Importance of Tear Film Instability in Dry Eye Disease in Office Workers Using Visual Display Terminals: The Osaka Study NORIHIKO YOKOI, MIKI UCHINO, YUICHI UCHINO, MURAT DOGRU, MOTOKO KAWASHIMA, AOI KOMURO, YUKIKO SONOMURA, HIROAKI KATO, KAZUO TSUBOTA, AND SHIGERU KINOSHITA PURPOSE:
To evaluate the relationship between subjective symptoms and clinical signs in dry eye disease (DED) in office workers using visual display terminals (VDTs). DESIGN: Cross-sectional study. METHODS: This study involved 672 Japanese young and middle-aged office workers who use VDTs. The subjects completed questionnaires designed to detect subjective symptoms and risk factors for DED. Dry eye tests, including tear film break-up time (TBUT), cornealconjunctival staining with fluorescein and lissamine green, and the Schirmer test, were performed. Based on the Japanese diagnostic criteria for DED, the subjects were classified into 3 groups: definite DED, probable DED, and non-DED. Between each group, subjective symptoms and clinical signs were compared. RESULTS: Of the 672 subjects, 561 (374 male, 187 female) completed the questionnaire (response rate: 83.5%). Definite DED was diagnosed in 65 subjects (11.6%), probable DED in 303 subjects (54.0%), and non-DED in 193 subjects (34.4%). The mean subjective symptom score was significantly less in subjects with probable DED (2.05 ± 0.42) and non-DED (1.63 ± 0.38) than in those with definite DED (2.19 ± 0.40) (P < .05 and P < .01, respectively). In the subjects with probable DED, a subgroup with positive subjective symptoms and abnormal TBUT (£5 seconds) was categorized as short TBUT-type DED, and it was found that they had a higher subjective symptom score (2.09 ± 0.40), equivalent to that of those with definite DED (P [ .269). CONCLUSIONS: Despite no or minor epithelial damage, the severity of subjective symptoms was greater in short TBUT-type DED, most likely attributable to tear film instability. Thus, it might prove important to evaluate TBUT to successfully treat those patients. (Am J Ophthalmol 2015;159:748–754. Ó 2015 by Elsevier Inc. All rights reserved.)
Accepted for publication Dec 16, 2014. From the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan (N.Y., A.K., Y.S., H.K., S.K.); and the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan (M.U., Y.U., M.D., M.K., K.T.). Inquiries to Norihiko Yokoi, Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto 602-0841, Japan; e-mail: [email protected]
748
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2015 BY
T
HE PREVALENCE OF DRY EYE DISEASE (DED) HAS BEEN
increasing owing to changes in lifestyle driven by information technology (IT). In a previous epidemiologic study involving Japanese office workers using visual display terminals (VDTs), the prevalence of clinically diagnosed DED was 10.1% in male subjects and 21.5% in female subjects, and severe symptoms of DED were observed in 26.9% and 18.7% of the male and female subjects, respectively.1 In 2009, the personal computer ownership rate reached 87.2% in Japan, and the rapid spread of IT devices has promoted the daily use of VDTs for the visualization of information. Hence, the number of VDT users and the amount of time they spend using their respective terminals have both dramatically increased. Continuous use of VDT displays results in decreased blinking and a subsequent increase in ocular surface dryness, which is known to be a causative factor in DED cases. Excess aqueous evaporation from the ocular surface tear film easily occurs during VDT use because the tear film break-up time (TBUT) is shorter than the interval between blinks.2 It has been reported that using a VDT for more than 4 hours a day (compared to less than 2 hours daily) increases the risk of DED (odds ratio: 1.83).1 Work-related prolonged VDT use is considered to increase the risk of ocular disorders including eye strain and accommodative spasm, as well as DED. Thus, collecting the diagnostic and therapeutic data about VDT use–related ocular disorders is vital. To date, there are limited data on the prevalence and the risk factors of DED in VDT users. The relationship between VDT use–associated DED and shorter TBUT has been described previously;3–7 however, there is insufficient epidemiologic evidence for the prevalence and risk factors of DED subtypes in VDT users. Under the supervision of the Japanese Dry Eye Society, we conducted a large-scale epidemiologic study in office workers using VDTs in Japan (The Osaka Study).8 The Osaka Study was a questionnaire-based assessment of DED symptoms combined with dry eye examinations carried out by dry eye specialists investigating the epidemiology, risk factors, and pathology of DED. In this present study, we evaluated the relationship between DED subjective symptoms and clinical signs based on the Japanese dry eye diagnostic criteria established in 2006.9 Furthermore, we investigated the characteristics of probable DED with
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_5 seconds and normal tear secretion (short TBUTTBUT < type DED) in order to study the independent association of definite DED with reduced TBUT in VDT office workers using VDTs.
METHODS THIS STUDY FOLLOWED THE TENETS OF THE DECLARATION
of Helsinki, the Ethical Guidelines for Clinical Research (issued on December 28, 2004 by the Ministry of Health, Labor and Welfare [MHLW] of Japan), and the Ethical Guidelines for Epidemiological Research (issued on June 17, 2002 by the MHLW). The protocol of this institutional and cross-sectional study was approved prospectively by the Institutional Review Board of Ryogoku Eye Clinic, Tokyo, Japan. STUDY POPULATION:
Under the supervision of the Japanese Dry Eye Society, the authors randomly selected 2 large companies listed on the Japanese stock market and sent a letter to the industrial physician in charge of health management in each company; the letter explained the purpose of the study and requested their participation. The only company that responded to our letter and consented to participate was enrolled in this study. The employees working in the central office of the company were informed, via a website, of the study’s general outline and ophthalmic clinical examinations. We enrolled those employees who agreed to participate in the study after providing them with background information and receiving their consents via the website to undergo the ophthalmic examinations. Exclusion criteria included any employee who reported a history of refractive surgery or who was deemed inappropriate for this study by the ophthalmologists. To ensure the human rights and personal security of each participant, we took strict measures to protect the privacy of participants’ personal information (ie, special care in handling of their collected information; exclusion of individually identifiable information from the questionnaire; exclusion of individually identifiable information from the data to be published; and exclusive use of the data for the purposes of the study).
QUESTIONNAIRE:
We administered a web-based dry eye questionnaire to evaluate subjective DED symptoms and to obtain information on each participant’s age, sex, and usage of VDT devices. The questionnaire used in the study was developed by Toda and associates,10 and included 12 questions pertaining to the diagnostic symptoms of DED. The frequency of each symptom was evaluated as never (1 point), sometimes (2 points), often (3 points), and constantly (4 points), and the mean point value of all symptoms was defined as the DED symptom score. Subjects who answered ‘‘often’’ or
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‘‘constantly’’ for at least 1 item were defined as being symptom positive for DED. To validate our symptom evaluation method, it was compared with a well-established method, the Dry Eye Severity Index Score (DESIS), which is a severity grading system based on the translated version of the Ocular Surface Disease Index (OSDI) questionnaire11 into Japanese.12 Each DESIS item was evaluated as never (0), rarely (1), occasionally (2), often (3), and always (4), and the total number of points scored on 29 questions was converted to a scale ranging from 0 to 100. CLINICAL EVALUATION:
Seven ophthalmologists from the Japanese Dry Eye Society performed the ophthalmic examinations at the health-care institute of the participating company, located in Osaka, Japan. Subjects who used contact lenses (CLs) underwent the examination more than 1 day after removing their CLs.
