Development of the visual system – both ocular and neurologic components – is incomplete at birth, even in healthy full-term infants, and its maturation is influenced by many factors including visual stimulation and postnatal nutrition. Visual development is complex and can be affected by many pathophysiological mechanisms. These can involve abnormalities in refraction, retinal definition, optic nerve transmission; maturation of the visual cortex in the occipital lobe and integration of visual data; and external factors such as nutrition and light deprivation. Severe neonatal visual problems are rare, but if left undiagnosed and untreated, can lead to long-term or even permanent visual deficits . In contrast, refraction (or focusing) anomalies, which usually result in reduced visual acuity (blurred vision), are relatively common , although early screening for visual defects, diagnosis, and treatment can help to normalize them.
Amblyopia or ‘lazy eye’ is the most common cause of visual loss in children. Functional amblyopia, impaired visual acuity in one or both eyes despite optimum optical correction, often with no overt visual pathology, can occur when amblyopia, due to an underlying disease or condition such as cataract (organic amblyopia), is corrected. Functional amblyopia is due to poor interpretation of the image by the brain as the brain has adjusted to seeing a blurred image. If treated early enough, the brain can relearn how to interpret the image and vision will improve.
During the first few years of life, infants and children are more susceptible to visual development problems. During specific sensitive periods, normal visual input is vital for normal visual development and, conversely, abnormal visual input can result in long-term sight problems. Guidelines recommend early identification and correction of the pathological visual deprivation mechanism during this period to allow normal visual development and to prevent permanent visual problems .
A joint policy statement on vision screening in infants and children published in 2007 by the American Association for Pediatric Ophthalmology and Strabismus (AAPOS) and the American Academy of Ophthalmology (AAO) advocate a rigorous screening program during preschool years to enable detection and diagnosis of treatable eye disease . Beginning in the preschool years, vision screening using an acuity chart should include screening for reduced vision in one or both eyes from amblyopia, uncorrected refractive errors or other eye defects, and misalignment of the eyes (strabismus) .
Early detection of a faulty visual deprivation mechanism and functional amblyopia has been made easier in recent years with advances in screening techniques. The conditions can be screened for almost immediately after birth, and so every effort should be made to screen as early as possible to avoid permanent visual impairment. Screening can also differentiate between functional amblyopia due to a pathological visual deprivation mechanism and organic amblyopia due to an underlying defect. This is important because, if diagnosed early, functional amblyopia can be reversed using occlusion therapy. This is true even in the presence of an underlying anatomic defect of the eye. In this case, visual recovery may be limited, yet many of these children will have an underlying element of functional amblyopia in addition to their ‘organic’ vision loss, which can be treated with amblyopia therapy with many children recovering at least some vision. Screening is particularly important in preterm infants (usually defined as infants born at <37 weeks gestation, but screening is usually performed in all infants born <32 weeks), who, being born at an earlier stage of ocular and central nervous system (CNS) development, have a particularly high risk of abnormal visual development and long-term/permanent visual impairment compared with full-term infants .
In normal development of the ocular process, both neurological and optical components of the visual system are immature at birth; basic visual capacity is established shortly after birth and improves rapidly during the first year . A normal process, known as emmetropization, occurs soon after birth to reduce birth hyperopia and is complete in 82% of full-term infants by 12 months . Emmetropization is the normal physiological process of eye growth, involving increased axial length in response to the normal hyperopia of the neonate eye. However, maturation of the visual system continues for several years and, for some components and aspects of visual capability, does not reach full maturity until the late teens .
Developments in embryology
Prenatal evaluation of ocular development using fetal ultrasound or magnetic resonance imaging (MRI) may allow the detection and confirmation of malformational anomalies such as microphthalmia by comparison of fetal ocular growth with established linear growth rates [9,10]. In a recent retrospective study, data were analyzed from ocular parameters measured in 127 fetuses with a morphologically normal CNS using multiple single-shot T2 fast spin-echo 1.5 Tesla MRI . Findings suggest a quadratic growth model indicating slowing of growth toward the end of gestation; lens growth and interocular distance plateau after 36 weeks of gestation, while globe growth plateaus after 42 weeks .
