The Open Ophthalmology Journal


ISSN: 1874-3641 ― Volume 11, 2017

Evaluation of Ocular Surface Disease in Asian Patients with Primary Angle Closure



Tan Ee Ling1, 2, Khairuddin Othman1, Ong Poh Yan2, Rasdi Abdul Rashid1, Cheong Min Tet1, Azhany Yaakob1, Liza-Sharmini Ahmad Tajudin1, *
1 Department of Ophthalmology, School of Medical Sciences, Health Campus Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
2 Department of Ophthalmology, Hospital Selayang, Selangor, Malaysia

Abstract

Objective:

To evaluate the incidence of ocular surface disease (OSD) and to determine the effects of topical pressure-lowering drugs on ocular surface disease in primary angle closure patients.

Methods:

This was a cross-sectional comparative study comparing primary angle closure glaucoma (PACG) patients (Group A) with primary angle closure and primary angle closure suspect (Group B). Group A was treated with topical pressure-lowering drugs; Group B was not. Data on ocular diagnosis and details of treatment were obtained from medical records. Ocular surface disease incidence was assessed using the Ocular Surface Disease Index (OSDI) questionnaire and from clinical signs using Schirmer’s test, tear break-up time and corneal fluorescein stain. Predictive Analytic Software 20 and STATA analysis software were used for statistical analyses.

Results:

Group A demonstrated a higher rate of OSD (OSDI 52.3%, Schirmer’s test 70.5%, tear break-up time (TBUT) 75%, corneal staining 77.3%) compared to Group B (OSDI 39.0%, Schirmer’s test 73.2%, TBUT 58.5% and cornea staining 14.6%) except for Schirmer’s test. There was a significant difference in mean score of OSDI (p=0.004), TBUT (p=0.008) and cornea staining (p<0.001) between two groups. Primary angle closure glaucoma treated with more than two medications and for more than three years had worse ocular surface disease parameters but without statistical significant difference.

Conclusion:

Ocular surface disease is common in PACG patients treated with topical pressure-lowering drugs. Topical pressure-lowering drugs caused significant OSD symptoms and signs except for tear production in PACG patients. Thorough evaluation of ocular surface disease is important to ensure appropriate treatment and intervention in PACG patients.

Keywords: Primary angle closure glaucoma, Ocular surface disease, Ocular surface disease index questionnaires, Schirmer’s test, Tear break-up time, Cornea fluorescein staining.


Article Information


Identifiers and Pagination:

Year: 2017
Volume: 11
First Page: 31
Last Page: 39
Publisher Id: TOOPHTJ-11-31
DOI: 10.2174/1874364101711010031

Article History:

Received Date: 11/10/2016
Revision Received Date: 09/01/2017
Acceptance Date: 11/01/2017
Electronic publication date: 28/02/2017
Collection year: 2017

© 2017 Ling et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at Department of Ophthalmology, School of Medical Sciences, Health Campus Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia; Tel: +609 7676353; Fax: +609 7653370; Emails: liza@usm.my; sharminiliz@live.com




INTRODUCTION

Ocular surface disease (OSD) is defined as a group of ocular disorders that affect various component of the ocular surface [1Lemp MA. Report of the National Eye Institute/Industry Workshop on clinical trials in dry eyes. CLAO J 1995; 21(4): 221-32.
[PMID: 8565190]
]. OSD is due to increased tear osmolarity, inflammation and disruption of the ocular surface [1Lemp MA. Report of the National Eye Institute/Industry Workshop on clinical trials in dry eyes. CLAO J 1995; 21(4): 221-32.
[PMID: 8565190]
, 2Bron AJ, Abelson MB, Ousler G, et al. Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007; 5(2): 108-52.
[http://dx.doi.org/10.1016/S1542-0124(12)70083-6] [PMID: 17508118]
]. Risk factors for OSD include the elderly, women especially menopausal women, the Asian population, multiple systemic co-morbidities and ocular diseases [3Schein OD, Muñoz B, Tielsch JM, Bandeen-Roche K, West S. Prevalence of dry eye among the elderly. Am J Ophthalmol 1997; 124(6): 723-8.
[http://dx.doi.org/10.1016/S0002-9394(14)71688-5] [PMID: 9402817]
-8Chun YH, Kim HR, Han K, Park Y-G, Song HJ, Na K-S. Total cholesterol and lipoprotein composition are associated with dry eye disease in Korean women. Lipids Health Dis 2013; 12(1): 84.
[http://dx.doi.org/10.1186/1476-511X-12-84] [PMID: 23734839]
]. Chronic use of topical ophthalmic solutions is another major contributing factor in OSD [9Foulks GN, Lemp MA, Jester JV, Sutphin J Jr, Murube J, Novack GD. Challenges and pitfalls in clinical trials of treatments for dry eye. Ocul Surf 2003; 1(1): 20-30.
[http://dx.doi.org/10.1016/S1542-0124(12)70004-6] [PMID: 17075626]
].

