Abstract
Objectives
To examine the effect of a dietary supplement containing bilberry extract (BE) on eye fatigue induced by acute video display terminal (VDT) loads.
Design and setting
A prospective, randomized, double-blind, placebo-controlled study was performed from August 2012 to February 2013 in the Medical Corporation Jico-kai Yagi Hospital, and the Shinyokohama Shinoharaguchi Orthopedic Surgery and Dermatology Clinic, in Japan.
Participants
Two hundred eighty-one office workers aged 20–40 years that used VDTs were screened by critical flicker fusion (CFF) and near point accommodation (NPA).
Intervention
The participants were randomized to either a BE (480 mg/day) or placebo (vehicle) group, and took allocated capsule, daily, for 8 weeks.
Measurements
The CFF, NPA, contrast visual acuity, functional visual acuity, keratoconjunctival epithelial damage, and fluorescein tear film break-up time were examined, and 18 subjective symptoms of eye fatigue were evaluated by questionnaire. Adverse events were reported via medical interviews. Data were collected both before and after VDT load at baseline, and 4, and 8 weeks after daily supplementation with either BE or placebo.
Results
Of 281 participants screened, 88 having relatively lower levels of CFF and NPA were enrolled in the study. Of these, 37 control and 43 BE group subjects completed the study. The VDT load-induced reduction in CFF was alleviated after 8 weeks of BE supplementation (95% confidence interval, 0.10–1.60; p=0.023), in contrast to placebo supplementation, while NPA variation was not. Of the subjective symptoms of eye fatigue, VDT load-induced ocular fatigue sensation, ocular pain, eye heaviness, uncomfortable sensation, and foreign body sensation were mitigated more in the BE group than in the control group, at week 8 (p<0.05). There were no severe adverse events in either group.
Conclusions
BE supplementation improved some of the objective and subjective parameters of eye fatigue induced by VDT loads.
Key words: Eye fatigue, video display terminal, bilberry extract, anthocyanins
Introduction
The recent increase in the amount of daily work performed at video display terminals (VDTs) has resulted in a concurrent increase in various symptoms associated with eye fatigue, as well as musculoskeletal complaints involving the shoulders, neck and back, and headaches (1, 2). The symptoms of eye fatigue include ocular pain, dry eye sensation or excess tearing, and blurred vision, and these symptoms may impair visual health and the quality of vision (3, 4, 5, 6). A number of clinical studies have demonstrated a significant association between eye fatigue and psychophysiological eye functions, which can be assessed by objective ophthalmic parameters such as critical flicker fusion (CFF) and near point accommodation (NPA) (1, 2, 7, 8, 9, 10). Eye fatigue may impair the quality of VDT workers’ performances, via loss of visual concentration, and/or impair their quality of life by undermining visual health (11, 12, 13).
To resolve this issue, nutraceutical approaches utilizing micronutrient supplements for therapeutic and/or preventive treatment of eye fatigue are currently under investigation, in response to the general interest in the dietary constituents for health maintenance (14, 15). Several dietary constituents, such as n-3 long-chain fatty acids (16), carotenoids (e.g., lutein) (17), polyphenols (e.g., anthocyanins) (18, 19, 20), and anti-oxidants (21) have been reported to be effective in improving visual acuity and/or other eye functions. Of these dietary ingredients, anthocyanins and berry extracts rich in anthocyanins have been most intensively studied in humans with regard to their effect on vision, including many early studies carried out in several European countries in the 1960s (22). These early studies suggesting the ability of anthocyanins to prevent visual disturbance and/or eye fatigue have led to more recent clinical trials using dietary supplementation with anthocyanins, alone (18, 19, 20) or in combination with fish oil and lutein (23). However, VDT load-related eye fatigue may involve multiple signs or symptoms; thus, further information is required to determine whether anthocyanins constitute a useful supplement for the preservation of ocular health in those working with VDTs.
In this randomized, double-blind, placebo-controlled trial in subjects working at a VDT daily who reported VDT-related eye fatigue, we investigated the effect of a micronutrient supplement containing anthocyanin-rich bilberry extract on acute VDT load-induced signs of ocular disorders and symptoms of eye fatigue.
Materials and Methods
Ethics
This study adhered to all the guidelines set forth in the Declaration of Helsinki (amended in 2008) and the Ethical Guidelines for Epidemiological Research (enacted by the Japanese Government in 2004). It was approved by the Yagi Hospital Ethical Review Board, Tokyo, Japan. All subjects received a full explanation of the procedures undertaken in the study, and written informed consent from each subject was obtained prior to the study. To ensure privacy, all records were identified via an anonymous subject identification number.
