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Progress in Retinal and Eye Research 33 (2013) 67e84

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Progress in Retinal and Eye Research

journal homepage: www.elsevier .com/locate/prer

Amblyopia and binocular visionq

Eileen E. Birch a,b,*,1

a Pediatric Laboratory, Retina Foundation of the Southwest, Dallas, TX, USA2

bDepartment of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA

a r t i c l e i n f o

Article history:Available online 29 November 2012

Keywords:AmblyopiaBinocular visionStereoacuityTreatmentAnisometropiaStrabismus

q The research was conducted at the Retina Founda* Pediatric Laboratory, Retina Foundation of the Sou

E-mail address: ebirch@retinafoundation.org.1 Percentage of work contributed by each author in2 Please note that the Retina Foundation of the Sou

1350-9462/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.preteyeres.2012.11.001

a b s t r a c t

Amblyopia is themost common cause of monocular visual loss in children, affecting 1.3%e3.6% of children.Current treatments are effective in reducing the visual acuity deficit but many amblyopic individuals areleft with residual visual acuity deficits, ocular motor abnormalities, deficient fine motor skills, and risk forrecurrent amblyopia. Using a combination of psychophysical, electrophysiological, imaging, risk factoranalysis, and fine motor skill assessment, the primary role of binocular dysfunction in the genesis ofamblyopia and the constellation of visual and motor deficits that accompany the visual acuity deficithas been identified. These findings motivated us to evaluate a new, binocular approach to amblyopiatreatment with the goals of reducing or eliminating residual and recurrent amblyopia and of improvingthe deficient ocular motor function and fine motor skills that accompany amblyopia.

� 2012 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681.1. Amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681.2. Clinical profile of amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681.3. Amblyopia treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681.4. Failures of amblyopia treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691.5. Insights from treatment failures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

2. Amblyopia and binocular vision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .712.1. Stereoacuity and amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 712.2. Risk factors for persistent amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732.3. Fusional suppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742.4. Gaze instability, binocular vision, and amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752.5. Motor skills in amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

3. Binocular treatment of amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .773.1. Perceptual learning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783.2. Treating binocular dysfunction amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

4. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804.1. Screening for amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804.2. Diagnosis of amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804.3. Optimizing treatment for amblyopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

tion of the Southwest.thwest, 9900 North Central Expressway, Suite 400, Dallas, TX 75231, USA. Tel.: þ1 214 363 3911; fax: þ1 214 363 4538.

the production of the manuscript is as follows: Birch 100%.thwest will have a new address as of December 15, 2012: 9600 North Central Expressway, Suite 100, Dallas, TX 75231.

All rights reserved.

E.E. Birch / Progress in Retinal and Eye Research 33 (2013) 67e8468

1. Introduction Group, 2002a). Both studies included children with strabismic,anisometropic, or combined-mechanism amblyopia referred by

1.1. Amblyopia

Amblyopia is diminished vision that results from inadequatevisual experience during the first years of life. Typically, amblyopiais clinically defined as reduced visual acuity accompanied by one ormore known amblyogenic factors, such as strabismus, anisome-tropia, high refractive error, and cataract. Amblyogenic factorsinterfere with normal development of the visual pathways duringa critical period of maturation. The result is structural and func-tional impairment of the visual cortex, and impaired form vision.

Although amblyopia can be bilateral, it most commonly affectsone eye of children with strabismus, anisometropia, or both. Theprevalence of strabismus, anisometropia, and amblyopia has beenreported in a number of recent population-based studies ofpreschool children and school children in the United States, theUnited Kingdom, Netherlands, Sweden, and Australia (Table 1).

Overall, results of the studies are consistent, with a meanprevalence of 2.8% for strabismus, 3.5% for anisometropia, and 2.4%for amblyopia. With 625 million children under the age of 5 yearsworldwide, more than 15 million may have amblyopia, and morethan half of themwill not be identified before they reach school age(Wu and Hunter, 2006). Many affected children will suffer irre-versible vision loss that could have been prevented. The conse-quences of not identifying and treating strabismus and amblyopiaearly include permanent visual impairment, adverse effects onschool performance, poor fine motor skills, social interactions, andself-image (Choong et al., 2004; Chua andMitchell, 2004; Horwoodet al., 2005; O’Connor et al., 2010b; O’Connor et al., 2009; Packwoodet al., 1999; Rahi et al., 2006; Webber et al., 2008a,b). Importantly,permanent monocular visual impairment due to amblyopia is a riskfactor for total blindness if the better eye is injured or if the felloweye is affected by disease later in life (Harrad and Williams, 2003).

The predominant theory is that amblyopia results when there isa mismatch between the images to each eye; one eye is favoredwhile the information from the other eye is suppressed (Harradet al., 1996). Because amblyopia typically affects visual acuity inone eye, amblyopia is often considered to be a monocular disease.Thus, the mainstay of treatment for amblyopia has been patching ofthe normal fellow eye to improve the monocular function of theamblyopic eye. However, there are significant shortcomings to thisapproach to understanding and treating amblyopia. Our researchstudies on amblyopia have revealed that binocular dysfunctionplaysan important role in amblyopia and has laid the groundwork fora new approach for the development of more effective treatment.

1.2. Clinical profile of amblyopia

Two large studies have defined the clinical profile of amblyopicchildren (Birch and Holmes, 2010; Pediatric Eye Disease Investigator

Table 1Prevalence of strabismus, anisometropia, and amblyopia in recent (2001e2012) populat

Site N

BPEDS (Friedman et al., 2009; Giordano et al., 2009) US 2546MEPEDS (Multi-Ethnic Pediatric Eye Disease Study, 2008) US 6014NICHS (Donnelly et al., 2005) UK 1582ALSPAC (Williams et al., 2008) UK 7825RAMSES (Groenewoud et al., 2010) N 2964SCHC (Kvarnstrom et al., 2001) S 3126SPEDS (Pai et al., 2012) A 1422SMS (Huynh et al., 2006; Robaei et al., 2006) A 1765Mean

US ¼ United States, UK ¼ United Kingdom, N ¼ Netherlands, S ¼ Sweden, A ¼ Australia

multiple community- and university-based pediatric ophthalmolo-gists. In the Pediatric Eye Disease Investigator Group (PEDIG) study,we assessed the clinical characteristics of 409 children age 3e6.9 years with moderate amblyopia who were enrolled in a multi-center randomized study of amblyopia treatment (Pediatric EyeDisease Investigator Group, 2002a). Strabismus or anisometropiaeach accounted for about 40% of amblyopia, with just over 20% ofamblyopia in children with both strabismus and anisometropia(Fig. 1). Overall, mean refractive error in the amblyopic eyewas þ4.52 D and in the fellow eye was þ2.83 D, but fellow eyerefractive error was higher in the strabismic children (þ3.54 D) andlower in the anisometropic children (þ1.95 D).

In a second study, we examined the clinical profile of 250amblyopic children less than 3 years old in the Dallas area (Birchand Holmes, 2010); 82% of amblyopia was associated with stra-bismus, 5% with anisometropia, and 13% with both (Fig. 1), a strik-ingly different distribution of amblyogenic factors compared withthe older cohort. Mean refractive error in the amblyopic eyewas þ2.63 D, substantially lower than in the older cohort. Felloweye refractive error averaged þ2.60 D, similar to the overall meanfor the older cohort and, as with the older cohort, fellow eyerefractive error was higher in the strabismic children (þ2.59 D) andlower in the anisometropic children (þ0.94 D). Our studies, alongwith two additional studies from the UK (Shaw et al., 1988;Woodruff et al., 1994b), suggest that the factors responsible foramblyopia vary with age (Fig. 2). Strabismus is the overwhelminglythe factor most associated with amblyopia during the first year.Anisometropia, either alone or in combination with strabismus,becomes equally prominent as a cause of amblyopia by the thirdyear and, by the fifth year, is the causative factor in nearly two-thirds of amblyopic children.

The low percentage of amblyopia attributable to anisometropiain the <3 year cohort is unlikely to be the result of marked under-referral of anisometropia in this age range. Overall, in the parentstudy fromwhich the amblyopic children<3 years old were drawn,only 18% of the 67 of anisometropic children were diagnosed withamblyopia (Birch and Holmes, 2010). In contrast, almost 50% of the396 children with strabismus or strabismus with anisometropiawere diagnosed with amblyopia. This suggests that anisometropiamay develop later, and become an etiologic factor for amblyopiaprimarily after 3 years of age. Another alternative is that aniso-metropia may be present early but requires a longer duration thanstrabismus to cause amblyopia.

1.3. Amblyopia treatment

Current treatments for amblyopia rely on depriving the healthy,fellow eye of vision to force use of the amblyopic eye. Theassumption is that the primary deficit in amblyopia is a monocular

ion-based studies of children.

