Eileen E. Birch - US grants

DESCRIPTION: Congenital and infantile onset binocular imbalance affect the visual maturation of 3-4% of U.S. infants. These conditions have the potential to cause both amblyopia and abnormalities in binocular vision. Even after treatment which is successful in restoring clear media, good alignment, and normal acuity, less than 1% of patients achieve normal stereoacuity. During the previous grant period, early treatment for infantile esotropia and congenital unilateral cataract were shown to significantly improve stereoacuity and alignment. Proposed studies will build on these findings by evaluating whether further improvements in stereoacuity can be achieved when surgical alignment is accomplished at the onset of the critical period for stereopsis, whether severity of impairment of stereopsis is influenced more strongly by onset of misalignment or by duration of misalignment, weather better stereoacuity outcomes are associated with better long term alignment, and whether progressive occlusion therapy for deprivation amblyopia improves stereoacuity outcomes. The PI recent work with nasal-temporal asymmetries in the VEP motion response suggest a closer link to suppression than to stereopsis. Proposed studies will evaluate this hypothesis in infants and children with infantile or late onset esotropia or incomitant strabismus. In order to determine whether these sensory anomalies co-develop, VEP motion asymmetry, suppression, and stereopsis will also be evaluated in a group of infants at high risk for strabismus. The PI will also explore whether vertical motion asymmetries co-develop with or are predictive of dissociated vertical deviations. Using a newly developed hyperacuity protocol, she will evaluate the development of positional acuity deficits in amblyopic infants, examine their relationship with resolution deficits, and determine whether positional acuity provides a useful approach to monitor/predict the success of occlusion therapy. During the past grant period, she developed three tests of binocular sensory and motor function, the Infant Random Dot Stereocards, the Preschool Randot Stereoacuity test, and the video Hirschberg system. In the upcoming grant period, she will evaluate the accuracy, reliability, and validity of these tests. The video Hirschberg system will also be used to study the co-development of eye alignment and stereopsis in normal infants and the development of abnormal fixation patterns in pediatric patients. On the basic science side, these studies will help to define the necessary and sufficient conditions for the development of stereopsis. On the clinical side, better stereoacuity outcomes should provide more stable eye alignment and better quality of life.

DESCRIPTION: Most infant formulas provide ample alpha-linolenic acid (LNA) but formula fed infants are at risk for docosahexaenoic acid (DHA) deficiency due to their limited ability to metabolize this long-chain polyunsaturated fatty acid (LCP) from LNA during the first months of life. Formula-fed infants have abnormal fatty acid composition of red blood cells, retina and brain when compared with breast-fed infants, who obtain pre-formed DHA via human milk. Formula-fed infants whose diets lack both LNA and DHA exhibit less sensitive rod electroretinographic (ERG) function, poorer cortical visual evoked potential (VEP) acuity, poorer preferential-looking (PL) acuity, and lower scores on Fagan and Bayley tests. A specific need for dietary DHA in preterm and term infants is the focus of studies during the current grant period and the PI interim results support the essentiality of DHA for optimal maturation of visual function. 1. To delineate the role of DHA in supporting optimal maturation of cortical function. VEP and especially PL acuity have been widely used as indices of general maturation of the cortex or central nervous system; the motivation for these studies has been the quantification of subtle differences related to LCP composition of neural membranes. The PI proposes a series of studies to more directly evaluate cortical function via random dot stereoacuity and tests of cognitive function administered at 39 weeks, 4 years and 9 years of age. These data, coupled with VEP and PL acuity data, will also be used to examine the validity of the hypothesis that VEP and PL acuity provide indices of cortical maturation through analyses of concurrent and predictive validity for cognitive performance. 2. To evaluate the need for dietary supplementation following early weaning. Based on our data which support the essentiality of DHA in the term diet, we will address the question of whether DHA is essential in the post-weaning diet. Common practice in the US is a short 6-8 week period of breast-feeding; yet preliminary evidence suggests that a dietary supply of DHA is essential for at least 17 weeks. This study will be the first test of the essentiality of DHA in the post-weaning diet in the context of a randomized trial. 3. To evaluate the functional role of DHA in the neural retinal membranes of human infants. While there have been a number of studies on the role of DHA in neural membranes in vertebrates, little is known about the role of DHA in the neural membranes of the human infant. The functional effects of dietary DHA supply on activation and inactivation phases of the phototransduction cascade and the synaptic efficiency of the photo-receptor-bipolar junction will be evaluated in the context of a randomized trial. These data will provide the first test of the hypothesis that changes in neural membrane fatty acid composition lead to altered transduction and neurotransmission in the human infant. 4. To assess the capacity of human infants to synthesize DHA in vivo and in vitro. Based on the PI recent finding that in vivo elongation/desaturation of essential fatty acids (EFAs) in infants is limited, he plans to evaluate the impact of fetal growth, gestational age and diet on in vivo EFA conversion. in vivo studies will be complemented by in vitro investigations of LCP biosynthesis in fetal retinal tissue as a function of time in culture, gestational age and fatty acid substrate. Data from the in vivo and in vitro studies will assist in defining endogenous LCP biosynthetic capacity and optimal lipid composition for routine and specialty infant formulas.

