JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 31, Number 6, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2014.0124
Effect of Glaucoma Medication in Tear Film Osmolarity of Patients Without Symptoms of Ocular Discomfort Ioannis Halkiadakis, Georgios A. Kontadakis, Dimitra Tsiakou, Eleni Patsea, Panagiotis Mitropoulos, and Artemios S. Kandarakis
Abstract
Purpose: To evaluate tear film osmolarity in patients with no symptoms of ocular discomfort treated with intraocular pressure (IOP)-lowering medication and compare it with tear film osmolarity of controls. Methods: This was a cross-sectional study of 61 patients with glaucoma or ocular hypertension (study group) and 32 age-matched normals (control group). Neither group of patients reported ocular discomfort. Tear film osmolarity was measured with the TearLab Osmolarity System (TearLab Corp, San Diego, CA), and results were compared between groups. Correlation of osmolarity with parameters associated with medication use (time, number of medications, and number of instillations) was assessed. Results: Mean age of the patients in the medication group was 71 – 10.18 years and in the control group was 69 – 10.23 years (P = 0.247). In the medication group, the tear film osmolarity was 295.56 – 12.54 mOsms/L and in the control group, it was 294.84 – 14.73 mOsms/L (P = 0.807). Regarding the percentage of patients with tear film hyperosmolarity (osmolarity ‡ 316 mOsms/L), in the group of normal patients, 3 had osmolarity more than or equal to the selected cutoff value (9.3%) and in the medication group, 7 patients (8.2%). Difference of the percentage between groups was not statistically significant (P = 0.999, chi-square test). Tear film osmolarity in the medication group was not correlated to any of the parameters related to treatment. Conclusions: Patients treated with IOP-lowering medication do not exhibit tear film hyperosmolarity as long as they do not report symptoms of ocular discomfort.
Introduction
G
laucoma medication is considered to cause ocular surface discomfort to a variable degree in many of the treated patients. Patients with glaucoma are obliged to receive intraocular pressure (IOP)-lowering medication on a chronic basis. Most of the currently available drops contain preservatives such as benzalkonium chloride, which is considered to be a major cause for ocular surface disease (OSD).1–4 OSD encompasses several clinical presentations, including dry eye, meibomian gland dysfunction, and blepharitis.4–7Significant overlap exists between these clinical entities. Prevalence of OSD among glaucoma-treated patients varies in different studies reaching the remarkable percentage of 59% in a relatively recent study.8 Quantifying OSD is complex, given that symptoms vary between patients with similar clinical presentation9 and that there is no definite quantitative parameter that can be absolutely correlated to the degree of the disease. Scoring of symptoms and specific signs of the disease such as super-
ficial punctuated keratitis, tear break-up time, and tear secretion are the most widely used parameters in everyday practice to evaluate qualitatively and quantitatively OSD. Recently, a multicenter study concluded that tear osmolarity is the best single metric both to diagnose and classify dry eye disease.10 Studies of patients with dry eye of subjectively and clinically ranked severity show a good correlation of osmolarity scores with the severity of OSD.11–13 The use of tear film osmolarity for the grading of OSD severity in patients with glaucoma has already been reported.14,15 The purpose of the present study is to investigate the effect of glaucoma medication on tear film osmolarity of patients without clinically significant subjective symptoms of dry eye.
Methods This was a comparative cross-sectional study of patients treated with topical IOP-lowering medication for the management of glaucoma and age-matched controls. Patients
Ophthalmiatreio Eye Hospital of Athens, Athens, Greece.
330
TEAR OSMOLARITY IN GLAUCOMATOUS PATIENTS
included in the study did not report dry eye symptoms. A short questionnaire was used to evaluate dry eye symptoms. The content of the short questionnaire included the following 2 symptom questions: (1) How often do your eyes feel dry (not wet enough)? and (2) how often do your eyes feel irritated? The patient was given 4 choices as to the frequency of the symptoms, which was scored as follows: never, sometimes, often, and constantly. Responses were recorded on a standardized form. The third question was as follows: Have you ever been diagnosed (by a clinician) as having dry eye syndrome? For this question, the participant’s answer was recorded as ‘‘Yes’’ or ‘‘No.’’ On the basis of this short questionnaire, a subject was considered as having dry eye symptoms and excluded from the study, if there was the presence of both dryness and irritation either constantly or often or if there was a report of a previous clinical diagnosis of dry eye syndrome. A previous study reported good sensitivity and specificity of this questionnaire in a large cohort and concluded that it may prove useful in a busy clinic or large epidemiologic studies.16 In the group of patients treated with IOP-lowering medication, we included patients with glaucoma or ocular hypertension who presented for their regular follow-up visit in the Glaucoma Department of the Opthalmiatreio Eye Hospital of Athens between January 2012 and March 2012. Patients in that group were treated with IOP-lowering medication for at least 1 year before inclusion in the study. In the control group, we included patients presenting in the Outpatient Department of the Ophthalmiatreio Eye Hospital of Athens for examinations during the same period and were not treated with IOP-lowering medication. Exclusion criteria for both groups were apart from symptoms of dry eye disease and regular use of artificial tears, any other ocular disease requiring medical treatment, ocular surgery within 6 months before inclusion in the study, and any other systemic disease affecting ocular surface and tear film such as diabetes mellitus and connective tissue diseases. The research followed the tenets of the Declaration of Helsinki. Institutional review board (IRB) approval was obtained for the study.