Despite the advent of surgical and laser therapies, topical pressure-lowering agents remain the popular choice of treatment in glaucoma. Topical pressure-lowering agents are non-invasive, convenient for patients and easier to discontinue in the presence of side effects or complications [10Kaštelan S, Tomić M, Metež Soldo K, Salopek-Rabatić J. How ocular surface disease impacts the glaucoma treatment outcome. Biomed Res Int 2013; 2013: 696328.
[http://dx.doi.org/10.1155/2013/696328] [PMID: 24224176]
]. OSD may be induced by topical pressure-lowering agents through chronic toxicity to the preservatives especially benzalkonium chloride (BAK) and active ingredients, alteration of the tear film stability and direct injury to the ocular epithelial surface [11Mantelli F, Tranchina L, Lambiase A, Bonini S. Ocular surface damage by ophthalmic compounds. Curr Opin Allergy Clin Immunol 2011; 11(5): 464-70.
[http://dx.doi.org/10.1097/ACI.0b013e32834a95c9] [PMID: 21822131]
, 12Actis AG, Rolle T. Ocular surface alterations and topical antiglaucomatous therapy: a review. Open Ophthalmol J 2014; 8: 67-72.
[http://dx.doi.org/10.2174/1874364101408010067] [PMID: 25317218]
]. The majority of glaucoma patients require multiple medications to achieve the target pressure for a long period, and this further increases the risk for OSD [13Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120(6): 701-13.
[http://dx.doi.org/10.1001/archopht.120.6.701] [PMID: 12049574]
-15Rossi GC, Pasinetti GM, Scudeller L, Raimondi M, Lanteri S, Bianchi PE. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol 2013; 23(3): 296-302.
[http://dx.doi.org/10.5301/ejo.5000220] [PMID: 23335308]
].

The diagnosis and management of OSD among glaucoma patients are often neglected. The prevalence of OSD among medically treated glaucoma patients was reported to range from 20% to 59% [16Miljanović B, Dana R, Sullivan DA, Schaumberg DA. Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol 2007; 143(3): 409-15.
[http://dx.doi.org/10.1016/j.ajo.2006.11.060] [PMID: 17317388]
, 17Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea 2010; 29(6): 618-21.
[http://dx.doi.org/10.1097/ICO.0b013e3181c325b2] [PMID: 20386433]
]. The majority of the previous studies on OSD were conducted on primary open angle glaucoma (POAG) or ocular hypertensive patients [14Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 2002; 86(4): 418-23.
[http://dx.doi.org/10.1136/bjo.86.4.418] [PMID: 11914211] [PMCID: PMC1771067]
, 16Miljanović B, Dana R, Sullivan DA, Schaumberg DA. Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol 2007; 143(3): 409-15.
[http://dx.doi.org/10.1016/j.ajo.2006.11.060] [PMID: 17317388]
, 17Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea 2010; 29(6): 618-21.
[http://dx.doi.org/10.1097/ICO.0b013e3181c325b2] [PMID: 20386433]
]. To the best of our knowledge, there is no study examining OSD in primary angle closure glaucoma (PACG) patients.

