1. Introduction
Dermatochalasis is a common sign of periocular aging often seen in middle-aged and elderly people and is characterized by loose and redundant eyelid skin. Histologically, dermatochalasis is associated with macrophage-related subclinical inflammation, elastolysis, lymphostasis, reduced elastic fibers and disarranged collagen fibers [
1,
2]. Dermatochalasis-associated lymphangiectasia progresses significantly with age [
3]. Moreover, skeletal muscle mass decreases by 3–8% per decade from the age of 30 years and increases further after the age of 65 years [
4]. The orbicularis oculi muscle is a skeletal muscle that demonstrates fiber thinning with age [
5]. Decreased orbicularis oculi muscle mass contributes to decreased muscle strength and function in the elderly [
6]. Blinking is associated with the orbicularis oculi muscle and meibum secretion [
7,
8], but less so with the overlying eyelid skin. Despite this, dermatochalasis-associated redundant skin can interfere with lid hygiene and cause lid-margin inflammation and meibomian gland dysfunction (MGD). However, the effect of dermatochalasis on meibomian gland function has been less well studied.
The Standardized Patient Evaluation of Eye Dryness (SPEED) questionnaire assesses the frequency and severity of subjective symptoms [
9], and the Ocular Surface Disease Index (OSDI) questionnaire assesses the frequency of dry-eye symptoms and their effect on vision-related functions [
10]. Although the SPEED and OSDI questionnaire scores are significantly correlated [
11], the SPEED questionnaire scores more strongly correlate with evaporative dry-eye parameters, whereas the OSDI questionnaire scores more strongly correlate with aqueous tear-deficient dry-eye parameters [
12]. However, age and self-perceived health affect the scoring of subjective symptoms, whereas the presence of systemic diseases, including Sjögren syndrome, facial rosacea, rheumatoid arthritis, and peripheral artery disease as well as smoking history, increases the objective signs [
11,
13,
14,
15]. This could contribute to the discordance between the subjective symptoms and objective signs during dry-eye assessment.
Aging leads to changes in the meibomian gland but not in the meibum component [
16]. Interferometry is used to measure the lipid-layer thickness (LLT) and blink patterns of each patient. Together with meibomian gland secretion evaluation and meibography, lipid-layer interferometry is a useful technique for dry-eye assessment, both at initial diagnosis and treatment follow-up for MGD [
11,
14]. The amount of lipid secretion in MGD correlates with dry-eye parameters and ocular symptoms [
11,
17,
18,
19]. Meibomian dropout has been widely used as a diagnostic and treatment follow-up parameter for MGD [
11,
18,
20,
21,
22]. Lid hygiene has been advocated in the management of MGD [
23,
24]. However, compliance in dry-eye disease management is a major challenge [
25], and the effects of lid hygiene on meibomian gland (MG) parameters have been less well delineated. In this study, we evaluated the severity of dermatochalasis and its impact on dry-eye patients. We also evaluated the effect of lid hygiene treatment on subjective and objective dry-eye parameters.
4. Discussion
In the evaluation of tear-film lipid-related parameters, we regarded LLT as a short-term indicator, MGE as an intermediate indicator, and the severity of structural loss (meiboscale grade) as a long-term indicator. Meibomian dropout, as a diagnostic parameter for MGD, has a sensitivity of 96.7% and a specificity of 85% [
20]. Patients with more severe dermatochalasis also had higher meiboscale grades (
Table 3), which was higher for the upper lids (
Table 6A) whose MG orifices are closer to the dermatochalasis overhanging skin. Thus, we suggest that dermatochalasis could contribute to MG loss severity. Redundant skin could have hindered eyelid cleaning, and accumulated sebum could have induced inflammation of the MG orifice, especially in the upper eyelids, which resulted in functional obstruction of the MG with less MGE at the intermediate stage and structural loss with higher meiboscale grades at the late stage.
Our results are similar to those of previous studies showing that the LLT increases with age [
11,
18] and is significantly correlated with both meibomian gland expressibility and morphology in obstructive MGD [
14,
18,
19]. The positive association between MGE and LLT (
Table 3B) indicated that fewer secreting meibomian glands would lead to a lower LLT. Increased meibomian gland structural loss would also result in less secreted meibum. Theoretically, there should be a negative association between meiboscale grade and LLT. However, LLT correlated negatively with meiboscale grade only in the lower lid in our study. More than one third of DM-4 patients had an LLT ≥ 100 nm (
Table 4), and the odds ratio of having an LLT ≥ 100 was 2.59 (
p < 0.001) for patients with DM-4. As DM-4 patients had a median meiboscale grade of 1.5, sources of lipid other than meibum should have contributed to the measured LLT. Since sebum also contributes to the tear-film lipid-layer [
30], other lipids may have been measured by the interferometry. Sebum in the dermatochalasis skin folds may have contributed to the increased LLT. This paradoxical LLT measurement result confounded the negative correlation between meiboscale grade and LLT of the upper lid. Eyelid cleaning 1 day before interferometry could potentially reduce the confounding effect.
