1040-5488/14/9102-0150/0 VOL. 91, NO. 2, PP. 150Y155 OPTOMETRY AND VISION SCIENCE Copyright * 2014 American Academy of Optometry

ORIGINAL ARTICLE

Evaluation of Age-Related Changes in Noninvasive Tear Breakup Time Jiaxu Hong*, Zuguo Liu*, Jing Hua†, Anji Wei*, Feng Xue*, Yujing Yang†, Xinghuai Sun*, and Jianjiang Xu*

ABSTRACT Purpose. To establish normal noninvasive tear film breakup time (NI-BUT) values in the Chinese population and investigate age-related changes in NI-BUT using a newly developed Keratograph. Methods. Forty normal volunteers with a mean age of 32.8 T 16.7 years were recruited for this study. Clinical and demographic data, including age, gender, fluorescein tear film breakup time (FBUT), and Schirmer I test values were collected from the subjects. Noninvasive tear film breakup time was measured using a new method based on a corneal topographer equipped with a modified scan software. The correlations between the NI-BUT, age, and gender were determined. Results. In total, a significant difference between the NI-BUT and the FBUT was found (4.9 T 2.4 seconds vs. 9.0 T 3.0 seconds; p G 0.001). No statistically significant difference in the NI-BUT was observed between the male and female subjects (5.5 T 2.0 seconds vs. 4.5 T 2.5 seconds; p = 0.137). In addition, no significant correlation was detected between the NI-BUT and age (0.143, p = 0.321). Conclusions. The NI-BUT values found in this study are much lower than those of previous reports. Our results show no significant differences in tear film stability with age. The tear physiology of the Chinese population may not be the same as in Western populations. (Optom Vis Sci 2014;91:150Y155) Key Words: physiology, tear breakup time, imaging, aging

T

he stability of the tear film plays an important role in the optical quality of the eye.1 The most widely performed examination to assess tear film stability involves measuring the fluorescein tear breakup time (FBUT) using a slit-lamp microscope with the aid of fluorescein vital dye. In addition, it is possible to assess tear breakup using noninvasive methods, including tear film lipid layer interferometry,2,3 the xeroscope, and the Tearscope (Keeler, Windsor, UK).4,5 However, these methods rely on subjective judgment and are prone to be influenced by the fluorescein dye, resulting in poor to moderate repeatability. Recently, we reported that measurements of noninvasive tear film breakup time (NI-BUT) obtained with a newly developed corneal topographer are available for the NI-BUT assessment in normal

subjects and may provide a simple noninvasive screening test for dry eyes with acceptable sensitivity, specificity, and repeatability.6,7 Current literature indicates that the correlation between tear film stability and age is paradoxical. Some studies have demonstrated that both the FBUT and the NI-BUT decreased with age.8Y10 Another study showed no significant change in tear film stability with age.11 However, none of these studies have been conducted in mainland China. As the largest population in the world, the Chinese have a high age-specific prevalence of dry eyes.12Y14 Therefore, the aims of this study are to establish normal NI-BUT values in the Chinese population and to determine their relationship with age and gender.

METHODS *MD, PhD † MD Department of Ophthalmology and Visual Science, Eye, Ear, Nose, and Throat Hospital, School of Shanghai Medicine, Fudan University, Shanghai, China (JH, AW, FX ,YY, XS, JX); Health Communication Institute, Fudan University, Shanghai, China (JH); Xiamen University, Fujian, China (JH, ZL); Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts (JH); and State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, Shanghai, China (XS).

Subjects All subjects were recruited from the community. We excluded subjects with chronic irritative ocular symptoms, including foreign body sensations, tearing, itching, hyperemia, and eye discharge. Contact lens wearers and subjects with FBUT values shorter than 5 seconds, Schirmer I test results shorter than 10 mm every 5 minutes, positive corneal dye staining, or ocular surface

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Age-Related Changes in Tear Breakup TimeVHong et al.

abnormalities, such as an ocular allergy, infectious conjunctivitis, meibomian gland dysfunction, and continuous eye drop use were not included in this study. In total, 50 asymptomatic subjects met our criteria. The group consisted of 30 women and 20 men, with an average age of 32.8 T 16.7 years. In this study, data were collected from the right eye of each subject. Written informed consent was obtained from all subjects before examination. The research followed the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Shanghai Eye, Ear, Nose, and Throat Hospital of Fudan University.

