Best Paper from Karnataka Ophthalmological Society (6´) : Utility of Meibography in the Evaluation of Dry Eye

Dr. Sulatha V. Bhandary ( B11799 )

ABSTRACT

Objective

To evaluate meibomian gland dysfunction using non-contact infrared meibography and compare the results with the conventional dry eye tests like Schirmer’s test and Tearfilm Break Up Time test.

Design

Case- Control study.

Participants

The study included a total of 170 subjects- 85 cases and 85 controls.

Methods

This case control study was conducted at a tertiary care center in South India between October 2015 and June 2017. Eighty five adults with dry eye symptoms and 85 controls underwent Ocular Surface Disease Index (OSDI) questionnaire, Tearfilm Break Up Time (TBUT), Schirmer’s test and Noncontact Infrared Meibography and the results were compared and p values calculated. A non-mydriatic fundus camera (3nethra) was used to capture the meibography images. The association of age and gender with meibomian gland dropout was studied.

Results

In our study, meibography was able to pick up a statistically significant number of cases that were missed on OSDI questionnaire (p<0.05), Schirmer’s test(p=0.002) and Tear film break up time (p<0.05). It also showed an increase in meibomian gland dropout with age, but no significant change among the males or females.

Conclusion

Non-contact Infrared Meibography is a novel technique used to directly image the meibomian glands and thereby, assess meibomian gland drop out and dysfunction. It is a non-invasive, useful, quick, simple

Meibography in Dry Eye

and patient-friendly test and helps to identify more cases of dry eye compared to other conventional tests.

INTRODUCTION

Dry eye is a multifactorial disease that affects the ocular surface and tearfilm leading to symptoms of ocular discomfort, altered vision and tear film instability. ^[1] Various tests have been developed over time to try to diagnose dry eye. These include different questionnaires, Rose Bengal Staining, Schirmer’s test,

Tearfilm Breakup Time, Tear meniscus height, lysozyme assay etc. ^[2] There is no gold standard test for

the diagnosis of dry eye and often, treatment is initiated based on the symptoms of the patient. ^[1]

It is essential to carry out screening on asymptomatic individuals who are at-risk to have dry eye. These subjects may ultimately develop dry eye as a result of various biological, pharmacological or environmental events such as hormonal changes, drug exposure, increased wind speeds, low humidity,and high temperatures. ^[3,4] An ideal screening test must be simple, cost-effective, efficient and applicable to a definable population. Meibography is a specialized imaging modality that helps to directly visualize the morphology of meibomian glands in vivo.^[5] It is of two main types. Contact meibography was the initial technique, that was intoduced in the 1970’s.^[6] Non-contact meibography is the novel method. It is quicker, more patient friendly and simpler to use.^[7]

In this case control study, we have performed the traditional dry eye tests, along with non-contact meibography on all the cases and controls, in order to assess the efficacy of meibography to evaluate dry eye. We have also tried to assess if meibography was able to pick up dry eye subjects missed by the traditional dry eye tests.

Meibography in Dry Eye

MATERIALS AND METHODS

This was a case control study conducted at the Ophthalmology outpatient department of a tertiary care center in south India between October 2015 and June 2017. The study group included 85 cases with symptoms of dry eye such as gritty/ foreign body sensation/ burning of the eyes and 85 controls with no symptoms of dry eye. Patients with infective conditions of the eye, immediate postoperative patients, and those not willing for the study were excluded. This study was approved by the Institutional Ethical Committee of Kasturba Hospital, Manipal and carried out in accordance with the Declaration of Helsinki. Informed consent was obtained from all the individual participants included in the study. Sample size for estimation of proportion was calculated using the formula n= z²1-α/2pq/ (pd) ² Where z1-α/2 = 1.96 at 95% confidence level p= proportion of correct detection of dry eye; q= 1-p pd= relative precision Anticipating 85% proportion of correct detection of dry eye, with 0.085 relative precision at 95% confidence level, a minimum of 68 participants need to be screened. n= (1.96) ²x 0.85 x 0.15/ (0.85x 0.1) ^{2 =} 68 per group In our study, 85 cases and 85 controls were recruited.