TEAR FUNCTION TESTS EVALUATION: Ophthalmic
AND
OCULAR
SURFACE
examinations included the assessment of corneal and conjunctival vital staining with fluorescein and lissamine green, respectively; measurement of TBUT; and the Schirmer test. Briefly, corneal and conjunctival epithelial damage was evaluated by the double vital staining method.13 Two microliters each of 1% sodium fluorescein and preservative-free 1% lissamine green were instilled into the conjunctival sac using a micropipette to evaluate epithelial damage of the cornea and bulbar conjunctiva, respectively. The ocular surface was divided into 3 sections (the nasal conjunctiva, the cornea, and the temporal conjunctiva), each of which was graded 0–3 for severity, and the overall epithelial damage was scored on a scale of 0–9.14 TBUT measurement and the Schirmer test were performed to assess tear film stability and tear fluid secretion, respectively. TBUT was measured using a fluorescein dye solution. After instillation of the solution, the subjects were instructed to blink 3 times to ensure adequate mixing of the fluorescein dye with the tear film. The time interval between the third blink and appearance of the first dark spot in the cornea was consecutively measured by stopwatch, with the mean of 3 measurements regarded as the TBUT in this study. The Schirmer test was performed without topical anesthesia after all of the other examinations had been performed. Strips of filter paper (Whatman No. 41; Showa Yakuhin Kako Co Ltd, Tokyo, Japan) were placed for 5 minutes at the outer third of the temporal lower conjunctival fornix, with the subject spontaneously blinking. The strips were then removed, and the length of the filter paper wetted by the spontaneous blinks was recorded in millimeters. To avoid the influence of stimulation by ocular surface staining, the Schirmer test was performed after a 10-minute interval. To prevent air conditioning from influencing the examinations, no air conditioning device was used in the examination room. The room temperature and humidity were
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maintained at 25.0–26.5 8 C and 60%–65%, respectively, during the examinations. All subjects were prohibited from using a VDT for 1 hour prior to the examinations.
TABLE 1. Allocation of Osaka Study Subjects Into Groups Based on Diagnosis of Dry Eye Disease
DIAGNOSIS OF DRY EYE DISEASE:
DED was diagnosed based on the results of the clinical evaluation and our questionnaire, which used the dry eye diagnostic criteria defined in 2006 by the Japanese Dry Eye Society.9 These criteria included the presence of: (1) positive DED symptoms; (2) qualitative or quantitative abnormalities of the _5 seconds or Schirmer tear film in 1 or both eyes (TBUT of < _5 mm); and (3) corneo-conjunctival epithetest results of < _3 out of 9 points). The lial damage (total staining score of > presence of all 3 criteria was necessary for a diagnosis of definite DED. The presence of 2 of the 3 criteria in 1 or both eyes was necessary for a diagnosis of probable DED, while the presence of 1 or no positive criteria indicated nonDED. The eye fulfilling the most criteria was used to make the diagnosis. When both eyes met the same number of criteria, the eye with (1) the higher staining score and (2) the shorter TBUT was used for the diagnosis. If the staining score and TBUT were the same in both eyes, the right eye was used for the diagnosis. Based on the diagnostic criteria, the subjects were placed into either the definite DED, probable DED, or non-DED group, and the subjective symptom score was then compared among the groups.
SUBGROUP ANALYSIS OF THE SHORT TEAR BREAK-UP TIME–TYPE DRY EYE DISEASE GROUP: We performed a sub-
group analysis of the short TBUT subtype in the probable DED group. In this study, short TBUT was defined as _5 seconds) with a normal Schirmer abnormal TBUT (< test value (>5 mm). The subjects with short TBUT in the probable DED group were assigned to the short TBUT– type DED subgroup. The subjective symptom scores of each group were then analyzed and compared. To assess the status of tear film lipid secretion, meibomian gland function was evaluated using the meibomian gland dysfunction (MGD) grading system established by Shimazaki and associates.15 In brief, when meibomian gland secretion was absent after application of moderate pressure to the eyelid, meibomian gland function was defined as abnormal. Differences in the subjective symptoms between the subjects in the short TBUT subgroup and the other subjects were evaluated. Furthermore, the differences between the short TBUT–type DED group and the definite DED group were evaluated to characterize short TBUT–type DED. STATISTICAL ANALYSIS:
For discrete variables, the calculated mean values were analyzed using the Student t test and the Tukey test to compare 2 groups and 3 groups, respectively. For categorical variables, the Fisher exact test was used. The P values were 2-sided and the level of significance was set at 5% (P < .05). SAS 9.2 software for Windows (SAS Institute Inc, Cary, North Carolina, USA) was used for the data analysis.
750
N (%) Short TBUT Others
Definite DED
Probable DED
Non-DED
65 (11.6%) 50 (8.9%) 15 (2.7%)
303 (54.0%) 244 (43.5%) 59 (10.5%)
193 (34.4%) 76 (13.5%) 117 (20.9%)
DED ¼ dry eye disease; TBUT ¼ tear film break-up time.
RESULTS THE STUDY PERIOD WAS FROM AUGUST 1, TO SEPTEMBER 1,
2011. The questionnaire was sent electronically to 672 eligible workers in the participating company; 561 workers (83.5%) responded and were enrolled in the study (374 male and 187 female subjects; mean age: 43.2 years). The mean (6SD) age of the male and female subjects was 45.1 (68.9; range: 26.0–64.0) and 39.5 (67.3; range: 24.0–60.0) years, respectively. Based on the responses to the 12-item questionnaire, 399 subjects (71.1%) were DED positive and 162 subjects (28.9%) were DED negative. The mean DED symptom score (mean 6 SD) was 1.92 6 0.46, and the mean number of symptoms was 2.5 6 2.5. The most frequently occurring symptoms included ‘‘eye fatigue’’ (48.1%), ‘‘dry sensation’’ (32.4%), and ‘‘blurred vision’’ (25.0%). Vital staining indicated that corneo-conjunctival epithe_3) lial damage was present in 90 subjects (16.0%; score > but not in 471 subjects (84.0%; score 0–2). The corneoconjunctival epithelial damage was generally mild in severity _5 secand the positive rate was low. TBUT was abnormal (< onds) in 441 subjects (78.6%) and normal (>5 seconds) in 120 subjects (21.4%). Of the 561 subjects who took the Schirmer test, 95 subjects (16.9%) showed abnormal values _5 mm) and 466 subjects (83.1%) showed normal values (< (>5 mm). Most subjects (66.0%, n ¼ 370) had a TBUT of < _5 seconds and a Schirmer test value of >5 mm (short TBUT subgroup). The subjects were diagnostically classified into 1 of 3 categories: definite DED (n ¼ 65; 11.6%); probable DED (n ¼ 303; 54.0%); and non-DED (n ¼ 193; 34.4%). Of the 303 probable DED subjects, 244 subjects (80.5%) were included in the short TBUT subgroup and 59 subjects (19.5%) in the ‘‘others’’ subgroup (Table 1). The mean 12-item symptom score was significantly higher in the definite DED group (2.19 6 0.40) than in the probable DED (2.05 6 0.42) and non-DED (1.63 6 0.38) groups (Tukey test, for each group P < .01) (Table 2). This result suggests that the severity of dry eye symptoms is associated with the diagnostic criteria of DED. A similar relationship was observed with DESIS. Associations between the clinical findings and DED symptom scores are shown in Table 3. In the subjects
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TABLE 2. Comparison of the 12-Item Symptom Score With the Dry Eye Severity Index in Assessing the Severity of Dry Eye Disease in Osaka Study Subjects Subjective Symptom
Diagnosis
Mean 6 SD (N)
P Value
Symptom score by 12 items (0–4)
1. Definite DED 2. Probable DED 3. Non-DED 1. Definite DED 2. Probable DED 3. Non-DED
2.19 6 0.40 (65) 2.05 6 0.42 (303) 1.63 6 0.38 (193) 31.8 6 13.6 (65) 28.1 6 14.0 (303) 17.1 6 9.1 (193)
1:2 P ¼ .028a 1:3 P ¼ .000b 2:3 P ¼ .000b 1:2 P ¼ .073 1:3 P ¼ .000b 2:3 P ¼ .000b
DESIS (0–100)
DED ¼ dry eye disease; DESIS ¼ dry eye severity index score; SD ¼ standard deviation of the mean. P value was calculated using the Tukey test. a P < .05. b P < .01.