Asians are more at risk to develop PACG. Prevalence of PACG has been reported between 0.46% and 1.19% among Asians [26Cheng JW, Zong Y, Zeng YY, Wei RL. The prevalence of primary angle closure glaucoma in adults Asians: a systematic review and meta-analysis. PLoS One 2014; 9(7): e10322.
[http://dx.doi.org/10.1371/journal.pone.0103222]
]. PACG among Asians is difficult to manage as compared to primary open angle glaucoma (POAG) [18He M, Foster PJ, Johnson GJ, Khaw PT. Angle-closure glaucoma in East Asian and European people. Different diseases? Eye (Lond) 2006; 20(1): 3-12.
[http://dx.doi.org/10.1038/sj.eye.6701797] [PMID: 15688051]
-20Wang N, Wu H, Fan Z. Primary angle closure glaucoma in Chinese and Western populations. Chin Med J (Engl) 2002; 115(11): 1706-15.
[PMID: 12609093]
]. Most often multiple medications to achieve the target pressure are needed [18He M, Foster PJ, Johnson GJ, Khaw PT. Angle-closure glaucoma in East Asian and European people. Different diseases? Eye (Lond) 2006; 20(1): 3-12.
[http://dx.doi.org/10.1038/sj.eye.6701797] [PMID: 15688051]
, 21Liza-Sharmini AT, Sharina YN, Dolaboladi AJ, Zaid NA, Azhany Y, Zunaina E. Clinical presentation, severity and progression of primary angle closure in malays. Med J Malaysia 2014; 69(1): 21-6.
[PMID: 24814624]
]. Acute angle closure (AAC) in PACG may further increase the risk of OSD due to a sudden spike of intraocular pressure (IOP) and inflammation [22Lowe RF. Primary acute angle-closure glaucoma damage to cornea and lens. Br J Ophthalmol 1965; 49(9): 460-5.
[http://dx.doi.org/10.1136/bjo.49.9.460] [PMID: 5832306] [PMID: PMC506142]
]. Similar to OSD, women are more at risk to develop PACG [3Schein OD, Muñoz B, Tielsch JM, Bandeen-Roche K, West S. Prevalence of dry eye among the elderly. Am J Ophthalmol 1997; 124(6): 723-8.
[http://dx.doi.org/10.1016/S0002-9394(14)71688-5] [PMID: 9402817]
, 4Jie Y, Xu L, Wu YY, Jonas JB. Prevalence of dry eye among adult Chinese in the Beijing Eye Study. Eye (Lond) 2009; 23(3): 688-93.
[http://dx.doi.org/10.1038/sj.eye.6703101] [PMID: 18309341]
, 23Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006; 90(3): 262-7.
[http://dx.doi.org/10.1136/bjo.2005.081224] [PMID: 16488940]
]. Ocular biometry of Asian women predisposed them to develop PACG [24Seah SK, Foster PJ, Chew PT, et al. Incidence of acute primary angle-closure glaucoma in Singapore. An island-wide survey. Arch Ophthalmol 1997; 115(11): 1436-40.
[http://dx.doi.org/10.1001/archopht.1997.01100160606014] [PMID: 9366676]
, 25Foster PJ, Johnson GJ. Glaucoma in China: how big is the problem? Br J Ophthalmol 2001; 85(11): 1277-82.
[http://dx.doi.org/10.1136/bjo.85.11.1277] [PMID: 11673287] [PMCID: PMC1723754]
]. Based on these findings, the risk of OSD in PACG patients is postulated to be higher. The main objective of this study was to determine the incidence of OSD based on the signs and symptoms of OSD in Asian patients with primary angle closure suspect (PACS), primary angle closure (PAC) and PACG.

MATERIAL AND METHODS

A cross-sectional comparative study was conducted involving 85 patients (44 PACG patients and 41 PAC/PACS patients). The study subjects were recruited from the ophthalmology clinic of Hospital Selayang in Selangor and Hospital Universiti Sains Malaysia (HUSM) in Kelantan between May 2012 and March 2014. Ethical approval was received from the human research ethics committee, Universiti Sains Malaysia and the National Medical Research Registry, Malaysia. This study was conducted in accordance with the Declaration of Helsinki for human research.

Subjects were divided into two groups: PACG patients treated with topical pressure-lowering agents (Group A) and PAC and PACS patients who were treated with laser peripheral iridotomy (LPI) but without topical pressure-lowering agents treatment (Group B, control group). The inclusion criteria included a confirmed diagnosis of PACG, PAC and PACS based on the International Society of Geographical and Epidemiological Ophthalmology (ISGEO) [27Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002; 86(2): 238-42.
[http://dx.doi.org/10.1136/bjo.86.2.238] [PMID: 11815354] [PMCID: PMC1771026]
], age between 40 years old and 75 years old, history of laser peripheral iridotomy (LPI) at least 6 months prior to recruitment and able to understand Ocular Surface Disease Index (OSDI) questionnaires.

Those with a visual acuity worse than 6/60 with the Snellen chart or 1 by the logMAR chart, current or past history of instillation of other topical eye drops other than topical pressure-lowering agents in the past 3 months and a history of previous ocular surgery (including cornea transplant, cataract surgery and glaucoma filtering surgery) were excluded. Patients with a history of other external ocular diseases, e.g. meibomianitis, pterygium, and nasolacrimal duct obstruction, were excluded. In addition, those with a previous ocular infection or dry eye and systemic disease with known presentation of dry eye, e.g. Sjogren syndrome and other connective tissue diseases, were excluded. Contact lens wearer and patients with punctal plugs were also excluded.