Basic demographic profile including age, gender and place of residence were documented. Visual acuity assessment was done, followed by slit lamp evaluation of anterior segment. The structured Ocular Surface Disease Index (OSDI) questionnaire was answered by each patient to assess presence of dry eye. The Tearfilm Breakup Time (TBUT) was then assessed, followed by Schirmer’s test, intraocular pressure examination and dilated fundus evaluation. The OSDI score was then calculated using the following formula:

Meibography in Dry Eye

OSDI = Sum of scores for all the questions asked X 25 Total number of questions answered Using OSDI score, patients were then categorized as- Normal (Score 0-12), Mild symptoms (score 13-22), Moderate symptoms (Score 23-32) or Severe symptoms (Score 33-100). ^[8] Stability of the tear film was assessed by the Tearfilm Break-Up Time (TBUT). This was performed by staining the lower bulbar conjunctiva with 2% fluorescein dye. The subject was asked to blink 3-4 times to evenly distribute the fluorescein over the cornea. He /she was then, positioned at the slit lamp and examined under cobalt blue filter. The time interval between the last blink and the first appearance of a dry spot was measured with a stop watch. ^[9] This was graded as follows ^[10]– >/=10 seconds – Normal, 5-9 seconds -Mild to moderate, < 5 seconds- Severe. Tear production was assessed by the Schirmer’s test. The Schirmer test without anesthesia is a well-standardized test that has been conventionally used for the diagnosis of dry eye.^[11] Whatman No 1 Schirmer’s strips are inserted over the lower eyelid margin, at the junction of medial two-thirds and lateral one-third. The patient is asked to keep his eyes closed. The length of the Schirmer’s strip that has been wetted is read at the end of 5 minutes. Then, one drop of topical anaesthetic (paracaine) is instilled in each eye. Whatman No 1 strips are then, inserted over the lower eyelid margin, and the length of the strip wetted at the end of 5 minutes is noted. This was then graded as follows- > 10 mm – Normal, 6-10mm – Mild to moderate and <5 mm – Severe tear film deficiency.

 

The meibomian glands were imaged by using the technique of non-contact infrared meibography. The portable non mydriatic camera with a 40 degrees’ field of view and optical resolution of 10 u was used to capture the images. The everted upper and lower eyelids of each eye were imaged for every patient. This was then graded as follows, using the meiboscore- Grade 0- No meibomian gland loss, Grade 1-Loss of <1/3^rd of total meibomian gland area, Grade 2- Loss of 1/3^rd – 2/3^rd of total meibomian gland

 

Meibography in Dry Eye

area and Grade 3- Loss of >2/3^rd of total meibomian gland area. ^[12] The total meibography score was calculated as the sum of meibography score of upper eyelid and lower eyelid (Figure 1)

Statistical analysis was done by the Chi square test and a p<0.05 was considered statistically significant.

 

RESULTS

Among the 85 cases, 33 (38.8%) were males and 52 (61.1%) were females. The ages ranged from 18- 75 years, with a mean of 46.23 years for males, and 32.45 years for females. Among the 85 controls, 42

(49.41%) were males, and 43 (50.58%) were females. The ages ranged from 18-75 years, with a mean age of 47.82 years for males, and 34.45 years for females.

Using the OSDI questionnaire, among cases, 20 subjects (23.5%) were normal, 48 (56.4%) had mild-moderate, and 17 (20%) had severe dry eye. This shows that the OSDI questionnaire is effective in identifying dry eye cases and grading its severity. Among controls, 81 (95.2%) were normal, 4 (4.7%) had mild- moderate and none had severe dry eye.

Using the TBUT, among cases, 19 subjects (22.3%) were normal, 40 (47%) had mild- moderate dry eye and 26 (30.5%) had severe dry eye. Among controls, 70 (82.3%) were found to be normal, 15 (17.6%) had mild- moderate dry eye and none had severe dry eye. Thus, the TBUT is quite effective in detecting cases of dry eye.