Study design. This study was a prospective, randomized, placebo-controlled, parallel design dietary-supplement trial. It was designed to assess the efficacy and safety of taking a dietary supplement containing BE (BE supplement), to alleviate acute VDT-induced eye disorders as evaluated by ophthalmic examination, and subjective symptoms related to eye fatigue as evaluated by questionnaire. The study was performed from August 2012 to February 2013 in two clinical service organization centers, the Medical Corporation Jico-kai Yagi Hospital, and the Shinyokohama Shinoharaguchi Orthopedic Surgery and Dermatology Clinic, in Japan. The study was registered with the University Hospital Medical Information Network in Japan (UMIN000008766).
Subjects
We recruited male and female Japanese office workers aged 20–40 years, who used VDTs at work daily and complained of VDT-induced subjective symptoms of eye fatigue. Based on our preliminary investigation and previous studies related to VDT-induced fatigue (24), we screened the participants via CFF and the NPA, between August 2012 and September 2012. The resulting data were ranked, and the 88 participants whose data for both CFF and NPA were at the bottom of the rank were included as the intervention study subjects. Interventions were performed from October 2012 to December 2012. Individuals were excluded if they had: best corrected visual acuity < 1.0; high myopia; current or a history of severe eye disease(s), i.e., strabismus, cataract, glaucoma; a risk of developing seasonal allergy during the period between July and December; a history of LASIK operation within the last 3 months; or allergy to the test supplement. Participants were also excluded if they were routinely using BE (or BE-enriched food), currently taking medicine for vision improvement, or were undergoing medical treatment. We excluded subjects who have habitual medication for their symptoms. The participants were allowed to withdraw from the study at any time-point with any reasons but were not allowed to use other treatment for reducing the eye fatigue as long as were participants of the study, although they were aware of such medication. This protocol was also approved by the Yagi Hospital Ethical Review Board, and informed consent was carefully obtained from each participant. Additional exclusion criteria were as follows: a history of any other serious diseases requiring medical treatment; participation in another clinical trial within the month prior to the start of the present study; expecting a pregnancy or lactation during the study period; the presence of any health disorders according to the results of the questionnaire.
Ophthalmic examinations
CFF (Hz) was measured with a blinking light-emitting diode and a vision target at a wave-length of 660 nm (red color) using a Handy Flicker HF-II (Neitz Instruments Co., Ltd., Tokyo, Japan) according to the manufacturer’s instructions (reference interval, 36–50 Hz; mean value, 41.3 ± 3.4 Hz). NPA (Diopters) was determined using a NP Accomodometer (Kowa Co., Ltd., Nagoya, Japan). Average contrast sensitivity values and functional visual acuity values were measured using a CSV-1000 Lan C Contrast Testing Instrument (Vector Vision, Dayton, OH, USA) and an AS-28 Continuous Functional Visual Acuity Measurement System (Kowa Co., Ltd,) respectively. The measurement of tear film break up time and the assessment of keratoconjunctival epithelial damage based on fluorescein staining scores of the cornea and conjunctiva were performed by a number of the authors of this report (M.K., S.I., E.I., A.S.) who are appropriately specialized, in accordance with the methods described in a previous report (25). For these examinations, 2 µL of a preservative-free 1% fluorescein dye was instilled using a micropipette, to not cause abnormal tear dynamics. The data were obtained before and after an acute VDT load at each of the time-points investigated, which were baseline, and week (wk) 4 and wk 8 after the initiation of intervention.
Assessment of subjective symptoms self-reported via a questionnaire
The occurrence, frequency, and/or intensity of subjective symptoms of eye fatigue were evaluated using a questionnaire comprised of 18 questions. Subjects were instructed to answer the questions with the use of a 100-mm Visual Analog Scale, or a score of 0 to 10. In both cases, higher scales or scores indicated more severe symptoms. The data were obtained before and after an acute VDT-load at each of the time-points investigated, which were baseline, and wk 4 and wk 8 after the initiation of intervention.
Intervention
The dietary supplements administered were BE supplement capsules (160 mg BE per capsule; Wakasa Seikatsu Co., Ltd., Kyoto, Japan) or placebo capsules containing only vehicles (starch, crystalline cellulose, and calcium stearate). All eligible subjects were randomly assigned (1:1) to take either the BE supplement capsules (BE group) or the placebo capsules (control group). The subjects were required to take 3 capsules once daily after breakfast, with the aid of a sufficient amount of water, throughout the 8-week intervention period. All subjects were also instructed to self-record their allocated capsule intake status and any adverse events in a study diary throughout the intervention period. For blinding, the placebo capsules were also colored similar to the BE capsule, and both placebo and BE capsules were packed in the non-transparent bag and provided.
VDT loading
Acute VDT loads were imposed by having the subjects play Microsoft® Solitaire Version 5.1 and ‘BLOCK1. 30’ for 60 minutes each (2 hours in total), in an air-conditioned room at 25°C and 50% humidity. Prior to the start of this task, subjects received 180 ml of water at baseline, and allocated capsules together with 180 ml of water at wk 4 and wk 8.
