Meibomian gland dysfunction in Graves’ orbitopathy Young Shin Kim, MD,* Ae Young Kwak, MD,† Sang Yeul Lee, MD, PhD,† Jin Sook Yoon, MD, PhD,† Sun Young Jang, MD*,‡ ABSTRACT ● RÉSUMÉ Objective: To examine morphologic changes in the meibomian glands associated with patients with Graves’ orbitopathy (GO) using a novel meibography imaging system, and to evaluate its correlation with GO clinical manifestations. Design: Retrospective, observational case series. Participants: Fifty-one GO patients and 31 normal control participants. Methods: This retrospective study examined 51 GO patients and 31 normal control participants. The structure of the meibomian gland was assessed using the meibography imaging system. All of the participants completed the Ocular Surface Disease Index (OSDI) questionnaire. The tear film break-up time (BUT) was measured. The palpebral fissure height, exophthalmos, and eyelid retraction were also assessed. Results: The meibography score, tear film BUT, and OSDI indicated statistically significant differences between the GO and normal groups: The tear film BUT was shorter and the OSDI and meibography score were higher in the GO patient group. There was a significant negative correlation between the meibography score and the tear film BUT in GO patients (r ¼ –.503 and p o .001). In the multivariable linear regression analysis, the meibography score of the GO patients had a positive association with exophthalmos and palpebral fissure height. Conclusions: Compared with the normal control participants, GO patients had more unstable tear films and severe symptoms of dry eye. Using the meibography system, the authors found that GO patients had a higher prevalence of obstructive type meibomian gland dysfunction and changes in meibomian glands increased, with proptosis and lid fissure widening. Objet : Examiner les changements morphologiques des glandes de Meibomius chez les patients atteints d’orbitopathie de Graves (OG) à l’aide d’un nouveau système d’imagerie, et évaluer les corrélations entre cette méthode et les manifestations cliniques d’OG. Nature : Observation rétrospective d’une série de cas. Participants : 51 patients atteints d’OG et un groupe témoin composé de 31 sujets normaux. Méthodes : Cette étude rétrospective porte sur l’examen de 51 patients atteints d’OG et de 31 sujets normaux. Nous avons évalué la structure de la glande de Meibomius à l’aide d’un nouveau système d’imagerie (meibography imaging system). Tous les sujets ont répondu au questionnaire Ocular Surface Disease Index (indice de maladie de la surface oculaire ou IMSO) et ont subi un test du temps de rupture du film lacrymal (TRFL). La hauteur de la fissure palpébrale, l’exophtalmie et la rétraction de la paupière ont aussi été évaluées. Résultats : Les résultats de l’imagerie, du TRFL et de l’IMSO ont montré des différences statistiquement significatives entre le groupe des patients atteints d’OG et le groupe témoin : le temps de rupture était inférieur, et l’IMSO et le résultat de l’imagerie étaient supérieurs chez les patients atteints d’OG. Nous avons aussi constaté une corrélation négative significative entre le résultat de l’imagerie et le TRFL chez les patients atteints d’OG (r ¼ 0,503 et p o 0,001). La régression linéaire multivariables a démontré une corrélation positive entre le résultat de l’imagerie des patients atteints d’OG, et l’exophtalmie et la hauteur de la fissure palpébrale. Conclusions : Comparativement aux sujets témoins normaux, les patients atteints d’OG avaient un temps de rupture du film lacrymal plus instable et des symptômes graves de sécheresse oculaire. Le nouveau système d’imagerie a permis aux auteurs de découvrir une prévalence supérieure de la dysfonction des glandes de Meibomius de type obstructive chez les patients atteints d’OG, et que l’exophtalmie et l’élargissement de la fissure palpébrale touchaient encore plus les glandes de Meibomius.
Graves’ orbitopathy (GO) is an inﬂammatory autoimmune disorder with an etiology that has not been completely elucidated.1,2 Dryness is the most common cause of ocular discomfort found in GO3; it has been reported that up to 85% of patients suffer with dry eye.4,5 The pathogenesis of dry eye in GO is not clear; however, previous studies have reported that T-cell–dependent inﬂammation, lacrimal gland
impairment, and increased tear evaporation and osmolarity caused by proptosis and lid ﬁssure widening may contribute to the development of dry eye symptoms.4,6,7 Meibomian gland dysfunction (MGD) is well known to aggravate dry eye, causing excessive evaporation of the tear ﬁlm.8–10 Recently, Arita et al.11 introduced a noncontact meibography system consisting of an infrared ﬁlter and an
From the *Department of Ophthalmology, Soonchunhyang University College of Medicine, Bucheon; †Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul; and ‡Yonsei University Graduate School of Medicine, Seoul, Korea.