We found a significant positive correlation between meiboscale grade and age (
Table 3B), which is consistent with a report that MG dropout increased with age [
11]. Our results also showed a negative association between MGE and age (
Table 3B). Both results implied fewer secreting glands, and thus, lower LLT in older patients. However, the LLT correlated positively with age in our study (
Table 3B), but these seemingly contradictory results have been seen previously [
11,
18,
21]. This confounding effect could also have been caused by dermatochalasis-related effects.
Given that dermatochalasis increases with age [
3] and females were older in our included patients, they should have had more severe dermatochalasis. However, males had more severe dermatochalasis, and the odds ratio of males, compared with females, having dermatochalasis > DM-3 was 1.375 (
p = 0.004), probably because double-eyelid surgery is more commonly performed among females in Taiwan.
Since the dermatochalasis severity was less in females (
Table 1B), there should have been less dermatochalasis-related thick LLT and thinner LLT. For all of the 2328 included patients, LLT was higher in females, consistent with a previous study finding that females had thicker LLT [
21]. More females also had an LLT ≥ 100 nm (
Table 6B). These seemingly contradictory results could have been caused by the periocular cosmetics commonly used by females. These cosmetics contain oil components but were incompletely cleaned. When lid hygiene was performed, both LLT and subjective symptoms decreased, although there were no changes in the intermediate indicator MGE and long-term indicator meiboscale grade (
Table 7). The improvement was less significant in the more severe DM-3 and DM-4 patients (
Table 7), which further confirmed that dermatochalasis interferes with regular lid hygiene, perpetuating the smoldering inflammation of the MG orifices, and causing intermediate functional obstruction of MGE and long-term progressive loss of MG.
For a cutoff value of ≤75 nm LLT, the sensitivity was 65.8% and the specificity was 63.4% for detecting MGD. With a cutoff value of ≤60 nm, the sensitivity was 47.9% and the specificity was 90.2% [
31]. In our study, 58.8% of all included patients had an LLT of ≤75 nm, whereas 51.5% of the DM-4 patients had an LLT of ≤75 nm. Furthermore, 37.8% of all included patients had an LLT of ≤60 nm, whereas 31.8% of the DM-4 patients had an LLT of ≤60 nm. Using these cutoff values could have missed a great proportion of patients with MGD in our scenario. The severity of dermatochalasis should be considered when interpreting LLT results. Performing a second examination after better lid hygiene would enhance the accuracy of meibomian gland-related assessments.
Dermatochalasis severity correlated negatively with symptoms (
Table 2B). This finding could result from the lower corneal sensitivity in older patients [
32] because the patients with more severe dermatochalasis were older and showed negative correlations among age and the SPEED and OSDI scores.
Dermatochalasis severity correlated positively with LLT (
Table 2B). LLT could be considered as the amount of secreted lipid divided by the area of distribution. It is possible that the smaller lid fissure, and thus the smaller surface area to be covered by the secreted meibum, resulted in a thicker LLT in patients with severe dermatochalasis. If true, lid hygiene should not change the LLT since it did not change the MGE and meiboscale grade, indicating that the amount of meibum secretion was not changed. In contrast, about 10% of the tear-film lipids are from sebum. It is more reasonable that an excessive amount of sebum in the dermatochalasis skin folds contributed more lipids to the tear-film and manifested as a thicker LLT. Removal of excessive periocular sebum by performing lid hygiene would thus reduce LLT. In this study, we confirmed that lid hygiene significantly decreased LLT, but not MGE and meiboscale grade. This confirmed that thick LLT in patients with severe dermatochalasis should have resulted at least partially from an abnormally large amount of sebum.
The severity of dermatochalasis correlated positively with meiboscale grade and negatively with MGE (
Table 3B), with stronger upper lid correlation. This is reasonable since the dermatochalasis is close to the upper lids. Lid hygiene-related inflammation and subsequent functional obstruction of the meibomian orifice would thus be more prominent in the upper lids. In contrast, LLT correlated positively with MGE in both the upper and lower lids but negatively with meiboscale grade only in the lower lid (
Table 3B). These findings are also conceivable as the LipiView II
® interferometer measures LLT in the lower tear meniscus. The correlation coefficients were greater between dermatochalasis and meiboscale grades than between LLT and meiboscale grades, which also indicated that the long-term impact of dermatochalasis on eyelid structures was more significant than the short-term LLT fluctuation.
