The neurovascular retina in retinopathy of prematurity

https://doi.org/10.1016/j.preteyeres.2009.06.003Get rights and content

Abstract

The continuing worldwide epidemic of retinopathy of prematurity (ROP), a leading cause of childhood visual impairment, strongly motivates further research into mechanisms of the disease. Although the hallmark of ROP is abnormal retinal vasculature, a growing body of evidence supports a critical role for the neural retina in the ROP disease process. The age of onset of ROP coincides with the rapid developmental increase in rod photoreceptor outer segment length and rhodopsin content of the retina with escalation of energy demands. Using a combination of non-invasive electroretinographic (ERG), psychophysical, and image analysis procedures, the neural retina and its vasculature have been studied in prematurely born human subjects, both with and without ROP, and in rats that model the key vascular and neural parameters found in human ROP subjects. These data are compared to comprehensive numeric summaries of the neural and vascular features in normally developing human and rat retina. In rats, biochemical, anatomical, and molecular biological investigations are paired with the non-invasive assessments. ROP, even if mild, primarily and persistently alters the structure and function of photoreceptors. Post-receptor neurons and retinal vasculature, which are intimately related, are also affected by ROP; conspicuous neurovascular abnormalities disappear, but subtle structural anomalies and functional deficits may persist years after clinical ROP resolves. The data from human subjects and rat models identify photoreceptor and post-receptor targets for interventions that promise improved outcomes for children at risk for ROP.

Introduction

Preterm birth introduces a tiny infant into an extrauterine world for which the infant's tissues and organs are incompletely prepared. In this external environment, the immature neurovascular tissues of the visual system, the retina and the brain, are particularly susceptible to injury (Volpe, 2009). The earlier the preterm birth, the greater the risk for damage to the retina and visual pathways. The clinical entity involving the retina is called retinopathy of prematurity (ROP); abnormalities of the retinal vasculature are the clinical hallmark of ROP. A growing body of evidence, however, demonstrates that the neural retina is critically involved in the ROP disease process. The onset of ROP is at approximately 32 weeks gestational age (term ≅40 weeks) regardless of the gestation at birth (Palmer et al., 1991). Interestingly, this coincides with the rapid developmental elongation of the rod outer segments and increase in retinal rhodopsin content (Fig. 1). As this rapid maturation occurs, putative energy demands of the rod escalate due to increase in turnover of outer segment material and the rod's circulating current.

Our studies of ROP are dedicated to delineating the closely allied neural and vascular components of the disease and the resulting retinal and visual dysfunction. Such an approach can identify targets for interventions that will give children with ROP the best possible visual outcome. The increasing number of children with ROP motivates the quest for further knowledge about neurovascular processes upon which improved management, and eventually prevention, of ROP will be based.

Due to advances in neonatal care, infants born as early as 22–24 weeks gestation survive. Each year in the United States, an estimated 10,000 infants are born prematurely (Penn et al., 2008). Of those born extremely prematurely (gestational age <31 weeks or birth weight <1250 g), approximately half develop ROP. In the majority, the disease is mild and resolves spontaneously. Nonetheless, ROP remains a leading cause of permanent, bilateral visual impairment in developed countries (Steinkuller et al., 1999). An estimated 1100 to 1500 each year have severe ROP that requires treatment, and approximately 500 of these infants are blinded by ROP (www.nei.nih.gov/health/rop). Worldwide, a hundred times that number are blind from ROP (Gilbert, 2008). The risk of ROP blindness is particularly high in middle income countries where premature infants survive but screening programs for ROP or management of ROP are not well established (Gilbert, 2008). Although in countries with advanced neonatal care and established screening programs, the rates of retinal detachment and blindness due to ROP are quite low, even mild ROP causes residual retinal and visual dysfunction (Reisner et al., 1997, Hansen and Fulton, 2000b, Fulton et al., 2001, O'Connor et al., 2002a, Barnaby et al., 2007, Hammer et al., 2008).