University College of Medicine, 170, Jomaru-ro, Wonmi-gu, 420-767, Bucheon, Korea; [email protected]
Originally received Mar. 24, 2015. Accepted Jun. 3, 2015 Correspondence to: Sun Young Jang, MD, Department of Ophthalmology, Soonchunhyang University Bucheon Hospital, Soonchunhyang
CAN J OPHTHALMOL — VOL. 50, NO. 4, AUGUST 2015
Can J Ophthalmol 2015;50:278–282 0008-4182/15/$-see front matter & 2015 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2015.05.012
Meibomian gland dysfunction in GO—Kim et al. infrared charge coupled device video camera. Meibography is a useful technique to evaluate the morphology of the meibomian glands and to determine gland function. However, no reports have been published that evaluate MGD in patients with GO. The most common clinical sign of GO is eyelid retraction.3 The authors assumed that the prevalence of MGD would be higher in GO patients compared with normal populations as a result of poor eyelid blinking caused by proptosis or lid ﬁssure widening contributing to the development of dry eye. This study examined the morphologic changes in the meibomian glands in patients with Graves’ orbitopathy (GO) using a novel meibography system and evaluated the correlation with the clinical manifestations of GO.
METHODS Study population
The present investigation was a retrospective, clinic-based study conducted in compliance with the Institutional Review Board of Yonsei University College of Medicine. Written informed consent was obtained from all of the patients and normal control participants before clinical assessment. In total, 51 eyes of 51 GO patients and 31 eyes of 31 normal control participants who visited the department of ophthalmology in Yonsei University from November 2011 to January 2012 were evaluated in this study. Data were obtained from 1 eye from each participant. The diseased eyes were selected in GO patients who had unilateral eye involvement. Otherwise, the eye was randomly selected. Patients were excluded if they had any other ophthalmic disorder or additional systemic disease. The control participants were randomly selected from patients who visited the clinic for other reasons and had no signs and symptoms of dry eye or other ocular inﬂammation. Neither the patients nor the control participants had used any topical medications other than artiﬁcial tear eye drops for 3 months before entering the study. All of the patients and control participants underwent complete ophthalmic evaluations, including visual acuity test, intraocular pressure measurement, slit-lamp examination, eyelid ﬁssure measurement, exophthalmos measurement by Hertel exophthalmometer, and ocular motility examination. Eyelid lag, edema, conjunctival injection, and chemosis were also assessed. GO was diagnosed in patients with Graves’ disease (GD) who presented at least 1 of the clinical features, including exophthalmos 4 17 mm, lid retraction (upper eyelid margin at or above the limbus), lid lag (immobility of upper eyelid during down gaze), restrictive extraocular myopathy (enlarged extraocular muscle enlargement by computed tomography), and compressive optic neuropathy. Meibography score
The meibography score, which reﬂects the structure and function of the meibomian gland, was graded according
to the meibography imaging (BG-4M, Topcon, Tokyo, Japan) in GO patients and normal control participants. Images of the meibomian glands in the upper and lower eyelids were obtained. The meibography scores were graded according to the extent of the meibomian gland dropout as described by Arita et al.11,12 The meibography score was calculated as the sum of the score from the upper and lower eyelid. The Ocular Surface Disease Index questionnaire
The subjective symptom scores of dry eye were evaluated according to the Ocular Surface Disease Index (OSDI) questionnaire, which was developed to measure the severity of dry eye and accepted by the Food and Drug Administration (FDA) for use in clinical trials.13 We used the OSDI questionnaire translated into Korean; it was composed of 12 questions and split into 3 sections; symptoms of ocular irritation (3 questions), functional problems (6 questions), and the environmental triggers that contribute to dry eye (3 questions). Ocular symptoms were evaluated using a 5-point scale of the following frequencies: none of the time (0 points), some of the time (1 point), half of the time (2 points), most of the time (3 points), and all of the time (4 points). Tear film break-up time
Tear ﬁlm instability was measured by tear ﬁlm break-up time (BUT), which is the time required for dry spots to appear on the corneal surface after blinking. To measure tear ﬁlm BUT, a ﬂuorescein strip was moistened and applied to the inferior palpebral conjunctiva in the eyes of patients and normal control participants. The patient was asked to blink 3 times and look straight forward, the precorneal tear ﬁlm was examined with a slit-lamp, and the elapsed times before initial formation of dry spots were recorded. Table 1—Clinical characteristics of the 51 patients with Graves’ orbitopathy Parameter Mean age ⫾ SD, y Female:male sex, n Bilateral:unilateral, n Duration of GD, mo, mean ⫾ SD Duration of GO, mo, mean ⫾ SD Follow-up period, mo, mean ⫾ SD Initial CAS, mean ⫾ SD Active GO, n (%) (CAS Z 4) Smokers, n (%) Steroid treatment during the follow-up, n (%) Thyroid function, n Hyperthyroidism, (%) Hypothyroidism, (%) Euthyroidism, (%) Thyroid treat modalities, n Antithyroid drug, (%) Radioactive iodine therapy, (%) Surgery, (%) None, (%)
GO Patients (n ¼ 51) 42.35 ⫾ 12.80 34:17 47:4 47.7 ⫾ 49.4 27.5 ⫾ 17.9 24.5 ⫾ 13.6 2.31 ⫾ 1.59 17 (33.3) 14 (27.5) 38 (74.5) 8 (15.7) 0 (0) 43 (84.3) 39 3 1 8
(76.5) (5.9) (1.9) (15.7)
GD, Graves’ disease; GO, Graves’ orbitopathy; CAS, Clinical Activity Score.