TABLE 3. Associations Between Dry Eye Symptom Score and Ophthalmic Examination Values in Osaka Study Subjects Schirmer Test (N) Subjective Symptom Score
Symptom score by 12 items (0–4) DESIS (0–100)
TBUT Test (N)
Normal (>5 mm)
Abnormal _5 mm) (
5 s)
_5 s) Abnormal (
5 secwith abnormal (< onds), the mean subjective symptom scores (mean 6 SD) were 1.95 6 0.46 and 1.82 6 0.45, respectively, indicating a statistically significant difference (Student t test, P ¼ .006). In the subjects with normal ( were 1.91 6 0.45 and 2.02 6 0.47, respectively, and were significantly different (P ¼ .030). There was no significant difference in DED symptom score between the subjects with normal (1.92 6 0.46 mm) and abnormal (1.92 6 0.46 mm) Schirmer test values (P ¼ .987). DESIS analysis showed a similar tendency, suggesting that subjective symptom scores were significantly associated with TBUT (P ¼ .009) and staining score (P ¼ .022) but not with the Schirmer test value (P ¼ .705). To analyze the probable DED category in detail, we compared DED symptoms following classification of the probable DED type into the short TBUT subtype and ‘‘others’’ subtype. Most of the subjects had normal VOL. 159, NO. 4
meibomian gland function, and only 3.1%, 3.5%, and 3.1% of subjects showed abnormal function in the definite DED, short TBUT subtype of the probable DED, and nonDED groups, respectively, and there was no statistically significant difference among the groups (P ¼ .463). Others in the probable DED group had normal meibomian lipid secretion. Table 4 shows the association between the symptom score and diagnosis of DED in cases in which the probable DED was divided into subgroup, short TBUT–type DED, and ‘‘others.’’ The mean DED symptom scores were significantly different between the definite DED group and ‘‘others’’ in the probable DED or non-DED groups (Tukey test, P < .01), but not between the definite DED group and the short TBUT subtype (P ¼ .269). DESIS analysis showed a similar tendency. The results suggested that DED symptoms in the short TBUT subtype of the probable DED group were comparable to those in the definite DED group.
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TABLE 4. Associations Between the Symptom Score and Diagnosis of Dry Eye Disease in Osaka Study Subjects Subjective Symptom Score
Symptom score by 12 items (0–4)
DESIS (0–100)
Definite DED Short TBUT–type DED Other probable DED Non-DED Definite DED Short TBUT–type DED Other probable DED Non-DED
Mean 6 SD (N)
P Value
2.19 6 0.40 (65) 2.09 6 0.40 (229) 1.93 6 0.44 (74) 1.63 6 0.38 (193) 31.8 6 13.6 (65) 29.1 6 13.9 (229) 24.9 6 14.0 (74) 17.1 6 9.1 (193)
.269 .001a .000a .402 .006a .000a
DED ¼ dry eye disease; DESIS ¼ dry eye severity index score; SD ¼ standard deviation of the mean; TBUT ¼ tear film break-up time. P value was calculated using the Tukey test in comparing to definite DED. a P < .01.
Furthermore, we investigated the difference in DED symptoms between the subjects in the short TBUT subgroup included in the definite DED and probable DED groups and ‘‘other’’ subjects. Symptoms included eye fatigue (53.0%), dry sensation (35.9%), uncomfortable sensation (24.3%), and blurred vision (24.3%) in the short TBUT subgroup and eye fatigue (38.7%), blurred vision (26.2%), and dry sensation (25.7%) in the ‘‘others’’ subgroup. However, there was a statistically significant between-group difference in 5 items: eye fatigue (P ¼ .002), eye pain (P ¼ .038), red eye (P ¼ .039), uncomfortable sensation (P ¼ .041), and dry sensation (P ¼ .014). Analysis of the Schirmer test and vital staining results showed a statistically significant between-group difference in blurred vision only (P ¼ .037) and 2 symptoms (redness, P ¼ .034 and dry sensation, P ¼ .001), respectively, suggesting that abnormal TBUT may be a strong contributor to the frequency of symptoms.
DISCUSSION DED IS DEFINED AS A MULTIFACTORIAL DISEASE OF THE
tear film and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability, with potential damage to the ocular surface.16 Thus, DED negatively affects the quality of vision.17,18 Continuous VDT work is a major causative factor of DED, because of the blink-rate decrease owing to tear film disturbance and resultant ocular surface dryness induced by continual gazing at the display terminal. The frequency of blinking (normally 20 blinks per minute) decreases to approximately one half when reading and from one third to one fourth when using a VDT.19 In a previous report, it was suggested that a long duration of VDT work might induce lacrimal gland hypofunction resulting in DED.20 The rapid advance of IT devices and visualization of information will 752
further increase the prevalence of DED; use of VDT devices is inevitable in business and daily life. Therefore, an understanding of DED pathology, establishment of reliable diagnostic methodology, and development of effective management and therapy strategies are needed to provide appropriate treatment for DED. Diagnosis of DED based on well-established criteria is essential to the treatment of DED. The Dry Eye Work Shop (DEWS) is engaged in the study of DED and published an International Expert Committee Report in 2007.16 This report covered a wide range of findings on DED, but not diagnostic criteria. In Japan, contemporaneous with the preparation of the DEWS report, the Dry Eye Society published a revised list of diagnostic criteria along with the definition of DED in 2006.9 Traditionally, the association between DED symptoms and clinical signs has been considered weak21; however, a study suggested that the severity of DED had a stronger relationship with subjective symptoms than with clinical signs.22 The criteria of the Japanese Dry Eye Society focus on the association of diagnosis with symptoms and aim to reflect this association by adding the diagnostic category ‘‘probable DED’’ to the conventional 2 categories (‘‘definite DED’’ and ‘‘non-DED’’). Uchino and associates reported an association between the use of VDTs by Japanese office workers and DED in a population-based cohort study, and suggested more prevalence of DED among female subjects, contact lens wearers, and workers who use VDTs for prolonged periods.1 However, in this cohort study, diagnosis of DED was based on selfreports. No study has evaluated the association between VDT use and DED diagnosed by DED experts using ophthalmic examinations. In our study of office workers continuously using VDTs, detailed subjective symptoms of DED were investigated to evaluate the relationship between subjective symptoms and clinical signs, including disturbance of the tear film and corneo-conjunctival epithelial damage. The results suggested that the subjective
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symptoms more clearly reflect the diagnosis of DED, if the intermediate category (probable DED) is adopted to the diagnostic criteria of the Japanese Dry Eye Society. These criteria will provide more precise diagnosis of DED and lead to more appropriate treatment. Since most of the subjects in the study population had _5 seconds), we could analyze DED with short TBUT (< abnormal TBUT value in detail. While 78.6% of the study population had short TBUTs, only 16.9% had abnormal Schirmer test values. This result indicated that most VDT workers with DED had abnormal tear film stability in spite of normal tear secretion. DED was etiologically classified into 2 categories: (1) ‘‘tear-deficient dry eye,’’ caused by a failure of lacrimal secretion; and (2) ‘‘evaporative dry eye,’’ caused by such factors as MGD. The short TBUT-type DED is not likely to be placed in the ‘‘tear-deficient dry eye’’ category because of normal Schirmer test values. Moreover, in the study, normal meibomian gland secretion was found in almost all subjects, and no relationship was observed between meibomian secretion and the TBUT. This may suggest that the short TBUT-type