Patients’ evaluation Patients included in the study underwent a complete ophthalmic evaluation with ophthalmic and general health history assessment, visual acuity assessment, slit-lamp examination of anterior and posterior segments, and IOP measurement. From the ophthalmic history, we recorded the following parameters regarding topical medication use: the total number of IOP-lowering medications, the total duration of treatment, and the total number of instillations of medication per day. Tear film osmolarity was measured with a commercially available noninvasive diagnostic test, the TearLab Osmolarity System (TearLab Corp, San Diego, CA), as described previously.15,17 Tear film osmolarity was measured twice in 1 eye of each patient. The mean of the 2 measurements was used for the analysis of the results. If both eyes were eligible for the study, the right eye was included. This system collects and analyzes a 50-nL tear sample from the inferior lateral meniscus with single use test cards. The tear osmolarity is assessed with a temperature-corrected electrical impedance measurement (mOsms/L). To avoid diurnal fluctuation of tear osmolality, all measurements were taken in the morning, between 8.00 and 11.00 AM.
331
Statistical analysis The parameters used for statistical analysis were the tear film osmolarity, the age of the patients, and the parameters assessed from the ophthalmic history regarding topical medication use. Differences of tear film osmolarity between groups were assessed with the independent samples t-test. Correlation between quantitative variables was assessed with the Pearson’s correlation. The chi-square test was used to compare the percentage of patients in each group with tear film hyperosmolarity defined as tear film osmolarity more than or equal to 316 mOsms/L.18 A 5% significance level was selected. Statistical analysis was performed using PASW Statistics 18 software (SPSS, Inc., Chicago, IL).
Power and sample size calculation To calculate a sample size for our study, we used the results of a previous study on tear film osmolarity of glaucoma patients, assuming that the standard deviation (SD) and the mean difference in our population would be similar to the previously reported.15 We assessed the proper sample size in each group to have 85% power of detecting a difference between mean tear film osmolarity with a type I error probability of 5%. We planned to recruit 1 control per 2 experimental subjects. If the true difference in the experimental and control means was 5.6 and the SD was 8, as previously reported, we had to study 56 experimental subjects and 28 control subjects to be able to reject the null hypothesis. The Power analysis was performed using the Power and Sample Size Calculation (PS) program (http:// biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize).
Results A total of 93 patients were included in the study, 61 in the medication group and 32 in the control group. Mean age of the patients in the medication group was 71 (SD 10.18) and in the control group, 69 (SD 10.23, P = 0.247, confidence interval of the difference [CI] - 7.02 to 1.83). The demographics of the study population are shown in Tables 1 and 2. We found no statistically significant difference in tear osmolarity between the medication group and the control group. In the medication group, the tear film osmolarity was 295.56 mOsms/L (SD 12.54) and in the control group, it was 294.84 mOsms/L (SD 14.73, P = 0.807, CI - 6.49 to 5.06). The median value of tear film osmolarity in the medication group was 294 mOsms/L (range 275–332) and in the control group, it was 288 mOsms/L (range 277–332). In both groups, tear film osmolarity was not found to have a statistically significant correlation with the age of the patients (in the nontreatment group, Pearson’s r: 0.53, P = 0.773, in the treated group, Pearson’s r: - 0.78, P = 0.550). In the medication group, we did not find a statistically significant correlation of tear film osmolarity with the number of medications used (Pearson’s r: - 0.032, P = 0.808), the total duration of medication (Pearson’s r: 0.006, P = 0.965), and the total number of instillations per day (Pearson’s r: - 0.057, P = 0.660). Regarding the percentage of patients with tear film hyperosmolarity (osmolarity ‡ 316 mOsms/L), in the group of normal patients, 3 had osmolarity more than or equal to the selected cutoff value (9.3%) and in the medication group, 7 patients (8.2%). Difference of the percentage between
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HALKIADAKIS ET AL.
Table 1.
Sex, n (%) Male Female Age, years Mean – SD Median (range) IOP (mmHg) Mean – SD Median (range) CCT (mm) Mean – SD Median (range)
Patient Demographics and Assessed Clinical Parameters
All patients (n = 93)
Patients group (n = 61)
Control group (n = 32)
P-value for the comparison of 2 groups
46 (49) 47 (51)
37 (61) 24 (39)
9 (28) 23 (72)
70 – 10.5 72 (39–90)
71 – 10.18 72 (42–90)
69 – 10.23 73 (39–85)
0.247
16.73 – 0.32 Media 16 (10–38)
17.30 – 4.49 17 (10–38)
16.07 – 2.73 16 (12–22)
0.172
548.07 (36) 550 (478–660)
546 (36) 543 (478–660)
558 (35) 552 (481–607)
0.281
CCT, central corneal thickness; IOP, intraocular pressure; SD, standard deviation.
groups was not statistically significant (P = 0.999, chi-square test). Allocation in groups of normal osmolarity, mild to moderate hyperosmolarity, and severe hyperosmolarity was also similar in both groups (Table 3).
