Retina

The retina develops from neural ectoderm, with the retinal pigment epithelium (RPE) developing from the outer layer of the optic cup and the neurosensory retina developing from the inner layer of the optic cup (Figs. 1-11, 1-12, 1-13, 1-14, 1-18). As with the ciliary epithelium, invagination of the optic vesicle causes the apices of the inner nonpigmented layer to be directed

FIGURE 1-18A-C. (A) At approximately 38 days, the hyaloid vasculature surrounds the lens (L) with capillaries that anastomose with the tunica vasculosa lentis. Axial migration of mesenchyme forms the corneal stroma and endothelium (C). The retina (R) is becoming stratified while the pigment epithelium (PE) remains cuboidal. (B) By day 41, the retina has segregated into inner (IN) and outer (ON) neuroblastic layers. The ganglion cells are the first to differentiate, giving rise to the nerve fiber layer (arrowhead). The pigment epithelium has become artifactually separated from the neural retina in this specimen. (From Cook CS, Sulik KK. Scanning Electron Microsc 1986;III:1215—1227, with permission.) (C) Differentiation of the retina progresses from the central to the peripheral regions. At this time, the inner (IN) and outer (ON) neuroblastic layers are apparent at the posterior pole but, peripherally, the retina consists of outer nuclear and inner marginal zones. Between the inner and outer neu-roblastic layers is a clear zone, the transient fiber layer of Chievitz. PE, pigment epithelium; arrowhead, nerve fiber layer. (From Cook CS, Sulik KK. Scanning Electron Microsc 1986;III:1215-1227, with permission.)

outward, to face the apices of the outer pigmented layer, which are directed inward. Thus, the apices of these two cell layers are in direct contact. Primitive RPE cells are columnar, but by 5 weeks they change shape to form a single layer of cuboidal cells that exhibit the first pigment granules in the embryo. Bruch's membrane, the basal lamina of the RPE, is first seen during this time (optic cup stage) and becomes well developed by 6 weeks when the choriocapillaris is starting to form. By 4 months, the RPE cells take on a hexagonal shape on cross section and develop microvilli that interdigitate with projections from photorecep-tors of the nonpigmented layer.

By the sixth week postfertilization, the nonpigmented inner layer of the optic cup differentiates into an outer nuclear zone and an inner marginal zone. Cell proliferation occurs in the nuclear zone with migration of cells into the marginal zone. This process forms the inner and outer neuroblastic layers (Fig. 1-18B,C), separated by their cell processes, which make up the transient fiber layer of Chievitz. With further realignment of cells, this layer is mostly obliterated by 8 to 10 weeks gestation. The ganglion cells of the inner neuroblastic layer are the first to differentiate (7 th week), giving rise to a primitive nerve fiber layer (Fig. 1-18B,C, arrow).

By the 16th week, mitosis has nearly ceased and retinal differentiation commences, as does synaptic contact between retinal neurons.99 Cellular differentiation progresses in a wave from inner to outer layers and from central retina to peripheral retina (Fig. 1-18C). The ganglion cells give rise to a more defined nerve fiber layer that courses to the developing optic nerve. Cell bodies of the Mueller and amacrine cells differentiate in the inner portion of the outer neuroblastic layer; bipolar cells are found in the middle of the outer neuroblastic layer, with horizontal cells and photoreceptors maturing last, in the outermost zone of the retina.99 Early in development, retinal cells demonstrate neurite regeneration in vitro. This regenerative capability decreases with age and is lost postnatally in the rat at a time that corresponds to the time of eye opening and retinal maturation (equivalent to the eighth month of human gestation).106 Thy-1, the most abundant surface glycoprotein found in the retina, is primarily associated with ganglion cells and appears to regulate neurite outgrowth.97

Macular differentiation occurs relatively late, beginning in the sixth month.46 First, multiple rows of ganglion cells accumulate in the central macular area. At this time, the immature cones are localized in the central macular area while the rods develop in the periphery. At 7 months, the inner layers of the retina (including ganglion cells) spread out to form the central macular depression or primitive fovea. The cones in the foveal area elongate, allowing denser cone populations and enhanced foveal resolution. These changes in foveal cones continue until after birth. At birth, the fovea is fairly well developed and consists of a single row of ganglion cells, a row of bipolar cells, and a horizontal outer plexiform layer of Henle. It is not until several months postpartum that the ganglion cells and bipolar cells completely vacate the fovea centralis.

Retinal Vasculature

The fetal ophthalmic artery is a branch of the internal carotid artery and terminates into the hyaloid artery. The hyaloid artery enters the optic cup via the optic fissures and stalk (developing optic nerve) (see Fig. 1-12). At approximately 6 weeks gestation, the ophthalmic artery becomes entrapped in the optic cup as the optic fissure closes. The portion of the hyaloid artery within the optic stalk eventually becomes the central retinal artery, while the more terminal parts of the hyaloid artery arborize around the posterior aspect of the developing lens. The hyaloid artery gradually atrophies and regresses as branches of the hyaloid artery become sporadically occluded by macrophages.52,54 Regression of the hyaloid vasculature is usually complete by the fifth month of human gestation. Bergmeister's papilla represents a remnant of the hyaloid vasculature that does not regress; this is a benign anomaly consisting of a small fibrous glial tuft of tissue that emanates from the center of the optic disc.

