Tear film characteristics in patients with thyroid eye disease

Introduction

Thyroid eye disease (TED) is a chronic inflammatory condition of the orbit driven by immune mechanisms. While only 5% to 10% of patients exhibit orbital symptoms, up to 30% to 45% report complaints of dry eye (1). Dry eye can be categorized into three types: aqueous-deficient dry eye, reduced wettability, and evaporative dry eye. According to the diagnostic and treatment model for dry eye based on tear film, proposed by the Asian Dry Eye Society (ADES) in 2016, tear film break-up patterns (TFBUPs) are pivotal factors guiding diagnostic classification. Area and line breaks refer to aqueous-deficient dry eye, random breaks orient to evaporative dry eye, either dimple or spot breaks refer to reduced wettability dry eye (2). In 2021, Takahashi et al. reported that the TFBUPs in TED differ from those in simple dry eye. Line breaks were more frequently observed in TED. In addition, while random breaks in simple dry eye are usually only associated with minor ocular surface damage, those in TED were associated with a higher incidence of concomitant superior limbic keratoconjunctivitis (3). Nevertheless, Takahashi cannot figure out the correlation between dry eye and orbital inflammation, because clinical activity score (CAS) does not correspond to clinical conditions in Japanese population. This study aimed to analyze the correlation between the clinical manifestations of TED and tear film characteristics to better understand the pathophysiology of dry eye in patients with TED. We present this article in accordance with the STROBE reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-25-6/rc).

Methods

This descriptive cross-sectional study was conducted on TED patients who presented to the Oculoplastic and Neuro-Ophthalmology Department of Eye Hospital of Ho Chi Minh City from January to August 2024. A diagnosis of TED was made on the Bartley-Gorman criteria (4), and dry eye was diagnosed on the definition proposed by the ADES (2,5). Both eyes/sides were eligible in this study because TED can present differently between the two eyes/sides in the same patient (3). Eyes were excluded if they met one of the following criteria: severe lagophthalmos hindering blinking; lacrimal system disorders; history of orbital radiation; dry eye treated with artificial tears; or history of intraocular, eyelid, or orbital surgery.

Two groups of variables were collected. Group 1: clinical data, including age, sex, CAS (7-point scale), severity of TED based on the European Group on Graves’ Orbitopathy (EUGOGO) classification (6), palpebral fissure height (FH), and proptosis measured by Hertel’s exophthalmometer. Group 2: ocular surface parameters, including ocular surface disease index (OSDI), Schirmer I test, tear film break-up time (TBUT), and TFBUPs. Schirmer I test was performed under non-anesthetic conditions in 5 minutes. TBUT and TFBUPs were performed with fluorescein strips. The paper strip is moistened with saline water and then placed on the inferior fornix. The dye is distributed by blinking, and the patient is then asked to stare straight ahead without blinking. The tear film is observed under the cobalt blue light of a slit lamp with a yellow filter. The time, in seconds, between the last blink and the appearance of the first dry spot or hole in the tear film is measured and is equal to the TBUT. TFBUPs were classified into the following five patterns: area, line, spot, dimple, and random breaks (2,5). The area break was diagnosed when the upward movement of fluorescein was not observed or was limitedly observed in the lower cornea upon eyelid opening (2). The line break was diagnosed when a vertical line-shaped area of fluorescein was formed on the cornea immediately upon eyelid opening, and in which intensity decreased as upward movement of fluorescein was completed (2). The spot break was diagnosed when the spot-shaped areas of fluorescein formed after eyelid opening, where at least one spot remained through the upward movement of dye (2). Similarly, dimple break was diagnosed when an irregular but vertical line-shaped area of fluorescein formed near the central cornea, and in which intensity increased until the upward movement of fluorescein was completed (2). The random break was diagnosed when the fluorescein pattern formed could not be classified into the other four types (2). It generally occurs after the cessation of fluorescein upward movement. All of the tests were observed by only one examiner, and the result is the average of three measurements. The pattern that appears at least two out of three observations is recorded as the final result for TFBUPs.

We, the authors, obtained informed consent from each patient after a full explanation of the study, including its procedures, safety measures, and benefits of participation. Participation in the study was entirely voluntary, and participants had the right to withdraw at any time without facing discrimination or prejudice.

