1040-5488/15/9209-e222/0 VOL. 92, NO. 9, PP. e222Ye226 OPTOMETRY AND VISION SCIENCE Copyright * 2015 American Academy of Optometry
ORIGINAL ARTICLE
Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and Preservatives Norlina Ramli*, Gowri Supramaniam*, Amir Samsudin*, Azida Juana*, Mimiwati Zahari*, and May May Choo* ABSTRACT Purpose. To evaluate the prevalence of ocular surface disease (OSD) in glaucoma and nonglaucoma subjects using different clinical tests and to determine the effect of number of antiglaucoma medications and preservatives on OSD. Methods. This is a cross-sectional, case-comparison study at the Eye Clinic of the University of Malaya Medical Centre, Malaysia, between June 2012 and January 2013. Glaucoma subjects (n = 105) using topical antiglaucoma medications were compared with control subjects (n = 102) who were not on any topical medications. The presence of OSD was assessed using the tear film breakup time (TBUT) test, corneal staining, Schirmer test, and Ocular Surface Disease Index (OSDI) questionnaire grading. Results. The prevalence of OSD varied from 37 to 91% in the glaucoma group, depending on the type of clinical test. More subjects in the glaucoma group had corneal staining (63% vs. 36%, p = 0.004), abnormal Schirmer tests (39% vs. 25%, p = 0.049), and moderate OSDI symptoms (17% vs. 7%, p = 0.028). The percentage with abnormal TBUT increased with higher numbers of topical medications and was high with both benzalkonium chlorideYcontaining and preservative-free eye drops (90% and 94%, respectively, both p G 0.001). Benzalkonium chloride was associated with a nearly three times higher odds ratio of showing abnormal OSDI. Conclusions. Ocular surface disease is common in those using topical antiglaucoma medications. Abnormal TBUT is associated with increasing number of eye drops and benzalkonium chlorideYcontaining eye drops, although this also occurs with the use of preservative-free eye drops. (Optom Vis Sci 2015;92:e222Ye226) Key Words: ocular surface disease, glaucoma, antiglaucoma, tear film, preservative-free, benzalkonium chloride, BAK
O
cular surface disease (OSD) is a multifactorial disorder of the tear film, eyelids, cornea, and conjunctiva.1Y4 It is characterized by an inadequate quantity of tears, an unstable tear film, and ocular surface breakdown, which may all lead to visual interference. Additionally, OSD induces a variety of symptoms including irritation, burning, itching, tearing, stinging, and fluctuating visual acuity. Studies have shown that OSD is prevalent among glaucoma patients who require long-term therapy with intraocular pressure (IOP)Ylowering medications.3Y7 Repeated dosing of eye drops that contain preservatives meant to prevent contamination can cause adverse effects to the ocular surface, thus triggering OSD. Several studies have been carried out to assess the prevalence of OSD among glaucoma patients. Leung et al.5 reported OSD symptoms and signs in 22 to 78% of glaucoma patients, a variation in
prevalence rate that largely depended on the different tests used to assess the disorder. Fechtner et al.4 used the Ocular Surface Disease Index (OSDI) questionnaire and found 48% of their 630 patients to have OSD symptoms, whereas Garcia-Feijoo and Sampaolesi6 reported that 59% of their glaucoma patients had mild to severe OSD symptoms when similarly tested. Although these recent studies have reported a high prevalence of OSD in glaucoma patients, few have included a control group consisting of subjects not using topical medications.7 In this study, we evaluated the prevalence of OSD using different clinical tests in glaucoma subjects and compared them with this control group. We also determined the effect of number of different antiglaucoma medications and preservatives on OSD.
METHODS Study Design and Subjects
*MSOphth Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia (all authors).
We conducted a cross-sectional, case-comparison study to compare the prevalence of OSD between glaucoma and nonglaucoma
Optometry and Vision Science, Vol. 92, No. 9, September 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and PreservativesVRamli et al.
subjects and to evaluate the effect of number of different topical medications and preservatives on OSD. This study was conducted at the Eye Clinic of the University of Malaya Medical Centre, Kuala Lumpur, Malaysia, between June 2012 and January 2013. Ethical approval was obtained from the medical ethics committee of the center before commencement of the study. All patients signed a statement of informed consent in compliance with the tenets of the Declaration of Helsinki. Subjects 45 years and older who had been on antiglaucoma medications for at least 3 months were recruited into the glaucoma group (n = 105). The antiglaucoma medications used were latanoprost (Xalatan), timolol (Timo-Comod), brinzolamide (Azopt), and brimonidine (Alphagan-p). The control group consisted of patients who were not on any topical medications for the preceding 1 year (n = 102). Patients were excluded if they had conditions that could adversely affect tear film stability, such as lid margin disease, connective tissue disease, thyroid eye disease, history of chemotherapy or radiotherapy, history of ocular surgery, or allergy to any of the components in the agents used in this study, for example, fluorescein.
