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Preterm birth and visual development
Semin Neonatol 2001; 6:487–497 doi:10.1053/siny.2001.0077, available online at http://www.idealibrary.com on
Preterm birth and visual development Eileen E. Bircha and Anna R. O’Connor
Retina Foundation of the Southwest, Dallas, Texas, USA, and aUniversity of Texas Southwestern Medical Center, Dallas, Texas, USA
Key words: prematurity, vision, strabismus, ocular refraction, cortical blindness, acuity, visual evoked response, electroretinography, retina
Visual impairment, oculomotor abnormalities, and refractive error are prevalent among children with a history of preterm birth. These conditions may result from exposure of the immature visual system to early visual stimulation, from nutritional deficits that occur following the abrupt loss of placental maternal-to-fetal transfer of essential nutrients, and as secondary effects of systemic disease or complications associated with preterm birth. This chapter provides an overview of the structural and functional maturation of the visual system of the healthy preterm infant and of several forms of visual impairment that are prevalent in the low birth weight population. 2002 Published by Elsevier Science Ltd
Introduction While the last decade has seen major improvements in birth patterns, including prenatal care, declining numbers of women who smoke during pregnancy, and fewer cesarean deliveries, the prevalence of preterm birth has continued to increase since 1976. This increase is associated with increasing prevalence of multiple births as well as to changing maternal characteristics (more mothers over 35 years of age, more mothers with successful high risk pregnancies, more very young mothers). Preterm birth is a major cause of morbidity and also increases the risk of death from other perinatal conditions. However, recent advances in neonatology have led to dramatic improvements in survival rates. With more preterm infants surviving the neonatal and perinatal periods, the focus has begun to shift toward improving long-term functional outcomes for these high-risk infants. The focus of this chapter is on the effects of preterm birth for visual development and on the significant risk preterm birth poses for visual impairment. Preterm birth potentially plays an important role in visual development in two ways. First, Correspondence to: Eileen E. Birch, PhD, 9900 North Central Expressway, Suite 400, Dallas, TX 75231, USA. Tel: (214) 363-3911; Fax: (214) 363-4538; E-mail: [email protected]
1084–2756/02/$-see front matter
premature exteriorization removes the visual system from the nurturing intrauterine environment during a period of rapid maturation. The immature visual system is unnaturally subjected to external visual stimulation and its tissues can no longer depend on placental maternal-to-fetal transfer of essential nutrients. While the basic organization of the structures of the visual system appear to be specified innately, substantial immaturity is present in both preterm and term infants. It is clear that postnatal visual experience and nutrition can modify the fine structure and function of the visual system. Second, the overall immaturity of the preterm infant along with the many systemic associations and complications of preterm birth places the infant at significant risk for permanent visual impairment.
Structural immaturities of the visual system of the preterm infant Lids, globe, and nasolacrimal system The eyelids are fused until 24–25 weeks postconceptional age (PCA). In a study of eyelids opening in preterm neonates, Robinson et al. [1] found that the eyelids were closed during 55% of observation periods in infants less than 26 weeks PCA, 93% of observation periods at 28 © 2002 Published by Elsevier Science Ltd
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weeks PCA, and 60% of observation periods at 34 weeks PCA. The closed eyelids act as a red-pass filter, transmitting mostly long-wavelength light. When the eyelids are closed, neonatal eyelids transmitted about 50% more red light than adult eyelids [2]. No longitudinal studies of low birth weight populations provide the data to satisfactorily address the issues of rate of growth of the globe or separate out the effects of ROP and low birth weight per se. The ocular diameter measured in utero by ultrasound shows globe growth that is not linear, but has spurts between 16 and 20 weeks, 28 and 32 weeks and after 37 weeks [3]. On the other hand, post-mortem data support linear growth in the diameter and circumference of the eye [4]. The rate of growth is different for full term and preterm infants; axial length of the full term infants increases rapidly until the age of 4–5 months followed by a reduction in the rate of growth while axial lengths in the preterm group increase linearly until 12 months [5]. Preterm infants are capable of secreting tears but have reduced tear secretion, both basal and reflex compared with term infants prior to 40 weeks PCA [6]. Anterior segment In dim light, pupils of preterm infants under 31 weeks PCA are only about 4 mm in diameter and do not constrict to stimulating light [7]. The normal growth pattern of the cornea during development involves a significant reduction in the corneal curvature and an increase in diameter during the last weeks of gestation [8]. Keratometry readings have shown that the corneal curvature is steeper in low birth weight populations compared with term controls [9–11]. Studies of the anterior chamber depth in low birth weight children report differing results. In various studies, the mean anterior chamber depth at 40 weeks ranges from 2.0 mm to 2.4 mm [12,13]. Intraocular pressure (IOP) appears to be normal in premature infants [14]. The basic structure of the lens is in place by 14 weeks PCA; the nucleus of primary lens fibres and the hyaline capsule are present and the accumulation of secondary fibres on the central nuclear core is well underway. Together with an anterior network from the annular vessel, the hyaloid vascular system forms an intraocular network of blood vessels around the posterior part of the lens, which regresses between 28 and 34 weeks PCA.