Safety assessment. Subjects were instructed to report any adverse events at a medical interview conducted at every visit during the study period.
Statistical analysis
The data of a dominant eye in each case were analyzed. Continuous normally distributed data were expressed as means ± SE. Data were compared via the paired t-test for continuous variables, the Wilcoxon signed rank test for keratoconjunctival epithelial damage, and the Wilcoxon matched-pairs test for individual subjectively quantified symptoms. The baseline characteristics of the BE and placebo groups were compared using the unpaired t-test, or for the categorical variable ‘gender’, the Chi-square test. The unpaired t-test (for continuous variables) and the Mann-Whitney U test (for categorical variables) were used to assess the significance of differences in the VDT load-induced variation range for each parameter between the two groups. Statistical significance was deemed to be indicated where p < 0.05. For data analyses, PASW Statistics 18 (SPSS Japan, Tokyo, Japan) was used.
Results
Baseline characteristics of the subjects
Of the 281 participants screened by CFF and NPA, 88 were enrolled in the intervention study as described in the Materials and Methods section, and assigned to either the placebo group or the BE group (n = 44 per group). Thirty-seven of the placebo group (84%) and 43 of the BE group (98%) were included in the analyses. Five subjects (4 and 1 in the placebo and BE groups respectively) dropped out of the study during the intervention period for personal reasons, and 3 subjects in the placebo group were excluded from the efficacy analysis for the following reasons: 2 subjects discontinued taking the assigned study capsules, and 1 subject was discovered to have been using a topical eye medicine during the intervention period.
Table 1 shows the baseline characteristics of the randomized subjects who were assigned to either the placebo or the BE supplement group. There were no significant differences in any variables between the placebo and BE groups. The mean baseline CFF and NPA levels of the two groups measured before VDT load did not differ significantly, and both were within the normal ranges for clinical measurements. Although habitual contact lens wearers were included in both groups (control group, 5 [13.5%]; BE group, 8 [18.6%], P=0.538), there were no participants who had subtarsal papillae and meibomian dysfunction.
Table 1.
Baseline characteristics
| Variables | Placebo group (n=37) | BE group (n=43) | P-value |
|---|---|---|---|
| Age (years) | 30.8±0.9 | 30.6±0.9 | 0,859 |
| Gender (male/female) | 17/20 | 21/22 | 0,796 |
| Height (cm) | 165.28±1.3 | 165.87±1.2 | 0,922 |
| Body weight (kg) | 58.27±1.5 | 61.51±2.0 | 0,196 |
| Body-mass index (kg/m2) | 21.3±0.4 | 22.2±0. 6 | 0,133 |
| CFF, dominant eye (Hz) | 37.7±0.5 | 36.57±0.45 | 0,113 |
| NPA, dominant eye (Diopter) |
7.59±0.32 |
7.55±0.30 |
0,926 |
All values are expressed as the mean±SE, with the exception of gender. The P-values for all variables except gender were assessed by the unpaired t-test and that for gender by the Chi squared test.
Effects of BE on VDT-induced eye disorders assessed by ophthalmic examination
The results of VDT load-induced reduction in CFF and NPA are summarized in Table 2. CFF was reduced after VDT load compared with before the VDT load at baseline, in both the control and the BE group. Interestingly however, the range of variation in CFF due to VDT load was significantly reduced at wk 8 compared with baseline in the BE group (95% confidence interval, 0.10-1.60; p=0.023) but not the placebo group. Although there was no significant difference in the reduction range between the 2 groups, BE’s alleviating effect on CFF reduction was not observed in the placebo group.
Table 2.
CFF and NPA values measured before and after the acute VDT load at baseline and at weeks 4 and 8 of intervention
| Variables | Time point | Placebo group (n=37) | BE group (n=43) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Before VDT load | After VDT load | Variationa (relative change) | P Value b | Before VDT load | After VDT load | Variationa (relative change) | P Value b | ||
| CFF (Hz) | Baseline | 37.7±0.5 | 36.8±0.6 | 0.90±0.34 | - | 36.6±0.45 | 35.2±0.5 | 1.34±0.30 | - |
| wk 4 | 37.9±0.7 | 37.0±0.7 | 0.96±0.43 | 0.897 | 37.0±0.5 | 35.7±0.4 | 1.29±0.33 | 0.851 | |
| wk 8 | 36.8±0.7 | 36.3±0.6 | 0.47±0.41 | 0.331 | 35.7±0.4 | 35.2±0.4 | 0.47±0.29 | 0.023* | |
| NPA | Baseline | 7.59±0.32 | 7.38±0.34 | 0.22±0.19 | - | 7.55±0.30 | 7.44±0.30 | 0.11±0.12 | - |
| (Diopter) | wk 4 | 7.67±0.34 | 7.38±0.33 | 0.30±0.15 | 0.487 | 7.48±0.31 | 7.37±0.29 | 0.11±0.08 | 0.945 |
| wk 8 |
7.65±0.31 |
7.50±0.33 |
0.16±0.17 |
0.636 |
7.60±0.30 |
7.35±0.30 |
0.25±0.09 |
0.454 |
All values are expressed as the mean±SE. Variation showed the difference of the values between before, and after the VDT at each time point. a) Increment between before and after the VDT load. b) The within-group comparisons of VDT-induced variations at wk 4 or 8 with those at baseline was assessed by the paired Student’s t-test (*P< 0.05).