During the preparation of this work, the authors used the Curie AI tool for providing English grammar correction. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Statistical analysis

The data were analyzed using IBM SPSS Statistics 20 software. Qualitative results were presented as proportions (%) and rounded to one decimal place. Quantitative results were expressed as either mean or median, also rounded to one decimal place. The main statistical tests used included: the χ² test, t-test, Fisher’s exact test, Kruskal-Wallis test, analysis of variance (ANOVA), and Spearman’s correlation test. A statistically significant difference was considered when the P value was less than 0.05.

Ethical considerations

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional Ethics Committee of Pham Ngoc Thach University of Medicine (No. 936/TDHYKPNT-HDDD) and informed consent was taken from all individual participants.

Results

Clinical characteristics of patients with TED

A total of 60 eyes from 31 patients participated in the study, including 29 patients whose data were collected from both eyes and 2 patients whose data were collected from only one eye because the other eye was unable to blink sufficiently to form a tear film. Among the participants, 21 female patients and 10 male patients were included. The mean age was 45.32±12.58 years, with a distribution ranging from 19 to 70 years. The mean CAS was 2.63±2.01, with 33 eyes (55.00%) in the active phase. Most cases were classified as mild TED, observed in 40 eyes (66.67%), while 13 eyes (21.67%) were moderate-to-severe, and 7 eyes (11.67%) were sight-threatening. The mean FH was 9.67±2.21 mm, ranging from 6 to 15 mm. The mean value of proptosis was 19.48±2.76 mm, ranging from 15 to 26 mm.

Dry eye status

The OSDI showed a wide range of scores, from 2.50 to 88.89, with a mean score of 30.36±22.17. Both the Schirmer I test and TBUT also exhibited substantial variability. Schirmer I test ranged from 2 to 35 mm, with a mean value of 13.97±9.95 mm. TBUT ranged from 0 to 25 seconds, with a mean value of 7.62±6.78 seconds. Among the 60 eyes diagnosed with TED, 40 (66.67%) were diagnosed with dry eye (OSDI ≥13 and TBUT ≤5 seconds). Line break was observed in 23 eyes (57.5%), which was the most common pattern. Random break was found in 12 eyes (30.00%), which was the second most frequent. Other patterns, including dimple, area, and spot break, were observed in 2 eyes (5.00%), 2 eyes (5.00%), and 1 eye (2.50%), respectively (Figure 1).

Figure 1 Distribution of TFBUPs in TED. TED, thyroid eye disease; TFBUPs, tear film break-up patterns.

Correlation between clinical features of TED and tear film characteristics

The OSDI was not significantly correlated with age (P=0.19), palpebral FH (P=0.36), proptosis (P=0.92), or CAS (P=0.10) (Table 1). No statistically significant differences were observed in the OSDI, Schirmer I, or TBUT values between sexes (P=0.53, P=0.30, and P=0.88, respectively). No significant difference in OSDI was found among TED severity subgroups (P=0.77). However, there were significant differences across the TED severity subgroups (P<0.001 and P=0.047), with both the Schirmer I and TBUT values decreasing as the TED severity increased (Table 2). Both Schirmer I and TBUT demonstrated strong negative correlations with CAS (r=−0.78, P<0.001 and r=−0.61, P<0.001) and moderate negative correlations with proptosis (r=−0.38, P=0.003 and r=−0.39, P=0.002). Neither Schirmer I nor TBUT was significantly correlated with age (P=0.18 and P=0.89) or FH (P=0.07 and P=0.83) (Table 1).

Among 60 eyes, at a CAS of less than 3 points, the Schirmer I and TBUT values exhibit dispersion. However, as the CAS exceeds 3 points, the values are remarkably centralized around the linear correlation line (Figure 2).

Figure 2 Correlations between Schirmer I, TBUT, and CAS. CAS, clinical activity score; TBUT, tear film break-up time.

Among the five groups of TFBUPs, there were no statistically significant differences in sex (P=0.11), severity of TED (P=0.31) (Table 3), age (P=0.17), or FH (P=0.24) (Table 4). However, significant differences were observed in CAS (P=0.001) and proptosis (P=0.03). The CAS was the highest for area break, followed by line break, then random and spot break, and the lowest CAS was for dimple break. Similarly, the most pronounced exophthalmos was in the area break, followed by the line and spot break, and then the dimple and random break (Table 4).

