Longitudinal Development of Refractive Error in Children Treated With Intravitreal Bevacizumab or Laser for Retinopathy of Prematurity.

Purpose: To compare the patterns of longitudinal refractive error development during the first 3.5 years in children with severe retinopathy of prematurity (ROP) treated with intravitreal bevacizumab (IVB) or laser photocoagulation. Methods: This prospective cohort study enrolled extremely preterm infants (birth weight < 1000 g, gestational age 23-27 weeks) with type 1 ROP from multiple hospitals in Dallas between 1999 and 2017; IVB group (N = 22); laser group (N = 26). Cycloplegic retinoscopy was conducted from 0.04 years corrected age and every 0.5 to 1.0 years thereafter until 3.5 years old. Right eye spherical equivalent (SEQ) and astigmatism, anisometropia, and better-eye visual acuity were analyzed over time. Results: In all children, both eyes were treated with the same modality. At the final visit, the prevalence of myopia (SEQ ≤ -1D) was 82.7% in the laser group and 47.7% in the IVB group (P < 0.05) with a mean SEQ of -8.0D ± 5.8D in the laser group versus -2.3D ± 4.2D in the IVB group (P < 0.001). Longitudinal SEQ were best fit with a bilinear model. Before one year, the rate of SEQ change was -5.0D/year in the laser group, but only -3.5D/year in the IVB group (T = -5.14, P < 0.001); after one year, there was a significant flattening of these slopes (T = 6.23, P < 0.001). Anisometropia in the IVB group was significantly less than in the laser group (P < 0.05). Final visual acuity in both groups was similar at 0.47 logMAR (∼ 20/60). Conclusions: Children with severe ROP treated with IVB developed less myopic refractive error than those treated with laser largely because of a slower rate of refractive change during the first year of life. Translational Relevance: These findings may inform decisions regarding ROP treatment timing and modality.

A randomized clinical trial of contrast increment protocols for binocular amblyopia treatment.

BACKGROUND: Most clinical trials of contrast-rebalanced binocular amblyopia treatment used a contrast increment protocol of 10% daily with successful play. Paired with a definition of success requiring only 15-30 min/day of gameplay, this increment protocol could allow children to reach 100% fellow eye contrast in 3-9 hours; however, this may not provide adequate therapeutic time with reduced fellow eye contrast. The purpose of this study was to compare the original protocol against three alternative contrast increment protocols designed to increase the number of treatment hours. METHODS: In this prospective study, 63 amblyopic children (4-10 years; amblyopic eye visual acuity, 20/40-125) were randomly assigned one of four daily contrast increment protocols for 4 weeks, all starting with 20% fellow eye contrast: 10%, 5%, 0%, or 10% for first 4 weeks then reset to 20% and repeat 10% increment for the final 4 weeks. Children played contrast-rebalanced games for 1 hour/day, 5 days/week. Best-corrected visual acuity, stereoacuity, and suppression were assessed at baseline and every 2 weeks until the 8-week outcome visit. RESULTS: At baseline, mean amblyopic eye best-corrected visual acuity was 0.47 ± 0.14 logMAR (20/60), improving overall 0.14 ± 0.08 logMAR (1.4 lines; P < 0.0001) at 8 weeks. All four protocols resulted in similar improvement in visual acuity (0.13-0.16 logMAR; all Ps < 0.0002). Stereoacuity and suppression also improved (all Ps < 0.05). CONCLUSIONS: None of the new protocols resulted in less improvement than the original 10% contrast increment protocol. Contrast-rebalanced binocular games yielded significant improvements in visual acuity, stereoacuity, and suppression with or without daily contrast increments.

Baseline and Clinical Factors Associated with Response to Amblyopia Treatment in a Randomized Clinical Trial.

