Marshall Parks Lecture Binocular Sensory Outcomes in Accommodative ET

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1 Marshall Parks Lecture Binocular Sensory Outcomes in Accommodative ET Eileen E. Birch, PhD a,b Purpose: To review what is known about the normal maturational sequence for fusion and stereopsis and the binocular sensory deficits associated with accommodative esotropia (ET) and to explore the clues that accommodative ET provides about critical periods for binocular sensory function. Methods: Studies of binocular sensory function during infancy and early childhood are presented. Results: Most of the maturation of binocular sensory function occurs during the first year of life, yet a later abnormal visual experience such as the onset of accommodative ET can profoundly and permanently disrupt fusion and stereopsis. Conclusions: Some binocular sensory deficits may exist before the onset of accommodative ET, but others may result directly from abnormal binocular experience. The functional organization of the maturing visual system appears to be maximally sensitive to disruption by abnormal visual experience during the first months of life, but susceptibility continues until at least 4 years of age. (J AAPOS 2003;7:369-73) I n the past two decades, there has been an explosion of new information about the maturation of binocular sensory function during infancy and early childhood. One of the most intriguing outcomes from this research effort is that most of the maturation of binocular sensory function occurs during the first year of life, yet a later abnormal visual experience such as the onset of accommodative esotropia (ET) at 2 years of age can profoundly and permanently disrupt stereopsis. This article (1) summarizes data from my laboratory on the normal maturational sequence for fusion and stereopsis and on binocular sensory deficits associated with accommodative ETand (2) explores the clues accommodative ETprovides to help define critical periods for binocular sensory function. GROWTH CURVES FOR BINOCULAR SENSORY FUNCTION From the Retina Foundation of the Southwest a and the Department of Ophthalmology, UT Southwestern Medical Center, b Dallas, TX. This study was supported by grant awards from the National Eye Institute (Grant No.EY 05236), Bethesda, MD; the Delta Gamma Foundation of Dallas, Dallas, TX; and Fight for Sight post-doctoral fellowships, New York, New York. Presented as the Marshall M.Parks Lecture ( Sensory Outcomes in Acquired Strabismus ) at the 2002 Annual Meeting of the American Academy of Ophthalmology, Orlando, FL, Oct 20-23, Submitted February 10, Revision accepted August 5, Reprint requests: Eileen E.Birch, PhD, Retina Foundation of the Southwest, 9900 N Central Expressway, Suite 400, Dallas, TX Copyright 2003 by the American Association for Pediatric Ophthalmology and Strabismus /2003/$ doi: /j.jaapos The maturation of two aspects of binocular sensory function, fusion and stereopsis, have been studied. One approach to assessing fusion has been the four prism diopter (4PD) base-out test. 1 In this test, the infant is encouraged to fixate on a small toy, and then a 4PD base-out prism is introduced in front of one eye. If the infant appreciates the small shift in the image position away from the center of the fovea in one eye and makes a sequence of eye movements to re-establish bifoveal fixation, this is considered evidence of sensory fusion. The growth curve for this paradigm is presented in Figure 1. Few normal infants demonstrate fusion before 8 weeks of age, whereas most infants age 16 weeks or older readily produce the fusional vergence response. Sensory fusion also has been evaluated directly using both forced-choice preferential-looking 2 and visual evoked potential (VEP) test protocols. 3-6 Growth curves for sensory fusion from all three protocols for assessing sensory fusion are shown in Figure 1. In each protocol, few infants 4 weeks of age demonstrate fusion; however, by 12 to 16 weeks virtually all infants demonstrate sensory fusion. Growth curves for stereopsis have been determined using a wide variety of stimuli, including static line stereograms and both static and dynamic Randot (Stereo Optical, Chicago, IL) stereograms. Both forced-choice preferential-looking protocols, in which the infant s fixation preference for disparate over zero disparity patterns was assessed, and VEP protocols, in which cortical responses to changes in disparity are recorded, have been employed. Despite the wide variety of stimuli and response measures used, there is general agreement across studies that the onset of stereopsis occurs at approximately 15 weeks of age (Figure 2). 4,7-11 After the abrupt onset of stereopsis, the rate of stereoacuity maturation is rapid, with the infant achieving stereoacuity of 30 to 100 arc sec by 40 weeks (Figure 2). 4,7-11 Further slow improvement in stereoacuity continues through 18 to 24 months of age. 8 Journal of AAPOS December

