Analysis on the First Tear Film Break-up Point in Sjögren's Syndrome and non-Sjögren's Syndrome Dry Eye Patients

DOI: https://doi.org/10.21203/rs.3.rs-79470/v1

Abstract

Background：Tear film instability plays an important role in the course of Sjögren's Syndrome dry eye (SSDE) even though it is generally classified as aqueous-deficient dry eye. The measurement of the first tear film break-up point (FTBUP) helps to evaluate the most unstable position of the tear film on ocular surface. We aim to investigate the first tear film break-up point (FTBUP) in Sjögren's Syndrome dry eye (SSDE) and non-Sjögren's Syndrome dry eye (NSSDE) patients, and explore its correlation with dry eye indices.

Methods: Twenty-two SSDE patients (44 eyes) and 22 NSSDE patients (44 eyes) were enrolled in the study. Oculus Keratograph K5M was used to measure the FTBUP, the first and average non-invasive keratographic breakup time (f-NIKBUT and av-NIKBUT), and meibomian gland dropout. Other tests of tear film were also performed including Ocular Surface Dryness Index (OSDI), Schirmer I test, fluorescein break-up time and corneal fluorescein staining.

One-way ANOVA with Bonferroni adjustment was used to compare dry eye indices. The locations of the FTBUP were compared between SSDE and NSSDE patients using chi-square test. The correlations between the FTBUP and ocular symptoms and signs were investigated using Pearson’s correlation coefficient test.

Results: The FTBUP occurred at the supranasal quadrant in 12/88 eyes, supratemporal quadrant in 8/88 eyes, inferonasal quadrant in 34/88 eyes, and inferotemporal quadrant in 34/88 eyes. The percentage of the FTBUPs occurring at the inferior cornea was significantly higher in the SSDE group than in the NSSDE group (86.3% vs 68.1%, P=.042). Moreover, FTBUP was more frequently observed in the temporal area in SSDE patients with positive corneal fluorescein staining, as opposed to the nasal area in SSDE patients with negative corneal staining(P=.032).

Conclusion: Tear film was more unstable in the inferior cornea than other areas of cornea in both SSDE and NSSDE patients. The location of the FTBUP in SSDE patients had a close relationship with cornea fluorescein staining. 

Background

Dry eye is a multifactorial disease of the ocular surface in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.(1) Dry eye has become the focus of ophthalmologists because of its increasing morbidity and trend in young people. The tear film serves as the most anterior barrier of the ocular surface, reducing the exposure of the corneal epithelium to air and providing a smooth optical surface.(2–4) To maintain the quantity and quality of a healthy tear film, a sufficient volume of tears and normal properties of the lipid layer are necessary.(5) The loss of homeostasis of the tear film is the major characterization of dry eye, leading to varying degrees of ocular symptoms such as dryness, grittiness and a burning sensation.

Sjögren's syndrome is a severe autoimmune disorder that destroys exocrine glands, including lacrimal and salivary glands, with lymphocytic infiltration.(6) Sjögren's syndrome dry eye (SSDE) is generally classified as aqueous-deficient dry eye because of the hyposecretion of lacrimal glands that were attacked by activated T-cells.(7) Other pathologic changes, such as meibomian gland dropout and mucin deficiency, are often seen in SSDE.(8–10) The clinical manifestations in SSDE are more severe than those in non-Sjögren's syndrome dry eye (NSSDE), including worse tear secretion, shorter tear film break-up time, more intensive corneal epithelial staining, more severe ocular surface inflammation, fewer corneal nerve fibres and lower cellular density of epithelial cells.(9–14) Severe complications may be developed including corneal perforation/scleritis due to SS, and other organs may also be affected. Early recognition is important as patients with SS to prevent vision or life-threatening complications, unlike other autoimmune diseases, are first seen by eye care providers.(15–17)