SIGNIFICANCE: We sought to identify baseline and clinical factors that were predictive of the response to amblyopia treatment. We report that binocular amblyopia treatment may be especially effective for moderate amblyopia in orthotropic children. PURPOSE: We previously reported results from the primary cohort (n = 28) enrolled in a randomized clinical trial (NCT02365090), which found that binocular amblyopia treatment was more effective than patching. Enrollment of an additional 20 children was pre-planned to provide the opportunity to examine factors that may be predictive of response to amblyopia treatment. METHODS: Forty-eight children (4 to 10 years old) were enrolled, with 24 randomized to contrast-rebalanced binocular game treatment (1 hour a day, 5 days a week) and 24 to patching treatment (2 hours a day, 7 days a week). The primary outcome was change in amblyopic eye best-corrected visual acuity at the 2-week visit. Baseline factors examined were age at enrollment, visual acuity, stereoacuity, and suppression. Clinical factors were etiology, age at diagnosis, prior treatment, and ocular alignment. RESULTS: At 2 weeks, visual acuity improvement was significantly greater with the binocular game than patching. Children with moderate amblyopia and orthotropia had more visual acuity improvement with binocular game play than did those with severe amblyopia. In addition, children who spent more time playing the binocular game had more improvement. We were not able to confidently identify any baseline or clinical factors that were associated with response to patching treatment. CONCLUSIONS: Binocular amblyopia treatment was more effective among orthotropic children with moderate amblyopia than among children with microtropia or severe amblyopia.

Binocular amblyopia treatment with contrast-rebalanced movies.

BACKGROUND: Binocular amblyopia treatments promote visual acuity recovery and binocularity by rebalancing the signal strength of dichoptic images. Most require active participation by the amblyopic child to play a game or perform a repetitive visual task. The purpose of this study was to investigate a passive form of binocular treatment with contrast-rebalanced dichoptic movies. METHODS: A total of 27 amblyopic children, 4-10 years of age, wore polarized glasses to watch 6 contrast-rebalanced dichoptic movies on a passive 3D display during a 2-week period. Amblyopic eye contrast was 100%; fellow eye contrast was initially set to a lower level (20%-60%), which allowed the child to overcome suppression and use binocular vision. Fellow eye contrast was incremented by 10% for each subsequent movie. Best-corrected visual acuity, random dot stereoacuity, and interocular suppression were measured at baseline and at 2 weeks. RESULTS: Amblyopic eye best-corrected visual acuity improved from 0.57 ± 0.22 at baseline to 0.42 ± 0.23 logMAR (t26 = 8.09; P < 0.0001; 95% CI for improvement, 0.11-0.19 logMAR). Children aged 3-6 years had more improvement (0.21 ± 0.11 logMAR) than children aged 7-10 years (0.11 ± 0.06 logMAR; t25 = 3.05; P = 0.005). Children with severe amblyopia (≥0.7 logMAR) at baseline experienced greater improvement (0.24 ± 0.12 logMAR) than children with moderate amblyopia at baseline (0.12 ± 0.06 logMAR; t25 = 3.49; P = 0.002). CONCLUSIONS: In this cohort, passive viewing of contrast-rebalanced dichoptic movies effectively improved visual acuity in amblyopic subjects. The degree of improvement observed was similar to that previously reported for 2 weeks of binocular games treatment and with 3-4 months of occlusion therapy.

Improved Binocular Outcomes Following Binocular Treatment for Childhood Amblyopia.