Ocular Surface Assessment All subjects underwent a detailed ocular examination as in a previous study,8 which included tear film breakup time (TBUT) test, corneal staining with fluorescein, Schirmer test, and OSDI questionnaire grading. The examiner was blinded to the diagnosis of the subjects. The right eye of each patient was analyzed unless it did not meet the inclusion criteria, in which case the left eye (if it met the criteria) was used instead. The TBUT test was performed by applying fluorescein solution onto the inferior palpebral conjunctiva after gentle depression of the lower eyelid. The subject was asked to blink two times. The tear film was examined using a slit lamp with cobalt blue light. The interval between the last blink and the appearance of a first hypofluorescent spot or streak was recorded as the TBUT. A clinically abnormal TBUT was defined as less than or equal to 10 seconds. The grading for corneal staining was based on that described by Miyata et al.9 Presence of superficial punctate keratopathy (SPK) was graded according to the area and density of lesions. Briefly, after fluorescein staining, the area of SPK was graded as A0 when punctate staining was absent, A1 when it occupied less than onethird of the cornea, A2 when it occupied one-third to two-thirds
e223
TABLE 2.
Prevalence of OSD based on abnormal clinical tests in the glaucoma and control groups Clinical test
Glaucoma group, Control group, n (%) n (%)
TBUT e 10 s Corneal staining (any) Schirmer test G 10 mm OSDI, normal OSDI, mild OSDI, moderate OSDI, severe
96 (91.4) 66 (62.9) 41 (39.0) 66 (62.9) 21 (20.0) 18 (17.1) 0 (0)
83 (81.4) 37 (36.3) 25 (24.5) 76 (74.5) 19 (18.6) 7 (6.9) 0 (0)
p 0.331 0.004 0.049 0.401 0.752 0.028 V
of the cornea, and A3 when it occupied greater than two-thirds of the cornea. The density was graded as D0 when there was no punctate staining, D1 when it was sparse, D2 when it was moderate, and D3 when it was high and the lesions overlapped. The combination of the area and density grade represented the final grade, such as A2D3. The Schirmer test was performed by first instilling one drop of 0.5% proparacaine. After 1 minute, any visible fluid in the inferior fornix and lid margin was gently dried with a cotton swab. A precalibrated filter strip was then placed between the lower fornix and lower eyelid margin and left in place for 5 min. The strip was removed after 5 min and the amount of wetting was recorded. A clinically abnormal Schirmer test was defined as less than 10 mm. Upon completion of the ocular examination, subjects were asked questions from the 12-item OSDI questionnaire. This disease-specific quality-of-life questionnaire is used to quantify the impact of dry eye on vision-related quality of life and has been reported to have excellent test-retest reliability.4,5 The three measured components include ocular discomfort, function, and environmental triggers. Each individual item within the components refers to a 1-week recall period; the responses to each item refer to the frequency of the associated symptom. Possible responses ranged from 0 (none of the time) to 4 (all of the time). The sum of scores for all questions was used to calculate the final score, which ranged from 0 to 100. Scores between 0 and 12 were classified as normal; between 13 and 22, mild; between 23 and 32, moderate; and between 33 and 100, severe OSD.
Statistical Analysis
0.076 0.709
Statistical analysis was performed using the Statistical Package for the Social Sciences, Version 17.0 (SPSS Inc, Chicago, IL). Descriptive statistics presented as frequencies and percentages were used to summarize the demographic data of the patients. The W2 test was used to determine the difference between the glaucoma and control groups. Odds ratios were calculated for further analysis when indicated. A p value of less than 0.05 was considered to be statistically significant.
0.183
RESULTS
TABLE 1.
Demographic characteristics of subjects in the glaucoma and control groups
Age, mean T SD, y Sex, n (%) Male Female Ethnicity, n (%) Malay Chinese Indian
Glaucoma group (n = 105)
Control group (n = 102)
68.0 T 9.6
66.8 T 8.9
48 (45.7) 57 (54.3)
44 (43.1) 58 (56.9)
20 (19.0) 47 (44.8) 38 (36.2)
25 (24.5) 33 (32.4) 44 (43.1)
p
A total of 207 subjects participated in this study. Of these, 105 subjects were in the glaucoma group. The demographic characteristics of subjects are summarized in Table 1. There were no
Optometry and Vision Science, Vol. 92, No. 9, September 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
e224 Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and PreservativesVRamli et al. TABLE 3.
