Abstract
Amblyopia affects development of children's monocular vision and binocular function and becomes a largely intractable problem with increasing aging. This study is to investigate the binocular function and evaluate efficacy of digital therapy in children 8–13 years of age with anisometropic amblyopia. The patients in the digital therapy group performed the training with the digital amblyopia therapeutic software. The visual acuity and binocular function (perceptual eye position [PEP], suppression, and stereopsis) were examined at the first visit and 3-month post-treatment. Twenty-three cases in the control group and 25 cases in the digital therapy group were enrolled. The results revealed that 3-month digital therapy can effectively improve corrected distance visual acuity (CDVA) and improve the binocular function, including PEP, suppression, and second-order stereopsis in children with anisometropic amblyopia, 8–13 years of age. Digital therapy for amblyopia can effectively improve monocular CDVA of amblyopic eyes and binocular function in older children with anisometropic amblyopia.
Introduction
Amblyopia, also known as lazy eye, is a visual development-related disease due to visual deprivation and/or abnormal binocular interaction. It can be classified into different types based on its etiology: Strabismic amblyopia, refractive amblyopia, anisometropic amblyopia, and deprivation amblyopia. Anisometropic amblyopia refers to amblyopia caused by a significant difference in refractive error between the two eyes, with a spherical lens power difference of ≥1.50 diopters or a cylindrical lens power difference of ≥1.00 diopters, resulting from higher refractive error in one eye.
Children with amblyopia not only have reduced visual acuity but also experience impaired binocular visual function. The sensitive period of visual development is crucial for the occurrence and reversal of amblyopia. Treatment for amblyopia is believed to be most effective before 6–8 years of age.1–4 Older children show less response to traditional treatment due to factors such as initial visual acuity, amblyopia type, duration of treatment, and treatment methods.3,5 Poor compliance, particularly with patching therapy, is the primary factor affecting the efficacy of amblyopia treatment in older children, with ∼59 percent of children and families experiencing this issue.6,7
Digital therapy for amblyopia has emerged, utilizing digital devices like computers, smartphones, and tablets.4,8–11 It offers personalized and refined treatment plans, making the treatment more enjoyable for patients. Digital therapy provides controllability and traceability during the treatment process, leading to improved compliance in older children and enhancing therapeutic outcomes.8,10
Digital therapy for amblyopia operates on the plasticity principle of the visual cortex, stimulating its plasticity through specific training programs. 7 It improves the visual cortex's ability to process visual information and can enhance visual sensitivity and resolution by displaying high contrast images. 12 In addition, digital therapy utilizes neuroplasticity to establish new neural connections between different brain regions, further improving visual ability in amblyopia.13,14 It repeatedly trains the amblyopic eyes to process specific aspects of the image, such as shape, color, and spatial position.7–12,14
We propose a hypothesis that digital therapy with consistently high adherence over 3-month training at home would enhance binocular function and stereopsis, as well as improve visual acuity in children with anisometropic amblyopia, 8–13 years of age, who missed the critical period of visual development. To test this hypothesis, we conducted a study to investigate the visual acuity and binocular function changes after digital therapy, and evaluate the feasibility and efficacy of the therapy.
Methods
Subjects
Anisometropic amblyopia patients 8–13 years of age were recruited at the Ophthalmic Clinic of People's Hospital of Leshan from March 2017 to September 2018. The inclusion criteria for patients were as follows: (a) The strabismus deviation <10 prism diopters (D) measured by the alternate prism cover test at both distance (6 m) and near (33 cm), (b) astigmatic anisometropia of >1.00 D and/or hyperopic anisometropia of >1.50 D, (c) corrected distance visual acuity (CDVA) of the amblyopic eye <0.8, and (d) anisometropic amblyopia newly diagnosed.
The exclusion criteria were as follows: (a) Unable to cooperate with the treatment or quit the study, (b) had a history of eye surgery, (c) had coexisting ocular disease, (d) had a history of systemic disease such as in the heart, liver, or kidney, and mental diseases, and (e) strabismus or history of strabismus surgery and eccentric fixation. This study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of People's Hospital of Leshan. All included patients had informed consent.