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Retina All cell types in the retina appear in a central-toperipheral gradient during fetal development [15,16]. Mitosis in the retina ceases by 14 weeks PCA in the future fovea but continue out to at least 29 weeks PCA in the far periphery [16]; more mature human fetal retinas have not been studied. However, since rod photoreceptors continue to be generated in the far periphery of monkey retinas into the third postnatal week (equivalent to several months postnatal in the human infant), it is likely that peripheral rod photoreceptors are also continuing to be generated in humans beyond 40 weeks PCA. Stem cells have been identified at the peripheral margins of adult mammalian retina [17]. With the exception of the rod-free foveal area in the centre of the retina, rods and cones are intermixed but with different topographic distributions. Even at the earliest stages of fetal development, only cones are found in the central most retina [18]. At 22 weeks PCA, central and midperipheral rods and cones are beginning to differentiate while photoreceptors in the far periphery are still undergoing mitosis [19]. By 24 weeks PCA, the outer plexiform layer has reached the midperiphery, both rods and cones have inner segments, and photoreceptors in the central retina have rudimentary outer segments [19]. Outer segments and the outer plexiform layer are present throughout the retina by 28 weeks PCA but outer segments in the far periphery are still very small. The rod-free fovea is a highly specialized region of the central retina that contains the densely packed specialized cone photoreceptors that subserve detailed pattern vision. Detailed anatomic studies have shown that neither the migration of cone photoreceptors toward the foveal pit nor the movement of ganglion cells away from the foveal pit is complete until well beyond 57 weeks PCA. Moreover, the fine anatomic structure of foveal cone photoreceptors is not mature until at least 4 years of age [20]. Clinically, the macula appears pigmented but indistinct on ophthalmoscopy up to 34 weeks PCA. A distinct macular annular reflex is present by 36 weeks PCA but the foveal light reflex is not typically present until 42 weeks PCA [21] (Table 1). Optic nerve and lateral geniculate nucleus Each adult optic nerve contains about 1 million optic fibres, approximately half of which terminate
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Table 1. Structural developement of the visual system Postconceptual age (weeks) Eyelids
Anterior segment
Retina
Optic nerve CNS
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 >40 Eyelids fused Small, fixed pupils Reduced tear secretion Regression of hyaloid vascular system Corneal curvature Corneal diameter Cell mitosis complete in central area Cell mitosis continues in the periphery Cell All cell layers Migration of cone photoreceptors toward the foveal pit differentiation present begins in centre and midperiphery Macular pigmented but Migration of cone undefined photoreceptors toward the foveal pit
Overproduction of nerve fibres
Foveal light reflex present by 42 weeks Elimination of supernumerary optic Myelination of optic nerve fibres nerve and tract – 2 years Segmentation of inputs to the dorsal Increase of synapses in lateral geniculate nucleus rapid visual cortex until increase of synapses in visual cortex puberty
in the ipsilateral and half in the contralateral dorsal lateral geniculate nucleus (LGNd). Terminations from each of the two optic nerves are arranged in six separate layers of alternating ipsilateral and contralateral fibres. During the second trimester of fetal development, each nerve contains about 2.85 million optic fibres; the supernumerary fibres are later eliminated during the third trimester in coordination with the segmentation of inputs to the LGNd, suggesting that an active process eliminates contralateral fibres from some layers and ipsilateral fibres from other layers [22]. Myelination of the optic nerve and tract is incomplete at term and continues to increase until 2 years postnatal [23]. Clinically, optic disc morphology is affected by preterm birth [24]. Initially, it has an elliptic contour but after 2 months becomes round or slightly oval that may relate to other studies that have reported tilted discs [25,26].
Visual cortex There are no detailed data on the development of visual centres in the fetal or preterm infant human brain. However, excellent data are available from the rhesus monkey, an animal model that shares most of the complex structural and functional features of the human visual system [27]. Late fetal and early postnatal development of the cerebral cortex in both humans and monkeys is characterized by rapid increase in the number of synaptic contacts followed by a gradual decline in late infancy which continues until puberty [27–29]. It is well known that the initial period of cortical maturation during infancy is susceptible to alteration from environmental influences, particularly the visual cortex for which the role of abnormal visual experience in disrupting normal maturation is well established [30–32]. Most of these data
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Table 2. Functional development of the visual system
were based on studies of postnatal development of animals or humans born at term, but recently Rakic and colleagues [31] have examined the role of the visual environment in monkeys born prematurely. They found that premature visual stimulation does not affect the rate of synaptic accretion and overproduction that proceeded according to postconceptional age rather than postnatal age. On the other hand, the size, type, and laminar distribution of synapses were significantly different between animals born prior to, versus at, term. Thus, it appears that preterm visual experience modifies the visual cortex primarily by strengthening, modifying, or eliminating synapses that have already been formed rather than by regulating the rate of synapse production.
response recorded in the presence of an adapting background and the 30 Hz flicker cone response are similar to adult responses by 57 weeks PCA. Rod responses mature at a slower rate. At 34–36 weeks PCA, the rod response amplitude is considerably reduced (only about 2% of the adult amplitude) and in some infants non-detectable. Even at 57 weeks PCA, considerable immaturity of the rod response is present (still only 23% of the adult amplitude). More detailed analysis of the rod photoreceptor response shows that both rod sensitivity and the maximum saturated rod photoresponse mature during this perinatal period but sensitivity approaches adult levels earlier than the maximum photoresponse [35] (Table 2).
Functional immaturities of the visual system of the preterm infant
VEP
ERG Electroretinograms (ERGs) are massed electrical signals generated by the retina in response to visual stimulation. The full-field bright flash ERG provides an objective measure of the health and maturity of the retina, including the rod and cone photoreceptors and the inner retina. Full-field ERGs to bright white flashes of light have been recorded from preterm infants as early as 34 weeks PCA [33,34]. The response shows considerable immaturity at 36 weeks PCA, both in terms of amplitude and implicit time. The response rapidly matures in healthy preterm infants, so that by 57 weeks PCA, both amplitude and implicit time are approaching adult values. ERG protocols are available to study rod or cone responses in isolation. Cone responses mature rapidly in the perinatal period; both the cone
Visual evoked potential (VEPs) are massed electrical signals generated by the occipital cortex in response to visual stimulation. The transient light flash VEP is a complex waveform with multiple positive and negative peaks. Source localization and intracortical recording studies suggest that the transient light flash VEP reflects primarily the activity of the striate and extrastriate cortex [36–39]. There are also some wavelets in the transient light flash VEP that appear to be subcortical in origin. These wavelets are not major components of the VEP in healthy infants but may be relatively more prominent in infants for whom the cortical components are missing [36,37,40]. Thus, the presence of a transient light flash VEP cannot be taken as unequivocal evidence for cortical function unless it is established that the response is not comprised of subcortical wavelets. Flash VEPs have been recorded from preterm infants as early as 24 weeks PCA. At this early stage of development, only a single long latency negative peak is seen in the response [41]. The youngest infants reported to show a positive peak
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in the flash VEP were 32 weeks PCA [42,43]. When present, the latency of the positive peak decreases from about 220 msec at 34 weeks PCA to 190 msec at 40 weeks PCA, and 120 msec by 52 weeks PCA. The positive peak is present in virtually all healthy infants by 46 weeks PCA [42–44]. It is not clear whether changes in the waveform with age reflect visual development or changes in alertness of the infants with age. The majority of the pattern reversal VEP response is generated by the cortical projection of the macular area of the retina, i.e., the central 6 to 8 degrees of the visual field. It reflects primarily the activity of the striate cortex [45,46]. There have been no reports of pattern reversal VEPs in neonates who lack functional striate and extrastriate cortex. Thus, the presence of a pattern reversal VEP may be a good indicator of the presence of cortical function. Transient pattern reversal VEPs have been recorded from preterm infants as early as 30 weeks PCA [47,48]. At this age, the pattern reversal response contains a single positive peak with a latency of about 330 msec. Latency decreases to 240 msec by 40 weeks PCA and 125 msec by 53 weeks PCA. Beyond 44 weeks PCA, the waveform becomes more complex with multiple peaks and latency grows progressively shorter [49]. Steady-state pattern VEPs have been recorded from preterm infants as early as 35 weeks PCA with large pattern elements and slow pattern reversal rates [50,51]. Responses to smaller pattern elements and faster alternation rates can be recorded as the infants mature [51,52]. The pattern VEP reversal protocol can be expanded to provide a measure of visual acuity by examining the relationship between amplitude and check or stripe size. The earliest VEP acuities reported are from infants at 36 weeks PCA; at this age VEP acuity is about 20/200. VEP acuity matures rapidly to about 20/60 at 57 weeks PCA and to 20/30 by 66 weeks PCA [53,54]. Subtle continued improvements in VEP acuity continue well beyond the first year of life. PL Preferential looking (PL) provides a behavioural approach to assessment of visual function based on an observation originally made by Fantz [55] that an infant, given a choice between two stimuli varying along some dimension, can indicate his ability to discriminate between the two stimuli by
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looking more at one than the other. Teller and colleagues [56,57] modified preferential looking into a rigorous psychophysical paradigm that could provide useful, reliable, and valid data about various aspects of infant visual function. The most common application of preferential looking is to measure infant visual acuity by pairing a black-andwhite striped grating pattern with an adjacent gray pattern matched for overall luminance. After a series of gratings is presented (ranging from coarse to fine), acuity is estimated as the finest grating for which the infant showed a consistent looking preference. The pattern element size of the grating is usually specified in cycles per degree of visual angle (where one cycle=one black and one white stripe) but can easily be converted to other, more familiar notations (such as Snellen equivalent or logMAR). PL acuity has been measured as early as 32 weeks PCA; at that time point mean acuity is about 20/2000. PL acuity improves to about 20/400 at 42 weeks PCA, 20/150 at 57 weeks PCA, and 20/60 by 92 weeks PCA [58]. Mature acuity (20/20) is not achieved until after 3 years of age. PL acuity lags behind VEP acuity during development; the VEP reflects the maturity of the retina and striate cortex while PL responses also require visual attention and oculomotor fixation responses.