With the development of imaging technologies, new quantitative examinations with good repeatability have been introduced for the clinical evaluation of dry eye. The Oculus Keratograph 5M (Wetzlar, Germany) has been suggested to be a noninvasive, valid and stable way to evaluate tear film stability and dynamics through the measurement of the first tear film break-up point (FTBUP) and noninvasive keratograph tear film break-up time (NIKBUT).(18) Nevertheless, only a few studies have focused on the location of FTBUP in dry eyes.(19),(20) It has been reported that the peripheral domain of the inferior quadrant and the central domain of the superior quadrant were the most common FTBUP areas in patients with cataract and dry eye.(21) However, no study has compared the location of FTBUP between SSDE and NSSDE patients, and the clinical relevance of the location of FTBUP has yet to be explored. We expected that the location of FTBUP would differ between SSDE and NSSDE in terms of the differences of tear film stability and corneal epithelial lesion, which would be beneficial for the early recognition of SS. This cross-sectional comparative study evaluated FTBUP of SSDE and NSSDE using the Oculus Keratograph and investigated its correlation with other dry eye examinations.

Methods

Patients

Forty-four patients were recruited consecutively from the dry eye clinic at the Eye, Ear, Nose & Throat Hospital of Fudan University from March to October 2019. Written informed consent was obtained from all the participants.

The diagnosis of primary and secondary Sjögren's syndrome was made based on the 2012 American College of Rheumatology (ACR) classification criteria.(22) The inclusion criteria for dry eye included the presence of at least one of the following dry eye symptoms (dryness, burning sensation, grittiness, photophobia, pain, tickle); Schirmer I test <5 mm/5 min or 5 mm/5 min < Schirmer I test < 10 mm/5 min with positive fluorescein staining; BUT < 5 s or 5 s < BUT < 10 s with positive fluorescein staining. The exclusion criteria were a history of ocular surgery within 6 months; concomitant ocular lesions such as acute inflammation or infection, glaucoma, etc.; a history of wearing contact lens; ocular trauma; eyelid abnormalities; pregnancy or lactation; systematic diseases that would probably affect tear function except primary and secondary Sjögren's syndrome; medications that would alter the ocular surface; and patients who could not cooperate during the examinations.

Forty-four eyes of 22 SSDE patients (20 females, 2 males, average age 58.32 ± 12.11 years) and 44 eyes of 22 NSSDE patients (19 females, 3 males, average age 53.41 ± 11.78 years) met the inclusion criteria. Among the 22 SSDE patients, 20 patients were not newly diagnosed (4 months to 10 years since initial diagnosis), and 19 were receiving topical cyclosporine A eye drop treatment. None of the NSSDE patients had topical immunosuppressive medications.

Ocular examinations

With the help of a trained interviewer, the participants completed the Ocular Surface Disease Index (OSDI) before the ocular examinations to ensure that the clinical examination would not influence their responses. After that, all subjects underwent a thorough dry eye examination including the Oculus Keratograph 5M (FTBUP, meibography, NIKBUT, and tear meniscus height) and slit-lamp biomicroscopy (Fluorescein tear film break-up time (FBUT) and corneal fluorescein staining). The Schirmer I test was performed at the end to avoid any impact on the other examinations. The time of examination was from 9 a.m. to 12 a.m. The room was quiet with a constant temperature of 25ºC and humidity of 50%. None of the patients used any eyedrops on the day of examination.

Ocular Surface Disease Index (OSDI)

The OSDI questionnaire included twelve questions to quantify ocular disability during a one-week recall period. The participants were assessed on three main subscales: ocular symptoms, vision-related functions and limitations, and environmental stimulant.(23) A higher OSDI value (0-100) indicated more severe ocular discomfort.

FBUT

The fluorescein strips (Jingming, Tianjing, China) were moistened by a drop of borate buffer; excessive fluid was shaken off to instil a minimal volume fluorescein into the lower fornix. The patients were required to blink naturally several times and then keep the eyes open and look straight ahead. Under the cobalt blue light of the slit lamp, the time (seconds) from the last blink to the first appearance of dry spots on the corneal surface was recorded as FBUT. The examination was performed three times for each eye. The average FBUT was calculated.

Corneal Fluorescein Staining

Corneal fluorescein staining was graded under the cobalt blue filter after the measurement of FBUT. The optimal observation time was within 1–3 min after fluorescein instillation.(24) The corneal surface was divided into five areas as proposed by the US National Eye Institute,(25) and the punctate staining in each area was recorded as a score of 0–3: 0: no staining; 1: <15 dots; 2: 16–20 dots; 3: >30 dots, strip/bulk staining or corneal filaments. The range of the total score was 0–15. Scores ≥ 1 were considered positive fluorescein staining.

