Core Messages

■Proper alignment of the eyes requires information sharing (fusion) between monocular visual input channels in the CNS; the first locus for fusion in the CNS of primates is the striate cerebral cortex (area V1).

■Fusion behaviors and V1 binocular connections are immature at birth, maturing during a critical period in the first months of life; maturation of fusion and V1 binocular connections requires correlated (synchronized) input from each eye.

■Nasalward biases are present innately in the neural pathways of normal primates before maturation of binocularity.

■Esotropia and the associated nasalward gaze biases of infantile strabismus can be produced

reliably in normal primates by impeding the maturation of fusional/binocular connections in V1.

■Infantile esotropia occurs predominantly in human infants who have perinatal insults that would impair correlated visual input to V1.

■Surgical realignment of the eyes during the critical period of normal binocular maturation may achieve functional sensory and motor cures.

■If surgery fails to restore bifoveal fusion, subnormal fusion (micro-esotropia/monofixation) may be achieved within boundaries set by the properties of neurons in V1 and extrastriate cortex.

■Late-onset (e.g., accommodative) esotropia is easier to treat because the fusional connections in V1 matured substantially before the emergence of eye misalignment.

5.1Esotropia as the Major Type of Developmental Strabismus

Esotropia is the leading form of developmental strabismus. Therefore, unraveling the causal mechanism and response to treatment is an important public health issue. The purpose of this chapter is to review knowledge gained over the last two decades that: (a) implicates cerebral cortex maldevelopment as the cause, and (b) explains how repair of cortical circuits may be the key to functional cures.

5.1.1Early-Onset (Infantile) Esotropia

Esotropia has a bimodal, age-of-onset distribution. The largest peak (comprising ~40% of all strabismus) occurs at or before age 12–18 months, with a second, smaller “late onset” esotropia peak at age 3–4 years. Children with

early-onset esotropia are predominantly emmetropic [1], whereas late-onset esotropia is associated commonly with a substantial hypermetropic refractive error (accommodative esotropia). The most prevalent form of developmental strabismus in humans is concomitant, constant, nonaccommodative, early-onset esotropia. Most of these cases have onset in the first 12 months of life, i.e., infan- tile-onset. Infantile esotropia may be considered the paradigmatic form of strabismus in all primates, as it is also the most frequent type of natural strabismus observed in monkeys [2].

5.1.2Early Cerebral Damage as the Major Risk Factor

If infantile esotropia is a paradigmatic form of strabismus, investigations designed to reveal pathophysiologic

mechanisms should begin by asking what factors contribute to its causation. At highest risk are infants who su er cerebral maldevelopment from a variety of causes (Table 5.1), especially insults to the parieto-occipital cor-

5tex and underlying white matter (geniculostriate projections or optic radiations) [3, 5–7]. Periventricular and intraventricular hemorrhage in the neonatal period increases the prevalence of infantile strabismus 50–100- fold. Less specific cerebral insults, e.g., from very low birth weight (with or without retinopathy of prematu-

rity) or Down syndrome, increase the risk above that of otherwise healthy infants by factors of 20–30-fold [4, 7–10].

5.1.3Cytotoxic Insults to Cerebral Fibers

The occipital lobes in newborns are vulnerable to damage [6, 12–14]. Premature infants frequently su er injury to the optic radiations near the occipital trigone. Balanced binocular input requires equally strong projections from each eye through this periventricular zone. The fibers connect the lateral geniculate laminae to the ocular dominance columns (ODCs) of the striate cortex. The projections are immature at birth and the quality of signal flow would be critically dependent upon the function of oligodendrocytes, which insulate the visual fibers. Neonatal oligodendrocytes are especially vulnerable to cytotoxic insult [15]. The striate cortex is also susceptible to hypoxic injury because it has the highest neuron-to-glia ratio in the entire cerebrum [16] and the highest regional cerebral glucose consumption [17].

5.1.4Genetic Influences on Formation of Cerebral Connections

Genetic factors also play a causal role. Large-scale studies have documented that ~30% of children born to a strabismic parent will themselves develop strabismus [18]. Twin studies reveal a concordance rate for monozygous twins of 73% [19]. Less than 100% concordance implies that intrauterine or perinatal (“environmental”) factors alter the expression of the strabismic genotype. Maumenee and associates analyzed the pedigrees of 173 families containing probands with infantile esotropia [20]. The results suggested a multifactorial or Mendelian codominant inheritance pattern. Codominant means that both alleles of a single gene contribute to the phenotype but with di erent thresholds for expression of each allele. These genes could conceivably encode cortical neurotrophins, or axon guidance and maturation. Any of these genetically modulated factors could increase the susceptibility to disruption of visual cortical connections in otherwise healthy infants.

5.1.5Development of Binocular Visuomotor Behavior in Normal Infants

Esotropia is rarely present at birth. For this reason alone, “infantile esotropia” is a more appropriate descriptor than “congenital esotropia.”Constant misalignment of the visual axes appears typically after a latency of several months, becoming conspicuous on average between the ages of 2 and 5 months [11, 21, 22]. To understand visuomotor maldevelopment in strabismic infants during this period, it is helpful to understand the development of binocular fusion and vergence in normal infants (Table 5.2) during the same 2–5-month postnatal interval.