Does precocious visual experience have an accelerating or deleterious effect on visual development? Both stimulating and harmful effects of early precocious exposure to light or patterned visual stimulation have been suggested in the literature. Damage could be inflicted, for example, by changing the rate of synaptic production, interfering with the normal process of elimination of supernumerary synapses, or by disrupting the normal sequential differentiation of neurons or their connections. Stimulating effects could derive from early activation of visual experience-dependent neuronal pathways, enhancing their rate of maturation. With one exception [59], data in the literature suggest that preterm birth has no accelerating effect on the maturation of any ERG responses [33,50,60]. Looking at the same issue from another perspective, it is also clear that bilateral occlusion of preterm infants from birth to 31 weeks PCA (to protect them from possible deleterious effects of
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early light exposure) yields no change in the developmental profile for ERG responses [61]. In general, VEP and FPL acuity studies have found slight or no accelerating effect on the rate of acuity development [51,62,63–69]. In fact, while there appears to be little difference in acuity between healthy preterm and term infants during the first 57 weeks PCA, preterm infants may have an overall slower rate of acuity development so that, by 66 weeks PCA, acuity is significantly poorer in the preterm group. In addition, FPL acuity at 57 weeks PCA of preterm infants occluded until 31 weeks PCA had FPL acuities similar to those of preterm and term infants who had not been occluded [61].
Visual impairment While the previous sections described the maturational sequence for the structures and basic functions of the visual system in healthy preterm infants, it is clear that the overall immaturity of the preterm infant along with the many systemic associations and complications of preterm birth places the infant at significant risk for permanent visual impairment. Indeed, poor visual outcomes are noted in about 3% of the preterm population and severe visual impairment is present in about 1% [70–72]. Some cases of visual impairment are the result of retinopathy of prematurity, which is covered in detail in other chapters and so will not be addressed here. Many other premature children are visually impaired as a result of large refractive errors, strabismus, and/or cortical visual impairment. Refractive error Refractive error occurs when there is a mismatch between the axial length of the eye and its optical components (the power of the lens and corneal curvature). During normal development, infants born at term typically have mild hypermetropia (farsightedness) that gradually diminishes through a visually guided growth process called emmetropization. Among preterm infants, there is a higher prevalence of myopia (nearsightedness) than among term infants, despite the reduction in axial length; prevalence of hypermetropia is similar in the two groups [73–75]. Among preterm infants, myopia is associated with several indices of general
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health (e.g., bronchopulmonary dysplasia, shorter gestation, lower birth weight) as well as to severity of acute ROP and treatment with cryotherapy. An extreme form of myopia, called ‘myopia of prematurity’ has an infantile onset [76]. Various aetiologies have been proposed for myopia of prematurity, ranging from bone mineral deficiency that leads to dolichocephalic deformation of the skull and orbits [77] to a failure of the normal process of emmetropization [78,79]. Subtle or dramatic changes in retinal signalling associated with mild or severe acute ROP may alter eye growth signals. Acute ROP also might delay or halt the normal migration of the photoreceptors toward the fovea resulting in alterations of the microscopic topography of the central retina and acuity deficits sufficient to alter the visually driven feedback mechanism in emmetropization. In addition to myopia of prematurity, there is an increase in the prevalence of all myopia in the low birth weight population to more than double the prevalence found in term children [80,81]. Finally, there are also reports of an increase in other refractive errors, astigmatism [70] and anisometropia (unequal refractive error in the two eyes) [75,82] compared with full term controls. Uncorrected refractive error leads to chronic blurring which, during early visual development, may have a deleterious effect on long-term visual acuity outcome [83]. Myopia of prematurity is a special case in which refractive error may progress rapidly, the blur is so great that infants may suffer from visual deprivation amblyopia, and the infant is at risk for nystagmus and retinal detachment. Even if corrected with spectacles or contact lenses early, myopia of prematurity places the infant at high risk for developing anisometropia since large refractive errors can place the growing eye outside the range within which the normal process of emmetropization can function and because early fitting with optical correction itself can interfere with emmetropization. Anisometropia can lead to secondary visual disorders, including amblyopia and strabismus. Strabismus There are many studies that report the prevalence of strabismus (misalignment of the visual axes) among preterm infants. In various studies, the prevalence ranges from 3.1% in 6-month-olds without ROP to 57% in 5-year-olds who were born at
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less than 28 weeks PCA [84,85]. Nonetheless, it is clear that the prevalence of strabismus is higher in the preterm population than in the term population and that the high prevalence is associated with refractive error, severity of acute and cicatricial ROP, and several indices of general health status (including birthweight, severity of IVH, and severity of lung dysfunction). Not only is the prevalence of strabismus higher among preterm children but also the types of strabismus present are different, with a relative increase in exotropia in the low birth weight cohort [72]. The prevalence of pseudostrabismus is also higher among preterm infants since changes in the retina associated with ROP that alter the position of the visual axes (e.g., macular ectopia) can lead to the cosmetic appearance of strabismus. Strabismus places the infant at risk for amblyopia and abnormalities of binocular vision [86–88]. Amblyopia in turn places the infant at risk for anisometropia, which can further exacerbate the visual deficit [89]. Strabismus places the infant at risk for abnormalities in binocular vision, including reduced stereoacuity [90,91]. CVI Cortical visual impairment is more prevalent among preterm infants than term infants and may be associated with congenital infections or malformations, perinatal asphyxia, intraventricular haemorrhage, periventricular leukomalacia, syndromes, or other neurological disorders. Severe intraventricular haemorrhage is strongly associated with poor acuity outcome [92,93] and, even in those cases with normal acuity outcomes, other vision problems (such as, strabismus or nystagmus) may be present [93]. Jacobson et al. [94] have reported that cortical visual impairment is often clustered with other visual problems; e.g., cortical visual impairment associated with PVL is often accompanied by fixation difficulties, strabismus, nystagmus, visual field defect and ocular motility disturbances. Virtually all children with cortical visual impairment have abnormal flash VEPs, pattern VEPs, or both. Deficits in preferentiallooking acuity have been reported to be associated with intraventricular haemorrhage and periventricular leukomalacia [95,96]. In addition to ROP, refractive error, strabismus, and cortical visual impairment, other forms of visual impairment that have been reported for the
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preterm population including nystagmus [97–99], glaucoma [9,100–102], optic nerve hypoplasia [25,26], and eye movement and reading disorders [103].