Age Strabismus Anisometropia Amblyopia

0.5e6 yr 2.2% 4.5% 1.3%0.5e6 yr 2.4% 4.1% 2.0%8e9 yr 4.0% e 2.0%7 yr 2.3% e 3.6%7 yr e e 3.4%10 yr 3.1% e

2.5e6 yr e e 1.9%5e8 yr 2.8% 2.6% 1.8%

2.8% 3.8% 2.4%

.

Fig. 1. In the <3-year-old cohort, (Birch and Holmes, 2010) 82% of amblyopia wasassociated with strabismus, 5% with anisometropia, and 13% with combined mecha-nisms. 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 wasassociated with strabismus, 37% with anisometropia, and 24% with combined mech-anism (p < 0.001 for each of the 3 paired comparisons). Among children with stra-bismus in the <3-year-old cohort, 62% had infantile esotropia (onset �6 months ofage), 22% had accommodative esotropia, 10% had acquired nonaccommodative eso-tropia (onset �7 months of age), and 6% had other types of strabismus.

E.E. Birch / Progress in Retinal and Eye Research 33 (2013) 67e84 69

visual acuity deficit caused by preference for fixation by the felloweye. By depriving the fellow eye of vision, suppression of theamblyopic eye is eliminated and visual experience will promotedevelopment or recovery of visual acuity. Patching, atropine, andfilters that penalize the fellow eye have been used to treat ambly-opia for hundreds of years (Loudon and Simonsz, 2005). Only in thelast 15 years have randomized clinical trials been conducted toevaluate the effectiveness of amblyopia treatment and to begin to

Fig. 2. Strabismic amblyopia was diagnosed much more commonly than anisome-tropic or combined-mechanism amblyopia in children <3 years of age (Birch andHolmes, 2010). This finding is in sharp contrast to the PEDIG report of approxi-mately equal proportions of patients with amblyopia attributable to strabismus andanisometropia, and approximately a quarter of the amblyopic patients exhibiting both(Pediatric Eye Disease Investigator Group, 2002a). Two UK studies of amblyopic chil-dren, which included younger children than the PEDIG study, found the cause to bestrabismus in a greater percentage than the PEDIG study (45%e57%), a lowerpercentage to be anisometropic (17%), and about the same percentage to be combinedmechanism (27%e35%) (Shaw et al., 1988; Woodruff et al., 1994b). This summary of all4 studies suggests that one source of the differences in the proportion of amblyopiaattributable to strabismus may be age.

define optimal treatment protocols. The Pediatric Eye DiseaseInvestigator Group (PEDIG) has conducted a series of randomizedclinical trials of amblyopic treatment for children ages 3e17 yearsold. To date, our major results are:

� A period of 16e22 weeks of treatment with optical correctionalone leads to an improvement of�0.2 logMAR (2 lines) in bothchildren with anisometropic amblyopia (Cotter et al., 2006)and children strabismic or combined mechanism amblyopia(Cotter et al., 2012). In nearly one-third of amblyopic childrentreated with optical correction, amblyopia completed resolved.Similar results have been reported by the Monitored OcclusionTreatment of Amblyopia Study (MOTAS) Cooperative Group,and the Randomized Occlusion Treatment of Amblyopia(ROTAS) Cooperative Group studies (Stewart et al., 2011). Thus,refractive correction as the sole initial treatment for amblyopiais a viable option.

� Patching is an effective treatment for amblyopia. After stablevisual acuity was achieved with spectacle wear, 3- to 7-year-oldamblyopic children who were randomized to patching treat-ment had further visual acuity improvement of 0.22 logMAR(2.2 lines) (Wallace et al., 2006).

� For moderate amblyopia, a prescribed patching dose of 2 h/dayresults in the same visual acuity outcome as a prescribedpatching dose of 6 h/day (Repka et al., 2003) and, for severeamblyopia, 6 h/day yields similar results to 12 h/day (Holmeset al., 2003). Objective monitoring of compliance withprescribed patching in a similar UK study suggests that thesimilar visual acuity outcomes may have been due to lack ofcompliance with the higher prescribed doses; i.e., the twotreatment groups may have actually received similar dosesdespite assignment to different doses (Stewart et al., 2007b).

� Atropine and patching result in similar improvements in visualacuity when used as the initial treatment of moderate ambly-opia in children aged 3e6 years (Pediatric Eye DiseaseInvestigator Group, 2002b). Most children had �0.3 logMAR(3 lines) improvement in visual acuity and about 75% achieved20/30 or better visual acuity within 6 months (Pediatric EyeDisease Investigator Group, 2002b).

� Among children with severe amblyopia (>0.7 logMAR), treat-ment on weekends with atropine led to an average improve-ment of 0.45 logMAR (4.5 lines) (Repka et al., 2009).

� Treatment of amblyopia can be effective beyond 7 years of age,although the rate of response to treatment may be slower, mayrequire a higher dose of patching, and the extent of recoverymay be less complete (Holmes et al., 2011; Pediatric EyeDisease Investigator Group, 2003, 2004).

The PEDIG results, along with results from MOTAS and ROTASare summarized in Fig. 3.

1.4. Failures of amblyopia treatment

Not all amblyopic children achieve normal visual acuity despitetreatment. Although 73e90% have improvements in visual acuitywith various treatment modalities alone or in combination, (Repkaet al., 2003; Repka et al., 2004; Repka et al., 2005; Rutstein et al.,2010; Stewart et al., 2004b; Wallace et al., 2006) 15e50% fail toachieve normal visual acuity even after extended periods of treat-ment (Birch and Stager, 2006; Birch et al., 2004; Repka et al., 2003;Repka et al., 2004; Repka et al., 2005; Rutstein et al., 2010; Stewartet al., 2004b; Wallace et al., 2006; Woodruff et al., 1994a). Onepossible explanation for the failure to achieve normal visual acuityis that the treatment was started too late. Both experimental andclinical data support the hypothesis that there is an early sensitive

Fig. 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 representmean improvement of visual acuity (logMAR) with 3e6 months of treatment. When more than one randomized clinical trial evaluated similar treatment plans, the range of meansreported in the various studies is provided.

E.E. Birch / Progress in Retinal and Eye Research 33 (2013) 67e8470

period during which strabismus and anisometropia can lead toabnormal visual development, conventionally considered to be thefirst 7 years of life. As a consequence, there is also a widely heldassumption that treatment during this early period is critical forobtaining optimal visual acuity outcome. A recent meta-analysis of4 multi-center amblyopia treatment studies (Holmes et al., 2011)reported that 7- to 13-year-old children were significantly lessresponsive to amblyopia treatment than children less than 7 yearsold. However, the meta-analysis failed to find a significant differ-ence in treatment response between the 3- and 4-year olds and the5- and 6-years olds. On the one hand, these results appear tosupport the concept of a critical period for treatment that coincideswith the critical period for visual development. On the other hand,poor response to treatment among older children could simplyreflect poor compliance with treatment; none of these treatmentstudies included an objective measure of compliance with patchingand glasses. In fact, we have observed approximately the sameprevalence of unresolved amblyopia in children whose amblyopiatreatment was initiated during the first year of life (Birch andStager, 2006; Birch et al., 1990; Birch et al., 2004) as we andothers have observed when treatment is not initiated until 3e6 years of age (Birch and Stager, 2006; Birch et al., 2004; Repkaet al., 2003; Repka et al., 2004; Repka et al., 2005; Rutstein et al.,2010; Stewart et al., 2004b; Wallace et al., 2006; Woodruff et al.,1994a). This suggests that delay in treatment is not the solereason for failure to recover normal visual acuity.

An alternative explanation for failure to achieve normal visualacuity is lack of compliance with treatment. Using objectiveocclusion dose monitoring devices, it has been demonstrated thatcompliance varies widely among children treated for amblyopia

and that visual acuity outcome is related to compliance (Loudonet al., 2002, 2003; Stewart et al., 2004b; Stewart et al., 2007a,b).Randomized clinical trials have supported the use of educationaland motivational material for the children and the parents toimprove compliance (Loudon et al., 2006; Tjiam et al., 2012).However, none of these studies has yet demonstrated thatimproved compliance reduces the proportion of children who failto achieve normal visual acuity with amblyopia treatment.

A third possible reason for failure to achieve normal visualacuity with standard treatments for amblyopia is that currenttreatments are inadequate. In other words, perhaps more intensivetreatment is needed as a “final push” to overcome residualamblyopia. Recently, the Pediatric Eye Disease Investigator Groupconducted amulti-center randomized clinical trial for childrenwithresidual amblyopia do 0.2e0.5 logMAR who had stoppedimproving with 6 h of prescribed daily patching or daily atropine(Wallace et al., 2011a). We found that an intensive combinedtreatment of patching and atropine did not result in better visualacuity outcomes after 10 weeks compared with a control group inwhich treatment was gradually discontinued.