Among the 33 eyes in the active phase of TED, 29 (87.88%) had dry eye. The most common TFBUP was line break, which was observed in 21 eyes (72.41%). Area break was found in 2 eyes (6.90%), and random break was found in 6 eyes (20.69%). In the active phase, dimples or spot breaks were not observed. In contrast, the dry eye prevalence was only 40.74% (11 eyes) among 27 non-active TED eyes. The distribution of TFBUPs in the non-active TED group also differs from the active TED group, with random break, which refers to evaporative dry eye, was the most common pattern, which was observed in 6 eyes (54.54%). Either line or dimple break was found in 2 eyes (18.18%). One eye (9.09%) had spot break, and no area break was found in non-active TED eyes.

Discussion

The evaluation of TFBUPs via fluorescein staining is a safe, convenient method that provides valuable results. In this context, assessing the TFBUPs in TED patients has garnered attention because the method can be performed even when the upper eyelid cannot be everted—a common limitation in the active phase of TED.

Compared with the distribution of TFBUPs in general dry eye patients studied by Shigeyasu et al. (7), we found that only the line break had a comparable proportion (51.6%) and was the most common pattern. The random break, however, was less common in general dry eye patients (13.5%) than in TED patients in this study and in Takahashi’s research (3). The remaining three break-up patterns also showed some differences when comparing general dry eye patients to TED patients (Table 5).

In this study, the Schirmer I score and TBUT were critical indices for evaluating dry eye, as they were significantly associated with TED. These findings reaffirm the role of TED in dry eye pathogenesis. However, even parameters with no statistically significant differences or correlations provide a more comprehensive understanding of the relationship between TED and dry eye.

The Schirmer I values decreased significantly with increasing severity of TED. However, the palpebral FH was not correlated with the Schirmer I results (P=0.07), suggesting that aqueous-deficient dry eye in TED involves distinct pathophysiological mechanisms unrelated to FH. Previous studies on the mechanisms linking TED to tear film and dry eye have explored how TED impacts tear film dynamics. Gilbard et al. (8) noted that higher palpebral fissures and increased blink frequency led to more corneal damage and greater tear film osmolarity, attributing evaporative dry eye to wider fissures. However, in 2006, Tear Film and Ocular Surface Society (TFOS) reported that increased blink frequency was a protective reaction to ocular surface damage in TED rather than a causative factor for dry eye. Instead, a reduced blink frequency, which is often caused by proptosis and wide palpebral fissures, contributes to evaporative dry eye (9). Recent studies have further elucidated the mechanisms that meibomian gland dysfunction (MGD) caused by incomplete blinking leads to evaporative dry eye (1). Takahashi’s study on TED patients who underwent orbital decompression surgery revealed that despite resolving proptosis and eyelid issues, most patients’ dry eye symptoms persisted (10). In addition to evaporative dry eye, which has been extensively studied previously, aqueous-deficient dry eye, which is independent of FH, is also a major pathogenic mechanism. Schirmer I showed a strong inverse correlation with CAS, suggesting that inflammation in active TED might damage the lacrimal gland. Eckstein et al. provided evidence of thyroid-stimulating hormone receptor (TSHR) expression in lacrimal gland acinar cells, supporting the hypothesis that autoimmune inflammation during active TED damages the lacrimal gland, leading to aqueous deficiency (11). Although the sample size of this study is small due to TED being a rare disease, this is a hypothesis worth considering.

In this study, 87.88% of the 33 eyes with active TED had dry eye, 79.31% exhibiting area and line break-up patterns, indicating aqueous-deficient dry eye. The area break was associated with the highest CAS, whereas the dimple break corresponded to the lowest CAS (mean of 1.5 scores). These findings differ from Takahashi’s results, which revealed no significant CAS differences across the TFBUPs groups (P=0.08) (3). However, owing to special ethnic characteristics in the Japanese population, the CAS may not reliably reflect TED activity in those studies (3), limiting their comparability with research on non-Japanese populations.

Conclusions

TED significantly impacts dry eye disease, particularly through inflammation during the active phase. In addition to managing and controlling TED, the diagnosis and treatment of dry eye, particularly aqueous-deficient dry eye, require careful attention and should address not only evaporative dry eye as previously studied. While orbital inflammation has been implicated in the pathogenesis of aqueous-deficient dry eye, there is no definitive conclusion regarding treatment options targeting this mechanism or their effectiveness. Therefore, further research is needed to address these unresolved issues and optimize treatment strategies for TED patients.

Acknowledgments

During the preparation of this work, the authors used the Curie AI tool for providing English grammar correction. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-25-6/rc

Data Sharing Statement: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-6/dss

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-25-6/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-25-6/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional Ethics Committee of Pham Ngoc Thach University of Medicine (No. 936/TDHYKPNT-HDDD) and informed consent was taken from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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