The primary concern of those caring for preterm infants is identification of acute ROP. At-risk infants have serial ophthalmoscopic examinations at preterm ages to evaluate the retina for blood vessels that are characteristic of ROP (Section on Ophthalmology American Academy of Pediatrics et al., 2006; Wilkinson et al., 2008). Infants are followed until ROP resolves spontaneously or requires treatment, or if no ROP develops, until the retinal blood vessels reach the ora serrata, the clinical definition of vascular maturity. The results of the multicenter Early Treatment of ROP study provide practical clinical criteria by which infants with ROP at high-risk for dangerous worsening are selected for treatment (Early Treatment for Retinopathy of Prematurity Cooperative Group, 2003). Standard treatment for ROP is laser ablation of the peripheral avascular retina. Cryotherapy continues to be used on occasion in severe cases. Fewer treated infants suffer retinal detachment and blindness; this indicates beneficial effects on both retinal structure and visual acuity. Fortunately, most ROP does not reach the criteria for treatment but rather spontaneously resolves by approximately term (Repka et al., 2000). Despite clinical resolution of the vascular abnormalities, there are numerous examples of persistent retinal and visual dysfunction as a consequence of ROP (Dobson et al., 1994, Cryotherapy for Retinopathy of Prematurity Cooperative Group, 2001, Fulton et al., 2001, Fulton et al., 2005, Barnaby et al., 2007, Hammer et al., 2008).

The cells of the retina, starting with the photoreceptors, participate in the first steps of visual processing and mediate a wide range of visual functions. The retina is also a controller of eye growth and refractive development (Troilo, 1992, Wallman, 1993). Thus, it is not surprising that prematurity and ROP are associated with both altered visual function and altered eye growth. In addition to clinical abnormalities of the retina, infants born prematurely are at risk for developing a range of structural and functional ophthalmic sequelae, including impaired ocular growth; increased incidence and magnitude of refractive error, particularly myopia; acuity deficits; field defects; and strabismus.

Ocular structures become identifiable early in embryonic development and continue to grow and develop throughout gestation into the early post-term years. Early departure from the protective intrauterine environment is associated with increased corneal curvature, increased lens power, and shallower anterior chamber depth, each of which can contribute to myopia (see below). Although it is these anterior segment features that are often taken as evidence that preterm birth arrests development of the ocular structures, we note that whether born preterm (regardless of ROP status) or at term, the ratio of anterior to posterior segment depth is approximately 0.6 in infants and approximately 0.45 in children. Axial length is typically shorter in preterm than in full term eyes. Because this is offset by the higher refractive power of the anterior segment, the magnitude of myopia in former preterms is greater than would be expected based on axial length. Nonetheless, among former preterms, axial length is greater in myopic than in emmetropic eyes. (Mann, 1964, Fledelius, 1976, Fledelius, 1981, Fledelius, 1982a, Fledelius, 1982b, Fledelius, 1992, Fledelius, 1996a, Fledelius, 1996b, Fielder et al., 1986, Gordon and Donzis, 1986, Gallo and Fagerholm, 1993, Fielder and Quinn, 1997, Choi et al., 2000, Kent et al., 2000, O'Connor et al., 2002a, O'Connor et al., 2006a, Cook et al., 2003, Cook et al., 2008, Jirasek, 2004, Snir et al., 2004, Mutti et al., 2005, Baker and Tasman, 2008, Mactier et al., 2008).

Term born infants are typically hyperopic and many have astigmatism in infancy (Mohindra et al., 1978, Atkinson et al., 1980, Fulton et al., 1980, Howland and Sayles, 1984, Saunders, 1995, Mayer et al., 2001, Mutti et al., 2005). For example, until age 4 months, the mean spherical equivalent is ≥2 diopters and cylindrical errors (≥0.75 diopter) occur in 25–40%. Normally, coordinated growth of the eye's refractive components during the first postnatal years causes refractive error to approach zero; this developmental process is called emmetropization (Troilo, 1992, Wallman, 1993).

Infants born prematurely, either with or without ROP, are on average less hyperopic than term born infants. However, the incidence of all types of refractive conditions - myopia, high hyperopia, astigmatism, and anisometropia – is higher than in the full term population. Thus, the normal, exquisite regulation of ocular growth appears to be diminished following preterm birth. (Saunders et al., 2002, Cook et al., 2003, Cook et al., 2008, Snir et al., 2004)

