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Pathophysiology of Retinopathy of Prematurity
Acknowledgments
The authors thank Maria Isabel Gomez for her expert help in organization and formatting the manuscript.
Introduction
Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide and is increasing in emerging countries able to save premature infants but without resources to provide optimal care. , ROP, first identified as retrolental fibroplasia (RLF) in the United States, was reported by Terry as a white mass behind the lens, which likely represented fibrovascular tissue and an underlying total retinal detachment. The cause was unknown, and studies in animals were done to understand causes. It was not until the 1950s that Arnall Patz observed that use of high oxygen concentrations in preterm infants without respiratory distress was associated with RLF. He performed a small clinical trial followed by a multicenter trial with Kinsey that showed high unregulated oxygen in preterm infants at birth was one cause of RLF. When oxygen was regulated, RLF virtually disappeared. However, additional advances in neonatology permitted ever smaller and younger preterm infants to survive, and the newly termed ROP reemerged with earlier stages identified and classified. We have since come to realize that high oxygen at birth is not the only factor in the pathophysiology of ROP in extremely premature infants nowadays.
Anatomy and General Physiology of the Retina
The eye has unique optical properties allowing light to be focused onto the photoreceptors, which are deep within the layers of the neural retina ( Fig. 166.1A ). Two-thirds of the focusing power of the eye is attributed to the cornea and one-third to the lens. The cornea, lens, vitreous, and neural retina are transparent aside from retinal vessels that cast shadows on the retina and can be appreciated by optical coherence tomography (OCT), which provides structure of the retinal layers in vivo (see Fig. 166.1B ). Once light is processed by photoreceptors through phototransduction, the signal is synaptically transmitted from the photoreceptors to bipolar cells and then from the bipolar cells to the ganglion cells. The axons of the ganglion cells create the optic “nerve,” which comprises approximately 1 million nerve fibers that transmit the visual message through bundles and pathways in the brain to the occipital cortex, where the message is interpreted as vision. Signal processing through synaptic communication occurs within the retina through multiple distinct classes of cells that include different types of bipolar cells, amacrine cells, horizontal cells, and glia to result in increased synaptic gain (see Fig. 166.1A ).
The inner retina includes nine layers extending from the inner limiting membrane to the photoreceptors. The photoreceptor outer segments interact with the apical processes of a monolayer of epithelial cells, called the retinal pigment epithelium (RPE) , which has tight junctions and makes up the outer blood-retinal barrier. The basal side of the RPE rests on a collagen and elastin sandwich called Bruch membrane that includes the cell membranes of the fenestrated choriocapillaris (see Fig. 166.1C ). The RPE performs multiple processes, including transport of substances from the inner retina to the outer choroidal circulation and from the choroid to the retina, important steps in the visual cycle; phagocytosis of the outer segments of the photoreceptors; and secretion of factors.
On the scleral-most side of the Bruch membrane is the choriocapillaris. The choriocapillaris is one of three layers of the choroid, which has one of the highest blood flows of any tissue in the body, estimated to be 500 to 2000 mL/min/100 g tissue. The high flow of the choroid is believed to provide a heat sink for metabolic activities performed by the RPE. Besides heat, photooxidation in the outer retina also may increase oxidative stress. Mechanisms to reduce reactive oxygen are believed to include antioxidative properties of melanin within the RPE, inner retinal macular pigment (lutein and zeaxanthin), and absorbed ascorbate, tocopherol, and glutathione.
The photoreceptors are normally avascular and obtain nutrients and oxygen from the choroid. Based on studies in cats and macaques, the PO 2 of the retinal layers was determined. During dark adaption, approximately 90% of the oxygen to the photoreceptors is from choroid and 10% from the retina, whereas in light-adapted states, the choroid provides 100% of the oxygenation. The retinal vasculature provides oxygenation of the inner retina from the ganglion cell layer to the inner nuclear layer and makes up the inner blood retinal barrier (see Fig. 166.1A ). In adults, the retinal vasculature accounts for approximately 4% of the ocular blood flow (estimates of 40.8 to 52.9 μL/min). The inner retinal oxygenation ranges from approximately 10 mm Hg in the light-adapted retina to approximately 20 mm Hg in the dark-adapted retina. In the fovea, where the retina is thinner and devoid of vessels and inner retinal neurons, the oxygen consumption is lower than in the parafoveal region, where interneural connections exist, and suggests that interneural synaptic connections consume additional oxygen (see Fig. 166.1A ).
Development of the Retina and Ocular Vasculatures
Much of the understanding of the development of the retina and ocular circulations is assimilated from studies in human tissue, other species, and embryology. Studies using animal models or genetically modified mice provide a deeper understanding of molecular mechanisms involved, although differences between human and other species need to be considered. An important difference is that the retinal vasculature is complete by term birth in the human but is incomplete in rodents, and for this reason full-term rodents are often exploited in studies related to vascular development and ROP. In human, immunohistochemical studies are helpful, but it is difficult to obtain autopsy tissue from preterm infant eyes that may characterize changes after birth and before the development of ROP, which occurs often 1 to 2 months after birth.
Embryology
The retina is first recognized as the optic pit in the anterior neuroectoderm at day 23 of gestation and develops into a two-layered structure of neural retina and the RPE known as the optic cup, which remains attached to the brain by an optic stalk. Continued growth of the optic cup causes the formation of a fissure that ultimately closes around day 33 and through which the hyaloidal artery enters the eye. The process is complicated and involves many coordinated cellular and molecular events. As neural layers form, synapses between retinal cells develop, and these processes drive metabolism and the need for oxygen.