2 370 Birch Journal of AAPOS Volume 7 Number 6 December 2003 FIG 1. Growth curves for fusion. Each plot shows the cumulative percentage of infants who showed positive evidence for fusion in each protocol. FIG 2. Growth curves for stereopsis. Upper panel, Each plot shows the cumulative percentage of infants who showed positive evidence for stereopsis in each protocol. Lower panel, median stereoacuity in each protocol as a function of age. ACCOMMODATIVE ESOTROPIA Accommodative ETis a form of strabismus characterized by convergent misalignment of the visual axes that is associated with hypermetropia and/or abnormal accommodative convergence-to-accommodation ratio. Typically, accommodative ETinitially presents as an intermittent esodeviation at age 1.5 to 4 years. 12 The prevalence of accommodative EThas been estimated to be 1% to 2% in the United States. 13,14 Treatment with optical correction (hypermetropic correction and/or bifocal correction) usually is successful in re-establishing alignment, but surgical correction is necessary in approximately 30% of cases. 15,16 FIG 3. Prevalence of accommodative esotropia among relatives of affected children. PREEXISTING BINOCULAR SENSORY ABNORMALITY IN ACCOMMODATIVE ESOTROPIA Despite the relative maturity of fusion and stereopsis by 18 to 24 months of age, approximately 10% of children with hypermetropia 4.00 PD develop accommodative ET at 18 to 48 months. 17 The late onset of esodeviation, along with the finding that not all children with hypermetropia 4.00 PD are affected, suggests that there may be a pre-existing abnormality in binocular sensory function in some children. A study of inheritance patterns in accommodative ET was conducted because many parents report a positive family history. 18 Eighty-six families were interviewed. Siblings were examined, and adult relatives were carefully questioned about type of deviation, age of onset, and refractive error during early childhood. Adults medical records were consulted whenever available. Current eye examinations were not obtained from adults because many of the adults with a positive history for accommodative ET reported that they outgrew the condition and no longer wore hypermetropic correction. We developed a standardized questionnaire to verify accommodative ETby asking specific questions about the age of onset, the type of spectacle correction, and other treatment to verify to the best of our ability that the adult did have a positive history of accommodative ETrather than another form of strabismus. Overall, 25% of first-degree relatives (eg, siblings and parents) were affected, and 12% of second-degree relatives (eg, grandparents, aunts, uncles) were affected. Only 2% to 3% of third- and fourth-degree relatives (eg, aunts, uncles, grandparents) were affected, similar to the prevalence in the general population. This high prevalence of accommodative ETamong first- and second-degree relatives is consistent with a genetic basis and, possibly, a pre-existing sensory abnormality (Figure 3). As a complementary approach to evaluating the hypothesis that a pre-existing binocular sensory abnormality may be associated with accommodative ET, binocular sensory function was evaluated in the earliest stage of the

3 Journal of AAPOS Volume 7 Number 6 December 2003 Birch 371 FIG 4. Longitudinal stereoacuity data for six children with accommodative ET. C or I indicates whether the child initially presented with a constant or intermittent esodeviation, respectively. The arrow indicates the age at which each child achieved constant orthoposition as a result of treatment. disease, ie, in newly diagnosed patients who still had only intermittent esodeviations. 