Section 1: Basic Sciences in Retina

INTRODUCTION

The retina is a thin multilayer of mainly neuronal cells derived from ectoderm. Much like the film of a camera, the retina is charged with the critical task of receiving, modulating, and transmitting visual stimuli from the external world to the optic nerve and, ultimately, the visual cortex of the brain. Adequate conveyance of visual signals depends largely upon the highly specialized anatomy of the retina, and a variety of insults to the retina can generate pathological processes which disrupt this delicate structure and lead to retinal diseases. This chapter provides a brief overview of normal retinal anatomy, as well as key pathological changes seen in major diseases of the retina.

KEY CONCEPTS AND FUNDAMENTALS

NORMAL RETINAL ANATOMY

The retina is a thin, delicate, transparent sheet of tissue derived from neuroectoderm. It comprises the sensory neurons that begin the visual pathway. The neural retina (neuroretina) is divided into nine layers: layer of inner and outer segments of the photoreceptors (rods and cones), external limiting membrane, outer nuclear layer, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, nerve fiber layer, and internal limiting membrane (Figure 2.1). Light must traverse these many layers before initiating signal transduction in the rods and cones. Below these photoreceptors reside the retinal pigment epithelium (RPE), a monolayer of cuboidal cells characterized by a high concentration of melanosomes from which the cells derive their pigmented color. The RPE cells help to nourish the overlying neurosensory retina, facilitating the diffusion of nutrients from the choroid and the removal of waste or worn-out photoreceptors segments. Each RPE has numerous apical membrane extensions, servicing up to 45 photoreceptors and reaching up to 50% the height of the outer photo­ receptor segment. The extracellular space between the photoreceptors and RPE is filled with a glycosaminoglycan ground substance, termed the interphotoreceptor matrix. The basement membrane of the RPE comprises the cuticular portion (inner layer) of Bruch’s membrane.

The rod and cone layer is composed of the outer and inner segments of the rod and cone cells, referred to together as the photoreceptor cells. The outer segment contains stacks of membrane discs, which enclose visual pigment molecules and are constantly renewed. New discs are added to the base of the outer segment at the cilium. At the same time, old discs are displaced outwards, eventually being pinched off at the photoreceptor tip and engulfed by the apical processes of the RPE in a diurnal cycle. Anatomically, the outer segment constricts at the cilium, beginning the inner segment, which is divided into the mitochondriarich outer ellipsoid and Golgi body and ribosome-rich inner myoid. The external limiting membrane, separating the inner and outer segments from the photoreceptor nuclei, is not a true membrane but a series of dashes formed by the terminal bar attachments of the cell bodies of rods, cones, and Müller cells. The outer nuclear layer contains the nuclei of the photoreceptor cells (both rod and cone cells). The outer plexiform

layer is formed by the axons of the photoreceptor cells and their synapses with bipolar cells. In the perifovealar area, the axons of the cones take a tangential or oblique course to meet the excentric-positioned neurons of inner retina and ganglion cells, referred to as the nerve fibre layer of Henle.

Several distinct cell types compose the inner neural retina (Figure 2.1). Bipolar cells (glutamatergic or glycinergic neurons) connect the photoreceptor cells ultimately with the dendrites of the ganglion cells in the outer plexiform layer. Horizontal cells are mainly GABAnergic (gamma-aminobutyric acid) neurons that connect to either rod cells or cone cells and synapse with bipolar cells, where on and off responses are generated, to regulate signal transduction. Amacrine cells receive excitatory glutamatergic input from bipolar cells and primarily inhibitory input from other amacrine cells mediated by GABAC receptors. Amacrine cells can synapse back on to bipolar cells, other amacrine cells, and ganglion cells. Müller cells act as specialized glial cells to form retinal scaffolding, support the inner segments of the photoreceptors, and create the acellular fibrous internal limiting membrane. The nuclear bodies of all these distinct cell types compose the inner nuclear layer. The axons of the bipolar and amacrine cells connect to the dendrites of the ganglion cells to compose the inner plexiform layer. The ganglion cell layer contains the nuclei of the ganglion cells. Their axons en route to the optic disc form the nerve fiber layer. The internal limiting membrane is a basement membrane structure, formed by the footpads of the Müller cells.