Number of subjects who presented with different numbers of abnormal tests in the glaucoma and control groups No. abnormal tests 0 1 2 3 4
Glaucoma group, n (%)
Control group, n (%)
p
2 (1.9) 21 (20.0) 33 (31.4) 40 (38.1) 9 (8.6)
14 (13.7) 34 (33.3) 32 (30.5) 18 (17.6) 4 (3.9)
0.002 0.080 0.903 0.004 0.166
statistically significant differences between the glaucoma and control groups in terms of age, sex, or ethnicity. The prevalences of OSD based on different clinical tests are shown in Table 2. The percentage with abnormal TBUT was larger in the glaucoma group, but this was not statistically significant. Corneal staining with any form of corneal epitheliopathy ranging from A1D1 to A3D3 was more common in the glaucoma group than in the control group (63% vs. 36%, p = 0.011). There were more patients in the glaucoma group who had abnormal Schirmer tests (39% vs. 25%, p = 0.049). The OSDI did not show any statistically significant differences in the prevalence of normal or mild OSD symptoms between the glaucoma and control groups but was statistically significant when compared between patients with moderate OSD symptoms (17% vs. 7%, p = 0.028). No patients had scores in the severe OSD range. There were more glaucoma subjects with two, three, and four abnormal OSD tests, although this was statistically significant only in the threeYabnormal test group (Table 3). Up to four different types of IOP-lowering eye drops were used by the individual glaucoma subjects, the most common being latanoprost (81%) and timolol (55%). There were no increased differences in Schirmer test and OSDI results as the number of eye drops increased. However, abnormal TBUT and corneal staining was observed with the use of eye drops, with an increasing trend with higher numbers of eye drops (Table 4). In the glaucoma group, the IOP-lowering eye drops were either preserved with benzalkonium chloride (BAK, in latanoprost and brinzolamide) or purite (brimonidine), or nonpreserved (timolol). Benzalkonium chloride was present in at least 81% of eye drops used by the glaucoma patients. There were no differences in Schirmer test and OSDI results with the different eye drops and preservatives. However, both BAK-containing and preservativefree eye drops resulted in significantly higher proportions with abnormal TBUT scores (Table 5); a further analysis showed that BAK was associated with nearly three times higher odds ratio of showing abnormal OSDI compared with purite-preserved or
nonpreserved eye drops (odds ratio, 2.94; 95% confidence interval, 1.01 to 8.52).
DISCUSSION This study demonstrated a high prevalence of OSD among glaucoma subjects, which was in keeping with the findings of several other studies.3Y7 We observed a variation in OSD detection with the different clinical tests. Corneal staining for SPK showed that 63% of our glaucoma subjects had some form of corneal epitheliopathy. This finding adds to the already extensive body of research indicating that corneal pathologies are frequently seen in patients on antiglaucoma medications.3Y7 Superficial punctate keratopathy may have been caused by instability of the tear film or lysis of the corneal epithelial cells, a result of the effect of preservatives found in antiglaucoma medications.2 Although there have been studies that reported the reliability of corneal staining,9 OSDI,10 and TBUT11 in detecting OSD, the ideal test remains contentious.8,12,13 Our results show different pickup rates with the different tests, and this may be attributed to variations in definitions used to define OSD. Leung et al.5 suggested that this could also be attributed to the lack of specificity of these clinical tests. Sullivan et al.8 found that corneal staining, TBUT, and Schirmer test lack the power to distinguish between mild and moderate stages, and as such were only informative with the more severe forms of the disease. The authors further found that tear osmolarity was superior in demonstrating correlation across different disease severity; however, this parameter was not investigated in our study. There was no statistically significant difference between the proportions with abnormal TBUT in both glaucoma and control groups. This could be partly contributed by age-related dry eye disease in both groups. Alternatively, it could also be due in part to the nonspecific nature of the test, which reflects gross function of the lipid layer of the tear film. We postulate that glaucoma medications and preservatives may have little impact on this layer of the tear film and instead have more impact on the mucin layer on the ocular surface, which is reflected on the corneal staining test that showed a significant difference between the groups. Consistent with findings from other studies,3Y7,14 we report high prevalences of OSD in subjects who used one or more antiglaucoma medications. Additionally, there was an increasing trend with higher numbers of eye drops. Pisella et al.15 demonstrated the correlation between increased signs and symptoms of OSD with the number of antiglaucoma medications used, whereas Becquet et al.16 found increased ocular damage with high doses of these eye drops. Ghosh et al.7 showed that each additional eye
TABLE 4.
Prevalence of glaucoma subjects with normal and abnormal TBUT and SPK based on the number of antiglaucoma medications used No. antiglaucoma medications Normal TBUT, n (%) Abnormal TBUT, n (%) 1 2 3 4
6 (5.8) 2 (1.9) 1 (0.9) 0
49 (47.2) 31 (29.1) 15 (14.1) 1 (1.0)
p G0.001 G0.001 G0.001 V
SPK absent, n (%) SPK present, n (%) 22 (21.2) 15 (14.1) 2 (1.9) 0
33 (31.8) 18 (16.9) 14 (13.1) 1 (1.0)
Optometry and Vision Science, Vol. 92, No. 9, September 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
p 0.882 0.601 0.003 V
Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and PreservativesVRamli et al.
e225
TABLE 5.