19 Despite the intermittency of their esodeviations, 40% of the children exhibited abnormal stereopsis, consistent with a possible congenital deficit. In contrast, three separate measures of fusion (4PD base-out test, Worth Four-Dot test at 33 cm, and motion VEP) were normal at this early stage of the disease. It is important to note that although 40% of patients with newly diagnosed esodeviations already had profound deficits in stereopsis, the other 60% had normal stereoacuity. Longitudinal data from six patients with accommodative ETwho were representative of the range of binocular sensory function encountered at follow-up are shown in Figure 4. In the top row, two patients who had constant esodeviation on the initial visit are shown. As expected, in the presence of ET, neither patient showed evidence of stereopsis. Although both of these patients achieved orthoposition with spectacle correction within 2 months of their initial visit, neither showed improvement in stereoacuity. The experience of these two patients is consistent with the theory that a congenital deficit in binocular sensory function may predispose some children to accommodative ET, although it is also possible that the initial brief period of constant esodeviation was sufficient to profoundly disrupt stereopsis. The other patients shown in Figure 2 initially did not have profound deficits in stereopsis, consistent with an initially normal binocular sensory system that is susceptible to abnormal visual experience but also responsive to treatment. In the second row are two patients who initially presented with intermittent ETand subnormal stereoacuity (3000 arc sec). After being treated with spectacles, both patients showed marked improvement in stereoacuity to near-normal (left) or normal (right) stereoacuity. Finally, two patients who initially presented with intermittent esodeviations and normal stereoacuity are presented in the third row. Both of these patients initially achieved orthophoria with spectacle correction but had such poor compliance with spectacle wear that a constant esodeviation developed. Constant orthoposition was achieved in both patients with full-time spectacle wear only after a long period ( 3 months) of constant esodeviation. Both developed marked deficits in stereoacuity that did not improve after surgical alignment. Just these few cases clearly demonstrate the diversity of binocular sensory function in accommodative ET. Because it is not yet possible to determine which patient with subnormal stereopsis may show full recovery with treatment, prompt re-establishment of orthoposition is a priority for all patients with accommodative ET.

4 372 Birch Journal of AAPOS Volume 7 Number 6 December 2003 TABLE 1. Relative risk for accommodative ET after successful surgery for infantile ET Relative Risk for Risk Factor Accommodative ET (95% CI) Onset of infantile ET 4 mo 1.2 ( ) Initial deviation 50 PD 1.0 ( ) Hyperopia 3.50 PD 1.2 ( ) Aligned at 6 mo 1.4 ( ) Aligned at 12 mo 1.4 ( ) Duration of misalignment 3 m 2.1 ( ) Increased hyperopia after surgery 2.3 ( ) Postoperative stability of alignment 1.1 ( ) Amblyopia treatment 1.4 ( ) Fail Worth 4-dot at near 1.2 ( ) Nil stereopsis 2.1 ( ) CI: confidence interval; ET: esotropia; PD: prism diopters. RISK FACTORS FOR ACCOMMODATIVE ESOTROPIA IN LOW HYPERMETROPIA TABLE 2. Relative risk for accommodative ET among children with low to moderate hypermetropia Spherical Equivalent Increased Relative Risk for Accommodative ET Associated with Anisometropia (95% CI) 2.00 PD 7.8 ( ) 3.00 PD 2.1 ( ) 4.00 PD 1.3 ( ) CI: confidence interval; ET: esotropia; PD: prism diopters. Although many children who develop accommodative ET have hypermetropia 4.00 PD and/or abnormal accommodative convergence-to-accommodation ratio, some children with hypermetropia 4.00 PD also develop accommodative ET. The identification of risk factors for the development of accommodative ETin this population could provide insight about the etiology of strabismus. Within the population of patients with low hypermetropia at risk for accommodative ET, two relatively homogeneous subgroups were identified: children with infantile ET 20 and children with anisometropia. 21 Most children with infantile EThave low hypermetropic errors ( 3.00 PD). Yet, after undergoing surgical alignment to correct infantile ET, 60% develop accommodative ET at approximately 3 years of age. 20 Risk factor analysis of potential clinical, treatment, and sensory factors is summarized in Table 1 (adapted from Birch et al 20 ). Increasing hypermetropia after the initial surgery for infantile ET, duration of infantile ET 3 months after onset, and absence of stereopsis were identified as factors that each doubled the risk for accommodative ETin this cohort. The last two factors are likely closely related because duration of infantile ET 3 months has been shown to be related to poor binocular sensory outcomes. 