Procedure Slit lamp biomicroscopic examinations and nondilated fundus examinations were performed to exclude other possible ocular diseases. Particular attention was paid to eyelid margins, tarsal and bulbar conjunctiva, and the cornea. The NI-BUT assessment was performed initially, followed by a slit lamp investigation, tear film FBUT measurement (using 2 KL of a preservative-free 1% fluorescein dye), and fluorescein vital staining of the ocular surface. Last, the Schirmer I test was performed. The time between the tests was longer than 15 minutes. For the NI-BUT measurement, all subjects underwent imaging with a Keratograph (Oculus, Wetzlar, Germany) equipped with modified TF-scan software, as our previous study has described.6 In brief, four IR diodes were set on the Keratograph and arranged in two pairs, located one above the other. The red ring illumination used for corneal topography was deactivated; this ensured a dark background for the examination. An illuminated ring pattern was then projected onto the cornea. For NI-BUT measurement, the subject was asked to keep his or her eyes open as long as possible. Irregularities in the reflected image were observed closely. Special attention was given to distortions and gaps in individual rings and the time such deviations from the original ring pattern took to occur. All examinations were recorded on video. At the start of the recording, the subject was asked to blink his or her eyes three times and then to keep them open. The recording was discontinued at the next eye blink. This procedure was repeated three times. In the current study, the NI-BUT was evaluated for each subject using TF-scan software.

Statistical Analysis Statistical analysis was performed using SPSS version 17.0 (SPSS Inc., USA). Values are presented as mean T SD. The Mann-Whitney U test was used to analyze the differences in the values between groups. The Spearman correlation was used to

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compare the parameters. A value of p G 0.05 was considered statistically significant.

RESULTS A total of 50 normal control subjects were recruited for the study. All subjects were of Chinese ethnicity. Table 1 shows that there was no significant difference in age, FBUT, Schirmer, and NI-BUT values between male and female groups. As shown in Fig. 1, the values of the NI-BUT measurement could be read easily by the newly developed Keratograph. The NI-BUT was detected and then generated automatically. For all subjects, the values of the NI-BUT were significantly less than those of the FBUT (4.9 T 2.4 seconds vs. 9.0 T 3.0 seconds; p G 0.001) but correlated well with those of the FBUT (0.343, p G 0.05; Fig. 2A). In addition, no significant correlation was detected between the NI-BUT and age (0.143, p = 0.321; Fig. 2B). The FBUT values were similar when a comparison was carried out according to age (0.255, p = 0.074; Fig. 2C). However, we revealed a statistically high decline of the Schirmer test values with advancing age (j0.328, p G 0.05; Fig. 2D). The correlation analysis is shown in the scattergram plot in Table 2 and Fig. 2.

DISCUSSION To our knowledge, this is the first study investigating agerelated changes of the NI-BUT in mainland Chinese population using the newly developed Keratograph. This study revealed no significant difference in the NI-BUT values between female and male subjects. More importantly, no age-related decline of the NI-BUT in normal eyes was detected. Another important finding is that the NI-BUT values measured by this technique were significantly lower than those of the FBUT, but they did show good correlation with the FBUT. The NI-BUT can be measured by using a Tearscope,12 a modified bowl perimeter (xeroscope),4,13 a keratometer,14,15 and a portable noninvasive tear assessment instrument.16,17 Differences in the NI-BUT results have been reported by different investigators, even when similar noninvasive techniques are used.18 It is supposed that minor differences in instruments, observation procedure, discontinuity criteria, and the number of NI-BUT measurements made might account for the data discrepancies. It should be noted that the Oculus Keratograph in the current study records significantly lower NI-BUT values than previous NI-BUT assessments. It is speculated that this may be because the Keratograph records the first incident of tear film breakup, regardless of how small the area is or where it occurs on the cornea. However, previous NI-BUT measurements could not detect such

TABLE 1.

Characteristics of study subjects Parameters

All subjects (n = 50)

Male subjects (n = 20)

Female subjects (n = 30)

Age, y 32.8 T 16.7 (range, 17Y74) 29.0 T 13.9 (range, 17Y74) 35.4 T 18.1 (range, 17Y72) Tear breakup time, s 9.0 T 3.0 (range, 5.3Y17.4) 9.5 T 3.7 (range, 5.3Y17.4) 8.8 T 2.6 (range, 6.0Y14.8) Schirmer I test, mm/5 min 14.7 T 5.7 (range, 10Y30.0) 16.7 T 7.1 (range, 10.0Y30.0) 13.4 T 4.2 (range, 10.0Y23.0) Noninvasive tear breakup time, s 4.9 T 2.4 (range, 0.3Y9.1) 5.5 T 2.0 (range, 2.7Y9.1) 4.5 T 2.5 (range, 0.3Y9.0) *The Mann-Whitney U test was performed on male and female subjects. Optometry and Vision Science, Vol. 91, No. 2, February 2014