Using the Schirmer’s test, among cases, 20 subjects (23.5%) were normal, 33 (38.8%) had mild-moderate dry eye, and 32 (37.6%) had severe dry eye. Among controls, 70 subjects (82.3%) were normal, 15 (17.6%) had mild- moderate dry eye and none had severe dry eye. Thus, Schirmer’s test is quite useful in picking up dry eye.

Using non-contact infrared meibography, for cases and controls, the patients were graded according to the meiboscore (Figure 1).

Meibography in Dry Eye

Among cases, 24.7% had grade 0, 35.2% had grade 1, 28.2% had grade 2 and 11.7% had grade 3 meibomian gland drop out. Among controls, 51.7% had grade 0, 37.6% had grade 1, 10.5% had grade 2, and none had grade 3 meibomian gland dropout (Figure 2).

Forty four patients who were found to be normal with Schirmer’s test, had mild to moderate MGD which shows that meibography picked up a significantly large number of patients (p=0.002) missed by the Schirmer’s test (Table 1).

Thirty three patients who had mild to moderate dry eye with meibography, were found to be normal with TBUT, which shows that meibography picked up a significantly large number of patients (p<0.05) missed by the TBUT (Table 2).

Forty eight patients who were found to be normal with OSDI, had mild to moderate dry eye with meibography, which shows that meibography picked up a significantly large number of patients (p<0.05) missed by the OSDI (Table 3).

The association between age and meibomian gland dropout was studied, which showed that meibomian gland drop out increases with age (Figure 3).

The association between gender and meibomian gland dropout was assessed by the Chi Square test and p=0.983 was obtained which shows no statistical significance.

DISCUSSION

Our study was aimed at assessing the utility of meibography in the evaluation of dry eye. Secondly, we also aimed to find out if patients who had normal values with the conventional dry eye tests, showed any evidence of meibomian gland dysfunction (MGD) on meibography.

The conventional dry eye tests which we have used in our study have several limitations. The Schirmer’s test has a high tendency for false negatives if not carried out correctly. The illumination, humidity, air velocity, correct placement of Schirmer’s strips etc have a bearing on the test results. ^[13]

Meibography in Dry Eye

In our study, meibography was able to pick up a number of cases that were missed on Schirmer’s. This was in contrast to the study by Matalia et al where there was no statistical significance between the Schirmer’s values of normal subjects and MGD patients. ^[14]

Tearfilm break up time has also conventionally been used to diagnose dry eye. However, there are some factors that cause low reproducibility of the test such as partial blinking, uneven mixing of fluorescein in the tearfilm, concentration of fluorescein, time lag between the appearance of the dry spot and its discovery by the observer, etc.^[15]

TBUT measures tear film stability, and hence, can indirectly assess the function of meibomian glands. According to various studies, it has been proven that MGD leads to decreased TBUT. However, numerous causes of aqueous-deficient and evaporative dry eye can lead to decreased TBUT and it is

therefore, not diagnostic of MGD.^[16] In our study, meibography picked up a significant number of patients with dry eye as compared to TBUT, which was also proven by Matalia et al. Meibography also picked up many subjects missed by the OSDI questionnaire.

Meibography is a novel technique used to directly image the meibomian glands and thereby, assess meibomian gland drop out and dysfunction. The techniques of meibography itself have undergone several advancements. Meibography is still not being routinely practiced in many clinics, probably because of the need for operator expertise and the finances involved.

A noncontact meibography system has been used in our study, which includes an infrared filter and an infrared charge-coupled device video camera. Although other meibography systems also include infrared films, infrared video cameras, and infrared light, they all required a transilluminating light probe, which was directly applied to the eyelid (contact meibography), which caused a lot of patient discomfort.^[17,18]

Meibography in Dry Eye

In contrast, as developed by Arita et al in 2008,^[19] a transilluminating light probe is not necessary, making this meibography system more patient friendly. Without causing patient discomfort, this technique of non-contact meibography allows a quick and easy imaging of the upper and lower eyelids of both eyes within 1 minute. Thus, by using this method, meibography can be utilized as a routine examination during daily clinical practice. The recent innovation of pen device portable meibography, has the potential to be used as a screening tool to evaluate dry eye in outside camps and in the community.

