ORIGINAL STUDY
`
`Prevalence of Ocular Surface Disease in Glaucoma Patients
`
`Eamon W. Leung, MD, Felipe A. Medeiros, MD, PhD, and Robert N. Weinreb, MD
`
`Purpose: To examine the prevalence of ocular surface disease
`(OSD) in glaucoma patients.
`
`Methods: This was a cross-sectional study. One hundred and one
`patients, 18 years of age or older, with open-angle glaucoma or
`ocular hypertension were consecutively recruited for the study.
`Patients with a history of use of cyclosporine, steroids, topical
`ocular nonsteroidal anti-inflammatory drugs, or punctal plugs
`within the last 3 months were excluded. Each patient completed
`an Ocular Surface Disease Index questionnaire and underwent
`evaluation by Schirmer test, corneal and conjunctival lissamine
`green staining, and tear break-up time.
`
`Results: Using Ocular Surface Disease Index for measuring
`symptoms of dry eye, 60 (59%) patients reported symptoms in at
`least 1 eye. Severe symptoms were reported by 27 (27%)
`patients. Schirmer testing showed 62 (61%) patients with
`decrease in tear production in at least 1 eye. Severe tear
`deficiency was presented in 35 (35%) patients. Corneal and
`conjunctival lissamine green staining showed positive results in
`22 (22%) patients. None had severe staining. Tear break-up time
`showed abnormal tear quality in 79 (78%) patients and severe
`decrease in tear quality was found in at least 1 eye in 66 (65%)
`patients. Multivariate logistic regression models were used to
`investigate the association between the number of benzalkonium
`chloride (BAK)-containing eyedrops and results on the clinical
`tests of OSD. After adjustment for age and sex, each additional
`BAK-containing eyedrop was associated with an approximately
`2 times higher odds of showing abnormal results on the
`lissamine green staining test (odds ratio = 2.03; 95% confidence
`interval: 1.06 to 3.89; P = 0.034).
`
`Conclusion: A large proportion of patients with open-angle
`glaucoma or ocular hypertension had signs and/or symptoms of
`OSD in at least 1 eye. The coexistence of OSD and the use of
`BAK-containing medications may impact vision-related quality
`of life in this patient population.
`
`surface disease, dry eyes,
`Key Words: glaucoma, ocular
`banzalkonium chloride, ocular hypertension
`
`Received for publication July 2, 2007; accepted September 27, 2007.
`From the Department of Ophthalmology, Hamilton Glaucoma Center,
`University of California, San Diego, La Jolla, CA.
`Supported in part by a research grant from Alcon Laboratories Inc.
`Dr Medeiros has acted as a consultant or received research support from
`Alcon Laboratories Inc, Allergan Inc, and Pfizer Inc. Dr Weinreb
`has acted as a consultant or received research support from Alcon
`Laboratories Inc, Allergan Inc, Merck, and Pfizer Inc.
`Reprints: Felipe A. Medeiros, MD, PhD, Hamilton Glaucoma Center,
`University of California, San Diego, 9500 Gilman Drive, La Jolla,
`CA 92093-0946 (e-mail: fmedeiros@eyecenter.ucsd.edu).
`Copyright r 2008 by Lippincott Williams & Wilkins
`
`350
`
`(J Glaucoma 2008;17:350–355)
`
`O cular surface disease (OSD) is a leading cause of
`
`patient visits to ophthalmologists.1–6 In the United
`States, the prevalence of symptomatic OSD is estimated
`to be 15% among individuals aged 65 years or older.7 It is
`characterized by an inadequate quantity of tears, an
`unstable tear film secondary to poor quality of tears,
`ocular surface breakdown, and/or symptoms such as
`irritation, burning,
`foreign body sensation, dryness,
`photophobia,
`fatigue, and fluctuating visual acuity.
