Rethinking amblyopia 2020

Abstract

Recent work has transformed our ideas about the neural mechanisms, behavioral consequences and effective therapies for amblyopia. Since the 1700's, the clinical treatment for amblyopia has consisted of patching or penalizing the strong eye, to force the "lazy" amblyopic eye, to work. This treatment has generally been limited to infants and young children during a sensitive period of development. Over the last 20 years we have learned much about the nature and neural mechanisms underlying the loss of spatial and binocular vision in amblyopia, and that a degree of neural plasticity persists well beyond the sensitive period. Importantly, the last decade has seen a resurgence of research into new approaches to the treatment of amblyopia both in children and adults, which emphasize that monocular therapies may not be the most effective for the fundamentally binocular disorder that is amblyopia. These approaches include perceptual learning, video game play and binocular methods aimed at reducing inhibition of the amblyopic eye by the strong fellow eye, and enhancing binocular fusion and stereopsis. This review focuses on the what we've learned over the past 20 years or so, and will highlight both the successes of these new treatment approaches in labs around the world, and their failures in clinical trials. Reconciling these results raises important new questions that may help to focus future directions.

Keywords: Amblyopia; Mechanisms; Perceptual learning; Sensitive periods; Stereopsis; Videogames; Visual acuity.

Fig. 1. Amblyopia functional loss ‘map’.

Mean locations of 11 clinically defined categories in two-factor space for a large population of patients (427) with amblyopia or its risk factors. Factor 1 is closely related to three different acuity measures, and Factor 2 is closely related to the two contrast sensitivity measures. The diagonal bars show one standard error of the mean measured along the principal axes of the elliptical distributions. From McKee, Levi & Movshon, 2003.

Fig. 2. The sensitive period.

This cartoon illustrates several hypotheses regarding neural plasticity during development. The blue curve shows plasticity increasing during early development when the neural system is immature, peaking and rapidly diminishing to zero when function is consolidated. The red curve is similar, but with residual plasticity extending into adulthood. The green curve illustrates removal of the factors (brakes) that limit plasticity and restore levels of neural plasticity in adults.

Fig. 3. Change in visual acuity vs. Age of Treatment.

Summary of 3 clinical trials: Trial ATS1 compared daily atropine to occlusion for at least 6 hours/day; trial ATS2A compared 6 hours/day versus full-time patching for severe amblyopia and trial ATS2B compared 6 hours versus 2 hours/day of patching in patients with moderate amblyopia. The tiny dots are the individual data from ≈ 800 patients; the large symbols show the mean idata in ≈ 1 year bins; included also are the mean data from an additional study (PEDIG 2005) that examined the effectiveness of treatment in children ages 7 to 17. A positive change in acuity is improvement. (after Holmes and Levi, 2018). Also shown here (red diamonds) are data from a small group of adult amblyopes who underwent intensive treatment (see text) from Kupfer, 1957. The red line is a fit to the mean PEDIG data.

Fig. 4.. Improvement in visual acuity vs hours of training.

VA improvement data (pre-post) from a broad range of experimental treatment studies in adults and children with amblyopia, as a function of hours of treatment. Small blue solid circles represent monocular perceptual learning or video game treatment, and the small red open circles indicate dichoptic/binocular treatment, replotted from Gambacorta et al., 2018 (fig. 6. Error bars are the SEMs). The black line shows the time course of monitored occlusion (solid line from Stewart et al., 2007). The solid green triangles are from studies using inverse occlusion (Zhou et al., 2019, inverted triangle) and inverse occlusion plus exercise (upright triangle, Lunghi et al., 2018). The large symbols show the results of recent large scale RCTs of dichoptic/binocular treatment, for both the experimental and control groups. The dotted horizontal line extending from 0.0 on the Y axis indicates no improvement in visual acuity.