Thorough ocular examinations, including slit-lamp biomicroscopy, gonioscopy, fundus examination and intra-ocular pressure (IOP), were conducted by two investigators (KO and RAR) to determine the eligibility of the patients. The type and number of topical pressure-lowering agents, duration of treatment and presence of AAC were retrieved from patients’ medical records. Duration of the treatment was the duration in months from the initiation of treatment and time of recruitment for this study. The presence of systemic diseases, such as diabetes mellitus, hypertension and hyperlipidaemia, was also documented.

The diagnosis of OSD was based on the scoring of the symptoms and signs of OSDI, which were based on the validated Bahasa Malaysia version of the OSDI questionnaire. Clinical signs were based on the scoring on the Schirmer’s test without anaesthesia, tear break-up time (TBUT) and cornea staining. We selected only one eye per subject for the study; if both eyes were eligible, the right eye was selected.

OSDI Questionnaires

A trained member of the medical staff was responsible for face-to-face interviews with the subjects. The Bahasa Malaysia version of the OSDI questionnaire consists of 12 items. Each item was graded on a scale of 0 to 4: 0=none of the time; 1=some of the time; 2=half the time; 3=most of the time; and 4=all the time. The total OSDI score is calculated using the following formula:

OSDI= [(sum of the OSDI score) × 100] / [(total number of questions answered) × 4].

Clinical Evaluation for OSD

The sign for the detection of OSD was conducted by the primary investigator (TEL), who was blinded from the OSDI questionnaire outcome and other clinical data.

Schirmer’s Test (Without Anaesthesia)

Schirmer’s test was performed in a confined room with the fan or air-conditioner switched off. Topical anaesthesia was not applied during the test. The round bend of the sterile Schirmer’s paper strip (Optitech Eyecare, Allahabad, India) was hooked in the lower cul-de-sac over the junction of the temporal and central one-third of the lower lid margin. The subjects were then asked to gently close their eyelids for 5 minutes before the removal of the strip. The amount of wetting was measured by reading the calibrated scale printed on the paper strip. If the tear front moved unevenly, measurement was made from the notch to the middle of the diagonal line. Abnormal Schirmer’s test is defined as less than 10 mm of wetting after 5 minutes [28Danjo Y. Diagnostic usefulness and cutoff value of Schirmers I test in the Japanese diagnostic criteria of dry eye. Graefes Arch Clin Exp Ophthalmol 1997; 235(12): 761-6.
[http://dx.doi.org/10.1007/BF02332860] [PMID: 9439968]
]; this is further divided into mild abnormal (8–10 mm of wetting), moderate abnormal (5-7 mm) and severe (less than 5 mm) [28Danjo Y. Diagnostic usefulness and cutoff value of Schirmers I test in the Japanese diagnostic criteria of dry eye. Graefes Arch Clin Exp Ophthalmol 1997; 235(12): 761-6.
[http://dx.doi.org/10.1007/BF02332860] [PMID: 9439968]
].

Tear Break-up Time

TBUT is the time measured from when the eyelid is opened to the appearance of the first dry spot formation after the instillation of the fluorescein stain into the inferior cul-de-sac. It is used to measure the distribution of tears on the ocular surface and tear film stability. A fluorescein strip (Bausch & Lomb, Surrey, UK) was used in this clinical test, and sterile normal saline solution was used to wet the fluorescein at the tip of the strip. The stopwatch was used to measure the time. The TBUT was then assessed using a slit lamp (Topcon Corp, Tokyo, Japan) at 10X magnification, using cobalt blue illumination. The fluorescein-stained pre-corneal tear film was observed by moving the slit lamp horizontally at a slow rate from side to side with an unaltered angle between the light and the microscope to identify a black gap or dry spot formation. At the first appearance of a dry spot, the stopwatch was stopped and this was considered as TBUT. The test was repeated two times on each eye, and the mean TBUT was calculated for each eye separately. The normal cut-off value designated in this study was ≥10; 7–9 seconds was considered mild, 5–6 seconds considered moderate and <5 seconds considered severe [29Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 2008; 17(5): 350-5.
[http://dx.doi.org/10.1097/IJG.0b013e31815c5f4f] [PMID: 18703943]
].

Cornea Staining

After assessing the tear break-up time, the cornea was assessed for any staining. The grading of staining was based on the National Eye Institute system [2Bron AJ, Abelson MB, Ousler G, et al. Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007; 5(2): 108-52.
[http://dx.doi.org/10.1016/S1542-0124(12)70083-6] [PMID: 17508118]
]. The amount of staining was graded according to stain intensity: 0, no staining; 1, slight staining; 2, moderate staining; and 3, intense staining.