DED should not be included in the ‘‘evaporative dry eye’’ category. Shimazaki-Den and associates reported that the messenger RNA levels of membrane-associated mucin (MUC16) and secretory mucin (MUC5AC) were lower in eyes with unstable tear film as demonstrated by short TBUT, as well as in tear-deficient dry eye.4 Decreased expression of mucins may be the main factor affecting the dysfunction of ocular surface wettability and tear film stability.23,24 Liu and associates reported that tear hyperosmolarity is linked to tear film instability and thus results in ocular discomfort, burning, and stinging.25 Under the hypertonic condition, some electrolytes reportedly have an effect on corneal epithelial dysfunction, including the expression of membrane-associated mucin.26 Unfortunately, we did not check tear osmolarity or the content of electrolytes in this study. Further study is needed to clarify what causes the decrease in mucin expression in eyes with little corneoconjunctival epithelial damage. To diagnose patients with DED, the Schirmer test value and ocular surface staining score tend to be used. On the other hand, our findings suggest that the symptoms and TBUT may be more relevant diagnostic parameters for detecting DED in office workers using VDTs because the majority of the DED in those subjects has normal tear secretion and no ocular surface staining.8 It remains unclear whether or not these DED cases are at a relatively late stage of development. In addition to the DED symptoms, the tear
film instability is easily detected on the core mechanisms of DED in comparison to the invisible changes of the ocular surface, such as the lower expression of MUC16.16 Severe symptoms were reported by subjects with short TBUT-type DED in this study. These subjects had probable DED according to the diagnostic criteria in Japan and a DED symptom score comparable to that of subjects with definite DED. Common symptoms reported by subjects with short TBUT-type DED were ‘‘eye fatigue,’’ ‘‘dry sensation,’’ and ‘‘uncomfortable sensation.’’ Impaired tear film stability may cause dry and uncomfortable sensations irrespective of tear volume. The collapse of the tear film after blinking affects the ocular higher-order aberrations and functional visual acuity in DED.27–30 Disturbance of the tear film in the pupillary zone (owing to enhanced accommodative stress induced by alteration in retinal images resulting from increases in higher-order aberrations) is considered to be the cause of asthenopia. Thus, VDT workers with short TBUT, even if diagnosed with probable DED, will need active dry eye treatment for subjective symptoms and improvement of visual function. Drugs that improve tear film stability will be effective for the treatment of DED in VDT workers. Diquafosol sodium enhances tear film stability by altering water and mucin secretion from conjunctival tissue, and therefore would be expected to be effective for the treatment of short TBUT-type DED.31,32 As for the limitations of this study, since only young and middle-aged office workers participated in this study, we may have to distinguish the results from those obtained from older-aged subjects with DED. At the least, the Japanese diagnostic criteria of DED could be used to identify the DED patients who can be successfully treated; however, a much larger population with more elderly subjects may be needed to conclude whether these criteria can be generalized, or not, for all DED patients. In conclusion, the severity of subjective symptoms was found to be significantly related to the diagnostic categories (definite DED, probable DED, and non-DED) based on the dry eye diagnostic criteria established in Japan in 2006. The subjects with short TBUT (ie, the dominant subtype in the study) in the probable DED group (compared with those in the definite DED group) reported higher DED symptom scores. The prevalence of DED attributable to VDT work will continue to increase. Therefore, further studies are highly warranted to establish screening and prophylactic procedures using TBUT and standard medical treatment for DED, as well as to elucidate its pathology.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. The author make the following financial disclosures: Norihiko Yokoi: consultant for Kissei Co, Ltd, Nagano, Japan; and Rohto Co, Ltd, Osaka, Japan. Shigeru Kinoshita: consultant for Santen Pharmaceutical Co, Ltd, Osaka, Japan; and Otsuka Pharmaceutical Co, Ltd, Tokyo, Japan. Kazuo Tsubota: consultant for Santen Pharmaceutical Co, Ltd, Osaka, Japan; Acu Focus, Inc, Irvine, California, USA; Bausch & Lomb Inc, Rochester, New York, USA; Pfizer Inc, New York, New York, USA; and Laboratoires The´a, Clermont-Ferrand, France. This study was supported in part by Grants-in-Aid for scientific research from the Japanese Ministry of Education, Culture, Sports, Science and Technology. Provision of facilities, transport of equipment, data analysis, and data management were supported by Santen Pharmaceutical Co, Ltd, Osaka. The funding organization had no role in the design or conduct of this research. The authors have no proprietary or commercial interest in any of the materials discussed in this article. Contributions of authors:
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conception and design of study (M.U., N.Y., Y.U., M.D., M.K., S.K., K.T.); analysis and interpretation (M.U., M.D.); writing the article (N.Y., M.U., Y.U., M.D., M.K.); critical revision of the article (N.Y., M.U., Y.U., M.D.); final approval of the article (N.Y., M.U., Y.U., M.D., M.K., A.K., Y.S., H.K., S.K., K.T.); data collection (N.Y., M.U., Y.U., M.D., M.K., A.K., Y.S.); provision of materials, patients, or resources (N.Y., M.U., Y.U., M.D.); statistical expertise (N.Y., M.U., Y.U.); literature search (N.Y., M.U., Y.U., M.D.); administrative, technical, or logistic support (N.Y., M.U., Y.U., M.D., M.K., S.K., K.T.).
REFERENCES 1. Uchino M, Schaumberg DA, Dogru M, et al. Prevalence of dry eye disease among Japanese visual display terminal users. Ophthalmology 2008;115(11):1982–1988. 2. Yaginuma Y, Yamada H, Nagai H. Study of the relationship between lacrimation and blink in VDT work. Ergonomics 1990;33(6):799–809. 3. Toda I, Shimazaki J, Tsubota K. Dry eye with only decreased tear break-up time is sometimes associated with allergic conjunctivitis. Ophthalmology 1995;102(2):302–309. 4. Shimazaki-Den S, Dogru M, Higa K, Shimazaki J. Symptoms, visual function, and mucin expression of eyes with tear film instability. Cornea 2013;32(9):1211–1218. 5. Yamamoto Y, Yokoi N, Higashihara H, et al. Clinical characteristics of short tear film breakup time (BUT)-type dry eye. Nihon Ganka Gakkai Zasshi 2012;116(12):1137–1143 [in Japanese]. 6. Himebaugh NL, Begley CG, Bradley A, Wilkinson JA. Blinking and tear break-up during four visual tasks. Optom Vis Sci 2009;86(2):E106–114. 7. Schlote T, Kadner G, Freudenthaler N. Marked reduction and distinct patterns of eye blinking in patients with moderately dry eyes during video display terminal use. Graefes Arch Clin Exp Ophthalmol 2004;242(4):306–312. 8. Uchino M, Yokoi N, Uchino Y, Dogru M. Prevalence of dry eye disease and its risk factors in visual display terminal users: the Osaka study. Am J Ophthalmol 2013;156(4):759–766. 9. Shimazaki J, Tsubota K, Kinoshita S, et al. Definition and diagnosis of dry eye 2006. Atarashii Ganka 2007;24(2): 181–184 [in Japanese]. 10. Toda I, Fujishima H, Tsubota K. Ocular fatigue is the major symptom of dry eye. Acta Ophthalmol (Copenh) 1993;71(3): 347–352. 11. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118(5):615–621. 12. Uchino Y, Uchino M, Dogru M, Ward S, Yokoi N, Tsubota K. Changes in dry eye diagnostic status following implementation of revised Japanese dry eye diagnostic criteria. Jpn J Ophthalmol 2012;56(1):8–13. 13. Kaido M, Matsumoto Y, Shigeno Y, Ishida R, Dogru M, Tsubota K. Corneal fluorescein staining correlates with visual function in dry eye patients. Invest Ophthalmol Vis Sci 2011; 52(13):9516–9522. 14. van Bijsterveld OP. Diagnostic tests in the Sicca syndrome. Arch Ophthalmol 1969;82(1):10–14. 15. Shimazaki J, Sakata M, Tsubota K. Ocular surface changes and discomfort in patients with meibomian gland dysfunction. Arch Ophthalmol 1995;113(10):1266–1270. 16. No authors listed. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee
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of the International Dry Eye Work Shop (2007). Ocul Surf 2007;5(2):75–92. Goto E, Yagi Y, Matsumoto Y, Tsubota K. Impaired functional visual acuity of dry eye patients. Am J Ophthalmol 2002;133(2):181–186. Kaido M, Ishida R, Dogru M, Tsubota K. The relation of functional visual acuity measurement methodology to tear functions and ocular surface status. Jpn J Ophthalmol 2011;55(5): 451–459. Tsubota K, Nakamori K. Dry eyes and video display terminals. N Engl J Med 1993;328(8):584. Nakamura S, Kinoshita S, Yokoi N, et al. Lacrimal hypofunction as a new mechanism of dry eye in visual display terminal users. PLoS One 2010;5.e11119. Nichols KK, Nichols JJ, Mitchell GL. The lack of association between signs and symptoms in patients with dry eye disease. Cornea 2004;23(8):762–770. Begley CG, Chalmers RL, Abetz L, et al. The relationship between habitual patient-reported symptoms and clinical signs among patients with dry eye of varying severity. Invest Ophthalmol Vis Sci 2003;44(11):4753–4761. Watanabe H. Significance of mucin on the ocular surface. Cornea 2002;21(2 Suppl 1):S17–S22. Rolando M, Zierhut M. The ocular surface and tear film and their dysfunction in dry eye disease. Surv Ophthalmol 2001; 45(Suppl 2):S203–210. Liu H, Begley C, Chen M, et al. A link between tear instability and hyperosmolarity in dry eye. Invest Ophthalmol Vis Sci 2009;50(8):3671–3679. Woodward AM, Senchyna M, Argu¨eso P. Differential contribution of hypertonic electrolytes to corneal epithelial dysfunction. Exp Eye Res 2012;100:98–100. Koh S, Maeda N, Kuroda T, et al. Effect of tear film break-up on higher-order aberrations measured with wavefront sensor. Am J Ophthalmol 2002;134(1):115–117. Goto E, Ishida R, Kaido M, et al. Optical aberrations and visual disturbances associated with dry eye. Ocul Surf 2006; 4(4):207–213. Ishida R, Kojima T, Dogru M, et al. The application of a new continuous functional visual acuity measurement system in dry eye syndromes. Am J Ophthalmol 2005;139(2):253–258. Koh S, Maeda N, Hori Y, et al. Effects of suppression of blinking on quality of vision in borderline cases of evaporative dry eye. Cornea 2008;27(3):275–278. Shimazaki-Den S, Iseda H, Dogru M, Shimazaki J. Effects of diquafosol sodium eye drops on tear film stability in short BUT type of dry eye. Cornea 2013;32(8):1120–1125. Uchino Y, Tsubota K. Effect of switching treatment from existing therapy to 3% diquafosol sodium eyedrops for dry eye in VDT users. Atarashii Ganka 2013;30(6):871–874 [in Japanese].
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To evaluate the relationship between subjective symptoms and clinical signs in dry eye disease (DED) in office workers using visual display terminals (VDTs). DESIGN: Cross-sectional study. METHODS: This study involved 672 Japanese young and middle-aged office workers who use VDTs. The subjects completed questionnaires designed to detect subjective symptoms and risk factors for DED. Dry eye tests, including tear film break-up time (TBUT), cornealconjunctival staining with fluorescein and lissamine green, and the Schirmer test, were performed. Based on the Japanese diagnostic criteria for DED, the subjects were classified into 3 groups: definite DED, probable DED, and non-DED. Between each group, subjective symptoms and clinical signs were compared. RESULTS: Of the 672 subjects, 561 (374 male, 187 female) completed the questionnaire (response rate: 83.5%). Definite DED was diagnosed in 65 subjects (11.6%), probable DED in 303 subjects (54.0%), and non-DED in 193 subjects (34.4%). The mean subjective symptom score was significantly less in subjects with probable DED (2.05 ± 0.42) and non-DED (1.63 ± 0.38) than in those with definite DED (2.19 ± 0.40) (P < .05 and P < .01, respectively). In the subjects with probable DED, a subgroup with positive subjective symptoms and abnormal TBUT (£5 seconds) was categorized as short TBUT-type DED, and it was found that they had a higher subjective symptom score (2.09 ± 0.40), equivalent to that of those with definite DED (P [ .269). CONCLUSIONS: Despite no or minor epithelial damage, the severity of subjective symptoms was greater in short TBUT-type DED, most likely attributable to tear film instability. Thus, it might prove important to evaluate TBUT to successfully treat those patients. (Am J Ophthalmol 2015;159:748–754. Ó 2015 by Elsevier Inc. All rights reserved.)
Accepted for publication Dec 16, 2014. From the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan (N.Y., A.K., Y.S., H.K., S.K.); and the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan (M.U., Y.U., M.D., M.K., K.T.). Inquiries to Norihiko Yokoi, Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto 602-0841, Japan; e-mail: [email protected]
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2015 BY
T
HE PREVALENCE OF DRY EYE DISEASE (DED) HAS BEEN
increasing owing to changes in lifestyle driven by information technology (IT). In a previous epidemiologic study involving Japanese office workers using visual display terminals (VDTs), the prevalence of clinically diagnosed DED was 10.1% in male subjects and 21.5% in female subjects, and severe symptoms of DED were observed in 26.9% and 18.7% of the male and female subjects, respectively.1 In 2009, the personal computer ownership rate reached 87.2% in Japan, and the rapid spread of IT devices has promoted the daily use of VDTs for the visualization of information. Hence, the number of VDT users and the amount of time they spend using their respective terminals have both dramatically increased. Continuous use of VDT displays results in decreased blinking and a subsequent increase in ocular surface dryness, which is known to be a causative factor in DED cases. Excess aqueous evaporation from the ocular surface tear film easily occurs during VDT use because the tear film break-up time (TBUT) is shorter than the interval between blinks.2 It has been reported that using a VDT for more than 4 hours a day (compared to less than 2 hours daily) increases the risk of DED (odds ratio: 1.83).1 Work-related prolonged VDT use is considered to increase the risk of ocular disorders including eye strain and accommodative spasm, as well as DED. Thus, collecting the diagnostic and therapeutic data about VDT use–related ocular disorders is vital. To date, there are limited data on the prevalence and the risk factors of DED in VDT users. The relationship between VDT use–associated DED and shorter TBUT has been described previously;3–7 however, there is insufficient epidemiologic evidence for the prevalence and risk factors of DED subtypes in VDT users. Under the supervision of the Japanese Dry Eye Society, we conducted a large-scale epidemiologic study in office workers using VDTs in Japan (The Osaka Study).8 The Osaka Study was a questionnaire-based assessment of DED symptoms combined with dry eye examinations carried out by dry eye specialists investigating the epidemiology, risk factors, and pathology of DED. In this present study, we evaluated the relationship between DED subjective symptoms and clinical signs based on the Japanese dry eye diagnostic criteria established in 2006.9 Furthermore, we investigated the characteristics of probable DED with
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_5 seconds and normal tear secretion (short TBUTTBUT < type DED) in order to study the independent association of definite DED with reduced TBUT in VDT office workers using VDTs.
