CLINICAL SCIENCE
Eyelid Changes Related to Meibomian Gland Dysfunction in
Early Middle-Aged Patients Using Topical Glaucoma
Medications
Ji Hong Kim, MD,*† Yong Un Shin, MD, PhD,*† Mincheol Seong, MD, PhD,*†
Hee Yoon Cho, MD, PhD,*† and Min Ho Kang, MD, PhD*†
Purpose: To investigate the relationship between topical glaucoma
medications and meibomian gland dysfunction (MGD) in early
middle-aged patients with glaucoma.
Methods: In this cross-sectional study, 50 patients with glaucoma
younger than 50 years who had used topical glaucoma medications
for more than 6 months and 40 normal controls of similar age were
included. Patients in each group were graded for MGD (0–4) using
slit-lamp microscopy. Tear film breakup time (BUT), ocular surface
staining, and Marx line scores were also evaluated. Differences
between both groups were analyzed statistically.
Results: The prevalence of MGD was 82% in the group using
topical glaucoma medications and 52.5% in the control group. The
average period of topical glaucoma medication use was 27.4 months.
There were significant differences in the breakup time and Marx line
score according to the presence of MGD. Although the duration of
topical glaucoma medication use and the severity of MGD did not
show a significant correlation, the degree of MGD and the Marx line
score were significantly correlated.
Conclusions: Glaucoma eye drops may be one factor affecting the
eyelid changes associated with MGD. The Marx line score may be
used as an index to evaluate MGD in patients with glaucoma.
Key Words: meibomian gland dysfunction, glaucoma, dry eye
syndrome
(Cornea 2017;0:1–5)
M eibomian gland dysfunction (MGD) is a chronic,
diffuse abnormality of the meibomian glands, com-
monly characterized by obstruction of the terminal ducts and
qualitative/quantitative changes in glandular secretion.1,2 As
a primary cause of evaporative dry eye, MGD causes eye
discomfort, tear film changes, and ocular surface disease.3
Received for publication September 11, 2017; revision received October 30,
2017; accepted October 31, 2017.
From the *Department of Ophthalmology, Hanyang University College of
Medicine, Seoul, Korea; and †Department of Ophthalmology, Hanyang
University Guri Hospital, Guri, Korea.
The authors have no funding or conflicts of interest to disclose.
Reprints: Min Ho Kang, MD, PhD, Department of Ophthalmology, Hanyang
University Guri Hospital, #153 Gyeongchun-ro, Guri 19923, Korea
(e-mail: ocularimmunity@gmail.com).
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Ophthalmic factors, aging, systemic factors, and medications
all increase the risk of developing MGD.4
Although topical glaucoma medications are used as
primary treatment for glaucoma, these medications also have
various side effects, including ocular surface disease.5,6 The
number of medications, duration of use, and exposure to
preservatives are all known risk factors for ocular surface
disease in patients with glaucoma.7 Recent studies have
examined the relationship between MGD and glaucoma
medications in older patients.8,9 In these studies, the use of
long-term topical glaucoma medications was associated with
the development of MGD. However, because aging itself is
a risk factor that increases the incidence of MGD, it is also
necessary to study younger age groups.
Thus, we aimed to investigate the effect of topical
glaucoma medications on MGD in early middle-aged patients
with glaucoma. The degree of MGD was assessed by evaluating
the Marx line, which can be clearly observed along the inner
eyelid after application of a fluorescent dye solution to the
eyelid.10 We also assessed the grade of MGD according to the
nature of excreted meibum and the ease with which meibum was
excreted after applying digital pressure to the eyelids.11 Finally,
we investigated changes in the ocular surface by evaluating the
tear breakup time (BUT) and performing ocular surface staining.
MATERIALS AND METHODS
Subjects
This cross-sectional study included 50 early middle-aged
(younger than 50 years) patients with glaucoma who had been
on long-term use of topical glaucoma medications for more than
6 months. Forty age-matched healthy subjects with no systemic
disease or ocular disease were included as controls. To calculate
the number of subjects required for the study, a pilot study was
conducted on 10 patients with glaucoma and 10 normal subjects.
As a result, the prevalence of MGD was 80% in patients with
glaucoma and 50% in normal controls. When the type 1 error