Statistical Analysis

Predictive Analytic Software (PASW) 20 and STATA analysis software were used for statistical analyses. The difference in the mean of the OSD parameters between PACG and PAC/PACS was analysed with the independent t-test. Comparison between OSD parameters with the number of medications, duration of treatment and presence of AAC was analysed using the Mann–Whitney test. Multivariate linear regression was performed to determine the predictor factors for each OSD parameter.

RESULTS

A total of 85 subjects (85 eyes) were recruited. There were 44 (51.8%) PACG patients treated with topical pressure-lowering agents (Group A) and 41 (48.2%) angle closure patients (19 PAC and 22 PACS) not treated with topical pressure-lowering agents (Group B). PACG patients (Group A) were older (Table 1), and there was a 2:1 preponderance of female participants. The PACG patients had significantly poorer visual acuity and a higher IOP at initial presentation (Table 1). The mean duration since diagnosis of the disease for Group A and B was 5.2(2.7) years and 4.2 (3.8) years respectively (Table 1). Half (50%) of the PACG patients required three or more anti-glaucoma medication (Table 1).

Table 1
Demographic and general ophthalmic characteristics of Group A and Group B.


The incidence of signs and symptoms of OSD was higher in Group A compared to Group B except for Schirmer’s test. More than half (52.3%) of the PACG patients reported abnormal OSDI scores. In general, more than two-third of the PACG patients demonstrated abnormal Schirmer’s test (70.5%), TBUT (75%) and cornea fluorescein staining (77.3%). Normal OSDI score and normal cornea staining were observed in 61% and 85.4% of patients in group B respectively. However, more than half of them (Group B) demonstrated abnormal TBUT (58.5%) and Schirmer’s test (73.2%). Patients in Group A demonstrated statistically higher OSDI scores, lower TBUT and cornea fluorescein staining compared to Group B (Table 2). However, there was no significant difference in Schirmer’s test between the two groups (Table 2).

Table 2
Comparison of the mean score of OSDI, Schirmer’s test, TBUT and cornea staining between Group A and Group B.


In general, PACG patients who were treated with more than two topical pressure-lowering agents demonstrated shorter duration in TBUT, less tears production (Schirmer’s test) and abnormal corneal staining but without statistically significant difference except for corneal staining (Table 3). PACG patients treated with more than two topical pressure-lowering agents had statistically worse positive cornea fluorescein staining (Table 3). However, they demonstrated better OSDI score than those treated with less or equal to two medications (Table 3).

Table 3
Mean difference in clinical parameters in primary angle closure glaucoma (PACG) patients in association with the number of topical pressure-lowering agents and duration of treatment.


The mean duration of treatment in this study was 5.2 ± 2.7 years; PACG patients treated longer than 3 years had worse OSD parameters except on the Schirmer’s test, but these did not reach statistical significance. In multivariate linear regression, visual acuity showed an exponential linear relationship with the mean OSDI score (Table 4). Age had a negative association with Schirmer’s test and mean TBUT but showed a positive linear association with the cornea staining test (Table 4). The number of topical pressure-lowering agents had a strong positive linear association with both TBUT and cornea staining.

Table 4
Multivariate analysis of OSD parameters.


DISCUSSION

There was a high incidence (52.3%) of OSD based on symptoms and signs in PACG patients treated with topical pressure-lowering agents; however, this was comparable with reported studies on POAG and ocular hypertension patients [16Miljanović B, Dana R, Sullivan DA, Schaumberg DA. Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol 2007; 143(3): 409-15.
[http://dx.doi.org/10.1016/j.ajo.2006.11.060] [PMID: 17317388]
, 17Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea 2010; 29(6): 618-21.
[http://dx.doi.org/10.1097/ICO.0b013e3181c325b2] [PMID: 20386433]
]. The rate of OSD in angle closure patients (PACS and PAC) was also found to be higher than the general population by indirect comparison [30Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM. Prevalence of dry eye among an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology 2003; 110(6): 1096-101.
[http://dx.doi.org/10.1016/S0161-6420(03)00262-8] [PMID: 12799232]
-32Smith JA. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007; 5(2): 93-107.
[http://dx.doi.org/10.1016/S1542-0124(12)70082-4] [PMID: 17508117]
]. To the best of our knowledge, this is the first study specifically reporting OSD in angle closure patients. The high percentage of OSD is not surprising as the majority of recruited angle closure patients were older women at postmenopausal age group (mean age 63.4 ± 7.1 years), which further increased their susceptibility to OSD [33Versura P, Campos EC. Menopause and dry eye. A possible relationship. Gynecol Endocrinol 2005; 20(5): 289-98.
[http://dx.doi.org/10.1080/09513590400027257] [PMID: 16019376]
]. Moreover, this present study involved the Asian population who are more susceptible to develop OSD [30Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM. Prevalence of dry eye among an elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology 2003; 110(6): 1096-101.
[http://dx.doi.org/10.1016/S0161-6420(03)00262-8] [PMID: 12799232]
].