In contrast, there were no consistent modifications of the VDT load-induced variations in NPA of either group, throughout the intervention period. Comparisons of the variation ranges of CFF and NPA between the BE and control groups at wk 8 also did not show significant differences (data not shown). With regard to other ophthalmic parameters, contrast sensitivity, functional visual acuity, tear film break up time and keratoconjunctival epithelial damage, there were no significant differences in VDT load-induced variations in either the placebo group or the BE group, at any time-points (data not shown).
Effects of BE on VDT-induced impairment of subjective symptoms of eye fatigue
Table 3 shows the VDT load-induced alterations in individual scores for 18 subjective symptoms at baseline, wk 4 and wk 8. The variations of the values were compared both within the group at baseline, wk 4 and wk 8, and between the two groups at wk 4 and wk 8.
Table 3.
Scores for 18 subjective symptoms of eye fatigue and related ophthalmic conditions measured before and after imposing the VDT load at baseline weeks 4 and 8 of intervention
| Placebo group (n=37) | BE group (n=43) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Symptom | Time point | Before VDT load | After VDT load | Variationa | P Value b | Before VDT load | After VDT load | Variationa | P Value b | P Value c |
| Ocular | Baseline | 21.3±4.2 | 54.0±4.5 | 32.7±3.3 | - | 19.9±3.7 | 48.9±3.7 | 29.0±3.0 | - | 0.405 |
| fatigue | wk 4 | 13.1±3.3 | 41.2±4.3 | 28.2±3.3 | 0.27 | 15.8±3.1 | 32.5±3.5 | 16.7±3.1 | 0.001** | 0.014† |
| sensation | wk 8 | 12.2±3.1 | 35.4±4.1 | 23.2±2.8 | 0.010** | 11.8±2.5 | 25.7±2.9 | 14.0±3.0 | 0.000** | 0.029† |
| Ocular | Baseline | 10.8±3.2 | 32.8±5.4 | 22.0±3.8 | - | 5.9±1.9 | 25.7±3.9 | 19.9±3.4 | - | 0.677 |
| pain | wk 4 | 7.3±2.6 | 24.4±4.7 | 17.1±3.5 | 0.227 | 10.1±3.2 | 17.0±3.4 | 6.9±3.1 | 0.001** | 0.032† |
| wk 8 | 8.0±2.6 | 22.5±4.3 | 14.5±3.0 | 0.028* | 5.2±1.9 | 9.4±2.6 | 4.2±2.2 | 0.000** | 0.007†† | |
| Stiffshoulder | Baseline | 27.0±4.7 | 53.0±5.4 | 26.1±4.1 | - | 21.6±3.9 | 42.5±4.9 | 20.9±3.8 | - | 0.357 |
| low backpain | wk 4 | 20.3±3.8 | 43.4±5.1 | 23.0±3.6 | 0.446 | 17.4±3.4 | 29.4±3.9 | 12.0±2.8 | 0.019* | 0.016† |
| wk 8 | 16.0±3.9 | 38.5±5.3 | 22.4±3.9 | 0.352 | 15.3±2.8 | 30.0±3.8 | 14.7±3.1 | 0.191 | 0.125 | |
| Dry eye | Baseline | 24.2±5.0 | 45.4±5.8 | 21.2±3.9 | - | 18.3±3.9 | 39.5±4.2 | 21.1±3.4 | - | 0.993 |
| sensation | wk 4 | 14.8±2.9 | 29.3±4.5 | 14.5±3.0 | 0.134 | 15.0±3.7 | 25.5±3.7 | 10.4±3.3 | 0.004** | 0.359 |
| wk 8 | 13.6±2.8 | 29.1±4.4 | 15.5±3.5 | 0.229 | 12.0±2.9 | 21.2±3.5 | 9.2±2.8 | 0.001** | 0.16 | |
| Eye | Baseline | 18.7±4.5 | 44.3±5.3 | 25.6±4.2 | - | 18.0±3.5 | 36.6±4.1 | 18.6±2.7 | - | 0.154 |
| heaviness | wk 4 | 9.6±2.6 | 30.5±4.4 | 20.9±3.4 | 0.353 | 8.9±2.0 | 22.1±3.5 | 13.2±3.3 | 0.141 | 0.109 |