Discussion According to the International Dry Eye Workshop (DEWS), the use of antiglaucoma medication is an extrinsic cause of evaporative dry eye.4 Increase in tear film osmolarity is the core mechanism in the pathophysiology of dry eye and takes place both in evaporative dry eye and in aqueous deficient dry eye.4 Furthermore, tear film osmolarity, as a clinical indicator, correlates with disease severity as determined by grading of signs and symptoms of the disease.9–13 In the present study, we used a recently devel-
Table 2. Specific Diagnosis, Types of Medication, and Parameters of Treatment of Patients in the Medication Group
Diagnosis POAG CACG PEXG OHT Type of medication PA monotherapy BB monotherapy AA monotherapy CAI monotherapy Combination
Treatment parameters Number of drugs Number of instillations Total time of treatment (years)
n
%
25 1 15 20
41 2 24 33
18 1 0 2 40
30 2 0 3 65
Mean
SD
1.67 2.87 5.12
0.75 1.84 4.89
AA, alpha-agonist; BB, beta-blockers; CACG, chronic angle closure glaucoma; CAI, carbonic anhydrase inhibitors; OHT, ocular hypertension; PA, prostaglandin analogs; PEXG, pseudoexfoliative glaucoma; POAG, primary open-angle glaucoma.
oped platform for the evaluation of tear film osmolarity of asymptomatic patients treated with IOP-lowering medication. Results of the present study indicate that tear film osmolarity is not affected in asymptomatic patients receiving antiglaucomatous treatment. Previous studies have proposed several cutoff values for the diagnosis and grading of dry eye. According to Tomlinson et al.,18 tear hyperosmolarity, defined by a referent of 316 mOsm/L, was superior in the overall accuracy to any other single test for dry eye diagnosis (Lactoplate, Schirmer test, and Rose Bengal staining). Lemp et al.10 proposed a cutoff value of 312 mOsm/L as having exhibited 73% sensitivity and 92% specificity to distinguish normal and patients having mild to moderate dry eye. In a study by Versura et al.,12 tear film osmolarity 305 mOsm/L was selected as a cutoff value for dry eye, 309 mOsm/L for moderate dry eye, and 318 mOsm/L for severe dry eye. In the present study, both treated patients and controls had a mean tear film osmolarity lower than all proposed cutoff values10,12,18 for dry eye diagnosis and equal to previous reported normal values.10 For our analysis, we chose 316 mOsm/L as a cutoff value according to Tomlinson et al.18 The percentage of patients surpassing this value did not differ between groups. Consequently, the majority of participants in our study may not be identified as suffering from dry eye, based on the osmolarity scores. Results of the present study indicate that in treated patients who do not report symptoms of OSD, tear film osmolarity is not increased in comparison to normal controls. The 2 previous
Table 3. Number and Percentage of Patients in Each Group with Normal Osmolarity, Mild to Moderate Hyperosmolarity, and Severe Hyperosmolarity Using Cutoff Values n (%) Osm < 305 305 £ Osm < 318 Osm ‡ 318 Total
Control group 24 6 2 32
Medication group
(75) (19) (6) (100)
Osm, measured tear film osmolarity (mOsm/L).
49 7 5 61
(80) (11) (8) (100)
TEAR OSMOLARITY IN GLAUCOMATOUS PATIENTS
studies14,15 examining tear film osmolarity of glaucomatous patients included patients under treatment without specifically excluding symptomatic patients. In contrast to the present study, Labbe´ et al.14 reported that mean tear film osmolarity in glaucomatous patients under treatment was 308.8 mOsms/L (SD 15.4) and that 47.5% of the patients had tear film osmolality > 308 mOsm/L. Several reasons may account for the difference in the results. The most important is that the patient population was different. In contrast to the present study, 60% of their patients were symptomatic. Furthermore, the mean duration of treatment was 8.6 years, whereas in the present study, the mean duration of treatment was 5.12 years. No control group was measured in the former study. Results of the present study also contradict a previous study by Lee et al.15According to the former study, mean tear film osmolarity in normals was 301.4 – 7.7 mOsm/L, slightly increased compared to the previous reported normal values, whereas in glaucoma-treated patients, 307.0 – 9.3 mOsm/L, respectively. However, mean number of glaucoma medications in this study was 2.9 – 1.5, whereas in the present study was 1.7 – 0.7. Most of the time, if more than 2 medications are used, a b-blocker is included in the treatment scheme. B-blockers may exacerbate the dry eye symptom more than any other topical medication.1 Consequently, this study indicates that in contrast to symptomatic patients, in treated patients with no ocular discomfort symptoms, tear film osmolarity may not be affected. Recently, Garcia-Feijoo et al.19 suggested that treatment duration < 6 years and 1–2 IOPlowering medications were generally associated and correlated with mild OSD symptoms, and thus, the difference in results may reflect that our