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Kim et al Cornea Volume 0, Number 0, Month 2017
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 FIGURE 2. Classification of antiglaucoma medications (A, a
expressibility, to evaluate the severity of MGD. The Marx adrenergic agonists; B, b-blockers; B + A, b-blockers + a
line is a clear line visible in the inner eyelid when a fluorescein adrenergic agonists; B + C, b-blockers + carbonic anhydrase
dye solution is applied to the eyelid margin. After instilling inhibitors; PG, prostaglandin analogs; PG + B, prostaglandin
the fluorescein solution, the score was calculated by the analogs + b-blockers).
following criteria according to the position of the Marx line in
the slit-lamp examination: 0, the Marx line runs entirely along Statistical Analysis
the conjunctival side of the meibomian orifices; 1, parts of the All statistical analyses were performed using SPSS for
Marx line touch the meibomian orifices; 2, the Marx line runs Windows, version 17.0 (SPSS, Inc, Chicago, IL). The
through the meibomian orifices; and 3, the Marx line runs characteristics of the glaucoma group and the control group
along the eyelid margin side of the meibomian orifices.10 We were compared using the Student t test and the x2 test,
used only the Marx line score of the lower eyelid. respectively. The glaucoma group and the control group were
As another method of MGD staging, digital pressure divided according to the presence of MGD, and the Kruskal–
was applied to the lower eyelid, and the degree of meibum Wallis test was used to compare the ocular test results of each
expressibility was evaluated using the following criteria: 0, group. The Kruskal–Wallis test was also used to compare the
clear meibum was easily expressed; 1, cloudy meibum was results of ocular tests according to the MGD grade and ac-
expressed with mild pressure; 2, cloudy meibum was ex- cording to eyelid clinical parameters by the topical glaucoma
pressed with more than moderate pressure; and 3, meibum medication type. The correlation between MGD grade and
could not be expressed even with hard pressure.11 duration of topical glaucoma medications was evaluated using
All subjects also underwent ocular surface testing. BUT the Pearson test. All parameters are expressed as mean 6 SD.
was measured as the time from the last blink to the first P , 0.05 was considered statistically significant.
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 RESULTS
conjunctiva were stained according to the Oxford scheme.12 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 1. Numbers of antiglaucoma medications taken by FIGURE 3. Prevalence of MGD with glaucoma medications
patients. 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 medications. In the control group, the prevalence was as high
patient (2%) used 3 drugs (Fig. 1). Twenty-five patients (40%) as 50%, which was similar to the prevalence of MGD
were using prostaglandin analog monotherapy, 16 patients reported in previous studies of patients in Asia. When
(25%) were using a mixture of b-blockers and carbonic comparing the 2 groups according to the degree of MGD,
anhydrase inhibitors, and 8 patients (12%) were treated with severe MGD was more common in patients on glaucoma
a mixture of b-blockers and a adrenergic agonists (Fig. 2). medications than in controls. These results indicate that
MGD was more prevalent in patients with glaucoma glaucoma eye drops cause changes in the eyelids and
(n = 41, 82%) than in controls (n = 21, 52.5%). There was generate MGD.
a statistically significant difference between both groups Arita et al8 compared the changes in meibomian glands
according to the MGD stage, with grade 3 MGD observed in eyes receiving glaucoma eye drops with their paired eyes
only in the glaucoma group (Fig. 3). not receiving glaucoma medications. Arita et al found that the
The ocular test results of patients with glaucoma and eyes treated with glaucoma medications showed more
controls were first compared according to the presence of MGD. changes in the meibomian glands; moreover, the ocular
Among the ocular surface test results examined, BUT was surface test results in the treated eyes were worse. Uzunos-
statistically significantly reduced in the group with MGD; this manoglu et al9 examined the effect of glaucoma eye drops on
finding was true in both patients with glaucoma and in controls (P MGD and ocular surface disease in patients using long-term
, 0.001). The fluorescein score was also decreased in the group topical glaucoma medications. They found that ocular surface
with MGD, but this difference was not statistically significant (P test results were worse in patients using glaucoma eye drops
= 0.129). Regarding tests related to eyelid changes, both Marx than in controls. However, there were no significant differ-
line score and MGD grade were higher in the group with MGD; ences between Ocular Surface Disease Index scores, BUT, or
these findings were true in both patients with glaucoma and in ocular surface staining between patients with glaucoma with
controls (P = 0.007 and P , 0.001, respectively) (Table 1). With MGD versus those without MGD. Because the average
respect to ocular tests according to the MGD grade, only the patient age was older than 60 years in these studies and
Marx line score showed a significant difference in the grade; the aging is a well-known risk factor for MGD progression, we
score was comparable to the MGD grade (P = 0.044) (Table 2). performed a study of early middle-aged patients with
There was no significant correlation between the glaucoma. Nevertheless, similar to previous studies, our study
duration of glaucoma drug use and the MGD grade showed higher MGD grades in patients with glaucoma than in
(Fig. 4). Similarly, there were no significant differences in controls. We found that glaucoma eye drop use correlated
age, duration of glaucoma drug use, and eyelid parameters with a high prevalence of MGD, even when the effects of
(eg, Marx line score and MGD grade) according to the aging are excluded.