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p* 0.187 0.781 0.099 0.137

152 Age-Related Changes in Tear Breakup TimeVHong et al.

FIGURE 1. Output of NI-BUT measurement using newly modified corneal tomography. Real-time images of the first breakup time were obtained in the figure. For each image, the left part showed real-time video, the top right part demonstrated the progress of tear film breakup over time, and the bottom right part illustrated the final result of NI-BUT. The first NI-BUT is automatically marked (red pane), and the values of NI-BUT are generated automatically using digital imaging software. The first NI-BUT in this subject was 8.7 seconds.

small regions of breakup. Another possible reason is that the interference in the image capture process, such as unconscious blinking during the Oculus Keratograph measurement, might also be identified as the tear film break up automatically. Further research on modifying the instrumentation software is required to facilitate the application of the NI-BUT measures by the Keratograph in clinical practice. As we know, tear film breakup time is defined as the interval between a complete blink and the first randomly distributed dry spots. The invasive FBUT was assessed by observing the fluoresceinstained tear film with the cobalt-blue filter on slit lamp. By this technique, FBUT is denoted as the time interval between complete blink and the first appearance of a black spot or streak in the tear film. However, the traditional NI-BUT is measured by observing a grid pattern or a keratometer mire projected onto the corneal surface, which is the time taken for the keratometric mires to be distorted after a complete blink. As our previous studies pointed out, the values of the NI-BUT detected by this technique were lower than those of the FBUT.6 Interestingly, results from other studies have been divergent. Mengher et al.19 measured the NI-BUT in nine healthy subjects to investigate the effect of fluorescein instillation on tear film stability. They found that fluorescein instillation reduced tear film stability in the treated group compared with that in the control group, thus making it likely that the NI-BUT may be longer than the FBUT.19 Cho et al.20 sampled 61 subjects from different countries. The NI-BUT values were higher than the FBUT values in both white and Chinese subjects, but there was no significant correlation between the two.20 Notably, with a comparable corneal autorefractor-keratometer designed for measuring the NI-BUT, Gumus et al.21 examined 45 patients with dysfunctional tear syndrome and 25 asymptomatic control subjects and showed that the NI-BUT values were shorter than those of the FBUT, as identified by biomicroscopy. Similarly, data from Goto et al.14 taken from 34 patients who underwent LASIK for myopia revealed that results with NI-BUT are also shorter than with slit lamp examination

breakup time. The exact reasons for these conflicting reports are still not well known. One reason might be that the NI-BUT assessment is fluorescein dyeYfree, whereas sodium fluorescein dye is added to the eye during FBUT testing. Another possibility for the resulting difference could be because of different methodologies for NI-BUT measurement in previous studies. In our study, the corneal Keratograph measured something different; that is, the change in corneal power occurring earlier than tear breakup measured in conventional slit lamp examination, such as a change of the refractive power of the tear film layer rather than the disruption of the tear film layer. Further research is still warranted to address this issue. On the issue of gender, our study showed no statistically significant difference in the NI-BUT between female and male participants. Previous studies have also reported some notable observations regarding the relationship between changes in the NI-BUT and gender. Cho et al.20 reported that gender was not an influential factor for NI-BUT measurement of normal subjects. Also, Mohidin et al.9 demonstrated no significant difference in the NI-BUT between males and females. It should be noted that both studies enrolled Asian and white subjects. This affords more generalization to our findings. Overall, we provide new evidence that there was no appreciable gender difference in the NI-BUT and raise the possibility of using this newly developed Keratograph in clinical practice, which could eliminate the potential effect originating from gender difference. As shown in Table 3, few studies reported whether there are age-related changes in the NI-BUT. Our study found no correlation between the NI-BUT and age, which is in agreement with a previous report.15 The authors showed no significant relationship between age and tear-thinning time, a noninvasive method assessing the tear stability similar to the NI-BUT, in Chinese, Indian, and African individuals; there did appear to be a difference for white subjects. However, Mohidin et al.9 showed a decrease in the NI-BUT with age in the Malay population.9 This divergence from the published literature may be explained by the following

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Age-Related Changes in Tear Breakup TimeVHong et al.

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FIGURE 2. Correlations between age and tear film stability. The values of the noninvasive tear film breakup time correlated precisely with those of the fluorescein tear film breakup time (0.343, p G 0.05; A). No significant correlation was detected between age and the noninvasive tear film breakup time (0.143, p = 0.321; B) or between age and the fluorescein tear film breakup time (0.255, p = 0.074; C). However, significant positive correlations were noted between age and the Schirmer I test (j0.328, p G 0.05; D).

reasons. First, previous methods assessing the NI-BUT rely on subjective judgment. It is commonly believed that qualitative analysis by subjective pattern recognition is prone to be biased by personal experience. In contrast, the NI-BUT is automatically marked, and values of NI-BUT are generated automatically by TABLE 2.