Myopia, the most common refractive error in preterms, typically develops in infancy and persists thereafter. In addition to ROP, low birth weight and gestational age may be independent risk factors for myopia. Both the prevalence and the magnitude of myopia increase with increasing severity of ROP and are greater in treated than in untreated eyes. Two large, multicenter, randomized ROP treatment trials, the Cryotherapy for ROP (CRYO-ROP) study and the Early Treatment for ROP (ETROP) study, concluded that treatment itself does not influence refractive status in eyes with severe ROP. Whether treatment is done for threshold or for high-risk pre-threshold ROP, the refractive outcome is the same. (Fletcher and Brandon, 1955, Zacharias et al., 1962, Fledelius, 1976, Fledelius, 1981, Fledelius, 1996a, Scharf et al., 1978, Dobson et al., 1981, Nissenkorn et al., 1983, Gallo and Lennerstrand, 1991, Kim et al., 1992, Quinn et al., 1992, Quinn et al., 1998, Quinn et al., 2001, Quinn et al., 2008, Page et al., 1993, Robinson and O'Keefe, 1993, Lue et al., 1995, Pennefather et al., 1997, Holmstrom et al., 1998, Ricci, 1999, Choi et al., 2000, Kent et al., 2000, O'Connor et al., 2002a, O'Connor et al., 2006a, O'Connor et al., 2006b, Saunders et al., 2002, Cook et al., 2003, Cook et al., 2008, Snir et al., 2004, Davitt et al., 2005, Holmstrom and Larsson, 2005, Sahni et al., 2005)

Acuity, the most commonly measured visual function, is usually reported to be lower in preterm than in term born infants and children. Acuity deficits range from subtle to severe, with the magnitude of the deficit related to the severity of ROP. (Birch and Spencer, 1991, Robinson and O'Keefe, 1993, Dobson et al., 1994, O'Connor et al., 2004, Palmer et al., 2005, Spencer, 2006).

Eyes with a history of ROP show visual field constriction compared to those of preterms with no ROP. Eyes with no ROP have fields similar to term born eyes. Comparison of fields in treated versus untreated eyes with severe ROP show that the former are slightly more constricted. The small field reduction due to treatment is considered to be of little or no functional significance and is outweighed by the benefit of preventing retinal detachment. (Quinn et al., 1996, Myers et al., 1999, Cryotherapy for Retinopathy of Prematurity Cooperative Group, 2001).

The prevalence of strabismus is higher in the preterm than in the term born population and increases with increasing ROP severity. Strabismus in preterms, as in other children, may be associated with anisometropia and amblyopia but also with other sequelae of preterm birth including encephalopathy of prematurity. (Graham, 1974, Roberts and Rowland, 1978; Friedmann et al., 1980, Kushner, 1982, Snir et al., 1988, Gallo et al., 1991, Laws et al., 1992, Page et al., 1993, Robinson and O'Keefe, 1993, Tuppurainen et al., 1993, Bremer et al., 1998, Holmstrom et al., 1999, Holmstrom et al., 2006, Pennefather et al., 1999, Pott et al., 1999, Ricci, 1999, O'Connor et al., 2002b, Sahni et al., 2005, VanderVeen et al., 2006a, Volpe, 2009).

At the preterm ages during which clinical ROP becomes active, both the neural retina and the retinal vasculature are immature (Hendrickson, 1994, Provis et al., 1997, Provis, 2001). The choroidal vasculature, which directly supplies the adjacent photoreceptors, develops in advance of the retinal vasculature (Gogat et al., 2004). Over the ages during which rod outer segments are maturing, all other retinal cell types have differentiated, and all retinal laminae are identifiable. The rod outer segments are the last retinal structures to reach maturity (Grun, 1982). During developmental elongation of the rod outer segments, the rhodopsin content of the retina increases along a logistic growth curve (Fig. 1). Infants at age 5 weeks (95% confidence interval, CI: 0–10 weeks) and rats at age 18.7 days (95% CI: 18.2–19.2 days) are estimated to have half the rhodopsin content of adults (Bonting et al., 1961, Fulton et al., 1991a, Fulton et al., 1998a, Fulton et al., 1999a, Hendrickson, 1994). By term, the number of retinal cells present in the primate retina is approximately the same as in adults (Packer et al., 1990). As the eye grows, the same number of cells pave a larger retinal area (Robb, 1982). Thus, the spatial distribution of cells varies with age but the same number of cells is available to respond to full-field flashes of light such as those used in electroretinography (ERG). In primate extramacular retina, cones reach maturity before rods (Hendrickson and Drucker, 1992, Hendrickson, 1994). In the macula, the maturation of those cones that are destined to become foveal cones and the maturation of the parafoveal rods lag that of the more peripheral photoreceptors (Dorn et al., 1995, Fulton et al., 1996, Timmers et al., 1999). During normal foveal development, there is an interplay of neural and vascular elements (Provis et al., 2000, Springer and Hendrickson, 2004a, Springer and Hendrickson, 2004b, Springer and Hendrickson, 2005).