Finally, it has been suggested that children who fail to recovernormal visual acuity with standard amblyopia treatmentsmay havesubtle retinal, optic nerve, or gaze control abnormalities that limittheir potential for visual acuity recovery (Giaschi et al., 1992;Lempert, 2000, 2003, 2004, 2008a,b). Abnormal macular thickness(Al-Haddad et al., 2011; Altintas et al., 2005; Dickmann et al., 2009;Huynh et al., 2009; Walker et al., 2011), optic disc dysversion(Lempert and Porter, 1998), optic nerve hypoplasia (Lempert,2000), and gaze instability (Regan et al., 1992) have all beendescribed in subsets of patients with amblyopia. To evaluate

E.E. Birch / Progress in Retinal and Eye Research 33 (2013) 67e84 71

whether changes in the retina, optic nerve, or gaze control maylimit some children’s response to amblyopia treatment, we evalu-ated each of these aspects of the visual system in 26 children withpersistent residual strabismic, anisometropic, or combined mech-anism amblyopia. We compared the retina, optic nerve, and gazecontrol characteristics of their amblyopic eyes with those of thefellow eyes, with age-matched nonamblyopic children who hadstrabismus or anisometropia (n ¼ 12), and with age-matchednormal controls (n ¼ 48) (Subramanian et al., in press). Allamblyopic children had been treated with glasses, patching, and/oratropine for 0.8e5 years, had a residual visual acuity deficit, and noimprovement in visual acuity despite treatment and excellentcompliance for at least 6 months prior to enrollment.

Images of the macula were obtained with the Spectralis(Heidelberg Engineering) spectral domain OCT (SD-OCT) using theeye-tracking feature (ART). Each child had one to three line scanscentered on the optic disc to measure horizontal and vertical discdiameter, and one to three mm high-resolution peripapillary RNFLcircular scans, and one to three high-resolution macular volumescans. Optic disc dysversion (tilt) was quantified by calculating theratio of vertical to horizontal disc diameters. Optic nerve hypo-plasiawas quantified by calculating the area of the ellipse specifiedby the vertical and horizontal diameters. In order to assess possiblesectoral hypoplasia, (Lee and Kee, 2009) RNFL thickness wasautomatically segmented using the Spectralis software thatprovided average thickness measurements for each of 6 RNFLsectors centered on the optic disc [temporal superior (TS),temporal (T), temporal inferior (TI), nasal inferior (NI), nasal (N),nasal superior (NS)] together with a global average (G). Totalmacular thickness and sectional volumes were automaticallydetermined by software provided by Heidelberg Engineering forthe Spectralis SD-OCT, using a modified ETDRS circle grid (center,middle and outer rings: 1, 2, and 3 mm). To assess gaze control, eyemovements during attempted steady fixation in primary gaze(binocular and monocular) were recorded using an infrared eyetracker.

As shown in Fig. 4, no abnormalities were apparent in macularstructure, and there were no significant differences in macularthickness between the amblyopic and fellow eyes, nonamblyopiceyes, or normal control eyes. Nor were there significant differencesamong these groups in optic disc diameter or shape (dysversion), orin peripapillary RNFL thickness (Fig. 4). Children with persistentamblyopia had eyemovement abnormalities in both amblyopic andfellow eyes, including infantile nystagmus (13%), fusion maldevel-opment nystagmus (47.8%), and saccadic oscillations (39.1%). Somenon-amblyopic eyes of children with strabismus or anisometropiaalso had saccadic oscillations (44.4%) or fusion maldevelopmentnystagmus (11.1%). Normal controls showed no gaze abnormalities.Thus, retinal and optic nerve abnormalities cannot explain persis-tent amblyopia. Gaze instabilities are typically bilateral, but may bea plausible explanation of persistent amblyopia in a subset ofchildren who have asymmetric gaze instability (more instability inthe amblyopic eye).

Even among the 50e85% of children who do achieve normalvisual acuity with amblyopia treatment, the risk for recurrence ofamblyopia is high. In a series of prospective, longitudinal studies ofinfantile and accommodative esotropia conducted in our laboratoryover the past 22 years, (Birch, 2003; Birch et al., 2005; Birch andStager, 2006; Birch et al., 1990; Birch et al., 2004; Birch et al.,2010) 80% of esotropic children were treated for amblyopia atleast once during the first 5 years of life; �60% had recurrentamblyopia that required re-treatment during the 5-year follow-up.PEDIG reported that 25% of successfully treated amblyopic childrenexperience a recurrence within the first year off treatment (Holmeset al., 2004).

1.5. Insights from treatment failures

Residual and recurrent amblyopia remain unexplained. Thestudies reviewed in Sections 1.3 and 1.4 all have one importantfeature in common; amblyopia treatment was monocular. Yet thepredominant theory is that amblyopia arises when there isa mismatch between the images to each eye. In other words,abnormal binocular experience is the primary cause. This promptedus to investigate the link between amblyopia and binocular func-tion from a number of different approaches. Our investigationshave evaluated the role of binocular dysfunction in the dispropor-tionate loss of optotype visual acuity in strabismic amblyopia(Section 2.1), in the risk for persistent, residual amblyopia (Section2.2), in asymmetric fusional suppression (Section 2.3), in the gazeinstabilities associated with amblyopia (Section 2.4), and in the finemotor skill deficits that are present in amblyopic children andadults (Section 2.5). As evidence about the primary role of binoc-ular dysfunction in amblyopia has accumulated, we have worked todevelop approaches to amblyopia treatment (Section 3).

2. Amblyopia and binocular vision

2.1. Stereoacuity and amblyopia

Strabismic and anisometropic amblyopia differ in the spectrumof associated visual deficits despite their common effect on visualacuity. Strabismic amblyopia is associated with disproportionatelygreater deficits in optotype visual acuity and vernier acuitycompared with grating acuity, but anisometropic amblyopia isassociated with proportional deficits in optotype, vernier, andgrating acuity (Levi and Klein, 1982; Levi and Klein, 1985). Thereare two hypotheses regarding the source of differences in thepattern of visual deficits between anisometropic and strabismicamblyopia. First, the differences may reflect fundamentallydifferent pathophysiological processes (etiology hypothesis) (Levi,1990; Levi and Carkeet, 1993). For example, sparse/irregularsampling may be associated with binocular competition betweentwo discordant images in strabismus but not between the sharpvs. defocused images in anisometropia. The second hypothesis isthat the different constellations of spatial deficits in anisome-tropic and strabismic amblyopia reflect the degree of visualmaturation present at the onset of amblyopia (effective agehypothesis); (Levi, 1990; Levi and Carkeet, 1993) that is, aniso-metropic amblyopia may arise at an age where visual maturationis more complete. The low prevalence of anisometropic amblyopicin children <3 years old (Section 1.2) is consistent with theeffective age hypothesis. The effective age hypothesis predicts thatvisual functions that mature earliest will be less susceptible todisruption by abnormal visual experience. Much of the data fromadult with amblyopia is consistent with both of these ideas butdirect tests of the alternative hypotheses were not possible inadults because complete clinical histories are rarely available toprecisely document etiology and the time course over whichamblyopia developed.

We designed a study to overcome this limitation by evaluatingvernier, resolution and recognition acuities of amblyopic childrenwho were enrolled in a prospective study of visual maturationduring infancy and early childhood, i.e., amblyopic children withknown age of onset and etiology (Birch and Swanson, 2000). Wefound that strabismic amblyopia, whether it had infantile onset orpreschool age onset, was associated with disproportionately largeroptotype and vernier acuity deficits compared to grating acuitydeficits (Fig. 5). Moreover, looking only at the subgroup of ambly-opic children with infantile onset (Fig. 5), we observed differencesin the pattern of visual deficits. Children with infantile strabismic

Fig. 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 ¼ 26), there were no significant differences in total macular thickness or in any of the ETDRS macular sectors (second panel) betweenamblyopic 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 wereno 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 usedto quantify optic disc dysversion (Horiz:Vert disc diameter ratio). No significant differences were found for amblyopic vs. fellow eyes (H/Vambly ¼ 1.15 � 0.18; H/Vfellow ¼ 1.14 � 0.17;p ¼ 0.87). Hypoplasia (assessed by area of the optic disc, mm2) did not differ for amblyopic vs. fellow eyes (Areaambly ¼ 1.88 � 0.44; Areafellow ¼ 2.10 � 0.61; p ¼ 0.26).

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amblyopia had disproportionately larger optotype and vernieracuity deficits compared to grating acuity deficits but childrenwithinfantile anisometropic amblyopia had proportional deficits inoptotype, vernier, and grating acuity. These data support theetiology hypothesis. Infantile anisometropic amblyopia resultsfrom blurred vision in one eye during the first years of life; in infantmonkeys, experimentally induced blur leads to a selective loss ofneurons tuned to high spatial frequencies (Kiorpes et al., 1998;Kiorpes and McKee, 1999). On the other hand, infantile strabismusdisrupts the binocular connections of cortical neurons and can lead

to the development of a fixation preference for one eye anda constellation of monocular visual deficits in the non-preferred eyein which optotype and vernier acuity are especially compromised(Kiorpes et al., 1998; Kiorpes and McKee, 1999). However, it isimportant to note that anisometropic amblyopia, whose eyes arealigned but who lack central binocular function, resemble thosewith strabismic amblyopia in their pattern of visual deficits (Leviet al., 2011). Thus, it appears that the presence or absence ofbinocular function drives the pattern of visual deficits, not thepresence or absence of strabismus.