Assessment of FTBUP and NIKBUT

The Oculus Keratograph 5M was used to assess the location of FTBUP. The regularity of the tear film surface changed when the tear film broke up, which was captured and presented as a colour-coded tear map (Fig. 1A). The corneal surface was divided into four quadrants around the pupil: supranasal, inferonasal, supratemporal and inferotemporal, as shown in Fig. 1A. The break-up area with the shortest NIKBUT was recorded as the location of FTBUP. The first and average NIKBUT were also evaluated. All tests were repeated three times for each eye. 

Meibography and Measurement of the Tear Meniscus Height

The images of the upper and lower eyelids of the meibomian gland were captured by the Oculus Keratograph 5M (Fig. 1B), and ImageJ software (National Institutes of Health, USA, https://imagej.nih.gov/ij/) was used to qualitatively analyse the dropout rate of meibomian glands, as previously reported.(26) The tear meniscus height was measured three times, as previously reported,(27) by the use of infrared images taken at the central point of the lower lid margin. The average values were calculated.

Schirmer I Test

The Schirmer test without anaesthesia (Schirmer I test) is a reliable and objective test to evaluate basic tear flow.(1) A Schirmer paper strip (5 × 40 mm, Jingming, Tianjing, China) was folded at the notch, and the folded end was placed into the temporal one-third portion of the lower conjunctival fornix. Patients were asked to close their eyes gently for 5 min. The length of wetting from the notch was measured.

Statistics Analysis

The statistical analysis was performed using SPSS software (version 24, SPSS Inc, Chicago, IL). Tabulated data are presented as the mean ± SD. One-way ANOVA with Bonferroni adjustment was used to compare the mean age, OSDI value, Schirmer I test, tear meniscus height, FBUT, NIKBUT, and fluorescein staining score between SSDE and NSSDE groups. The chi-square test was used to make comparisons of FTBUP between SSDE and NSSDE groups and dry eye patients with or without corneal fluorescein staining. The differences in meibomian gland dropout between SSDE and NSSDE groups were also analysed by the chi-square test. Pearson’s correlation coefficient test was used to analyse the relationship among dry eye-related indices in SSDE and NSSDE. A P value less than 0.05 was considered statistically significant.

Results

OSDI Values, Tear Production, Tear Film Stability and Corneal Fluorescein Staining Score

The OSDI values were significantly higher in SSDE patients (56.91±16.25) than in NSSDE patients (28.03±13.62) (P<.001). The values of the Schirmer I test, tear meniscus height, FBUT and first noninvasive keratograph tear film break-up time (f-NIKBUT) in SSDE were 62%, 32%, 50% and 26% lower than those in NSSDE (P<.001; P=.001; P<.001; P=.031; Table 1). The average noninvasive keratograph tear film break-up time (av-NIKBUT) was similar between SSDE and NSSDE (P=.091). The corneal fluorescein staining scores were 4-fold higher in SSDE than in NSSDE patients (3.61±4.46 vs 0.16±0.57, P<.001) (Table 1). The number of patients with positive fluorescein staining in SSDE was almost 4 times higher than that in NSSDE (29/44 eyes vs 6/44 eyes, P<.001) (Table 2).

Table 1

Demographic Data and Clinical Characteristics of SSDE and NSSDE patients.

 

NSSDE（n=44）

SSDE（n=44）

P

Age

Sex

OSDI score

53.41±11.78

3M/19F

13.45±6.54

58.32±12.11

2M/20F

27.31±7.80

.057

.644

＜.001

Schirmer I test(mm/5min)

9.32±7.75

3.57±4.35

＜.001

TMH(mm)

.19±0.08

0.13±0.08

.001

FBUT(s)

3.43±1.74

1.70±1.80

＜.001

f-NIKBUT(s)

5.60±3.78

4.15±2.26

.031

Av-NIKBUT(s)

7.98±4.60

6.36±4.32

.091

FL score

0.16±0.57

3.61±4.46

＜.001

TMH, Tear meniscus height; FBUT, Fluorescein break-up time; f-NIKBUT, first-noninvasive keratograph tear film break-up time; Av-NIKBUT, average-noninvasive keratograph tear film break-up time; FL score, Fluorescein staining score.

