Ocular Surface Disease and Glaucoma: How to Evaluate Impact on Quality of Life

Abstract

Purpose:

To record signs and symptoms of ocular surface disease (OSD) in patients treated with Intra Ocular Pressure (IOP)-lowering medications; to evaluate the relationship between signs and symptoms; and to identify how to diagnose and follow OSD and its impact on the quality of life in such patients.

Methods:

A prospective observational study of enrolled consecutive topically treated open-angle glaucoma or ocular hypertension patients: patients presenting systemic or ocular conditions that could interfere with ocular surface status were excluded. Enrolled patients underwent a complete ophthalmic examination comprehensive of evaluation of tear film break-up time (TF-BUT) and fluorescein corneal staining (keratitis punctatae) and who completed the Italian version of both the National Eye Institute-Visual Function Questionnaire (NEI-VFQ) 25 and the Glaucoma Symptom Scale (GSS) questionnaires.

Results:

233 patients adhered to a study protocol. Punctatae keratitis was detected in 70 (30%) eyes; abnormal TF-BUT in 67 (28.8%) patients: 97 patients (42.1%) presented an OSD. The abnormal values were gender-independent, keratitis was statistically related to age (P=0.01) and number of instillations/die (P=0.0007). TF-BUT was related to the IOP value (P<0.0001). The NEI ocular pain subscale was statistically related to TF-BUT (P=0.017); GSS was both related to TF-BUT and punctatae keratitis (P<0.00001).

Conclusions:

Many patients present an OSD related to therapy, and this affects their quality of life. The use of fixed combinations to reduce surface exposition and of benzalkonium chloride-free formulations should be encouraged to reduce and contain the onset or worsening of this secondary condition in glaucoma patients. The GSS has shown a good relation to signs and should be routinely used to evaluate the impact of OSD on the quality of life.

Introduction

The Report of the International Dry Eye Workshop (DEWS) referred that dry eye syndrome (DES) is one of the most prevalent eye diseases and reasons for seeking eye care among older people.¹ A review of the epidemiology of dry eye, based on data from the largest studies of dry eye, suggested that its prevalence lies in the range of 5%–30% of the population aged 50 years and older.¹ The Beaver Dam cohort study found that the overall prevalence of dry eye was 14.4%, ranging from 8.4% in subjects younger than 60 years to 19.0% in those older than 80 years.² The DEWS defined the dry eye as a “multifactorial disease of the tears and ocular surface resulting in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.”

The DEWS classified dry eye as caused by decreased tear secretion or by increased evaporation (by intrinsic or extrinsic causes). There are many extrinsic causes of increased tear evaporation: the prolonged use of preserved topical drugs is one of these, inducing an immunologic and/or toxic response from the ocular surface.³

Glaucoma patients are therefore at risk to develop DES/ocular surface disease (OSD) at least for 2 reasons: (1) open angle glaucoma (OAG) is typically a disease of the elderly, (the prevalence of OAG in people over 40 years is 2.1% (95% CI 1.7 to 2.5), and ranges from 0.3% (95% CI 0.1 to 0.5) in people aged 40 years to 3.3% (95% CI 2.5 to 4.0) in people aged 70 years⁴; and (2) glaucoma patients are usually chronically treated with preserved topical drugs since, to date, only few intraocular pressure (IOP)-lowering drugs are available as preservative free.

Recent studies, in fact, have pointed out that patients with ocular hypertension (OHT) and primary OAG (POAG) have been shown to suffer OSD in a higher prevalence than in a normal population.^5–8

The concomitant presence of the 2 conditions (POAG/OHT and OSD) may impact on the quality of life perception.^7,8

The main purposes of this study were to record symptoms of OSD in chronically treated glaucoma/OHT patients and to identify the relationship, if any, between signs and symptoms to know how to evaluate the impact of OSD on glaucoma patients' quality of life.

Methods

This was an observational, cross-sectional study. It was carried out at the University Eye Clinic of Pavia in accordance with the Declaration of Helsinki after approval by the Local Ethics Committee. All patients were recruited consecutively during a regular follow-up visit: topically treated glaucoma (POAG, pseudoexfoliative, pigmentary) or OHT patients were enrolled and all subjects gave written informed consent before enrollment.

The diagnosis of glaucoma required: presence of glaucomatous optic nerve head (ONH) confirmed by an expert fundus examination and at least 3 reliable Humphrey 24-2 full threshold visual field tests performed on different days showing a glaucomatous or suspected glaucomatous defect.