Fig. 6. Grating and optotype acuities for 106 children with mild-to-moderate ambly-opia (Bosworth and Birch, 2003). Amblyopic children with preserved stereopsis (graysymbols) fall near the 1:1 line (gray line), consistent with similar loss of grating acuityand optotype acuity. Amblyopic children with nil stereoacuity (yellow symbols) fall tothe right of the 1:1 line, consistent with similar greater loss optotype acuity of opto-type acuity than grating acuity. The mean optotype grating acuity difference was0.13 � 0.13 logMAR for amblyopic children with preserved stereopsis and0.22 � 0.16 logMAR for amblyopic children with nil stereoacuity (F1,104 ¼ 10.4;p ¼ 0.0016).

Fig. 5. Grating acuity and vernier acuity at 6e9 years of age for 20 amblyopic childrenenrolled in a prospective study at the time of diagnosis during infancy (Birch andSwanson, 2000). The solid line shows the predicted relationship if comparable defi-cits were present for both vernier and grating acuity so that the normal grating:vernieracuity ratio of 8:1 was maintained. Data from amblyopic children with infantileanisometropia fall near the prediction line. Data from amblyopic children withinfantile esotropia fall above the prediction line, i.e., there is a disproportionally largerloss in vernier acuity.

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We tested the hypothesis that regardless of the etiology ofamblyopia, those who have nil stereoacuity experience a dispro-portionate loss in optotype acuity, and this loss exceeds what isseen in amblyopia with preserved stereopsis (Bosworth and Birch,2003). Optotype acuity, Teller grating acuity, and stereoacuity wereevaluated in 106 children with moderate amblyopia (0.3e0.7 logMAR) due to anisometropia, strabismus, or both. Overall,amblyopic children had 2 times worse optotype acuity than gratingacuity. Regardless of age at onset or etiology, amblyopic childrenwith nil stereoacuity had large optotype-grating acuity discrep-ancies (Fig. 6), Our data suggest that the residual monocularsampling mosaic provides adequate information for gratingdetection but is inadequate to represent the local spatial relation-ships needed for optotypes. These data support the hypothesizedlink between impaired binocular function and the neural under-sampling/disarray associated with amblyopia.

2.2. Risk factors for persistent amblyopia

Independent support for a strong link between binoculardysfunction and amblyopia has come from our studies of persistentresidual amblyopia. To evaluate potential risk factors for persistentamblyopia, (Birch et al., 2007) we enrolled 130 consecutive childrenwith infantile esotropia or accommodative esotropia in a prospec-tive, longitudinal study at the time of their initial diagnosis, andconducted regular follow-up visits to assess visual acuity andstereoacuity through visual maturity (mean age¼ 9.5 years). On thebasis of the longitudinal data set, the children were classified as:never amblyopic, recovered (treated for amblyopia and currently0.1 logMAR or better visual acuity and 0.1 logMAR or less inter-ocular difference in visual acuity), or persistent amblyopic (lengthyand/or repeated attempts to treat amblyopia with one or moretreatment modalities but visual acuity remained 0.2 logMAR orpoorer and 0.2 logMAR or more interocular difference in visualacuity persisted). Four risk factors for amblyopia were evaluated:

age of onset of esotropia, delay in referral to an ophthalmologist,age at surgery, and initial refractive error.

Early onset of esotropia might be a risk factor for persistentamblyopia because it may represent more severe disease (Tychsen,2005) or because early onset may result in a longer duration ofabnormal visual experience (Birch, 2003; Birch et al., 2000;Tychsen, 2005, 2007; Tychsen et al., 2004) The incidence ofamblyopia was high in children diagnosed with esotropia; 80% ofthe children with infantile esotropia and 74% of the children withaccommodative esotropia developed amblyopia. In neither theinfantile esotropia cohort nor the accommodative esotropia cohort,was there an association between age at onset of esotropia and theprevalence of persistent amblyopia (Fig. 7).

Delay in referral was evaluated as a risk factor for persistentamblyopia because it is known that a shorter duration of esotropiaoptimizes stereoacuity outcomes (Birch, 2003; Birch et al., 2000;Birch et al., 2005; Fawcett et al., 2000; Fawcett and Birch, 2003) andstereopsis may reduce the risk for moderate to severe amblyopia(Bosworth and Birch, 2003; McKee et al., 2003). Among childrenwho were referred for treatment within 3 months of onset ofesotropia, only 12% of the infantile esotropia cohort and 14% of theaccommodative esotropia cohort developed persistent amblyopia.Among those who were not referred for treatment for more than3 months post-onset, 42% of the infantile esotropia cohort and 56%of the accommodative esotropia cohort developed persistentamblyopia; i.e., a 3.5e4 times elevated risk for persistent amblyopiawas associated with delayed referral (Fig. 7). Within the infantileesotropia cohort, we were also able to evaluate whether age atsurgery was a risk factor for persistent amblyopia (surgical treat-ment in the accommodative esotropia cohort was rare). Very earlysurgery, by 6 months of age, may preserve stereopsis in childrenwith infantile esotropia (Birch et al., 1998; Birch et al., 2000; Ing,1991; Ing and Okino, 2002; Wright et al., 1994). Nonetheless, wefound no significant differences in age at surgery among those whonever had amblyopia, those who recovered, and those who devel-oped persistent amblyopia (Fig. 7).

Initial refractive error was evaluated as a risk factor for persis-tent amblyopia because amblyopia may be more prevalent inchildren with moderate to high hyperopia (American Academy of

Fig. 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 initialdiagnosis 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 groupswere 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 ¼ 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 ¼ 11.1, p ¼ 0.002).

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Ophthalmology, 2011) and because spherical anisometropia of 1.00D or more had been shown previously to be associated withincreased risk for amblyopia in hyperopic children with no stra-bismus (Weakley,1999, 2001) Neither the infantile esotropia cohortnor the accommodative esotropia cohort exhibited an associationbetween initial spherical equivalent refractive error and the prev-alence of persistent amblyopia. On the other hand, initial aniso-metropia was a strong risk factor for persistent amblyopia. Amongchildrenwith less than 1.00 D initial anisometropia, only 12% of theinfantile esotropia cohort and 16% of the accommodative esotropiacohort developed persistent amblyopia. Among those with 1.00 Dor more initial anisometropia, 39% of the infantile esotropiacohort and 50% of the accommodative esotropia cohort developedpersistent amblyopia; i.e., a 3.1e3.3 times elevated risk for persis-tent amblyopia was associated when anisometropia of at least 1.00D was present at the initial visit (Fig. 7).

In a related study, we determined whether nil stereoacuity wasassociated with risk for poor response to amblyopia treatment(Bosworth and Birch, 2003). Seventy-one children were enrolledin a prospective study of amblyopia treatment when they were4e6 years old. At enrollment 66% had nil stereoacuity; followingtwo years of treatment, 55% remained amblyopic. In contrast,among children who had measurable stereoacuity, only 25%remained amblyopic. Thus the risk for persistent amblyopiawas 2.2times greater among children with nil stereoacuity.

Taken together, these data demonstrate that risk for persistentamblyopia is elevated in infantile esotropia and accommodativeesotropia if there is a long delay between onset and treatment andby anisometropia. The finding that the same two risk factors greatlyelevate the risk for abnormal stereoacuity and persistent amblyopiasupports the hypothesis that there is a link between binocularfunction and persistent amblyopia. In individuals with preservedbinocular function, the fellow eye may maintain a binocular grid offine receptive fields so that input to the weaker eye is not severelyundersampled. Treatment plans designed to preserve stereoacuitymay help to minimize the additional loss in optotype acuity asso-ciated with neural undersampling.

2.3. Fusional suppression

When information from the two eyes is combined and binoculardisparity is used to decode depth, monocular position information islost. “Fusional suppression” is the term coined byMcKee and Harrad(1993) to describe the suppression of monocular position informa-tion in the presence of a standing non-zero binocular disparity. Theywere able to measure the suppression of monocular position infor-mation in terms of diminished visual evoked potential (VEP)amplitude in response to vernier offsets when a standing non-zerodisparity was introduced. We used this paradigm to investigate thelink between the fusional suppression that occurs in normal binoc-ular vision and the suppression of the amblyopic eye in accommo-dative esotropia (Fu et al., 2006). We chose to study children withaccommodative esotropia have a wide range of stereoacuity, fromnormal to nil, which makes it easier to observe the relationshipsamong stereoacuity, fusional suppression, and amblyopia.