Den et al concluded that the meibomian gland dropout became positive after 40 years of age. In addition, changes in meibomian glands develop earlier in men than in women and changes in the elderly

are more severe in men than in women.^[20] Our study also showed that meibomian gland drop out increases with age. However, it did not show any predilection for males or females.

In our study, the meiboscore did not correlate with TBUT or Schirmer test value in all patients. The explanation for this is that the Schirmer’s test measures the aqueous volume of the tearfilm, so it need not correlate with meibomian gland changes. Also, the TBUT depends on the aqueous and mucous layers, in addition to the lipid layer, which could be why it did not correlate with meibomian gland changes. These findings are in accordance with the study by Den et al.

A number of studies have reported an association between meibomian gland changes and gender. Some studies showed that sex hormones such as androgens, estrogen, and progesterone influence the lipid

profile, as well as the gene expression pattern in meibomian glands.^[21] The age-related changes of meibomian glands may be associated with a gradual decrease in androgens after 20 years of age.

Meibography in Dry Eye

However, further research is necessary to elucidate the mechanisms underlying the gender differences in age-related changes of meibomian glands.

There are numerous factors involved in the development of dry eye syndrome and ocular surface disorders. The clinical significance of these meibography findings in dry eye diagnosis and MGD need to be evaluated in future studies of patients with dry eye and MGD.

Schaumberg et al proved that aging is associated with alterations in the lipid composition of meibomian

gland secretions.^[4] A limitation of meibography is that, it evaluates only morphologic changes of the meibomian glands and cannot detect quality changes in the meibum. The relative significance of these changes in the quality of meibum and the morphologic changes of meibomian glands in the diagnosis and pathogenesis of MGD are yet to be clarified.

To conclude, noncontact meibography is a non-invasive, useful, quick, simple and patient-friendly method to obtain information about the meibomian gland structure. It is sensitive and specific for meibomian gland dysfunction, and helps to pick up cases of dry eye missed by the conventional dry eye tests. Meibomian gland dropout increases with age. Our study did not show any gender predilection for meibomian gland dropout. Additional studies are required to further elucidate the pathologic mechanisms of meibomian gland diseases and to establish better diagnostic criteria for MGD.Meibography in Dry Eye

REFERENCES

1. Epidemiology of dry eye. Report of the Epidemiology Subcommittee of the Dry Eye WorkShop (DEWS). Ocul Surf 2007;5:93-107.
2. Tiffany JM. Tears in health and disease. Eye 2003; 17: 923–26.
3. Mengi SA, Deshpande SG. “Ocular drug delivery,” in Controlled and Novel Drug Delivery, N. K. Jain, Ed. 82–90, CBS Publishers and Distributors, New Delhi, India, 1997.
4. Schaumberg DA, Sullivan DA, Dana MR. Epidemiology of dry eye syndrome. Adv Exp Med Biol 2002; 506: 989–98.
5. Wise RJ, Sobel RK, Allen RC. Meibography: A review of techniques and technologies. Saudi JOphthalmol 2012; 26: 349–56.

6. Robin JB, Jester JV, Nobe J, Nicolaides N, Smith RE. In vivo transillumination biomicroscopy and photography of meibomian gland dysfunction. A clinical study. Ophthalmology 1985; 92:1423–6.
7. Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Fukuoka S et al. Proposed diagnostic criteria for obstructive meibomian gland dysfunction. Ophthalmology 2009;116:2058–63.
8. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118:615-21.
9. Lee JH, Kee CW. The Significance of Tearfilm Breakup Time in the Diagnosis of Dry Eye Syndrome; Kor J Ophthalmol 1988; 2: 69-71.
10. Yiu SC. Dry eye disease: A review of diagnostic approaches and treatments; Saudi J Ophthalmol 2014; 28:(3) 173-81.
11. Phadatare SP, Momin M, Nighojkar P, Askarkar S, Singh KK. A Comprehensive Review on Dry Eye Disease: Diagnosis, Medical Management, Recent Developments, and Future Challenges;Meibography in Dry EyeHindawi Publishing Corporation, Advances in Pharmaceutics; Volume 2015, Article ID 704946, 12 pages