The hyaloid vasculature is the primary source of nutrition to the embryonic retina. Regression of the hyaloid vasculature serves to stimulate retinal vessel angiogenesis. Spindle-shaped mesenchymal cells from the wall of the hyaloid vein at the optic disc form buds that invade the nerve fiber layer during the fourth month of gestation.6 Subsequently, solid cords of mesenchymal cells within the inner retina canalize and contain occasional red blood cells at approximately 5 months gestation. In situ differentiation of craniofacial angioblasts has been demonstrated in avian species using polyclonal antibodies to quail endothelial cells.75 Vascular budding and further differentiation form the deeper capillary network in the retina.73 The primitive capillaries have laminated walls consisting of mitotically active cells secreting basement membrane.95 Those cells in direct contact with the bloodstream differentiate into endothelial cells while the outer cells become pericytes. Tissue culture experiments have demonstrated that the primitive capillary endothelial cells are multipotent and can redifferentiate into fibroblastic, endothelial, or muscle cells, possibly illustrating a common origin of these different tissue types.6 Pigment epithelium derived factor (PEDF) has been demonstrated to inhibit angio-genesis of the cornea and vitreous. Inadequate levels may play a permissive role in ischemia-driven aberrant vascularization.33 The central retinal artery grows from the optic nerve to the periphery, forming the temporal and nasal retinal arcades. By approximately 5 months, the retinal arcades have progressed to the equator of the eye. At this time, the long and short posterior ciliary arteries are well developed, with the long posterior artery supplying the anterior segment and the short posterior artery supplying the choroid. The retinal arteries grow from the optic nerve toward the ora serrata and reach the nasal periphery first (by 8 months).73 Even at birth, however, there is usually a crescent of avascular retina in the temporal periphery. The fact that a newborn infant has an immature temporal retina without complete vascularization may explain why there have been scattered cases of retinopathy of prematurity in full-term infants. Oxygen affects angiogenesis and seems to play a role in stimulating and retarding vessel growth.83 In immature kitten retinas, increased oxygen concentration causes atrophy and regression of capillaries whereas hypoxia increases capillary arborization.79 Endothelial cell growth is also promoted by low oxygen tension, and endothelial growth is inhibited by high oxygen tension.7 Vasoendothelial growth factor (VEGF) both stimulates and maintains normal vessel growth to the peripheral retina. High oxygen downregulates VEGF, stopping the normal process of peripheral vascularization.2,58,84 These findings give rise to the hypothesis that retinopathy of prematurity (ROP) is secondary to initial increased oxygen concentration, which results in inhibition or retraction of peripheral capillary networks (vaso-obliteration).5 This lack of peripheral capillary network subsequently results in retinal hypoxia increased VEGF then secondary endothelial cell growth and neovascularization (i.e., ROP).82 There is evidence that strict curtailment of O2 dose early in a premature infants course reduces the incidence of severe ROP.112a

VITREOUS

The primary vitreous first appears at approximately 5 weeks gestation and consists of the hyaloid vessels surrounded by mesenchymal cells, collagenous fibrillar material, and macrophages (see Fig. 1-12). Most of the mesenchymal cells are of neural crest origin. The secondary vitreous forms at approximately 8 weeks at the time of fetal fissure closure (see Fig. 1-13).9 It circumfer-entially surrounds the primary vitreous containing the hyaloid vessels. The secondary vitreous consists of a gel containing compact fibrillar network, primitive hyalocytes, monocytes, and a small amount of hyaluronic acid.19 Primitive hyalocytes produce collagen fibrils that expand the volume of the secondary vitreous. At the end of the third month, the tertiary vitreous forms as a thick accumulation of collagen fibers between the lens and optic cup (Fig. 1-19). These fibers are called the marginal bundle of Drualt. Drualt's bundle has a strong attachment to the inner layer of the optic cup and is the precursor to the vitreous base and lens zonules. The early lens zonular fibers appear

primary vitreous, secondary vitreous, and tertiary vitreous. The primary vitreous includes the hyaloid artery and associated matrix; it extends centrally from the optic nerve to the retrolental space. The secondary vitreous surrounds the primary vitreous; it has less vasculature and is clearer than the primary vitreous. The tertiary vitreous forms between the lens equator and the area of the ciliary body; the lens zonules develop within the fibrillar matrix in this. Note that eyelids are fused at this stage.

primary vitreous, secondary vitreous, and tertiary vitreous. The primary vitreous includes the hyaloid artery and associated matrix; it extends centrally from the optic nerve to the retrolental space. The secondary vitreous surrounds the primary vitreous; it has less vasculature and is clearer than the primary vitreous. The tertiary vitreous forms between the lens equator and the area of the ciliary body; the lens zonules develop within the fibrillar matrix in this. Note that eyelids are fused at this stage.

to be continuous with the inner limiting membrane of the non-pigmented epithelial layer covering the ciliary muscle. Toward the end of the fourth month of gestation, the primary vitreous and hyaloid vasculature atrophies to a clear, narrow central zone, Cloquet's canal. Apoptosis occurs during hyaloid vessel regression.51 Persistence of the primary vitreous and failure of the posterior tunica vasculosa lentis to regress can result in persistent hyperplastic vitreous (PHPV). PHPV consists of a fibrovascular membrane that extends from the optic nerve along the hyaloid remnant and covers the posterior capsule of the lens. During the fifth month of gestation, an attachment forms between the ciliary body and the lens (Weiger's ligament, or capsulohyaloidal ligament). Later in development, at approximately 5 to 6 months, the hyaloid system completely regresses and the hyaloid artery blood flow ceases. At birth, Cloquet's canal persists as an optically clear zone emanating from the optic nerve to the back of the lens. Cloquet's canal is a remnant of primary vitreous. Most of the posterior vitreous gel at birth is secondary vitreous with the vitreous base and zonules representing tertiary vitreous.

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