Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : October 24, 2022
Accepted : November 11, 2022
Published online : December 31, 2022
doi:10.24659/gsr.9.4_194

Original article

Subjective symptoms of glaucoma patients treated with topical medication
Manami Kuze 1), Masahiko Ayaki 2)
1) Department of Ophthalmology, Matsusaka Central Hospital, Matsusaka, Mie, Japan
2) Otake Eye Clinic, Yamato, Kanagawa, Japan

Abstract

Objective: The purpose of this study is to investigate the association between the frequency of ocular symptoms andlaboratory values in glaucoma patients undergoing ophthalmic topical medication.
Methods: A multivariate analysis was conducted to examine the association between major ocular symptoms (eye strain,
blurred vision, photophobia, dryness, discomfort, and pain) and laboratory findings related to glaucoma and dry eye in 1,000
patients (mean age 67. 5 years, 493 males) undergoing antiglaucoma eyedrops. The frequency of ocular symptoms during thesame period and for the same age group was also obtained.
Results: 37.3 % of the glaucoma group had any of the major ocular symptoms, and the percentages of patients with ocularsymptoms were eye strain in 22.9 %, blurred vision in 23.0 %, photophobia in 13.1%, dryness in 17.9 %, discomfort in 14.8 %,and pain in 6.3 %. These frequencies were less frequent than in all 1, 804 patients aged 60 - 69 years (mean 64.9 years) seenin the same period. Test values were associated with symptoms: mean deviation (MD) values for visual field were associatedwith eye strain (β = 0.073, p = 0.034), photophobia ( β = - 0.0720, p = 0.036), and pain (β = - 0.074, p = 0.033) and macular
ganglion cell layer thickness was weakly associated with pain (β = - 0.0872, p = 0.0342).
Conclusion: The subjective symptoms of glaucoma patients are weakly and infrequently associated with test values,
suggesting that topical medication is safely administered. Concurrently, adherence to periodic examinations and topical
medication is a concern, so it is important to explain the condition and treatment carefully to increase adherence, even if
subjective symptoms are poor.

KEY WORDS: glaucoma, dry eye, topical medication, subjective symptoms
Introduction
In the Guidelines for Glaucoma Treatment (5th edition)
published by the Japanese Glaucoma Society in 2022, glaucoma
is defined as "a disease characterized by characteristic changes
in the optic nerve and visual field and functional andstructural abnormalities of the eye that can usually be correctedor suppressed by lowering the intraocular pressure sufficiently,"
and approximately 5 % of patients over 40 years old areconsidered to have glaucoma 1, 2). The disease is asymptomaticin the early stages, and as optic neuropathy progresses, visual
field constriction and visual impairment occur in the latestages, usually in a slow and irreversible manner. The formof glaucoma that causes glaucomatous optic neuropathy
with an intraocular pressure (IOP) always below 20 mmHg
is classified as normal tension glaucoma, which accounts
for about 80 % of glaucoma cases in Japan, and is not easily
detected by ordinary medical examinations 1, 2). Glaucoma
is an important health problem because it is a typical aging

disease with high frequency and is closely related to diabetes
and glycative stress 3). Diabetic patients are more susceptible
to glaucoma than healthy individuals due to a tendency towardhigher intraocular pressure and optic nerve fragility 4, 5).
Neovascular glaucoma is the most common form ofglaucoma associated with diabetes mellitus, and other forms
include lens-capsular glaucoma caused by mature cataracts.
Early detection and early treatment are important, and at thesame time, adherence is crucial, as lifelong hospital visits andtreatment are required. Studies have shown that glaucoma
patients have difficulty perceiving visual field abnormalities
because they are complemented by both eyes and adjusted
in the brain 6 - 8). Visual symptoms appear only in advanced
cases, whereas preservatives, an additive in antiglaucoma
eyedrops, cause ocular surface abnormalities 9, 10) and develop
as dry eye symptoms. Elderly patients are less likely to beaware of dry eye symptoms than younger patients 11).
Recent advances in diagnostic techniques and thedevelopment of topical medication have led to an increase