METHODS THIS STUDY FOLLOWED THE TENETS OF THE DECLARATION
of Helsinki, the Ethical Guidelines for Clinical Research (issued on December 28, 2004 by the Ministry of Health, Labor and Welfare [MHLW] of Japan), and the Ethical Guidelines for Epidemiological Research (issued on June 17, 2002 by the MHLW). The protocol of this institutional and cross-sectional study was approved prospectively by the Institutional Review Board of Ryogoku Eye Clinic, Tokyo, Japan. STUDY POPULATION:
Under the supervision of the Japanese Dry Eye Society, the authors randomly selected 2 large companies listed on the Japanese stock market and sent a letter to the industrial physician in charge of health management in each company; the letter explained the purpose of the study and requested their participation. The only company that responded to our letter and consented to participate was enrolled in this study. The employees working in the central office of the company were informed, via a website, of the study’s general outline and ophthalmic clinical examinations. We enrolled those employees who agreed to participate in the study after providing them with background information and receiving their consents via the website to undergo the ophthalmic examinations. Exclusion criteria included any employee who reported a history of refractive surgery or who was deemed inappropriate for this study by the ophthalmologists. To ensure the human rights and personal security of each participant, we took strict measures to protect the privacy of participants’ personal information (ie, special care in handling of their collected information; exclusion of individually identifiable information from the questionnaire; exclusion of individually identifiable information from the data to be published; and exclusive use of the data for the purposes of the study).
QUESTIONNAIRE:
We administered a web-based dry eye questionnaire to evaluate subjective DED symptoms and to obtain information on each participant’s age, sex, and usage of VDT devices. The questionnaire used in the study was developed by Toda and associates,10 and included 12 questions pertaining to the diagnostic symptoms of DED. The frequency of each symptom was evaluated as never (1 point), sometimes (2 points), often (3 points), and constantly (4 points), and the mean point value of all symptoms was defined as the DED symptom score. Subjects who answered ‘‘often’’ or
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‘‘constantly’’ for at least 1 item were defined as being symptom positive for DED. To validate our symptom evaluation method, it was compared with a well-established method, the Dry Eye Severity Index Score (DESIS), which is a severity grading system based on the translated version of the Ocular Surface Disease Index (OSDI) questionnaire11 into Japanese.12 Each DESIS item was evaluated as never (0), rarely (1), occasionally (2), often (3), and always (4), and the total number of points scored on 29 questions was converted to a scale ranging from 0 to 100. CLINICAL EVALUATION:
Seven ophthalmologists from the Japanese Dry Eye Society performed the ophthalmic examinations at the health-care institute of the participating company, located in Osaka, Japan. Subjects who used contact lenses (CLs) underwent the examination more than 1 day after removing their CLs.
TEAR FUNCTION TESTS EVALUATION: Ophthalmic
AND
OCULAR
SURFACE
examinations included the assessment of corneal and conjunctival vital staining with fluorescein and lissamine green, respectively; measurement of TBUT; and the Schirmer test. Briefly, corneal and conjunctival epithelial damage was evaluated by the double vital staining method.13 Two microliters each of 1% sodium fluorescein and preservative-free 1% lissamine green were instilled into the conjunctival sac using a micropipette to evaluate epithelial damage of the cornea and bulbar conjunctiva, respectively. The ocular surface was divided into 3 sections (the nasal conjunctiva, the cornea, and the temporal conjunctiva), each of which was graded 0–3 for severity, and the overall epithelial damage was scored on a scale of 0–9.14 TBUT measurement and the Schirmer test were performed to assess tear film stability and tear fluid secretion, respectively. TBUT was measured using a fluorescein dye solution. After instillation of the solution, the subjects were instructed to blink 3 times to ensure adequate mixing of the fluorescein dye with the tear film. The time interval between the third blink and appearance of the first dark spot in the cornea was consecutively measured by stopwatch, with the mean of 3 measurements regarded as the TBUT in this study. The Schirmer test was performed without topical anesthesia after all of the other examinations had been performed. Strips of filter paper (Whatman No. 41; Showa Yakuhin Kako Co Ltd, Tokyo, Japan) were placed for 5 minutes at the outer third of the temporal lower conjunctival fornix, with the subject spontaneously blinking. The strips were then removed, and the length of the filter paper wetted by the spontaneous blinks was recorded in millimeters. To avoid the influence of stimulation by ocular surface staining, the Schirmer test was performed after a 10-minute interval. To prevent air conditioning from influencing the examinations, no air conditioning device was used in the examination room. The room temperature and humidity were
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maintained at 25.0–26.5 8 C and 60%–65%, respectively, during the examinations. All subjects were prohibited from using a VDT for 1 hour prior to the examinations.
TABLE 1. Allocation of Osaka Study Subjects Into Groups Based on Diagnosis of Dry Eye Disease
DIAGNOSIS OF DRY EYE DISEASE:
DED was diagnosed based on the results of the clinical evaluation and our questionnaire, which used the dry eye diagnostic criteria defined in 2006 by the Japanese Dry Eye Society.9 These criteria included the presence of: (1) positive DED symptoms; (2) qualitative or quantitative abnormalities of the _5 seconds or Schirmer tear film in 1 or both eyes (TBUT of < _5 mm); and (3) corneo-conjunctival epithetest results of < _3 out of 9 points). The lial damage (total staining score of > presence of all 3 criteria was necessary for a diagnosis of definite DED. The presence of 2 of the 3 criteria in 1 or both eyes was necessary for a diagnosis of probable DED, while the presence of 1 or no positive criteria indicated nonDED. The eye fulfilling the most criteria was used to make the diagnosis. When both eyes met the same number of criteria, the eye with (1) the higher staining score and (2) the shorter TBUT was used for the diagnosis. If the staining score and TBUT were the same in both eyes, the right eye was used for the diagnosis. Based on the diagnostic criteria, the subjects were placed into either the definite DED, probable DED, or non-DED group, and the subjective symptom score was then compared among the groups.
SUBGROUP ANALYSIS OF THE SHORT TEAR BREAK-UP TIME–TYPE DRY EYE DISEASE GROUP: We performed a sub-
group analysis of the short TBUT subtype in the probable DED group. In this study, short TBUT was defined as _5 seconds) with a normal Schirmer abnormal TBUT (< test value (>5 mm). The subjects with short TBUT in the probable DED group were assigned to the short TBUT– type DED subgroup. The subjective symptom scores of each group were then analyzed and compared. To assess the status of tear film lipid secretion, meibomian gland function was evaluated using the meibomian gland dysfunction (MGD) grading system established by Shimazaki and associates.15 In brief, when meibomian gland secretion was absent after application of moderate pressure to the eyelid, meibomian gland function was defined as abnormal. Differences in the subjective symptoms between the subjects in the short TBUT subgroup and the other subjects were evaluated. Furthermore, the differences between the short TBUT–type DED group and the definite DED group were evaluated to characterize short TBUT–type DED. STATISTICAL ANALYSIS:
For discrete variables, the calculated mean values were analyzed using the Student t test and the Tukey test to compare 2 groups and 3 groups, respectively. For categorical variables, the Fisher exact test was used. The P values were 2-sided and the level of significance was set at 5% (P < .05). SAS 9.2 software for Windows (SAS Institute Inc, Cary, North Carolina, USA) was used for the data analysis.
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N (%) Short TBUT Others
Definite DED
Probable DED
Non-DED
65 (11.6%) 50 (8.9%) 15 (2.7%)
303 (54.0%) 244 (43.5%) 59 (10.5%)
193 (34.4%) 76 (13.5%) 117 (20.9%)
DED ¼ dry eye disease; TBUT ¼ tear film break-up time.