Purpose: Childhood amblyopia can be treated with binocular games or movies that rebalance contrast between the eyes, which is thought to reduce depth of interocular suppression so the child can experience binocular vision. While visual acuity gains have been reported following binocular treatment, studies rarely report gains in binocular outcomes (i.e., stereoacuity, suppression) in amblyopic children. Here, we evaluated binocular outcomes in children who had received binocular treatment for childhood amblyopia. Methods: Data for amblyopic children enrolled in two ongoing studies were pooled. The sample included 41 amblyopic children (6 strabismic, 21 anisometropic, 14 combined; age 4-10 years; ≤4 prism diopters [PD]) who received binocular treatment (20 game, 21 movies; prescribed 9-10 hours treatment). Amblyopic eye visual acuity and binocular outcomes (Randot Preschool Stereoacuity, extent of suppression, and depth of suppression) were assessed at baseline and at 2 weeks. Results: Mean amblyopic eye visual acuity (P < 0.001) and mean stereoacuity improved (P = 0.045), and mean extent (P = 0.005) and depth of suppression (P = 0.003) were reduced from baseline at the 2-week visit (87% game adherence, 100% movie adherence). Depth of suppression was reduced more in children aged <8 years than in those aged ≥8 years (P = 0.004). Worse baseline depth of suppression was correlated with a larger depth of suppression reduction at 2 weeks (P = 0.001). Conclusions: After 2 weeks, binocular treatment in amblyopic children improved visual acuity and binocular outcomes, reducing the extent and depth of suppression and improving stereoacuity. Binocular treatments that rebalance contrast to overcome suppression are a promising additional option for treating amblyopia.

Binocular iPad Game vs Patching for Treatment of Amblyopia in Children: A Randomized Clinical Trial.

IMPORTANCE: Fellow eye patching has long been the standard treatment for amblyopia, but it does not always restore 20/20 vision or teach the eyes to work together. Amblyopia can be treated with binocular games that rebalance contrast between the eyes so that a child may overcome suppression. However, it is unclear whether binocular treatment is comparable to patching in treating amblyopia. OBJECTIVES: To assess the effectiveness of a binocular iPad (Apple Inc) adventure game as amblyopia treatment and compare this binocular treatment with patching, the current standard of care. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a randomized clinical trial with a crossover design at a nonprofit eye research institute. Between February 20, 2015, and January 4, 2016, a total of 28 patients were enrolled in the study, with 14 randomized to binocular game treatment and 14 to patching treatment. INTERVENTIONS: Binocular game and patching as amblyopia treatments. MAIN OUTCOMES AND MEASURES: The primary outcome was change in amblyopic eye best-corrected visual acuity (BCVA) at the 2-week visit. Secondary outcomes were change in stereoacuity and suppression at the 2-week visit and change in BCVA at the 4-week visit. RESULTS: Among 28 children, the mean (SD) age at baseline was 6.7 (1.4) years (age range, 4.6-9.5 years), and 7 (25%) were female. At baseline, the mean (SD) amblyopic eye BCVA was 0.48 (0.14) logMAR (approximately 20/63; range, 0.3-0.8 logMAR [20/40 to 20/125]), with 14 children randomized to the binocular game and 14 to patching for 2 weeks. At the 2-week visit, improvement in amblyopic eye BCVA was greater with the binocular game compared with patching, with a mean (SD) improvement of 0.15 (0.08) logMAR (mean [SD], 1.5 [0.8] lines) vs 0.07 (0.08) logMAR (mean [SD], 0.7 [0.8] line; P = .02) after 2 weeks of treatment. These improvements from baseline were significant for the binocular game (mean [SD] improvement, 1.5 [0.8] lines; P < .001) and for patching (mean [SD] improvement, 0.7 [0.8] line; P = .006). Depth of suppression improved from baseline at the 2-week visit for the binocular game (mean [SD], 4.82 [2.82] vs 3.24 [2.87]; P = .03) and for patching (mean [SD], 4.77 [3.10] vs 2.57 [1.67]; P = .004). Patching children crossed over to binocular game treatment, and all 28 children played the game for another 2 weeks. At the 4-week visit, no group difference was found in BCVA change, with children who crossed over to the binocular games catching up with children treated with binocular games, for a mean (SD) improvement of 0.17 (0.10) logMAR (mean [SD], 1.7 [1.0] lines) for the binocular game vs a mean (SD) improvement of 0.16 (0.12) logMAR (mean [SD], 1.6 [1.2] lines) for the patching crossover (P = .73). CONCLUSIONS AND RELEVANCE: A binocular iPad game was effective in treating childhood amblyopia and was more efficacious than patching at the 2-week visit. Binocular games that rebalance contrast to overcome suppression are a promising additional option for treating amblyopia. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02365090.