We also included angle closure patients with a history of AAC attack. AAC with a sudden spike of IOP may affect the ocular surface [22Lowe RF. Primary acute angle-closure glaucoma damage to cornea and lens. Br J Ophthalmol 1965; 49(9): 460-5.
[http://dx.doi.org/10.1136/bjo.49.9.460] [PMID: 5832306] [PMID: PMC506142]
]. Systemic diseases, such as diabetes, hypertension and hyperlipidaemia commonly co-existed in glaucoma patients [34Lama P. Systemic diseases and glaucoma the glaucoma book. Springer 2010; pp. 689-709.
[http://dx.doi.org/10.1007/978-0-387-76700-0_60]
-36Morrison JC, Pollack IP. Glaucoma: science and practice. New York: Thieme 2003.
[http://dx.doi.org/10.1055/b-002-51008]
]. These systemic diseases and their treatment can directly or indirectly affect the ocular surface, causing dry eyes diseases [37Rolando M, Zierhut M. The ocular surface and tear film and their dysfunction in dry eye disease. Surv Ophthalmol 2001; 45(Suppl. 2): S203-10.
[http://dx.doi.org/10.1016/S0039-6257(00)00203-4] [PMID: 11587144]
]. It is possible that the high prevalence of OSD that we found was influenced by the presence of systemic co-morbidities; however, excluding them would be impossible, especially in elderly subjects.

In this study, we determined the proportion of OSD based on the presence of clinical signs and symptoms. The OSDI is used to assess the symptoms or subjective measurement of dry eye [32Smith JA. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007; 5(2): 93-107.
[http://dx.doi.org/10.1016/S1542-0124(12)70082-4] [PMID: 17508117]
, 38Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the ocular surface disease index. Arch Ophthalmol 2000; 118(5): 615-21.
[http://dx.doi.org/10.1001/archopht.118.5.615] [PMID: 10815152]
, 39Amparo F, Schaumberg DA, Dana R. Comparison of two questionnaires for dry eye symptom assessment: the Ocular Surface Disease Index and the Symptom Assessment in Dry Eye. Ophthalmology 2015; 122(7): 1498-503.
[http://dx.doi.org/10.1016/j.ophtha.2015.02.037] [PMID: 25863420]
]; it rapidly evaluates OSD to provide a valid and reliable score that reflects good sensitivity and specificity [38Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the ocular surface disease index. Arch Ophthalmol 2000; 118(5): 615-21.
[http://dx.doi.org/10.1001/archopht.118.5.615] [PMID: 10815152]
]. However, the OSDI questionnaire assesses vision-related quality of life [40Pflugfelder SC, Baudouin C. Challenges in the clinical measurement of ocular surface disease in glaucoma patients. Clin Ophthalmol 2011; 5: 1575-83.
[http://dx.doi.org/10.2147/OPHTH.S24410] [PMID: 22125404]
]. Thus, we excluded patients with visual acuity worse than logMar 1. As expected, visual acuity of PACG patients was significantly poorer than PACS/PAC patients. Visual acuity may affect the OSDI score, giving rise to falsely abnormal scores in PACG. The score of the OSDI is also affected by pain tolerance; women are known to have lower pain tolerance than men [41Fillingim RB, Maixner W, Eds. Gender differences in the responses to noxious stimuli Pain forum. Elsevier 1996., 42Fillingim RB, Ness TJ. Sex-related hormonal influences on pain and analgesic responses. Neurosci Biobehav Rev 2000; 24(4): 485-501.
[http://dx.doi.org/10.1016/S0149-7634(00)00017-8] [PMID: 10817845]
].

The percentage of abnormal OSD signs in the present study was higher compared to the findings of Ghosh et al. [57Ghosh S, O'Hare F, Lamoureux E, et al. Prevalence of signs and symptoms of ocular surface disease in individuals treated and not treated with glaucoma medication. Clin Exp Ophthalmol 2012; 40: 675-81.
[http://dx.doi.org/10.1111/j.1442-9071.2012.02781.x] [PMID: 22394358]
], who studied the presence of OSD signs in various types of glaucoma. In our study, the percentage of abnormal TBUT and cornea staining was significantly higher in the PACG group. However, the percentage of abnormal Schirmer’s tests was almost equal in both the PACG and control groups. Perhaps, lipid and mucin layers were more affected in the PACG patients treated with topical pressure-lowering drugs [43Liu W, Li H, Lu D, et al. The tear fluid mucin 5AC change of primary angle-closure glaucoma patients after short-term medications and phacotrabeculectomy. Mol Vis 2010; 16: 2342-6.
[PMID: 21139981] [PMCID: PMC2994764]
, 44Baffa LdoP, Ricardo JR, Dias AC, et al. Tear film and ocular surface alterations in chronic users of antiglaucoma medications. Arq Bras Oftalmol 2008; 71(1): 18-21.
[http://dx.doi.org/10.1590/S0004-27492008000100004] [PMID: 18408831]
].