Correlations between tests Parameters

Age

Tear breakup time 0.255 Schirmer I test j0.328* Noninvasive tear 0.143 breakup time

Tear breakup time Schirmer I test n/a 0.064 0.343*

n/a n/a 0.064

*The correlation coefficient indicates significance levels were p G 0.05.

digital imaging software in the newly developed Keratograph, making the results more accurate and stable. Second, a direct comparison between the results of previous studies and our own study is not possible because of the different sample size, age distribution, and race. Nonetheless, our results may provide greater insight into the association of tear film stability and age. The current study reveals that Schirmer test values decreased inversely to age. Similarly, Mathers et al.22 reported a decline in the tear production throughout the life of normal subjects. Despite the fact that Schirmer test results of Ozdemir and Temizdemir23 were found to be insignificant statistically, they indicated a gradual decrease with advancing age. It remains unclear as to why tear production decreases with age. Decreased sex hormone levels that correlated to advancing age might contribute to this process.24 Several limitations of our study should be noted. First, we did not obtain the NI-BUT values in subjects younger than 17 years

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154 Age-Related Changes in Tear Breakup TimeVHong et al. TABLE 3.

Noninvasive tear breakup time in normal subjects between different reports Reports Cho et al., 1993 Cho et al., 1995 Patel et al., 1995

Mohidin et al., 2002 Wang et al., 2007 Gumus et al., 2010 Pult et al., 2011 Hong et al., the current study, 2013

Sample (n)

Age, y

7 36 25 25 25 25 25 48 36 25 47 50

n/a n/a n/a 22.9 T 4.4† 20.4 T 3.0† 34.3 T 6.4† 22.6 T 3.7* 15.8 T 9.4* 45.1 T 15.4 48.2 T 16.6 n/a 32.8 T 16.7†

Age range, y Gender distribution (n) 25Y32 17Y34 20Y40 19Y34 17Y32 21Y45 18Y30 7Y60 20Y70 n/a 19Y70 17Y74

5:2 15:21† 9:16† 14:11 10:15 22:3 13:12 27:21† 20:16 13:12 17:30 20:30†

NI-BUT, s

Population

19.4 T 16.3 14.6 T 11.9 11.6 T 8.3 9.8 T 3.9 14.6 T 11.9 11.8 T 15.9 19.9 T 8.3 32.4 T 15.2 16.7 T 7.6 4.9 T 1.6 15.2 (8.1Y25)‡ 4.9 T 2.4*

Asian (Chinese) Asian (Chinese) White (UK) Asian (Chinese) Asian (Indian) African White (UK) Asian (Malays) n/a n/a n/a Asian (Chinese)

*Significant correlation with the NI-BUT was reported. †No correlation with the NI-BUT was reported. ‡Median (interquartiles).

old, and thus we were unable to carry out quantitative analysis for this group. Second, our study is based on cross-sectional data rather than prospective longitudinal data. A prospective study design allows for a more accurate approach to the analysis of the correlation between the NI-BUT and age. However, such conditions are often very difficult to achieve because of the limitation of time and cost. Finally, we included more female than male subjects in this study. However, because there was no gender difference in the NI-BUT, this effect may be limited. In conclusion, this study reports on the first community-based investigation of the mean NI-BUT value assessed by the new Keratograph in mainland Chinese subjects. There was no significant difference in the NI-BUT between female and male subjects. In addition, no age-related changes of the NI-BUT were detected. When using this new tear stability analysis system for screening dry eye problems, clinicians should take note of the low NI-BUT values in Chinese subjects. Independent investigations on other races are needed to validate the findings of our study.

ACKNOWLEDGMENTS This work was supported by grants from the Key Clinic Medicine Research Program, the Ministry of Health, China (201302015); the National Science and Technology Research Program, the Ministry of Science and Technology, China (2012BAI08B01); the National Natural Science Foundation of China (81170817, 81200658); and the Scientific Research Program, Science and Technology Commission of Shanghai Municipality, Shanghai (13441900900, 13430720400, 134119a8800, 13430710500). The sponsor or funding organization had no role in the design or conduct of this research. The authors declare no financial relationship with the organization that sponsored the research. Received March 22, 2013; accepted September 3, 2013.

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Jianjiang Xu Eye, Ear, Nose, and Throat Hospital Fudan University 83 Fenyang Rd Shanghai 200031 China e-mail: [email protected]

Optometry and Vision Science, Vol. 91, No. 2, February 2014

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Evaluation of age-related changes in noninvasive tear breakup time.

To establish normal noninvasive tear film breakup time (NI-BUT) values in the Chinese population and investigate age-related changes in NI-BUT using a...
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