patient population consisted of patients with early and mild disease. Labbe´ et al.14 found that there was a correlation of the number of topical medications, the time under medication, and the number of instillations with the tear film osmolarity scores of their study group. In contrast, in the present study, there was no correlation of parameters related to topical medication use (number of medications, total treatment duration, number of instillations) with tear film osmolarity in the group of treated patients. Similar to the present study, Lee et al.15 found that age, gender, number, and duration of topical antiglaucoma medication use did not significantly contribute to the severity of tear film osmolarity. Many components of eye drop formulations can induce a toxic response from the ocular surface. Of these, the most common offenders are preservatives, such as benzalkonium chloride (BAK), which is a component of most preserved IOP-lowering topical medications. BAK increases OSD by disrupting tear film and increasing conjunctival inflammation. Therefore, many physicians prefer switching their treatment scheme to nonpreserved preparations. Recent studies indicate that switching from a preserved medication to a nonpreserved substance decreases tear film osmolality and also decreases symptoms of dry eyes.20,21 Which patients, if not all, should be treated with nonpreserved medication is a controversial matter.7 None of the patients in the present study used preservative-free medication. Results of the present study should, however, be interpreted with caution as they do not take into account issues of persistence and adherence to glaucoma treatment. Although all patients were interviewed about their adherence to the medication scheme with great diligence, poor adherence and compliance are common problems with glaucoma medica-
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tion and could have biased the results of the present study.22 Furthermore, as recent studies have found that tear film osmolarity is not the single indicator of dry eye disease, Sullivan et al.23 did not find any strong correlation between tear osmolarity and other signs of dry eyes and Messmer et al.24 did not find any significant difference in tear osmolarity between dry eye patients and controls. A potential explanation is that tear osmolarity values are reported to be highly variable in patients with dry eye disease, and indeed this high variability has been proposed as one of the hallmarks of the disease.25 The lack of correlation is not only constrained to tear osmolarity but also to other signs of the disease and is a fundamental characteristic of the heterogeneity of the condition, the multiple subtypes of dry eyes, and the variety of etiologies classified under dry eye disease. In conclusion, this study demonstrated that patients treated with IOP-lowering medication do not report symptoms of ocular discomfort and appear not to exhibit tear film hyperosmolarity.
Author Disclosure Statement No competing financial interests exist.
References 1. Valente, C., Iester, M., Corsi, E., and Rolando, M. Symptoms and signs of tear film dysfunction in glaucomatous patients. J. Ocul. Pharmacol. Ther. 27:281–285, 2011. 2. Whitson, J.T., Trattler, W.B., Matossian, C., Williams, J., and Hollander, D.A. Ocular surface tolerability of prostaglandin analogs in patients with glaucoma or ocular hypertension. J. Ocul. Pharmacol. Ther. 26:287–292, 2010. 3. Thygesen, J., Aaen, K., Theodorsen, F., Kessing, S.V., and Prause, J.U. Short-term effect of latanoprost and timolol eye drops on tear fluid and the ocular surface in patients with primary open-angle glaucoma and ocular hypertension. Acta Ophthalmol. Scand. 78:37–44, 2000. 4. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop. Ocul Surf. 5:75–92, 2007. 5. Foulks, G.N., Nichols, K.K., Bron, A.J., Holland, E.J., McDonald, M.B., and Nelson, J.D. Improving awareness, identification, and management of meibomian gland dysfunction. Ophthalmology. 119(Suppl):S1–S12, 2012. 6. Nelson, J.D., Shimazaki, J., Benitez-del-Castillo, J.M., et al. The international workshop on meibomian gland dysfunction: report of the definition and classification subcommittee. Invest. Ophthalmol. Vis. Sci. 52:1930–1937, 2011. 7. Stalmans, I., Sunaric Me´gevand, G., et al. Preservative-free treatment in glaucoma: who, when, and why. Eur. J. Ophthalmol. 23:518–525, 2013. 8. Leung, E.W., Medeiros, F.A., and Weinreb, R.N. Prevalence of ocular surface disease in glaucoma patients. J. Glaucoma. 17:350–355, 2008. 9. Sullivan, B.D., Crews, L.A., So¨nmez, B., et al. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea. 31:1000–1008, 2012. 10. Lemp, M.A., Bron, A.J., Baudouin, C., et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am. J. Ophthalmol. 151:792–798, 2011. 11. Sullivan, B.D., Whitmer, D., Nichols, K.K., et al. An objective approach to dry eye disease severity. Invest. Ophthalmol. Vis. Sci. 51:6125–6130, 2010.