`OSD symptoms can be debilitating and often severe,
`affecting a patient’s quality of life and ability to work.8
`Several
`factors are considered to influence the
`prevalence of OSD, such as age, sex, and race.9 In
`addition, OSD is associated often with other ocular
`diseases, such as meibomian gland dysfunction and
`blepharitis. Use of preservative-containing eyedrops also
`has been implicated in the development or worsening of
`OSD.10,11 A deleterious effect of benzalkonium chloride
`(BAK) on the ocular surface has been demonstrated in
`vitro as well as in vivo in both animals and humans.
`Preservatives have a detergent effect on the lipid layer of
`the tear film12 and also can decrease the density of goblet
`cells in the conjunctival epithelium.13 These actions result
`in a reduction in the stability of the precorneal tear film,
`compromising its ability to provide protection and
`trophic factors to the cornea.
`Glaucoma patients are presumably at a higher risk
`for developing OSD, as both diseases are more common
`in older patients. Further, glaucoma patients are usually
`treated with preservative-containing pressure-lowering
`eyedrops that may contribute to OSD. However, there
`is a paucity of data with regard to the prevalence of OSD
`in glaucoma patients.
`The purpose of the current study was to investigate
`the prevalence of symptoms and signs of OSD in patients
`with glaucoma.
`
`METHODS
`The study was carried out with the approval of the
`Institutional Review Board of the University of Califor-
`nia, San Diego, in accordance with the requirements of
`the Code of Federal Regulations on the Protection of
`Human Subjects, and in accord with the Health Insurance
`Portability and Accountability Act (HIPPA) regulations.
`All patients were recruited consecutively during a regular
`scheduled glaucoma clinic appointment at the Shiley Eye
`
`J Glaucoma  Volume 17, Number 5, August 2008
`
`ALCON 2017
`Apotex Corp. v. Alcon Research, Ltd.
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`

`J Glaucoma  Volume 17, Number 5, August 2008
`
`Prevalence of Ocular Surface Disease in Glaucoma Patients
`
`Center of the University of California, San Diego, from
`October 2006 to February 2007.
`Inclusion criteria for the study included (1) being 18
`years of age or older, of both sexes and all races; (2)
`signature on the informed consent document; (3) a clinical
`diagnosis of primary open-angle, pseudoexfoliation, or
`pigment-dispersion glaucoma, or ocular hypertension
`in both eyes; and (4) the ability to read and complete
`the Ocular Surface Disease Index (OSDI) questionnaire
`written in English (Fig. 1). A diagnosis of glaucoma was
`established on the basis of the presence of visual field
`defect (GHT outside normal
`limits and/or PSD with
`P<5%) and/or the presence of signs of glaucomatous
`optic neuropathy (rim thinning, excavation, and/or
`retinal nerve fiber layer defects). Patients with ocular
`hypertension had a history of intraocular pressure of
`above 22 mm Hg without signs of glaucomatous optic
`neuropathy or visual field loss. Exclusion criteria included
`(1) an inability to understand the trial procedures, and
`thus the inability to give informed consent; (2) current use
`or use within the last 3 months of Restasis, steroids, or
`topical ocular nonsteroidal anti-inflammatory drugs; (3)
`current use of punctal plugs; and (4) previous glaucoma,
`corneal, or conjunctival surgery.
`After providing informed consent, qualified patients
`were given the OSDI questionnaire (Fig. 1) to complete.14
`Demographic information, a brief medical history, and
`information on concomitant medicine use, including use
`of artificial
`tears, were obtained from the patient’s
`medical records. After completing the OSDI question-
`naire, patients underwent 3 standard clinical tests of the
`ocular surface in the order listed, including Schirmer test
`
`(without anesthesia), corneal and conjunctival lissamine
`green staining, and tear break-up time (TBUT). All
`the questionnaires and examinations were completed in
`1 day.