DESCRIPTION (Adapted From The Applicant's Abstract): The fatty acid content of neural tissues in the brain changes throughout development, with progressive enrichment of phospholipids with long chain polyunsaturated fatty acids (LCPs), especially during the last pre-natal trimester and the first 6 months post-natal. Under optimal conditions, LCPs are supplied to the fetus via placental transfer and to the infant via breast-feeding post-natally. However, only 60% of U.S. newborns are breast-fed and 60-80% of breast-fed infants are weaned by 12 weeks of age. Formula feeding deprives infants of pre-formed LCPs since they are not provided in U.S. infant formulas. The last trimester of pre-natal development and the first year of life are periods of rapid increase in the number of synapses and dendritic arborizations in the brain. Since these processes require the deposition of LCPs in neuronal membranes, any limitation of LCP supply may modify the growth and function of the central nervous system. While the focus of research on LCP supplementation of infant formula has been on the first 2-4 months of life, little is known about the critical period during which dietary LCPs influence the maturation of cortical function. In Aim 1, we will conduct a randomized trial of LCP supplementation of term infants during months 4-12. We will delineate the critical period for cortical LCP accretion by comparing neurodevelopmental outcomes from this cohort with our existing term infant data sets from randomized trials of LCP supplementation during the first weeks or months of life. The argument that LCPs are present in human milk as a basis for their inclusion in infant formula is compelling but limited by the lack of data on the short-term and long-term effects of dietary LCP supplements in formula-fed infants. In Aim 2, metabolic and nutritional effects of LCPs will be evaluated in terms of alterations in hemostasis, antioxidant defense mechanisms, and lipid profiles. These functional and biochemical parameters are considered of particular importance to assessing the short-term and long-term safety of LCP-supplementation to the nation's infant formula supply. Visual evoked potential and preferential looking acuity have been used widely as outcome measures in studies of infant LCP nutrition, with the inference that these visual outcomes are related to other aspects of cortical function; i.e., cognitive function. In Aim 3, we propose to obtain the first long-term cognitive outcome data for large samples of infants who participated in randomized trials of LCP-supplemented formula. By relating long-term outcomes to visual cortical function during infancy, we will directly evaluate the predictive of early visual tests for long-term cognitive outcomes.

Description (provided by applicant): Congenital and early onset binocular imbalance, including esotropia (ET) and cataracts affect 2-4% of infants in the U.S. Binocular imbalance during visual development has the potential to cause amblyopia and abnormalities in binocular vision. Over 90% of patients with congenital and early onset binocular imbalance require occlusion therapy, spectacle correction, and/or surgery, and many require repeated interventions. Abnormal binocular sensory function is associated with higher risk for multiple eye muscle surgeries, dissociated vertical deviation, latent nystagmus, and amblyopia. Thus, the cost of early onset binocular imbalance is significant. During the current grant period, we found that binocular vision initially develops normally in infantile ET but is disrupted by abnormal binocular experience. This result suggested that very early surgery might prevent the deficit but, although we found a higher prevalence of stereopsis after very early surgery, normal stereoacuity was rare. We propose to pursue this surprising result by investigating the hypothesis that infantile ET is associated with initially normal development of the coarse, peripheral disparity sensitivity but a congenital absence or irreversible abnormality of the disparity sensitivity in the central visual field. Furthermore, we will investigate whether a congenital deficit in central disparity sensitivity is associated with vergence abnormalities in infantile ET. Several of our studies during the current grant support a link between binocular dysfunction and amblyopia. We will test the hypotheses that asymmetric binocular interactions predispose some esotropic infants and children to develop amblyopia, that weaning from occlusion therapy acts to diminish asymmetry, and that persistent residual amblyopia results from asymmetry that resists treatment. Relatively little is known about amblyopia in children <3 years of age. In the upcoming grant period, we will characterize the natural history of amblyopia during the first 3 years of life, determine whether different patterns of response to treatments and different risks associated with treatments are present in this age range, and evaluate new approaches to the detection and monitoring of amblyopia in infants and young children. While we have a good grasp on the effects of unilateral deprivation amblyopia and treatment protocols for dense congenital unilateral cataracts, a number of important questions remain about the effects of other types of cataracts on the developing visual system. We propose to define the critical period for visual acuity outcome in dense congenital bilateral cataracts, examine the effects of partial cataracts on visual maturation, and evaluate the critical period(s) for ocular motor development in children with dense congenital cataracts. Taken together, these five Aims directly address a stated goal of the NEI National Plan, namely "to investigate the development of visual function in children at high risk for amblyopia and strabismus, determine underlying mechanisms, and develop and disseminate information about detection methods and therapeutic interventions for restoring normal vision." PUBLIC HEALTH RELEVANCE: Congenital and early onset binocular imbalance due, for example, to esotropia and cataracts affect 2-4% of infants in the U.S. Over 90% of patients with congenital and early onset binocular imbalance require occlusion therapy, spectacle correction, and/or surgery, and many require repeated interventions. The aim of the proposed studies is to define the necessary and sufficient conditions for the development of normal binocular vision and to enhance treatment outcomes of patients with conditions that are associated with congenital and early onset binocular imbalance.

