Binocular treatment of amblyopia: from the laboratory to clinical trials

Over the last 10 years, numerous psychophysical studies have indicated that binocular mechanisms are structurally intact but functionally suppressed in amblyopia (1-8). Many of these studies have used a contrast balancing approach, whereby the contribution of each eye to binocular vision is equated or “balanced” by presenting higher contrast stimulus elements to the amblyopic eye than the fellow eye (6). Using this approach, the strength of suppression can be quantified by measuring the magnitude of interocular contrast difference required for normal binocular combination. When suppression strength has been correlated with other clinical measures, stronger suppression has been associated with worse stereoacuity and worse amblyopic eye visual acuity indicting a link between the monocular and binocular deficits in amblyopia (5,7).

Current binocular treatments for amblyopia emerged from psychophysical studies of binocular combination and are based on the hypothesis that repeated stimulation of intact binocular mechanisms using contrast balanced stimuli can improve both binocular and monocular vision in amblyopia (9,10). Numerous case-series and laboratory-based studies have reported improved stereopsis, visual acuity and contrast sensitivity in adults and children with amblyopia following binocular treatment in the form of psychophysical tasks, modified videogames or dichoptic moviesJeny (9,11-18)). Non-human animal studies have also supported the concept of binocular amblyopia treatment (19).

Recently, binocular treatments in the form of modified dichoptic videogames viewed through red/green glasses have been tested within randomized clinical trials. Kelly et al. (20) reported that 2 weeks of binocular treatment in the form of an engaging tablet-based videogame called Dig Rush improved visual acuity significantly more that patching in 4–10-year-old children. However, other large-scale clinical trials have found no effect of binocular treatment. Holmes et al. (21) observed that binocular treatment induced numerically less visual acuity improvement in 5–12-year-old children than patching and Gao et al. (22) found that binocular treatment was no different from placebo for improving visual acuity and stereopsis in a sample starting at 7 years of age with no upper age limit. The very recently reported results of Holmes et al. (23) in children aged 7–12 years exhibit a similar pattern of results. Holmes et al. (23) observed no difference in visual acuity or stereopsis improvement between a group treated with the Dig Rush videogame and a control group who received only optical treatment. In fact, neither group showed clinically meaningful improvements in any of the outcome measures reported.

What might explain the discrepancy between the initial case-series/laboratory studies and the recent randomized clinical trials? Randomized clinical trials typically control for many more sources of bias than case-series or laboratory studies and therefore are less likely to observe erroneous treatment effects. However, a number of the earlier studies did attempt to account for placebo effects by including controls such as a monocular treatment condition (17). In addition, one well-controlled randomized clinical trial did show a convincing treatment effect (20). Therefore, other factors may also be involved. One such factor is treatment adherence. The first two large-scale clinical trials of binocular treatment (21,22) used a modified version of the videogame Tetris that failed to engage participants. This resulted in poor adherence. The pattern of adherence in these two randomized clinical trials is different from many of the case-series and laboratory-based studies cited above where participants were closely monitored and therefore achieved 100% adherence. In their recent study, Holmes et al. (23) used a more engaging videogame and observed improved adherence, but adherence still did not approach the 100% level of the earlier studies. It is important to note that none of the three negative clinical trials (21-23) observed a dose-response relationship for binocular treatment, which suggests that adherence may not be a critical factor. However, calculating binocular treatment dose may be more complex than simply recording the amount of time that the treatment videogame was active. Outside of controlled laboratory settings, it is impossible to know whether study participants wore the required red green glasses correctly or whether the game was being played by the patient or by another family member. Perhaps more importantly, the treatment may have been split up into small blocks throughout the day or combined with other activities such as watching television or operating a cell-phone. We don’t yet understand the impact of these factors on binocular treatment response.

Patient demographics may also have played a role in the results of previous randomized clinical trials. Kelly et al. (20), who reported a positive treatment effect, enrolled younger participants (mean age 6.7 years). In contrast, the three negative trials enrolled relatively older participants [Holmes et al. 2016, mean age 9.6 years (21); Holmes et al. 2019, mean age 8.4–8.6 years (23); Gao et al. 2018, mean age 22.1–21.0 years (22)]. This was reasonable based on the promising laboratory results that reported treatment effects in adult participants (4,10). However, older patients with amblyopia may be less likely to exhibit vision improvements (24,25) and therefore the effects of poor or intermittent adherence may be exacerbated. Other unknown factors such as the optimal rate of interocular contrast change and previous treatment for amblyopia may also be more influential in older participants. As stated by Holmes et al. (23), the results of the ongoing Pediatric Eye Disease Investigator Group (PEDIG) clinical trial of Dig Rush in younger patients (NCT02983552) will help to shed light on this issue.

The randomized clinical trials reported by Holmes et al. (21), Gao et al. (22), and most recently by Holmes et al. (23) followed gold standard protocols and reflect the real-world engagement of study participants with one of the world’s first prescribed videogame treatments. However, the negative results do not necessarily disprove the hypothesis that underpins binocular treatment. In particular, the results may reflect the difficulty of deploying binocular treatment in the home environment. Future home-based studies with more advanced adherence monitoring systems involving gaze tracking and/or supervised in-office randomized clinical trials are required to address these questions.

Acknowledgments

Funding: B Thompson is supported by funding from the Natural Sciences and Engineering Council of Canada (NSERC; grants RPIN-05394 and RGPAS 477166) and the Canadian Institutes of Health Research (CIHR: grants PJT-156174 and PJT-201604).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aes.2019.03.01). The author reports grants from Canadian Institutes of Health Research, grants from National Science and Engineering Research Council, from Health Research Council of New Zealand, during the conduct of the study; In addition, Dr. Thompson has a patent Binocular vision assessment and/or therapy with royalties paid. Dr. Thompson is a named inventor on two patents relating to the binocular treatment of amblyopia (US12528934 and US8006372 B2).