The retina measures about 0.4 mm in thickness at the border of the optic nerve head and tends to become thinner toward the periphery until it reaches approximately 0.14 mm at the ora serrata. The clinical macula is a 1.5-mm circular area in the neural retina, 0.35 mm thick on the outside and sloping down to 0.18 mm at the foveola. In this region cones reach a high density: 4000–5000/mm2 in the macula and 15000/ mm2 in the fovea. Rods reach their greatest density 20° from the fixation point. Foveal cones can match with up to five ganglion cells, while on average the retinal ganglion cells match with roughly 130 different photoreceptors. Metabolic supply is mainly provided to the neural retina by the central retinal artery, which divides into four arteriole branches at the optic disc. The arterioles are 7–8 smooth-muscle cells thick and run in the nerve fiber layer below the internal limiting membrane. Capillary-free zones extend 150 µm around the retinal arteries and within the 400-µm diameter of the foveola. Photoreceptors receive their metabolic supply from the choroid through osmosis across Bruch’s membrane and through the RPE.

With age, changes in the normal retina include a shallower optic disc surrounded by focal subtle choroidal atrophy, lipofuscin in the RPE, and few small drusen between the RPE and Bruch’s membrane.1,2

RETINAL PATHOLOGY

As illustrated above, the retina is an extremely complex structure. One can imagine that its intricate nature can easily result in many different and unique congenital and developmental abnormalities. Similarly, a variety of insults to the retina – including degenerative processes, drug toxicities, inflammation, vascular abnormalities, infection, and neoplastic changes – can result in a broad spectrum of retinal pathology. The

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Retina in Sciences Basic • 1 section

the RPE and is characterized by ill-defined yellow-whitish round and linear fishtail or pisiform lesions at the level of the RPE. The main pathology demonstrates loss of RPE and photoreceptors in the macular area. In the RPE there is displacement of nuclei, aggregation of melanin granules, accumulation of mucopolysaccharides, and variation in cell size. In addition, cystoid macular edema and some nodular drusen can be found. When the characteristic lesions are seen throughout the fundus the disorder is known as fundus flavimaculatus. Patients may be genotyped for common mutations in ABCA4 gene associated with the recessive form of this disease or the gene that codes for ELOVL4 in the dominant form.9 Vitelliform dystrophy (Best’s disease) will reveal yellowish round lesions that look like the yolk of a fried egg clinically. Pathologically there is RPE and photoreceptor cell atrophy, accumulation of abnormal lipofuscin in residual RPE and deposition of periodic acid–Schiff-positive material in the macula. Best’s disease is caused by mutations in VMD2 (hBEST1). Bestrophin, the gene product of hBEST1, is a regulatory part of a Ca2+ channel or a Ca2+-dependent Cl– channel.9 Central areolar pigment epithelial dystrophy is a disturbance of RPE with areas of depigmentation, fine clumping, proliferation with lipid accumulation, and possible complete atrophy of RPE. Atrophy is limited to the central area and not seen in the periphery. Other such

disorders of the macula include North Carolina macular dystrophy, familiar drusen, Sorsby’s dystrophy, pattern dystrophy of the pigment epithelium of Marmor–Byers, foveomacular vitelliform dystrophy, dominant slowly progressive macular dystrophy of Singerman– Berkow–Patz, butterfly-shaped pigment dystrophy of the fovea, macroreticular dystrophy of the RPE, Sjögren’s reticular dystrophy of the RPE, pigment epithelial dystrophy of Noble–Carr–Siegel, and benign concentric annular macular dystrophy.

Diffuse photoreceptor damage is characteristic in either rod–cone or cone–rod dystrophy. In cone–rod dystrophy a loss of photoreceptors occurs mainly in the central macula, along with attenuation of the RPE. Ultrastructure reveals accumulation of abnormal lipofuscin granules in the RPE and enlargement and distortion of the cone photoreceptor pedicles. Retinitis pigmentosa is a classic manifestation of rod–cone dystrophy and presents with photoreceptor atrophy from equator to periphery, RPE migration into the retina, mainly surrounding the retinal vessels, and retinal and optic nerve gliosis. Mutations in the rhodopsin and peripherin/RDS genes account for about 25% of all cases of autosomal-dominant retinitis pigmentosa. The gene for X-linked retinitis pigmentosa, the most severe type of retinitis pigmentosa, has been localized to the Xp21 region.10

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