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12. Versura, P., Profazio, V., and Campos, E.C. Performance of tear osmolarity compared to previous diagnostic tests for dry eye diseases. Curr. Eye Res. 35:553–564, 2010. 13. Suzuki, M., Massingale, M.L., Ye, F., et al. Tear osmolarity as a biomarker for dry eye disease severity. Invest. Ophthalmol. Vis. Sci. 51:4557–4561, 2010. 14. Labbe´, A., Terry, O., Brasnu, E., Van Went, C., and Baudouin, C. Tear film osmolarity in patients treated for glaucoma or ocular hypertension. Cornea. 31:994–999, 2012. 15. Lee, S.Y., Wong, T.T., Chua, J., Boo, C., Soh, Y.F., and Tong, L. Effect of chronic anti-glaucoma medications and trabeculectomy on tear osmolarity. Eye (Lond). 27:1142– 1150, 2013. 16. Gulati, A., Sullivan, R., Buring, J.E., et al. Validation and repeatability of a short questionnaire for dry eye syndrome. Am. J. Ophthalmol. 142:125–131, 2006. 17. Jacobi, C., Jacobi, A., Kruse, F.E., and Cursiefen, C. Tear film osmolarity measurements in dry eye disease using electrical impedance technology. Cornea. 30:1289–1292, 2011. 18. Tomlinson, A., Khanal, S., Ramaesh, K., Diaper, C., and McFadyen, A. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest. Ophthalmol. Vis. Sci. 47:4309–4315, 2006. 19. Garcia-Feijoo, J., and Sampaolesi, J.R. A multicenter evaluation of ocular surface disease prevalence in patients with glaucoma. Clin. Ophthalmol. 6:441–446, 2012. 20. Uusitalo, H., Chen, E., Pfeiffer, N., et al. Switching from a preserved to a preservative-free prostaglandin preparation in topical glaucoma medication. Acta Ophthalmol. 88:329– 336, 2010. 21. Janulevicien_e, I., Derkac, I., Grybauskiene, L., Paulauskait_e, R., Gromnickaite, R., and Kuzmien_e, L. Effects of preservative-free tafluprost on tear film osmolarity, tolerability, and
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intraocular pressure in previously treated patients with openangle glaucoma. Clin. Ophthalmol. 6:103–109, 2012. Reardon, G., Kotak, S., and Schwartz, G. Objective assessment of compliance and persistence among patients treated for glaucoma and ocular hypertension: a systematic review. Clin. Ophthalmol. 5:441–463, 2011. Sullivan, B.D., Crews, L.A., Messmer, E.M., Foulks, G.N., Nichols, K.K., Baenninger, P., Geerling, G., Figueiredo, F., and Lemp, M.A. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications. Acta Ophthalmol. 2014;92:161–166. Messmer, E.M., Bulgen, M., and Kampik, A. Hyperosmolarity of the tear film in dry eye syndrome. Dev. Ophthalmol. 45:129–138, 2010. Amparo, F., Jin, Y., Hamrah, P., Schaumberg, D.A., and Dana, R. What is the value of incorporating tear osmolarity measurement in assessing patient response to therapy in dry eye disease? Am. J. Ophthalmol. 157:69–77, 2014.
Received: September 30, 2014 Accepted: March 16, 2015 Address correspondence to: Dr. Ioannis Halkiadakis Ophthalmiatreio Athinon El. Venizelou 26 & Sina 2 Athens 106 72 Greece E-mail: [email protected]
Effect of Glaucoma Medication in Tear Film Osmolarity of Patients Without Symptoms of Ocular Discomfort Ioannis Halkiadakis, Georgios A. Kontadakis, Dimitra Tsiakou, Eleni Patsea, Panagiotis Mitropoulos, and Artemios S. Kandarakis
Abstract
Purpose: To evaluate tear film osmolarity in patients with no symptoms of ocular discomfort treated with intraocular pressure (IOP)-lowering medication and compare it with tear film osmolarity of controls. Methods: This was a cross-sectional study of 61 patients with glaucoma or ocular hypertension (study group) and 32 age-matched normals (control group). Neither group of patients reported ocular discomfort. Tear film osmolarity was measured with the TearLab Osmolarity System (TearLab Corp, San Diego, CA), and results were compared between groups. Correlation of osmolarity with parameters associated with medication use (time, number of medications, and number of instillations) was assessed. Results: Mean age of the patients in the medication group was 71 – 10.18 years and in the control group was 69 – 10.23 years (P = 0.247). In the medication group, the tear film osmolarity was 295.56 – 12.54 mOsms/L and in the control group, it was 294.84 – 14.73 mOsms/L (P = 0.807). Regarding the percentage of patients with tear film hyperosmolarity (osmolarity ‡ 316 mOsms/L), in the group of normal patients, 3 had osmolarity more than or equal to the selected cutoff value (9.3%) and in the medication group, 7 patients (8.2%). Difference of the percentage between groups was not statistically significant (P = 0.999, chi-square test). Tear film osmolarity in the medication group was not correlated to any of the parameters related to treatment. Conclusions: Patients treated with IOP-lowering medication do not exhibit tear film hyperosmolarity as long as they do not report symptoms of ocular discomfort.