DESCRIPTION (provided by applicant): Infantile and accommodative esotropia (ET) affect 2-3% of children in the U.S. Infantile and accommodative ET disrupt binocular visual experience during the first years of life and may cause amblyopia and severe and permanent impairment of stereoacuity. Amblyopia can be treated but, due to recurrence and persistence of residual amblyopia, it remains the most common form of monocular visual impairment in young adults. Our collaborative research group is now poised to address three critical issues. Aim 1: Current consensus on infantile and accommodative ET is that that early detection and prompt intervention to realign the visual axes can preserve normal stereoacuity. However, our recent work challenges the accepted paradigm and has led us to hypothesize that a congenital deficit in disparity sensitivity is present in the central visual field. We propose to use stereo VEPs, disparity vergence, and accommodative disparity vergence to examine an alternative hypothesis for the first time - that there is a congenital defect in disparity sensitivity in the central 4¿ i infants with infantile ET and in a large subset of children with accommodative ET. These studies will give us a new, broad understanding of binocular deficits infantile and accommodative ET and have a direct translational impact on the clinical evaluation of the risk/benefits of very earl intervention. Aim 2: It is unknown why some children with ET alternate fixation and avoid amblyopia while others develop a preference for one eye and amblyopia. Based on data from primate models of amblyopia and visual evoked potential data on suppression in amblyopic infants and adults, our hypothesis is that asymmetry in suppressive binocular cortical interactions may predispose some esotropic infants and children to develop amblyopia. In addition, we hypothesize that persistent residual amblyopia despite prolonged or repeated treatment is due to the presence of strong asymmetry in suppressive binocular interactions that fails to diminish with occlusion therapy. We propose to use a novel method that allows us to quantify suppressive interactions to determine whether asymmetries in suppression precede amblyopia, whether these asymmetries resolve when treatment is effective, and whether persistent and recurrent amblyopia result from persistent asymmetric suppression. Aim 3: In a unique approach to determining the visual signal that guides emmetropization, we will utilize an infant cohort that shares the distribution of initial refractive errors of normal infants but failsto undergo emmetropization during the first year of life; i.e., infants with infantile esotropia. This approach will be used to identify the missing visually guided mechanism that normally stimulates axial growth to reduce infantile hyperopia. In a prospective evaluation of a preschool/school-age infantile ET cohort, we will, for the first time, examine the influence of axil and peripheral refractive error, accommodation, and ocular shape on the onset and progression of myopic axial growth in school-age children whose emmetropization had previously been inhibited.

Project Summary/Abstract Amblyopia is a neurodevelopmental vision disorder that affects 3% of children. It results from discordant visual experience during childhood, most often from strabismus or anisometropia. Strabismic and anisometropic amblyopia impair the visual acuity and contrast sensitivity of one eye. Typically, disrupted binocular vision (reduced or nil stereoacuity and interocular suppression), and ocular motor abnormalities are also present. These deficits are associated with reduced fine motor skills and reading speed even during binocular viewing. In turn, these associated deficits may affect academic success and self-esteem in children. During the current project period, we identified an association between abnormal binocular vision and fixation instability, discovered that interocular suppression precedes the onset of amblyopia, that the severity of suppression is correlated with the depth of amblyopia, that suppression is reduced with binocular amblyopia treatment, and investigated new binocular amblyopia treatments designed to reduce suppression and improve visual acuity. While our binocular treatment led to sustained improvement in visual acuity, these early studies were limited in 4 respects: 1) the treatment protocols were designed for short-term treatment trials, lasting <4 weeks so the maximum improvement with binocular treatment is unknown, 2) none of the treatment protocols were specifically designed to improve stereoacuity, 3) visual acuity was the primary outcome measure in all of the studies, so we know little about the relative effectiveness of patching versus binocular treatment in rehabilitating fine motor kills, reading speed, and self-esteem, and 4) the treatments have only been applied to amblyopic children age 4 years and older. Our collaborative research group is now poised to address these critical issues. In Aim 1, we will evaluate the effectiveness of enhanced binocular amblyopia treatments in achieving a more complete and stable recovery. In Aim 2, we will evaluate the effects of successful amblyopia treatment (patching or binocular treatment) on fine motor skills, reading speed, and self-perception. In Aim 3, we will evaluate a novel visual acuity measurement for <3-year-old children using a device that induces and measures reflexive eye movements (OKN) to moving fields of vanishing optotypes. Upon conclusion, our investigation of enhanced binocular treatment protocols and the effects of amblyopia treatment on the performance of everyday tasks will inform the design of new, more effective amblyopia treatments and the adoption of new outcome measures (reading, fine motor skills, and self-esteem) for clinical trials. In addition, we will have an accurate method to diagnose and monitor amblyopia in 1- to 3-year old children that will allow us to conduct future amblyopia treatment trials in this age range.