The diagnosis of OHT required: IOP >21 mmHg on at least 2 consecutive visits at the time of first diagnosis, absence of glaucomatous ONH confirmed by an expert fundus examination and at least 3 normal reliable Humphrey 24-2 full threshold visual field tests performed on different days.

To be eligible, patients needed to be 18 years of age or older; to be topically treated with benzalkonium chloride-preserved IOP lowering medications; and to be able to read and complete 2 questionnaires, the 25 item National Eye Institute-Visual Function Questionnaire (NEI-VFQ 25) and the Glaucoma Symptoms Scale (GSS), in their Italian version.^9,10

Patients presenting systemic or ocular conditions (such as rheumatoid arthritis; Sjogren Syndrome; rosacea; infectious disease; previous glaucoma, conjunctival, or corneal surgery …) that could interfere with ocular surface status were excluded.

Qualified patients were submitted to an anterior segment evaluation comprehensive of some ocular surface status examinations (described below), IOP measurement, and optic nerve evaluation; and completed 2 quality of life questionnaires (1 generic and 1 eye specific) during the same visit. Both questionnaires were completed before the visit with the Ophthalmologist to avoid interference with visit results.

The 25-item NEI-VFQ is a vision-targeted nondisease-specific instrument designed to measure the impact of some ocular disorders on vision-related quality of life. The scoring procedure for the NEI-VFQ 25 converts the precoded numeric values of items to a score from 0 to 100, higher scores always reflecting better health-related quality of life. This questionnaire includes 12 subscales: general vision, difficulty with near-vision activities, difficulty with distance-vision activities, limitations in social functioning due to vision, role limitations due to vision, dependency on others due to vision, mental health symptoms due to vision, driving difficulties, limitations with peripheral and color vision, ocular pain (OP), and general health.⁹

The GSS includes 10 ocular complaints, some of nonvisual nature (burning/smarting/stinging, tearing, dryness, itching, soreness/tiredness, feeling of something in the eye: GSS Symptom score) and some of visual nature (blurry/dim vision, hard to see in daylight, hard to see in dark places, halos around lights: GSS Function score), common among patients treated for glaucoma. For each eye, the questionnaire provides a score ranging from 0 to 100, with 0 representing presence of a very bothersome problem and 100 representing absence of a problem. The final GSS score is an unweighted average of the responses to all 10 items; the GSS subscale Symptom score (Symp-6) is an unweighted average of all items that comprise the particular subscale.¹⁰

The OP scale and the general mean score for the NEI-VFQ 25 and the Symp-6 score for the GSS have been considered for the statistical analysis.

About signs, according to the literature,^11,12 the presence of OSD was recorded by the concomitant reduced fluorescein tear film break-up time (TF-BUT) and the presence of punctate keratitis.

Tear film stability was assessed using the fluorescein TF-BUT method. A drop of 2% fluorescein was instilled and the patient asked to blink several times. The time required for the first area of TF-BUT to appear after a complete blink was determined using the cobalt blue filter on the slit lamp biomicroscope. The lower (worse) score of the average of 2 readings of both eyes for each individual was used for analysis. TF-BUT values greater than or equal to 10 s were coded as normal and TF-BUT values less than 10 s as abnormal.^13,14

The presence of corneal surface damage was determined by staining the cornea with fluorescein. The presence of corneal staining was defined as more than one dot of fluorescein staining over the corneal surface. Superficial punctate keratitis was graded according to a 4-degree staining scale by determining the density of the lesion¹⁵ on a 0→3 scale, where 0 is absence of keratitis punctatae, 1=Mild (a few punctatae of staining, but less than 10% coverage of the corneal surface; 2=Moderate (10%–50% coverage of the corneal surface); and 3=Severe (more than 50% coverage of the corneal surface).

The same observer, blinded to current therapy, performed the fluorescein staining and the break-up time to minimize the variability of these evaluations.

The presence of OSD was defined as the concomitant presence of TF-BUT<10 s and the presence of superficial punctate keratitis.

For each subject, date of birth, gender, and race were recorded. For each eye, the number of instillations per day, the number of years of topical treatment, and the IOP value in mmHg were collected.

The functioning (visual field, function-related quality of life) was not considered because the expected range of function loss due to dry eye was narrow in this study (all selected patients had best corrected visual acuity of 0.8 in the worst eye).