The stimulus paradigm was to record VEPs in response tooscillating vernier positional offsets of a stripe pattern presented toone eye (Fig. 8). What was varied between the test two conditionswas the pattern in the other eye, which could either have 0 minbinocular disparity or 5 min binocular disparity. Since it wasa standing (static) disparity, it could only influence VEP amplitudethrough its indirect effect on the vernier positional responsegenerated by the other eye; i.e., fusional suppression. In a cohort of37 children with accommodative esotropia, we found that all 8children with normal stereoacuity and 10 children with deficientstereoacuity had normal fusion suppression (see Fig. 9 for a repre-sentative set of data from a normal control child). Amplitudes ofresponses to vernier offsets were diminished in the presence ofa standing binocular disparity. The vernier responses were similarin each eye and the degree of fusional suppression was similarregardless of which eye viewed the vernier stimulus and which eyeviewed the static disparity stimulus. Childrenwith accommodativeET and nil stereoacuity but no amblyopia (n ¼ 11) showed little ifany fusional suppression; VEP amplitudes were similar whether ornot a standing binocular disparity was present (not shown). Results

Fig. 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 nostanding binocular disparity present (left), 5 static segments interspersed with 4oscillating segments that aligned and misaligned at 2 Hz. The magnitude of themisalignment offset was swept in 7 steps from 10 to 1 min over each 7 s trial while theother 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 viewedthe vernier offsets. The standing disparity condition was similar except that the othereye viewed static multi-bar target with 5 min standing disparity. As in the othercondition, the VEP was elicited by the making and breaking of co-linearity in the eyethat viewed the vernier offsets; any difference in VEP amplitude between the twoconditions is due to a suppressive effect of the static binocular disparity on themonocular vernier position response.

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from the 8 amblyopic children had a distinct pattern; fusionalsuppression was noted when the standing disparity was presentedto the fellow eye but no suppression was observed when thestanding disparity was presented to the amblyopic eye (Fig. 9).These data from children with accommodative esotropia supportan association between asymmetric fusional suppression andamblyopia. Moreover, the evidence that suppression is present and,at least in part, involves the same mechanisms responsible for

Fig. 9. VEP responses to monocular oscillating vernier offsets recorded from a child with ndisparity (Fu et al., 2006). For the child with normal vision, vernier responses are similardecreased VEP amplitude, consistent with fusional suppression. The amount of suppressiondisparate stimulus (yellow symbols). For the amblyopic child (right), the amblyopic eye hasthe standing disparity is introduced to the fellow eye, fusion suppression is observed (yellowfusional suppression is observed (yellow triangles). Fusion suppression is asymmetric in th

fusion in normal binocular vision suggests that restoration ofbinocular function may be possible in amblyopia.

2.4. Gaze instability, binocular vision, and amblyopia

Abnormal visual experience during infancy or early childhoodthat interferes with binocular fusion is invariably associated withgaze instability, most often fusion maldevelopment nystagmussyndrome (FMNS) (Tychsen et al., 2010). FMNS is a commonlyassociated with strabismus and amblyopia. It is characterized bya conjugate horizontal slow-phase nasalward drift of eye position,with temporalward corrective flicks. Because the slow drift isalways nasalward, a switch in fixation eye results in an immediatereversal of the direction of the drift. This feature makes it easilydistinguishable from infantile nystagmus (INS). Studies of non-human primates demonstrated that FMNS can result from theloss of binocular connections in the striate cortex that occurs inexperimental models of strabismus and anisometropia. In a seriesof elegant experiments, Tychsen et al. (2010) have demonstratedthat the prevalence and severity of FMNS increases as the period ofdecorrelated abnormal binocular experience is lengthened, witha duration in primates that is equivalent to 3 months in humansresulting in 100% prevalence. Tychsen et al. (2010) propose that thebinocular maldevelopment of the striate cortex is passed on todownstream extrastriate regions of cerebral cortex that driveconjugate gaze, including medial superior temporal area and thatunbalanced monocular activity may result in one hemispherebecoming more active than the other, resulting in nasalward driftbias that typifies FMNS.

We evaluated the link between binocular vision, gaze instability,and amblyopia in a group of 33 children �5 years of age withhyperopic anisometropia (Birch et al., 2012). Hyperopic anisome-tropia places the child at risk for abnormal stereoacuity andmicrostrabismus, which is noted clinically as a temporalward “flick”as each assumes fixation on cover testing. The dominant hypothesisis that abnormal sensory experience due to anisometropia leadsto foveal suppression, which in turn leads to microstrabismus(American Academy of Ophthalmology, 2011). We proposed an

ormal vision (left) and an amblyopic child (right) with 0 or 5 min standing binocularfor each eye (gray symbols). The addition of a standing binocular disparity results inis similar regardless of which eye views the vernier target and which views the static,slightly, but consistently lower, amplitude vernier responses than the fellow eye. Whencircles). However, when the standing disparity is introduced in the amblyopic eye, no

e amblyopic child.

Fig. 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 eachimage, the small blue dots mark the location of the 750 fixation points acquired during the 30 s test period. The Nidek MP-1 calculated three ellipses to describe the areas thatenclose 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 andmicrosaccades were present and nearly all of the fixation points fell inside of the 1 deg fixation circle shown in red (BCEA ¼ 0.8 deg2). In the center is a more typical anisometropicchild, who shows moderate fixation instability (BCEA ¼ 5.9 deg2). On the right, a child with substantial fixation instability is shown (BCEA ¼ 10.8 deg2).

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alternative hypothesis; namely, that disruption of bifoveal fusion byanisometropia has a direct effect on ocular motor function. Fixationstability was measured using the Nidek MP-1 microperimeter,which combines a non-mydriatic infrared fundus camera to obtainreal time retinal images and a liquid crystal display (LCD) to presenta fixation target. The fixation target was a 1� radius red circular ring,displayed in the center of the LCD screen. Children were provideda chin rest and forehead rest andwere instructed to fixate steadily atthe center of the ring. Initially, a reference fundus imagewith 1 pixel(0.1 deg) resolution was captured, and a high contrast retinallandmark in the frozen image was identified by the examiner.During the 30 s test period, software calculated shifts in horizontaland vertical eye position between the reference image and the real-time fundus image at 25 Hz. A scattergraph of the fixation pointswas displayed and fixation stability was quantified as the area of the95% bivariate contour ellipse (BCEA); i.e., an ellipse that provided thebest fit to the boundary of 95% of the 750 fixation points acquiredduring the 30 s test interval. Stereoacuity was measured using thePreschool Randot Stereoacuity Test. Examples of the fixationstability data obtained from 3 children with hyperopic anisome-tropia are shown in Fig. 10.

All children with normal stereoacuity had normal fixationstability (Fig.11). Childrenwith abnormal stereoacuity had unstablefixation, and children with nil stereoacuity had the most instability

Fig. 11. Fixation instability during 30 s of attempted steady fixation for 33 childrenwith hyperopic anisometropia (Birch et al., 2012). Age-matched normal controls hada mean BCEA ¼ 2.1 � 0.9 deg2 (yellow line), with a 95% tolerance range of 0.2e3.8 deg2

(yellow shaded area). Anisometropic children with normal stereoacuity (bifoveal;20e60 arcsecs) had normal fixation stability. Children with reduced stereoacuity of100e800 arcsecs (monofixation) had significantly more fixation instability thannormal (p ¼ 0.008) and those with nil stereoacuity were significantly more unstablethan those with normal stereoacuity and those with reduced stereoacuity (p < 0.001for both comparisons).

(Fig. 11). Although there was moderate variability among children,there was a strong correlation between stereoacuity and fixationinstability (BCEA area); rs ¼ 0.54, p ¼ 0.002. We were also able toexport the raw eye movement data to analyze waveforms andcategorize eyemovements as normal (with or without square-waveoscillations), FMNS, or INS (Fig. 12).

None of the children with normal stereoacuity had FMNSwaveforms, 67% of children with abnormal stereoacuity had FMNSwaveforms, and nearly all of the children with nil stereoacuity hadFMNSwaveforms (Fig. 13). Thus, the temporalward flick that is seenduring cover testing in children with hyperopic anisometropia islikely evidence of a direct effect of disruption of bifoveal fusion byanisometropia on ocular motor function; i.e., the decorrelation ofretinal images caused by anisometropia results in FMNS. Note thatthis FMNS is often very small in amplitude, making it difficult toappreciate clinically except with close observation, like duringcover testing. More importantly, in most children with anisome-tropia, we observed FMNS only in intermittent, small amplitudebursts, so it may not always be obvious during a brief clinicalexamination. Our data are consistent with the model of FMNSproposed by Tychsen, Wong, and colleagues in which correlatedvisual experience is necessary for the development of stereopsisand balanced gaze (Tychsen et al., 2010). Decorrelated visualexperience, due to anisometropia can lead to stereoacuity deficits

Fig. 12. Eye position records derived from the Nidek MP-1 for the 3 anisometropicchildren shown in Fig. 10 (Birch et al., 2012). The top trace shows eye position for thechild with normal fixation stability (Fig. 10, left); overall, fixation is accurate, with onlymicrosaccades and a brief saccadic oscillation. The middle trace shows the typicalanisometropic child (Fig. 10, middle); it shows the classic waveform of FMNS with slowdrifts nasalward, and rapid re-fixating temporalward saccades. The bottom traceshows the anisometropic child with extreme fixation instability (Fig. 10, right); highfrequency, large amplitude FMNS is evident.