The aqueous layer is known to be commonly affected in OSD [45Ophthalmology AAO. Disorder of ocular surface. Basic and Clinical Science Course 8 ed. 1997-1998.]. Schirmer’s test has been reported to have less specificity in the diagnosis of dry eye disease [46Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol 2011; 151(5): 792-798.e1.
[http://dx.doi.org/10.1016/j.ajo.2010.10.032] [PMID: 21310379]
]. Furthermore, the test is easily affected by reflex tearing due to discomfort during the procedure and delayed removal of the strip [40Pflugfelder SC, Baudouin C. Challenges in the clinical measurement of ocular surface disease in glaucoma patients. Clin Ophthalmol 2011; 5: 1575-83.
[http://dx.doi.org/10.2147/OPHTH.S24410] [PMID: 22125404]
, 47Sullivan BD, Crews LA, Sönmez B, et al. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea 2012; 31(9): 1000-8.
[http://dx.doi.org/10.1097/ICO.0b013e318242fd60] [PMID: 22475641]
], and these may cause an incorrect high value in both the PACG and control groups. In general, there was a lack of association between the signs and symptoms of OSD in the present study. Similar findings were also observed in different populations [16Miljanović B, Dana R, Sullivan DA, Schaumberg DA. Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol 2007; 143(3): 409-15.
[http://dx.doi.org/10.1016/j.ajo.2006.11.060] [PMID: 17317388]
, 47Sullivan BD, Crews LA, Sönmez B, et al. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea 2012; 31(9): 1000-8.
[http://dx.doi.org/10.1097/ICO.0b013e318242fd60] [PMID: 22475641]
]. Evidence of signs of ocular surface damage may be present despite the absence of OSD symptoms [48Sullivan BD, Crews LA, Messmer EM, et al. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications. Acta Ophthalmol 2014; 92(2): 161-6.
[http://dx.doi.org/10.1111/aos.12012] [PMID: 23279964]
]. In the current study, cornea staining correlated best with the ocular surface symptoms, which was in agreement with the findings of Sullivan and associates [47Sullivan BD, Crews LA, Sönmez B, et al. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea 2012; 31(9): 1000-8.
[http://dx.doi.org/10.1097/ICO.0b013e318242fd60] [PMID: 22475641]
]. This could have been due to a lack of specificity of the other tests and the variation of value of the tests [46Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol 2011; 151(5): 792-798.e1.
[http://dx.doi.org/10.1016/j.ajo.2010.10.032] [PMID: 21310379]
, 47Sullivan BD, Crews LA, Sönmez B, et al. Clinical utility of objective tests for dry eye disease: variability over time and implications for clinical trials and disease management. Cornea 2012; 31(9): 1000-8.
[http://dx.doi.org/10.1097/ICO.0b013e318242fd60] [PMID: 22475641]
].