Ophthalmologic and orthoptic examination
Full cycloplegia was obtained after instillation of topical 1 percent atropine, three times a day for 3 days before their visit. Objective refraction with an autorefractor (Topcon KR8900, Tokyo, Japan) and retinoscopy were obtained before subjective refraction. CDVA was examined in both amblyopic and fellow eyes following cycloplegic refraction. After 3 weeks, the eyeglass prescription and CDVA were re-examined.
The diagnosis of amblyopia followed the expert consensus on amblyopia diagnosis in China (2011). 15 Visual acuity was converted to Logarithm of the minimum angle of resolution (LogMAR) values. LogMAR CDVA of the amblyopic eye ≥0.7 was defined as severe anisometropic amblyopia, ≥0.3 and <0.7 as moderate amblyopia, and <0.3 as mild amblyopia. 16
Treatment protocols
For the control group, the treatment protocols consisted of refractive correction, patching of the contralateral eye (6 hours daily for severe amblyopia, 4 hours daily for moderate amblyopia, and 2 hours for mild amblyopia), and near visual activities with the amblyopic eye, such as stringing beads, for 20 minutes twice daily.
For the digital therapy group, the treatment protocols included refractive correction and patching (the same patching protocol as the control group), along with the use of digital amblyopia therapeutic software developed by the National Engineering Research Center for Healthcare Devices. The patients logged into their accounts and completed two sessions comprising four training procedures. They wore red-green anaglyphic glasses and performed the training twice a day for 20 minutes in each session.
All patients were followed up at 3 months after the treatment protocols were initiated. Perceptual eye position (PEP), interocular suppression, and stereoacuity were measured by an evaluation system generated by MATLAB pretreatment and 3 months post-treatment. 16 The examinations were carried out by the same skilled operator. Stereopsis was recorded as “nil” if the largest disparity could not be passed.
Statistical analysis
SPSS 23.0 software (IBM, Armonk, NY) for windows was used to analyze the data. Shapiro-wilk test was used to check the normality of data distribution. Continuous data were expressed as mean (M) and standard deviation (SD), or as median, minimum and maximum values for normal and non-normal distribution, respectively. Categorical data were expressed as frequencies and percentages. First, the baseline characteristics of the two groups were compared using t-test or Mann–Whitney U test, or Pearson's χ 2 test or Fisher's exact test, according to the variable type and distribution of data.
Second, repeated-measures analysis of variance (ANOVA) was performed to evaluate main effects of time and group. Simple effect analysis was performed after main effect analysis using Bonferroni correction method. Pearson's correlation or Spearman's rank correlation was performed to determine the associations between LogMAR CDVA and PEP. χ 2 test was performed to analyze the correlation between improvement of suppression and stereopsis. p Values <0.05 were considered statistically significant.
Results
Demographic and clinical characteristics of subjects
A total of 48 patients with anisometropic amblyopia participated in this study, with 17 (35.42 percent) classified as severe amblyopia, 14 (29.17 percent) as moderate amblyopia, and 17 (35.42 percent) as mild amblyopia. These patients were randomly assigned to either the digital therapy group (n = 25) or the control group (n = 23) using a random number table. The mean LogMAR CDVA of the amblyopic eye was 0.57 (SD = 0.30) in the control group and 0.56 (SD = 0.30) in the digital therapy group. Baseline characteristics did not show any significant difference between the two groups (Table 1).
Demographic and Clinical Characteristics of Subjects' Corrected Distance Visual Acuity
CDVA, corrected distance visual acuity; df, degrees of freedom; LogMAR, logarithm of the minimum angle of resolution; M, mean; SD, standard deviation.
Compliance
The children in both groups were instructed to undergo daily training. In the control group, compliance data were reported by parents or guardians using a form. Only 14 patients (60.87 percent) completed the required near visual activities training on a daily basis. In the digital therapy group, compliance data were collected through the database records of their personal training accounts and training records. Out of the 25 patients in this group, 21 (84.00 percent) completed digital amblyopia training twice a day, while the remaining 4 patients received training at least once a day.
Corrected distance visual acuity
There was no statistically significant difference in the main effect of group (control vs. digital therapy) (F(1,46) = 0.71, p = 0.40). However, the main effect of time (pretreatment vs. post-treatment) and the interaction between group and time were found to be significant (time: F(1,46) = 93.19, p < 0.001; time between group: F(1,46) = 6.23, p = 0.01). Further simple effect analysis of group showed that there was no significance at pretreatment (p = 0.88) and post-treatment (p = 0.07). Simple effect analysis of time showed that there was significance both in the control group (p < 0.001) and in the digital therapy group (p < 0.001) (Table 2).