Development of refractive error in individual children with regressed retinopathy of prematurity.

PURPOSE: We investigated longitudinally the refraction development in children with regressed retinopathy of prematurity (ROP), including those with and those without a history of peripheral retinal laser photocoagulation. METHODS: Longitudinal (0-7 years) cycloplegic refraction data were collected prospectively for two groups of preterm children: severe ROP group included those with regressed ROP following bilateral panretinal laser photocoagulation (n = 37; median gestational age [GA] = 25.2; range, 22.7-27.9 weeks) and mild/no ROP group included those with spontaneously regressed ROP or no ROP (n = 27; median GA = 27.1; range, 23.1-32.0 weeks). Analyses were based on spherical equivalent (SEQ), anisometropia, astigmatism, and age (corrected for gestation). RESULTS: The prevalence, magnitude, and rate of myopic progression all were significantly higher in the severe ROP group than in the mild/no ROP group. Longitudinal SEQ in the severe ROP group were best fit with a bilinear model. Before 1.3 years old, the rate of myopic shift was -4.7 diopters (D)/y; after 1.3 years, the rate slowed to -0.15 D/y. Longitudinal SEQ in the mild/no ROP group was best fit with a linear model, with a rate of -0.004 D/y. Anisometropia in the severe ROP group increased approximately three times faster than in the mild/no ROP group. In the severe ROP group, with-the-rule astigmatism increased significantly with age. CONCLUSIONS: The severe ROP group progressed rapidly toward myopia, particularly during the first 1.3 years; anisometropia and astigmatism also increased with age. The mild/no ROP group showed little change in refraction. Infants treated with laser photocoagulation for severe ROP should be monitored with periodic cycloplegic refractions and provided with early optical correction.

Foveal avascular zone and foveal pit formation after preterm birth.

BACKGROUND: Vascularisation of the macula takes place between 24 and 27 weeks post-conception. Preterm birth may affect the formation of the foveal avascular zone (FAZ) and foveal depression, and displacement of inner retinal layers away from the incipient fovea. OBJECTIVE: To examine whether vascular abnormalities accompany an inner retinal abnormality, and whether they are coincident. METHODS: High-density spectral domain optical coherence tomography volume scans were obtained from 24 preterm children and 34 full-term controls (5-16 years). Matlab programs were used to quantify total retinal thickness, thickness of individual retinal layers and metrics of foveal morphology. Summed voxel projections for the ganglion cell layer-inner nuclear layer were used to identify the FAZ. RESULTS: Preterm children had significantly smaller FAZ diameters than controls (p<0.0001). The foveal pits of preterm children were significantly shallower and less steep (p<0.0001) and total retinal thickness at the fovea was significantly increased (p<0.0001) compared to controls. The ganglion cell layer-inner plexiform layer and outer nuclear layer were significantly (p≤0.0001) thicker in preterm children than in controls. CONCLUSIONS: Preterm birth results in abnormal foveal vascularisation, a failure of the inner retinal neurons to migrate away from the fovea, and an elevated outer nuclear layer ratio. The spatial coincidence of inner retinal and vascular abnormalities in preterm children supports the hypothesis that aspects of foveal development are interdependent.

Characteristics of peripapillary retinal nerve fiber layer in preterm children.