| wk 8 | 11.0±3.2 | 25.4±4.4 | 14.4±3.2 | 0.032* | 9.6±2.6 | 15.5±2.6 | 5.9±2.5 | 0.000** | 0.039† | |
| Blurred | Baseline | 0.95±0.32 | 1.70±0.36 | 0.76±0.21 | - | 1.12±0.26 | 1.53±0.32 | 0.42±0.28 | - | 0.173 |
| vision | wk 4 | 1.24±0.33 | 1.51±0.32 | 0.27±0.18 | 0.037* | 1.02±0.28 | 1.02±0.24 | 0.00±0.21 | 0.155 | 0.128 |
| wk 8 | 0.81±0.24 | 1.11±0.26 | 0.30±0.22 | 0.081 | 0.65±0.16 | 0.91±0.18 | 0.26±0.18 | 0.946 | 0.607 | |
| Excess | Baseline | 1.00±0.37 | 1.03±0.28 | 0.03±0.20 | - | 0.44±0.17 | 0.72±0.22 | 0.28±0.16 | - | 0.974 |
| tearing | wk 4 | 0.57±0.26 | 0.97±0.30 | 0.41±0.17 | 0.149 | 0.33±0.11 | 0.38±0.16 | 0.05±0.14 | 0.074 | 0.043† |
| wk 8 | 0.41±0.17 | 0.68±0.19 | 0.27±0.16 | 0.097 | 0.28±0.13 | 0.23±0.08 | -0.05±0.10 | 0.119 | 0.085 | |
| Eye | Baseline | 0.76±0.20 | 2.08±0.30 | 1.32±0.25 | - | 0.84±0.20 | 1.35±0.26 | 0.51±0.24 | - | 0.028† |
| redness | wk 4 | 0.68±0.21 | 1.51±0.31 | 0.84±0.19 | 0.064 | 0.52±0.12 | 1.14±0.19 | 0.62±0.15 | 0.626 | 0.419 |
| wk 8 | 0.70±0.19 | 1.30±0.29 | 0.59±0.18 | 0.007** | 0.40±0.12 | 0.77±0.17 | 0.37±0.14 | 0.345 | 0.386 | |
| Dazzled | Baseline | 0.51±0.18 | 1.30±0.31 | 0.78±0.21 | - | 0.72±0.22 | 1.26±0.30 | 0.53±0.24 | - | 0.132 |
| vision | wk 4 | 0.65±0.19 | 1.00±0.27 | 0.35±0.15 | 0.042* | 0.48±0.15 | 0.55±0.16 | 0.07±0.16 | 0.033* | 0.238 |
| wk 8 | 0.54±0.18 | 0.73±0.21 | 0.19±0.17 | 0.017* | 0.47±0.15 | 0.63±0.16 | 0.16±0.15 | 0.077 | 0.331 | |
| Double | Baseline | 0.43±0.16 | 1.05±0.27 | 0.62±0.18 | - | 0.56±0.18 | 1.12±0.28 | 0.56±0.20 | - | 0.372 |
| vision | wk 4 | 0.70±0.23 | 1.00±0.28 | 0.30±0.22 | 0.201 | 0.36±0.12 | 0.48±0.15 | 0.12±0.10 | 0.005** | 0.191 |
| wk 8 | 0.49±0.16 | 0.81±0.19 | 0.32±0.15 | 0.323 | 0.35±0.13 | 0.44±0.13 | 0.09±0.11 | 0.007** | 0.168 | |
| Frustration | Baseline | 0.62±0.21 | 1.78±0.37 | 1.16±0.26 | - | 0.56±0.24 | 1.56±0.31 | 1.00±0.20 | - | 0.92 |
| wk 4 | 0.59±0.24 | 2.05±0.44 | 1.46±0.32 | 0.199 | 0.48±0.23 | 1.26±0.36 | 0.79±0.33 | 0.079 | 0.005†† | |
| wk 8 | 0.49±0.24 | 1.65±0.41 | 1.16±0.33 | 0.851 | 0.47±0.21 | 1.56±0.41 | 1.09±0.34 | 0.533 | 0.562 | |
| Stuffy | Baseline | 1.14±0.34 | 3.30±0.47 | 2.16±0.34 | - | 1.02±0.29 | 2.35±0.39 | 1.33±0.27 | - | 0.103 |
| head | wk 4 | 0.78±0.27 | 2.68±0.48 | 1.89±0.38 | 0.396 | 0.90±0.27 | 1.52±0.30 | 0.62±0.24 | 0.011* | 0.010†† |
| wk 8 | 0.68±0.25 | 2.16±0.40 | 1.49±0.32 | 0.031* | 0.65±0.21 | 1.53±0.29 | 0.88±0.25 | 0.155 | 0.14 | |
| Headache | Baseline | 0.68±0.29 | 2.08±0.43 | 1.41±0.28 | - | 0.63±0.27 | 1.58±0.38 | 0.95±0.25 | - | 0.146 |
| wk 4 | 0.68±0.26 | 1.86±0.48 | 1.19±0.39 | 0.286 | 0.71±0.27 | 1.07±0.29 | 0.36±0.22 | 0.048* | 0.147 | |
| wk 8 | 0.41±0.18 | 1.46±0.43 | 1.05±0.35 | 0.144 | 0.44±0.17 | 0.98±0.25 | 0.53±0.20 | 0.122 | 0.702 | |
| Eye | Baseline | 0.84±0.26 | 1.59±0.38 | 0.76±0.27 | - | 0.56±0.16 | 0.91±0.23 | 0.35±0.21 | - | 0.299 |