Blinking is associated with orbicularis oculi and meibum secretion [
7,
8]. The orbicularis oculi muscle fibers become thin [
5] with loss of muscle strength and function in the older population [
6]. These changes decrease orbicularis oculi muscle function, which decreases the blink efficacy and leads to meibum stagnation, thus further causing MGD and meibomian gland atrophy [
8].
Meibomian gland atrophy results in tear-film instability and subsequently leads to more dry-eye symptoms and a high blinking rate [
11,
33,
34], which is a compensatory mechanism commonly observed in patients with dry-eye disease and is triggered by reduced tear-film stability and the resulting discomfort [
33,
34]. Our results showing a positive correlation between the number of total blinks and SPEED/OSDI questionnaire scores confirmed that the number of total blinks is associated with subjective discomfort [
11,
35]. This could be a compensatory mechanism to protect against progressive meibomian gland loss.
There were fewer partial blinks in patients with more severe dermatochalasis (
Table 5). The smaller lid fissures in these patients possibly made complete blinking easier because the excursion of the orbicularis muscles for a complete blink was shorter. Similarly, there was less partial blinking in males, which also could have resulted from the more severe dermatochalasis (i.e., smaller lid fissures) in males.
Only 27.7% (644/2328) of all enrolled patients were lid hygiene compliant for 3 months and completed comprehensive examinations. Among them, lid hygiene significantly decreased LLT (
Table 7B), indicating that the LLT contained meibum from the MG and from skin sebum, which could be removed by lid hygiene. However, the improvement was less significant in patients with more severe dermatochalasis, emphasizing the importance of lid folds on lid hygiene. Lid hygiene also did not change the MGE and meiboscale grade (
p = 0.127 and 0.740, respectively), suggesting that subjective symptoms and LLT were short-term indicators of dry eyes, and both improved quickly with lid hygiene. In contrast, functional obstruction of MG took longer to improve [
23,
24] and was an intermediate indicator of MGD. The structural changes in meiboscale grade were even more permanent and were long-term indicators of MGD. In a study, meibomian gland atrophy was unchanged 6 months after thermal pulsation treatment [
22]; however, another study reported an improvement [
23]. In contrast, the decrease in Schirmer test results (
p < 0.001) and increase in FTBUTs (
p = 0.004) after lid hygiene in our study indicated decreased reflex tearing and stabilization of tear-film when the abnormally excessive sebum and/or meibum were cleared by lid hygiene.
The study strength was the large sample of patients who visited a single ophthalmologist at the dry-eye center. Moreover, the treatment rationale and patient-education program remained consistent throughout the study period. We identified dermatochalasis as a factor contributing to the severity of MGD. However, the correlation was weak, with a low correlation coefficient. This is similar to a previous study that reported non-significant or weakly significant correlations between clinical parameters [
18], with correlation coefficients of <0.2. This could be attributed to the multifactorial nature of dry-eye disease [
36] and the discordance between subjective symptoms and objective signs [
14]. In addition, structural changes in the meibomian glands are a result of chronic MGD rather than a short-term effect, such as after cataract/corneal surgery [
37,
38,
39] and lid hygiene, as shown in this study. The temporal effects on the change in LLT, MGE, and meiboscale grade vary, which may contribute to the disparity that is frequently encountered in dry-eye studies.
One limitation is the retrospective nature of our study. Patient dropout due to suboptimal compliance is a major issue. However, the results reflected a real-world scenario and are thus readily applicable to most daily practices. Another limitation is that we defined compliance as returning to the clinic for follow-up examinations, but lid hygiene possibly was not fully performed. Thus, the true lid hygiene compliance rate could have been overestimated. In contrast, some patients with good compliance may have improved so much that they did not return for further follow-up examinations, which would have led to an underestimation of compliance. Another limitation is that we did not include systemic conditions in the analysis. Patients with systemic diseases showed more severe dry-eye disease signs [
15], whereas patients with lower self-perceived health had higher discordance between symptoms and signs [
13]. Not including these factors in this study could have led to the low correlation coefficients. A third limitation is that we did not recruit patients with less severe dry eye symptoms as they were encouraged not to visit tertiary medical center in our health care system. Further study to enroll patients with less severity in the general ophthalmology clinics to verify the association between DM severity and MGD would facilitate the generalization.