Corresponding to: Masahiko Ayaki MD, PhD
Otake Eye Clinic
521-8 Sjimotsuruma, Yamato Kanagawa 242- 0001 Japan
TEL : +81-46-278-0033 FAX : +81-46-278-0032
e-mail: mayaki@olive.ocn.ne.jp
Co-authors: Kuze M, manakuze@yahoo.co.jp

Glycative Stress Research 2022; 9 (4): 194 -198
(c) Society for Glycative Stress Research_ 19 4 _Glycative Stress Researchin the number of cases that are detected early and treatedwith prostaglandin monotherapy, and it has been reported
that many cases have few symptoms from glaucoma or dryeye 12). Although glaucoma is a serious disease occasionallyleading to blindness, the lack of symptoms and side effects
may make it difficult to motivate patients to continue regularcheckups and topical medication. In this study, we analyzed
subjective symptoms in 1,000 glaucoma patients undergoing
topical medication and reported new findings.

Methods
The subjects were 1,000 consecutive patients who visited
ophthalmology outpatient clinics at four clinics in the Chubu
and Kanto regions between January 2015 and December 2020,
with corrected visual acuity of 0.8 or better in both eyes andat least six months after the start of antiglaucoma eyedrops,
and were included in the glaucoma group. Subjective
symptoms were defined as eye strain, blurred vision,
photophobia, dryness, discomfort, and pain. These werethe most common symptoms among patients who visitedthe ophthalmology outpatient clinic for the first time. All
patients aged 60 to 69 years who visited the ophthalmology
outpatient clinic at the same time were also asked about their
symptoms.
Glaucoma-related examinations included visual acuity,
IOP, fundus, visual field (Humphrey ® perimetry, Carl Zeiss
Meditec, Inc, Dublin, CA, USA), and optical coherence
tomography (RS-3000, Nidek Co., Ltd, Gamagori, Aichi,
Japan). Corneal tear tests included corneal staining withfluorescein (classified as score 0 to 2 according to severity),
and tear break-up time (Tear Break-up time, BU T; cases
shorter than 5 seconds were considered as shortened cases).
Topical medication used was as follows. For
antiglaucoma eyedrops, prostanoid receptor agonists were0.005 % latanoprost, 0.004 % travoprost, 0.0015 % tafluprost,
0.03 % bimatoprost, 0.12 % isopropyl unoprostone, beta
blockers were 0.5 % timolol, 2 % carteolol, and combination
products were latanoprost/timolol, travoprost/timolol,
tafluprost/timolol, timolol/dorzolamide, timolol/brinzolamide,carteolol/dorzolamide. For dry eye eyedrops, hyaluronan
preparation was 0.1% hyaluronic acid, mucin secretagoquewere 0.3 % dicuafosol and 2 % levapamide, and steroid was
0.1 % fluorometholone.

Ethical standards
This study was approved by the Kanagawa Medical
Association (approved November 12, 2018, approval number
krec2059006), Shinseikai Toyama Hospital (approved
May 3, 2 015, approval number 150503 -1), Komoro
Kosei General Hospital (approved July 4, 2016, approval
number 2802), Tsukuba Central Hospital (approved June
1, 2018, approval number 180602), and the Ethics Review
Committee of Tsukuba Central Hospital (approved June 1,
2018, approval number 180602). This study was conductedin accordance with the " Declaration of Helsinki" and the" Ethical Guidelines for Medical Research Involving Human
Subjects".

Statistical analysis
Data from the right eye were used for statisticalanalysis, and the MD value of the visual field was the sumof the two eyes. Standardized partial regression coefficientswere calculated using ophthalmologic examination values
and contents of the topical medication as dependent variables
and ocular symptoms as independent variables, adjusted forage and sex, and correlations were examined. Symptoms
were divided into visual symptoms (eye strain, blurred vision,
photophobia) and non-visual symptoms (dryness, discomfort,pain). Statistical software StatFlex (Artec, Osaka, Japan) was
used.