Maturation of the central nervous system components
Visual capabilities in neonates are dependent on the development of visual pathways including those in the visual cortex located in the occipital lobe of the brain, and lateral geniculate nucleus (LGN) in the thalamus, and synaptic development of the neurons linking the eyes with the LGN and the visual cortex .
The LGN is immature at birth and a rapid increase in postsynaptic surfaces is seen in the first few months after birth, slowing by 2 years. Synaptogenesis in the cortex is also rapid after birth, with a maximum synaptic density at about 8–9 months, followed by a loss of synapses, stabilizing at about 11 years . A neonate has approximately three times fewer cones at birth than in adulthood, which partially explains the blurred vision . The subsequent pruning of the initial overgrowth relates to a period of physiological and behavioral changes in visual function and the risk of development of amblyopia is highest during this period. While the precise functional significance for the loss of synapses is unclear, it is thought to relate to the reduction in CNS plasticity as the nervous system matures .
Structural development of the eye
Postnatal structural eye development includes maturation of the macula region of the retina, maturation of the fovea, and eyeball growth [12,14]. While the peripheral retina is relatively mature at birth, differentiation and maturation of the fovea (which is responsible for central vision and has the highest visual acuity) and the macula retinal layers (responsible for colors and contrasts, precise visual acuity, and stereoscopic vision) begins at 6 weeks and continues up to 8 months of age [12,15]. In normal development, the rate of eyeball growth is linked to child growth and so emmetropization occurs as a natural part of the growth process .
In a study utilizing multifocal electroretinography (ERG) in 23 full-term infants and 10 adults, differences in ERG were thought to relate to differences in central retina processing between infants and adults . ERG has also been used to show that peripheral cone development is more advanced than rod development in infants . Foveal cone density, important for precise, detailed vision, increases from 18 cones/100 μm at 1 week postnatal to 42 cones/100 μm in the adult . Cone migration from the retinal periphery to the macula area contributes to the increasing density.
In general, eyeball growth is faster in younger children and slows with age [9,19,20]. A MRI eye study of fetuses and children aged 0–13 years shows a rapid eyeball growth curve in utero and from birth to 18 months . During the emmetropization process, there is an increase in light focusing on the retina as a result of increased axial length of the eyeball, corneal applanation, and reduced lens refraction. This phenomenon explains the relative low hyperopia in infants with short ocular axial length who will become emmetropic adults .
Normal visual capability milestones
Visual capability is dependent on normal function of both neurological and ocular components. Evaluation of capability is made by assessing the individual types of vision. These include central vision, stereoscopic (binocular) vision, refraction, color vision, contrast vision, scotopic/photopic (dark/light) vision (retina/rods), and tracking (following and saccades), (retina, oculomotor muscles). Infant visual responses should be compared with those expected in infants with normal visual development.
Abnormal visual development
There is a paucity of data on the prevalence of visual problems in neonates and infants. In a recent observational study carried out in child daycare centers in Canada, of 946 children aged 1.6–11.6 years (mean 4.2 years) screened for functional vision, 14% were found to have a significant vision disorder .
Visual problems often have an organic basis or are the result of ocular anomalies, for example malformations, cataracts, glaucoma, and other syndromes, or can be secondary to peri-natal abnormalities (premature birth), or postnatal events (trauma, infections, tumors), or external factors. In the aforementioned study, the main visual problems reported were hyperopia (4.8%), amblyopia (4.7%), and strabismus (4.3%), whereas myopia (1.1%) and anisometropia (1.4%) were relatively uncommon .
Studies have demonstrated the existence of sensitive periods during which infants are more vulnerable to visual development anomalies and require normal visual input for normal development; however, the specific timing of the sensitive period of visual development varies depending on the specific aspect of vision being considered . For example, the critical window for normal development of grating acuity is from birth to at least 5 years old, whereas the window is up to approximately 10 years for Snellen acuity, and at least to early teenage years for peripheral vision .