 

The location of FTBUP

In general, FTBUP occurred more frequently at the inferior cornea than at the superior cornea in both SSDE (inferior 86.3% vs superior 13.6%, P<.001) and NSSDE (inferior 68.2% vs superior 31.8%, P=.023). Moreover, the percentage of FTBUP occurring at the inferior cornea was significantly higher in SSDE than in NSSDE group (P=.042).

Further analysis showed that FTBUP of SSDE was found in the supranasal quadrant in 4 (9.1%) eyes, in the supratemporal quadrant in 2 (4.5%) eyes, in the inferonasal quadrant in 17 (38.6%) eyes, and in the inferotemporal quadrant in 21 (47.7%) eyes; in NSSDE, the number of eyes with FTBUP in each of the respective quadrants was 8(18.2%) eyes, 6 (13.6%) eyes, 17 (38.6%) eyes and 13 (29.5%) eyes. Although the distributions of FTBUP in the four quadrants in SSDE and NSSDE were not identical,

no significant difference was found between the two groups (P=.173). (Table 2).

Table 2

Regional difference of FTBUP between SSDE and NSSDE, positive fluorescein staining and negative

 

 

Supranasal

(n/%)

Supratemporal

(n/%) 

Inferonasal

(n/%)

Inferotemporal

(n/%) 

Total

(n/%)

P value

 

SSDE

FL (-)

4 (26.7%)

0 (0.0%)

5 (33.3%))

6 (40.0%)

15 (100.0%)

.032a

.173*∆

.042*‡

FL (+)

0 (0.0%)

2 (6.9%)

12 (41.4%))

15 (51.7%)

29 (100.0%)

Total

4 (9.1%)

2 (4.5%)

17 (38.6%))

21 (47.7%)

44 (100.0%)

＜.001c

 

 

 

 

 

 

 

 

NSSDE

FL (-)

7 (18.4%)

6 (15.8%)

14 (36.8%)

11 (28.9%)

38 (100.0%)

.928a

FL (+)

1 (16.7%)

0 (0.0%)

3 (50.0%)

2 (33.3%)

6 (100.0%)

Total

8 (18.2%)

6 (13.6%)

17 (38.6%)

13 (29.5%)

44 (100.0%)

.023c

 

Total

20（22.7%）

68（77.3%）

 

＜.001e

 

 

 

 

 

 

 

FL (-)

SSDE

4 (26.7%)

0 (0.0%)

5 (33.3%))

6 (40.0%)

15 (100.0%)

.387b

.049**∆

.010**‡

NSSDE

7 (18.4%)

6 (15.8%)

14 (36.8%)

11 (28.9%)

38 (100.0%)

Total

11 (20.8%)

6 (11.3%)

19 (35.8%)

17 (32.1%)

53 (100.0%)

.013d

 

 

 

 

 

 

FL (+)

SSDE

0 (0.0%)

2 (6.9%)

12 (41.4%))

15 (51.7%)

29 (100.0%)

.232b

NSSDE

1 (16.7%)

0 (0.0%)

3 (50.0%)

2 (33.3%)

6 (100.0%)

Total

1 (2.9%)

2 (5.7%)

15 (42.9%)

17 (48.6%)

35 (100.0%)

＜.001d

 

Total

20（22.7%）

68（77.3%）

 

＜.001e

 

SSDE, Sjögren's Syndrome Dry Eye; NSSDE, non- Sjögren's Syndrome Dry Eye; FL, Cornea Fluorescein staining

*∆: Cochran–Mantel–Haenszel2 test between SSDE and NSSDE groups in four different quadrants.

*‡: Cochran–Mantel–Haenszel2 test between SSDE and NSSDE groups in superior and inferior quadrants.

**∆: Cochran–Mantel–Haenszel χ2 test between FL (-) and FL (+). patients in four different quadrants.

**‡: Cochran–Mantel–Haenszel χ2 test between FL (-) and FL (+). patients in superior and inferior quadrants.

a: Cochran–Mantel–Haenszel2 test between FL (-) and FL (+) in SSDE and NSSDE groups.

b: Cochran–Mantel–Haenszel2 test between SSDE and NSSDE groups in FL (-) and FL (+) patients.

c: Binomial test between superior quadrants and inferior quadrants in SSDE and NSSDE groups.

d: Binomial test between superior quadrants and inferior quadrants in FL (-) and FL (+) patients.

e: Binomial test between superior quadrants and inferior quadrants.