Prevalence of glaucoma subjects with normal and abnormal TBUT and SPK based on the type of preservatives found in antiglaucoma medications Preservative BAK Purite BAK + purite Preservative-free
Normal TBUT, n (%)
Abnormal TBUT, n (%)
p
SPK absent, n (%)
SPK present, n (%)
p
8 (10.4) 0 0 1 (5.6)
69 (89.6) 2 (100.0) 8 (100.0) 17 (94.4)
G0.001 V V G0.001
33 (42.9) 0 3 (37.5) 3 (16.7)
44 (57.1) 2 (100.0) 5 (62.5) 15 (83.3)
0.210 V 0.480 0.005
drop was associated with about two times higher rates of impaired TBUT and attributed this to the preservatives in the eye drops. Most of the subjects with OSD in this study were using preservativecontaining eye drops, particularly those containing BAK. We found rates of abnormal OSDI nearly three times higher in subjects who were prescribed antiglaucoma drops containing BAK. This preservative has been identified as one of the agents causing OSD, by reducing the density of the conjunctival goblet cells17Y20 and damaging the corneal epithelial cells.1,2,16,17 Both acute and chronic exposure to BAK can lead to inflammatory changes in the ocular surface and decrease TBUT.16Y18 In a study of patients treated for glaucoma for at least 1 year, flow cytometry demonstrated a greater expression of inflammatory markers (Human Leukocyte AntigenDR [HLA-DR] and Intercellular Adhesion Molecule 1 [ICAM-1]) in those receiving BAK-preserved eye drops than in normal patients or those receiving preservative-free drops. The use of preservatives was associated with a lower expression of the ocular surface mucin marker MUC5AC, and the lowest MUC5AC levels were associated with the highest HLA-DR and ICAM-1 levels.19 Finally, we also found a high prevalence of abnormal TBUT and SPK in glaucoma subjects using the preservative-free timolol eye drops. Although preservative-free timolol has been described as nontoxic to the corneal epithelium,3,21,22 a study by Ayaki et al.23 showed a slight cytotoxic effect of timolol without preservatives, although this was less than when compared with the effect of timolol with preservatives. This finding warrants further investigation into the effect of preservative-free antiglaucoma drops on OSD. One of the limitations of this study was that we did not adjust for changes in treatment over the disease course. Patients who had previously used preservative-containing eye drops but then later prescribed with preservative-free eye drops may have only reported their latest prescription and hence overestimate the effect of the latter medication.
CONCLUSIONS Glaucoma subjects on topical antiglaucoma drops have a significantly higher prevalence of OSD than those who are not on any medications. The prevalence may increase with increasing numbers of eye drops and using BAK-containing eye drops, which is likely to be due to toxic effects of the preservative.
ACKNOWLEDGMENTS The authors thank Dr. Mohammadreza Peyman for his help with the statistical analysis and Ms. Audrey Looi for her help in editing the manuscript for publication. There are no conflicts of interest to declare. Received August 7, 2014; accepted January 30, 2015.
REFERENCES 1. Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther 2001;18:205Y15. 2. Cha SH, Lee JS, Oum BS, Kim CD. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro. Clin Experiment Ophthalmol 2004;32:180Y4. 3. Ayaki M, Iwasawa A, Inoue Y. Toxicity of antiglaucoma drugs with and without benzalkonium chloride to cultured human corneal endothelial cells. Clin Ophthalmol 2010;4:1217Y22. 4. 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;29:618Y21. 5. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 2008;17:350Y5. 6. Garcia-Feijoo J, Sampaolesi JR. A multicenter evaluation of ocular surface disease prevalence in patients with glaucoma. Clin Ophthalmol 2012;6:441Y6. 7. Ghosh S, O’Hare F, Lamoureux E, Vajpayee RB, Crowston JG. Prevalence of signs and symptoms of ocular surface disease in individuals treated and not treated with glaucoma medication. Clin Experiment Ophthalmol 2012;40:675Y81. 8. Sullivan BD, Whitmer D, Nichols KK, Tomlinson A, Foulks GN, Geerling G, Pepose JS, Kosheleff V, Porreco A, Lemp MA. An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci 2010;51:6125Y30. 9. Miyata K, Amano S, Sawa M, Nishida T. A novel grading method for superficial punctate keratopathy magnitude and its correlation with corneal epithelial permeability. Arch Ophthalmol 2003;121:1537Y9. 10. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118:615Y21. 11. Nichols KK, Mitchell GL, Zadnik K. The repeatability of clinical measurements of dry eye. Cornea 2004;23:272Y85. 12. Dougherty BE, Nichols JJ, Nichols KK. Rasch analysis of the Ocular Surface Disease Index (OSDI). Invest Ophthalmol Vis Sci 2011; 52:8630Y5. 13. Mathews PM, Ramulu PY, Friedman DS, Utine CA, Akpek EK. Evaluation of ocular surface disease in patients with glaucoma. Ophthalmology 2013;120:2241Y8. 14. Stewart WC, Stewart JA, Nelson LA. Ocular surface disease in patients with ocular hypertension and glaucoma. Curr Eye Res 2011; 36:391Y8. 15. Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 2002;86:418Y23. 16. Becquet F, Goldschild M, Moldovan MS, Ettaiche M, Gastaud P, Baudouin C. Histopathological effects of topical ophthalmic preservatives on rat corneoconjunctival surface. Curr Eye Res 1998;17:419Y25.