5.1.6Development of Sensorial Fusion and Stereopsis

Binocular disparity sensitivity and binocular fusion are absent in infants less than several months of age, as demonstrated by several methods, most notably studies that have used forced preferential looking (FPL) techniques [23–25, 27, 28]. The FPL studies show that stereopsis emerges abruptly in humans during the first 3–5 months of postnatal

life, achieving adult-like levels of sensitivity. Sensitivity to crossed (near) disparity appears on average several weeks before that to uncrossed (far) disparity [24]. During this same interval infants begin to display an aversion to stimuli that cause binocular rivalry (i.e., nonfusable stimuli). Visually evoked potentials in normal infants,recorded using dichoptic viewing and dichoptic stimuli, show comparable results [43, 48, 49]. Onset of binocular signal summation occurs after, but not before, ~3 months of age.

5.1.7Development of Fusional Vergence and an Innate Convergence Bias

5Fusional vergence eye movements mature during an equivalent period in early infancy. In the first 2 months of

life, alignment is unstable and the responses to step or ramp changes in disparity are often markedly inaccurate [32, 33]. The inaccuracy cannot be ascribed to errors of accommodation. Accommodative precision during this period consistently exceeds that of fusional (disparity) vergence [29, 30, 33].

Studies of fusional vergence development in normal infants reveal an innate bias for convergence [32, 33]. Transient convergence errors of large degree exceed divergence errors by a ratio of 4:1. The fusional vergence response to crossed (convergent) disparity is also intact earlier and substantially more robust than that to divergent disparity. The innate bias favoring fusional convergence in primates persists after full maturation of normal binocular disparity sensitivity. Fusional convergence capacity exceeds the range of divergence capacity by a mean ratio of 2:1 [50, 51].

5.1.8Development of Motion Sensitivity and Conjugate Eye Tracking (Pursuit/OKN)

The innate nasalward bias of the vergence pathway has analogs in the visual processing of horizontal motion, both for perception and conjugate eye tracking. In the first months of life, VEPs elicited by oscillating grating stimuli (motion VEPs) show a pronounced nasotemporal asymmetry under conditions of monocular viewing [35–38]. The direction of the asymmetry is inverted when viewing with the right vs. left eye. Monocular FPL testing reveals greater sensitivity to nasalward motion [39]. Monocular pursuit and optokinetic tracking show strong biases favoring nasalward target motion when viewing with either eye [40, 41, 43–45]. Optokinetic after-nystagmus (slow phase eye movement in the dark after extinction of stimulus motion) is characterized by a consistent nasalward drift of eye position [42]. These nasalward motion biases are most pronounced before the onset of sensorial fusion and stereopsis, but systematically diminish thereafter.

5.1.9Development and Maldevelopment of Cortical Binocular Connections

Knowledge of visual cortex development (Table 5.3) is important for understanding the neural mechanisms that could cause strabismus, for several reasons. First, the visual cortex is the initial locus in the CNS at which visual signals from the two eyes are combined and a combination of visual signals is necessary to generate the vergence error commands that guide eye alignment. Second, the most common form of strabismus (esotropia) appears coincident with maturation of cortically mediated, binocular, sensorimotor behaviors in normal infants. Third, perinatal insults to the immature visual cortex are linked strongly to subsequent onset of strabismus. And finally, the constellation of sensory and motor deficits in infantile strabismus can be explained by known cortical pathway mechanisms.

5.1.10Binocular Connections Join Monocular Compartments Within Area V1 (Striate Cortex)

A erents from each eye are segregated in monocular lamina of the lateral geniculate nucleus (LGN) and at the input layer (4C) of ODCs of the striate cortex, or visual area V1 (Fig. 5.1) [52, 53]. The first stage of binocular processing in the primate CNS is made possible by horizontal connections between ODCs of opposite ocularity, above and below layer 4C [52, 68, 70]. Physiological recordings in normal neonatal and adult monkeys show monocular responses in layer 4C and binocular responses from the majority of neurons in V1 layers 4B and 2–6 [52, 54, 63]. The binocular responses in the neonate are cruder and weaker than those recorded in normal adult [58, 59, 77]. Binocular disparity sensitive neurons are present in the neonatal cortex, but the spatial tuning is poor and they are characterized by a high binocular suppression (inhibition) index. The immature neuronal response properties are attributed to unrefined, weak excitatory horizontal binocular connections between ODCs. These axonal connections help define the segregation of ODCs [62, 77]. ODC borders are immature (fuzzy) at birth but adult-like (sharply defined) by 3–6 weeks postnatally [60, 78] (the equivalent of 3–6 months in humans, 1 week of monkey visual development is comparable with 1 month in humans [79]).

Striate cortex (area V1) is the first CNS locus for binocular processing

segregated in LGN and input layer (4C) in V1

Maturation of binocular connectivity

in V1 requires correlated RE/LE input

V1 feeds forward to extrastriate visual areas MT/MST which control ipsiversive eye tracking and gaze holding

V1 feed forward connections to MT/MST at birth are monocular from ODCs driven by the contralateral eye

MST inputs from the ipsilateral eye require maturation of binocular V1/MT connections

MST neurons encode both vergence and pursuit/OKN

Convergence motoneurons are more numerous