Statistical analysis

Descriptive statistics were produced for demographic, clinical, and laboratory characteristics of cases. Mean and standard deviation (SD) are presented for normally distributed variables, and median and interquartile range for non-normally distributed variables. For group comparison (in particular, to compare patients with and without OSD, abnormal BUT, and keratitis), parametric (Students') or nonparametric (Mann–Whitney) tests were used according to data distribution, for continuous variables (age, NEI, OP, subscale, GSS symptom score, IOP, etc.); the Pearson's χ² test (the Fisher's exact test where appropriate) for categorical variables. Correlation between symptoms and signs was assessed by means of the Spearman's correlation coefficient.

Results are reported for 1 eye only, since results for the other are very similar.

Results

233 patients completed the study. Most patients suffered from POAG (184 subjects, 78.9%), 37 patients (15.8%) presented OH, 6 (2.6%) pseudoexfoliation; 5 (2.2%) normal tension glaucoma and 1 (0.4%) pigmentary glaucoma. Examined patients were regularly followed from (mean±SD) 5.2±5.1 years.

Women totaled 144 (61.8%). All selected patients were Caucasian. Mean age was 68.7±11.8 years; mean IOP was 17.4±3.9 mmHg, mean visual acuity was 0.88±0.24 decimals.

166 (71.5%) patients were on a single medication [89 (38.2%) patients on beta-blockers; 42 (18%) on beta-blocker/carbonic anhydrase inhibitor fixed combination; 28 (12.2%) on prostaglandin analogues, 5 (2.2%) on beta-blocker/prostaglandin fixed combination, and 2 (0.9%) on alpha-agonist]; 26 (11.2%) on 2; 7 (3%) on 3; and 1 (0.4%) on 4.

Table 1 reports comparisons between patients with and without OSD, abnormal BUT, and keratitis. Overall, TF-BUT was abnormal in 67 (28.7%) eyes, independently of age (P=0.921) and gender (P=0.66), but related to IOP (P<0.0001). Patients with abnormal BUT present significantly worse OP and GSS score (P=0.017 and <0.001, respectively).

Table 1.

Comparison of Patients with Ocular Surface Disease Versus no Ocular Surface Disease, with Abnormal Versus Normal Tear Film Break-up Time, and with Present Versus Absent Punctate Keratitis in Terms of Demographic, Clinical, and Quality of Life Characteristics

	OSD			TF-BUT			Punctate keratitis
Variables	Present N=97	Absent N=136	P-value	Abnormal N=67	Normal N=166	P-value	Present N=70	absent N =163	P-value
Age (mean±SD) (years)	70.3±9.4	67.7±12	0.204	68.6±11.7	68.7±12	0.921	71.9±10	67.3±12.3	0.01
Gender: females n (%)	60 (41.6)	84 (58.3)	0.55	43 (29.9)	101 (70.1)	0.66	45 (31.2)	99 (68.7)	0.79
Intraocular pressure (mmHg) (mean±SD)	16.2±3.8	17.8±3.7	0.001	15.7±3.2	17.9±3.7	<0.001	16.9±3.7	17.4±3.7	0.24
Number of daily instillation (median [IQR])	2 [2–3]	2 [1–2]	0.083	2 [1–3]	2 [2–2]	0.52	2 [2–3]	2 [1–2]	0.0007
TF-BUT (sec) (median [IQR])	6 [4–7]	10 [9–12]	<0.001	NA	NA	NA	6 [5–10]	10 [8–11]	<0.001
Punctate keratitis (0–4 grade) (Median [IQR])	2 [1–2]	0 [0–0]	<0.001	1 [0–2]	0 [0–0]	<0.001	NA	NA	NA
Years since topical therapy started (years) (median [IQR])	12 [10–15]	2 [1–4]	0.0000	10 [1–14]	3 [1–5]	0.0001	10 [9–15]	2 [1–4]	<0.001
NEI-VFQ ocular pain	77.5±19	81.5±18	0.120	72.1±20.5	78.7±15.3	0.017	76±19.3	77.5±20	0.68
NEI-VFQ total mean	80.1±14.2	87.2±24.7	0.045	78.7±15.3	85.9±24.2	0.056	79.1±15.1	84.5±23.2	0.14
GSS symptom scale	57.6±23.1	75.9±19	<0.001	59.9±23.2	73.4±19.7	<0.001	58.2±22	73.7±20.1	<0.001

OSD, ocular surface disease; TF-BUT, tear film break-up time; IQR, interquartile range; NEI-VFQ, National Eye Institute-Visual Function Questionnaire; GSS, Glaucoma Symptom Scale.

