The ora serrata – named for its marginal notches – forms the peripheral edge of the retina as the junction between the multilayered optical retina and the monolayered, nonpigmented epithelium of the ciliary body. The anatomic characteristics of this region are due to its thinness, avascularity, and close relationship to the vitreous base and zonular fibers. The vitreous base normally extends from 2 to 4 mm posterior to the ora. The vitreous cortex collagen fibrils insert into the internal limiting membrane of the retina. Vitreoretinal adhesion is particularly strong along the posterior margin of the vitreous base, making this a common site for retinal tears. As the retina approaches the ora there is gradual loss of the nerve fiber layer, ganglion cell layer, and plexiform layers. These layers are replaced with neuroglia and Muller’s cells, which serve as structural support for the entire retina. Both the ILM, into which vitreous base inserts, and the ELM, which continues between the pigmented and nonpigmented layers of pars plana, are thickened.

1.1.3 Microanatomy of the Retina Neurons

The cells within the retina fall into one of three groups: neuronal, glial, and vascular. The neural cells give the retina its primary function: converting light energy into electrical signals. This is

accomplished through intricate interaction between the three types of neural cells: photoreceptors, interneurons, and ganglion cells. The photoreceptor cells, the rods and cones, are the primary neurons in the visual pathway. The dense packing of the photoreceptors, combined with their precise axial arrangement, provides for detection of individual photons and the accurate construction of an image. Any change from this axial arrangement causes alteration in vision: micropsia if the cells are abnormally separated, such as with subretinal fluid; metamorphopsia if the alignment is lacking; loss of acuity if the axial alignment is sufficiently disturbed so that the photoreceptor is no longer axial to the inciting light.

The cone cells are comprised of four portions: inner segments, outer segments containing the visual pigment, a perikaryal region containing the cell nucleus, and a synaptic terminal. The light-absorbing visual pigment in rods, rhodopsin, is composed of the light-sensitive chromophore retinal, which is attached to the protein opsin.7 This is most sensitive to light with a wavelength of 500 nm. The three different types of cones each contains one lightsensitive pigment, resulting in three different spectral sensitivities. The blue, green, and yellow cone pigments are maximally absorbent at 450, 530, and 565 nm, respectively.

The photoreceptor outer segments have two important connections: to the inner segments (cell bodies of the photoreceptors) and to the

extracellular matrix, which separates it from the retinal pigment epithelium. The matrix is synthesized by both the photoreceptors and RPE.8 The acid mucopolysaccharides of the matrix are likely synthesized in the photoreceptor inner segments; disturbances of this would result in separation of photoreceptors from RPE, such as in an exudative retinal detachment. The nuclei of the cones form the outer nuclear layer and lie 3–4 mm internal to the outer limiting membrane. The photoreceptors form junctions with interneurons and Muller cells; the plasma membrane of each photoreceptor and Muller cell is differentiated into a dense band known as the outer limiting membrane. Rods and cones do not contact each other; they are insulated from each other by the Muller cells. The Muller cells contact each other in zonulae adherentes, which are thought to form a diffusion barrier between the intercellular space of the inner retina and the extracellular matrix between the photoreceptor outer segments and the pigment epithelium.

The outer plexiform layer lies between the inner and outer nuclear layers. The synaptic zone, with numerous intercellular junctions and synapses between neural and glial processes, creates the middle limiting membrane. This resembles the outer limiting membrane and may act as a partial barrier to diffusion of fluid and larger molecules. Exudates, hemorrhages, and cysts may be prevented from spreading through the entire retina.

The inner plexiform layer is located between the ganglion and inner nuclear cell layers. In addition to Muller cell branches and retinal blood vessels, it contains synaptic processes of the bipolar, ganglion, and amacrine cells. There are an enormous number of synapses within the inner plexiform layer – 2.9 million dyads (a dyad is a synaptic pair) per square millimeter.9 Each dyad consists of a bipolar cell making contact with two processes: one from a ganglion cell and the other from an amacrine cell.

The ganglion cell bodies form a distinct layer between the inner plexiform layer and the nerve fiber layer. Through much of the retina there is 1 ganglion cell for every 100 rods and 4–6 cones; however, in the macula the ganglion cell-to-photo- receptor ratio is higher, creating a smaller receptor field for each ganglion cell and, therefore, greater image resolution. Though there are no ganglion cells at the foveal center, the ganglion cells are so

densely packed within the macula that there may be two or more for every cone.10 There are two major groups of ganglion cells: midget and diffuse. The midget ganglion cells cover small areas (<10 mm2) and synapse with only one midget bipolar cell, though each midget bipolar cell may synapse with numerous ganglion cells. On the other hand are the diffuse ganglion cells, also referred to as large and polysynaptic. The ganglion cells’ dendrites synapse with retinal bipolar and amacrine cells and the axons synapse with cells in the lateral geniculate body.