ROP has effects on the function of the photoreceptors and post-receptor retina that persist even after its active phase (Sections 2 Human ROP: the neural retina and its vasculature, 3 Rat models of ROP). The late-maturing central retina appears to be particularly vulnerable to these effects. ROP, even if mild, affects the development of the central retina (Barnaby et al., 2007). Residual effects on the structure and function of the central retina are detectable years after ROP was active (Reisner et al., 1997, Hansen and Fulton, 2000b, Fulton et al., 2005, Hammer et al., 2008). Subtle deficits also occur in peripheral retinal function and persist into adolescence and early adulthood (Reisner et al., 1997, Hansen and Fulton, 2000b, Fulton et al., 2001, Moskowitz et al., 2005a).

Our investigations include human subjects (Section 2) and rat models of ROP (Section 3). A two-way bridge of information is built by investigations of these two classes of subjects, with each motivating the other.

In our quest to understand the neurovascular components in ROP, we study human subjects using non-invasive measures of retinal function and structure. Analysis of function depends on electroretinographic and psychophysical measures. Structure is investigated using image analysis of the retinal vasculature displayed in digital fundus photographs and ultra-high resolution adaptive optics imaging of the retinal laminae and intra-retinal vasculature. We pair these measures with clinical history and assessments. In this report, results are mainly from infants and children tested at post-term ages, weeks to years after ROP was an active clinical issue. Of course, studies at post-term ages examine the consequence of a disease that is no longer active. It is from these post-term results, coupled with clinical history from the days in the newborn intensive care unit onward, that we draw inferences about the acute disease processes that were active at preterm ages. Data from rat models of ROP studied before and after the peak of acute disease also aid in interpretation of results from human subjects.

Former preterms who are subjects in our studies had Severe ROP that was successfully treated, Mild ROP, or No ROP (Table 1). Thus, the subjects whose data are reported herein have been free of the mechanical effects of retinal detachment that have secondary effects on retinal neurons and blood vessels. The subjects were monitored in the nursery at preterm ages by serial examinations using indirect ophthalmoscopy, and clinical data were collected for each subject from infancy onward. The schedule of examinations in the nursery was modeled on those used in the Cryotherapy for ROP (CRYO-ROP) and Early Treatment for ROP (ETROP) multicenter treatment trials (Cryotherapy for Retinopathy of Prematurity Cooperative Group, 1988, Hardy et al., 2004). Those whom we categorized as Severe had ROP that reached criteria for treatment. Using the International Classification of ROP (ICROP), the maximum severity was stage 3; some had plus disease (International Committee for the Classification of Retinopathy of Prematurity, 2005). Those whom we categorized as Mild had ROP that did not reach criteria for treatment (Cryotherapy for Retinopathy of Prematurity Cooperative Group, 1988, Early Treatment for Retinopathy of Prematurity Cooperative Group, 2003). In these subjects, the ROP resolved by term and left no detectable retinal residua on clinical examination. According to ICROP, the maximum severity of their ROP was stage 1 or 2 in zone 2 or 3 (International Committee for the Classification of Retinopathy of Prematurity, 2005). Also included in our studies are former preterms who had serial examinations at preterm ages and never had ROP; these are termed No ROP. For brevity, we designate all former preterms subjects as ROP subjects and categorize them as None, Mild, or Severe (Table 1). We exclude from this report those who progressed to retinal detachment that could confound the main effects of ROP on retinal function. We also tested healthy, term born infants, children, and adults as control subjects.

Throughout this paper, we report age as corrected age in weeks post-term. Corrected age equals postnatal age minus the difference between term (40 weeks) and gestational age at birth [Corrected Age = Postnatal Age − (Term − Gestational Age)]. For instance, the corrected age of an infant born at 26 weeks gestation and tested at postnatal age 24 weeks is 10 weeks: 24 − (40 − 26) = 10.

We also study rat models of ROP. Controlled exposure of rats with immature retinal vasculature and neurons to ambient oxygen levels above or below those encountered in room air induces retinopathy. Two oxygen exposure protocols produce retinopathy that spans the gamut of severity of the ROP included in our human studies (Penn et al., 1995, Liu et al., 2006a, Akula et al., 2007a). Similar effects on key neural and vascular parameters are found in these rat models and human subjects (Fulton et al., 2009). ERG and image analyses of the retinal vasculature plus anatomic, biochemical, and molecular studies of the neurovascular elements have been performed in rats during the active phase as well as during the resolution of the ROP disease process. The rat results provide a conceptual framework for understanding the neurovascular elements not only in the rats, but also in the human subjects.