Visual deprivation mechanisms
Visual deprivation mechanisms are thought to have a major impact on visual development in neonates because of the impact of visual experience in early life on eyeball growth [16,22–24], neural circuits [25–27], and perceptual and cognitive development .
Eyeball growth and increased axial length
In most children, increased axial length results in normal emmetropia because of the fact that most infants are naturally hyperopic at birth. However, in contrast to the normal emmetropization process, visual deprivation such as blurred vision, caused by partial cataract, lack of hyperopia, or myopia for example, leads to increased eyeball growth and excessive increase in axial length (myopic shift), whereas the lens is not affected significantly [22,24]. A vicious circle of visual impairment, increased axial length, and subsequent or increased myopia ensues. Left uncorrected, this leads to further increases in axial length and increasingly severe myopia. In a 1-year study of ocular growth relative to refractive error in 1775 Asian children aged 6–10 years at enrolment, axial growth was faster in younger children and in those with myopia versus emmetropia, that is children with normal vision (P < 0.01), and hyperopia (P < 0.01). Axial length elongation slowed with age in all children regardless of the type of refractive error, and the depth of the anterior chamber deepened by 9 or 10 years and then became shallower by age 12 . The longest axial lengths and deepest anterior chambers were seen in those with myopia. However, Asian populations are naturally genetically determined as myopic (68.6% in this study), which supposes that these children must have been undercorrected, creating blurred vision and increasing myopic shift. In the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) study investigating refractive error and axial length in children aged 6–14 years at enrolment who became myopic (n = 604) or remained emmetropic (n = 374), those who became myopic had less hyperopia and longer axial lengths than emmetropes, before and after the onset of myopia (P < 0.0001) .
A possible mechanism for linking control of the axial length growth rate to vision during the emmetropization process in infants involves stimulation of the dopaminergic system via the retina  and secretion of eyeball growth factors , although a range of other external factors and biological growth control pathways, including retinoic acid receptors, serotonin, melatonin, and nitric oxide, may also be involved .
The impact of form deprivation and imposed defocusing on type of refractive error and ocular shape has been studied in rhesus monkeys. One study showed that, in a similar fashion to humans, form deprivation in infant primates resulted in alteration of the shape of the posterior globe and depth of the vitreous chamber and this influenced the type of peripheral refractive errors observed . Form deprivation and full-field or regional hyperopic defocus results in relative central axial myopia and relative peripheral hyperopia due to specific changes in eyeball shape (reduction in oblate shape). The effects in terms of regional refractive error and changes in ocular shape are dependent on the location of the visual deprivation [31,32]. In a study in infant rhesus monkeys, visual signals from the fovea were shown not to be essential for normal emmetropization or for any changes in ocular growth due to induced form deprivation . In another study conducted in infant rhesus monkeys by the same group, peripheral retina deprivation resulted in a disruption in the emmetropization process characterized by acceleration of axial elongation . In two subsequent studies, experimentally imposed blurring of peripheral vision resulted in changes in the shape and pattern of peripheral refractions in a regionally selective manner, indicating that peripheral hyperopia may play a role in the development of myopia [31,32].
A recently published review on myopia genetics has highlighted the identification of myopia susceptibility genes and the impact of abnormal gene expression in the eye and environmental factors on myopia risk including early-onset myopia in infants . Experimental myopia induced in mice has also been shown to be associated with elongation of the vitreous chamber as in humans and primates .