was set to 0.05 and the power was set to 0.80, the minimum
sample size required was 38 in each group. To increase statistical
power, 12 patients with glaucoma and 2 controls were added,
and a total of 50 patients with glaucoma and 40 controls
participated in the study. For the patients with glaucoma,
a detailed history of the number, type, and period of use of
topical glaucoma medication(s) was obtained. Exclusion criteria
were contact lens wear, history of ocular surgery, systemic
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Kim et al
diseases (including diabetes and rheumatic diseases, which can
affect the ocular surface), and ocular diseases that can cause
cicatricial MGD. All patients underwent ophthalmologic exami-
nations including assessment of visual acuity, intraocular
pressure, slit-lamp examination, and fundus examination. Our
study protocol complied with the Declaration of Helsinki and
was approved by the Institutional Review Board of Hanyang
University Guri Hospital. Informed consent was obtained from
all participants after the details of the study were explained.
Examinations
MGD is defined as the presence of terminal obstruction
of the meibomian gland visible by slit-lamp examination and
resistance to meibum expressibility. We used the Marx line
score and staging system, which is based on meibum
expressibility, to evaluate the severity of MGD. The Marx
line is a clear line visible in the inner eyelid when a fluorescein
dye solution is applied to the eyelid margin. After instilling
the fluorescein solution, the score was calculated by the
following criteria according to the position of the Marx line in
the slit-lamp examination: 0, the Marx line runs entirely along
the conjunctival side of the meibomian orifices; 1, parts of the
Marx line touch the meibomian orifices; 2, the Marx line runs
through the meibomian orifices; and 3, the Marx line runs
along the eyelid margin side of the meibomian orifices.10 We
used only the Marx line score of the lower eyelid.
As another method of MGD staging, digital pressure
was applied to the lower eyelid, and the degree of meibum
expressibility was evaluated using the following criteria: 0,
clear meibum was easily expressed; 1, cloudy meibum was
expressed with mild pressure; 2, cloudy meibum was ex-
pressed with more than moderate pressure; and 3, meibum
could not be expressed even with hard pressure.11
All subjects also underwent ocular surface testing. BUT
was measured as the time from the last blink to the first
appearance of the corneal dry spot after instilling the
fluorescein dye solution. Ocular surface staining was graded
from 0 to 5 depending on the extent to which the cornea and
conjunctiva were stained according to the Oxford scheme.12
FIGURE 1. Numbers of antiglaucoma medications taken by
patients.
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FIGURE 2. Classification of antiglaucoma medications (A, a
adrenergic agonists; B, b-blockers; B + A, b-blockers + a
adrenergic agonists; B + C, b-blockers + carbonic anhydrase
inhibitors; PG, prostaglandin analogs; PG + B, prostaglandin
analogs + b-blockers).
Statistical Analysis
All statistical analyses were performed using SPSS for
Windows, version 17.0 (SPSS, Inc, Chicago, IL). The
characteristics of the glaucoma group and the control group
were compared using the Student t test and the x2 test,
respectively. The glaucoma group and the control group were
divided according to the presence of MGD, and the Kruskal–
Wallis test was used to compare the ocular test results of each
group. The Kruskal–Wallis test was also used to compare the
results of ocular tests according to the MGD grade and ac-
cording to eyelid clinical parameters by the topical glaucoma
medication type. The correlation between MGD grade and
duration of topical glaucoma medications was evaluated using
the Pearson test. All parameters are expressed as mean 6 SD.
P , 0.05 was considered statistically significant.
RESULTS
Mean age of the patients with glaucoma was 41.6 6 5.2
years, and mean age of the control group was 39.6 6 4.7 years.
The difference between the groups was not statistically
significant (P = 0.113). Thirty-six (72%) patients with
FIGURE 3. Prevalence of MGD with glaucoma medications
according to the MGD grade (P , 0.001).
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Cornea  Volume 0, Number 0, Month 2017 Eyelid Changes in Early Middle-Aged Patients with Glaucoma Medications