| itching | wk 4 | 0.76±0.24 | 1.49±0.35 | 0.73±0.18 | 0.667 | 0.55±0.13 | 0.55±0.15 | 0.00±0.15 | 0.119 | 0.000†† |
| wk 8 | 0.59±0.18 | 0.73±0.27 | 0.14±0.17 | 0.013* | 0.49±0.17 | 0.77±0.20 | 0.28±0.20 | 0.638 | 0.845 | |
| Uncom | Baseline | 1.24±0.30 | 3.19±0.50 | 1.95±0.40 | - | 0.86±0.17 | 2.35±0.27 | 1.49±0.25 | - | 0.675 |
| fortable | wk 4 | 1.00±0.26 | 2.59±0.40 | 1.59±0.27 | 0.543 | 0.86±0.17 | 1.19±0.24 | 0.33±0.22 | 0.000** | 0.000†† |
| sensation | wk 8 | 0.92±0.22 | 2.14±0.44 | 1.22±0.29 | 0.107 | 0.84±0.19 | 1.28±0.24 | 0.44±0.24 | 0.000** | 0.021† |
| Sensitivity | Baseline | 1.14±0.30 | 2.35±0.43 | 1.22±0.28 | - | 1.26±0.29 | 1.56±0.33 | 0.30±0.29 | - | 0.003†† |
| to thebright | wk 4 | 0.78±0.23 | 1.65±0.31 | 0.86±0.24 | 0.147 | 0.83±0.20 | 0.93±0.23 | 0.10±0.14 | 0.378 | 0.008†† |
| light | wk 8 | 0.68±0.21 | 1.73±0.33 | 1.05±0.22 | 0.552 | 0.67±0.19 | 0.77±0.20 | 0.09±0.14 | 0.398 | 0.000†† |
| Foreign | Baseline | 1.05±0.33 | 2.27±0.49 | 1.22±0.32 | - | 0.86±0.25 | 1.53±0.32 | 0.67±0.29 | - | 0.172 |
| body | wk 4 | 1.03±0.30 | 1.73±0.38 | 0.70±0.24 | 0.165 | 0.43±0.14 | 0.74±0.22 | 0.31±0.19 | 0.145 | 0.038† |
| sensation | wk 8 | 0.70±0.22 | 1.59±0.35 | 0.89±0.22 | 0.54 | 0.53±0.18 | 0.74±0.19 | 0.21±0.15 | 0.084 | 0.006†† |
| Eyed | Baseline | 0.84±0.23 | 1.03±0.30 | 0.19±0.13 | - | 0.70±0.19 | 0.56±0.18 | -0.14±0.12 | - | 0.096 |
| ischarge | wk 4 | 0.65±0.23 | 0.68±0.21 | 0.03±0.09 | 0.484 | 0.36±0.13 | 0.33±0.12 | -0.02±0.08 | 0.408 | 0.48 |
| wk 8 |
0.46±0.16 |
0.46±0.18 |
0.00±0.08 |
0.264 |
0.37±0.13 |
0.28±0.10 |
-0.09±0.09 |
0.803 |
0.258 |
All values are expressed as the means±SE. Variation showed the difference of the values between before, and after the VDT at each time-point. a) Increment between before and after the VDT load. b) The within-group comparison of VDT load-induced variations in scores at wk 4 and wk 8 with those at baseline was performed using Wilcoxon’s signed rank test (*p <0.05, **p < 0.01). c) The between-group differences in VDT load-induced variations in scores at each time-point (baseline,wk 4, wk 8) was assessed by the Mann-Whitney U test († < 0.05, †† < 0.01).
In the BE group, VDT load-induced increase and worsening of the symptom scores were mitigated at wk 8 compared with baseline, for dry eye sensation, double vision, and uncomfortable sensation (p<0.05), and these effects were not observed in the control group. Moreover, in the BE group at wk 8, variations were significantly decreased, and VDT load-induced eye fatigue was mitigated compared with control group at wk 8, in terms of ocular fatigue sensation, ocular pain, eye heaviness, uncomfortable sensation, and foreign body sensation (p<0.05). Among these effects, all but those relating to eye heaviness were already apparent at wk 4 (p<0.05).
