Chapter 73 Why do humans develop strabismus?
DEVELOPMENTAL NON-PARALYTIC STRABISMUS
EARLY-ONSET (INFANTILE) ESOTROPIA
EARLY CEREBRAL DAMAGE AS THE MAJOR RISK FACTOR
CYTOTOXIC INSULTS TO CEREBRAL FIBERS
GENETIC INFLUENCES ON FORMATION OF CEREBRAL CONNECTIONS
DEVELOPMENT OF BINOCULAR VISUOMOTOR BEHAVIOR IN NORMAL INFANTS
DEVELOPMENT OF SENSORIAL FUSION AND STEREOPSIS
DEVELOPMENT OF FUSIONAL VERGENCE AND AN INNATE CONVERGENCE BIAS
DEVELOPMENT OF MOTION SENSITIVITY AND CONJUGATE EYE TRACKING (PURSUIT/OPTOKINETIC NYSTAGMUS)
DEVELOPMENT AND MALDEVELOPMENT OF CORTICAL BINOCULAR CONNECTIONS
PERSISTENT NASALWARD VISUOMOTOR BIASES IN STRABISMIC PRIMATE
REPAIR OF STRABISMIC HUMAN INFANTS: THE HISTORICAL CONTROVERSY
REPAIR OF HIGH-GRADE FUSION IS POSSIBLE
TIMELY RESTORATION OF CORRELATED BINOCULAR INPUT: THE KEY TO REPAIR
VISUAL CORTEX MECHANISMS IN MICROESOTROPIA (MONOFIXATION SYNDROME)
NEUROANATOMIC FINDINGS IN AREA V1 OF MICROESOTROPIC PRIMATES
EXTRASTRIATE CORTEX IN MICROESOTROPIA
ACQUIRED (NON-INFANTILE) ESOTROPIA
SUMMARY OF STRABISMUS NEUROSCIENCE KNOWLEDGE
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
Early cerebral damage as the major risk factor
What factors contribute to strabismus causation? At highest risk are infants who suffer cerebral maldevelopment from a variety of causes (Table 73.1), especially insults to the parieto-occipital cortex and underlying white matter (geniculostriate projections or optic radiations).5–8 Periventricular and intraventricular hemorrhage in the neonatal period increases the prevalence of infantile strabismus 50–100 fold.9 Less specific cerebral insults, e.g. very low birth weight (with or without retinopathy of prematurity) or Down’s syndrome, increase the risk by 20- to 30-fold.8–12
Table 73.1 Cerebral damage risk factors for infantile-onset strabismus
| Type | Prevalence strabismus | Author(s) |
|---|---|---|
| Intraventricular hemorrhage with hydrocephalus | 100% | Tamura and Hoyt 19875 |
| Cerebral visual pathway white matter injury | 76% | Khanna et al. 20099 |
| Occipitoparietal hemorrhage and/or leukomalacia | 54–57% | Pike et al. 19946 Hoyt 20037 |
| Very low birth weight infants (< 1500 g) | 33%* | van Hof-van Duin et al. 19898 |
| Very low birth weight (< 1251 g) and prethreshold retinopathy of prematurity | 30% | VanderVeen et al. 200610 |
| Very low birth weight (< 1251 g) and normal neuroimaging | 17% | Khanna et al. 20099 |
| Down’s syndrome | 21–41% | Hiles et al. 197411 Shapiro and France 198512 |
| Healthy full-term infants | 0.5–1.0% | PEDIG 200223 |
* Additional 17% of infants had persistent asymmetric optokinetic nystagmus (OKN).
Cytotoxic insults to cerebral fibers
The occipital lobes in newborns are vulnerable to damage.7,13–15 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.23–25 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.26–30 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.31–33 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.35–37
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.40–43 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.31,45–48 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:
1. The visual cortex is the initial locus in the CNS at which signals from the two eyes are combined; a combination of visual signals is necessary to generate the vergence error commands that guide eye alignment.
2. The most common form of strabismus (esotropia) appears coincident with maturation of cortically mediated, binocular, sensorimotor behaviors in normal infants.
3. Perinatal insults to the immature visual cortex are linked to subsequent strabismus.
4. The constellation of sensory and motor deficits in infantile strabismus can be explained by known cortical pathway mechanisms.
Table 73.3 Development of neural pathways in normal and strabismic primate
| 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 | • Before maturation of binocularity, a nasalward movement bias is apparent when viewing with either eye (RE viewing evokes leftward pursuit/OKN/gaze drift; LE viewing evokes rightward pursuit/OKN/gaze drift) • Nasalward and temporalward neurons are present in equal numbers within V1/MT but nasalward have innate connectivity advantage | |
| MST inputs from the ipsilateral eye require maturation of binocular V1/MT connections | ||
| MST neurons encode both vergence and pursuit/OKN |