Introduction
G
laucoma medication is considered to cause ocular surface discomfort to a variable degree in many of the treated patients. Patients with glaucoma are obliged to receive intraocular pressure (IOP)-lowering medication on a chronic basis. Most of the currently available drops contain preservatives such as benzalkonium chloride, which is considered to be a major cause for ocular surface disease (OSD).1–4 OSD encompasses several clinical presentations, including dry eye, meibomian gland dysfunction, and blepharitis.4–7Significant overlap exists between these clinical entities. Prevalence of OSD among glaucoma-treated patients varies in different studies reaching the remarkable percentage of 59% in a relatively recent study.8 Quantifying OSD is complex, given that symptoms vary between patients with similar clinical presentation9 and that there is no definite quantitative parameter that can be absolutely correlated to the degree of the disease. Scoring of symptoms and specific signs of the disease such as super-
ficial punctuated keratitis, tear break-up time, and tear secretion are the most widely used parameters in everyday practice to evaluate qualitatively and quantitatively OSD. Recently, a multicenter study concluded that tear osmolarity is the best single metric both to diagnose and classify dry eye disease.10 Studies of patients with dry eye of subjectively and clinically ranked severity show a good correlation of osmolarity scores with the severity of OSD.11–13 The use of tear film osmolarity for the grading of OSD severity in patients with glaucoma has already been reported.14,15 The purpose of the present study is to investigate the effect of glaucoma medication on tear film osmolarity of patients without clinically significant subjective symptoms of dry eye.
Methods This was a comparative cross-sectional study of patients treated with topical IOP-lowering medication for the management of glaucoma and age-matched controls. Patients
Ophthalmiatreio Eye Hospital of Athens, Athens, Greece.
330
TEAR OSMOLARITY IN GLAUCOMATOUS PATIENTS
included in the study did not report dry eye symptoms. A short questionnaire was used to evaluate dry eye symptoms. The content of the short questionnaire included the following 2 symptom questions: (1) How often do your eyes feel dry (not wet enough)? and (2) how often do your eyes feel irritated? The patient was given 4 choices as to the frequency of the symptoms, which was scored as follows: never, sometimes, often, and constantly. Responses were recorded on a standardized form. The third question was as follows: Have you ever been diagnosed (by a clinician) as having dry eye syndrome? For this question, the participant’s answer was recorded as ‘‘Yes’’ or ‘‘No.’’ On the basis of this short questionnaire, a subject was considered as having dry eye symptoms and excluded from the study, if there was the presence of both dryness and irritation either constantly or often or if there was a report of a previous clinical diagnosis of dry eye syndrome. A previous study reported good sensitivity and specificity of this questionnaire in a large cohort and concluded that it may prove useful in a busy clinic or large epidemiologic studies.16 In the group of patients treated with IOP-lowering medication, we included patients with glaucoma or ocular hypertension who presented for their regular follow-up visit in the Glaucoma Department of the Opthalmiatreio Eye Hospital of Athens between January 2012 and March 2012. Patients in that group were treated with IOP-lowering medication for at least 1 year before inclusion in the study. In the control group, we included patients presenting in the Outpatient Department of the Ophthalmiatreio Eye Hospital of Athens for examinations during the same period and were not treated with IOP-lowering medication. Exclusion criteria for both groups were apart from symptoms of dry eye disease and regular use of artificial tears, any other ocular disease requiring medical treatment, ocular surgery within 6 months before inclusion in the study, and any other systemic disease affecting ocular surface and tear film such as diabetes mellitus and connective tissue diseases. The research followed the tenets of the Declaration of Helsinki. Institutional review board (IRB) approval was obtained for the study.
Patients’ evaluation Patients included in the study underwent a complete ophthalmic evaluation with ophthalmic and general health history assessment, visual acuity assessment, slit-lamp examination of anterior and posterior segments, and IOP measurement. From the ophthalmic history, we recorded the following parameters regarding topical medication use: the total number of IOP-lowering medications, the total duration of treatment, and the total number of instillations of medication per day. Tear film osmolarity was measured with a commercially available noninvasive diagnostic test, the TearLab Osmolarity System (TearLab Corp, San Diego, CA), as described previously.15,17 Tear film osmolarity was measured twice in 1 eye of each patient. The mean of the 2 measurements was used for the analysis of the results. If both eyes were eligible for the study, the right eye was included. This system collects and analyzes a 50-nL tear sample from the inferior lateral meniscus with single use test cards. The tear osmolarity is assessed with a temperature-corrected electrical impedance measurement (mOsms/L). To avoid diurnal fluctuation of tear osmolality, all measurements were taken in the morning, between 8.00 and 11.00 AM.
331
Statistical analysis The parameters used for statistical analysis were the tear film osmolarity, the age of the patients, and the parameters assessed from the ophthalmic history regarding topical medication use. Differences of tear film osmolarity between groups were assessed with the independent samples t-test. Correlation between quantitative variables was assessed with the Pearson’s correlation. The chi-square test was used to compare the percentage of patients in each group with tear film hyperosmolarity defined as tear film osmolarity more than or equal to 316 mOsms/L.18 A 5% significance level was selected. Statistical analysis was performed using PASW Statistics 18 software (SPSS, Inc., Chicago, IL).
Power and sample size calculation To calculate a sample size for our study, we used the results of a previous study on tear film osmolarity of glaucoma patients, assuming that the standard deviation (SD) and the mean difference in our population would be similar to the previously reported.15 We assessed the proper sample size in each group to have 85% power of detecting a difference between mean tear film osmolarity with a type I error probability of 5%. We planned to recruit 1 control per 2 experimental subjects. If the true difference in the experimental and control means was 5.6 and the SD was 8, as previously reported, we had to study 56 experimental subjects and 28 control subjects to be able to reject the null hypothesis. The Power analysis was performed using the Power and Sample Size Calculation (PS) program (http:// biostat.mc.vanderbilt.edu/wiki/Main/PowerSampleSize).