Results
The mean age of the 1,000 glaucoma patients was 67. 5± 13.3 years, 493 were male, and antiglaucoma eyedrops
consisted of prostanoid receptor agonists in 85.1 %(latanoprost 54.1 %, tafluprost 14.0 %, travoprost 11.0 %,bimatoprost 6.0 %), beta-blockers in 18.1% (timolol 11.9 %,carteolol 6.2 %), and combination drugs in 9.7 %. Dry eye
topical medication consisted of hyaluronic acid, 28.6 %,dicuafosol 18.8 %, levapamide 1.0 %, and steroids 1.1%.
The mean equivalent spherical power was −2.44 ± 3.43
D, IOP was 13.37 ± 3.42 mmHg, MD of visual field was−7.38 ± 6. 4 7 dB, macular nerve fiber layer thickness was
76.34 ± 14.76 μm, peripapillary nerve fiber layer thickness
was 88.78 ± 19.50 μm, the number of glaucoma medication
averaged 1.4 ± 0.6 vial, and the frequency of glaucoma
medication per day was 1.8 ± 1.2. BUT was 3.86 ± 2.07
seconds (58.5 % of shortened cases), corneal staining score
was 0.43 ± 0.68.
In the glaucoma group, 37.3 % had any of the major
symptoms, and the percentages of patients with ocularsymptoms were eye strain in 22.9 %, blurring in 23.0 %,photophobia in 13.1%, dryness in 17.9 %, discomfort in
14.8 %, and pain in 6.3 %. All 1,804 patients aged 60 to 69
years (mean 64.9 ± 2.7 years, 777 males) in the same period
had subjective symptoms of eye strain in 28.1%, blurring in
24.6 %, photophobia in 18.6 %, dryness in 21.7 %, discomfort
in 19.7 %, and pain in 7.1%; BUT was 4.01 ± 2.08 seconds(55.9 % of shortened cases); corneal staining score was 0.26
± 0. 55.
Multivariate analysis showed that test values correlatedwith symptoms as follows: visual field MD and eye strain(β = 0.073, p = 0.034), photophobia (β = − 0.072, p =0.036), pain (β = − 0.074, p = 0.033), macular ganglion
cell layer thickness and pain ( β = − 0.087, p = 0.034), andprostaglandin analogues and pain (β = − 0.0851, p = 0.0123,
Table1 ). Visual symptoms were associated with peripapillary
optic ganglion cell layer thickness ( β = 0.099, p = 0.011)
and number of glaucoma topical medication (β = 0.073, p= 0.028); none were associated with non-visual symptoms.
There were 28.7% of dry eye topical medication users, whichcorrelated with dryness (β = 0.141, p = 0.003, Table 2).

_ 195 _

Subjective Symptoms of Glaucoma Patients treated with Topical Medication

Table 1. Correlation between ocular symptoms and glaucoma test values.

AgeSex
Eye strain
Blurred vision
Photophobia
Dryness
Discomfort
Pain
Visualsymptoms
Nonvisual
symptoms

MD A

Macularnerve fiber
layer thickness

Peripapillary
nerve fiber
layer thickness

Numberof glaucoma
medication

Frequencyof glaucoma
medication

Use ofprostaglandin
analogue- 0.1868< 0.0001*- 0.1106
0.0059- 0.1767< 0.0001*

0.00930.77800. 02210.5048-0.0050(0.8801)

0. 07370.0346 *0.04710.25620.06510.10770.01770.60380.02710.4287-0.0330(0.3342)0.08350.0134 *-0.0167(0.6200)- 0.01800.6001- 0. 0519
0.1297- 0.0720
0.0359 *0.05590.13950.01130.7599- 0.0739
0.0333 *- 0.0172
0.61220.01830.5907- 0.0101
0.8035- 0.0361
0.37700.0056
0.8923- 0.0843
0.0360 *0.04580.25630.00970.80910.00600.8571-0.0256
0.4 457

0. 01120.73820.00420.89980.10940.0012 *- 0.0249
0.5901- 0.0245
0.5867- 0.0872
0.0342 *- 0.0326
0.4538- 0.0686
0.0851- 0.02280.5008-0.00900.810 7
- 0.000 4
0.99 05- 0. 0151
0. 65 61

- 0.0766
0.0560- 0.0465
0.2320- 0.0069
0.8355- 0. 0105
0.75140.01330.74040.00640.8854-0.012 90.72970.01320.72000.09850.0113 *0.07280.0282 *0. 0630
0.05740.0324(0.3346)

0.0165(0.6238)-0.0277(0.4602)0.0305(0.4066)- 0.0851(0.0123 *)- 0.0279(0.3989)- 0.0433(0.1918)

Upper numbers indicate standardized partial regression coefficients, lower numbers indicate p values; *p < 0.05, adjusted for age and sex. A = sum of
MD values for both eyes in the Humphrey visual field meter 24-2 program. MD, mean deviation.