Punctatae keratitis was present in 70 (30%) patients: 43 (18.4%) patients presented grade 1 keratitis, 24 (10.3%) grade 2, and 3 (1.3%) grade 3. The presence of punctatae keratitis was gender-independent (P=0.79), but was related to age (P=0.01) and to the number of instillations per day (P=0.0007). Patients with keratitis presented significantly worse GSS (P<0.001).

OSD was present in 97 (41.6%) patients with no difference by gender (P=0.550) and age (P=0.204). OSD was statistically related to the amount of years of topical treatment (P<0.0001) and to the IOP value (P=0.001).

Regarding symptoms, patients with OSD present significantly worse total mean NEI and GSS score (P=0.045 and <0.001, respectively).

Correlation between symptoms and signs is reported in Table 2. Briefly, symptoms were all moderately, but significantly, related to each other; TF-BUT was fairly correlated to NEI-VFQ OP, NEI-VFQ total mean and GSS, while keratitis was not correlated to any.

Table 2.

Spearman's Correlation Coefficient (P-value) for Correlation Between Symptoms and Signs

	NEI-VFQ ocular pain	NEI-VFQ total mean	GSS symptom scale	Keratitis right eye	Keratitis left eye	TF-BUT right eye
NEI-VFQ total mean	0.59 (<0.001)
GSS symptom scale	0.70 (<0.001)	0.45 (<0.001)
Keratitis right eye	−0.10 (0.34)	−0.24 (0.02)	−0.14 (0.17)
Keratitis left eye	−0.03 (0.79)	−0.13 (0.19)	−0.10 (0.33)	0.83 (<0.001)
TF-BUT right eye	0.25 (0.01)	0.26 (0.01)	0.24 (0.02)	−0.41 (<0.001)	−0.36 (0.00)
TF-BUT left eye	0.23 (0.02)	0.25 (0.01)	0.21 (0.04)	−0.41 (<0.001)	−0.42 (<0.001)	0.93 (<0.001)

Discussion

OSD is one of the most prevalent eye diseases and reasons for seeking eye care among older people.¹ A recent review of the prevalence of OSD in glaucoma/OHT patients, based on data from the latest studies, pointed out that 42% (lying in the range of 20%–59%) of the glaucoma population presented OSD, that is severe in 36% (range: 14%–66%).¹⁶

Literature has therefore confirmed that glaucoma and OHT patients often develop OSD: these concomitant conditions must be investigated and searched to reduce patient's discomfort due to OSD onset.

Data from the present study recorded an OSD in 42.1% of our patients, according with published data. In 2006, Tsai et al. observed that the prevalence of glaucoma in patients with severe OSD was 66%.⁵ Leung et al. in 2008 found that 59% of glaucoma patients reported symptoms of dry eye.⁶ Rossi in 2009⁷ and Fechtner in 2010⁸ found a high prevalence of OSD among medically treated glaucoma patients (27.8%, but 40% in patients taking 2/3 drugs and 48%, respectively). The high prevalence of this disease suggests that the routine evaluation of the ocular surface should become mandatory in patients assuming topical therapies to control IOP values.

The logistic regression analysis has pointed out that a particular attention should be focused on those patients treated from long time and with more benzalkonium chloride (BAK) preserved instillations per eye. This finding confirms the importance to reduce the exposition of the ocular surface to topical therapies prescribing, when available, BAK-free medications and fixed combinations; and also suggests considering different therapeutic options (laser/surgery) when a patient is young and therefore will need treatment for a long period.

Our main question was: how can we easily diagnose OSD and its impact on the quality of life in glaucoma subjects in the routine clinical practice? Previous literature underlined an apparent lack of association between measured signs and recorded symptoms^17,18 since patient's self-assessment of OSD severity may differently relate to objective signs: However, the symptom score of the GSS, in the present study, has shown to be a valid tool to detect the impact of OSD on glaucoma patients since it has revealed a significant relationship to all objective signs. There are different questionnaires to examine the quality of life in glaucoma patients¹⁹ or in subjects suffering from OSD¹: in our clinic, we routinely use the GSS for several years. The simplicity, brevity, and psychometric properties of the GSS support its use in clinical practice and research to quantify symptoms in patients with glaucoma.

We want to add some considerations.

1. About our prevalence's results, the present study had some limits that could have affected findings:

a. patients were old, but glaucoma is typically a disease of the elderly,⁴ and we have excluded all those patients with known anterior segment ocular diseases

b. all subjects were treated with BAK-preserved eye drops, but to date, only a few medications are available as preservative free, at least in Italy.