In infants, prolonged visual deprivation, due to partial or complete obstruction, lack of light stimulus (e.g., cataract), strabismus, or uncorrected difference in refractive error between the two eyes (anisometropia), can result in amblyopia [37–39]. Prolonged uncorrected visual deprivation leads to functional amblyopia, whereas strabismus or cataract can also cause organic amblyopia. Regardless of the etiology, amblyopia is usually unilateral: the visual acuity of one eye is reduced by the dominance of the other eye, and is a common visual impairment in children . Associated symptoms include poor stereoscopic depth perception, poor spatial acuity, low contrast sensitivity, and reduced motion sensitivity; however, despite these symptoms, amblyopia is often diagnosed in routine ocular examination and eye tests, and children (and parents and teachers, etc.) may not be aware of the condition because of compensation by the other eye.
In strabismus, neonates present with permanently or intermittently misaligned eyes (i.e., the visual axes of the eyes are misaligned), which usually self-corrects in the first few months after birth with reduction of accommodation spasms. In some infants, the eyes remain misaligned. The risk of amblyopia is higher in children with esotropic strabismus as this is more likely to be constant, whereas exotropic strabismus tends to be intermittent . Unilateral cataracts in infants can also cause functional deprivation amblyopia in addition to organic amblyopia .
Regardless of the original type of visual deprivation, the causal mechanism of functional deprivation amblyopia is the sustained reduced or lack of neural transmission of signals from the impaired eye (binocular competition) to the LGN, leading to atrophy of the neural components involved [27,40,41]. The risk of amblyopia is greatest in infants and young children because of the plasticity of the neurological components of vision and, as it is a problem related to visual development, new-onset amblyopia is extremely rare in adults . Amblyopia is seen in adults, but only persisting as untreated or unresolved amblyopia from childhood.
Fortunately, the plasticity of the developing CNS also means that amblyopia can be reversed if the condition is detected early and the causal visual deprivation is corrected , hence the need for early detection and treatment. However, if left untreated, continued visual deprivation can cause permanent morphological changes and atrophy of the LGN leading to permanent amblyopia [27,42].
The risk of amblyopia is increased during the sensitive window in early infancy [12,43]; this appears to correlate with a period of physiological and behavioral changes in visual function due to the initial overgrowth of neural presynaptic and postsynaptic elements in the visual cortex, and subsequent reduction to mature levels .
Developmental issues in preterm infants and neonates
Preterm birth is associated with a high risk of visual impairments such as oculomotor and refractive abnormalities . These may be due to early stimulation of an immature visual system (immature eyeball axial length and retinal vascularization), caused by nutritional deficits  or secondary to an underlying systemic disease or to complications associated with preterm birth .
Refractive anomalies are approximately eight times more common in preterm than in term infants [7,45]. Preterm babies can have retinopathy of prematurity (ROP), which is associated with a failure to emmetropize, resulting in high levels of refractive error, particularly the development of myopia, but the risk of refractive error is also increased in preterm babies without ROP [7,45]. Myopia and strabismus are more prevalent in premature than in full-term babies, particularly those with low birth weight, because the visual system is immature at birth .
Although not clearly understood, refractive impairment and myopia in preterm babies is thought to be associated with a range of factors, including increased keratometric value (curvature) of the cornea, decreased depth of the anterior chamber, and higher refractive power of the lens (lens thickness) [45,47]. In a 6-year longitudinal study investigating refractive status in 65 premature Korean infants with and without ROP, myopia was observed to appear at 6 months of age, increasing in severity up to 3 years . Researchers concluded that the main factors associated with increased severity of myopia of prematurity included shallower anterior chambers, thicker lenses, and higher axial lengths, but the corneal curvature was not found to influence myopia . The higher axial length is caused by visual deprivation because of the immaturity of the visual system: blurred vision leading to increased eyeball length . In infants with ROP, severe (or cicatricial, grade 4/5) retinopathy was an independent risk factor for myopia, whereas cryotherapy for ROP did not appear to influence myopia occurrence or severity . In a commentary on the work by Choi et al., Fledelius  pointed out that the established main contributory factor in ordinary myopia is increased axial length, whereas, in myopia of prematurity, axial lengths are relatively short, but remain elongated compared to those seen in infants without myopia.