Optometry and Vision Science, Vol. 92, No. 9, September 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
e226 Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and PreservativesVRamli et al. 17. Rolando M, Brezzo V, Giordano G, Campagna P, Burlando S, Calabria G. The effect of different benzalkonium chloride concentrations on human normal ocular surface. In: Van Bijsterveld OP, Lemp MA, Spinelli D, eds. The Lacrimal System. Amsterdam, the Netherlands: Kugler and Ghedini Publications; 1991;89Y91. 18. Pauly A, Meloni M, Brignole-Baudouin F, Warnet JM, Baudouin C. Multiple endpoint analysis of the 3D-reconstituted corneal epithelium after treatment with benzalkonium chloride: early detection of toxic damage. Invest Ophthalmol Vis Sci 2009;50:1644Y52. 19. Baudouin C, Pisella PJ, Fillacier K, Goldschild M, Becquet F, De Saint Jean M, Bechetoille A. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology 1999;106:556Y63. 20. de Jong C, Stolwijk T, Kuppens E, de Keizer R, van Best J. Topical timolol with and without benzalkonium chloride: epithelial permeability and autofluorescence of the cornea in glaucoma. Graefes Arch Clin Exp Ophthalmol 1994;232:221Y4.
21. Beneyto P, Perez TM. Effect of continued treatment with timolol maleate on corneal endothelium: a fluorophotometric study. Cornea 1998;17:600Y3. 22. Denoyer A, Ossant F, Arbeille B, Fetissof F, Patat F, Pisella PJ. In vivo assessment of corneal epithelial toxicity of timolol with benzalkonium chloride using very-high-frequency ultrasound imaging. J Fr Ophtalmol 2006;29:11Y8. 23. Ayaki M, Yaguchi S, Iwasawa A, Koide R. Cytotoxicity of ophthalmic solutions with and without preservatives to human corneal endothelial cells, epithelial cells and conjunctival epithelial cells. Clin Experiment Ophthalmol 2008;36:553Y9.
Amir Samsudin Department of Ophthalmology, Faculty of Medicine University of Malaya 50603 Kuala Lumpur Malaysia e-mail: [email protected]
Optometry and Vision Science, Vol. 92, No. 9, September 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
ORIGINAL ARTICLE
Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and Preservatives Norlina Ramli*, Gowri Supramaniam*, Amir Samsudin*, Azida Juana*, Mimiwati Zahari*, and May May Choo* ABSTRACT Purpose. To evaluate the prevalence of ocular surface disease (OSD) in glaucoma and nonglaucoma subjects using different clinical tests and to determine the effect of number of antiglaucoma medications and preservatives on OSD. Methods. This is a cross-sectional, case-comparison study at the Eye Clinic of the University of Malaya Medical Centre, Malaysia, between June 2012 and January 2013. Glaucoma subjects (n = 105) using topical antiglaucoma medications were compared with control subjects (n = 102) who were not on any topical medications. The presence of OSD was assessed using the tear film breakup time (TBUT) test, corneal staining, Schirmer test, and Ocular Surface Disease Index (OSDI) questionnaire grading. Results. The prevalence of OSD varied from 37 to 91% in the glaucoma group, depending on the type of clinical test. More subjects in the glaucoma group had corneal staining (63% vs. 36%, p = 0.004), abnormal Schirmer tests (39% vs. 25%, p = 0.049), and moderate OSDI symptoms (17% vs. 7%, p = 0.028). The percentage with abnormal TBUT increased with higher numbers of topical medications and was high with both benzalkonium chlorideYcontaining and preservative-free eye drops (90% and 94%, respectively, both p G 0.001). Benzalkonium chloride was associated with a nearly three times higher odds ratio of showing abnormal OSDI. Conclusions. Ocular surface disease is common in those using topical antiglaucoma medications. Abnormal TBUT is associated with increasing number of eye drops and benzalkonium chlorideYcontaining eye drops, although this also occurs with the use of preservative-free eye drops. (Optom Vis Sci 2015;92:e222Ye226) Key Words: ocular surface disease, glaucoma, antiglaucoma, tear film, preservative-free, benzalkonium chloride, BAK
O
cular surface disease (OSD) is a multifactorial disorder of the tear film, eyelids, cornea, and conjunctiva.1Y4 It is characterized by an inadequate quantity of tears, an unstable tear film, and ocular surface breakdown, which may all lead to visual interference. Additionally, OSD induces a variety of symptoms including irritation, burning, itching, tearing, stinging, and fluctuating visual acuity. Studies have shown that OSD is prevalent among glaucoma patients who require long-term therapy with intraocular pressure (IOP)Ylowering medications.3Y7 Repeated dosing of eye drops that contain preservatives meant to prevent contamination can cause adverse effects to the ocular surface, thus triggering OSD. Several studies have been carried out to assess the prevalence of OSD among glaucoma patients. Leung et al.5 reported OSD symptoms and signs in 22 to 78% of glaucoma patients, a variation in
prevalence rate that largely depended on the different tests used to assess the disorder. Fechtner et al.4 used the Ocular Surface Disease Index (OSDI) questionnaire and found 48% of their 630 patients to have OSD symptoms, whereas Garcia-Feijoo and Sampaolesi6 reported that 59% of their glaucoma patients had mild to severe OSD symptoms when similarly tested. Although these recent studies have reported a high prevalence of OSD in glaucoma patients, few have included a control group consisting of subjects not using topical medications.7 In this study, we evaluated the prevalence of OSD using different clinical tests in glaucoma subjects and compared them with this control group. We also determined the effect of number of different antiglaucoma medications and preservatives on OSD.