TABLE 1. Clinical Results of Ocular Tests of Patients With Glaucoma and Controls
Glaucoma With Glaucoma Without Control With Control Without
Parameter MGD (n = 41) MGD (n = 9) MGD (n = 21) MGD (n = 19) P
Age, yrs 42.0 6 4.9 38.2 6 5.3 40.5 6 3.6 38.7 6 5.7 0.045
BUT, s 3.5 6 1.7 8.9 6 1.7 4.9 6 1.9 10.3 6 2.5 ,0.001
Fluorescein score 0.38 6 0.65 0.44 6 0.72 0.05 6 0.22 0.26 6 0.45 0.129
Marx line score 2.6 6 1.8 1.0 6 1.3 2.1 6 1.4 1.0 6 0 0.007
MGD grade 1.8 6 0.7 0 1.3 6 0.5 0 ,0.001
P , 0.05 (indicated in bold) was considered statistically significant.
BUT, breakup time; MGD, meibomian gland dysfunction.

glaucoma used 1 drug, 13 (26%) used 2 drugs, and only 1
patient (2%) used 3 drugs (Fig. 1). Twenty-five patients (40%)
were using prostaglandin analog monotherapy, 16 patients
(25%) were using a mixture of b-blockers and carbonic
anhydrase inhibitors, and 8 patients (12%) were treated with
a mixture of b-blockers and a adrenergic agonists (Fig. 2).
MGD was more prevalent in patients with glaucoma
(n = 41, 82%) than in controls (n = 21, 52.5%). There was
a statistically significant difference between both groups
according to the MGD stage, with grade 3 MGD observed
only in the glaucoma group (Fig. 3).
The ocular test results of patients with glaucoma and
controls were first compared according to the presence of MGD.
Among the ocular surface test results examined, BUT was
statistically significantly reduced in the group with MGD; this
finding was true in both patients with glaucoma and in controls (P
, 0.001). The fluorescein score was also decreased in the group
with MGD, but this difference was not statistically significant (P
= 0.129). Regarding tests related to eyelid changes, both Marx
line score and MGD grade were higher in the group with MGD;
these findings were true in both patients with glaucoma and in
controls (P = 0.007 and P , 0.001, respectively) (Table 1). With
respect to ocular tests according to the MGD grade, only the
Marx line score showed a significant difference in the grade; the
score was comparable to the MGD grade (P = 0.044) (Table 2).
There was no significant correlation between the
duration of glaucoma drug use and the MGD grade
(Fig. 4). Similarly, there were no significant differences in
age, duration of glaucoma drug use, and eyelid parameters
(eg, Marx line score and MGD grade) according to the
glaucoma medication class (Table 3).
DISCUSSION
In our study of early middle-aged patients, the preva-
lence of MGD was greater than 80% in patients on glaucoma
medications. In the control group, the prevalence was as high
as 50%, which was similar to the prevalence of MGD
reported in previous studies of patients in Asia. When
comparing the 2 groups according to the degree of MGD,
severe MGD was more common in patients on glaucoma
medications than in controls. These results indicate that
glaucoma eye drops cause changes in the eyelids and
generate MGD.
Arita et al8 compared the changes in meibomian glands
in eyes receiving glaucoma eye drops with their paired eyes
not receiving glaucoma medications. Arita et al found that the
eyes treated with glaucoma medications showed more
changes in the meibomian glands; moreover, the ocular
surface test results in the treated eyes were worse. Uzunos-
manoglu et al9 examined the effect of glaucoma eye drops on
MGD and ocular surface disease in patients using long-term
topical glaucoma medications. They found that ocular surface
test results were worse in patients using glaucoma eye drops
than in controls. However, there were no significant differ-
ences between Ocular Surface Disease Index scores, BUT, or
ocular surface staining between patients with glaucoma with
MGD versus those without MGD. Because the average
patient age was older than 60 years in these studies and
aging is a well-known risk factor for MGD progression, we
performed a study of early middle-aged patients with
glaucoma. Nevertheless, similar to previous studies, our study
showed higher MGD grades in patients with glaucoma than in
controls. We found that glaucoma eye drop use correlated
with a high prevalence of MGD, even when the effects of
aging are excluded.
We included only obstructive type MGD in our study.
Obstructive MGD is the most common form of MGD and is
caused by obstruction of the terminal duct.13 Obstructive
MGD occurs through hyperkeratinization of the terminal duct
because of factors such as aging, hormone imbalance, and eye
drop use.14,15 Glaucoma eye drops exert toxic effects,

TABLE 2. Clinical Results of Ocular Tests of Patients With Glaucoma According to the MGD Grade
Parameter Grade 0 MGD (n = 9) Grade 1 MGD (n = 19) Grade 2 MGD (n = 16) Grade 3 MGD (n = 6) P
Age, yrs 38.2 6 5.3 41.2 6 5.4 42.1 6 4.6 43.7 6 4.9 0.163
BUT, s 8.9 6 1.7 3.5 6 1.3 4.0 6 1.9 2.1 6 1.0 0.057
Fluorescein score 0.44 6 0.72 0.21 6 0.39 0.47 6 0.72 0.57 6 0.98 0.557
Marx line score 1.0 6 1.3 2.5 6 1.6 2.2 6 1.9 3.4 6 1.7 0.044
BUT, breakup time; MGD, meibomian gland dysfunction.