Predictive value of early tests of visual function Abnormal flash or pattern VEPs are found in virtually all children with cortical visual impairment. Abnormal VEPs have proved to be accurate predictors of visual outcome in hypoxic-ischaemic encephalopathy [104,105]. While there are some parallels between asphyxia and hypoxic-ischaemic injury in the preterm brain, VEPs were not predictive of long-term outcome among preterm infants with intraventricular haemorrhage or periventricular leukomalacia [106]. Overall, most authors have concluded that VEP tests conducted in preterm infants during the first few months following birth only reliably predict outcome in cases of severe visual impairment. Abnormalities in flash VEPs have been demonstrated in infants with grade III or higher intraventricular haemorrhage but not in infants with milder haemorrhage; the abnormal response may reflect subcortical rather than cortical function and be predictive of long-term cortical visual impairment [107]. Abnormal flash VEPs are common in infants with periventricular low-density masses [108]; absence of one or more of the components of the flash VEP and/or increased latency of the components has been found in all affected infants. Normal flash VEPs were found in 88% of preterm infants with normal CAT scans. It is well established that preferential-looking acuity test results obtained during the first year of life are predictive of visual outcome, particularly in identifying severe visual impairment [63,109–111]. Specific to preterm infants, there have been several studies that address the predictive values of preferential-looking acuity screening of ‘high-risk’ preterm infants. In general, screening studies have concluded that acuity tests during infancy can identify cases of severe visual impairment which are likely to persist but are relatively insensitive to mild to moderate visual impairments [112,113]. The predictive value for screening acuity tests appears to increase when the screening is conducted at later or multiple ages during infancy [114]. In addition, several studies have addressed the predictive value of preferential-looking acuity testing for
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populations of preterm infants afflicted with specific conditions associated with prematurity or who are susceptible to a specific risk factor. Preferentiallooking acuity test results obtained during the first year are predictive of long-term acuity outcomes in preterm infants with ROP [115], following perinatal asphyxia [116], intraventricular haemorrhage [96], and cystic leukomalacia [117].
Nutrition Some dietary deficiencies during infancy may have long-term adverse effects on visual function. Studies have addressed the role of dietary taurine, vitamins A and E, and other essential nutrients. Recently, there has been intense focus on differences in the long-chain polyunsaturated fatty acid levels in human milk versus infant formula. Over 60% of the structural material in brain is lipids, including cholesterol and phosphoglycerides of neural membranes that are rich in docosahexaenoic acid (DHA). As a component of the central nervous system with a common embryonic origin, the retina contains similarly high levels of DHA as structural lipids, particularly in the metabolically active photoreceptor outer segments. Changes in the relative concentrations of brain and retinal phospholipids, especially large changes in DHA concentrations, during late fetal development may be reflected in cellular and neural maturation. There have been several randomized clinical trials in which the visual development of infants who were randomly assigned to receive formulas with or without DHA was studied (for review, see San Giovanni [118]). The evidence suggests that formula-fed preterm infants are at particular risk from DHA deficiency because they are deprived of the last trimester of placental maternal-to-fetal transfer of DHA and have limited capacity to endogenously synthesize DHA from the precursor fatty acids provided by infant formulas. Preterm infants fed commercial formulas without DHA show lower DHA levels in red blood cell membranes and cerebral cortex [119–123], poorer retinal function [33,34], and poorer acuity [51]. Thus, an adequate supply of long-chain polyunsaturated fatty acids, preferably through breastfeeding, may be of vital importance to the developing eye and brain of preterm infants. While some countries now have commercial preterm infant formulas that provide DHA, many (including the United States) do not.