`the
`(without anesthesia),
`For the Schirmer test
`patients were asked to look up and the lower eyelid was
`drawn gently downward and temporally. The rounded
`bent end of the sterile strip was hooked in the lower cul-
`de-sac over the junction of the temporal and central one-
`third of the lower eyelid margin. The testing period was
`initiated. To minimize the potential
`for conjunctival
`staining from this test, the patients were asked to gently
`close their eyelids until 5 minutes had elapsed and the
`strips were removed. As the tear front would continue
`advancing a few millimeters after it had been removed
`from the eyes, the tear front was marked with a pencil
`after 5 minutes. The amount of wetting was measured
`using the graduated paper scale included in the box of
`strips. If the tear front had moved unevenly, we measured
`from the notch to the middle of the diagonal line. Only
`whole numbers rounding up to the next whole number
`were recorded if the tear front was at or at greater than
`the half-millimeter mark. After Schirmer testing, a 25-mL
`drop of freshly prepared lissamine green was instilled
`using a micropipette. The drop was gently delivered from
`the tip of
`the micropipette to the lower palpebral
`conjunctiva. Using white light of moderate intensity,
`staining at the corneal region and the interpalpebral
`region of the nasal and temporal conjunctiva was graded
`using the Oxford Scheme.11 Corneal and conjunctival
`lissamine green staining was evaluated after 30 seconds
`but before 2 minutes had elapsed after instillation.
`
`FIGURE 1. Ocular Surface Disease Index questionnaire.
`
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`Leung et al
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`J Glaucoma  Volume 17, Number 5, August 2008
`
`Subsequently, 5 mL of a 2% sodium fluorescein solution
`was instilled into the inferior cul-de-sac. The drop at the
`tip of the delivery micropipette was gently touched to the
`lower palpebral conjunctiva. Examination was performed
`with the slit lamp at 10 times magnification and TBUT
`was measured over the cornea using cobalt illumination.
`Patients were asked to blink normally and the time for
`tear break-up was measured only up to 10 seconds.
`The findings in case of each patient were designated
`as normal, mild to moderate, or severe for each individual
`measure. The severity designations used for the Schirmer
`test were the following: >10 mm, normal; 6 to 10 mm,
`mild to moderate; and 0 to 5 mm, severe.10 The severity
`designations used for lissamine green staining using the
`Oxford scheme were the following: 0 to I, normal; II to
`III, mild to moderate; and IV to V, severe. The severity
`designations used for TBUT were the following: Z10
`seconds, normal; 5 to 9 seconds, mild to moderate; and
`<5 seconds, severe. The 12 items of the OSDI ques-
`tionnaire were graded on a scale of 0 to 4: 0, none of the
`time; 1, some of the time; 2, half of the time; 3, most of the
`time; and 4, all of the time. The total OSDI score was
`calculated using the following formula: OSDI = [(sum of
`scores for all questions answered)  100]/[(total number
`of questions answered)  4].10 Thus, the OSDI was scored
`on a scale of 0 to 100. To maximize the sum of the
`sensitivity and specificity values, the severity designations
`used for the OSDI score were the following: 0 to 5.9,
`normal; 6.0 to 14.9, mild to moderate; and Z15.0,
`severe.10 The criteria for disease severity were set up a
`priori for the study.
`For each patient, we considered the eye that showed
`worse results for each specific test. If both the eyes had
`equally severe results on a particular test, then 1 eye was
`chosen randomly by the flip of a coin.
`A multivariate logistic regression model was used to
`evaluate the relationship between the use of eyedrops and
`results on the OSDI questionnaire and clinical tests of
`OSD. The results of each test were categorized as normal/
`abnormal and entered as dependent variables. The
`number of BAK-containing eyedrops was entered. The
`model was adjusted for age and sex, also entered as
`independent variables.
`
`RESULTS
`One hundred and one patients (202 eyes) partici-
`pated and completed all the tests involved in the study.
