Dolores Bradley

Early versus delayed repair of infantile strabismus in macaque monkeys: I. ocular motor effects

INTRODUCTION The appropriate age for surgical correction of esotropic strabismus in human infants is controversial; some clinicians advocate surgery before age 6 months, and others recommend observation and surgery at older ages. Infantile (congenital) esotropia in humans and monkeys is known to be accompanied by a constellation of eye movement abnormalities caused by maldevelopment of cerebral visual motor pathways. The purpose of this study was to determine how early versus delayed correction of strabismus influences development and/or maldevelopment of these eye movement pathways. METHODS Optical strabismus was created in infant macaques by fitting them with prism goggles on day 1 of life. The early correction group (2 experimental and 1 control) wore the goggles for a period of 3 weeks (the equivalent of 3 months before surgical repair in humans). The delayed correction group (3 experimental and 1 control) wore the goggles for a period of 3 or 6 months (the equivalent of 12 or 24 months before surgical repair in humans). Several months after the goggles were removed, the monkeys were trained to perform visual fixation, smooth pursuit, and optokinetic nystagmus (OKN) tasks for a juice reward. Eye movements were recorded using binocular search coils. The performance of the early versus delayed infant monkey groups was also compared with that of a group of adult monkeys who had unrepaired, naturally occurring infantile esotropia. RESULTS Early correction monkeys developed normal eye movements and exhibited ocular motor behaviors that were indistinguishable from normal control animals. They regained normal binocular eye alignment and showed stable fixation (no latent nystagmus). Monocular horizontal smooth pursuit and large field OKN were symmetric. In contrast, delayed correction monkeys showed persistent esotropia, latent fixation nystagmus, dissociated vertical deviation, and pursuit/OKN asymmetry. Animals who had the longest delay in correction of the optical strabismus exhibited eye movement abnormalities as severe as those of adult animals with uncorrected, natural esotropia. CONCLUSIONS Early correction of strabismus in primates prevents maldevelopment of eye movements driven by cerebral motor pathways. Our results provide additional evidence that early strabismus correction may be beneficial for brain development in human infants.

The neural mechanism for Latent (fusion maldevelopment) nystagmus.

Latent nystagmus (LN) is the by-product of fusion maldevelopment in infancy. Because fusion maldevelopment--in the form of strabismus and amblyopia--is common, LN is a prevalent form of pathologic nystagmus encountered in clinical practice. It originates as an afferent visual pathway disorder. To unravel the mechanism for LN, we studied patients and nonhuman primates with maldeveloped fusion. These experiments have revealed that loss of binocular connections within striate cortex (area V1) in the first months of life is the necessary and sufficient cause of LN. The severity of LN increases systematically with longer durations of binocular decorrelation and greater losses of V1 connections. Decorrelation durations that exceed the equivalent of 2-3 months in human development result in an LN prevalence of 100%. No manipulation of brain stem motor pathways is required. The binocular maldevelopment originating in area V1 is passed on to downstream extrastriate regions of cerebral cortex that drive conjugate gaze, notably MSTd. Conjugate gaze is stable when MSTd neurons of the right and left cerebral hemispheres have balanced binocular activity. Fusion maldevelopment in infancy causes unbalanced monocular activity. If input from one eye dominates and the other is suppressed, MSTd in one hemisphere becomes more active. Acting through downstream projections to the ipsilateral nucleus of the optic tract, the eyes are driven conjugately to that side. The unbalanced MSTd drive is evident as the nasalward gaze-holding bias of LN when viewing with either eye.

Duration of Binocular Decorrelation Predicts the Severity of Latent (Fusion Maldevelopment) Nystagmus in Strabismic Macaque Monkeys

PURPOSE Infantile esotropia is linked strongly to latent fixation nystagmus (LN) in human infants, but many features of this comorbidity are unknown. The purpose of this study was to determine how the duration of early-onset strabismus (or timeliness of repair) affects the prevalence of LN in a primate model. METHODS Optical strabismus was created in infant macaques by fitting them with prism goggles on day 1 of life. The goggles were removed after 3 (n = 2), 12 (n = 1) or 24 weeks (n = 3), emulating surgical repair of strabismus in humans at 3, 12, and 24 months of age, respectively. Eye movements were recorded by using binocular search coils. RESULTS Each animal in the 12- and 24-week groups exhibited LN and manifest LN, normal spatial vision (no amblyopia), and constant esotropia. The 3-week duration monkeys had stable fixation (no LN) and normal alignment indistinguishable from control animals. In affected monkeys, the longer the duration of binocular decorrelation, the greater the LN: mean slow-phase eye velocity (SPEV) in the 24-week animals was three times greater than that in the 12-week monkey (P = 0.03); mean LN intensity in the 24-week monkeys was three times greater than that in the 12-week monkey (P = 0.03). CONCLUSIONS Binocular decorrelation in primates during an early period of fusion development causes permanent gaze instability when the duration exceeds the equivalent of 3 months in humans. These findings support the conclusion that early correction of infantile strabismus promotes normal development of cerebral gaze-holding pathways.