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Summary The preterm infant is exposed to premature visual stimulation and its tissues can no longer depend on placental maternal-to-fetal transfer of essential nutrients. While the maturation of the structures of the visual system apparently proceeds along an innately specified course in the healthy infant, there exists substantial risk of visual impairment resulting from premature exteriorization of the maturing visual system as well as from the systemic associations and complications of preterm birth. References 1 Robinson J, Moseley MJ, Thompson JR, Fielder AR. Eyelid opening in preterm neonates. Arch Dis Child 1989; 64: 943–948. 2 Robinson J, Moseley M, Fielder AR, Bayliss S. Light transmission measurements and phototherapy eyepatches. Arch Dis Child 1991; 66: 59–61. 3 Birnholz JC. Ultrasonic fetal ophthalmology. Early Hum Dev 1985; 12: 199–209. 4 Harayama K, Amemiya T, Nishimura H. Development of the eyeball during fetal life. J Pediatr Ophthalmol Strabismus 1981; 18: 37–40. 5 Hirano S, Yamamoto Y, Takayama H, Sugata Y, Matsuo K. Ultrasonic observation of eyes in premature babies. VI. growth curves of ocular axial length and its components. Acta Soc Ophthalmol Jpn 1979; 83: 1679–1693. 6 Isenberg SJ, Apt L, McCarty J, Cooper LL, Lim L, Del Signore M. Development of tearing in preterm and term neonates. Arch Ophthalmol 1998; 116: 773–776. 7 Isenberg SJ, Molarte A, Vazquez M. The fixed and dilated pupils of premature neonates. Am J Ophthalmol 1990; 110: 168–171. 8 Donzis PB, Insler MS, Gordon RA. Corneal curvatures in premature infants. Am J Ophthalmol 1985; 99: 213– 215. 9 Hittner HM, Rhodes LM, McPherson AR. Anterior segment abnormalities in cicatricial retinopathy of prematurity. Annual Meeting American Academy of Ophthalmology 1979; 00: 803–818. 10 Gallo JE, Fagerholm P. Low-grade myopia in children with regressed ROP. Acta Ophthalmol (Copenh) 1993; 71: 519–523. 11 Fledelius HC. Ophthalmic changes from age of 10 to 18 years. Part III ultrasound oculometry and keratometry of anterior eye segment. Acta Ophthalmol (Copenh) 1982; 60: 393–402. 12 Isenberg SJ, Neumann D, Cheong YY, Ling YLF, McCall LC, Ziffer AJ. Growth of the internal and external eye in term and preterm infants. Ophthalmology 1995; 102: 827–830. 13 O’Brien C, Clark D. Ocular biometry in pre-term infants without retinopathy of prematurity. Eye 1994; 8: 662– 665. 14 Tucker SM, Enzenauer RW, Levin AV, Morin JD, Hellmann J. Corneal diameter, axial length, and IOP
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Preterm birth and visual development Eileen E. Bircha and Anna R. O’Connor
Retina Foundation of the Southwest, Dallas, Texas, USA, and aUniversity of Texas Southwestern Medical Center, Dallas, Texas, USA
Key words: prematurity, vision, strabismus, ocular refraction, cortical blindness, acuity, visual evoked response, electroretinography, retina
Visual impairment, oculomotor abnormalities, and refractive error are prevalent among children with a history of preterm birth. These conditions may result from exposure of the immature visual system to early visual stimulation, from nutritional deficits that occur following the abrupt loss of placental maternal-to-fetal transfer of essential nutrients, and as secondary effects of systemic disease or complications associated with preterm birth. This chapter provides an overview of the structural and functional maturation of the visual system of the healthy preterm infant and of several forms of visual impairment that are prevalent in the low birth weight population. 2002 Published by Elsevier Science Ltd
Introduction While the last decade has seen major improvements in birth patterns, including prenatal care, declining numbers of women who smoke during pregnancy, and fewer cesarean deliveries, the prevalence of preterm birth has continued to increase since 1976. This increase is associated with increasing prevalence of multiple births as well as to changing maternal characteristics (more mothers over 35 years of age, more mothers with successful high risk pregnancies, more very young mothers). Preterm birth is a major cause of morbidity and also increases the risk of death from other perinatal conditions. However, recent advances in neonatology have led to dramatic improvements in survival rates. With more preterm infants surviving the neonatal and perinatal periods, the focus has begun to shift toward improving long-term functional outcomes for these high-risk infants. The focus of this chapter is on the effects of preterm birth for visual development and on the significant risk preterm birth poses for visual impairment. Preterm birth potentially plays an important role in visual development in two ways. First, Correspondence to: Eileen E. Birch, PhD, 9900 North Central Expressway, Suite 400, Dallas, TX 75231, USA. Tel: (214) 363-3911; Fax: (214) 363-4538; E-mail: [email protected]
1084–2756/02/$-see front matter
premature exteriorization removes the visual system from the nurturing intrauterine environment during a period of rapid maturation. The immature visual system is unnaturally subjected to external visual stimulation and its tissues can no longer depend on placental maternal-to-fetal transfer of essential nutrients. While the basic organization of the structures of the visual system appear to be specified innately, substantial immaturity is present in both preterm and term infants. It is clear that postnatal visual experience and nutrition can modify the fine structure and function of the visual system. Second, the overall immaturity of the preterm infant along with the many systemic associations and complications of preterm birth places the infant at significant risk for permanent visual impairment.
Structural immaturities of the visual system of the preterm infant Lids, globe, and nasolacrimal system The eyelids are fused until 24–25 weeks postconceptional age (PCA). In a study of eyelids opening in preterm neonates, Robinson et al. [1] found that the eyelids were closed during 55% of observation periods in infants less than 26 weeks PCA, 93% of observation periods at 28 © 2002 Published by Elsevier Science Ltd
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weeks PCA, and 60% of observation periods at 34 weeks PCA. The closed eyelids act as a red-pass filter, transmitting mostly long-wavelength light. When the eyelids are closed, neonatal eyelids transmitted about 50% more red light than adult eyelids [2]. No longitudinal studies of low birth weight populations provide the data to satisfactorily address the issues of rate of growth of the globe or separate out the effects of ROP and low birth weight per se. The ocular diameter measured in utero by ultrasound shows globe growth that is not linear, but has spurts between 16 and 20 weeks, 28 and 32 weeks and after 37 weeks [3]. On the other hand, post-mortem data support linear growth in the diameter and circumference of the eye [4]. The rate of growth is different for full term and preterm infants; axial length of the full term infants increases rapidly until the age of 4–5 months followed by a reduction in the rate of growth while axial lengths in the preterm group increase linearly until 12 months [5]. Preterm infants are capable of secreting tears but have reduced tear secretion, both basal and reflex compared with term infants prior to 40 weeks PCA [6]. Anterior segment In dim light, pupils of preterm infants under 31 weeks PCA are only about 4 mm in diameter and do not constrict to stimulating light [7]. The normal growth pattern of the cornea during development involves a significant reduction in the corneal curvature and an increase in diameter during the last weeks of gestation [8]. Keratometry readings have shown that the corneal curvature is steeper in low birth weight populations compared with term controls [9–11]. Studies of the anterior chamber depth in low birth weight children report differing results. In various studies, the mean anterior chamber depth at 40 weeks ranges from 2.0 mm to 2.4 mm [12,13]. Intraocular pressure (IOP) appears to be normal in premature infants [14]. The basic structure of the lens is in place by 14 weeks PCA; the nucleus of primary lens fibres and the hyaline capsule are present and the accumulation of secondary fibres on the central nuclear core is well underway. Together with an anterior network from the annular vessel, the hyaloid vascular system forms an intraocular network of blood vessels around the posterior part of the lens, which regresses between 28 and 34 weeks PCA.