METHODS Study Design and Subjects
*MSOphth Department of Ophthalmology, University of Malaya, Kuala Lumpur, Malaysia (all authors).
We conducted a cross-sectional, case-comparison study to compare the prevalence of OSD between glaucoma and nonglaucoma
Optometry and Vision Science, Vol. 92, No. 9, September 2015
Copyright © American Academy of Optometry. Unauthorized reproduction of this article is prohibited.
Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and PreservativesVRamli et al.
subjects and to evaluate the effect of number of different topical medications and preservatives on OSD. This study was conducted at the Eye Clinic of the University of Malaya Medical Centre, Kuala Lumpur, Malaysia, between June 2012 and January 2013. Ethical approval was obtained from the medical ethics committee of the center before commencement of the study. All patients signed a statement of informed consent in compliance with the tenets of the Declaration of Helsinki. Subjects 45 years and older who had been on antiglaucoma medications for at least 3 months were recruited into the glaucoma group (n = 105). The antiglaucoma medications used were latanoprost (Xalatan), timolol (Timo-Comod), brinzolamide (Azopt), and brimonidine (Alphagan-p). The control group consisted of patients who were not on any topical medications for the preceding 1 year (n = 102). Patients were excluded if they had conditions that could adversely affect tear film stability, such as lid margin disease, connective tissue disease, thyroid eye disease, history of chemotherapy or radiotherapy, history of ocular surgery, or allergy to any of the components in the agents used in this study, for example, fluorescein.
Ocular Surface Assessment All subjects underwent a detailed ocular examination as in a previous study,8 which included tear film breakup time (TBUT) test, corneal staining with fluorescein, Schirmer test, and OSDI questionnaire grading. The examiner was blinded to the diagnosis of the subjects. The right eye of each patient was analyzed unless it did not meet the inclusion criteria, in which case the left eye (if it met the criteria) was used instead. The TBUT test was performed by applying fluorescein solution onto the inferior palpebral conjunctiva after gentle depression of the lower eyelid. The subject was asked to blink two times. The tear film was examined using a slit lamp with cobalt blue light. The interval between the last blink and the appearance of a first hypofluorescent spot or streak was recorded as the TBUT. A clinically abnormal TBUT was defined as less than or equal to 10 seconds. The grading for corneal staining was based on that described by Miyata et al.9 Presence of superficial punctate keratopathy (SPK) was graded according to the area and density of lesions. Briefly, after fluorescein staining, the area of SPK was graded as A0 when punctate staining was absent, A1 when it occupied less than onethird of the cornea, A2 when it occupied one-third to two-thirds
e223
TABLE 2.
Prevalence of OSD based on abnormal clinical tests in the glaucoma and control groups Clinical test
Glaucoma group, Control group, n (%) n (%)
TBUT e 10 s Corneal staining (any) Schirmer test G 10 mm OSDI, normal OSDI, mild OSDI, moderate OSDI, severe
96 (91.4) 66 (62.9) 41 (39.0) 66 (62.9) 21 (20.0) 18 (17.1) 0 (0)
83 (81.4) 37 (36.3) 25 (24.5) 76 (74.5) 19 (18.6) 7 (6.9) 0 (0)
p 0.331 0.004 0.049 0.401 0.752 0.028 V
of the cornea, and A3 when it occupied greater than two-thirds of the cornea. The density was graded as D0 when there was no punctate staining, D1 when it was sparse, D2 when it was moderate, and D3 when it was high and the lesions overlapped. The combination of the area and density grade represented the final grade, such as A2D3. The Schirmer test was performed by first instilling one drop of 0.5% proparacaine. After 1 minute, any visible fluid in the inferior fornix and lid margin was gently dried with a cotton swab. A precalibrated filter strip was then placed between the lower fornix and lower eyelid margin and left in place for 5 min. The strip was removed after 5 min and the amount of wetting was recorded. A clinically abnormal Schirmer test was defined as less than 10 mm. Upon completion of the ocular examination, subjects were asked questions from the 12-item OSDI questionnaire. This disease-specific quality-of-life questionnaire is used to quantify the impact of dry eye on vision-related quality of life and has been reported to have excellent test-retest reliability.4,5 The three measured components include ocular discomfort, function, and environmental triggers. Each individual item within the components refers to a 1-week recall period; the responses to each item refer to the frequency of the associated symptom. Possible responses ranged from 0 (none of the time) to 4 (all of the time). The sum of scores for all questions was used to calculate the final score, which ranged from 0 to 100. Scores between 0 and 12 were classified as normal; between 13 and 22, mild; between 23 and 32, moderate; and between 33 and 100, severe OSD.
Statistical Analysis
0.076 0.709
Statistical analysis was performed using the Statistical Package for the Social Sciences, Version 17.0 (SPSS Inc, Chicago, IL). Descriptive statistics presented as frequencies and percentages were used to summarize the demographic data of the patients. The W2 test was used to determine the difference between the glaucoma and control groups. Odds ratios were calculated for further analysis when indicated. A p value of less than 0.05 was considered to be statistically significant.
0.183
RESULTS
TABLE 1.