Comparison of Logarithm of the Minimum Angle of Resolution Corrected Distance Visual Acuity and Perceptual Eye Position Deviation Improvement
p < 0.05; ***p < 0.001.
ANOVA, analysis of variance; G, group; η 2 , eta-squared; PEP, perceptual eye position; T, time.
Perceptual eye position
For horizontal PEP (target 3°), the main effect of group did not reveal any significant difference (F(1,46) = 2.43, p = 0.12). However, the main effect of time and the interaction between group and time were found to be significant (time: F(1,46) = 96.81, p < 0.001; time between group: F(1,46) = 50.63, p < 0.001). Further simple effect analysis of group showed that there was no significance at pretreatment (p = 0.99), while significant difference in group was found at post-treatment (p < 0.001). Simple effect analysis of time showed that there was no significance in the control group (p = 0.07), while significant difference was found in the digital therapy group (p < 0.001) (Table 2).
For horizontal PEP (target 1°), the main effect of group did not reveal any significant difference (F(1,46) = 1.88, p = 0.17). However, the main effect of time and the interaction between group and time were found to be significant (time: F(1,46) = 35.80, p < 0.001; time between group: F(1,46) = 31.10, p < 0.001). Further simple effect analysis of group showed that there was no significance at pretreatment (p = 0.65), while significant difference in group was found at post-treatment (p < 0.001). Simple effect analysis of time showed that there was no significance in the control group (p = 0.78), while significant difference was found in the digital therapy group (p < 0.001) (Table 2).
For vertical PEP (target 3°), the main effect of group did not reveal any significant difference (F(1,46) = 1.40, p = 0.24). However, the main effect of time and the interaction between group and time were found to be significant (time: F(1,46) = 138.38, p < 0.001; time between group: F(1,46) = 104.62, p < 0.001). Further simple effect analysis of group showed that there was no significance at pretreatment (p = 0.41), while significant difference in group was found at post-treatment (p = 0.001). Simple effect analysis of time showed that there was no significance in the control group (p = 0.29), while significant difference was found in the digital therapy group (p < 0.001) (Table 2).
For vertical PEP (target 1°), the main effect of group, time, and the interaction between group and time was found to be significant (group: F(1,46) = 12.11, p = 0.001; time: F(1,46) = 138.38, p < 0.001; time between group: F(1,46) = 104.62, p < 0.001). Further simple effect analysis of group showed that there was no significance at pretreatment (p = 0.83), while significant difference in group was found at post-treatment (p < 0.001). Simple effect analysis of time showed that there was no significance in the control group (p = 0.19), while significant difference was found in the digital therapy group (p < 0.001) (Table 2).
Suppression
The improvement of suppression was compared. A significant difference was found in the elimination of suppression after a 3-month treatment between the control group and the digital therapy group (χ 2 (1) = 5.30, p = 0.02) (Table 3).
Comparison of Suppression and Stereopsis Improvement
p < 0.01.
Nil, the largest disparity could not be passed and no stereopsis was detected.
Stereopsis
There was no significant difference in recovery of zero-order and first-order stereopsis after a 3-month treatment between the control group and the digital therapy group (zero-order stereopsis: χ 2 (1) = 1.08, p = 0.30; first-order stereopsis: χ 2 (1) = 1.21, p = 0.27). However, significant difference was found in recovery of second-order stereopsis in the digital therapy group (χ 2 (1) = 6.92, p = 0.01) (Table 3).
Correlation
There was no correlation between LogMAR CDVA and PEP (horizontal PEP-target 3°: r = 0.22, p = 0.34; vertical PEP-target 3°: r = 0.17, p = 0.48; horizontal PEP-target 1°: r = 0.19, p = 0.43; vertical PEP-target 1°: r = 0.08, p = 0.75). Elimination of suppression was correlated with the establishment of second-order stereopsis (χ 2 = 34.98, p < 0.001; Crammer V = 0.73).