`Thirty-nine patients were invited to participate in the
`study, but chose not to participate owing to transporta-
`tion issues, time limitation, and/or concerns about the
`study safety. Seventy-nine (78%) patients had a diagnosis
`of open-angle glaucoma and 22 (22%) patients were
`diagnosed with ocular hypertension. Forty-six (45%)
`patients were using 1 eyedrop, 37 (36%) patients were
`using 2 eyedrops, and 10 (10%) patients were using 3
`eyedrops. Eight patients (8%) were not using any topical
`ocular medication. The mean ± SD age of the partici-
`pants who completed the study was 67 ± 12 years,
`
`ranging from 36 to 90 years. Sixty-six (65%) patients
`were males.
`Table 1 summarizes the results obtained on the
`OSDI questionnaire and on the 3 clinical tests. The
`overall prevalence of OSD varied from 22% to 78%,
`depending on the specific test evaluated. Using OSDI for
`measuring symptoms of dry eye, 60 (59%) patients
`reported symptoms in at least 1 eye. Severe symptoms
`were reported by 27 (27%) patients. Schirmer testing
`showed that 62 (61%) patients had at least 1 eye with a
`decreased tear production. Severe tear deficiency was
`present in 35 (35%) patients. Corneal and conjunctival
`lissamine green staining showed positive results in 22
`(22%) patients. None had severe staining. TBUT showed
`abnormal tear quality in 79 (78%) patients and a severe
`decrease in tear quality was found in at least 1 eye in 66
`(65%) patients.
`To further analyze the data, we dichotomized the
`results of the OSDI questionnaire and clinical tests to
`normal versus abnormal. Results indicating mild to
`moderate disease as well as severe disease were grouped
`as abnormal. Figure 2 shows the agreement between the
`results. Only 11 patients (11%) had abnormal results on
`all 3 tests. All of these patients also reported symptoms of
`OSD on the OSDI questionnaire.
`Figure 3 shows
`the relationship between the
`presence of symptoms as assessed by the OSDI ques-
`tionnaire and the results of the 3 clinical tests. Patients
`with OSDI symptoms often had normal testing [Schirmer
`test (64%), lissamine green staining (58%), and TBUT
`(55%)]. There was no correlation between the results on
`these clinical tests and the presence of symptoms of OSD.
`We also investigated the relationship between the
`use of BAK-containing eyedrops and presence of OSD
`symptoms and signs. Results of multivariate logistic
`regression models adjusting for age and sex are shown
`in Table 2. After adjustment for age and sex, each
`additional BAK-containing eyedrop was associated with
`an approximately 2 times higher odds of
`showing
`abnormal results on the lissamine green staining test
`(odds ratio = 2.03; 95% confidence interval: 1.06 to 3.89;
`P = 0.034). No relationship was observed between the
`number of BAK-containing eyedrops and results on
`the other clinical tests. Figures 4A to D illustrates the
`relationship between the number of BAK-containing
`eyedrops used and the results on the OSDI questionnaire
`and OSD clinical tests.
`
`TABLE 1. Number (%) of Patients With Each Result on the
`OSDI, Schirmer Test, Lissamine Green Staining, and TBUT
`
`Test Results
`
`OSDI
`
`Schirmer
`Test
`
`39 (39%)
`27 (27%)
`
`Lissamine
`Green
`Staining
`
`79 (78%)
`22 (22%)
`
`TBUT
`
`22 (22%)
`13 (13%)
`
`Normal
`Mild/
`moderate
`Severe
`
`41 (41%)
`33 (33%)
`
`27 (27%)
`
`35 (35%)
`
`0 (0%)
`
`66 (65%)
`
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`J Glaucoma  Volume 17, Number 5, August 2008
`
`Prevalence of Ocular Surface Disease in Glaucoma Patients
`
`discriminate between normal, mild to moderate, and
`severe OSD as defined by both the physician’s assessment
`of severity and a composite disease-severity score. More-
`over, the OSDI has been demonstrated to have good
`sensitivity and specificity in distinguishing between
`normal subjects and patients with OSD.14 In our study,
`59% of the patients reported symptoms of dry eye and
`severe symptomatology was reported by 27% of the
`overall group of patients. Although a high prevalence of
`OSD symptoms was reported by our patients,
`the
`correlation with results of the other OSD clinical tests
`was poor. A large proportion of patients who reported
`symptoms on the OSDI questionnaire had normal results
`on the clinical tests. Conversely, a significant proportion
`of patients with abnormal results on the OSD clinical
`tests had normal results on the OSDI questionnaire. This
`is in agreement with previous studies that have also found
`a poor correlation between objective and subjective signs
`of dry eye disease.15,16
`In view of the difficulties in diagnosing OSD in
`prevalence studies, the use of a test battery of measure-
`ments has been suggested to include the use of a validated
`questionnaire of symptoms, as well as tests to demon-
`strate ocular surface damage, tear instability, and tear
`hyperosmolarity. If a combination of positive symptoms
`on the OSDI questionnaire and at least one abnormal
`OSD clinical test was used to diagnose OSD in our
`population, the prevalence figures would be 14%, 35%,
`or 48% depending on the clinical test used (lissamine
`green staining, Schirmer test, or TBUT, respectively).