Ocular Circulations
Oxygen is provided through the help of several circulations, the hyaloidal circulation, the choroidal circulation, and the retinal circulation. Each develops through one or more processes, namely hemovasculogenesis, vasculogenesis, or angiogenesis. Hemovasculogenesis is the development of vessels and all components of the blood system, including the hematopoietic and erythropoietic ones, from a common precursor called a hemangioblast . Vasculogenesis is the de novo development of vessels from mesenchymal precursor cells called angioblasts . Angiogenesis is the formation of vasculature by budding from existing vessels.
As the optic fissure closes, the hyaloidal circulation and primary vitreous form at approximately 4 to 5 weeks of age through hemovasculogenesis, , which becomes maximal at 2 to 3 months of age and then regresses by approximately 36 weeks gestation (see Fig. 166.1D ). Several mechanisms involved in hyaloid regression were determined in murine eyes and included angiopoieitin-2–induced Wnt7b production by macrophages leading to endothelial cell arrest along with angiopoietin-2 suppression of Akt survival signaling and neuronal activation of vascular endothelial growth factor receptor 2 (VEGFR2), thereby reducing the supply of vascular endothelial growth factor (VEGF) to maintain the hyaloid. As the hyaloidal circulation regresses, the retinal vasculature begins to develop at about 12 to 14 weeks gestation.
The choroid also begins by hemovasculogenesis at close to the time of the hyaloidal circulation, approximately 5 weeks of age. , The choroid has three layers, the choriocapillaris, Sattler layer, and Haller layer. The choriocapillaris becomes fenestrated at 24 to 26 weeks gestation. The choroid matures from posterior (near the optic nerve) to the peripheral eye.
Finally, the retinal vasculature develops as the hyaloidal vessels regress. The retina initially develops by vasculogenesis, which is believed to support the posterior retina around the optic nerve (called the posterior pole ) up to approximately 22 weeks gestational age (GA). Initially, angioblasts migrate toward the inner retina from the outer neuroblastic layer and express CD39 and CXCR4, which is the receptor for a stromal cell–derived factor (SDF-1). Following vasculogenesis, the ensuing retina is vascularized by angiogenesis. Astrocytes and their precursors are also believed to be important, having been identified in advance of human retinal vessels. , These PAX2 + nonendothelial cells migrate out and sense physiologic hypoxia. In response to hypoxia, the astrocytes upregulate VEGF, which is important in angiogenesis and in the development of the inner retinal vascular plexus that extends out to the ora serrata by 36 weeks gestation nasally and 40 weeks temporally ( Fig. 166.2A ). , The retinal circulation includes three main plexi, but other plexi have been identified in adults using OCT angiography. The inner plexus is completed prior to the deeper plexi. Müller cell glia are believed important in the development of the deeper retinal plexi. These three vasculatures are tightly regulated to ensure oxygenation of the developing eye.
Pathophysiology of Retinopathy of Prematurity
Ashton’s Original Two-Phased Hypothesis
When RLF was identified in the United States, scientists exposed full-term healthy newborn animals to various stresses that premature infants then experienced to find out the cause. Several individuals are credited for identifying high oxygen at birth as damaging to newly developed retinal capillaries and include Michaelson, Campbell, and Ashton. Ashton found that full-term newborn animals in 70% to 80% inspired oxygen (FiO 2 ) delivered continuously for 4 days developed “vasoobliteration” of newly formed capillaries. Weaning to ambient air led to “vasoproliferation” of endothelial cells onto the vitreous collagen (intravitreal neovascularization). Later fibrovascular contraction between the retina and vitreous led to complex retinal detachments. Ashton’s observations created the initial two-phase hypothesis of the pathogenesis of ROP: high oxygen caused phase I “vasoobliteration” and subsequent weaning to room air led to relative hypoxia and stimulation of phase II “vasoproliferation” from an angiogenic factor or factors. (We now know that hypoxia-inducible factors [HIFs] are stabilized in hypoxia and translocate to cell nuclei to transcribe a number of angiogenic factors, most notably VEGF, erythropoietin, and angiopoietins.) Following seminal clinical trials by Patz and Kinsey, high oxygen at birth was found to cause RLF. With advancements in neonatal care, including the ability to regulate and monitor oxygen, RLF virtually disappeared, but with later survival of extremely premature infants, ROP reemerged.
Refined Two-Phased Hypothesis of Current day Retinopathy of Prematurity
A number of factors led to the need for a refined hypothesis of ROP. The adoption of indirect ophthalmoscopy by Schepens led to greater ability to examine the peripheral infant retina. It became appreciated that extremely preterm infants born at or less than 28 weeks GA and who survived to develop ROP had incompletely vascularized retinas, which was expected because retinal vascular development is not complete until 36 to 40 weeks of gestation. In addition, other stresses besides high oxygen at birth were associated with ROP, including oxygen fluctuations, poor growth, and oxidative stress, and these factors were associated with delayed retinal vascular development. Therefore the refined hypothesis includes phase I as not only high oxygen–induced damage to newly developed capillaries (compromised physiologic vascularity), but also delayed physiologic retinal vascular development, and phase II as vasoproliferation.
Differences in Retinopathy of Prematurity in Emerging Countries
The refined hypothesis relates to most developed countries that have resources for optimal prenatal and perinatal care, including the monitoring and regulation of oxygen. However, in emerging countries, ROP is on the rise because there are resources to save preterm infants but not to provide optimal prenatal nutrition, perinatal care, and regulate oxygen. , ROP then can have a component of oxygen-induced vasoobliteration, also known as aggressive retinopathy of prematurity (A-ROP) for its rapidity of progression, as well as delayed physiologic retinal vascular development in phase I followed by vasoproliferation in phase II.
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