Safety and tolerability
Five of 43 subjects (11.6%) in the BE group, and 5 of 37 subjects (13.5%) in the placebo group reported a collective total of 15 minor adverse events, the most common being headache (1 and 3 in the BE and placebo groups respectively) and malaise (2 each in the BE and placebo groups). Less frequent adverse events included gastritis (3 in the BE group), gastric distress (1 in the BE group), and tinnitus, throat pain, and nausea (1 each in the placebo group). All these self-recorded adverse events were mild in intensity, were only temporary, and were deemed by the investigator to be unrelated to the intervention.
Discussion
In VDT workers who complained of symptoms of eye fatigue, daily intake of BE yielded reductions in VDT load-induced CFF impairment by wk 8. The exacerbation of 5 symptoms related to eye fatigue after VDT load—ocular fatigue sensation, ocular pain, eye heaviness, uncomfortable sensation, and foreign body sensation—was mitigated to a significantly greater extent by BE. Thus, both an objectively measured parameter and subjectively quantified symptoms were alleviated after 8 weeks of daily BE intake. These results indicated that BE had mitigating effects on VDT load-induced eye fatigue.
VDTs may cause various visual problems such as visual strain blurring, and they have adverse effects on the visual nervous system (8, 9). Objectively measurable variations in visual function due to VDT load include reduced CFF and increased NPA (8). CFF has been considered to reflect neuron impulse transmission from retinal ganglion cells to the primary visual cortex, and is used as an indicator of eye fatigue (8). In this study, there was a significant decrease in CFF after VDT load, consistent with a previous report (8). The biological effect of BE on retinal neurons has been reported in the context of retinal ganglion cells; a previous report shows that bilberry anthocyanoside and/or its main anthocyanidin constituents (cyanidin, delphinidin, and malvidin) protect retinal ganglion cells against pharmaceutically-induced retinal damage in vitro and in vivo (26), although the impulse to the central nervous system was not analyzed in that report. Alternatively, BE may have affected photoreceptor cells; it has been reported that regeneration (27) or excessive degradation (28) of the visual pigment rhodopsin may be modulated by BE, although it is not known whether the changes in the photoreceptor cells described in these reports were related to eye fatigue. Otherwise, there may be a possibility that tear dysfunction is involved in the CFF change which was modulated by BE.
NPA reflects muscle fatigue of the ciliary body (8). Because anthocyanin is reported to relax ciliary smooth muscle (29), NPA variation after VDT load was hypothesized to be increased, but it was not significantly increased at any timepoints. The range of the variations in NPA after VDT load was relatively small in this study, thus the absence of a significant improvement by BE could be because the VDT load was rather mild in this study, and thus NPA was not affected. Further study to evaluate the effect of BE on NPA under more severe VDT loads would be of interest.
The subjectively quantified symptoms that were mitigated by BE included ocular fatigue sensation, and this could be related to blood flow (29). The effects of BE on blood flow have been reported in studies involving ingestion of anthocyanin-rich blackcurrant juices. These studies reported no decreases in transient refractive alteration after VDT (19), and vasorelaxation of the aorta (30) and the induction of peripheral blood flow (31). It would be interesting to determine the mechanisms underlying these observations.
VDTs often induce dry eye symptoms such as dry eye sensation and blurred vision, as shown by a previous study in which a questionnaire was administered to internet users (32). This may be because blink rate is reduced, and the tear volume is reduced by evaporation, such that the tear film is unstabilized during VDT work involving staring at the display (33). Dry eye sensation and foreign body sensation were improved in the BE group in this current study, suggesting that BE would be of value for the VDT workers.
In this study there was no significant difference between the BE group and the control group with regard to tear film break up time variation due to VDT load. This may be because the VDT load was too mild to elicit significant changes in tear film break up time; notably it was not significantly reduced after VDT load, even in the control group (Supplementary Table 1). This possibility is supported by a previous report showing that VDT loads of more than 8 hours increase the risk of dry eye (34). Thus, 2 hours of load in this study may have been too short. Moreover, tear film break up time variation after VDT load may not have been detected because the study participants were volunteers who already had dry eye sensation. VDT load of relatively short duration was one of the limitations of this study, and future studies involving VDT loads of longer duration, counting the number blinks, and measuring work efficiency are anticipated. Fluorescein staining also showed no significant difference in the VDT load-mediated variation between the BE and control groups at any time-points (Supplementary Table 1). In regards to Shirmer’s test after VDT load, there was no change in the BE group at wk 8, although it was exacerbated in the control group (Supplementary Table 1). These results may also have reflected the mildness of the VDT load in this study.
Supplementary Table 1.