CAN J OPHTHALMOL — VOL. 50, NO. 4, AUGUST 2015
Meibomian gland dysfunction in GO—Kim et al.
Fig. 1 — Representative case of a 46-year-old female with GO. Shortening of the meibomian gland was observed in the upper eyelid (A) and the lower eyelid (B). A 43-year-old female in the control group. The meibomian gland change was not observed in both upper (C) and lower eyelid (D).
Data analysis and statistics
The data were analysed using the Statistical Package for the Social Sciences version 21.0 (SPSS Inc, Chicago, Ill.). The Student t test and χ2 test were used to compare clinical parameters between GO patients and normal control participants. The correlations between various factors in GO patients were evaluated using Spearman’s correlation analysis and multivariable linear regression analysis. To prevent occurrence of multicollinearity, correlations between all independent variables were checked beforehand, and no high collinearity was observed. p values o .05 were considered statistically signiﬁcant.
RESULTS The participant group included 51 eyes of 51 GO patients and 31 eyes of 31 normal control participants. Table 2—Clinical parameters of GO patients and healthy participants GO Group (n ¼ 51) Sex (male/female) Mean age ⫾ SD Meibography score, mean ⫾ SD OSDI score, mean ⫾ SD BUT, mean ⫾ SD
Healthy Participants (n ¼ 31)
17/34 42.35 ⫾ 12.80 1.67 ⫾ 1.58
14/17 45.45 ⫾ 16.73 1.03 ⫾ 1.08
25.65 ⫾ 14.43 5.53 ⫾ 2.55
12.06 ⫾ 8.64 7.68 ⫾ 2.17
Table 3—Correlation between the meibography score and other factors in GO patients Meibography Score
.284 .380† .034† o.001† o.001†
OSDI, Ocular Surface Disease Index; BUT, break-up time. n
As determined by χ2 test. As determined by Student t test.
The clinical characteristics and demographics of the GO patients are summarized in Table 1. The GO patient population was composed of 34 women and 17 men with a mean age of 42.35 years. The mean duration of thyroid disease was 47.7 months and of GO was 27.5 months. The mean follow-up period was 24.5 months, and the number of patients who received steroid treatment during the follow-up was 38 (74.5%). For treatment of thyroid disease, 39 patients took antithyroid medications, 3 patients received radioiodine therapy, and 1 patient had surgery. The mean clinical activity score (CAS) was 2.31, and the number of active GO patients—those who presented a CAS score 4 4—was 17 (33.3%). The meibography score was 1.67 ⫾ 1.58 in GO patients and 1.03 ⫾ 1.08 in normal control participants, which was signiﬁcantly higher in the GO patient group (p ¼ .034). Representative meibography scans of GO and
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Age Exophthalmos Palpebral fissure height BUT OSDI score Clinical activity score
.383 .639 .626 –.503 .047 .281
.006 o.001 o.001 o.001 .741 .046
BUT, break-up time; OSDI, Ocular Surface Disease Index.
Meibomian gland dysfunction in GO—Kim et al. Table 4—Results of the multivariable linear regression model for meibography score in GO patients Meibography Score
Age Sex Exophthalmos Eyelid retraction Palpebral fissure height Clinical activity score Adjusted R2
.160 –.128 .379 .200 .332 .048
.158 .182 o.001 .075 .009 .597 .608
normal controls are shown in Figure 1. The mean OSDI score was signiﬁcantly higher in GO patients than in the normal control participants (p o .001). The mean tear ﬁlm BUT was signiﬁcantly shorter in GO patients compared with the normal control participants (p o .001) (Table 2). There was a signiﬁcantly negatively correlation between the meibography score and the tear ﬁlm BUT in GO patients (r ¼ –.503 and p o .001). However, the meibography scores of the GO patients were not signiﬁcantly correlated with the OSDI score (r ¼ .047 and p ¼ .741). The meibography score of the GO patients was signiﬁcantly positively correlated with exophthalmos, palpebral ﬁssure height, CAS, and age (Table 3). In the multivariable linear regression analysis, the meibography score of the GO patients had positive associations with exophthalmos and palpebral ﬁssure height (Table 4). The tear ﬁlm BUT of GO patients was signiﬁcantly negatively correlated with exophthalmos and CAS (r ¼ –.402, p ¼ .003 and r ¼ –.319, p ¼ .023, respectively). However, there were no signiﬁcant correlations between the OSDI score and any other factors (data not shown).
