Embryologically, the retina and its underlying epithelial layer have a common origin, the optic vesicle (see Chapter 4). Thus, the retina can be described as having 2 parts: (1) the neurosensory retina, containing the photoreceptors, neurons, and other elements; and (2) the retinal pigment epithelium (RPE).
The neurosensory retina is a thin, transparent structure that develops from the inner layer of the optic cup. The neurosensory retina is composed of neuronal, glial, and vascular elements (see Figs 2-33, 2-34).
In cross section, from inner to outer retina, the layers of the neurosensory retina are as follows (Fig 2-32):
internal limiting membrane
nerve fiber layer
ganglion cell layer
inner plexiform layer
inner nuclear layer
middle limiting membrane (see also Fig 1-4 in BCSC Section 12, Retina andVitreous)
outer plexiform layer (referred to as Henle fiber layer in the foveal region)
outer nuclear layer
external limiting membrane
rod and cone inner segments
rod and cone outer segments
These layers are discussed later in the chapter, in the section “Stratification of the neurosensory retina.” The retina is discussed in depth in BCSC Section 12, Retina and Vitreous.
The photoreceptor layer of the neurosensory retina consists of highly specialized neuroepithelial cells called rods and cones. There are approximately 100–125 million rods and 6–7 million cones in the human retina, an approximate ratio of 20:1. Each photoreceptor cell consists of an outer segment and an inner segment. The outer segments, surrounded by a mucopolysaccharide matrix, make contact with the apical processes of the RPE. Tight junctions or other intercellular connections do not exist between the photoreceptor cell outer segments and the RPE. The factors responsible for keeping these layers in apposition are poorly understood but probably involve active transport and other mechanisms, including van der Waals forces, oncotic pressure, and electrostatic forces.
Figure 2-32 Cross section of the retina illustrating its layers and the approximate location of the blood supply to these layers.
(Modified with permission from D’Amico DJ. Diseases of the retina. N Engl J Med. 1994;331:95–106.)
The rod photoreceptor consists of an outer segment that contains multiple laminated discs resembling a stack of coins and a central connecting cilium (Fig 2-33). The microtubules of the cilium have a 9-plus-0 cross-sectional configuration rather than the 9-plus-2 configuration found in motile cilia. The rod inner segment is subdivided into 2 additional elements: an outer ellipsoid containing numerous mitochondria, and an inner myoid containing a large amount of glycogen; the myoid is continuous with the main cell body, where the nucleus is located. The inner portion of the cell contains the synaptic body, or spherule, of the rod, which is formed by a single invagination that accommodates 2 horizontal-cell processes and 1 or more central bipolar dendrites (Fig 2-34). The outer segments of the cones have a different morphology depending on their location in the retina.
Figure 2-33 Rod and cone photoreceptor cells.
(Illustration by Sylvia Barker.)
The extrafoveal cone photoreceptors of the retina have conical ellipsoids and myoids, and their nuclei tend to be closer to the external limiting membrane than are the nuclei of the rods. Although the structure of the outer segments of the rods and cones is similar, at least 1 important difference exists. Rod discs are not attached to the cell membrane; they are discrete structures. Cone discs are attached to the cell membrane and are thought to be renewed by membranous replacement (see Fig 2-33).
The cone synaptic body, or pedicle, is more complex than the rod spherule. Cone pedicles synapse with other rods and cones as well as with horizontal and bipolar cell processes (see Fig 2-34). Foveal cones have cylindrical inner segments similar to rods but otherwise are cytologically identical to extrafoveal cones.
Horizontal cells make synaptic connections with many rod spherules and cone pedicles; they also extend cell processes horizontally throughout the outer plexiform layer. Bipolar cells are oriented vertically. Their dendrites synapse with rod or cone synaptic bodies, and their axons make synaptic contact with ganglion cells and amacrine cells in the inner plexiform layer.
The axons of the ganglion cells bend to become parallel to the inner surface of the retina, where they form the nerve fiber layer and later the axons of the optic nerve. Each optic nerve has more than 1 million nerve fibers. The nerve fibers from the temporal retina follow an arcuate course around the macula to enter the superior and inferior poles of the optic nerve head. The papillomacular fibers travel straight to the optic nerve from the fovea. The nasal axons also pursue a radial course. The visibility of the nerve fibers is enhanced when they are viewed ophthalmoscopically using green (red-free) illumination.
