Objective optical assessment of tear-film quality dynamics in patients with meibomian gland dysfunction and aqueous-deficient dry eye optical quality changes in different dry eye subtypes.

Purpose: To evaluate the optical quality and tear-film dynamics in patients with aqueous-deficient or evaporative subtype of dry eye disease (DED).
Methods: Twenty-five aqueous-deficient dry eye (ADDE) patients, 25 DED patients with meibomian gland dysfunction (MGD), and 25 healthy subjects were included in this study. Vision-related health-targeted quality of life was evaluated using the Ocular Surface Disease Index (OSDI) questionnaire. Dynamic recording with a double-pass system (Optical Quality Analysis System [OQAS]) was performed in right eyes. Scattered light was measured as the objective scatter index (OSI) at 0.5-second intervals over 20 seconds without blinking. Then, we recorded OSI every 0.5 seconds within a 20-second period with the subjects asked to blink freely. Several parameters were established to evaluate the dynamic alterations of optical quality and the effects of blinks: OSI, OSI standard deviation (SD), ΔOSI, ΔOSI/time, blinking change (BC), and blinking frequency (BF). Additional clinical examination included tear film break-up time (BUT), Schirmer I test (SIT), fluorescein staining grade (FL), meibomian gland quality, meibomian gland expressibility, and meibomian gland drop-out.
Results: The OSI, SD, ΔOSI, ΔOSI/time, BC, and BF were significantly higher in DED patients than controls (P < 0.01, respectively). The OSI, SD, ΔOSI, ΔOSI/time, BC, and BF were significantly higher in patients with MGD than patients with ADDE (P < 0.01). In the MGD group, BUT, FL staining score, lid abnormality, meibomian gland expressibility, and meibomian gland drop-out were correlated with Δ OSI and Δ OSI/time.
Conclusion: Dry eye patients with MGD had significant alterations of optical quality compared with ADDE patients. The double-pass system has potential to be a useful quantitative method to evaluate the optical quality and tear-film dynamics in patients with dry eye.

Dry eye disease (DED) is a common pathology of the ocular surface and tears, which can result in decreased visual acuity, ocular discomfort, and tear-film instability with potential damage risk to the cornea. DED has a substantial impact on the quality of the eye's optical system.[1] Any local change in tear-film thickness or regularity introduces additional aberrations into the optical system that decreases image quality. Aberrations and light scattering are the main causes of optical quality degradation. Previous studies reported that the Optical Quality Analysis System (OQAS) was susceptible to both aberration and scattering.[234] The behavior of the tear film is dynamic between each blink. Therefore, observing the real-time changes of the tear film might be a more direct and objective parameter to assess dry eye. Tan et al. evaluated the dynamic changes in optical quality in patients with DED and found that the objective scatter index (OSI), ΔOSI, ΔOSI/time, blinking change (BC), and blinking frequency (BF) were significantly higher in DED patients than controls.[5] The Δ OSI and Δ OSI/time were significantly higher in patients with severe DED than patients with mild disease.[6]

However, little has been reported regarding a correlation between objective optical quality data and dry eye subtypes. DED is divided into two categories: aqueous-deficient dry eye (ADDE) and evaporative dry eye. The primary cause of evaporative dry eye is meibomian gland dysfunction (MGD).[789] In this study, we evaluate and compare the dynamic changes in optical quality and blinking-related alterations induced by MGD and ADDE patients.

Methods

This study was conducted in accordance with the tenets of the World Medical Association of Helsinki and approved by the Jinling Hospital Institutional Review Board. Informed consent was obtained from all subjects after an explanation of the purpose and possible consequences of the study.

Fifty patients with DED (23 men and 27 women) and 25 controls were enrolled. The inclusion criteria for DED were a tear film break-up time (BUT) ≤10 seconds or Schirmer I test (SIT) ≤10 mm, the presence of dry eye symptoms, and fluorescein staining (FL) score <3 points. DED patients were separated into an ADDE group (25 patients) and an MGD group (25 patients). A diagnosis of ADDE was made on the basis of Schirmer's test ≤5 mm. MGD patients were defined as follows: at least one lid margin abnormality and poor meibomian gland expressibility (grade ≥ 1).[10] The exclusion criteria were the following: best corrected visual acuity <1.0, history of ocular surgery or trauma, contact lens wearing within the past 3 months, and other ocular diseases or topical treatment that may influence quality of vision.