2. About the signs/symptoms relationship it must be underlined that the GSS symptom score appeared to be the better tool in this study, but this observation must be confirmed in further studies with a larger population.

In conclusion, since glaucoma is a chronic condition that may impact on patients' quality of life by itself, glaucoma specialists should avoid any further condition that could negatively impact on these patients. OSD have been widely demonstrated to be more frequent in glaucoma patients treated for long periods with IOP-lowering medications containing BAK as a preservative; since the onset of OSD may worsen patients' quality of life, this further condition must be searched and treated as possible in all glaucoma and OHT patients. Based on study results, authors recommend to perform corneal staining and TF-BUT; and to submit GSS questionnaire to all glaucoma patients at each follow-up visit in the waiting room before the eye visit to take care of the impact of primary and secondary diseases on our patients' quality of life perception. The use of a questionnaire may also help record a patient's perception of ocular discomfort in a reproducible and repeatable way.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Report of the International Dry Eye Workshop (DEWS). The epidemiology dry eye disease. Ocul. Surf., 5:27–41. 2007.

Moss

S.E.

, Klein

B.E.

Prevalence of and risk factors for dry eye syndrome. Arch. Ophthalmol., 118:1264–1268. 2000.

Baudouin

, Pisella

P.J.

, Fillacier

et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology, 106:556–563. 1999.

EGS classification and terminology. Terminology and guidelines for glaucoma, 3rd. Savona: Dogma, 2008; 95–96.

Tsai

J.H.

, Derby

, Holland

E.J.

, Khatana

A.K.

Incidence and prevalence of glaucoma in severe ocular surface disease. Cornea, 25:530–532. 2006.

Leung

E.W.

, Medeiros

F.A.

, Weinreb

R.N.

Prevalence of ocular surface disease in glaucoma patients. J. Glaucoma., 17:350–355. 2008.

Rossi

G.C.

, Tinelli

, Pasinetti

G.M.

et al. Dry eye syndrome-related quality of life in glaucoma patients. Eur. J. Ophthalmol., 4:572–579. 2009.

Fechtner

R.D.

, Godfrey

D.G.

, Budenz

et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure–lowering medications. Cornea, 29:618–621. 2010.

Rossi

G.C.M.

, Milano

, Tinelli

The Italian version of the 25-item National Eye Institute Visual Function Questionnaire: translation, validity and reliability. J. Glaucoma., 12:213–220. 2003.

10.

Rossi

G.C.

, Pasinetti

G.M.

, Scudeller

et al. The Italian version of the Glaucoma Symptom Scale questionnaire: translation, validation and reliability. J. Glaucoma., 2012; 21[Epub ahead of print]10.1097/IJG.0b013e318225406c.

11.

Report of the International Dry Eye Workshop (DEWS). The definition and classification of dry eye disease. Ocul. Surf., 5:75–92. 2007.

12.

Korb

D.R.

Survey of preferred tests for diagnosis of the tear film and dry eye. Cornea, 19:483–486. 2000.

13.

Nichols

K.K.

, Nichols

J.J.

, Zadnik

Frequency of dry eye diagnostic test procedures used in various modes of ophthalmic practice. Cornea, 19:477–482. 2000.

14.

Pflugfelder

S.C.

, Tseng

S.C.

, Sanabria

, Kell

, Garcia

C.G.

, Felix

, Feuer

, Reis

B.L.

Evaluation of subjective assessment and objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irritation. Cornea, 17:38–56. 1998.

15.

Bron

A.J.

, Evans

V.E.

, Smith

J.A.

Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea, 22:640–649. 2003.

16.

Stewart

W.C.

, Stewart

J.A.

, Nelson

L.A.

Ocular surface disease in patients with ocular hypertension and glaucoma. Curr. Eye Res., 36:391–398. 2011.

17.

Begley

C.G.

, Chalmers

R.L.

, Abetz

et al. The relationship between habitual patient-reported symptoms and clinical signs among patients with dry eye of varying severity. Invest. Ophthalmol. Vis. Sci., 44:4753–4761. 2003.

18.

Nichols

K.K.

, Nichols

J.J.

, Mitchell

G.L.

The lack of association between signs and symptoms in patients with dry eye disease. Cornea, 23:762–770. 2004.

19.

Severn

, Fraser

, Finch

, May

Which quality of life score is best for glaucoma patients and why?

BMC Ophthalmol., 8:2. 2008.