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Retina All cell types in the retina appear in a central-toperipheral gradient during fetal development [15,16]. Mitosis in the retina ceases by 14 weeks PCA in the future fovea but continue out to at least 29 weeks PCA in the far periphery [16]; more mature human fetal retinas have not been studied. However, since rod photoreceptors continue to be generated in the far periphery of monkey retinas into the third postnatal week (equivalent to several months postnatal in the human infant), it is likely that peripheral rod photoreceptors are also continuing to be generated in humans beyond 40 weeks PCA. Stem cells have been identified at the peripheral margins of adult mammalian retina [17]. With the exception of the rod-free foveal area in the centre of the retina, rods and cones are intermixed but with different topographic distributions. Even at the earliest stages of fetal development, only cones are found in the central most retina [18]. At 22 weeks PCA, central and midperipheral rods and cones are beginning to differentiate while photoreceptors in the far periphery are still undergoing mitosis [19]. By 24 weeks PCA, the outer plexiform layer has reached the midperiphery, both rods and cones have inner segments, and photoreceptors in the central retina have rudimentary outer segments [19]. Outer segments and the outer plexiform layer are present throughout the retina by 28 weeks PCA but outer segments in the far periphery are still very small. The rod-free fovea is a highly specialized region of the central retina that contains the densely packed specialized cone photoreceptors that subserve detailed pattern vision. Detailed anatomic studies have shown that neither the migration of cone photoreceptors toward the foveal pit nor the movement of ganglion cells away from the foveal pit is complete until well beyond 57 weeks PCA. Moreover, the fine anatomic structure of foveal cone photoreceptors is not mature until at least 4 years of age [20]. Clinically, the macula appears pigmented but indistinct on ophthalmoscopy up to 34 weeks PCA. A distinct macular annular reflex is present by 36 weeks PCA but the foveal light reflex is not typically present until 42 weeks PCA [21] (Table 1). Optic nerve and lateral geniculate nucleus Each adult optic nerve contains about 1 million optic fibres, approximately half of which terminate
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Table 1. Structural developement of the visual system Postconceptual age (weeks) Eyelids
Anterior segment
Retina
Optic nerve CNS
20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 >40 Eyelids fused Small, fixed pupils Reduced tear secretion Regression of hyaloid vascular system Corneal curvature Corneal diameter Cell mitosis complete in central area Cell mitosis continues in the periphery Cell All cell layers Migration of cone photoreceptors toward the foveal pit differentiation present begins in centre and midperiphery Macular pigmented but Migration of cone undefined photoreceptors toward the foveal pit
Overproduction of nerve fibres
Foveal light reflex present by 42 weeks Elimination of supernumerary optic Myelination of optic nerve fibres nerve and tract – 2 years Segmentation of inputs to the dorsal Increase of synapses in lateral geniculate nucleus rapid visual cortex until increase of synapses in visual cortex puberty
in the ipsilateral and half in the contralateral dorsal lateral geniculate nucleus (LGNd). Terminations from each of the two optic nerves are arranged in six separate layers of alternating ipsilateral and contralateral fibres. During the second trimester of fetal development, each nerve contains about 2.85 million optic fibres; the supernumerary fibres are later eliminated during the third trimester in coordination with the segmentation of inputs to the LGNd, suggesting that an active process eliminates contralateral fibres from some layers and ipsilateral fibres from other layers [22]. Myelination of the optic nerve and tract is incomplete at term and continues to increase until 2 years postnatal [23]. Clinically, optic disc morphology is affected by preterm birth [24]. Initially, it has an elliptic contour but after 2 months becomes round or slightly oval that may relate to other studies that have reported tilted discs [25,26].
Visual cortex There are no detailed data on the development of visual centres in the fetal or preterm infant human brain. However, excellent data are available from the rhesus monkey, an animal model that shares most of the complex structural and functional features of the human visual system [27]. Late fetal and early postnatal development of the cerebral cortex in both humans and monkeys is characterized by rapid increase in the number of synaptic contacts followed by a gradual decline in late infancy which continues until puberty [27–29]. It is well known that the initial period of cortical maturation during infancy is susceptible to alteration from environmental influences, particularly the visual cortex for which the role of abnormal visual experience in disrupting normal maturation is well established [30–32]. Most of these data
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Table 2. Functional development of the visual system
were based on studies of postnatal development of animals or humans born at term, but recently Rakic and colleagues [31] have examined the role of the visual environment in monkeys born prematurely. They found that premature visual stimulation does not affect the rate of synaptic accretion and overproduction that proceeded according to postconceptional age rather than postnatal age. On the other hand, the size, type, and laminar distribution of synapses were significantly different between animals born prior to, versus at, term. Thus, it appears that preterm visual experience modifies the visual cortex primarily by strengthening, modifying, or eliminating synapses that have already been formed rather than by regulating the rate of synapse production.
response recorded in the presence of an adapting background and the 30 Hz flicker cone response are similar to adult responses by 57 weeks PCA. Rod responses mature at a slower rate. At 34–36 weeks PCA, the rod response amplitude is considerably reduced (only about 2% of the adult amplitude) and in some infants non-detectable. Even at 57 weeks PCA, considerable immaturity of the rod response is present (still only 23% of the adult amplitude). More detailed analysis of the rod photoreceptor response shows that both rod sensitivity and the maximum saturated rod photoresponse mature during this perinatal period but sensitivity approaches adult levels earlier than the maximum photoresponse [35] (Table 2).