Demographic characteristics of subjects in the glaucoma and control groups
Age, mean T SD, y Sex, n (%) Male Female Ethnicity, n (%) Malay Chinese Indian
Glaucoma group (n = 105)
Control group (n = 102)
68.0 T 9.6
66.8 T 8.9
48 (45.7) 57 (54.3)
44 (43.1) 58 (56.9)
20 (19.0) 47 (44.8) 38 (36.2)
25 (24.5) 33 (32.4) 44 (43.1)
p
A total of 207 subjects participated in this study. Of these, 105 subjects were in the glaucoma group. The demographic characteristics of subjects are summarized in Table 1. There were no
Optometry and Vision Science, Vol. 92, No. 9, September 2015
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e224 Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and PreservativesVRamli et al. TABLE 3.
Number of subjects who presented with different numbers of abnormal tests in the glaucoma and control groups No. abnormal tests 0 1 2 3 4
Glaucoma group, n (%)
Control group, n (%)
p
2 (1.9) 21 (20.0) 33 (31.4) 40 (38.1) 9 (8.6)
14 (13.7) 34 (33.3) 32 (30.5) 18 (17.6) 4 (3.9)
0.002 0.080 0.903 0.004 0.166
statistically significant differences between the glaucoma and control groups in terms of age, sex, or ethnicity. The prevalences of OSD based on different clinical tests are shown in Table 2. The percentage with abnormal TBUT was larger in the glaucoma group, but this was not statistically significant. Corneal staining with any form of corneal epitheliopathy ranging from A1D1 to A3D3 was more common in the glaucoma group than in the control group (63% vs. 36%, p = 0.011). There were more patients in the glaucoma group who had abnormal Schirmer tests (39% vs. 25%, p = 0.049). The OSDI did not show any statistically significant differences in the prevalence of normal or mild OSD symptoms between the glaucoma and control groups but was statistically significant when compared between patients with moderate OSD symptoms (17% vs. 7%, p = 0.028). No patients had scores in the severe OSD range. There were more glaucoma subjects with two, three, and four abnormal OSD tests, although this was statistically significant only in the threeYabnormal test group (Table 3). Up to four different types of IOP-lowering eye drops were used by the individual glaucoma subjects, the most common being latanoprost (81%) and timolol (55%). There were no increased differences in Schirmer test and OSDI results as the number of eye drops increased. However, abnormal TBUT and corneal staining was observed with the use of eye drops, with an increasing trend with higher numbers of eye drops (Table 4). In the glaucoma group, the IOP-lowering eye drops were either preserved with benzalkonium chloride (BAK, in latanoprost and brinzolamide) or purite (brimonidine), or nonpreserved (timolol). Benzalkonium chloride was present in at least 81% of eye drops used by the glaucoma patients. There were no differences in Schirmer test and OSDI results with the different eye drops and preservatives. However, both BAK-containing and preservativefree eye drops resulted in significantly higher proportions with abnormal TBUT scores (Table 5); a further analysis showed that BAK was associated with nearly three times higher odds ratio of showing abnormal OSDI compared with purite-preserved or
nonpreserved eye drops (odds ratio, 2.94; 95% confidence interval, 1.01 to 8.52).
DISCUSSION This study demonstrated a high prevalence of OSD among glaucoma subjects, which was in keeping with the findings of several other studies.3Y7 We observed a variation in OSD detection with the different clinical tests. Corneal staining for SPK showed that 63% of our glaucoma subjects had some form of corneal epitheliopathy. This finding adds to the already extensive body of research indicating that corneal pathologies are frequently seen in patients on antiglaucoma medications.3Y7 Superficial punctate keratopathy may have been caused by instability of the tear film or lysis of the corneal epithelial cells, a result of the effect of preservatives found in antiglaucoma medications.2 Although there have been studies that reported the reliability of corneal staining,9 OSDI,10 and TBUT11 in detecting OSD, the ideal test remains contentious.8,12,13 Our results show different pickup rates with the different tests, and this may be attributed to variations in definitions used to define OSD. Leung et al.5 suggested that this could also be attributed to the lack of specificity of these clinical tests. Sullivan et al.8 found that corneal staining, TBUT, and Schirmer test lack the power to distinguish between mild and moderate stages, and as such were only informative with the more severe forms of the disease. The authors further found that tear osmolarity was superior in demonstrating correlation across different disease severity; however, this parameter was not investigated in our study. There was no statistically significant difference between the proportions with abnormal TBUT in both glaucoma and control groups. This could be partly contributed by age-related dry eye disease in both groups. Alternatively, it could also be due in part to the nonspecific nature of the test, which reflects gross function of the lipid layer of the tear film. We postulate that glaucoma medications and preservatives may have little impact on this layer of the tear film and instead have more impact on the mucin layer on the ocular surface, which is reflected on the corneal staining test that showed a significant difference between the groups. Consistent with findings from other studies,3Y7,14 we report high prevalences of OSD in subjects who used one or more antiglaucoma medications. Additionally, there was an increasing trend with higher numbers of eye drops. Pisella et al.15 demonstrated the correlation between increased signs and symptoms of OSD with the number of antiglaucoma medications used, whereas Becquet et al.16 found increased ocular damage with high doses of these eye drops. Ghosh et al.7 showed that each additional eye
TABLE 4.