glaucoma medication class (Table 3). 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
DISCUSSION MGD occurs through hyperkeratinization of the terminal duct
In our study of early middle-aged patients, the preva- because of factors such as aging, hormone imbalance, and eye
lence of MGD was greater than 80% in patients on glaucoma 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
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Cornea Volume 0, Number 0, Month 2017 Eyelid Changes in Early Middle-Aged Patients with Glaucoma Medications
REFERENCES 12. Methodologies to diagnose and monitor dry eye disease: report of the
1. Gutgesell VJ, Stern GA, Hood CI. Histopathology of meibomian gland Diagnostic Methodology Subcommittee of the International Dry Eye
dysfunction. Am J Ophthalmol. 1982;94:383–387. WorkShop (2007). Ocul Surf. 2007;5:108–152.
2. Jester JV, Nicolaides N, Smith RE. Meibomian gland studies: histologic 13. Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on
and ultrastructural investigations. Invest Ophthalmol Vis Sci. 1981;20: meibomian gland dysfunction: executive summary. Invest Ophthalmol
537–547. Vis Sci. 2011;52:1922–1929.
3. Nelson JD, Shimazaki J, Benitez-del-Castillo JM, et al. The international 14. Nien CJ, Paugh JR, Massei S, et al. Age-related changes in the
workshop on meibomian gland dysfunction: report of the definition and meibomian gland. Exp Eye Res. 2009;89:1021–1027.
classification subcommittee. Invest Ophthalmol Vis Sci. 2011;52:1930– 15. Knop E, Knop N, Millar T, et al. The international workshop on
1937. meibomian gland dysfunction: report of the subcommittee on anatomy,
4. Schaumberg DA, Nichols JJ, Papas EB, et al. The international workshop physiology, and pathophysiology of the meibomian gland. Invest
on meibomian gland dysfunction: report of the subcommittee on the Ophthalmol Vis Sci. 2011;52:1938–1978.
epidemiology of, and associated risk factors for, MGD. Invest Oph- 16. Alm A, Stjernschantz J. Effects on intraocular pressure and side effects of
thalmol Vis Sci. 2011;52:1994–2005. 0.005% latanoprost applied once daily, evening or morning. A compar-
5. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface ison with timolol. Scandinavian Latanoprost Study Group. Ophthalmol-
disease in glaucoma patients. J Glaucoma. 2008;17:350–355. ogy. 1995;102:1743–1752.
6. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of 17. Arici MK, Arici DS, Topalkara A, et al. Adverse effects of topical
ocular surface complaints in patients with glaucoma using topical antiglaucoma drugs on the ocular surface. Clin Exp Ophthalmol. 2000;
intraocular pressure-lowering medications. Cornea. 2010;29:618– 28:113–117.
621. 18. Watson P, Stjernschantz J. A six-month, randomized, double-masked study
7. Rossi GC, Pasinetti GM, Scudeller L, et al. Risk factors to develop ocular comparing latanoprost with timolol in open-angle glaucoma and ocular
surface disease in treated glaucoma or ocular hypertension patients. Eur J hypertension. The Latanoprost Study Group. Ophthalmology. 1996;103:
Ophthalmol. 2013;23:296–302. 126–137.
8. Arita R, Itoh K, Maeda S, et al. Effects of long-term topical anti- 19. Baudouin C, Liang H, Hamard P, et al. The ocular surface of glaucoma
glaucoma medications on meibomian glands. Graefes Arch Clin Exp patients treated over the long term expresses inflammatory markers
Ophthalmol. 2012;250:1181–1185. related to both T-helper 1 and T-helper 2 pathways. Ophthalmology.
9. Uzunosmanoglu E, Mocan MC, Kocabeyoglu S, et al. Meibomian gland 2008;115:109–115.
dysfunction in patients receiving long-term glaucoma medications. 20. Pflugfelder SC, Baudouin C. Challenges in the clinical measurement of ocular
Cornea. 2016;35:1112–1116. surface disease in glaucoma patients. Clin Ophthalmol. 2011;5:1575–1583.
10. Yamaguchi M, Kutsuna M, Uno T, et al. Marx line: fluorescein staining 21. Baudouin C, Riancho L, Warnet JM, et al. In vitro studies of
line on the inner lid as indicator of meibomian gland function. Am J antiglaucomatous prostaglandin analogues: travoprost with and without
Ophthalmol. 2006;141:669–675. benzalkonium chloride and preserved latanoprost. Invest Ophthalmol Vis
11. Shimazaki J, Goto E, Ono M, et al. Meibomian gland dysfunction in Sci. 2007;48:4123–4128.
patients with Sjogren syndrome. Ophthalmology. 1998;105:1485– 22. Norn M. Meibomian orifices and Marx’s line. Studied by triple vital
1488. staining. Acta Ophthalmol (Copenh). 1985;63:698–700.
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