Section snippets

Stimulus specification

Troland values specify the retinal illuminance produced by a stimulus of 1 cd/m2 viewed through a 1 mm2 pupil (Pugh, 1988). Infants' eyes and pupils are smaller and their ocular media less dense than adults'. The retinal illuminance (E) produced by the stimulus (L, cd/m2) varies directly with pupil area (A, mm2) and transmissivity (τλ) of the ocular media (Section 2.5.1.2), and inversely with the square of the posterior nodal distance of the eye (d, mm) (Pugh, 1988):E=(A/d2)τλL

Thus, age related

Rat models of ROP

Models of ROP have been created in a variety of mammals (Madan and Penn, 2003). Oxygen exposures delivered at ages during which the neural retina and its vasculature are immature induce a retinopathy that models ROP. Several rat models of ROP have been created (Penn et al., 1994, Reynaud et al., 1995, Fulton et al., 1999b, Lachapelle et al., 1999, Dembinska et al., 2001, Liu et al., 2006a, Liu et al., 2006b, Akula et al., 2007a, Akula et al., 2007b). We have studied the model originated by Penn

Structure–function relationships

As detailed in Sections 2 Human ROP: the neural retina and its vasculature, 3 Rat models of ROP, a number of neurovascular structure–function relationships have already been demonstrated in human ROP and rat models of ROP. Further delineation of these relationships is needed to advance our understanding of the disease process and its consequences. Improved management of ROP can be built on this foundation.

To date, studies of structure and function have provided evidence that the rods are

Summary

The retina offers an accessible tissue for studies of neurovascular disease in the developing visual system. Our systems approach considers physically and temporally congruent neural and vascular components and demonstrates quantitative neurovascular relationships. Through a combination of non-invasive and molecular biological techniques, fundamental ROP disease processes are delineated in rat models. The information so gained is then translated to the human condition using efficient but

Acknowledgments

This work was supported by grants from the National Eye Institute (EY10597), the Massachusetts Lions Eye Research Fund, the March of Dimes Birth Defects Foundation, the Pearle Vision Foundation, the William Randolph Hearst Foundation, Knights Templar, and Fight for Sight. The authors gratefully acknowledge past and present research fellows, students, and assistants. We especially thank Susie Eklund for thorough and astute critique of this paper.

References (281)

  • T.R. Candy et al.

    Optical, receptoral, and retinal constraints on foveal and peripheral vision in the human neonate

    Vis. Res.

    (1998)
  • S. Cunningham et al.

    Transcutaneous oxygen levels in retinopathy of prematurity

    Lancet

    (1995)
  • B.V. Davitt et al.

    Prevalence of myopia at 9 months in infants with high-risk prethreshold retinopathy of prematurity

    Ophthalmology

    (2005)
  • M.N. Delyfer et al.

    Inherited retinal degenerations: therapeutic prospects

    Biol. Cell

    (2004)
  • V. Dobson et al.

    Cycloplegic refractions of premature infants

    Am. J. Ophthalmol.

    (1981)
  • M.C. Fletcher et al.

    Myopia of prematurity

    Am. J. Ophthalmol.

    (1955)
  • D.A. Fox et al.

    Age-related changes in retinal sensitivity, rhodopsin content and rod outer segment length in hooded rats following low-level lead exposure during development

    Exp. Eye Res.

    (1989)
  • A.B. Fulton et al.

    Cycloplegic refractions in infants and young children

    Am. J. Ophthalmol.

    (1980)
  • A.B. Fulton et al.

    Temporal summation in dark-adapted 10-week old infants

    Vis. Res.

    (1991)
  • A.B. Fulton et al.

    Recovery of the rod photoresponse in infant rats

    Vis. Res.

    (2003)
  • A.B. Fulton et al.

    The human rod ERG: correlation with psychophysical responses in light and dark adaptation

    Vis. Res.

    (1978)
  • J.E. Gallo et al.

    A population-based study of ocular abnormalities in premature children aged 5 to 10 years

    Am. J. Ophthalmol.

    (1991)
  • R.F. Gariano et al.

