invasive tear film breakup time (s) Tear film osmolarity (mOsmol/L) Aqueous tear production Tear meniscus height (mm) Schirmer value (mm) Meibomian gland function Tear film lipid layer grade Superior eyelid meibography grade Inferior eyelid meibography grade Number of meibomian glands yielding lipid secretions Expressed meibum grade Ocular surface characteristics Eyelid margin abnormality score JENVIS bulbar conjunctival hyperaemia score Conjunctival lissamine green staining score (out of 30) Corneal sodium fluorescein staining score (out of 25) Lid wiper epitheliopathy grade
Participants on prostaglandin analogue therapy Treated eye Fellow Eye p (n=29) (n=29)
RI PT
All participants Treated eye Fellow Eye (n=33) (n=33)
ACCEPTED MANUSCRIPT FIGURE LEGENDS
Figure 1: Non-invasive tear film breakup time of the eyes of participants treated with antiglaucoma medications and untreated fellow eyes. Each point represents the tear film
RI PT
breakup time of an individual eye. Bars represent the median tear film breakup time. Error bars represent the interquartile range. Asterisks denote statistically significant differences
SC
(p<0.05).
Figure 2: Tear film osmolarity of the eyes of participants treated with anti-glaucoma
M AN U
medications and untreated fellow eyes. Each point represents the tear film osmolarity of an individual eye. Bars represent the mean tear film osmolarity. Error bars represent the
TE D
standard deviation. Asterisks denote statistically significant differences (p<0.05).
Figure 3: Standardised JENVIS bulbar conjunctival hyperaemia scores of the eyes of participants treated with anti-glaucoma medications and untreated fellow eyes. Each point
EP
represents the conjunctival hyperaemia score of an individual eye. Bars represent the mean conjunctival hyperaemia score. Error bars represent the standard deviation. Asterisks
AC C
denote statistically significant differences (p<0.05).
ACCEPTED MANUSCRIPT
p=0.03*
RI PT M AN U
SC
20
EP
10
TE D
15
5
0
AC C
Non-invasive breakup time (s)
25
Treated eye
Fellow eye
ACCEPTED MANUSCRIPT
p=0.04*
RI PT M AN U
SC 300
EP
TE D
320
AC C
Tear film osmolarity (mOsmol/L)
340
280
Treated eye
Fellow eye
AC C
1
0
EP TE D
2
M AN U
SC
RI PT
JENVIS conjunctival hyperaemia score
ACCEPTED MANUSCRIPT
p=0.04*
3
Treated eye Fellow eye