Figure 2-34 Synaptic bodies of photoreceptors. A, Cone pedicle with synapses to several types of bipolar cells. B, Rod spherule with synapses to bipolar cells. FB = flat bipolar; FMB = flat midget bipolar; H = horizontal cell processes; IMB = invaginating midget bipolar; RB = rod bipolar.
(Illustration by Sylvia Barker.)
The neuronal elements and their connections in the retina are highly complex (Fig 2-35). Many types of bipolar, amacrine, and ganglion cells exist. The neuronal elements of 100–125 million rods and 6–7 million cones are interconnected, and signal processing within the neurosensory retina is significant.
Müller cells are glial cells that extend vertically from the external limiting membrane inward to the internal limiting membrane (see Fig 2-35). Their nuclei are located in the inner nuclear layer. Müller cells, along with the other glial elements (the fibrous and protoplasmic astrocytes and microglia), provide structural support and nutrition to the retina and are crucial to normal physiology. In addition, they contribute to the inner blood–retina barrier.
The retina is a highly metabolic structure, with the highest rate of oxygen consumption per unit weight in the body. The retinal blood vessels are analogous to the cerebral blood vessels and maintain the inner blood–retina barrier. This physiologic barrier is due to the single layer of nonfenestrated endothelial cells, whose intercellular junctions, under physiologic conditions, are impervious to tracer substances such as fluorescein and horseradish peroxidase (Fig 2-36). A basal lamina covers the outer surface of the endothelium and is surrounded by pericytes, or mural cells, which suppress endothelial proliferation and, along with glial cells, contribute to the inner blood–retina barrier (Fig 2-37).
A, Normal retinal layers (periodic acid–Schiff [PAS] stain). From vitreous to choroid: ILM = internal limiting membrane; NFL = nerve fiber layer; GCL = ganglion cell layer; IPL = inner plexiform layer; INL = inner nuclear layer; MLM = middle limiting membrane; OPL = outer plexiform layer; ONL = outer nuclear layer; ELM = external limiting membrane; PIS = photoreceptor inner segment; POS = photoreceptor outer segment; RPE = retinal pigment epithelium. B, Cell types of the retina.
(Part A courtesy of Robert H. Rosa, Jr, MD. Part B illustration by Paul Schiffmacher; revised by Cyndie C.H. Wooley.)
Müller cells and other glial elements are generally attached to the basal lamina of retinal blood vessels. Retinal blood vessels lack an internal elastic lamina and the continuous layer of smooth muscle cells found in other vessels in the body. In the absence of the latter, there is no autonomic regulation of the retinal vessels.
Figure 2-36 Blood–retina barriers. The inner blood–retina barrier is created by intercellular junctions between endothelial cells of the nonfenestrated retinal vessels. The outer blood–retina barrier consists of tight junctions between adjacent RPE cells. Left: Normal histologic section of rat retina. Right: Section of rat retina following injection of fluorescein. Note the containment of dye within the retinal vessels and the diffuse staining of the choroid by leakage of fluorescein from the fenestrated choriocapillaris. Further extravasation into the outer retina is blocked by the RPE.
(Reproduced with permission from Spalton D, Hitchings R, Hunter P. Atlas of Clinical Ophthalmology. 3rd ed. Oxford: Elsevier/Mosby; 2005:409.)
The retina possesses a dual circulation in which the inner retina is supplied by branches of the central retinal artery, and the outer retina is supplied by the choroid (see Fig 2-32). Retinal arterioles give rise to the superficial capillary plexus and the deep capillary plexus, which supply the ganglion cell layer and inner nuclear layer, respectively (Fig 2-38). The retinal vascular supply is discussed in detail in BCSC Section 12, Retina and Vitreous. The outer nuclear layer and remaining layers of the outer retina are perfused by the choroid. The outer plexiform layer represents a watershed zone in regard to perfusion. Perfusion by the 2 circulations can vary with the location in or thickness of the retina, as well as with light exposure. In approximately 18%–32% of eyes, a cilioretinal artery, derived from the posterior ciliary circulation, also supplies the macula.
Retinal vessels exhibit several characteristics. In contrast to choroidal vessels, retinal vessels demonstrate dichotomous branching. Also, retinal vessels do not normally cross the horizontal raphe. The occurrence of such suggests the presence of anastomoses, which can often be found in the temporal macula following retinal vein occlusions. Further, retinal arteries do not intersect with other arteries; similarly, retinal veins do not intersect with other veins. At arteriovenous crossings, the 2 vessels share a common sheath, which often represents the site of branch retinal vein occlusions.