Discussion
In this study, both groups showed improvements in CDVA after 3 months of therapy, but the digital therapy group exhibited significantly greater improvement compared to the control group. The control group engaged in near visual activities, while the digital therapy group completed online training with compliance data recorded in a database. The digital therapy group demonstrated better compliance than the control group, which was identified as a critical factor for efficacy.17,18 The novelty and playfulness of digital therapy contributed to its advantages and improved compliance.
Traditional amblyopia treatment involving eye patching and near visual activities focuses on monocular vision recovery, but often falls short in promoting binocular outcomes. However, with the advancement of technology, perception visual learning 19 and binocular approaches have emerged as effective methods in amblyopia treatment.4,8–11 In this study, we utilized digital amblyopia therapeutic software for binocular treatment. After 3 months of training, significant improvements were observed in binocular functions, including PEP, suppression, and coarse stereopsis, in the digital therapy group compared to the control group.
In addition to binocular treatment approaches, it is important to consider the impairment and restoration of binocular function in amblyopia patients. Studies have shown that a significant number of amblyopia patients exhibit deficiencies in zero-order, first-order, and second-order stereopsis even after visual acuity recovery.20,21 In this study, initial assessments of 48 children with amblyopia revealed suppressed amblyopic eyes and varying degrees of stereopsis impairment.
After 3 months of digital therapy, significant improvements were observed in coarse stereopsis. However, there were no significant improvement in fine stereopsis. It is speculated that this discrepancy may be due to the different mechanisms involved in processing coarse and fine stereopsis. Coarse stereopsis, related to static parallax in the peripheral visual field, may be established and mature at an early age, making it easier to restore. Fine stereopsis, involving higher-level cortical networks, requires a longer process of neural plasticity for reconstruction.22,23 Future research aims to further track the reconstruction process of fine stereopsis.
The study also revealed a connection between the restoration of coarse stereopsis and the elimination of amblyopic eye suppression. It has been suggested that unbalanced visual signals may contribute to poorer stereopsis in most amblyopia patients. 24 The development and establishment of stereopsis involve a continuous process of improvement and consolidation. Anisometropia, which causes a defocused state in one eye, leads to insufficient stimulation of the macular fovea in the anisometropic eye. The differing object image size and resolution formed by the two eyes make fusion challenging and hinder the establishment of stereopsis. 25 Digital therapy addresses this issue by providing distinct stimulation to each eye, utilizing red-green anaglyphic glasses for binocular therapy. This approach reduces inhibition and noise in amblyopic visual processing, facilitating binocular simultaneous vision, fusion, and ultimately establishing stereoscopic function. 26
Although no case of strabismus was clinically diagnosed, patients still exhibited deviations in PEP, which reflects central control of eye position in dichoptic condition. After training, PEP significantly improved in the digital therapy group, but remained unchanged in the control group. Lin reported abnormalities in PEP and fixation stability in children with amblyopia, with greater PEP deviation observed in cases of more severe amblyopia. 27 This suggests that examining binocular visual perception offers insights into impairments in binocular function in amblyopia. PEP deviation indicates abnormalities in the sensory and motor systems of the brain, which control both eyes. As PEP improves, visual acuity also shows improvement.
The study has two main limitations. First, the training course lasted for only 3 months, and the comparison of visual acuity and binocular function was conducted pretreatment and post-treatment within this time frame. We plan to extend the duration to 6 months in their next research phase. Second, there was no further comparative study conducted on different degrees of amblyopia. Based on the findings of this study, it is necessary to evaluate the effects of digital binocular training on amblyopia patients with varying degrees of severity over a longer duration.
In conclusion, this study demonstrates that a 3-month digital therapy intervention effectively improves monocular visual acuity and various aspects of binocular function, including PEP, suppression, and coarse stereopsis, in children 8–13 years of age with anisometropic amblyopia. The findings provide evidence supporting the notion that digital therapy is increasingly becoming a more scientific and effective approach compared to traditional methods of amblyopia treatment.
Footnotes
Author Disclosure Statement
No competing financial interests exist.
Funding Information
This study was supported by Science and Technology Project of Leshan City (no.: 17SZD232) and the Health Commission of Guangxi Zhuang Autonomous Region (Guangxi Medicine: Z2016605). The funding organizations had no role in the study design, conduct of this research, data analysis, or decisions in preparation or publishing of the article.