22 Thus, the high prevalence of accommodative ETamong children treated for infantile ETmay be the result of the disruption of binocular sensory function, which allows accommodative ETto occur at low levels of hypermetropic refractive error. Disruption of binocularity associated with anisometropia also may allow accommodative ETto occur at lower levels of refractive error. 21 Risk factor analysis of anisometropia as a function of amount of hypermetropia is summarized in Table 2 (adapted from Weakley and Birch 21 ). Anisometropia was found to increase the risk for accommodative ETby seven times in children with 2.00 PD refractive error and by two times in children with 3.00 PD refractive error. For children with hypermetropia 4.00 PD, anisometropia did not pose an additional risk for accommodative ET. ACCOMMODATIVE ESOTROPIA AND CRITICAL PERIODS Many children with accommodative EThave abnormal stereoacuity even after undergoing re-establishment of stable alignment by optical correction and/or surgery. For example, in a prospective cohort of 79 children with accommodative ETfollowed up for 4 to 11 years, we found that only 18% had normal Randot stereoacuity results at their most recent visit. The remaining children had subnormal (28%) or nil (39%) stereoacuity or could not be assessed because they never attained orthotropia (10%) or had deep amblyopia that precluded stereoacuity testing (5%). 23 The pervasiveness of abnormal binocular sensory function in a cohort with onset of esodeviation after most of the maturation of fusion and stereoacuity is complete must give important clues about critical periods in binocular sensory development. It is clear that the critical period for maturation is not the same as the critical period for susceptibility. Although fusion and stereoacuity are almost fully developed by 2 years of age, accommodative ETwith onset after age 2 can result in profound impairment of binocular sensory function. 23 A more detailed look at the critical period for susceptibility to abnormal visual experience was accomplished by constructing a mathematical model for a developmental weighting function to examine the relationship between age at onset and duration of abnormal visual experience and the long-term random dot stereoacuity outcome. Using onset, duration, and stereoacuity data from a cohort of 90 children with infantile ETand 60 children with accommodative ET, various shapes for the developmental weighting function were evaluated. Specifically, the best-fit location of peak sensitivity, the rate at which sensitivity exponentially increases to the peak, and the rate at which sensitivity exponentially decreases after the peak were determined by the maximum correlation between amount of normal binocular experience and long-term stereoacuity outcome. The best fit to the data is shown in Figure 5. Stereopsis is most susceptible to abnormal experience at 0.33 years (3.8 months) of age, ie, a relatively brief period of EToccurring at 3 to 4 months of age most

5 Journal of AAPOS Volume 7 Number 6 December 2003 Birch 373 FIG 5. Best fit for the mathematical model of a developmental weighting function to describe the critical period for susceptibility of stereopsis to abnormal visual experience based on stereoacuity outcome data from 90 children with infantile esotropia and 60 children with accommodative esotropia. profoundly disrupts stereopsis. Susceptibility decreases slowly beyond the peak but never decreases to zero. Nonetheless, the end of the critical period can be arbitrarily set at the age point below which 95% of the area-under-thecurve falls, ie, 4.8 years of age. Note, however, that in the model susceptibility does not decrease to zero at any age, and there is some evidence from studies of laser in situ keratomileusis monovision suggesting that prolonged anisometropia can induce stereoacuity deficits even in adults. 24 Very little is known about the critical period for recovery and whether it extends beyond the critical period for susceptibility. Duration of abnormal visual experience may be an important factor in limiting the potential for recovery. There is some evidence that constant misalignment of the visual axes 3 months duration may result in permanent deficits in binocular sensory function regardless of the age at onset of ETor the age at which treatment is effective in restoring alignment. 