Results A total of 93 patients were included in the study, 61 in the medication group and 32 in the control group. Mean age of the patients in the medication group was 71 (SD 10.18) and in the control group, 69 (SD 10.23, P = 0.247, confidence interval of the difference [CI] - 7.02 to 1.83). The demographics of the study population are shown in Tables 1 and 2. We found no statistically significant difference in tear osmolarity between the medication group and the control group. In the medication group, the tear film osmolarity was 295.56 mOsms/L (SD 12.54) and in the control group, it was 294.84 mOsms/L (SD 14.73, P = 0.807, CI - 6.49 to 5.06). The median value of tear film osmolarity in the medication group was 294 mOsms/L (range 275–332) and in the control group, it was 288 mOsms/L (range 277–332). In both groups, tear film osmolarity was not found to have a statistically significant correlation with the age of the patients (in the nontreatment group, Pearson’s r: 0.53, P = 0.773, in the treated group, Pearson’s r: - 0.78, P = 0.550). In the medication group, we did not find a statistically significant correlation of tear film osmolarity with the number of medications used (Pearson’s r: - 0.032, P = 0.808), the total duration of medication (Pearson’s r: 0.006, P = 0.965), and the total number of instillations per day (Pearson’s r: - 0.057, P = 0.660). Regarding the percentage of patients with tear film hyperosmolarity (osmolarity ‡ 316 mOsms/L), in the group of normal patients, 3 had osmolarity more than or equal to the selected cutoff value (9.3%) and in the medication group, 7 patients (8.2%). Difference of the percentage between
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Table 1.
Sex, n (%) Male Female Age, years Mean – SD Median (range) IOP (mmHg) Mean – SD Median (range) CCT (mm) Mean – SD Median (range)
Patient Demographics and Assessed Clinical Parameters
All patients (n = 93)
Patients group (n = 61)
Control group (n = 32)
P-value for the comparison of 2 groups
46 (49) 47 (51)
37 (61) 24 (39)
9 (28) 23 (72)
70 – 10.5 72 (39–90)
71 – 10.18 72 (42–90)
69 – 10.23 73 (39–85)
0.247
16.73 – 0.32 Media 16 (10–38)
17.30 – 4.49 17 (10–38)
16.07 – 2.73 16 (12–22)
0.172
548.07 (36) 550 (478–660)
546 (36) 543 (478–660)
558 (35) 552 (481–607)
0.281
CCT, central corneal thickness; IOP, intraocular pressure; SD, standard deviation.
groups was not statistically significant (P = 0.999, chi-square test). Allocation in groups of normal osmolarity, mild to moderate hyperosmolarity, and severe hyperosmolarity was also similar in both groups (Table 3).
Discussion According to the International Dry Eye Workshop (DEWS), the use of antiglaucoma medication is an extrinsic cause of evaporative dry eye.4 Increase in tear film osmolarity is the core mechanism in the pathophysiology of dry eye and takes place both in evaporative dry eye and in aqueous deficient dry eye.4 Furthermore, tear film osmolarity, as a clinical indicator, correlates with disease severity as determined by grading of signs and symptoms of the disease.9–13 In the present study, we used a recently devel-
Table 2. Specific Diagnosis, Types of Medication, and Parameters of Treatment of Patients in the Medication Group
Diagnosis POAG CACG PEXG OHT Type of medication PA monotherapy BB monotherapy AA monotherapy CAI monotherapy Combination
Treatment parameters Number of drugs Number of instillations Total time of treatment (years)
n
%
25 1 15 20
41 2 24 33
18 1 0 2 40
30 2 0 3 65
Mean
SD
1.67 2.87 5.12
0.75 1.84 4.89
AA, alpha-agonist; BB, beta-blockers; CACG, chronic angle closure glaucoma; CAI, carbonic anhydrase inhibitors; OHT, ocular hypertension; PA, prostaglandin analogs; PEXG, pseudoexfoliative glaucoma; POAG, primary open-angle glaucoma.
oped platform for the evaluation of tear film osmolarity of asymptomatic patients treated with IOP-lowering medication. Results of the present study indicate that tear film osmolarity is not affected in asymptomatic patients receiving antiglaucomatous treatment. Previous studies have proposed several cutoff values for the diagnosis and grading of dry eye. According to Tomlinson et al.,18 tear hyperosmolarity, defined by a referent of 316 mOsm/L, was superior in the overall accuracy to any other single test for dry eye diagnosis (Lactoplate, Schirmer test, and Rose Bengal staining). Lemp et al.10 proposed a cutoff value of 312 mOsm/L as having exhibited 73% sensitivity and 92% specificity to distinguish normal and patients having mild to moderate dry eye. In a study by Versura et al.,12 tear film osmolarity 305 mOsm/L was selected as a cutoff value for dry eye, 309 mOsm/L for moderate dry eye, and 318 mOsm/L for severe dry eye. In the present study, both treated patients and controls had a mean tear film osmolarity lower than all proposed cutoff values10,12,18 for dry eye diagnosis and equal to previous reported normal values.10 For our analysis, we chose 316 mOsm/L as a cutoff value according to Tomlinson et al.18 The percentage of patients surpassing this value did not differ between groups. Consequently, the majority of participants in our study may not be identified as suffering from dry eye, based on the osmolarity scores. Results of the present study indicate that in treated patients who do not report symptoms of OSD, tear film osmolarity is not increased in comparison to normal controls. The 2 previous
Table 3. Number and Percentage of Patients in Each Group with Normal Osmolarity, Mild to Moderate Hyperosmolarity, and Severe Hyperosmolarity Using Cutoff Values n (%) Osm < 305 305 £ Osm < 318 Osm ‡ 318 Total
Control group 24 6 2 32
Medication group
(75) (19) (6) (100)
Osm, measured tear film osmolarity (mOsm/L).