 

As shown in Table 2, the locations of FTBUP had difference between eyes with and without corneal fluorescein staining (P=.049). The eyes with fluorescein staining (91.5%) had a higher proportion of FTBUP occurring in the inferior quadrant than those without staining (67.9%) (P=.010). In SSDE with fluorescein staining, FTBUP occurred more frequently in the temporal quadrants (17 eyes, 58.6%). However, FTBUP was more likely to be seen in nasal quadrants in those without fluorescein staining (8 eyes, 60.0%) (P=.032). Nevertheless, corneal fluorescein staining did not affect the location of FTBUP in NSSDE patients (Table 2).

Meibomian Gland Dropout

The meibomian gland dropout rate in SSDE (upper 47.52±19.49% and lower 69.24±

20.69%) was significantly higher than that in NSSDE (upper 34.63±13.47% and lower 49.57±23.49%) (P=.001). The dropout of the lower eyelid was more severe than that of the upper eyelid in both groups (SSDE: upper 47.52±19.49% vs lower 69.24±20.69%, P<.001, NSSDE: upper 34.63±13.47% vs lower 49.57±23.79%, P=.001). Meibomian gland dropout of the upper eyelid, which was mostly found at the temporal part in both SSDE (18 eyes, 40.9%) and NSSDE (27 eyes, 61.4%) (Table 3), had a negative correlation with FBUT (R=-.227, P=.033) and av-NIKBUT (R=-.268, P=.012). No correlation was found between meibomian gland dropout and f-NIKBUT (Figure 2A).

Table 3

The distribution of meibomian gland dropout in SSDE and NNSDE.

 

Position of eyelid

NSSDE（%）

SSDE（%）

P value*

MG dropout of upper eyelid

Nasal part

6(13.6%)

10(22.7%)

.248

Central part

4(9.1%)

4(9.1%)

Temporal part

27(61.4%)

18(40.9%)

Undifferentiated

7(15.9%)

12(27.3%)

 

MG dropout of lower eyelid

Nasal part

13(29.5%)

13(29.5%)

.241

Central part

0(0%)

1(2.3%)

Temporal part

7(15.9%)

2(4.5%)

Undifferentiated

24(54.6%)

28(63.7%)

P value**

 

＜.001

＜.001

 

MG: Meibomian gland

*: 2 test of MG dropout between SSDE and NSSDE groups in upper and lower eyelid.

**: 2 test of MG dropout between upper eyelid and lower eyelid in NSSDE and SSDE groups.


The Correlations between OSDI Values and Dry Eye Examinations

The OSDI values showed a strong negative correlation with FBUT in both SSDE (R=-.749, P<.001) and NSSDE (R=-.705, P<.001). A moderate negative correlation between the OSDI values and av-NIKBUT was observed in NSSDE  (R=-.531, P<.001). However, no significant correlation was found between the OSDI and f-NIKBUT in the two groups (Figure 2B, 2C). In addition, the OSDI values had a weak positive correlation with corneal fluorescein staining scores in SSDE (R=.306, P=.044), which was not found in NSSDE (R=.112, P=.471). There was no significant correlation between the OSDI values and the Schirmer I test values and meibomian gland dropout in either SSDE or NSSDE groups.

Discussion

SSDE patients usually have more severe discomfort symptoms and ocular surface damage than NSSDE patients according to previous studies.(9-14) The current study obtained similar results: SSDE patients had higher OSDI values, less tear production, more unstable tear film, more severe corneal staining, and even a higher rate of meibomian gland dropout.

As far as FTBUP was concerned, we found that FTBUP predominantly occurred in the inferior quadrant, which was seen in 90% eyes of SSDE and 70% of NSSDE. This result was similar to previous studies focused on aqueous-deficient dry eye and meibomian gland dysfunction.(19, 20) Three possible reasons might contribute to the predominance of FTBUP in the inferior area. First, the inferior region had a thinner tear film than the superior region,(28-30) which was more likely to break up earlier. Second, subbasal nerve abnormalities caused by long-term ocular surface inflammation, especially in dry eye patients, are characterized with reduced density, abnormal morphology, impaired corneal sensation and abnormal blinking.(31, 32) Reduced blinking rate and incomplete blinking contributed to overexposure of the ocular surface, especially the interpalpebral area, and increased tear evaporation.(33) Third, a higher rate of meibomian gland dropout of the lower eyelid caused reduced lipid production in the inferior region, which also contributed to the instability of the inferior tear film. Therefore, FTBUP was more likely to occur in this area in both SSDE and NSSDE groups.