Prevalence of glaucoma subjects with normal and abnormal TBUT and SPK based on the number of antiglaucoma medications used No. antiglaucoma medications Normal TBUT, n (%) Abnormal TBUT, n (%) 1 2 3 4
6 (5.8) 2 (1.9) 1 (0.9) 0
49 (47.2) 31 (29.1) 15 (14.1) 1 (1.0)
p G0.001 G0.001 G0.001 V
SPK absent, n (%) SPK present, n (%) 22 (21.2) 15 (14.1) 2 (1.9) 0
33 (31.8) 18 (16.9) 14 (13.1) 1 (1.0)
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p 0.882 0.601 0.003 V
Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and PreservativesVRamli et al.
e225
TABLE 5.
Prevalence of glaucoma subjects with normal and abnormal TBUT and SPK based on the type of preservatives found in antiglaucoma medications Preservative BAK Purite BAK + purite Preservative-free
Normal TBUT, n (%)
Abnormal TBUT, n (%)
p
SPK absent, n (%)
SPK present, n (%)
p
8 (10.4) 0 0 1 (5.6)
69 (89.6) 2 (100.0) 8 (100.0) 17 (94.4)
G0.001 V V G0.001
33 (42.9) 0 3 (37.5) 3 (16.7)
44 (57.1) 2 (100.0) 5 (62.5) 15 (83.3)
0.210 V 0.480 0.005
drop was associated with about two times higher rates of impaired TBUT and attributed this to the preservatives in the eye drops. Most of the subjects with OSD in this study were using preservativecontaining eye drops, particularly those containing BAK. We found rates of abnormal OSDI nearly three times higher in subjects who were prescribed antiglaucoma drops containing BAK. This preservative has been identified as one of the agents causing OSD, by reducing the density of the conjunctival goblet cells17Y20 and damaging the corneal epithelial cells.1,2,16,17 Both acute and chronic exposure to BAK can lead to inflammatory changes in the ocular surface and decrease TBUT.16Y18 In a study of patients treated for glaucoma for at least 1 year, flow cytometry demonstrated a greater expression of inflammatory markers (Human Leukocyte AntigenDR [HLA-DR] and Intercellular Adhesion Molecule 1 [ICAM-1]) in those receiving BAK-preserved eye drops than in normal patients or those receiving preservative-free drops. The use of preservatives was associated with a lower expression of the ocular surface mucin marker MUC5AC, and the lowest MUC5AC levels were associated with the highest HLA-DR and ICAM-1 levels.19 Finally, we also found a high prevalence of abnormal TBUT and SPK in glaucoma subjects using the preservative-free timolol eye drops. Although preservative-free timolol has been described as nontoxic to the corneal epithelium,3,21,22 a study by Ayaki et al.23 showed a slight cytotoxic effect of timolol without preservatives, although this was less than when compared with the effect of timolol with preservatives. This finding warrants further investigation into the effect of preservative-free antiglaucoma drops on OSD. One of the limitations of this study was that we did not adjust for changes in treatment over the disease course. Patients who had previously used preservative-containing eye drops but then later prescribed with preservative-free eye drops may have only reported their latest prescription and hence overestimate the effect of the latter medication.
CONCLUSIONS Glaucoma subjects on topical antiglaucoma drops have a significantly higher prevalence of OSD than those who are not on any medications. The prevalence may increase with increasing numbers of eye drops and using BAK-containing eye drops, which is likely to be due to toxic effects of the preservative.
ACKNOWLEDGMENTS The authors thank Dr. Mohammadreza Peyman for his help with the statistical analysis and Ms. Audrey Looi for her help in editing the manuscript for publication. There are no conflicts of interest to declare. Received August 7, 2014; accepted January 30, 2015.
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e226 Ocular Surface Disease in Glaucoma: Effect of Polypharmacy and PreservativesVRamli et al. 17. Rolando M, Brezzo V, Giordano G, Campagna P, Burlando S, Calabria G. The effect of different benzalkonium chloride concentrations on human normal ocular surface. In: Van Bijsterveld OP, Lemp MA, Spinelli D, eds. The Lacrimal System. Amsterdam, the Netherlands: Kugler and Ghedini Publications; 1991;89Y91. 18. Pauly A, Meloni M, Brignole-Baudouin F, Warnet JM, Baudouin C. Multiple endpoint analysis of the 3D-reconstituted corneal epithelium after treatment with benzalkonium chloride: early detection of toxic damage. Invest Ophthalmol Vis Sci 2009;50:1644Y52. 19. Baudouin C, Pisella PJ, Fillacier K, Goldschild M, Becquet F, De Saint Jean M, Bechetoille A. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology 1999;106:556Y63. 20. de Jong C, Stolwijk T, Kuppens E, de Keizer R, van Best J. Topical timolol with and without benzalkonium chloride: epithelial permeability and autofluorescence of the cornea in glaucoma. Graefes Arch Clin Exp Ophthalmol 1994;232:221Y4.
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Amir Samsudin Department of Ophthalmology, Faculty of Medicine University of Malaya 50603 Kuala Lumpur Malaysia e-mail: [email protected]
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