RESULTS THE STUDY PERIOD WAS FROM AUGUST 1, TO SEPTEMBER 1,
2011. The questionnaire was sent electronically to 672 eligible workers in the participating company; 561 workers (83.5%) responded and were enrolled in the study (374 male and 187 female subjects; mean age: 43.2 years). The mean (6SD) age of the male and female subjects was 45.1 (68.9; range: 26.0–64.0) and 39.5 (67.3; range: 24.0–60.0) years, respectively. Based on the responses to the 12-item questionnaire, 399 subjects (71.1%) were DED positive and 162 subjects (28.9%) were DED negative. The mean DED symptom score (mean 6 SD) was 1.92 6 0.46, and the mean number of symptoms was 2.5 6 2.5. The most frequently occurring symptoms included ‘‘eye fatigue’’ (48.1%), ‘‘dry sensation’’ (32.4%), and ‘‘blurred vision’’ (25.0%). Vital staining indicated that corneo-conjunctival epithe_3) lial damage was present in 90 subjects (16.0%; score > but not in 471 subjects (84.0%; score 0–2). The corneoconjunctival epithelial damage was generally mild in severity _5 secand the positive rate was low. TBUT was abnormal (< onds) in 441 subjects (78.6%) and normal (>5 seconds) in 120 subjects (21.4%). Of the 561 subjects who took the Schirmer test, 95 subjects (16.9%) showed abnormal values _5 mm) and 466 subjects (83.1%) showed normal values (< (>5 mm). Most subjects (66.0%, n ¼ 370) had a TBUT of < _5 seconds and a Schirmer test value of >5 mm (short TBUT subgroup). The subjects were diagnostically classified into 1 of 3 categories: definite DED (n ¼ 65; 11.6%); probable DED (n ¼ 303; 54.0%); and non-DED (n ¼ 193; 34.4%). Of the 303 probable DED subjects, 244 subjects (80.5%) were included in the short TBUT subgroup and 59 subjects (19.5%) in the ‘‘others’’ subgroup (Table 1). The mean 12-item symptom score was significantly higher in the definite DED group (2.19 6 0.40) than in the probable DED (2.05 6 0.42) and non-DED (1.63 6 0.38) groups (Tukey test, for each group P < .01) (Table 2). This result suggests that the severity of dry eye symptoms is associated with the diagnostic criteria of DED. A similar relationship was observed with DESIS. Associations between the clinical findings and DED symptom scores are shown in Table 3. In the subjects
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TABLE 2. Comparison of the 12-Item Symptom Score With the Dry Eye Severity Index in Assessing the Severity of Dry Eye Disease in Osaka Study Subjects Subjective Symptom
Diagnosis
Mean 6 SD (N)
P Value
Symptom score by 12 items (0–4)
1. Definite DED 2. Probable DED 3. Non-DED 1. Definite DED 2. Probable DED 3. Non-DED
2.19 6 0.40 (65) 2.05 6 0.42 (303) 1.63 6 0.38 (193) 31.8 6 13.6 (65) 28.1 6 14.0 (303) 17.1 6 9.1 (193)
1:2 P ¼ .028a 1:3 P ¼ .000b 2:3 P ¼ .000b 1:2 P ¼ .073 1:3 P ¼ .000b 2:3 P ¼ .000b
DESIS (0–100)
DED ¼ dry eye disease; DESIS ¼ dry eye severity index score; SD ¼ standard deviation of the mean. P value was calculated using the Tukey test. a P < .05. b P < .01.
TABLE 3. Associations Between Dry Eye Symptom Score and Ophthalmic Examination Values in Osaka Study Subjects Schirmer Test (N) Subjective Symptom Score
Symptom score by 12 items (0–4) DESIS (0–100)
TBUT Test (N)
Normal (>5 mm)
Abnormal _5 mm) (
5 s)
_5 s) Abnormal (
5 secwith abnormal (< onds), the mean subjective symptom scores (mean 6 SD) were 1.95 6 0.46 and 1.82 6 0.45, respectively, indicating a statistically significant difference (Student t test, P ¼ .006). In the subjects with normal ( were 1.91 6 0.45 and 2.02 6 0.47, respectively, and were significantly different (P ¼ .030). There was no significant difference in DED symptom score between the subjects with normal (1.92 6 0.46 mm) and abnormal (1.92 6 0.46 mm) Schirmer test values (P ¼ .987). DESIS analysis showed a similar tendency, suggesting that subjective symptom scores were significantly associated with TBUT (P ¼ .009) and staining score (P ¼ .022) but not with the Schirmer test value (P ¼ .705). To analyze the probable DED category in detail, we compared DED symptoms following classification of the probable DED type into the short TBUT subtype and ‘‘others’’ subtype. Most of the subjects had normal VOL. 159, NO. 4
meibomian gland function, and only 3.1%, 3.5%, and 3.1% of subjects showed abnormal function in the definite DED, short TBUT subtype of the probable DED, and nonDED groups, respectively, and there was no statistically significant difference among the groups (P ¼ .463). Others in the probable DED group had normal meibomian lipid secretion. Table 4 shows the association between the symptom score and diagnosis of DED in cases in which the probable DED was divided into subgroup, short TBUT–type DED, and ‘‘others.’’ The mean DED symptom scores were significantly different between the definite DED group and ‘‘others’’ in the probable DED or non-DED groups (Tukey test, P < .01), but not between the definite DED group and the short TBUT subtype (P ¼ .269). DESIS analysis showed a similar tendency. The results suggested that DED symptoms in the short TBUT subtype of the probable DED group were comparable to those in the definite DED group.
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TABLE 4. Associations Between the Symptom Score and Diagnosis of Dry Eye Disease in Osaka Study Subjects Subjective Symptom Score
Symptom score by 12 items (0–4)
DESIS (0–100)
Definite DED Short TBUT–type DED Other probable DED Non-DED Definite DED Short TBUT–type DED Other probable DED Non-DED
Mean 6 SD (N)
P Value
2.19 6 0.40 (65) 2.09 6 0.40 (229) 1.93 6 0.44 (74) 1.63 6 0.38 (193) 31.8 6 13.6 (65) 29.1 6 13.9 (229) 24.9 6 14.0 (74) 17.1 6 9.1 (193)
.269 .001a .000a .402 .006a .000a
DED ¼ dry eye disease; DESIS ¼ dry eye severity index score; SD ¼ standard deviation of the mean; TBUT ¼ tear film break-up time. P value was calculated using the Tukey test in comparing to definite DED. a P < .01.
Furthermore, we investigated the difference in DED symptoms between the subjects in the short TBUT subgroup included in the definite DED and probable DED groups and ‘‘other’’ subjects. Symptoms included eye fatigue (53.0%), dry sensation (35.9%), uncomfortable sensation (24.3%), and blurred vision (24.3%) in the short TBUT subgroup and eye fatigue (38.7%), blurred vision (26.2%), and dry sensation (25.7%) in the ‘‘others’’ subgroup. However, there was a statistically significant between-group difference in 5 items: eye fatigue (P ¼ .002), eye pain (P ¼ .038), red eye (P ¼ .039), uncomfortable sensation (P ¼ .041), and dry sensation (P ¼ .014). Analysis of the Schirmer test and vital staining results showed a statistically significant between-group difference in blurred vision only (P ¼ .037) and 2 symptoms (redness, P ¼ .034 and dry sensation, P ¼ .001), respectively, suggesting that abnormal TBUT may be a strong contributor to the frequency of symptoms.