DISCUSSION This study investigated the morphologic changes in the meibomian glands associated with GO patients using a noncontact meibographic imaging technique. The results of this study demonstrated that the meibography scores were signiﬁcantly higher in the GO patients compared with the normal control participants. GO patients had a higher prevalence of obstructive MGD, which may serve as one of the mechanisms underlying GO-related dry eyes. Moreover, the meibography score of GO patients had a positive association with exophthalmos and palpebral ﬁssure height in this study. The authors postulate that it can be attributed to the lack of blinking as a result of proptosis and lid ﬁssure widening in GO patient, with decreasing excretion of the meibomian gland giving rise to the obstruction of the meibomian gland. A recent study of patients with poor eyelid blinking as a result of a lagophthalmos and lid retraction caused by facial nerve palsy reported that
dysfunction of the orbicularis oculi muscle decreased excretion of the meibomian gland and thus aggravated the MGD.9 Jang et al.14 reported a close relationship between the eyelids with an ocular prosthesis and MGD, suggesting that decreased and weakened eyelid blinking might be associated with MGD. Several studies have reported increased changes in the meibomian glands with aging in the normal population.11,15 However, in this study the meibography score from the GO patients had no association with age in the multivariable linear regression analysis. Den et al.15 reported that only a few patients o 50 years of age showed notable abnormalities in the lid margin or the meibomian glands. Because of the relatively younger patients in the present study, the correlation between changes in the meibomian gland and aging might not be apparent. The results of this study indicated that there was a signiﬁcantly negative correlation between the meibography score and the tear ﬁlm BUT in GO patients. In the normal population, it was known that the meibomian gland changes were not correlated with tear ﬁlm BUT because tear ﬁlm BUT depends not only on the oily layer of the tear ﬁlm but also on the aqueous and mucous layers.11,16 However, in the GO patients, aqueous and mucous layers are affected by evaporation because of increased corneal exposure. The tear ﬁlm BUT in the GO patients might be aggravated by MGD, resulting in increasing tear instability, loss of lubrication, and damage to the corneal epithelium, accordingly producing ocular discomfort related dry eye.17,18 Our results also indicated that the tear ﬁlm BUT was signiﬁcantly shorter in the GO patients, representing more unstable tear ﬁlm than the normal control participants, and the tear ﬁlm BUT was signiﬁcantly negatively correlated with exophthalmos in the GO patients. This may be attributed to proptosis, which increases evaporation of the lubricated surface through lid ﬁssure widening and also leads to increase tear osmolarity.7,19 Tear ﬁlm instability, which is an important pathogenesis of dry eye, was consistent with other GO patients in other studies.19,20 Gupta et al.21 reported that GO patients had relatively normal aqueous production; 81% of patients with GO had a normal result in the Schirmer test. Accordingly, the dry eye associated with GO may be attributed to evaporation caused by increased corneal exposure. The results of the present study indicate that the mean OSDI score was signiﬁcantly higher in GO patients compared with normal control participants. However, there was no signiﬁcant correlation between the OSDI score and the tear ﬁlm BUT. This is consistent with previous studies that demonstrated discrepancy between symptoms and signs of ocular dysfunction in dry eye patients.22–24 Moreover, the OSDI score had no correlation with the meibography score and factors associated with corneal exposure.
CAN J OPHTHALMOL — VOL. 50, NO. 4, AUGUST 2015
Meibomian gland dysfunction in GO—Kim et al. The OSDI score gave information not directly dependent on the ocular surface condition, which can vary, but also included other factors (e.g., psychological), which could be a relevant bias in a health status. A limitation of the present study is that the meibography method only evaluates morphologic changes in the meibomian glands and cannot detect quality changes in the meibum. Another limitation is the lack of data on diagnostic tests for dry eye. The tear osmolarity test gave an objective measure of the tear ﬁlm quality, directly evaluating a parameter considered of fundamental importance in the pathogenesis of the ocular surface dysfunction.25 Additional diagnostic tests should be performed to evaluate the extent of ocular surface damage (e.g., staining with rose Bengal, lissamine green, or ﬂuorescein dye) and aqueous tear ﬂow (e.g., Shirmer test).26
CONCLUSIONS In conclusion, the authors found that GO patients revealed a higher prevalence of obstructive type meibomian gland dysfunction and changes in meibomian glands increased with proptosis and lid ﬁssure widening. Therefore, it is important to check for MGD in GO patients with dry eye ocular symptoms and treat the condition if necessary.
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