Table 2. Correlations between ocular symptoms and lacrimal corneal test items.

AgeSex
Eye strain
Blurred vision
Photophobia
Dryness
Discomfort
Pain
Visualsymptoms
Nonvisual
symptoms

Cornealstaining score

Tear break-up
time

0.03520.2779- 0.0072
0. 8217

Use ofdry eyemedication

History of
intra- ocularlens surgery

0.02630.54560.2465< 0. 0 0 01*-0.1773< 0.0001 *0.2423< 0.0001 *- 0.175 00.0001 *0.01170.9214- 0.01050.74 6 4- 0.0612
0.0618- 0.0 499
0.1722- 0.09 05
0. 0115 *- 0.0884
0. 0 074 *- 0.01000.7599- 0.1617< 0. 0 0 01*

0. 0337
0. 4 4 65

0.05600.6579-0.0651
0.59640. 0332
0.36740.10140.50 47- 0.0686
0.57960.02500.44620.1610< 0.0001*

0.04830.14 47

0. 0515
0. 2597- 0.0 488
0.13 42- 0.0 252
0. 4 472

0.03520. 4222- 0.0 49 00.13 41

0.0921
0.0516

0.0 057
0. 8723

0.14100.0030 *0.0 4 0 4
0.379 6

0.0 456
0.14 7 7

0.19 45< 0.0 0 01 *0.00940.774 00.019 4
0. 5950- 0. 0123
0.70 87- 0.0 427
0.1837

0.0 065
0.8 4 03

Upper numbers indicate standardized partial regression coefficients, lower numbers indicate p values; *p < 0.05,
adjusted for age and sex.

_ 19 6 _Glycative Stress Research

Discussion
Subjective symptoms of glaucoma patients under
topical medication were not strongly correlated withglaucoma-related items and were more strongly related todry eye-related tests. Also, compared to 60 ~ 69 year olds inthe same age group, BUT and corneal staining scores wereslightly poorer, but subjective symptoms were somewhat lessfrequent. In comparison, hyaluronic acid products were usedin 28.1%, mucin products (Dicuafosol and Levapamide)in 35.3%, and steroids in 9.4 % of the general outpatientsin the previous report 9) on dry eye treatment, and there
was a trend toward more hyaluronic acid products and lessmucin products and steroids. This may be due to the large
number of patients with mild disease and the objective ofcounteracting the side effects of antiglaucoma eyedrops,
which may have led to less aggressive treatment. These
results suggest that there is little increase in subjective
symptoms or abnormalities in lacrimal corneal findings
during glaucoma topical medication. This is consistent witha previous report that examined lacrimal corneal findings,
sleep disturbance, and mood disturbance in patients treatedwith glaucoma topical medication alone and found little
effect of topical medication 12).
There is no strong correlation between glaucoma test
values and subjective symptoms, and there are three possible
reasons: patients are older 10), glaucoma is a mild disease, andantiglaucoma eyedrops have fewer side effects. The mean
IOP was well controlled at 13.37 mmHg with an averageof 1. 4 topical medication and an average of 1.8 drops perday, indicating that the treatment was effective enough withminimal medication and few side effects. This may be dueto the fact that prostanoid receptor agonists, which require
only once-daily topical medication, were used in most cases(85.1%), and their strong IOP-lowering effect and minimal
number of topical medication may have contributed to thegood results. The results of this study were based on a large
number of cases, and it seems safe to assume that recent
antiglaucoma eyedrops are generally being implemented
without problems. Concurrently, adherence to periodic
checkups and topical medication is a concern, and it isimportant to explain the condition and treatment carefully
to increase adherence, even if subjective symptoms are notapparent.
The main problem with antiglaucoma eyedrops is side
effects related to the ocular surface, such as discomfort in
the eye area due to dry eye symptoms, hyperemia, and eye
pain 13). These are believed to be largely due to the additive
benzalkonium chloride 10, 13, 14). Benzalkonium chloride
is used as a preservative in most ophthalmic eyedrops atconcentrations ranging from 0.001 % to 0.02 %. Because of
the interaction with the main drug, numerous cytotoxicity
studies with topical medication have been conducted, andeye drops with lower concentrations of benzalkonium
chloride or with preservatives other than benzalkonium
chloride have lower cytotoxicity 15). However, when patientsactually experience subjective symptoms, factors on the
drug side include the nature of the main drug, the number ofdrops, the number of drops, and factors on the patient side
include the cornea, conjunctiva, eyelid, blinking eye, tearfluid, and adherence. In particular, the recently frequently