DISCUSSION DED IS DEFINED AS A MULTIFACTORIAL DISEASE OF THE
tear film and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability, with potential damage to the ocular surface.16 Thus, DED negatively affects the quality of vision.17,18 Continuous VDT work is a major causative factor of DED, because of the blink-rate decrease owing to tear film disturbance and resultant ocular surface dryness induced by continual gazing at the display terminal. The frequency of blinking (normally 20 blinks per minute) decreases to approximately one half when reading and from one third to one fourth when using a VDT.19 In a previous report, it was suggested that a long duration of VDT work might induce lacrimal gland hypofunction resulting in DED.20 The rapid advance of IT devices and visualization of information will 752
further increase the prevalence of DED; use of VDT devices is inevitable in business and daily life. Therefore, an understanding of DED pathology, establishment of reliable diagnostic methodology, and development of effective management and therapy strategies are needed to provide appropriate treatment for DED. Diagnosis of DED based on well-established criteria is essential to the treatment of DED. The Dry Eye Work Shop (DEWS) is engaged in the study of DED and published an International Expert Committee Report in 2007.16 This report covered a wide range of findings on DED, but not diagnostic criteria. In Japan, contemporaneous with the preparation of the DEWS report, the Dry Eye Society published a revised list of diagnostic criteria along with the definition of DED in 2006.9 Traditionally, the association between DED symptoms and clinical signs has been considered weak21; however, a study suggested that the severity of DED had a stronger relationship with subjective symptoms than with clinical signs.22 The criteria of the Japanese Dry Eye Society focus on the association of diagnosis with symptoms and aim to reflect this association by adding the diagnostic category ‘‘probable DED’’ to the conventional 2 categories (‘‘definite DED’’ and ‘‘non-DED’’). Uchino and associates reported an association between the use of VDTs by Japanese office workers and DED in a population-based cohort study, and suggested more prevalence of DED among female subjects, contact lens wearers, and workers who use VDTs for prolonged periods.1 However, in this cohort study, diagnosis of DED was based on selfreports. No study has evaluated the association between VDT use and DED diagnosed by DED experts using ophthalmic examinations. In our study of office workers continuously using VDTs, detailed subjective symptoms of DED were investigated to evaluate the relationship between subjective symptoms and clinical signs, including disturbance of the tear film and corneo-conjunctival epithelial damage. The results suggested that the subjective
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symptoms more clearly reflect the diagnosis of DED, if the intermediate category (probable DED) is adopted to the diagnostic criteria of the Japanese Dry Eye Society. These criteria will provide more precise diagnosis of DED and lead to more appropriate treatment. Since most of the subjects in the study population had _5 seconds), we could analyze DED with short TBUT (< abnormal TBUT value in detail. While 78.6% of the study population had short TBUTs, only 16.9% had abnormal Schirmer test values. This result indicated that most VDT workers with DED had abnormal tear film stability in spite of normal tear secretion. DED was etiologically classified into 2 categories: (1) ‘‘tear-deficient dry eye,’’ caused by a failure of lacrimal secretion; and (2) ‘‘evaporative dry eye,’’ caused by such factors as MGD. The short TBUT-type DED is not likely to be placed in the ‘‘tear-deficient dry eye’’ category because of normal Schirmer test values. Moreover, in the study, normal meibomian gland secretion was found in almost all subjects, and no relationship was observed between meibomian secretion and the TBUT. This may suggest that the short TBUT-type DED should not be included in the ‘‘evaporative dry eye’’ category. Shimazaki-Den and associates reported that the messenger RNA levels of membrane-associated mucin (MUC16) and secretory mucin (MUC5AC) were lower in eyes with unstable tear film as demonstrated by short TBUT, as well as in tear-deficient dry eye.4 Decreased expression of mucins may be the main factor affecting the dysfunction of ocular surface wettability and tear film stability.23,24 Liu and associates reported that tear hyperosmolarity is linked to tear film instability and thus results in ocular discomfort, burning, and stinging.25 Under the hypertonic condition, some electrolytes reportedly have an effect on corneal epithelial dysfunction, including the expression of membrane-associated mucin.26 Unfortunately, we did not check tear osmolarity or the content of electrolytes in this study. Further study is needed to clarify what causes the decrease in mucin expression in eyes with little corneoconjunctival epithelial damage. To diagnose patients with DED, the Schirmer test value and ocular surface staining score tend to be used. On the other hand, our findings suggest that the symptoms and TBUT may be more relevant diagnostic parameters for detecting DED in office workers using VDTs because the majority of the DED in those subjects has normal tear secretion and no ocular surface staining.8 It remains unclear whether or not these DED cases are at a relatively late stage of development. In addition to the DED symptoms, the tear
film instability is easily detected on the core mechanisms of DED in comparison to the invisible changes of the ocular surface, such as the lower expression of MUC16.16 Severe symptoms were reported by subjects with short TBUT-type DED in this study. These subjects had probable DED according to the diagnostic criteria in Japan and a DED symptom score comparable to that of subjects with definite DED. Common symptoms reported by subjects with short TBUT-type DED were ‘‘eye fatigue,’’ ‘‘dry sensation,’’ and ‘‘uncomfortable sensation.’’ Impaired tear film stability may cause dry and uncomfortable sensations irrespective of tear volume. The collapse of the tear film after blinking affects the ocular higher-order aberrations and functional visual acuity in DED.27–30 Disturbance of the tear film in the pupillary zone (owing to enhanced accommodative stress induced by alteration in retinal images resulting from increases in higher-order aberrations) is considered to be the cause of asthenopia. Thus, VDT workers with short TBUT, even if diagnosed with probable DED, will need active dry eye treatment for subjective symptoms and improvement of visual function. Drugs that improve tear film stability will be effective for the treatment of DED in VDT workers. Diquafosol sodium enhances tear film stability by altering water and mucin secretion from conjunctival tissue, and therefore would be expected to be effective for the treatment of short TBUT-type DED.31,32 As for the limitations of this study, since only young and middle-aged office workers participated in this study, we may have to distinguish the results from those obtained from older-aged subjects with DED. At the least, the Japanese diagnostic criteria of DED could be used to identify the DED patients who can be successfully treated; however, a much larger population with more elderly subjects may be needed to conclude whether these criteria can be generalized, or not, for all DED patients. In conclusion, the severity of subjective symptoms was found to be significantly related to the diagnostic categories (definite DED, probable DED, and non-DED) based on the dry eye diagnostic criteria established in Japan in 2006. The subjects with short TBUT (ie, the dominant subtype in the study) in the probable DED group (compared with those in the definite DED group) reported higher DED symptom scores. The prevalence of DED attributable to VDT work will continue to increase. Therefore, further studies are highly warranted to establish screening and prophylactic procedures using TBUT and standard medical treatment for DED, as well as to elucidate its pathology.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. The author make the following financial disclosures: Norihiko Yokoi: consultant for Kissei Co, Ltd, Nagano, Japan; and Rohto Co, Ltd, Osaka, Japan. Shigeru Kinoshita: consultant for Santen Pharmaceutical Co, Ltd, Osaka, Japan; and Otsuka Pharmaceutical Co, Ltd, Tokyo, Japan. Kazuo Tsubota: consultant for Santen Pharmaceutical Co, Ltd, Osaka, Japan; Acu Focus, Inc, Irvine, California, USA; Bausch & Lomb Inc, Rochester, New York, USA; Pfizer Inc, New York, New York, USA; and Laboratoires The´a, Clermont-Ferrand, France. This study was supported in part by Grants-in-Aid for scientific research from the Japanese Ministry of Education, Culture, Sports, Science and Technology. Provision of facilities, transport of equipment, data analysis, and data management were supported by Santen Pharmaceutical Co, Ltd, Osaka. The funding organization had no role in the design or conduct of this research. The authors have no proprietary or commercial interest in any of the materials discussed in this article. Contributions of authors:
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conception and design of study (M.U., N.Y., Y.U., M.D., M.K., S.K., K.T.); analysis and interpretation (M.U., M.D.); writing the article (N.Y., M.U., Y.U., M.D., M.K.); critical revision of the article (N.Y., M.U., Y.U., M.D.); final approval of the article (N.Y., M.U., Y.U., M.D., M.K., A.K., Y.S., H.K., S.K., K.T.); data collection (N.Y., M.U., Y.U., M.D., M.K., A.K., Y.S.); provision of materials, patients, or resources (N.Y., M.U., Y.U., M.D.); statistical expertise (N.Y., M.U., Y.U.); literature search (N.Y., M.U., Y.U., M.D.); administrative, technical, or logistic support (N.Y., M.U., Y.U., M.D., M.K., S.K., K.T.).
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