Fig. 13. Prevalence of FMNS among 33 children with hyperopic anisometropia dividedinto 3 groups based on their stereoacuity (Birch et al., 2012).

Fig. 14. Mean fixation areas (95% BCEA) for amblyopic, non-amblyopic and normalcontrol children (Subramanian et al., 2012). Compared with children with strabismus,anisometropia, or both who were nonamblyopic, amblyopic children had significantlygreater fixation instability; mean BCEA for amblyopic eyes was significantly larger thanfor non-amblyopic right or left eyes (p � 0.02). Mean BCEA when fixating with theamblyopic 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 thantheir fellow eyes (p ¼ 0.01). Fixation stability of fellow eyes did not differ significantlyfrom right or left eyes of normal controls.

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and the gaze asymmetry of FMNS, a disruption of ocular motordevelopment. We propose that the temporalward re-foveatingFMNS “flicks” may mimic microstrabismus during cover testingbut are actually an ocular motor abnormality that directly resultsfrom binocularly decorrelated visual experience. If this hypothesisis correct, our proposal that binocular dysfunction plays a primaryrole in amblyopia leads us to also expect a relationship betweenamblyopia and fixation instability.

We investigated the relationship between fixation instabilityand amblyopic visual acuity deficits. Carpineto et al. (2007) re-ported that fixation instability was present in some children withmicrostrabismus and amblyopia. More recently, Gonzalez et al.(2012) reported significantly larger fixation areas (more insta-bility) in amblyopic eyes of 13 adults compared with fellow eyesand control eye. We quantified fixation stability in 89 amblyopicand nonamblyopic children with strabismus, anisometropia, orboth and an age-matched normal control group using the NidekMP-1 microperimeter to acquire eye position and BCEA to quantifyfixation instability (Subramanian et al., 2012). During attemptedsteady fixation with their amblyopic eyes, children had 3e5�greater fixation instability (larger BCEA areas) than when fixingwith their fellow eyes and compared with normal controls fixingmonocularly (Fig. 14).

There was a statistically significant positive correlation betweenvisual acuity and BCEA (r ¼ 0.58; p < 0.0001) for amblyopic eyes;amblyopic eyes with poorer visual acuity had greater fixationinstability and, thus, larger and wider bivariate contour ellipseareas. Categorical severity of fixation instability has been previouslyreported to be associated with depth of amblyopia (Carpineto et al.,2007). On the other hand, BCEA in 13 adults with amblyopia wasnot correlated with amblyopic eye visual acuity, although inter-ocular differences in visual acuity were correlated with BCEA(Gonzalez et al., 2012). Additionally, we found that amblyopic eyeshad highly elliptical BCEAs, with a much longer horizontal thanvertical axis, consistent with abnormal development of the ocularmotor system. Fixation instability along both the horizontal andvertical axes was about 1.5e2� larger for amblyopic eyes thannormal control eyes. This finding is consistent reports of predom-inantly horizontal square-wave oscillations and FMNS in amblyopicchildren (Felius et al., 2011; Felius et al., 2012).

2.5. Motor skills in amblyopia

Deficits in fine motor skills have been widely reported to bepresent in amblyopic individuals (Grant and Moseley, 2011). Most

of these studies aimed to evaluate the utility and value of rehabil-itation of the amblyopic eye as a “spare eye” and so relied on testingamblyopic individuals when they are forced use the amblyopic eyealone. However, if amblyopia is primarily the result of binoculardysfunction, we would also expect to see such deficits in binoculartask performance. We evaluated the effects of amblyopia on motorskills under binocular viewing conditions (O’Connor et al.,2010a,b); specifically we evaluated performance on the Purduepegboard (number of pegs placed in 30 s) and bead threading (timeto thread a set number of large and small beads in 143 individuals,47 of whom had manifest strabismus and 30 of whom hadamblyopia (21 strabismic amblyopia; 9 anisometropic amblyopia).Performance on the fine motor skills tasks was related to stereoa-cuity, with subjects with normal stereoacuity performing best onall tests (Fig. 15). Individuals with amblyopia were significantlyslower on both bead tasks than were those without amblyopia.However, when the statistical analysis was repeated with stereoa-cuity as a covariate, the difference between amblyopic and non-amblyopic individuals on the bead task was no longer statisticallysignificant. This result is in agreement with a previous report thatfinemotor skill performancewas related to the level of stereoacuitybut not to the presence of unilateral vision impairment in 3- to 4-year-old children (Grant et al., 2007). Webber et al. (2008a) havealso reported that both the amblyopia and stereoacuity deficitswere associated with reduced performance on fine motor skilltasks. Taken together, these results confirm that children withbinocular dysfunction have impaired fine motor skills and that thisimpairment is more closely related to the severity of binoculardysfunction than to the severity of amblyopia.

3. Binocular treatment of amblyopia

As noted above, current treatments for amblyopia are notsufficient to achieve normal visual acuity for 15e50% of amblyopicchildren. Even when normal visual acuity is achieved, amblyopiaoften recurs. Older children and adults with persistent amblyopiaare rarely treated because the predominant mindset is that decor-related binocular visual experience and habitual suppression of theamblyopic eye has caused permanent loss of binocular cells and

Fig. 15. Performance on fine motor tasks by amblyopic and nonamblyopic individualswith three levels of binocular function (O’Connor et al., 2010a,b). There was a signifi-cant difference in performance on the Purdue Pegboard and the large and small beadtasks (p < 0.03 in all cases). Post-hoc analyses demonstrated that those with normalstereoacuity performed significantly better than those with nil stereoacuity. Whencomparing 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 thatamblyopia 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 inspeed on the bead tasks was no longer statistically significant.

Fig. 16. Improvement in visual acuity with patching in 18 amblyopic adults whileplaying an action video game or a non-action video game for 20 h. Also shown is thevisual acuity improvement achieved with 20 h of patching while practicing a gratingacuity task (perceptual learning; PL) and with patching alone for 20 h (Li et al., 2011).

E.E. Birch / Progress in Retinal and Eye Research 33 (2013) 67e8478

changed the functional profile of cortical cells responsive to theamblyopic eye. However, the evidence discussed in Section 2suggests, although there is binocular dysfunction, the capacityfor binocular interaction is not absent. Moreover, interocularsuppression of the amblyopic eye may be preventing binocularinteraction. Taken together, these data suggest that there is a needfor a new, binocular approach to amblyopia treatment. The goal isto reduce the prevalence of residual amblyopia and preventamblyopia recurrence.

3.1. Perceptual learning

One new approach is perceptual learning. The effect of repeatedpractice on perceptual performance has become a focus of ambly-opia treatment, particularly for adults and older children who haveabandoned traditional approaches to treatment. It is clear thatnormal controls in the research laboratory who repeatedly practiceon a demanding visual task achieve significant and durableimprovement in their visual performance on that specific task (Levi,2012). More relevant, is the evidence that amblyopic individualswho practice a perceptual task improve not only on that specifictask, but also have generalized improvement when tested withother perceptual tasks (Levi, 2012).

Perceptual learning as a treatment for adult amblyopia hastypically been conducted with the fellow eye patched. The visualtask for training is designed to engage the amblyopic individual inmaking fine discriminations and to provide repeated exposure overmany hours. It has been suggested that perceptual learning is simplyan extension of the traditional effects of patching therapy, where theamblyopic individual must accomplish many visual discriminationsin everyday life. The argument that perceptual learning succeedswhere everyday experience fails in amblyopic adults is that the lessplastic brain of the adult requires “attention and action using theamblyopic eye, supervised with feedback” in order to provideeffective treatment (Levi, 2012). Even with 40e50 h of perceptuallearning, most adults achieve only 0.1e0.2 logMAR improvements

in visual acuity (1e2 lines) (Levi, 2012). The limited improvement invisual acuity, the dedicated time required for treatment, and theboredom/compliance issues associated with repetition of a percep-tual task, have limited the application of perceptual learning asa routine treatment for amblyopia. To overcome these limitations,research has turned toward the evaluation of video games asa potential treatment for amblyopia in adults. The rationale is thataction video games, in particular, engage visual attention andrequire demanding visual discriminations in a similar way to themore standard perceptual learning paradigms, but is able to sustainprolonged participation because of the story lines, varied visualtasks, and rewards provided by the games for making correctdiscriminations. A recent evaluation of an of-the-shelf action game(Medal of Honor: Pacific Assault) found that just 20 h of play withthe fellow eye patched resulted in a mean improvement of0.15 logMAR and that additional small gains in visual acuitycontinued in some amblyopic individuals through 80 h of play(Fig. 16) (Li et al., 2011). Interestingly, though, similar gains in visualacuity were experienced by amblyopic adults playing a non-actionvideo game (Sim City) or performing a simple perceptual learninggrating acuity task while patched. Patching alone was not sufficientto improve visual acuity (Fig. 16). Of course, the idea of visualstimulation as a part of amblyopia is not new. For many years, eyecare professionals have placed an emphasis on the child performing“near activities while patched”; i.e., the role of active, attentivevision in amblyopia recovery has been appreciated for many years.