Functional immaturities of the visual system of the preterm infant
VEP
ERG Electroretinograms (ERGs) are massed electrical signals generated by the retina in response to visual stimulation. The full-field bright flash ERG provides an objective measure of the health and maturity of the retina, including the rod and cone photoreceptors and the inner retina. Full-field ERGs to bright white flashes of light have been recorded from preterm infants as early as 34 weeks PCA [33,34]. The response shows considerable immaturity at 36 weeks PCA, both in terms of amplitude and implicit time. The response rapidly matures in healthy preterm infants, so that by 57 weeks PCA, both amplitude and implicit time are approaching adult values. ERG protocols are available to study rod or cone responses in isolation. Cone responses mature rapidly in the perinatal period; both the cone
Visual evoked potential (VEPs) are massed electrical signals generated by the occipital cortex in response to visual stimulation. The transient light flash VEP is a complex waveform with multiple positive and negative peaks. Source localization and intracortical recording studies suggest that the transient light flash VEP reflects primarily the activity of the striate and extrastriate cortex [36–39]. There are also some wavelets in the transient light flash VEP that appear to be subcortical in origin. These wavelets are not major components of the VEP in healthy infants but may be relatively more prominent in infants for whom the cortical components are missing [36,37,40]. Thus, the presence of a transient light flash VEP cannot be taken as unequivocal evidence for cortical function unless it is established that the response is not comprised of subcortical wavelets. Flash VEPs have been recorded from preterm infants as early as 24 weeks PCA. At this early stage of development, only a single long latency negative peak is seen in the response [41]. The youngest infants reported to show a positive peak
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in the flash VEP were 32 weeks PCA [42,43]. When present, the latency of the positive peak decreases from about 220 msec at 34 weeks PCA to 190 msec at 40 weeks PCA, and 120 msec by 52 weeks PCA. The positive peak is present in virtually all healthy infants by 46 weeks PCA [42–44]. It is not clear whether changes in the waveform with age reflect visual development or changes in alertness of the infants with age. The majority of the pattern reversal VEP response is generated by the cortical projection of the macular area of the retina, i.e., the central 6 to 8 degrees of the visual field. It reflects primarily the activity of the striate cortex [45,46]. There have been no reports of pattern reversal VEPs in neonates who lack functional striate and extrastriate cortex. Thus, the presence of a pattern reversal VEP may be a good indicator of the presence of cortical function. Transient pattern reversal VEPs have been recorded from preterm infants as early as 30 weeks PCA [47,48]. At this age, the pattern reversal response contains a single positive peak with a latency of about 330 msec. Latency decreases to 240 msec by 40 weeks PCA and 125 msec by 53 weeks PCA. Beyond 44 weeks PCA, the waveform becomes more complex with multiple peaks and latency grows progressively shorter [49]. Steady-state pattern VEPs have been recorded from preterm infants as early as 35 weeks PCA with large pattern elements and slow pattern reversal rates [50,51]. Responses to smaller pattern elements and faster alternation rates can be recorded as the infants mature [51,52]. The pattern VEP reversal protocol can be expanded to provide a measure of visual acuity by examining the relationship between amplitude and check or stripe size. The earliest VEP acuities reported are from infants at 36 weeks PCA; at this age VEP acuity is about 20/200. VEP acuity matures rapidly to about 20/60 at 57 weeks PCA and to 20/30 by 66 weeks PCA [53,54]. Subtle continued improvements in VEP acuity continue well beyond the first year of life. PL Preferential looking (PL) provides a behavioural approach to assessment of visual function based on an observation originally made by Fantz [55] that an infant, given a choice between two stimuli varying along some dimension, can indicate his ability to discriminate between the two stimuli by
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looking more at one than the other. Teller and colleagues [56,57] modified preferential looking into a rigorous psychophysical paradigm that could provide useful, reliable, and valid data about various aspects of infant visual function. The most common application of preferential looking is to measure infant visual acuity by pairing a black-andwhite striped grating pattern with an adjacent gray pattern matched for overall luminance. After a series of gratings is presented (ranging from coarse to fine), acuity is estimated as the finest grating for which the infant showed a consistent looking preference. The pattern element size of the grating is usually specified in cycles per degree of visual angle (where one cycle=one black and one white stripe) but can easily be converted to other, more familiar notations (such as Snellen equivalent or logMAR). PL acuity has been measured as early as 32 weeks PCA; at that time point mean acuity is about 20/2000. PL acuity improves to about 20/400 at 42 weeks PCA, 20/150 at 57 weeks PCA, and 20/60 by 92 weeks PCA [58]. Mature acuity (20/20) is not achieved until after 3 years of age. PL acuity lags behind VEP acuity during development; the VEP reflects the maturity of the retina and striate cortex while PL responses also require visual attention and oculomotor fixation responses.
Does precocious visual experience have an accelerating or deleterious effect on visual development? Both stimulating and harmful effects of early precocious exposure to light or patterned visual stimulation have been suggested in the literature. Damage could be inflicted, for example, by changing the rate of synaptic production, interfering with the normal process of elimination of supernumerary synapses, or by disrupting the normal sequential differentiation of neurons or their connections. Stimulating effects could derive from early activation of visual experience-dependent neuronal pathways, enhancing their rate of maturation. With one exception [59], data in the literature suggest that preterm birth has no accelerating effect on the maturation of any ERG responses [33,50,60]. Looking at the same issue from another perspective, it is also clear that bilateral occlusion of preterm infants from birth to 31 weeks PCA (to protect them from possible deleterious effects of
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early light exposure) yields no change in the developmental profile for ERG responses [61]. In general, VEP and FPL acuity studies have found slight or no accelerating effect on the rate of acuity development [51,62,63–69]. In fact, while there appears to be little difference in acuity between healthy preterm and term infants during the first 57 weeks PCA, preterm infants may have an overall slower rate of acuity development so that, by 66 weeks PCA, acuity is significantly poorer in the preterm group. In addition, FPL acuity at 57 weeks PCA of preterm infants occluded until 31 weeks PCA had FPL acuities similar to those of preterm and term infants who had not been occluded [61].