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Kim et al Cornea  Volume 0, Number 0, Month 2017

factor by studying patients younger than 50 years.22 Never-

FIGURE 4. Grade of MGD and duration of glaucoma treat-
ment. The treatment duration was not significantly different
between MGD grades (Pearson test, P = 0.649).
resulting in a decreased barrier function of the corneal
epithelium, goblet cell loss in the conjunctiva, decreased tear
production and turnover, and inflammatory changes.16–19
Many glaucoma medications also contain benzalkonium
chloride as a preservative, which is known to cause conjunc-
tival damage, goblet cell loss, and inflammation of the ocular
surface.20,21 In addition to affecting the eye surface, the
eyelids may be affected, resulting in eyelid inflammation and
obstruction of the terminal duct. Nearly all patients with
glaucoma included in this study were using glaucoma eye
drops containing benzalkonium chloride. This likely explains
the observed lack of correlation between the glaucoma drug
type and MGD degree in this study.
As a method of assessing the degree of MGD, we
determined the Marx line score. The Marx line is a clear line
visible from the inner margin of the eyelid when a fluorescent
dye solution is applied. In normal individuals, this line is
observed on the conjunctival side of the meibomian orifices.
With increasing age, this line gradually migrates to the eyelid
margin side of the meibomian orifices.22 Yamaguchi et al10
designed the Marx line score to range from 0 to 3 by
analyzing the positional relationship between the Marx line
and the meibomian orifices. In this study, the Marx line score
showed a strong correlation with the MGD grade, which was
measured as meibum expressibility after digital pressure.
Similar results were obtained in our study. Considering that
the Marx line score increases beyond 50 years of age, our
study was designed to exclude the effects of the age-related
theless, the severity of MGD was significantly higher in
patients using glaucoma eye drops compared with controls.
No previous study has examined the relationship
between the duration of glaucoma drug use and MGD grade.
We found that treatment duration was not significantly
different between patients with various MGD grades.
Although the prolonged use of glaucoma medications is
known to cause ocular surface disease because of cumulative
effects of the drug itself and benzalkonium chloride toxicity,
medication use does not seem to affect the severity of MGD if
the medication is used for more than 6 months. Although the
exact mechanism underlying this finding is unknown, poten-
tial explanations are that sensitivity to glaucoma drugs may
vary among individuals, as may the time it takes for the
eyelids to change. In addition, chronic changes in the eyelid
may be somewhat established after 6 months and may not
show any significant changes thereafter. A longitudinal study
is needed to test this hypothesis.
In addition, there was no difference in the duration of
drug use and the severity of MGD among glaucoma medica-
tion classes. Depending on the type of glaucoma medications,
the mechanisms that cause eyelid changes may vary. However,
long-term use of medications seems to produce similar results
in eyelids, regardless of the type of medications. Because most
glaucoma medications contain benzalkonium chloride as a pre-
servative, it may be insufficient to explain eyelid changes
entirely with the toxicity of each drug itself. Because glaucoma
medications without preservatives are being developed, further
studies on eyelid changes according to the presence or absence
of preservatives will be needed.
This study has several limitations. Because of the cross-
sectional nature of the study, a causal relationship between
glaucoma medication use and MGD occurrence could not be
established. Moreover, because most patients used glaucoma
medications containing preservatives, we could not confirm the
difference between MGD prevalence and severity according to
the glaucoma drug type. However, our study is distinguished
from previous studies in that the relationship between glaucoma
medication use and eyelid changes holds even greater weight
because the study was conducted in early middle-aged adults. In
addition, this is the first study to compare the prevalence of
MGD with the use of glaucoma medications.
In conclusion, glaucoma medications can contribute to
eyelid changes. However, medication duration does not
always increase the severity of MGD, and physicians should
check thoroughly for eyelid damage in patients, irrespective
of the treatment duration.

TABLE 3. Correlations Between Antiglaucoma Medications and Eyelid Clinical Parameters

Parameter PG (n = 14) B + C (n = 6) B + A (n = 6) PG + B (n = 4) A (n = 3) B (n = 3) Multiple (n = 14) P
Age, yrs 43.3 6 5.6 45.0 6 2.7 40.3 6 4.9 42.8 6 4.6 38.0 6 6.9 42.3 6 2.8 38.3 6 4.54 0.057
Duration 22.6 6 19.1 19.2 6 14.4 14.7 6 10.0 38.8 6 32.0 31.3 6 14.7 36.0 6 20.8 35.4 6 24.0 0.265
Max line score 2.69 6 2.32 4.00 6 1.26 2.17 6 1.72 1.50 6 0.57 2.33 6 2.08 3.0 6 0.00 1.36 6 1.28 0.071
MGD grade 1.65 6 0.84 1.17 6 1.17 0.67 6 0.52 1.25 6 0.96 1.67 6 1.16 2.33 6 1.16 1.50 6 0.94 0.227
A, a adrenergic agonists; B, b-blockers; B + A, b-blockers + a adrenergic agonists; B + C, b-blockers + carbonic anhydrase inhibitors; PG, prostaglandin analogs; PG + B,
prostaglandin analogs + b-blockers.

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Cornea  Volume 0, Number 0, Month 2017 Eyelid Changes in Early Middle-Aged Patients with Glaucoma Medications
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