DURATION OF BINOCULAR DECORRELATION IN INFANCY PREDICTS THE SEVERITY OF NASOTEMPORAL PURSUIT ASYMMETRIES IN STRABISMIC MACAQUE MONKEYS

PURPOSE Strabismus in human infants is linked strongly to nasotemporal asymmetries of smooth pursuit, but many features of this co-morbidity are unknown. The purpose of this study was to determine how the duration of early-onset strabismus (or timeliness of repair) affects the severity of pursuit asymmetries in a primate model. METHODS Binocular image decorrelation was imposed on infant macaques by fitting them with prism goggles on day 1 of life. The goggles were removed after 3 weeks (n=2), 12 weeks (n=2) or 24 weeks (n=3), emulating surgical repair of strabismus in humans at 3, 12, and 24 months of age, respectively. Two control monkeys wore plano lenses. Several months after the goggles were removed, horizontal smooth pursuit was recorded using binocular search coils and a nasal-bias index (NBI) was calculated. RESULTS Each animal in the 12- and 24-week groups developed a constant, alternating esotropic strabismus and a nasotemporal asymmetry of pursuit when viewing with either eye. Spatial vision was normal (no amblyopia). The 3-week duration monkeys were indistinguishable from control animals; they had normal eye alignment and symmetric pursuit. In the 12- and 24-week monkeys, the longer the duration of binocular decorrelation, the greater the pursuit asymmetry: for 15 degrees /s target motion, the NBI in the 12-week and 24-week animals was 16x and 22x greater respectively, than that in the 3-week animals (ANOVA, P=0.03). CONCLUSIONS Binocular decorrelation in primates during an early period of fusion development causes permanent smooth pursuit asymmetries when the duration exceeds the equivalent of 3 months in human. These findings support the conclusion that early correction of infantile strabismus promotes normal development of cerebral gaze pathways.

Decorrelation of cerebral visual inputs as the sufficient cause of infantile esotropia.

Background and Purpose Human infants at greatest risk for esotropia are those who suffer cerebral insults that could decorrelate signals from the two eyes during an early critical period of binocular, visuomotor development. The authors reared normal infant monkeys under conditions of binocular decorrelation to determine if this alone was sufficient to cause esotropia, and associated behavioral as well as neuroanatomic deficits. Methods Binocular decorrelation was imposed using prism-goggles for durations of 3–24 weeks (control monkeys wore piano goggles), emulating unrepaired strabismus of durations 3 months to 2 years in human infants. Behavioral recordings were obtained, followed by neuroanatomic analysis of ocular dominance columns and binocular, horizontal connections in the striate visual cortex (area V1). Results Concomitant, constant esotropia developed in each monkey exposed to decorrelation for a duration of 6–24 weeks. The severity of ocular motor signs (esotropia angle; dissociated vertical deviation; latent nystagmus; pursuit/optokinetic tracking asymmetry; fusional vergence deficits), and the loss of V1 binocular connections increased as a function of decorrelation duration. Stereopsis was deficient and motion visually evoked potentials were asymmetric. Monkeys exposed to decorrelation for 3 weeks showed transient esotropia, but regained normal alignment, visuomotor behaviors, and binocular V1 connections. Conclusions Binocular decorrelation is a sufficient cause of infantile esotropia when imposed during a critical period of visuomotor development. The systematic relationship between severity of visuomotor signs and severity of V1 connectivity deficits provides a neuroanatomic mechanism for these signs. Restoration of binocular fusion and V1 connections after short durations of decorrelation helps explain the benefits of early strabismus repair in humans.

Early Versus Delayed Correction of Infantile Strabismus in Macaque Monkeys: Effects on Horizontal Binocular Connections in the Striate Cortex

Objective: To determine how the duration of infantile strabismus influences the development of horizontal connections in V1. Methods: Six infant macaques were fitted with prisms, which were removed after 3 weeks (wks.), 3 months (mos.), or 6 mos. Two control monkeys wore plano lenses. The number of horizontal connections was determined using neuroanatomic techniques. Results: The 3-wks animal had equal number of monocular (51%) and binocular (49%) connections. In the 6-mos. animal, however, monocular connections (76%) were three times more abundant than binocular (24%) connections (p < 0.001). Conclusions: Longer duration of infantile strabismus causes greater deficit of binocular connections. Early correction of infantile strabismus is supported.

Early Versus Delayed Correction of Infantile Strabismus in Macaque Monkeys: Effects on Long-Term Eye Alignment

Purpose: To determine how the duration of infantile strabismus influences the eventual eye alignment. Methods: Six infant macaques were fitted with prisms, which were removed after 3 weeks (wks.), 3 months (mos.), or 6 mos. Two control monkeys wore plano lenses. Eye alignment was measured using search coils. Results: Longer duration of infantile strabismus is correlated with a more severe misalignment. The strabismus in the 6-mos. group was 96% greater than that in the 3-mos. group, which, in turn, was 25 times greater than that in the 3-wks group (p < 0.05). Conclusions: Longer duration of infantile strabismus causes larger-angle esotropia. Early correction of infantile strabismus is supported.