Figure 2-37 Inner blood–retina barrier. Electron micrograph of a retinal capillary in the inner nuclear layer. The inner blood–retina barrier consists of intercellular endothelial junctions (tight, adherens, and gap), pericytes, and contributions from glial cells (Müller cells, astrocytes). A = astrocyte; BL = basal lamina; E = endothelial cell; L = lumen; P = pericyte. Arrows = intercellular junctional complexes.
(Modified with permission from Klaassen I, Van Noorden CJ, Schlingemann RO. Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog Retin Eye Res. 2013;34:19–48, Fig 3.)
Stratification of the neurosensory retina
The neurosensory retina can be divided into several layers (Fig 2-39; see also Fig 2-35). The photoreceptor outer segments represent the outermost layer and interact with the apical processes of the RPE. A potential space exists between this outermost layer of the neurosensory retina and the RPE and is the plane of separation in retinal detachment. The roof of the subsensory space is demarcated by the external limiting membrane (ELM), which separates the photoceptor nucleus from its inner and outer segments (see Fig 2-33). The ELM is not a true membrane and is formed by the attachment sites of adjacent photoreceptors and Müller cells. It is highly permeable, allowing the passage of oxygen and macromolecules from the choroid into the outer retina.
Photoreceptor nuclei are found in the outer nuclear layer (ONL). The outer plexiform layer (OPL) is composed of synapses between the photoreceptors and bipolar cells. Horizontal-cell fibers descend into this region and regulate synaptic transmission. The OPL also accommodates the oblique axons of the rods and cones as they radiate from the foveal center. Because it contains more fibers, the OPL is thicker in the perifoveal region (see Fig 2-39). The radial fibers in this portion of the OPL are known as the Henle fiber layer. At the edge of the foveola, the Henle layer lies almost parallel to the internal limiting membrane, resulting in petaloid or star-shaped patterns when these extracellular spaces are filled with fluid or exudate (Fig 2-40).
Figure 2-38 OCT angiograms (right) demonstrate the superficial vascular plexus and the deep vascular plexus, which arise from retinal arterioles. The schematic (left) shows the retinal layers supplied by these plexuses.
(Angiograms courtesy of Vikram S. Brar, MD. Schematic by Mark Miller.)
Like the ELM, the middle limiting membrane (MLM) is not a true membrane but is rather a junctional system in the inner third of the OPL, where synaptic and desmosomal connections occur between photoreceptor inner fibers and processes of bipolar cells. It is sometimes apparent on OCT as a linear density. Retinal blood vessels ordinarily do not extend beyond this point.
The inner nuclear layer (INL) contains nuclei of bipolar, Müller, horizontal, and amacrine cells. The inner plexiform layer (IPL) consists of axons of the bipolar and amacrine cells and dendrites of the ganglion cells and their synapses. Amacrine cells, like the horizontal cells of the OPL, probably play an inhibitory role in synaptic transmission. The ganglion cell layer (GCL) is made up of the cell bodies of the ganglion cells that lie near the inner surface of the retina. The nerve fiber layer (NFL) is formed by axons of the ganglion cells. Normally, these axons do not become myelinated until after they pass through the lamina cribrosa of the optic nerve.
Like the ELM and MLM, the internal limiting membrane (ILM) is not a true membrane. It is formed by the footplates of the Müller cells and attachments to the basal lamina. The basal lamina of the retina is smooth on the vitreal side but appears undulatory on the retinal side, where it follows the contour of the Müller cells. The thickness of the basal lamina varies. The ILM is the point of contact of the retina and the cortical vitreous, the vitreoretinal interface.
Figure 2-39 Schematic section through the fovea. FAZ = foveal avascular zone; GCL = ganglion cell layer; INL = inner nuclear layer; IPL = inner plexiform layer; IS = inner segment of the photoreceptor; NFL = nerve fiber layer; ONL = outer nuclear layer; OPL = outer plexiform layer (Henle fiber layer); OS = outer segment of the photoreceptors; RPE = retinal pigment epithelium.
(Illustration by Sylvia Barker.)
Overall, cells and their processes in the retina are oriented perpendicular to the plane of the RPE in the middle and outer layers but parallel to the retinal surface in the inner layers. For this reason, deposits of blood or exudates tend to form round blots in the outer layers (where small capillaries are found) and linear or flame-shaped patterns in the NFL.
Drexler W, Morgner U, Ghanta RK, Kärtner FX, Schuman JS, Fujimoto JG. Ultra-high-resolution ophthalmic optical coherence tomography. Nat Med. 2001;7(4): 502–507.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.