3.2. Treating binocular dysfunction amblyopia

In most studies to date, perceptual learning has been appliedmonocularly with the same aim as patching therapy, to improvevisual acuity of the amblyopic eye.

Some improvements in stereoacuity have been found toaccompany the amblyopic eye visual acuity improvement, (Levi,2012) similar to the modest gains in stereoacuity that have beenreported to accompany successful patching therapy (Wallace et al.,2011b). However, a growing appreciation of the role of decorrela-tion of binocular stimulation in suppression of the amblyopic eyehas motivated a reformulation of amblyopia treatment. Decorre-lated binocular experience may not only compromise binocularfunction but also contribute to or cause the monocular deficits. Inother words, we have come to view binocular dysfunction as the

E.E. Birch / Progress in Retinal and Eye Research 33 (2013) 67e84 79

primary deficit and the monocular visual acuity deficit assecondary. In this framework, patching, with or without perceptuallearning treatment, treats the secondary monocular visual deficitsbut does not directly address the primary binocular deficit. Wewanted to find a new approach to treatment for amblyopia thatwould not only improve visual acuity of the amblyopic eye but alsoprovide repeated, correlated binocular visual experience. Unlessthe binocular dysfunction is treated, abnormal binocular visionmay result in residual amblyopia, and may trigger recurrence ofamblyopia.

Reducing contrast to the fellow eye to equate the visibilitybetween amblyopic and fellow eyes can allow binocular contrastsummation (Baker et al., 2007), and suprathreshold binocularinteractions in motion coherence and orientation discriminationtasks (Mansouri et al., 2008) to occur in at least some amblyopicindividuals. This suggests that the absence of binocular interactionsin amblyopia reported in the literature may have been due to theimbalance in the monocular signals rather than to an absence ofcapacity for binocular interaction. Hess et al. (2010) reportedimprovement in visual acuity and binocular vision followingseveral weeks of practice with a dichoptic motion coherence taskpresented via video gaming goggles. For the initial practice session,the contrast of the randomly moving dots in the fellow eye wasreduced to about 10% while the amblyopic eye coherent dots werepresented at 100% contrast. This allowed the amblyopic eye to“break-through” and observers were able to experience binocularvision. As the 10 amblyopic adults began to experience binocularvision, the contrast in the fellow eyewas gradually increased during3 or 4 sessions per week for 3e5 weeks until the two eyes workedtogether with more evenly matched contrasts. In addition toimprovements in binocular combination, visual acuity improved0.1e0.7 logMAR (Fig. 17) and stereoacuity improved in 6 of the 10adults. Knox et al. (2012) used the same device to administer oneweek of dichoptic treatment but used a more interesting videogame task (Tetris). As with the motion coherence task, the contrastof the fellow eye image was reduced to allow binocular vision tooccur. Five 1-h practice sessions during a one week were provided.The 14 amblyopic children (5e11 years old) has a medianimprovement of 0.09 logMAR in visual acuity (about 1 line) and 9 ofthe 14 also had improvements in stereoacuity (Fig. 17). Mostrecently Hess et al. (2012) and To et al. (2011) moved the dichoptic

Fig. 17. Visual acuity improvement following 5e20 h of dichoptic training to ambly-opic individuals using video game goggles to make motion coherence judgments (Hesset al., 2010) or play Tetris (Knox et al., 2012) or using a lenticular overlay on an iPod toplay Tetris (Hess et al., 2012; To et al., 2011). Despite the pilot studies having relativelyshort durations of dichoptic training and small cohorts, all 3 studies showed significantimprovement in visual acuity and stereoacuity.

Tetris game to an iPod platform to allow for more comfortable playand play at home. They evaluated the effects of dichoptic Tetrispractice (with low contrast to the fellow eye) in 10 amblyopic adultsand found found a median visual acuity improvement of 0.2 log-MAR after 10e19 one hour sessions (Fig. 17); 7 of the 10 adults alsohad improvements in stereoacuity. Taken together, these datasupport the hypothesis that a binocular approach to treatment ofamblyopia can be successful. Repeated experience with dichopticperceptual tasks led to modest improvements in monocular visualacuity and, in some cases, improved stereopsis.

To date, this approach largely has been limited to the laboratory,with the use of video game goggles and the need for administrationof practice sessions by trained staff, and limited to adults andschool-age children. We wanted to extend binocular treatment tothe preschool age range, to be used as an adjunct treatment alongwith patching (at separate times of day) to reduce residualamblyopia and to reduce risk for recurrence of amblyopia. Theextension to an iPod platform and lenticular display was a steptoward incorporating dichoptic training into clinical settings foradults and school-age children. However, it is difficult to extend thelenticular iPod to preschool children because the iPod requires finemotor skills and the lenticular display requires precise and steadyhead position to provide dichoptic stimulation. We worked withHess and To to adapt the dichoptic Tetris game for use on the largeriPad format, which is more compatible with the immature finemotor skills of young children, and anaglyphic dichoptic separation,which is not dependent on head position. We are currentlystudying the effects of anaglyphic dichoptic training on amblyopiaand risk for recurrence in 3- to 5-, 6- to 8-, and 9- to 11-year oldchildren with strabismic, anisometropic, or combined mechanismamblyopia (Birch et al., 2013). Many of the childrenwe are studyingwere enrolled in our prospective longitudinal study of visualdevelopment at time of initial diagnosis of strabismus or aniso-metropia. For these children we have detailed histories of visualacuity, treatment regimens, and response to treatment. An exampleof a child’s visual acuity history and visual acuity improvementwith the anaglyphic dichoptic training are shown in Fig. 18. While

Fig. 18. Visual acuity data from a child with anisometropic amblyopia before and afterdichoptic training (Birch et al., 2013). On the initial visit at 4.4 years old, best correctedvisual acuity for the amblyopic eye was 0.9 logMAR. Treatment with glasses, patching,atropine, and Bangerter filter resulted in improvement to 0.5e0.6 logMAR. Slightregression to 0.6e0.7 logMAR occurred, and visual acuity remained in this range forthe next 3 years with continued spectacle wear. At 9.9 years, the child enrolled in thedichoptic treatment study and showed 0.2 logMAR improvement to visual acuity of0.4 logMAR over the next 8 weeks. Three months after discontinuing dichoptictreatment, visual acuity for the amblyopic eye remained at 0.4 logMAR. Visual acuity ofthe fellow eye remained at 0.1 to 0.0 logMAR from age 7.4 yearse10.4 years.

Table 2Reported success rate for vision screening of preschool children by pediatricians andfamily care practitioners.

Study 2-Year-olds 3-Year-olds 4-Year-olds 5-Year-olds

Pediatric Research inOffice Settings(Wasserman et al.,1992)

0% 38% 71% 81%

Kemper and Clark (2006) 0% 38% 56% 73%Wall et al. (2002) 0% 37% 79% 91%Marsh-Tootle et al. (2008) 0% 12% 25% 48%Kemper et al. (2011) 0% 43% 64% 73%Range 0% 12e43% 25e79% 48e91%Mean 0% 34% 59% 73%

E.E. Birch / Progress in Retinal and Eye Research 33 (2013) 67e8480

still preliminary, our results from 23 children are consistent withthe data from the published laboratory studies of small cohorts ofamblyopic adults and school-age children. Many of the childrenhave improved stereoacuity after only 15e20 h of dichopticpractice, including some who achieve coarse stereopsis for thefirst time. In addition, there is an improvement in visual acuity of0.1e0.4 logMAR. That rehabilitation of binocular interaction isaccompanied by improved monocular visual acuity supports thehypothesis that binocular dysfunction plays a pivotal role inamblyopia, an appreciation of which is not currently reflected inclinical practice.

4. Future directions

As summarized above, there is accumulating evidence thatamblyopia and binocular function are linked and several note-worthy clues that binocular dysfunction is primary and monocularvisual acuity loss is secondary. This new understanding of ambly-opia provides a foundation for a broadened scope of research andfor crafting more effective treatments. The last 15 years has seen anexplosion of randomized clinical trials to evaluate treatments forchildren with amblyopia, and a shift from treatment based onconsensus to evidence-based treatment. Nonetheless, there remainmany unanswered questions about amblyopia screening, diagnosis,and treatment.