PURPOSE: To examine quantitatively characteristics of the peripapillary retinal nerve fiber layer (RNFL) in preterm children using Fourier-domain optical coherence tomography (FD-OCT). DESIGN: Prospective cross-sectional study. METHODS: A 3-mm high-resolution FD-OCT peripapillary RNFL circular scan centered on the optic disc was obtained from right eyes of 25 preterm children (10.6 ± 3.7 years old, 8 preterm and 17 with regressed retinopathy of prematurity with normal-appearing posterior poles) and 54 full-term controls (9.8 ± 3.2 years old). Images were analyzed using Spectralis FD-OCT software to obtain average thickness measurements for 6 sectors (temporal superior, temporal, temporal inferior, nasal inferior, nasal, nasal superior), and the global average. RESULTS: The RNFL global average for preterm children was 8% thinner than for full-term controls. In the preterm group, peripapillary RNFL thickness on the temporal side of the disc was 6% thicker than in full-term controls, while all other peripapillary RNFL sectors were 9% to 13% thinner. In the preterm group, temporal sector peripapillary RNFL thickness was correlated with gestational age (r = -0.47, P < .001), with foveal center total thickness (r = 0.48, P = .008, 1-tailed), and with visual acuity (r = 0.42; P = .026, 1-tailed). CONCLUSIONS: The significantly thinner RNFL global average for preterm children suggests that prematurity is associated with subclinical optic nerve hypoplasia. Significant correlations between temporal sector RNFL thickness and both the foveal thickness and visual acuity suggest that the peripapillary RNFL is related to abnormalities in macular development as a result of preterm birth.

Critical period for foveal fine structure in children with regressed retinopathy of prematurity.

PURPOSE: Midgestation is a critical period in the formation of the foveal avascular zone. The authors evaluated the effects of preterm birth on foveal structure in children with regressed retinopathy of prematurity. METHODS: Children with regressed retinopathy of prematurity with normal-appearing posterior poles (n = 26) and full-term control children (n = 56) were investigated. Frequency-domain optical coherence tomography 9-mm line scans across the fovea were obtained from right eyes. Using a customized segmentation program in MATLAB, total retinal thickness and the thickness of individual retinal layer regions were measured at the fovea (0°) and throughout ± 8°. RESULTS: Total thickness of the fovea in the retinopathy of prematurity group (287.7 ± 47.6 µm) was greater than that in the control group (230.1 ± 18.2 µm). Bilinear fitting was performed to examine the relationship between total thickness and gestational age. Before 28 weeks, foveal thickness decreased with gestational age (14.3 µm/week); after 28 weeks, foveal thickness decreased only slightly (2.73 µm/week). Inner retinal layers contributed to the difference in thickness between groups more than outer layers. Foveal thickness was correlated with gestational age at birth but not with visual acuity or refractive error. CONCLUSION: Preterm birth before 28 weeks of gestational age was associated with a failure of the inner retinal layers to migrate away from the fovea, resulting in increased foveal thickness.

Improvement in motor development following surgery for infantile esotropia.

PURPOSE: Infantile esotropia is associated with abnormal visual development and thus may delay the achievement of developmental milestones. Although early surgery can improve visual function, less is known about its effect on motor development. Here we address whether early surgery can improve motor development. METHODS: Recently, our lab devised the Infant Developmental Skills Survey, a 25-item questionnaire designed to assess sensorimotor and gross motor development. The questionnaire was completed by the parents of 3- to 10-month-old patients with infantile esotropia prior to surgery (n = 143) and the parents of 6- to 11-month-old patients following surgery (n = 58). A subset of parents (n = 40) completed the questionnaire both before and after surgery. For comparison, the questionnaire was completed by the parents of infants with normal ocular alignment (n = 194). RESULTS: Before surgery 4-, 5-, 6-, 7-, 9-, and 10-month-old patients showed delayed achievement of sensorimotor milestones (p < 0.01), and 5-, 9-, and 10-month-old patients demonstrated delayed attainment of gross motor milestones (p < 0.05) compared with normal children. However, following surgery, patients demonstrated a greater rate of sensorimotor development than age-matched controls (p < 0.0001) and caught up with normal children on both sensorimotor and gross motor skills. CONCLUSIONS: Prior to surgery, patients with infantile esotropia were delayed in their achievement of developmental milestones. However, following surgery, a comparison group of patients showed rapid development and possessed motor skills comparable to those of normal children, suggesting that early surgery is beneficial to both visual and motor development.