49 7 5 61
(80) (11) (8) (100)
TEAR OSMOLARITY IN GLAUCOMATOUS PATIENTS
studies14,15 examining tear film osmolarity of glaucomatous patients included patients under treatment without specifically excluding symptomatic patients. In contrast to the present study, Labbe´ et al.14 reported that mean tear film osmolarity in glaucomatous patients under treatment was 308.8 mOsms/L (SD 15.4) and that 47.5% of the patients had tear film osmolality > 308 mOsm/L. Several reasons may account for the difference in the results. The most important is that the patient population was different. In contrast to the present study, 60% of their patients were symptomatic. Furthermore, the mean duration of treatment was 8.6 years, whereas in the present study, the mean duration of treatment was 5.12 years. No control group was measured in the former study. Results of the present study also contradict a previous study by Lee et al.15According to the former study, mean tear film osmolarity in normals was 301.4 – 7.7 mOsm/L, slightly increased compared to the previous reported normal values, whereas in glaucoma-treated patients, 307.0 – 9.3 mOsm/L, respectively. However, mean number of glaucoma medications in this study was 2.9 – 1.5, whereas in the present study was 1.7 – 0.7. Most of the time, if more than 2 medications are used, a b-blocker is included in the treatment scheme. B-blockers may exacerbate the dry eye symptom more than any other topical medication.1 Consequently, this study indicates that in contrast to symptomatic patients, in treated patients with no ocular discomfort symptoms, tear film osmolarity may not be affected. Recently, Garcia-Feijoo et al.19 suggested that treatment duration < 6 years and 1–2 IOPlowering medications were generally associated and correlated with mild OSD symptoms, and thus, the difference in results may reflect that our patient population consisted of patients with early and mild disease. Labbe´ et al.14 found that there was a correlation of the number of topical medications, the time under medication, and the number of instillations with the tear film osmolarity scores of their study group. In contrast, in the present study, there was no correlation of parameters related to topical medication use (number of medications, total treatment duration, number of instillations) with tear film osmolarity in the group of treated patients. Similar to the present study, Lee et al.15 found that age, gender, number, and duration of topical antiglaucoma medication use did not significantly contribute to the severity of tear film osmolarity. Many components of eye drop formulations can induce a toxic response from the ocular surface. Of these, the most common offenders are preservatives, such as benzalkonium chloride (BAK), which is a component of most preserved IOP-lowering topical medications. BAK increases OSD by disrupting tear film and increasing conjunctival inflammation. Therefore, many physicians prefer switching their treatment scheme to nonpreserved preparations. Recent studies indicate that switching from a preserved medication to a nonpreserved substance decreases tear film osmolality and also decreases symptoms of dry eyes.20,21 Which patients, if not all, should be treated with nonpreserved medication is a controversial matter.7 None of the patients in the present study used preservative-free medication. Results of the present study should, however, be interpreted with caution as they do not take into account issues of persistence and adherence to glaucoma treatment. Although all patients were interviewed about their adherence to the medication scheme with great diligence, poor adherence and compliance are common problems with glaucoma medica-
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tion and could have biased the results of the present study.22 Furthermore, as recent studies have found that tear film osmolarity is not the single indicator of dry eye disease, Sullivan et al.23 did not find any strong correlation between tear osmolarity and other signs of dry eyes and Messmer et al.24 did not find any significant difference in tear osmolarity between dry eye patients and controls. A potential explanation is that tear osmolarity values are reported to be highly variable in patients with dry eye disease, and indeed this high variability has been proposed as one of the hallmarks of the disease.25 The lack of correlation is not only constrained to tear osmolarity but also to other signs of the disease and is a fundamental characteristic of the heterogeneity of the condition, the multiple subtypes of dry eyes, and the variety of etiologies classified under dry eye disease. In conclusion, this study demonstrated that patients treated with IOP-lowering medication do not report symptoms of ocular discomfort and appear not to exhibit tear film hyperosmolarity.
Author Disclosure Statement No competing financial interests exist.
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Received: September 30, 2014 Accepted: March 16, 2015 Address correspondence to: Dr. Ioannis Halkiadakis Ophthalmiatreio Athinon El. Venizelou 26 & Sina 2 Athens 106 72 Greece E-mail: [email protected]