Screening has been shown to result in reduced risk of ongoing eye problems. In an Israeli study evaluating the efficacy of a mass screening program for amblyopia and associated risk factors in infants, 808 infants systematically screened between the ages of 1 and 2.5 years had a lower rate of amblyopia at 8 years (1.0%), than a control cohort (n = 782) who did not undergo screening in infancy (2.6%; P = 0.0098). Furthermore, the prevalence of amblyopia with visual acuity 20/60 or less in the amblyopic eye was 0.1% in the screened population versus 1.7% in the nonscreened population (P = 0.00026) . Based on these data, screening had a negative predictive value of 99.6% and a positive predictive value of 62.1% . Despite problems in communication and attention, particularly in nonverbal infants, every effort should be made to screen for visual deficits at a few months of age to rule out functional amblyopia, as, at this age, the condition is reversible . The AAP/AAO/AAPOS and U.S. Preventive Services Task Force guidelines advocate that visual screening is carried at the level of the primary care doctor with appropriate referral to an ophthalmologist for those at high risk of vision problems or those suspected as having abnormal vision at any stage [3,4,51].
Evaluation by testing for visual acuity can be performed in newborns (3–12 months), and in preverbal (12–24 months) and verbal infants . Tests include preferential looking and visual tracking tests.
Preferential looking can be tested using static Teller acuity cards [53–55]; forced-choice preferential looking (FPL) or the Bébé vision test [56,57]; and other preferential looking or tracking tests, such as automated testing using computerized infrared oculography, which allows testing in preverbal infants . All methods employ a manual or automated system based on black and white patterns, usually vertical black and white bars or gratings on cards or screen. FPL can be used in neonates up to 6 months and is based on the premise that neonates dislike boring visual stimuli and will tend to look at a pattern rather than a plain display. In FPL, infants are shown a display containing a pattern (the stimulus) and the observer decides where the stimulus is located based on their observation of the infant's head and eye movements . As the highest spatial frequency that can be resolved by a child in preferential looking tests varies with age, the operant preferential looking (OPL) test has been adapted for use as a shorter screening procedure in children from as young as 6 months and up to 3 years by using the appropriate specific diagnostic grating frequency for the age of the child . Dobson et al. demonstrated a specific spatial frequency for each 6-month age group apart from 18 months. Use of specific spatial frequencies means that the test is shorter, more suitable for large-scale screening, and more likely to yield results in the time that a young child can be expected to remain cooperative.
In a study comparing the use of automated visual tracking (using photo-oculography) and preferential looking acuity cards to assess visual acuity in 51 healthy full-term infants from 3 to 93 days of age, the two methods were shown to correlate well with each other; automated visual tracking gave lower visual acuity measurements than preferential looking Teller acuity cards in the first 14 weeks of age . The reduced variation in the range of acuity with the automated procedure may be due to the objective nature of the test compared to the cards or may be due to greater attention, because the automated test uses movement instead of static patterns .
Visual evoked potential (VEP) testing  is used to assess communication between the eye and the brain and has been adapted for use in preverbal infants as an automated test known as sweep VEP . The sweep technique allows VEP to be measured in a few seconds, ensuring that the child's attention can be maintained and stable fixation achieved for a sufficient time to complete the test, even in newborns . However, as the test parameters are subjective and involve lengthy interpretation, sweep VEP is mainly used in the research setting.
ERG is used to assess retinal function by measuring the difference in electrical potential between the anterior eye surface and the face in response to a visual stimulus . The standard for clinical ERG, updated in 2008 by the International Society for Clinical Electrophysiology of Vision (ISCEV) , includes testing of rod, cone, and combined rod–cone responses; light-adapted and dark-adapted oscillatory potentials; and flicker .
Before any visual evaluation in children, a complete clinical examination should be performed, including examination under cycloplegia, to rule out a major refraction anomaly that needs to be corrected.