The number of topical pressure-lowering drugs and duration of treatment are associated with OSD in glaucoma patients [48Sullivan BD, Crews LA, Messmer EM, et al. Correlations between commonly used objective signs and symptoms for the diagnosis of dry eye disease: clinical implications. Acta Ophthalmol 2014; 92(2): 161-6.
[http://dx.doi.org/10.1111/aos.12012] [PMID: 23279964]
, 49Fukuchi T, Wakai K, Suda K, et al. Incidence, severity and factors related to drug-induced keratoepitheliopathy with glaucoma medications. Clin Ophthalmol 2010; 4(1): 203-9.
[http://dx.doi.org/10.2147/OPTH.S9716] [PMID: 20463785] [PMID: PMC2861924]
]. In the present study, number of medications and duration of treatment were not associated with abnormal signs and symptoms of OSD except for corneal staining. In contrast, there was evidence of a significant association between the mean OSDI score and the number of topical pressure-lowering drugs [17Fechtner RD, Godfrey DG, Budenz D, Stewart JA, Stewart WC, Jasek MC. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea 2010; 29(6): 618-21.
[http://dx.doi.org/10.1097/ICO.0b013e3181c325b2] [PMID: 20386433]
]. Histologically, there was evidence of subclinical inflammation in the conjunctival of glaucoma patients treated with topical pressure-lowering drugs [50Baudouin C, Renard JP, Nordmann JP, et al. Prevalence and risk factors for ocular surface disease among patients treated over the long term for glaucoma or ocular hypertension. Eur J Ophthalmol 2012; 0 [Epub ahead of print].
[http://dx.doi.org/10.5301/ejo.5000181] [PMID: 22729444]
, 51Broadway DC, Grierson I, OBrien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. I. The conjunctival cell profile. Arch Ophthalmol 1994; 112(11): 1437-45.
[http://dx.doi.org/10.1001/archopht.1994.01090230051020] [PMID: 7980133]
], but subclinical inflammation is not manifested clinically, which perhaps provides an explanation for our findings. Moreover, histo-morphological changes on the ocular surface epithelium can appear as early as 2 weeks after the commencement of medications [52Lewis RA, Katz GJ, Weiss MJ, et al. Travoprost 0.004% with and without benzalkonium chloride: a comparison of safety and efficacy. J Glaucoma 2007; 16(1): 98-103.
[http://dx.doi.org/10.1097/01.ijg.0000212274.50229.c6] [PMID: 17224758]
].

Multiple medications reduce tear secretion, tear stability and induce more cornea epithelial injury [53Inoue K, Okugawa K, Kato S, et al. Ocular factors relevant to anti-glaucomatous eyedrop-related keratoepitheliopathy. J Glaucoma 2003; 12(6): 480-5.
[http://dx.doi.org/10.1097/00061198-200312000-00007] [PMID: 14646683]
], which is what we showed even though our findings were not statistically significant. Detrimental effects of topical pressure-lowering drugs on the ocular surface have been shown in normal healthy subjects after a short duration of exposure [54Terai N, Müller-Holz M, Spoerl E, Pillunat LE. Short-term effect of topical antiglaucoma medication on tear-film stability, tear secretion, and corneal sensitivity in healthy subjects. Clin Ophthalmol 2011; 5: 517-25.
[http://dx.doi.org/10.2147/OPTH.S18849] [PMID: 21573041]
]. A higher prevalence of OSD was expected in patients treated for longer duration. Multiple topical pressure-lowering drugs and a longer duration of treatment may also cause cornea hypesthesia, leading to an underestimation of OSD symptoms [55Van Went C, Alalwani H, Brasnu E, et al. Corneal sensitivity in patients treated medically for glaucoma or ocular hypertension. J Fr Ophtalmol 2011; 34(10): 684-90.
[http://dx.doi.org/10.1016/j.jfo.2011.07.011] [PMID: 22093372]
]. However, duration has less of an effect on changes on the ocular surface. A significant reduction of goblet cells in conjunctiva was found in patients treated with topical pressure-lowering drugs for 3 years or more [51Broadway DC, Grierson I, OBrien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. I. The conjunctival cell profile. Arch Ophthalmol 1994; 112(11): 1437-45.
[http://dx.doi.org/10.1001/archopht.1994.01090230051020] [PMID: 7980133]
]; in contrast, there was no significant difference in the number of goblet cells between glaucoma patients treated ≥1 year and <1 year [56Turaçli E, Budak K, Kaur A, Mizrak B, Ekinci C. The effects of long-term topical glaucoma medication on conjunctival impression cytology. Int Ophthalmol 1997; 21(1): 27-33.
[http://dx.doi.org/10.1023/A:1005892426045] [PMID: 9298420]
]. These supported our findings that there was no significant difference in OSD signs between PACG patients treated with topical pressure-lowering drugs for >3years and ≤3 years. A major limitation in the sub-analysis of the effect of topical pressure drugs on the ocular surface of angle closure in this study was the relatively small sample size. The effect of topical pressure-lowering drugs on changes on the ocular surface is still inconclusive.

CONCLUSION

OSD is common in angle closure patients. A higher incidence was observed in PACG patients treated with topical pressure-lowering drugs, and there were significant severe OSD symptoms and cornea fluorescein staining in PACG patients. It is important to evaluate OSD during the management of angle closure patients, especially those with PACG.

LIST OF ABBREVIATIONS

TEL  = Tan Ee Ling
KO  = Khairuddin Othman
RAR  = Rasdi Abdul Rashid

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

We thank Mr. Hazwan bin Mat Din and Dr. Erica Kueh from the Department of Biostatistics, Health Campus, Universiti Sains Malaysia (USM) for their help in the statistical analysis of the data presented in this study.


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"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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