used brimonidine has a strong effect on the ocular surface
and eyelids, which may impair the continuation of topical
medication 16). In addition, many glaucoma patients are
elderly, and it is necessary to be aware of the development of
meibomian gland dysfunction caused by topical medication 17).
In the present case, only prostanoid receptor agonists,
β-blockers, and carbonic anhydrase inhibitors, which havebeen used in many cases without problems, were used, so
there may have been few complaints of subjective symptoms.
Diabetes mellitus is a representative disease with highglycative stress and various ocular complications such as
retinopathy, cataract, keratopathy, glaucoma and neuropathy.
With the onset of age-related macular degeneration and dryeye, which are ocular diseases that increase with age, thenumber of cases of multiple ocular complications is expected
to increase with age. Dry eye caused by topical medicationis also expected to be more likely to occur in the elderly anddiabetic patients 18). On the other hand, there is a reality inwhich subjective symptoms are scarce in the elderly despite
the presence of multiple diseases. As a result, we should beaware of the potential progression of glaucoma.
Two types of glaucoma closely related to diabetes
mellitus are neovascular glaucoma and lens cystic glaucoma.
The latter type of glaucoma originates in the lens andinvolves glycosylation of lens proteins (crystallins), while theformer is caused by proliferative membranes and pathologicalangiogenesis due to proliferative diabetic retinopathy and the
production of vascular endothelial growth factor (VEGF).
When diabetes causes impaired blood flow or ischemia in
the retina, retinal cells such as vascular endothelial cells,
amacrine cells, retinal ganglion cells, and müller glia cells
in the non-perfused region produce VEGF 19 - 22). From theviewpoint of glycative stress, it is possible that excessive
AGEs production may induce increased secretion of VEGF
and various inflammatory cytokines via stimulation of
RAGE on retinal cells. The mechanism of the effects ofglycative stress on glaucoma should be elucidated.

Research issues
The problem of this study is that future measurementsof quality of life and neuropsychiatric function would allow
for a more detailed assessment of the life and psychologicalimpact of glaucoma. Furthermore, comparisons with before
treatment can be made to clarify the effects of glaucoma
notification and treatment on patients. Although there aresome problems, a sufficient number of cases have beenstudied and compared with a control group, so it is thoughtthat certain findings have been obtained.

Conclusion
In patients undergoing antiglaucoma eyedrops, bothvisual symptoms due to glaucoma and non-visual symptoms
due to dry eye were generally unremarkable. In the treatmentof glaucoma patients undergoing ophthalmic treatment, it isimportant to recognize that patients' subjective symptoms areoften mild, and to explain test data, periodic examinations,and the purpose and significance of treatment in detail, in_ 19 7 _Subjective Symptoms of Glaucoma Patients treated with Topical Medication

order to improve and maintain adherence. We did not analyze
from the viewpoint of glycative stress in this study, but would
like to do so in the future.

Acknowledgments
The authors are indebted to Dr. Naohisa Nezu, Dr.
Kazuo Takei, Dr. Naoko Tachi, and Dr. Yoshihiro Hashimoto
for their cooperation. We are deeply grateful to Dr. Mico
Arai, orthoptist, Dr. Akiko Murakami, orthoptist, andDr. Hiroshi Yada, optometrists.

Conflict of interest declaration
There are no conflicts of interest regarding this study.

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