In children, testing color vision can be performed mainly using the Ishihara, Farnsworth D15, and other tests, but usually in verbal children (not before age 3). A modified acuity card technique has been used successfully for color vision testing in preschool infants . Testing for stereoscopy can be done at 12 months or earlier using the Lang, Wirt, and TNO tests [66,67].
A dietary source of long-chain polyunsaturated fatty acids (LC PUFAs) is important for visual development in neonates and infants [68–74]. Omega-3 fatty acid (FA) docosahexaenoic acid (DHA) and omega-6 FA arachidonic acid (ARA) appear to be important in the development of the ocular and associated neural tissues . LC PUFAs (DHA in particular) are found in the phospholipid layer of neuronal and retinal membranes and are thought to play a role in retinal and visual cortex maturation . Breast-feeding provides regular benefits in terms of visual development, thought to be partly due to the DHA in the breast milk [75–80]. Infant formula supplemented with DHA (1% or 0.05%) and ARA (0.10%) appears to improve visual development in premature infants [44,81], with prolonged benefits of LC PUFA supplementation (DHA 0.36% and ARA 0.72% [NB: the currently available formulation contains ARA 0.6%]) and linear improvement depending on the duration of supplemented milk feeding . Pooled data from four randomized studies were analyzed to investigate the relationship between duration of dietary LC PUFA supplementation of infant formula and visual acuity in 243 term infants. The primary outcome, visual acuity at 52 weeks of age as measured by sweep VEP, showed that longer duration of LC PUFA supply was associated with higher mean acuity (P < 0.001) regardless of whether the LC PUFAs were provided in formula containing 0.36% DHA and 0.72% ARA or in breast milk . These findings suggest that an infant's brain may not have sufficient stores of LC PUFAs to support the optimal maturation of the visual cortex. Other studies in full-term infants have also shown benefits with LC PUFA supplementation (DHA/ARA) in terms of visual acuity and neurodevelopmental outcomes, but others have failed to show significant beneficial effects [82–87]. In a study investigating the effects of maternal DHA supplementation on infant visual function, although the DHA content of breast milk and the DHA plasma concentration in the infant were increased, no benefits in terms of visual function were observed . In a review of studies involving LC PUFA supplementation in full-term infants, none of the individual studies found beneficial or harmful effects of LC PUFA supplementation on vision, irrespective of the type and duration of supplementation, and method of assessment .
The benefit of DHA in visual development is reinforced by the European Food Safety Authority statement, which suggests that a formula supplemented with at least 0.3% of total FA as DHA improves visual function at 12 months in term infants (either formula-fed or breast-fed).
Problems related to abnormal visual development in infants are common, but their occurrence can be minimized with more widespread use of early screening for visual deprivation and consequential functional amblyopia. Normal visual development is achieved after birth in progressive steps. Abnormal visual development can lead to handicap in adults. Two main pathological mechanisms can occur during a sensitive ‘window’ in early infancy. The mechanism of functional amblyopia is common, leading to a usually unilateral impaired vision, and results from inadequate visual input (organic amblyopia), but can be reversed with early re-education. The second mechanism is that of visual deprivation leading to excessively increased axial length because of blurred vision; this is axial myopia. It is important to be aware of the mechanisms involved in abnormal visual development so that these conditions can be screened for and treated early to prevent long-term or permanent visual deficits. This is particularly important in premature babies. Nutrition plays a key role in visual development, and infant formulas containing the LC PUFAs DHA and ARA found in breast milk may protect nonbreast-fed infants against visual development problems. This is reinforced by the European Food Safety Authority statement, which noted an association between intake of formula supplemented by DHA (at least 0.3%) and visual development at 12 months. Advances in our knowledge of fetal ocular development and imaging technology may allow earlier detection of ocular anomalies.
Medical writing assistance was provided by Mary Hines, from inScience Communications, a Wolters Kluwer business. This assistance was funded by Mead Johnson Nutrition. Other than support received for the preparation of this article, the authors have no financial interest in Mead Johnson Nutrition and its products.
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