`The prevalence figures of OSD in our study are
`higher than those reported in population-based preva-
`lence studies. The Melbourne Visual Impairment Project
`(MVIP) examined the prevalence of OSD in 926 patients
`aged 40 years and older.17 OSD was diagnosed in 10.8%
`by rose Bengal staining, 16.3% by Schirmer test, 8.6% by
`TBUT, 7.4% with 2 or more signs of the condition, and
`5.5% with any severe symptom.
`In the Salisbury
`population-based survey, 14.6% of the 2520 residents
`examined reported one or more symptoms of OSD often
`or all of the time.5,18 In the Beaver Dam Eye Study
`(BDES) cohort of 3722 patients aged from 48 to 91 years,
`the prevalence of OSD by self-reported history was found
`to be 14.4%.7 In a large study conducted in the United
`States, involving almost 40,000 women, the age-adjusted
`prevalence of OSD was 9.8% in women older than
`75 years.1
`The higher prevalence of OSD in our study has
`several possible explanations. We evaluated a specific
`population of clinic-based glaucoma patients within a
`tertiary referral practice. These patients may have more
`severe glaucoma and consequently may be treated with
`multiple preservative-containing eyedrops. Also,
`it
`is
`possible that some of these patients were even referred
`owing to OSD symptoms or
`signs. Whatever
`the
`explanations may be, our study demonstrates a high
`prevalence of OSD.
`It
`is
`important
`to emphasize,
`however, that our results may not be extrapolated to
`unselected populations of patients with glaucoma, and
`
`FIGURE 2. Agreement on the results obtained by the 3 clinical
`tests for diagnosing signs of dry eye disease.
`
`DISCUSSION
`A high prevalence of symptoms and signs of OSD
`were found in a population of patients with glaucoma or
`ocular hypertension. There is a lack of widely accepted
`criteria for diagnosing OSD. Several studies have relied
`only on reports of symptoms to diagnose the condition.
`The OSDI questionnaire was designed as a screening
`survey to assess symptoms and their impact on vision-
`related functions.14 This questionnaire has been reported
`to have excellent test-retest reliability and to effectively
`
`FIGURE 3. Relationship between the presence of symptoms as
`assessed by the Ocular Surface Disease Index questionnaire
`and the results of the Schirmer, lissamine green staining, and
`tear break-up time tests.