The current study showed a higher proportion of eyes with positive fluorescein staining and higher fluorescein staining scores in SSDE, which was in agreement with previous studies.(13, 34) Moreover, the location of FTBUP was strongly correlated with positive corneal fluorescein staining in SSDE. Amplified inflammatory response and desiccation stress of the ocular surface in SSDE could lead to the destruction of intracellular tight junctions of the corneal epithelium and consequent damage barrier function,(35, 36) which caused the infiltration of fluorescein in this area, as well as an unsmooth corneal surface and an unstable tear film. This might explain the observed strong correlation between the location of FTBUP and corneal fluorescein staining in SSDE.

The tear film serves as the most anterior refractive surface, playing an important role in maintaining optical quality.(37-39) Many studies have shown that irregular astigmatism and wavefront aberrations caused by an unstable tear film are increased in dry eye patients.(40, 41) A short tear film break-up time increased the post-blink higher order aberrations (HOAs) and ocular forward light scattering, leading to "fluctuated vision" or "glare".(42) Liu et al (43) reported that irregularity of the ocular surface was positively correlated with corneal fluorescein staining. Our previous study showed that SSDE patients had worse visual quality.(44) The current study confirmed that tear film instability and ocular surface damage might be possible reasons. Nevertheless, the impact of different locations of FTBUP on visual quality needs further investigation.

Qi et al (20) showed that meibomian gland dropout was positively correlated with OSDI values in patients with dry eye, while Zang et al (10) suggested that meibomian gland dropout was inconsistent with symptoms in SSDE. In our study, although SSDE patients had a higher rate of meibomian gland dropout than NSSDE patients, no significant correlation was found between meibomian gland dropout and OSDI values in either SSDE or NSSDE. Heterogeneity of the signs and symptoms of dry eye, which have a close relationship to the course and condition of the disease and corneal sensation, existed in different studies. Hence, mild or well-controlled SSDE patients may have fewer symptoms than severe or uncontrolled NSSDE patients.

Several limitations of the current study should be addressed. First, the OSDI questionnaire only evaluated ocular symptoms within the most recent week. However, most SSDE patients in our study had a long course of disease and might have decreased corneal sensation. The symptoms evaluated by the OSDI questionnaire may not be consistent with the ocular surface signs. Second, 90.9% of SSDE in the present study were not newly diagnosed, and 86.3% had already had immunosuppressant treatment such as cyclosporin A. Different treatment regimens might affect the results. The sample size was also limited. Further study with a larger number of newly diagnosed SSDE is needed to verify the findings of the current study and to investigate the impact of different locations of FTBUP on visual quality.

In conclusion, FTBUP was more likely to occur in the inferior quadrant in both SSDE and NSSDE. The location of FTBUP in SSDE had a close relationship with corneal fluorescein staining. Hence, the maintenance of an intact and healthy corneal epithelium is crucial to a stable tear film and good visual quality.

List Of Abbreviations

FTBUP   First tear film break-up point

SSDE   Sjögren's Syndrome Dry Eye

NSSDE   non-Sjögren's Syndrome Dry Eye

FBUT   Fluorescein tear film break-up time

NIKBUT   Noninvasive keratograph tear film break-up time

f-NIKBUT   first-Noninvasive keratograph tear film break-up time

av-NIKBUT   average-Noninvasive keratograph tear film break-up time

Declarations

Ethics approval and consent to participate

This study conformed to the Helsinki Declaration and was approved by the Ethics Committee of the Eye, Ear, Nose & Throat Hospital of Fudan University.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

The collection, analysis, and interpretation of data in this study were supported by the National Natural Science Foundation of China (NSFC) (81970767) and the Natural Science Foundation of Shanghai(SCST) (19ZR1408200)

Authors' contributions

QL provided the diagnosis of patients and the results under the slit-lamp microscope. SZ analyzed and interpreted the patient data, and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

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