4.1. Screening for amblyopia

Screening for amblyopia is a part of the regular well-child visitrecommended by the American Academy of Pediatrics. Screeningby a pediatrician or family care practitioner can identify amblyopiaat a time when treatment is most effective. Screening improvesvision outcomes. In a population-based, randomized longitudinalstudy, repeated early screening resulted in a 60% decreased prev-alence of amblyopia and improved visual acuity outcome at age7 years compared with surveillance only until school entry(Williams and Harrad, 2006; Williams et al., 2001; Williams et al.,2008). Amblyopia can be treated more effectively when treatedearly; the same study found a 70% lower prevalence of residualamblyopia after treatment when therapy was initiated before age3 years (Williams et al., 2001;Williams et al., 2002, 2003) However,pediatricians and family care practitioners experience considerabledifficulties in screening for amblyopia (Tingley, 2007). Mostprimary care providers in the United States still use visual acuitycharts as their primary approach to vision screening for amblyopia(Wall et al., 2002). Unfortunately, reading letters or numbers ona visual acuity chart requires a verbal, cooperative child and is notroutinely successful in children under 5 years old, too late for themost effective therapy. When the testing is conducted earlier,nonstandard symbols or chart formats are used and often they arenot presented in the linear or crowded formats needed to detectmild amblyopia. Table 2 summarizes recent studies that documenthow these difficulties impact the vision screening provided byprimary care physicians to preschool children.

Automated devices, like the SureSight� and PlusOptix� havebeen developed to try to improve upon visual acuity testing, byproviding a simple approach to screening for refractive error riskfactors, rather than screening for amblyopia directly. These devicesare attractive because they are designed for use by pediatric nurses,pediatric medical assistants, and even lay people. However, theseautomated devices miss many children with amblyopia and manynormal children are sent to the ophthalmologist for an unnecessaryeye examination, further increasing the cost of health care. Forexample, in the combined population-based cohorts of 2- to 6-yearold children from the NIH-sponsored Multi-Ethnic Pediatric Eye

Study (MEPEDS) and the Baltimore Pediatric Eye Study (BPEDS)(N ¼ 5710), only 14% of children with �1.00 D anisometropia hadamblyopia and only 60% of children with �2.00 D anisometropiahad amblyopia; (Cotter et al., 2011) i.e., screening for anisometropiaand will have low specificity for amblyopia. In addition, amblyopiarisk factor analysis failed to identify hyperopia a significant riskfactor for unilateral amblyopia (Tarczy-Hornoch et al., 2011).Because refraction screening devices cannot directly detect stra-bismus or amblyopia, many “at risk” children are referred forcomprehensive ophthalmic examinations at considerable cost intime and money to the family. Once these “at risk” children arereferred, they often are “monitored” with regularly scheduledophthalmic examinations for years, even though the data suggestthat only 9%e18% of the children “at risk” will ever developamblyopia.

Recently, Hunter and colleagues developed an alternativeapproach to screening for amblyopia, a binocular birefringencescanner called the “Pediatric Vision Scanner” or “PVS” (Hunteret al., 2004; Loudon et al., 2011; Nassif et al., 2004; Nassif et al.,2006). Simultaneous retinal birefringence scans of both eyesdetect whether fixation of a target is foveal (central), steady, andmaintained by identifying the unique polarization signal created bythe radially arranged Henle fibers (photoreceptor axons) thatemanate from the fovea(Hunter et al., 2004; Loudon et al., 2011;Nassif et al., 2004). In a pilot study of the PVS, Loudon et al. (2011)reported that all normal control children had at least 4 of 5 scansconsistent with bifoveal fixation, and that 62 of 64 amblyopicchildren failed to exhibit birefringence (97% sensitivity to ambly-opia). The PVS was able to detect amblyopia even in the 22 childrenwith anisometropic amblyopia and no strabismus (20/22;sensitivity ¼ 91%) and birefringence was normal in children withanisometropia without amblyopia (11/12; specificity ¼ 92%). Wehave independently confirmed these PVS results in anisometropicchildren with no strabismus (Yanni et al., 2012). Moreover, thesedata are consistent with the association between fixation instabilityand amblyopia in both anisometropic and strabismic individuals(Section 2.4) (Birch et al., 2012; Subramanian et al., 2012). Takentogether, the pilot data suggest that binocular birefringencescreening could provide more accurate identification of childrenwho need ophthalmological intervention.

4.2. Diagnosis of amblyopia

Diagnosis of amblyopia relies on the measurement of visualacuity. Reduced best corrected visual acuity in presence of anamblyogenic factor (usually strabismus or anisometropia) with noother ocular or visual cortical abnormality is currently the criticalcomponent of amblyopia diagnosis. However, most children<3 years old and some older children cannot complete a visualacuity test. Instead, the clinical diagnosis of amblyopia in children<3 years old must rely on fixation preference.

E.E. Birch / Progress in Retinal and Eye Research 33 (2013) 67e84 81

Recently, fixation preference has been disparaged as a methodfor assessing amblyopia. The basis for questioning the value offixation preference is found in two large (n ¼ 9970) population-based screening studies, MEPEDS and BPEDS (Cotter et al., 2009;Friedman et al., 2008). Both included primarily normal children;only 44 had �2 lines interocular difference in visual acuity. Withsuch a small sample of primarily mild amblyopia, it is not surprisingthat they reported low sensitivity of fixation preference. Onlya handful had strabismus, so most fixation preference testing reliedon themore difficult induced tropia (prism) test. Another limitationwas that fixation preference was tested without optical correctionwhile visual acuity was tested with optical correction. Given theselimitations, it is not surprising that they reported low specificity.Data collected from clinical cohorts support much higher sensi-tivity and specificity for detection amblyopia by fixation preferencein cohorts of children with strabismus (sensitivity 73%e93%;specificity 78%e97%) (Birch and Holmes, 2010; Kothari et al.,2009; Procianoy and Procianoy, 2010; Sener et al., 2002; Wrightet al., 1986) As noted in Section 1.2, 95% of amblyopic children<3 years old have strabismus, (Birch and Holmes, 2010) so weanticipate high sensitivity and specificity of fixation preference inthis age range where visual acuity cannot be tested with standardoptotypes. Whether small changes in fixation preference can beused to track treatment response remains an open question. Giventhe scarcity of evidence for treatment effects and risks of amblyopiatreatment (e.g., reverse amblyopia) in the <3 year age range, it isimperative to answer this question before we can begin to build anevidence base for treatment of amblyopia in children <3 years old.

4.3. Optimizing treatment for amblyopia

The cornerstone of amblyopia treatment is patching the “fellow”

eye to force use of the amblyopic eye. Recent randomized clinicaltrials have provided and extensive knowledge base for treatment ofamblyopia in children over 3 years old (Holmes et al., 2006; Repkaand Holmes, 2012; Stewart et al., 2011). Nonetheless, the highprevalence of persistent residual amblyopia and recurrent ambly-opia underscore the need for more effective treatments. Ourcurrent focus is to provide regular binocular experience to treatbinocular dysfunction by adjusting the contrast of dichoptic imagesto balance sensitivity differences between the amblyopic andfellow eyes and allow binocular interaction (Section 3.2). However,it is improbable that sensitivity differences are the only limitingfactor. Other approaches to treating binocular dysfunction, tailoredto the specific constellation of deficits present in the amblyopicindividual may be more effective. In addition, it may proveimpossible to fully restore binocular interaction. Such an outcomewould shift the emphasis toward amblyopia prevention. We know,for example, that early surgery for infantile esotropia can preservebinocular function and reduce the risk for persistent amblyopia(Birch and Stager, 2006; Birch et al., 2004). Clinical pearls, such asthe reduced risk for recurrent amblyopia when patching therapy istapered rather simply halted when the child attains equal visualacuities, may also point to new insights for the design of effectivebinocular treatments. Clearly, there is a need for a broader under-standing of the effects of decorrelated binocular visual experienceon the developing sensory and motor systems, the role ofsuppression in various forms of amblyopia, and the contribution ofbinocular dysfunction to residual and recurrent esotropia.

5. Summary

Amblyopia is widely viewed as a monocular disorder andtreatments for amblyopia, many of which have been used for

centuries, have traditionally focused on forcing use of the ambly-opic eye to recover monocular visual acuity.

Although this approach has had substantial success, and issupported by recent evidence from randomized clinical trials ofpatching and atropine treatment, many amblyopic individuals areleft with residual visual acuity deficits, ocular motor abnormalities,deficient fine motor skills, and high risk for recurrent amblyopia.Converging evidence points to the pivotal role of decorrelatedbinocular experience in the genesis of amblyopia and the associ-ated residual deficits. These findings suggest that a new treatmentapproach designed to treat the binocular dysfunction as theprimary deficit in amblyopia may be needed.

Conflicts of interest

None.

Acknowledgments

This work was supported by grants from the National EyeInstitute (EY05236 and EY022313), Thrasher Research Fund, PearleVision Foundation, One Sight Foundation, Knights Templar, andFight for Sight. The research depended on many importantcontributions by past and present post-doctoral fellows, the Dallas-area pediatric ophthalmologists who referred patients to theresearch projects and collaborated in data collection and analysis,research assistants, and interns. This research relied on the manycontributions of the families of amblyopic children who haveparticipated in these studies.

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