12. Nichols JJ, Berntsen DA, Mitchell GL, Nichols KK. An assessment of grading scales for meibography images. Cornea 2005;24: 382–8.
13. Nichols, KK, Mitchell GL, Zadnik K. The repeatability of clinical measurements of dry eye. Cornea2004;23:272-85

14. Matalia H, Ranganath A, Meda DR, Parekh R. Study of non-contact infrared meibography and non-invasive tear film break up time in normal and evaporative dry eye subjects. ESCRS 2014
15. McCulley JP, Shine WE. “The lipid layer of tears:dependent on meibomian gland function,”
16. Sullivan B. 4th International Conference on the Lacrimal Gland, Tear Film, & Ocular Surface and Dry Eye Syndromes 2004; Adv Exp Med Biol : 54-57.
17. Mathers WD, Daley T, Verdick R. Video imaging of the meibomian gland. Arch Ophthalmol 1994;112:448–9.
18. Yokoi N, Komuro A, Yamada H, Maruyama K, Kinoshita S. A newly developed video-meibography system featuring a newly designed probe. Jpn J Ophthalmol 2007;51:53–6.
19. Arita R, Itoh K, Inoue K, Amano S. Noncontact infrared meibography to document age-related changes of the meibomian glands in a normal population. Ophthalmology 2008;115:911–5.
20. Den S, Shimizu K, Ikeda T, Tsubota K, Shimmura S, Shimazaki J. Association between meibomian gland changes and aging, sex, or tear function. Cornea 2006;25:651–5.
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Meibography in Dry Eye

Tables-

 

			MEIBOGRAPHY				Total
			Normal	Mild-		Severe		SIGNIFICANCE
				Moderate
	Normal	n (%)	46	44		0	90
			(27.1%)	(25.9%)		(0.0%)	52.9%
SCHIRMERS	Mild-	n (%)	14	29		5	48	p = 0.002
	Mod.		(8.2%)	(17.1%)		(2.9%)	28.2%
	Severe	n (%)	7	19		6	32
			(4.1%)	(11.2%		(3.5%)	18.8%
Total		N	67	92		11	170
		(% of total)	(39.4%)	(54.1%)		(6.5%)	100.0%

Table 1– Comparing Schirmer’s test with Meibography: a cross tabulation

 

			MEIBOGRAPHY				Total	SIGNIFICANCE
			Normal	Mild-		Severe
				Moderate
		N	56	33		0	89
	Normal	(%)	(32.9%)	(19.4%)		(0.0%)	52.4%
TBUT	Mild-	N	9	43		3	55	p < 0.05
	Mod	(%)	(5.3%)	(25.3%)		(1.8%)	32.4%
	Severe	N	2	16		8	26
		(%)	(1.2%)	(9.4%)		(4.7%)	15.3%
Total			67	92		11	170
		% of Total	39.4%	54.1%		6.5%	100.0%

Table 2– Comparing TBUT with Meibography: a cross tabulation

 

Meibography in Dry Eye

			MEIBOGRAPHY				Total	SIGNIFICANCE
			Normal	Mild-		Severe
				Moderate
	Normal	N	52	48		1	101
		(%)	(30.6%)	(28.2%)		(0.6%)	59.4%
OSDI	Mild-	N	14	33		5	52
	Mod	(%)	(8.2%)	(19.4%)		(2.9%)	30.6%	p <0.05
	Severe	N	1	11		5	17
		(%)	(0.6%)	(6.5%)		(2.9%)	10.0%
Total		N	67	92		11	170
		% of Total	39.4%	54.1%		6.5%	100.0%

 

 

Table 3– Comparing OSDI with Meibography: a cross tabulation

 

Figure 1.

Figure 1- Meibomian gland images captured by the non mydriatic camera

 

The image shows grading of meiboscore as follows- Grade 0- No meibomian gland loss, Grade I- Loss of <1/3^rd of total meibomian gland area, Grade II- Loss of 1/3^rd – 2/3^rd of total meibomian gland area and Grade III- Loss of >2/3^rd of total meibomian gland area.