Amblyopia and binocular vision

Abstract

Amblyopia is the most common cause of monocular visual loss in children, affecting 1.3%-3.6% of children. Current treatments are effective in reducing the visual acuity deficit but many amblyopic individuals are left with residual visual acuity deficits, ocular motor abnormalities, deficient fine motor skills, and risk for recurrent amblyopia. Using a combination of psychophysical, electrophysiological, imaging, risk factor analysis, and fine motor skill assessment, the primary role of binocular dysfunction in the genesis of amblyopia and the constellation of visual and motor deficits that accompany the visual acuity deficit has been identified. These findings motivated us to evaluate a new, binocular approach to amblyopia treatment with the goals of reducing or eliminating residual and recurrent amblyopia and of improving the deficient ocular motor function and fine motor skills that accompany amblyopia.

Figure 1

In the<3-year-old cohort,(Birch and Holmes, 2010) 82% of amblyopia was associated with strabismus, 5% with anisometropia, and 13% with combined mechanisms. This finding is strikingly different from the PEDIG 3- to 6-year-old cohort,(Pediatric Eye Disease Investigator Group, 2002a) where only 38% of amblyopia was associated with strabismus, 37% with anisometropia, and 24% with combined mechanism (p<0.001 for each of the 3 paired comparisons). Among children with strabismus in the <3-year-old cohort, 62% had infantile esotropia (onset ≤6 months of age), 22% had accommodative esotropia, 10% had acquired nonaccommodative esotropia (onset ≥7 months of age), and 6% had other types of strabismus.

Figure 2

Strabismic amblyopia was diagnosed much more commonly than anisometropic or combined-mechanism amblyopia in children<3 years of age.(Birch and Holmes, 2010) This finding is in sharp contrast to the PEDIG report of approximately equal proportionsof patients with amblyopia attributable to strabismus and anisometropia, and approximately a quarter of the amblyopic patients exhibiting both.(Pediatric Eye Disease Investigator Group, 2002a) Two UK studies of amblyopic children, which included younger children than the PEDIG study, found the cause to be strabismus in a greater percentage than the PEDIG study (45%–57%), a lower percentage to be anisometropic (17%), and about the same percentage to be combined mechanism (27%–35%).(Shaw et al., 1988; Woodruff et al., 1994b) This summary of all 4 studies suggests that one source of the differences in the proportion of amblyopia attributable to strabismus may be age.

Figure 3

Summary of results from recent randomized clinical trials for the treatment of amblyopia conducted by the Pediatric Eye Disease Investigator Group (PEDIG) (Holmes et al., 2006; Quinn et al., 2004; Repka and Holmes, 2012), the Monitored Occlusion Treatment of Amblyopia Study (MOTAS) Cooperative Group, (Stewart et al., 2002, 2005; Stewart et al., 2004a; Stewart et al., 2004b; Stewart et al., 2007a) and the Randomized Occlusion Treatment of Amblyopia (ROTAS) Cooperative Group.(Stewart et al., 2007b) Values represent mean improvement of visual acuity (logMAR) with 3–6 months of treatment. When more than one randomized clinical trial evaluated similar treatment plans, the range of means reported in the various studies is provided.

Figure 4

Spectral domain optical coherence tomography (SD-OCT) scans of the amblyopic (top left) and non-amblyopic (top right) eyes of a child with persistent amblyopia.(Subramanian et al., in press) Overall (n=26), there were no significant differences in total macular thickness or in any of the ETDRS macular sectors (second panel) between amblyopic and fellow eyes (p>0.2 for all paired t-tests.) The third panel shows a sample SD-OCT scan of the RNFL obtained by SD-OCT and means for each RNFL sector; there were no significant differences in global RFNL thickness nor in any sector between amblyopic and fellow eyes (p>0.4 for all paired t-tests). The bottom panel illustrates the method used to quantify optic disc dysversion (Horiz:Vert disc diameter ratio). No significant differences were found for amblyopic vs. fellow eyes (H/V_ambly= 1.15 ±0.18; H/V_fellow= 1.14±0.17; p=0.87). Hypoplasia (assessed by area of the optic disc, mm²⁾ did not differ for amblyopic vs. fellow eyes (Area_ambly= 1.88±0.44; Area_fellow= 2.10±0.61; p=0.26).