All patients took the Ocular Surface Disease Index (OSDI) questionnaire. Scores on the OSDI ranged from 0 to 100, with higher scores indicating greater discomfort.[11] Then, patients underwent the following examinations by the same ophthalmologist.

BUT was evaluated by placing a single fluorescein strip over the inferior tear meniscus after instilling a drop of normal saline, and the elapsed times before initial formation of dry spots were recorded. The mean time for three attempts was recorded. SIT was performed without topical anesthesia by placing a standard SIT filter strip in the mid-lateral portion of the lower fornix. The amount of wetting was recorded after 5 minutes. FL score included corneal and conjunctival surface staining. Corneal staining was evaluated using the scale of five corneal regions (central, superior, temporal, nasal, and inferior). FL of the nasal and temporal conjunctiva was scored from 0 to 3 using a blue-free barrier filter.[12]

Meibomian gland expression was graded on a 4-point scale (quality: 0 = clear fluid, 1 = cloudy fluid, 2 = cloudy particulate fluid, 3 = inspissated like toothpaste; expressibility: 0 = all glands expssible, 1 = 3-4 glands expressible, 2 = 1-2 glands expressible, 3 = no glands expressible) following firm digital pressure to the eyelid margins. Lid margin abnormalities were scored as 0 (absent) or 1 (present) for the following 4 parameters: vascular engorgement, plugged meibomian gland orifices, anterior or posterior displacement of the mucocutaneous junction, and irregularity of the lid margin. If any of these signs was present, one point was assigned for each item, with a total possible score range of 0-4 points. Meibomian gland dropout was performed by using the Keratograph 5M (Oculus Optikgeraete GmbH, Wetzlar, Germany) for the central 15 meibomian glands. The meiboscores for the upper and lower eyelids were summed to obtain a score from 0 to 6 for each eye. It was graded using the following grades: 1 = no partial glands; 2 for ≤25% partial glands; 3 = 25-75% partial glands; 4 for ≥75% partial glands).[13] Scores from the upper and lower eyelids were added to give a composite value.

OQAS was designed to objectively determine the optical quality of the human eye in daily clinical practice.[14] The examination was performed in a room without illumination to achieve the largest possible natural pupil size, with controlled temperature and humidity. The value of OSI was measured just after the subject blinked and then in 0.5-second intervals over 20 seconds without the subject blinking. Then, the patients were asked to blink freely as usual for 20 seconds. Several parameters were calculated from the OSI values of dynamic tear film analysis, such as SD, ΔOSI, ΔOSI/time, BC and BF. Only the OSI values from the inter-blink period longer than 2 seconds were used for analysis, and the parameter definitions are shown in Table 1 and Fig. 1.

Table 1

Definition of OSI-related and blinking-related parameters in tear film analysis

Parameters	Definition
OSI standard deviation, SD	Mean value of the OSI, standard deviation
∆OSI	Mean value of the OSI changes
∆OSI/time	Mean value of the OSI changes over time
Blinking change, BC	Mean value of the OSI changer between marked blinks
Blinking frequency, BF	Number of blinks within 20 s

Figure 1

Example of tear film analysis with OQAS. Objective scatter index values, blink marks, and their corresponding DP images during the analysis were recorded

All statistical analyses were performed using SPSS, and data are expressed as the mean ± standard deviation. The Kruskal-Wallis test was used to compare the mean of each parameter among the three groups of tear dynamics parameters and the results of dry eye tests. A multivariate linear regression analysis was used to investigate the correlation between the related parameters. P values less than 0.05 were considered significant.

Results

The clinical test results are provided in Table 2. There was no significant difference in age or sex among the three groups. The OSDI score did not differ significantly between the MGD group and ADDE group.