    Expression of angiogenesis-related genes during retinal development

    Gene Expr. Patterns

    (2006)
  • C. Gilbert

    Retinopathy of prematurity: a global perspective of the epidemics, population of babies at risk and implications for control

    Early Hum. Dev.

    (2008)
  • R.A. Gordon et al.

    Myopia associated with retinopathy of prematurity

    Ophthalmology

    (1986)
  • M. Aguilar et al.

    Saturation of the rod mechanism of the retina at high levels of stimulation

    Optica Acta

    (1954)
  • L.P. Aiello

    Vascular endothelial growth factor and the eye: biochemical mechanisms of action and implications for novel therapies

    Ophthalmic Res.

    (1997)
  • J.D. Akula et al.

    Rod photoreceptor function predicts blood vessel abnormality in retinopathy of prematurity

    Invest. Ophthalmol. Vis. Sci.

    (2007)
  • J.D. Akula et al.

    The oscillatory potentials of the dark-adapted electroretinogram in retinopathy of prematurity

    Invest. Ophthalmol. Vis. Sci.

    (2007)
  • J.D. Akula et al.

    Effects of a vitamin-A derivative (AG-787-14-2) on retinal function in oxygen-induced retinopathy

    Invest. Ophthalmol. Vis. Sci.

    (2008)
  • J.D. Akula et al.

    The neurovascular relation in oxygen-induced retinopathy

    Mol. Vis.

    (2008)
  • M.A. Amato et al.

    Comparison of the expression patterns of five neural RNA binding proteins in the Xenopus retina

    J. Comp. Neurol.

    (2005)
  • G.B. Arden et al.

    Spare the rod and spoil the eye

    Br. J. Ophthalmol.

    (2005)
  • L.M. Askie et al.

    Oxygen-saturation targets and outcomes in extremely preterm infants

    N Engl. J. Med.

    (2003)
  • O. Ates et al.

    Oxidative DNA damage in retinopathy of prematurity

    Eur. J. Ophthalmol.

    (2009)
  • H.B. Barlow

    Dark and light adaptation

  • A.M. Barnaby et al.

    Development of scotopic visual thresholds in retinopathy of prematurity

    Invest. Ophthalmol. Vis. Sci.

    (2007)
  • D.G. Birch et al.

    Abnormal activation and inactivation mechanisms of rod transduction in patients with autosomal dominant retinitis pigmentosa and the pro-23-his mutation

    Invest. Ophthalmol. Vis. Sci.

    (1995)
  • E.E. Birch et al.

    Visual outcome in infants with cicatricial retinopathy of prematurity

    Invest. Ophthalmol. Vis. Sci.

    (1991)
  • J.K. Bowmaker et al.

    Visual pigments of rods and cones in a human retina

    J. Physiol.

    (1980)
  • D.L. Bremer et al.

    Strabismus in premature infants in the first year of life. Cryotherapy for retinopathy of prematurity cooperative group

    Arch. Ophthalmol.

    (1998)
  • R.M. Broekhuyse et al.

    Assay of S-antigen immunoreactivity in mammalian retinas in relation to age, ocular dimension and retinal degeneration

    Jpn. J. Ophthalmol.

    (1989)
  • A.J. Bron et al.

    The eyeball and its dimensions

  • K.T. Brown

    The electroretinogram: its components and their origins

    Vis. Res.

    (1968)
  • D.J. Calkins et al.

    M and L cones in macaque fovea connect to midget ganglion cells by different numbers of excitatory synapses

    Nature

    (1994)
  • T.L. Chan et al.

    Bipolar cell diversity in the primate retina: morphologic and immunocytochemical analysis of a new world monkey, the marmoset Callithrix jacchus

    J. Comp. Neurol.

    (2001)
  • J. Chang et al.

    The effects of dorzolamide on the rod photoreceptors

    Invest. Ophthalmol. Vis. Sci.

    (1997)
  • M.Y. Choi et al.

    Long term refractive outcome in eyes of preterm infants with and without retinopathy of prematurity: comparison of keratometric value, axial length, anterior chamber depth, and lens thickness

    Br. J. Ophthalmol.

    (2000)
  • L.C. Chow et al.

    Can changes in clinical practice decrease the incidence of severe retinopathy of prematurity in very low birth weight infants?

    Pediatrics

    (2003)
  • J.E. Clavadetscher et al.

    Spectral sensitivity and chromatic discriminations in 3- and 7-week-old human infants

    J. Opt. Soc. Am. A

    (1988)
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