BUT and Fluorescein staining score measured before and after VDT load, and Shirmer’s test measured after VDT load at baseline and at weeks 4 and 8 of intervention
| Placebo group (n=37) | BE group (n=43) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Variables | Time point | Before | After | Variationa | P Value b | Before | After | Variationa | P Value | P Value |
| VDT load | VDT load | (relative change) | VDT load | VDT load | (relative change) | |||||
| BUT(sec) | Baseline | 4.60±0.42 | 4.68±0.46 | 0.08±0.31 | - | 5.24±0.58 | 4.28±0.48 | -0.96±0.55 | - | 0.122 d |
| wk 4 | 4.91±0.56 | 4.62±0.67 | -0.29±0.47 | 0.494 b | 5.07±0.58 | 4.85±0.54 | -0.22±0.60 | 0.399b | 0.922 d | |
| wk 8 | 3.94±0.38 | 3.88±0.39 | -0.06±0.36 | 0.787 b | 4.35±0.44 | 4.32±0.49 | -0.03±0.33 | 0.207b | 0.958 d | |
| Fluorescein | Baseline | 0.68±0.16 | 1.56±0.24 | 0.88±0.22 | - | 0.59±0.14 | 1.12±0.19 | 0.54±0.13 | - | 0.246 e |
| staining | wk 4 | 0.91±0.21 | 1.29±0.23 | 0.38±0.16 | 0.178 c | 0.85±0.17 | 1.50±0.21 | 0.65±0.13 | 0.557c | 0.331 e |
| score | wk 8 | 0.71±0.17 | 1.29±0.23 | 0.59±0.13 | 0.482 c | 0.59±0.13 | 1.15±0.18 | 0.56±0.14 | 0.926c | 0.786 e |
| Shirmer’s | Baseline | - | 10.71±1.68 | - | - | - | 10.52±1.43 | - | - | 0.932 g |
| test (mm) |
wk 8 |
- |
7.06±1.29 |
- |
0.007* f |
- |
7.88±1.52 |
- |
0.130f |
0.689 g |
All values are expressed as the mean±SE. Variation showed the difference of the values between before and after the VDT at each time point. (a) Increment between before and after the VDT load. The within-group comparisons of VDT-induced variations at wk 4 or 8 with those atbaseline was assessed by the paired Student’s t-test (b) or Wilcoxon’s signed rank test (c) (*p < 0.05). The between-group differences in VDT load-induced variations in scores at each timepoint (baseline, wk 4, wk 8) was assessed by the unpaired Student’s t-test (d) or the Mann-Whitney U test (e) († < 0.05, †† < 0.01). The Shirmer’s test after VDT load were assessed by the paired Student’s t-test (f) for the within-group comparison at wk 8 with its at baseline (*p < 0.05), and the unpaired Student’s t-test (g) for the between-group differences at each time-point (baseline, wk 8).
Another limitation was that the participants wore no contact lenses during the VDT load in this study, although many of the VDT workers may have been contact lens users during the course of their normal VDT work in a daily life, which exacerbates dry eye (35). Thus, the current study may not have accurately reflected the actual work-place conditions of the VDT workers. The other limitations of the study are as follows: there was no indication of primary outcome, clinically meaningful effects, effect size, and sample size calculation at the start of the study; the sample size was relatively small; and habitual contact lens wearers were included in the participants. Considering these limitations, we performed further assessments using the Holm method, to find significant effects of BE in improving the variations in CFF compared with the baseline of BE group, and ocular pain, uncomfortable sensation, and foreign body sensation compared to the control group at wk 8. The follow-up period was only 2 months. Although the fact that there were significant effects in this short period support the possibility of BE’s practical use for reducing VDT-mediated eye fatigue, long-term results would be also required to determine its application to the clinical use.
The underlying molecular mechanisms responsible for the results of this study will be investigated in the future. BE contains antioxidants, and its biological effects have been shown in animal experiments suggesting that it may reduce oxidative stress to tissues (28). BE may have acted on the eye itself, the eye muscles, and/or the brain. Effects on the brain could regulate the sensory and motor neurons related to eye fatigue, reducing the oxidative stress that may be induced by excessive workload in these tissues, while future investigation is required to elucidate this. Although further information is required on the application of BE as a common intervention therapy for reducing eye fatigue in VDT workers, this study may contribute to understanding the wider effects of BE.
Acknowledgements: We appreciate members of the Medical Corporation Jico-kai Yagi Hospital and Shinyokohama Shinoharaguchi Orthopedic Surgery and Dermatology Clinic for technical assistance.
Ethical standards: The study complies with the current laws in Japan.
Conflict of Interest: This work was conducted by Wakasa Seikatsu Co. Ltd., of which E.O., and S.K., are employees, and from which Y.O. and K.T. receive financial support for the other study. M.K., E.I., and A.S. have no conflict of interest.
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