Table 2

Mean (± SD) values of tear function tests and ocular surface examinations in patients

Parameter	Control group	ADDE group	MGD group
Age (y)	43.12±18.27	43.12±18.27	43.12±18.27
Female (%)	55	59	52
OSDI	4.12±1.27	32.2±7.2*	38.2±5.6*,†
BUT (s)	12.25±3.05	6.02±1.05*	3.27±1.91*,†
SIT (mm)	25.1±8.2	1.98±0.92*	12.5±6.80*,†
FL staining score	0.0±0.1	6.23±2.19*	3.27±2.18*,†

*P<0.001 versus control group. †P<0.01 versus ADDE group

For the dry eye clinical tests, both the MGD and ADDE groups had lower TBUT and SIT and higher OSDI and FL staining scores than the control group (all P < 0.001). The SIT score was significantly lower in the ADDE group than in the MGD group (P = 0.000). The BUT and FL staining score were lower in the MGD group than in the ADDE group (P = 0.000 and P = 0.000, respectively). [Table 2 and Fig. 2].

Figure 2

Comparison of SIT, BUT, and FL scores between MGD and ADDE and the controls

Compared with normal subjects, MGD and ADDE patients had significant changes in OSI-related parameters and blinking parameters. The OSI, SD, ΔOSI, ΔOSI/time, BC, and BF were significantly higher in MGD and ADDE patients than the controls (all P < 0.001). Furthermore, the OSI, SD, ΔOSI, ΔOSI/time, BC, and BF were significantly higher in patients with MGD than patients with ADDE (all P < 0.001). The analyses of OSI-related and blinking-related parameters are shown in Table 3 and Fig. 3.

Table 3

Analysis lof OSI-related and blinking-related parameters

Parameter	Control group	ADDE group	MGD group
OSI	0.431±0.017	1.554±0.058*	2.386±0.118*,†
SD	0.178±0.011	0.401±0.024*	0.585±0.042*,†
∆OSI	0.024±0.009	0.325±0.026*	0.611±0.066*,†
∆OSI/time	0.004±0.000	0.676±0.057*	0.945±0.058*,†
BC	0.019±0.002	0.155±0.013*	0.252±0.017*,†
BF	2.680±0.150	4.000±0.216*	5.200±0.337*,†

*P<0.001 versus control group. †P<0.001 versus ADDE group

Figure 3

Comparison of OSI-related parameters: OSI (a), SD (b), ΔOSI (c), ΔOSI/time (d), BC (e), BF (f). Significant differences were observed between MGD and ADDE and the controls

In the MGD groups, TBUT and FL staining score were correlated with OSI, ΔOSI, ΔOSI/time, and BC (all P < 0.01). Lid abnormality was correlated with SD, ΔOSI, and Δ OSI/time (all P < 0.01). The meibomian gland expressibility score and meibomian gland drop-out were correlated with OSI, ΔOSI, ΔOSI/time, BC, and BF (all P < 0.01).

Discussion

The main finding of this study was that both OSI-related parameters and blinking-related parameters were greater in MGD eyes than in ADDE eyes.

In our study, both MGD and ADDE patients had significant alterations of optical quality compared with control subjects. The OSI, ΔOSI, ΔOSI/time, BC, and BF were significantly higher in MGD and ADDE patients than controls. The tear film is the first refractive surface of the visual system, and the only source of ocular scatter changes during the short time period was tear film alterations; therefore, the optical quality of the tear film can impact the quality of the retinal image. In ADDE group, the consistently greater values of optical quality are related to the low-tear volume and total tear protein. The deficiency of tear volume is accompanied by phenotypic alterations of the ocular surface, which can include corneal epithelial cell hyperplasia and stromal fibrosis. Deficiency of tear secretion or alterations of tear-film quality directly interfere with the quality of the optical system in ADDE patients.[15] In MGD group, irregular tear-film distribution and ocular surface damage are key factors in the complicated mechanisms of dry eye. The tear film is the first refractive surface of the visual system, and the ascending pattern of tear-film dynamics indicated that the tear film was unstable and gradually deteriorated in MGD patients. Beyond that, the instability of tear film and epithelial opacities associated with MGD might affect the scattered light. This result is in agreement with some previous studies. Koh et al. reported that significantly higher intraocular forward light scattering was noted in a dry eye group.[3] Tan et al. found that the OSI-related and blinking-related parameters was different between DED patients and controls.[5]