Figure 5

Grating acuity and vernier acuity at 6–9 years of age for 20 amblyopic children enrolled in a prospective study at the time of diagnosis during infancy.(Birch and Swanson, 2000) The solid line shows the predicted relationship if comparable deficits were present for both vernier and grating acuity so that the normal grating:vernier acuity ratio of 8:1 was maintained. Data from amblyopic children with infantile anisometropia fall near the prediction line. Data from amblyopic children with infantile esotropia fall above the prediction line, i.e., there is a disproportionally larger loss in vernier acuity.

Figure 6

Grating and optotype acuities for 106 children with mild-to-moderate amblyopia.(Bosworth and Birch, 2003) Amblyopic children with preserved stereopsis (grey symbols) fall near the 1:1 line (gray line), consistent with similar loss of grating acuity and optotype acuity. Amblyopic children with nil stereoacuity (yellow symbols) fall to the right of the 1:1 line, consistent with similar greater loss optotype acuity of optotype acuity than grating acuity. The mean optotype grating acuity difference was 0.13 ± 0.13 logMAR for amblyopic children with preserved stereopsis and 0.22 ± 0.16 logMAR for amblyopic children with nil stereoacuity (F_1,104 = 10.4; p = 0.0016).

Figure 7

Risk factors for amblyopia in 130 consecutive children with infantile esotropia or accommodative esotropia enrolled in a prospective longitudinal study at the time of initial diagnosis with follow-up to a mean age of 9.5 years.(Birch et al., 2007) No significant differences between nonamblyopic, recovered amblyopic, and persistent amblyopic groups were found for age of onset (upper left) or age at surgery (lower left). Delay in referral for treatment was associated with risk for amblyopia and persistent amblyopia (F = 12.6, p<0.001). Anisometropia ≥1.00 D on the initial visit was also associated with elevated risk for amblyopia and persistent amblyopia (F = 11.1, p=0.002).

Figure 8

Schematic of the stimuli used to assess fusional suppression.(Fu et al., 2006) Stimuli were dichoptic (anaglyphic) multi-bar vernier targets. When there was no standing binocular disparity present (left), 5 static segments interspersed with 4 oscillating segments that aligned and misaligned at 2 Hz. The magnitude of the misalignment offset was swept in 7 steps from 10 to 1 min over each 7 sec trial while the other eye viewed a static multi-bar target with 0 min standing binocular disparity. The VEP was elicited by the making and breaking of co-linearity in the eye that viewed the vernier offsets. The standing disparity condition was similar except that the other eye viewed static multi-bar target with 5 min standing disparity. As in the other condition, the VEP was elicited by the making and breaking of co-linearity in the eye that viewed the vernier offsets; any difference in VEP amplitude between the two conditions is due to a suppressive effect of the static binocular disparity on the monocular vernier position response.

Figure 9

VEP responses to monocular oscillating vernier offsets recorded from a child with normal vision (left) and an amblyopic child (right) with 0 or 5 min standing binocular disparity.(Fu et al., 2006) For the child with normal vision, vernier responses are similar for each eye (grey symbols). The addition of a standing binocular disparity results in decreased VEP amplitude, consistent with fusional suppression. The amount of suppression is similar regardless of which eye views the vernier target and which views the static, disparate stimulus (yellow symbols). For the amblyopic child (right), the amblyopic eye has slightly, but consistently lower, amplitude vernier responses than the fellow eye. When the standing disparity is introduced to the fellow eye, fusion suppression is observed (yellow circles). However, when the standing disparity is introduced in the amblyopic eye, no fusional suppression is observed (yellow triangles). Fusion suppression is asymmetric in the amblyopic child.

Figure 10

Examples of fixation stability obtained from 33 5- to 9-year-old children with hyperopic anisometropia using the Nidek MP-1 microperimeter.(Birch et al., 2012) On each image, the small blue dots mark the location of the 750 fixation points acquired during the 30 sec test period. The Nidek MP-1 calculated three ellipses to describe the areas that enclose 68%, 95%, and 99% of the fixation points; the 95% BCEA ellipse is highlighted in yellow. On the left is a child with steady fixation; only small amplitude drifts and microsaccades were present and nearly all of the fixation points fell inside of the 1 deg fixation circle shown in red (BCEA = 0.8 deg²). In the center is a more typical anisometropic child, who shows moderate fixation instability (BCEA = 5.9 deg²). On the right, a child with substantial fixation instability is shown (BCEA = 10.8 deg²).