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Black JM, Hess RF, Cooperstock JR, et al. The measurement and treatment of suppression in amblyopia. J Vis Exp 2012;e3927 [PubMed]
2. Ding J, Levi DM. Rebalancing binocular vision in amblyopia. Ophthalmic Physiol Opt 2014;34:199-213. [Crossref] [PubMed]
3. Hamm L, Chen Z, Li J, et al. Interocular suppression in children with deprivation amblyopia. Vision Res 2017;133:112-20. [Crossref] [PubMed]
4. Hess RF, Thompson B, Baker DH. Binocular vision in amblyopia: structure, suppression and plasticity. Ophthalmic Physiol Opt 2014;34:146-62. [Crossref] [PubMed]
5. Li J, Thompson B, Lam CS, et al. The role of suppression in amblyopia. Invest Ophthalmol Vis Sci 2011;52:4169-76. [Crossref] [PubMed]
6. Mansouri B, Thompson B, Hess RF. Measurement of suprathreshold binocular interactions in amblyopia. Vision Res 2008;48:2775-84. [Crossref] [PubMed]
7. Narasimhan S, Harrison ER, Giaschi DE. Quantitative measurement of interocular suppression in children with amblyopia. Vision Res 2012;66:1-10. [Crossref] [PubMed]
8. Zhou J, Huang PC, Hess RF. Interocular suppression in amblyopia for global orientation processing. J Vis 2013;13:19. [Crossref] [PubMed]
9. Hess RF, Mansouri B, Thompson B. A new binocular approach to the treatment of amblyopia in adults well beyond the critical period of visual development. Restor Neurol Neurosci 2010;28:793-802. [PubMed]
10. Hess RF, Thompson B. Amblyopia and the binocular approach to its therapy. Vision Res 2015;114:4-16. [Crossref] [PubMed]
11. Kelly KR, Jost RM, Wang YZ, et al. Improved Binocular Outcomes Following Binocular Treatment for Childhood Amblyopia. Invest Ophthalmol Vis Sci 2018;59:1221-8. [Crossref] [PubMed]
12. Li SL, Reynaud A, Hess RF, et al. Dichoptic movie viewing treats childhood amblyopia. J AAPOS 2015;19:401-5. [Crossref] [PubMed]
13. Knox PJ, Simmers AJ, Gray LS, et al. An exploratory study: prolonged periods of binocular stimulation can provide an effective treatment for childhood amblyopia. Invest Ophthalmol Vis Sci 2012;53:817-24. [Crossref] [PubMed]
14. Hamm LM, Chen Z, Li J, et al. Contrast-balanced binocular treatment in children with deprivation amblyopia. Clin Exp Optom 2018;101:541-52. [Crossref] [PubMed]
15. Bossi M, Tailor VK, Anderson EJ, et al. Binocular Therapy for Childhood Amblyopia Improves Vision Without Breaking Interocular Suppression. Invest Ophthalmol Vis Sci 2017;58:3031-43. [Crossref] [PubMed]
16. Vedamurthy I, Nahum M, Huang SJ, et al. A dichoptic custom-made action video game as a treatment for adult amblyopia. Vision Res 2015;114:173-87. [Crossref] [PubMed]
17. Li J, Thompson B, Deng D, et al. Dichoptic training enables the adult amblyopic brain to learn. Curr Biol 2013;23:R308-9. [Crossref] [PubMed]
18. Li J, Spiegel DP, Hess RF, et al. Dichoptic training improves contrast sensitivity in adults with amblyopia. Vision Res 2015;114:161-72. [Crossref] [PubMed]
19. Mitchell DE, Duffy KR. The case from animal studies for balanced binocular treatment strategies for human amblyopia. Ophthalmic Physiol Opt 2014;34:129-45. [Crossref] [PubMed]
20. Kelly KR, Jost RM, Dao L, et al. Binocular iPad Game vs Patching for Treatment of Amblyopia in Children: A Randomized Clinical Trial. JAMA Ophthalmol 2016;134:1402-8. [Crossref] [PubMed]
21. Holmes JM, Manh VM, Lazar EL, et al. Effect of a Binocular iPad Game vs Part-time Patching in Children Aged 5 to 12 Years With Amblyopia: A Randomized Clinical Trial. JAMA Ophthalmol 2016;134:1391-400. [Crossref] [PubMed]
22. Gao TY, Guo CX, Babu RJ, et al. Effectiveness of a Binocular Video Game vs Placebo Video Game for Improving Visual Functions in Older Children, Teenagers, and Adults With Amblyopia: A Randomized Clinical Trial. JAMA Ophthalmol 2018;136:172-81. [Crossref] [PubMed]
23. Pediatric Eye Disease Investigator Group. A Randomized Trial of Binocular Dig Rush Game Treatment for Amblyopia in Children Aged 7 to 12 Years. Ophthalmology 2019;126:456-66. [Crossref] [PubMed]
24. Fronius M, Cirina L, Ackermann H, et al. Efficiency of electronically monitored amblyopia treatment between 5 and 16 years of age: new insight into declining susceptibility of the visual system. Vision Res 2014;103:11-9. [Crossref] [PubMed]
25. Holmes JM, Lazar EL, Melia BM, et al. Effect of age on response to amblyopia treatment in children. Arch Ophthalmol 2011;129:1451-7. [Crossref] [PubMed]