Visual impairment While the previous sections described the maturational sequence for the structures and basic functions of the visual system in healthy preterm infants, it is clear that the overall immaturity of the preterm infant along with the many systemic associations and complications of preterm birth places the infant at significant risk for permanent visual impairment. Indeed, poor visual outcomes are noted in about 3% of the preterm population and severe visual impairment is present in about 1% [70–72]. Some cases of visual impairment are the result of retinopathy of prematurity, which is covered in detail in other chapters and so will not be addressed here. Many other premature children are visually impaired as a result of large refractive errors, strabismus, and/or cortical visual impairment. Refractive error Refractive error occurs when there is a mismatch between the axial length of the eye and its optical components (the power of the lens and corneal curvature). During normal development, infants born at term typically have mild hypermetropia (farsightedness) that gradually diminishes through a visually guided growth process called emmetropization. Among preterm infants, there is a higher prevalence of myopia (nearsightedness) than among term infants, despite the reduction in axial length; prevalence of hypermetropia is similar in the two groups [73–75]. Among preterm infants, myopia is associated with several indices of general
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health (e.g., bronchopulmonary dysplasia, shorter gestation, lower birth weight) as well as to severity of acute ROP and treatment with cryotherapy. An extreme form of myopia, called ‘myopia of prematurity’ has an infantile onset [76]. Various aetiologies have been proposed for myopia of prematurity, ranging from bone mineral deficiency that leads to dolichocephalic deformation of the skull and orbits [77] to a failure of the normal process of emmetropization [78,79]. Subtle or dramatic changes in retinal signalling associated with mild or severe acute ROP may alter eye growth signals. Acute ROP also might delay or halt the normal migration of the photoreceptors toward the fovea resulting in alterations of the microscopic topography of the central retina and acuity deficits sufficient to alter the visually driven feedback mechanism in emmetropization. In addition to myopia of prematurity, there is an increase in the prevalence of all myopia in the low birth weight population to more than double the prevalence found in term children [80,81]. Finally, there are also reports of an increase in other refractive errors, astigmatism [70] and anisometropia (unequal refractive error in the two eyes) [75,82] compared with full term controls. Uncorrected refractive error leads to chronic blurring which, during early visual development, may have a deleterious effect on long-term visual acuity outcome [83]. Myopia of prematurity is a special case in which refractive error may progress rapidly, the blur is so great that infants may suffer from visual deprivation amblyopia, and the infant is at risk for nystagmus and retinal detachment. Even if corrected with spectacles or contact lenses early, myopia of prematurity places the infant at high risk for developing anisometropia since large refractive errors can place the growing eye outside the range within which the normal process of emmetropization can function and because early fitting with optical correction itself can interfere with emmetropization. Anisometropia can lead to secondary visual disorders, including amblyopia and strabismus. Strabismus There are many studies that report the prevalence of strabismus (misalignment of the visual axes) among preterm infants. In various studies, the prevalence ranges from 3.1% in 6-month-olds without ROP to 57% in 5-year-olds who were born at
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less than 28 weeks PCA [84,85]. Nonetheless, it is clear that the prevalence of strabismus is higher in the preterm population than in the term population and that the high prevalence is associated with refractive error, severity of acute and cicatricial ROP, and several indices of general health status (including birthweight, severity of IVH, and severity of lung dysfunction). Not only is the prevalence of strabismus higher among preterm children but also the types of strabismus present are different, with a relative increase in exotropia in the low birth weight cohort [72]. The prevalence of pseudostrabismus is also higher among preterm infants since changes in the retina associated with ROP that alter the position of the visual axes (e.g., macular ectopia) can lead to the cosmetic appearance of strabismus. Strabismus places the infant at risk for amblyopia and abnormalities of binocular vision [86–88]. Amblyopia in turn places the infant at risk for anisometropia, which can further exacerbate the visual deficit [89]. Strabismus places the infant at risk for abnormalities in binocular vision, including reduced stereoacuity [90,91]. CVI Cortical visual impairment is more prevalent among preterm infants than term infants and may be associated with congenital infections or malformations, perinatal asphyxia, intraventricular haemorrhage, periventricular leukomalacia, syndromes, or other neurological disorders. Severe intraventricular haemorrhage is strongly associated with poor acuity outcome [92,93] and, even in those cases with normal acuity outcomes, other vision problems (such as, strabismus or nystagmus) may be present [93]. Jacobson et al. [94] have reported that cortical visual impairment is often clustered with other visual problems; e.g., cortical visual impairment associated with PVL is often accompanied by fixation difficulties, strabismus, nystagmus, visual field defect and ocular motility disturbances. Virtually all children with cortical visual impairment have abnormal flash VEPs, pattern VEPs, or both. Deficits in preferentiallooking acuity have been reported to be associated with intraventricular haemorrhage and periventricular leukomalacia [95,96]. In addition to ROP, refractive error, strabismus, and cortical visual impairment, other forms of visual impairment that have been reported for the
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preterm population including nystagmus [97–99], glaucoma [9,100–102], optic nerve hypoplasia [25,26], and eye movement and reading disorders [103].
Predictive value of early tests of visual function Abnormal flash or pattern VEPs are found in virtually all children with cortical visual impairment. Abnormal VEPs have proved to be accurate predictors of visual outcome in hypoxic-ischaemic encephalopathy [104,105]. While there are some parallels between asphyxia and hypoxic-ischaemic injury in the preterm brain, VEPs were not predictive of long-term outcome among preterm infants with intraventricular haemorrhage or periventricular leukomalacia [106]. Overall, most authors have concluded that VEP tests conducted in preterm infants during the first few months following birth only reliably predict outcome in cases of severe visual impairment. Abnormalities in flash VEPs have been demonstrated in infants with grade III or higher intraventricular haemorrhage but not in infants with milder haemorrhage; the abnormal response may reflect subcortical rather than cortical function and be predictive of long-term cortical visual impairment [107]. Abnormal flash VEPs are common in infants with periventricular low-density masses [108]; absence of one or more of the components of the flash VEP and/or increased latency of the components has been found in all affected infants. Normal flash VEPs were found in 88% of preterm infants with normal CAT scans. It is well established that preferential-looking acuity test results obtained during the first year of life are predictive of visual outcome, particularly in identifying severe visual impairment [63,109–111]. Specific to preterm infants, there have been several studies that address the predictive values of preferential-looking acuity screening of ‘high-risk’ preterm infants. In general, screening studies have concluded that acuity tests during infancy can identify cases of severe visual impairment which are likely to persist but are relatively insensitive to mild to moderate visual impairments [112,113]. The predictive value for screening acuity tests appears to increase when the screening is conducted at later or multiple ages during infancy [114]. In addition, several studies have addressed the predictive value of preferential-looking acuity testing for
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populations of preterm infants afflicted with specific conditions associated with prematurity or who are susceptible to a specific risk factor. Preferentiallooking acuity test results obtained during the first year are predictive of long-term acuity outcomes in preterm infants with ROP [115], following perinatal asphyxia [116], intraventricular haemorrhage [96], and cystic leukomalacia [117].
Nutrition Some dietary deficiencies during infancy may have long-term adverse effects on visual function. Studies have addressed the role of dietary taurine, vitamins A and E, and other essential nutrients. Recently, there has been intense focus on differences in the long-chain polyunsaturated fatty acid levels in human milk versus infant formula. Over 60% of the structural material in brain is lipids, including cholesterol and phosphoglycerides of neural membranes that are rich in docosahexaenoic acid (DHA). As a component of the central nervous system with a common embryonic origin, the retina contains similarly high levels of DHA as structural lipids, particularly in the metabolically active photoreceptor outer segments. Changes in the relative concentrations of brain and retinal phospholipids, especially large changes in DHA concentrations, during late fetal development may be reflected in cellular and neural maturation. There have been several randomized clinical trials in which the visual development of infants who were randomly assigned to receive formulas with or without DHA was studied (for review, see San Giovanni [118]). The evidence suggests that formula-fed preterm infants are at particular risk from DHA deficiency because they are deprived of the last trimester of placental maternal-to-fetal transfer of DHA and have limited capacity to endogenously synthesize DHA from the precursor fatty acids provided by infant formulas. Preterm infants fed commercial formulas without DHA show lower DHA levels in red blood cell membranes and cerebral cortex [119–123], poorer retinal function [33,34], and poorer acuity [51]. Thus, an adequate supply of long-chain polyunsaturated fatty acids, preferably through breastfeeding, may be of vital importance to the developing eye and brain of preterm infants. While some countries now have commercial preterm infant formulas that provide DHA, many (including the United States) do not.
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