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`Leung et al
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`J Glaucoma  Volume 17, Number 5, August 2008
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`TABLE 2. Results of Multivariate Logistic Regression Models for the Association Between Abnormal Results on the OSDI
`Questionnaire and on the Clinical Tests of Dry Eye Disease
`
`Variable
`
`Number of BAK-containing eyedrops
`(per additional medication)
`Age (per year)
`Sex (female)
`
`OSDI Odds Ratio
`(95% CI)
`
`Schirmer Test Odds Ratio
`(95% CI)
`
`Lissamine Green Staining
`Odds Ratio (95% CI)
`
`TBUT Odds Ratio
`(95% CI)
`
`1.42 (0.84 to 2.41)
`
`0.81 (0.49 to 1.35)
`
`2.03 (1.06 to 3.89)
`
`0.60 (0.32 to 1.14)
`
`1.06 (0.75 to 1.81)
`0.82 (0.35 to 1.91)
`
`1.26 (0.89 to 1.79)
`0.52 (0.22 to 1.23)
`
`1.29 (0.80 to 2.09)
`3.92 (1.41 to 10.92)
`
`1.24 (0.82 to 1.89)
`2.86 (0.86 to 9.47)
`
`A multivariate model was constructed for each test (OSDI, Schirmer test, lissamine green staining, TBUT), using the result of the test (abnormal versus normal) as the
`dependent variable, and the number of BAK-containing eyedrops, age, and sex as independent variables.
`CI indicates confidence interval.
`
`future studies should investigate OSD prevalence in this
`situation.
`In our study, we also investigated the relationship
`between the use of BAK-containing eyedrops and OSD
`symptoms and signs. A deleterious effect of BAK has
`been demonstrated both in vitro as well as in vivo.11 A
`concentration of 0.007% of BAK induces a lysis of 50%
`of cultured epithelial cells in less than 2 minutes.19
`Numerous reports have demonstrated that prolonged
`use of topical ocular medications preserved with BAK
`may exacerbate symptoms and signs associated with OSD
`and have adverse effects on the conjunctiva and cornea.
`These effects include the induction of subclinical inflam-
`mation, reduction of corneal epithelial barrier function,
`destabilization of the tear film, and an overall higher
`incidence of patient complaints of dryness and irritation
`in users of BAK-containing eyedrops.11 BAK exerts its
`damaging action mainly through a direct cytotoxic
`mechanism, accentuated by the cumulative effect of
`repeated administrations of preserved eyedrops.20 In our
`
`study, we found that the use of more BAK-containing
`eyedrops was significantly associated with a higher
`prevalence of abnormal results on the lissamine green
`test. In other words, patients using more BAK-containing
`eyedrops had more staining of their corneal/conjunctival
`surfaces,
`indicating the presence of OSD, even after
`adjustment for age and sex. Such a positive relationship
`was not observed for the other OSD clinical tests. This
`may be due to the lack of specificity of the Schirmer test
`and TBUT for diagnosing OSD. Our results agree with
`those of Pisella et al21 showing that symptoms and signs
`of OSD are more prevalent in glaucoma patients using
`preservative-containing eyedrops compared with patients
`using preservative-free eyedrops. It is important to note,
`however, that the cross-sectional design of our study does
`not allow one to state conclusively that the use of BAK-
`containing eyedrops is the cause of OSD in our patients.
`Our study has limitations. We were not able to
`evaluate the relationship between the type of medication
`and duration of therapy with clinical signs and symptoms
`
`FIGURE 4. Relationship between the number of benzalkonium chloride-containing eyedrops and the results of the Ocular Surface
`Disease Index questionnaire (A), Schirmer test (B), lissamine green staining (C), and tear break-up time (D).
`
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`J Glaucoma  Volume 17, Number 5, August 2008
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`Prevalence of Ocular Surface Disease in Glaucoma Patients
`
`of OSD. Many patients were referred while already on
`topical medications and it was difficult to ascertain the
`duration of therapy. Also, patients used different types
`of medications for different periods of time during the
`course of therapy. Moreover, some patients switched
`from one medication to another during treatment.
`Therefore, any attempt to correlate the types of medica-
`tions and duration of therapy with signs and symptoms of
`OSD would likely be inappropriate in this sample. Our
`study also did not have a control group that could have
`been useful to provide further insight into the relationship
`between the use of BAK-containing eyedrops and OSD.
`Further studies are required to evaluate this issue.
`In conclusion, our study indicates a high prevalence
`of symptoms and signs of OSD in patients with glaucoma
`or ocular hypertension. The coexistence of OSD and the
`use of BAK-containing medications may impact
`the
`vision-related quality of life.
`
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