16,22 CONCLUSION Maturation of binocular sensory function is nearly complete by 18 months of age, yet accommodative ET which has an onset beyond this critical period for maturation places the child at risk for permanent binocular sensory deficits. Some of these deficits may exist before the onset of accommodative ET, but others result directly from the abnormal binocular experience after the onset of the disease. The functional organization of the maturing visual system appears to be maximally sensitive to disruption by abnormal visual experience during the first months of life, but susceptibility continues until at least 4 years of age. Colleagues and postdoctoral fellows who have made significant contributions to the studies summarized in this manuscript include Priscilla Berry, MD, Rain Bosworth, PhD, Sherry Fawcett, PhD, Brett Jeffrey, PhD, Joel Leffler, MD, Anna O Connor, PhD, Marshall Parks, MD, Maria Pesheva, MD, Solange Salomão, PhD, David Stager Sr, MD, David Weakley, MD, and Weldon Wright, MD. References 1. Birch E, Fawcett S, Stager D. Co-development of VEP motion response and binocular vision in normal infants and infantile esotropes. Invest Ophthalmol Vis Sci 2000;41: Shimojo S, Bauer J, O Connell K, Held R. Pre-stereoptic binocular vision in infants. Vision Res 1986;26: Fawcett S, Birch E. Motion VEPs, stereopsis, and bifoveal fusion in children with strabismus. Invest Ophthalmol Vis Sci 2000;41: Birch E, Petrig B. FPL and VEP measures of fusion, stereopsis and stereoacuity in normal infants. Vision Res 1996;36: Norcia A, Hamer R, Jampolsky A, Orel-Bixler D. Plasticity of human motion processing mechanisms following surgery for infantile esotropia. Vision Res 1995;35: Petrig B, Julesz B, Kropfl W, Baumgartner G, Anliker M. Development of stereopsis and cortical binocularity in human infants: electro-physiological evidence. Science 1981;213: Birch E, Fawcett S, Morale S, Jeffrey B, O Connor A. Measurement of stereoacuity outcomes during infancy: infant random dot stereocards. Invest Ophthalmol Vis Sci 2002;43:A Birch EE, Salomao S. Infant random dot stereoacuity cards. J Pediatr Ophthalmol Strabismus 1998;35: Birch EE, Gwiazda J, Held R. Stereoacuity development for crossed and uncrossed disparities in human infants. Vision Res 1982;22: Birch EE, Gwiazda J, Held R. The development of vergence does not account for the onset of stereopsis. Perception 1983;12: Held R, Birch E, Gwiazda J. Stereoacuity of human infants. Proc Natl Acad Sci U S A 1980;77: American Academy of Ophthalmology. Pediatric ophthalmology and strabismus. San Francisco (CA): American Academy of Ophthalmology; Chew E, Remaly N, Tamboli A, Zhao J, Podgor M, Klebanoff M. Risk factors for esotropia and exotropia. Arch Ophthalmol 1994;112: Friedman Z, Neumann E, Hyams SW, Peleg B. Ophthalmic screening of 38,000 children, age 1 to 2 years, in child welfare clinics. J Pediatr Ophthalmol Strabismus 1980;17: Wilson ME, Bluestein EC, Parks MM. Binocularity in accommodative esotropia. J Pediatric Ophthalmol Strabismus 1993;30: Fawcett S, Birch E, Leffler J. Factors influencing stereoacuity outcomes in accommodative esotropia. J AAPOS 2000;4: Atkinson J. Infant vision screening: prediction and prevention of strabismus and amblyopia from refractive screening in the Cambridge Photorefraction Program. In: Simons K, editor. Early visual development, normal and abnormal. New York (NY): Oxford University Press; Birch E, Fawcett S, Leffler J, Shields S, Wheaton D. Pedigree analysis of accommodative esotropia. Paper presented at the 26th annual meeting of the American Association for Pediatric Ophthalmology and Strabismus, April 12-6, 2000, San Diego, CA. 19. Birch E, Fawcett S, Weakley D. Risk factors for accommodative esotropia among hyperopic children. Invest Ophthalmol Vis Sci 2000:A Birch E, Fawcett S, Stager D. Risk factors for the development of accommodative esotropia following treatment for infantile esotropia. J AAPOS 2002;6: Weakley DR Jr, Birch EE. The role of anisometropia in the development of accommodative esotropia. Trans Am Ophthalmol Soc 2000;98: Birch EE, Fawcett S, Stager DR. Why does early surgical alignment improve stereoacuity outcomes in infantile esotropia? J AAPOS 2000;4: Birch E, Stager Sr. D, Berry P, Leffler J. Stereopsis and long-term stability of alignment in esotropia. J AAPOS; In press. 24. Fawcett S, Alfieri C, Castleberry K, Herman W, Parks M, Birch E. Stereoacuity and bifoveal fusion in adults with longstanding surgical monovision. J AAPOS 2001;5:342-7.