Figure 11

Fixation instability during 30 sec of attempted steady fixation for 33 children with hyperopic anisometropia.(Birch et al., 2012) Age-matched normal controls had a mean BCEA = 2.1 ± 0.9 deg² (yellow line), with a 95% tolerance range of 0.2 to 3.8 deg² (yellow shaded area). Anisometropic children with normal stereoacuity (bifoveal; 20–60 arcsecs) had normal fixation stability. Children with reduced stereoacuity of 100–800 arcsecs (monofixation) had significantly more fixation instability than normal (p=0.008) and those with nil stereoacuity were significantly more unstable than those with normal stereoacuity and those with reduced stereoacuity ( p<0.001 for both comparisons).

Figure 12

Eye position records derived from the Nidek MP-1 for the 3 anisometropic children shown in Figure 10.(Birch et al., 2012) The top trace shows eye position for the child with normal fixation stability (Figure 10, left); overall, fixation is accurate, with only microsaccades and a brief saccadic oscillation. The middle trace shows the typical anisometropic child (Figure 10, middle); it shows the classic waveform of FMNS with slow drifts nasalward, and rapid re-fixating temporalward saccades. The bottom trace shows the anisometropic child with extreme fixation instability (Figure 10, right); high frequency, large amplitude FMNS is evident.

Figure 13

Prevalence of FMNS among 33children with hyperopic anisometropia divided into 3 groups based on their stereoacuity. (Birch et al., 2012)

Figure 14

Mean fixation areas (95% BCEA) for amblyopic, non-amblyopic and normal control children.(Subramanian et al., 2012) Compared with children with strabismus, anisometropia, or both who were nonamblyopic, amblyopic children had significantly greater fixation instability; mean BCEA for amblyopic eyes was significantly larger than for non-amblyopic right or left eyes (p ≤ 0.02). Mean BCEA when fixating with the amblyopic eye was significantly larger than for normal controls’ right or left eyes (p ≤ 0.01) left eyes. Amblyopic eyes also had significantly more fixation instability than their fellow eyes (p = 0.01). Fixation stability of fellow eyes did not differ significantly from right or left eyes of normal controls.

Figure 15

Performance on fine motor tasks by amblyopic and nonamblyopic individuals with three levels of binocular function.(O’Connor et al., 2010a, b) There was a significant difference in performance on the Purdue Pegboard and the large and small bead tasks (p< 0.03 in all cases). Post-hoc analyses demonstrated that those with normal stereoacuity performed significantly better than those with nil stereoacuity. When comparing those with reduced stereoacuity with those with normal stereoacuity, individuals with reduced stereoacuity were quicker than those with nil stereoacuity. Analysis of covariance between individuals with and without amblyopia found that amblyopia was associated with slower completion of both bead tasks (p< 0.04) but, when the analysis was repeated with stereoacuity as a covariate the difference in speed on the bead tasks was no longer statistically significant.

Figure 16

Improvement in visual acuity with patching in 18 amblyopic adults while playing an action video game or a non-action video game for 20 hours. Also shown is the visual acuity improvement achieved with 20 hours of patching while practicing a grating acuity task (perceptual learning; PL) and with patching alone for 20 hours. (Li et al., 2011)

Figure 17

Visual acuity improvement following 5–20 hours of dichoptic training to amblyopic individuals using video game goggles to make motion coherence judgments (Hess et al., 2010) or play Tetris (Knox et al., 2012) or using a lenticular overlay on an iPod to play Tetris.(Hess et al., 2012; To et al., 2011) Despite the pilot studies having relatively short durations of dichoptic training and small cohorts, all 3 studies showed significant improvement in visual acuity and stereoacuity.

Figure 18

Visual acuity data from a child with anisometropic amblyopia before and after dichoptic training.(Birch et al., 2013) On the intitial visit at 4.4 years old, best corrected visual acuity for the amblyopic eye was 0.9 logMAR. Treatment with glasses, patching, atropine, and Bangerter filter resulted in improvement to 0.5–0.6 logMAR. Slight regression to 0.6–0.7 logMAR occurred, and visual acuity remained in this range for the next 3 years with continued spectacle wear. At 9.9 years, the child enrolled in the dichoptic treatment study and showed 0.2 logMAR improvement to visual acuity of 0.4 logMAR over the next 8 weeks. Three months after discontinuing dichoptic treatment, visual acuity for the amblyopic eye remained at 0.4 logMAR. Visual acuity of the fellow eye remained at 0.1 to 0.0 logMAR from age 7.4 years to 10.4 years.