The ganglion cell axons course through the inner retina toward the optic nerve forming the nerve fiber layer. They remain unmyelinated until they reach the lamina cribrosa. Axons are in direct contact with each other without interposed glial cells, except for interdigitating Muller cell processes. The axons assume a generally radial course toward the optic nerve except for those immediately temporal to the disc, which form the papillomacular bundle. Since these axons are the first to develop, they form the center of the optic nerve. As axons converge at the optic nerves, the nerve fiber layer becomes thickest; it is thinnest over the macula and far periphery. As is true with all neurons, the axons cannot survive when detached from the cell bodies.11 Both proximal and distal degenerations are seen after acute retinal or optic nerve ischemia; funduscopically, this can be seen as cotton wool spots or optic disc edema. Though long believed to represent focal infarctions of the retinal nerve fiber layer, cotton wool spots may actually be boundary sentinels of inner retinal ischemia.12 Following axonal degeneration, defects in the nerve fiber layer can be seen on OCT or funduscopy.

Muller cells form tight junctions with other Muller cells and neural cells. In the outer retina a continuous row of zonulae adherentes forms the outer limiting membrane, a barrier to metabolite movement into and out of the retina.13 Muller cells constitute the majority of retinal glial cells but the astrocytes are more widely distributed between blood vessels and neurons.

1.1.4 Intercellular Spaces

Neural cells within the retina lie 10–20 mm apart, similar to spacing found in the brain. The intercellular

spaces are filled with low-density material that does not limit the diffusion of even large proteins.14 Large molecules move freely through the retina until reaching the external limiting membrane; intercellular spaces outside the ELM constitute the subretinal space – referred to as the interphotoreceptor matrix

– comprising glycosaminoglycans, glycoproteins, and filamentous structures.15 The most common interreceptor matrix protein is interstitial retinalbinding protein (IRBP), synthesized and secreted by rod photoreceptor cells. It binds all-trans retinal and 11-cis retinal. Little is known about other matrix proteins.

1.1.5 Internal Limiting Membrane

The ILM is the retina’s only true basement membrane. The outer portion consists of the basement membrane of the Muller cells, whereas the inner portion is formed by vitreous fibrils and mucopolysaccharides. It consists of laminin, BM proteoglycans, fibronectin, and collagen.16 The ILM is 2,000 nm thick over the macula but only 20 nm over the fovea, since the density of Muller cells decreases.17 Muller cell processes form a continuous but uneven border of attachment with the ILM. The exact nature of the vitreous attachment to the ILM is not known.

1.1.6 Circulation

The retina has the highest oxygen demand of any tissue in the body and relies on two circulations to meet this: the inner 2/3 of the retina relies on the retinal vasculature and the outer 1/3 relies on the choroidal circulation. The choroidal circulation has a high and variable flow rate, transferring molecules easily with the surrounding tissues, whereas the retinal circulation provides a lower, more constant flow with a high rate of oxygen extraction.18 The central retinal artery supplies the entire circulatory supply for the inner 2/3 of the retina, except for areas served by cilioretinal arteries, which are seen in 20% of eyes.

1.1.7 Arteries

The central retinal artery penetrates the optic nerve about 10 mm posterior to the globe. Its histological structure resembles that of other comparable sized arteries: a luminal diameter of 200 mm, a wall thickness of 35 mm, a single layer of endothelial cells, a subendothelial elastica, an internal elastic lamina, a medium of smooth muscle, and an external elastic lamina that merges with the adventitia. Degenerative diseases that affect muscular arteries, such as atherosclerosis and giant cell arteritis, also affect the intraneural retinal artery. The arteries within the retina are spared from giant cell arteritis because they lack an internal elastic lamina. Atherosclerosis, with its subendothelial plaque formation and hyperplasia of the intimal and endothelial layers, can affect any portion of the retinal artery. When the artery enters the eye, the elastic lamina is lost but the muscularis is unusually prominent.

The retinal circulation is autoregulated by tissue oxygen concentration, metabolic by-products, and intraocular and systemic blood pressures.19 It is unclear whether the retinal arteries are innervated by sympathetic or parasympathetic nerves but studies suggest that adrenergic-binding sites exist and that retinal blood flow can be altered by adrenergic agonists and antagonists.20,21 After entering the eye the retinal artery divides into superior and inferior branches, then to smaller branches with either dichotomous (equal-sized bifurcation) or side-arm branching. In smaller branches of the artery, the muscular layer thins from seven cell layers at the disc to two layers at the equator and the luminal diameter thins from 120 mm at the disc to 8–15 mm at the equator. The endothelial cells contain tight junctions that prevent the passage of large molecules into or out of the vascular lumens22; therefore, transfer of materials is limited to diffusion and endothelial pinocytosis. The arteries lie in the nerve fiber layer or ganglion cell layer, with only the smaller arterioles descending into the inner plexiform layer to supply capillaries.23 There exist strong connections between the arteries and cortical collagen in the ILM. Traction on the ILM can cause elevation of the retinal arteries without deeper retina traction. The arteries generally lie superficial to the veins but may lie as deep as the inner nuclear