We compared the OSI for a successive 20-second period of nonblinking between MGD and ADDE. To our knowledge, this is the first study to compare the difference in objective optical quality between dry eye subtypes. Compared with ADDE, the patients with MGD had a higher OSI score, which indicated that the optical quality of MGD eyes may have deteriorated with time after a blink. The OSI is defined as the ratio between the integrated light in the peripheral ring and the central peak of the OQAS image. It is a measure of the amount of light that is scattered as it passes through the ocular structures.[16] The effect of not blinking for 20 seconds, and thus of ocular surface drying, was analysed by the rate of change in the OSI. As we know, OQAS systems evaluate the optical quality of tears in front of the visual axis. Only the tear film located in front of the pupil area affects the value of OSI.[5] In ADDE patients, the initial distortion in tear-film stability is likely to occur in the inferior part of the cornea, particularly in the inferior nasal quadrant.[17] Jiang et al. found that the tear film break-up occurred most commonly in the peripheral domain of the inferior cornea and the central domain of the superior cornea.[18] In MGD eyes, the decrease in the tear-film lipid layer may cause evaporation of the tear film from the ocular surface, especially from the central cornea. Small local changes in the central cornea will affect overall ocular scatter. Except for these regional differences, the BUT and FL staining score were lower in the MGD group than in the ADDE group. The unsteady of tear film in MGD eyes may lead to irregularities in the corneal surface and irregular tear film distribution across the corneal epithelium. Tear film break-up contributes to the exposure of an irregular corneal epithelial surface and drastically increases intraocular scattering.

In addition, just to observe the real-time changes of the tear film, we analyzed several parameters related to OSI for 20 successive seconds of blinking freely, such as SD, ΔOSI, ΔOSI/time, BC, and BF. As far as we can ascertain, this is also the first study to compare the tear-film quality dynamics and blinking-related parameters between dry eye subtypes. Tear film changes are dynamic. With free blinking, patients had similar feelings during the examination as when looking at a computer screen in their daily lives.[19] We found that the SD, ΔOSI, ΔOSI/time, BC, and BF were significantly higher in MGD patients than ADDE patients. The SD, OSI, ΔOSI, ΔOSI/time, and BC were correlated with TBUT and FL staining score. The SD, ΔOSI, ΔOSI/time, and BC were more correlated with optical quality, and BF and TL were associated with both optical quality and ocular discomfort or irritation. As we know, blinking is important to distribute the tear fluid over the ocular surface, and supports secretion from the meibomian glands. An incomplete blink may result in a prolonged exposure of the corneal surface and poor tear-film quality, causing the poor blinking effect.[20] A very abnormal tear film or secretions from the palpebral margin may lead to a poor blinking effect with increased vision quality alterations after the blink.[21] Beyond that, patients with MGD had increased densities of palpebral conjunctival epithelial and substantia propria immune cells than ADDE patients. The inflammation of lid margins is associated with a decrease in Goblet cells and a breakdown of epithelial junctions, promoting bacterial flora proliferation.[22] The loss of homogeneity in the tear film may cause significant deterioration in the retinal image quality, including wavefront aberrations and light scattering.[23] Our results are in line with some present studies. Himebaugh et al. demonstrated that eyes with short TBUT showed significantly higher change rates in the optical quality parameters than did those with normal subjects.[24] Koh et al. reported that significantly higher corneal backward light scattering was found in dry eye subjects who had central superficial punctate keratopathy.[3]

Conclusion

In conclusion, our results suggest that the optical quality in MGD patients is more serious than ADDE patients, which could be related to tear instability, reflected by increased light scattering. The OSI-related parameters and blinking-related parameters seems to be a sensitive indicator of tear film-related changes in the ocular light scattering produced over time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.