Why do humans develop strabismus?

Chapter 73 Why do humans develop strabismus?

Early-onset (infantile) esotropia

Esotropia is the leading form of developmental strabismus; it has a bimodal, age-of-onset distribution. The largest peak (∼40% of all strabismus) occurs at or before age 12–18 months, with a second, smaller “late-onset” esotropia peak at 3–4 years. Children with early-onset esotropia are predominantly emmetropic:1 late-onset (accommodative) esotropia is associated with hypermetropia. The most prevalent form of developmental strabismus in humans is comitant, constant, non-accommodative, early-onset esotropia.2,3 Most cases have onset in the first 12 months of life, i.e. infantile-onset. Infantile esotropia is the paradigm for strabismus in all primates: it is the most frequent type of natural strabismus observed in monkeys.4

Cytotoxic insults to cerebral fibers

The occipital lobes in newborns are vulnerable to damage.7,1315 Premature infants frequently suffer injury to the optic radiations near the occipital trigone.9,16 Balanced binocular input requires equal projections from each eye through this periventricular zone. The fibers connect the lateral geniculate laminae to the ocular dominance columns of the striate cortex. The projections are immature at birth and the quality of signal flow is critically dependent upon the function of oligodendrocytes, which insulate the visual fibers. Neonatal oligodendrocytes are especially vulnerable to cytotoxic insult.17 The striate cortex is also susceptible to hypoxic injury because it has the highest neuron/glia ratio in the cerebrum18 and the highest regional cerebral glucose consumption.19

Genetic influences on formation of cerebral connections

Genetic factors also play a causal role. Large-scale studies show that ∼30% of children born to a strabismic parent will develop strabismus.20 Concordance rates for monozygous twins may be 73%.21 Less than 100% concordance implies that intrauterine or perinatal (“environmental”) factors alter the expression of the strabismic genotype. Pedgree analysis of families containing probands with infantile esotropia22 suggests a multifactorial or Mendelian co-dominant inheritance pattern. Co-dominant means that both alleles of a single gene contribute to the phenotype but with different thresholds for expression of each allele. These genes could encode cortical neurotrophins, or axon guidance and maturation. Any of these genetically modulated factors could increase susceptibility to disruption of visual cortical connections in otherwise healthy infants.

Development of binocular visuomotor behavior in normal infants

Esotropia is rarely present at birth; “infantile esotropia” is a more appropriate descriptor than “congenital esotropia.” Constant misalignment of the visual axes appears, typically, after several months, becoming conspicuous between 2 and 5 months.2325 To understand visuomotor maldevelopment in strabismic infants it is helpful to understand the development of binocular fusion and vergence in normal infants (Table 73.2) during the 2–5 month postnatal interval.

Table 73.2 Binocular development and visuomotor behaviors in infant primate

Immature behavior Chief findings before onset of mature behavior Investigator(s)
Binocular disparity sensitivity absent before ∼ 3–5 months

Binocular sensorial fusion absent before ∼ 3–5 months

Fusional (binocular) vergence unstable before ∼ 3–5 months

Nasalward bias of vergence pronounced before ∼ 3–5 months

Nasalward bias of cortically mediated motion sensitivity before ∼ 6 months

Nasalward bias of pursuit/OKN before ∼ 6 months

Nasalward bias of gaze-holding before ∼ 6 months

Development 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 using forced preferential looking (FPL) techniques.2630 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 several weeks before uncrossed (far) disparity.27 During this interval, infants begin to display an aversion to stimuli causing binocular rivalry, i.e. non-fusable stimuli. Visually evoked potentials (VEPs) in normal infants, recorded using dichoptic viewing and dichoptic stimuli, show comparable results.3133 Onset of binocular signal summation occurs after, not before, ∼3 months of age.

Development of fusional vergence and an innate convergence bias

Fusional 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 inaccurate34,35 and cannot be ascribed to errors of accommodation; accommodative precision during this period consistently exceeds that of fusional (disparity) vergence.3537

Studies of fusional vergence development in normal infants reveal an innate bias for convergence.34,35 Transient large convergence errors exceed divergence errors by 4 : 1. The fusional vergence response to crossed (convergent) disparity is intact earlier and substantially more robust than to divergent disparity. The innate bias favoring fusional convergence in primates persists after full maturation of binocular disparity sensitivity. Fusional convergence capacity exceeds the range of divergence capacity by a mean ratio of 2 : 1.38,39

Development of motion sensitivity and conjugate eye tracking (pursuit/optokinetic nystagmus)

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, monocular VEPs elicited by oscillating grating stimuli (motion VEPs) show a pronounced nasotemporal asymmetry.4043 The direction of the asymmetry is inverted when viewing with the right vs. left eye. Monocular FPL testing reveals greater sensitivity to nasalward motion.44 Monocular pursuit and optokinetic tracking show strong biases favoring nasalward target motion.31,4548 Optokinetic after nystagmus (slow phase eye movement in the dark after extinction of stimulus motion) shows a consistent nasalward drift of eye position.49 These nasalward motion biases are most pronounced before onset of sensorial fusion and stereopsis and diminish thereafter.

Development and maldevelopment of cortical binocular connections

Knowledge of visual cortex development (Table 73.3) is important for understanding the neural mechanisms that cause strabismus:

Table 73.3 Development of neural pathways in normal and strabismic primate

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Jun 4, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Why do humans develop strabismus?

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Neurobiological principle Physiology/anatomy Investigator(s)
Striate cortex (area V1) is the first CNS locus for binocular processing

Binocular structure + function in V1 is immature at birth

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