Chapter 1
Pathophysiology of Diabetic Retinopathy
Michael W. Stewart
1.1 Retinal Anatomy
1.1.1 History
The retina was first described by Herophilus of Chalcedon around 300 BC. It was named by Rufos of Ephesus (c. 110 AD) and appeared to early anatomists as a surrounding net which supported the vitreous. Though Galen noted structural similarities to the brain, he was unable to provide further understanding regarding its function. It was Kepler who first suggested that the retina served as the eye’s primary photoreceptor tissue. By using alcohol fixation, Treviranus (1835) performed the first detailed microscopic retinal studies. Only with the subsequent development of electron microscopy, trypsin digest, clinical fluorescein angiography, and optical coherence tomography have scientists been able to understand the retina’s cellular connections, ultrastructure, and retinal vasculature, as well as correlate anatomical and clinical findings.1
1.1.2 Anatomy
The retina is a translucent tissue lining the inside posterior 2/3 of the eye, extending from the macula to the ora serrata.2 It is attached firmly at the disc and ora and is contiguous with the axons of the
M.W. Stewart (*)
Department of Ophthalmology, Mayo School of Medicine, Jacksonville, FL 32082, USA
e-mail: stewart.michael@mayo.edu
optic nerve and the nonpigmented epithelium of the pars plana (see Fig. 1.1). Externally, there exist weak attachments to the retinal pigment epithelium via interdigitation between the RPE cells and photoreceptor outer segments. There are firm internal attachments to the vitreous at the optic nerve, macula, retinal vessels, and vitreous base.
The central 5–6 mm is referred to as the retina centralis, an area with more than 1 layer of ganglion cells. The clinical macula, also called the macula lutea owing to xanthophyll in ganglion and bipolar cells, is the central 1.5 mm and is bounded by the termination of the retinal vessels.3 The central 0.35 mm depression is called the fovea by clinicians and the foveola by anatomists; its photoreceptor layer is entirely composed of cones. The center of foveal depression – the clivus – is located 3.4 mm temporal and 0.8 mm inferior to the center of the optic disc (see Fig. 1.2).
Beyond the macula, the retina spreads peripherally past the vortex veins to the ora serrata. The average equatorial diameter is approximately 24.06–24.08 mm, thereby giving a theoretical retinal area of 1,206 mm.1,3 The peripheral termination of the retina is at the ora serrata. This lies between 5.73 mm (nasally) and 6.52 mm (temporally) posterior to Schwalbe’s line. The ora is defined by protruding anterior retinal extensions (teeth) separated by ciliary epithelium indentations (ora bays) from the pars plana. The strong adhesion of the vitreous to the peripheral retina and pars plana, the vitreous base, extends 1–2 mm anterior to the ora and 1.8–3 mm posterior to the ora bays.4
A cross section through the retina just outside the area centralis shows nine layers (internal–external) (see Fig. 1.3): nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, outer
D.J. Browning (ed.), Diabetic Retinopathy, DOI 10.1007/978-0-387-85900-2_1, |
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Fig. 1.1 This artistic rendition of the eye shows the retina (yellow in cross section) emanating from the optic nerve at the right, lining the inside surface of the choroid (red and blue), and terminating at the ora serrata
Fig. 1.2 The anatomic classification of areas of the posterior pole is contrasted with the clinical classification
plexiform layer, outer nuclear layer, external limiting membrane, rod and cone inner and outer segments, and retinal pigment epithelium. The retina is thickest around the disc and tapers to 0.18 mm at the equator and 0.11 mm at the ora since the density of all neural elements decreases peripherally.
The layered pattern of the retina enables the conversion of photic energy into neuronal signals. The outer segments of rods and cones convert light
energy into a membrane depolarization; in the outer plexiform layer, axons of photoreceptor cells synapse with dendrites of bipolar cells (first-order neurons) and the processes of horizontal cells (integrating neuronal cells); bipolar cells synapse in the inner plexiform layer with dendrites of ganglion cells (second-order neurons) and amacrine cells (provide crosswiring); ganglion cell axons comprise the nerve fiber layer and optic nerve until synapsing
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Fig. 1.3 This artistic rendition of the peripapillary retina shows the cellular layers from internal (left side of the drawing) to external (right side of the drawing). Not labeled are the inner plexiform layer (between the ganglion cell layer and the amacrine/bipolar/horizontal cell layer) and the outer plexiform layer (between the amacrine/bipolar/horizontal cell layer and the rod/cone cell layer). Active transport of water across the retinal pigment epithelium maintains retinal deturgescence
with third-order neurons in the lateral geniculate body. Axons of these cells radiate to the occipital cortex.
The central 0.4 mm zone of the macula is capillaryfree, obtaining its nutrients from the choriocapillaris.5 The foveal center (foveola) is 0.35 mm in diameter and free of rods and blue cones. Long and slender red and green cones are aligned perpendicular to the surface, thereby allowing the greatest light sensitivity. The inner foveal retina lacks the inner nuclear layer, inner plexiform layer, ganglion cell layer, and nerve fiber layer, which minimizes light scatter; it is composed of only Muller’s cell processes. The external plexiform layer has an unusual configuration: its axons turn at a right angle, assuming
a course parallel with the retina surface. After a short course parallel to the retina surface (while forming Henle’s layer), the axons go perpendicular to synapse with dendrites of overlying bipolar cells; this occurs outside the central 0.2 mm diameter of the foveola. Xanthophyll – lutein throughout the posterior pole, zeathanthin mostly in the foveal region – is found in bipolar and ganglion cells and gives the retina its characteristic yellow color. These pigments function to decrease chromatic aberration, absorb potentially toxic blue light, and scavenge free radicals.6
The parafovea is a 0.5 mm ring of retina that surrounds the fovea. This region is characterized by a large accumulation of ganglion and inner
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nuclear cells with a thickened Henle’s layer. The density of cones is lower than within the fovea,
and rods are beginning to be found. The nerve fiber layer is thickest in the papillomacular bundle.
What is Henle’s layer? The outer nuclear layer (ONL), composed of the cell bodies of the rods and cones, has nearly uniform thickness throughout the entire retina. Within the macula, however, the oblique axons displace the cones’ cell bodies from their synaptic pedicles in the outer plexiform layer (OPL). These oblique axons with accompanying Muller cell processes form Henle’s layer, which is absent in the peripheral retina.
The perifovea is the outermost ring of the area centralis. It comprises the ring from 1.25 to 2.75 mm from the foveal center, defines the periphery of the macula (5.5 mm diameter),
and corresponds to a visual field of 18.578. The perifovea begins where the ganglion cell layer has four nuclei and ends where it thins to a single layer.
How does a 5.5-mm diameter macula perceive a visual field of 188? Geometrically, an object creates an inverted image which falls upon the concave retina. An image that spans the 5.5 mm curvilinear macula would create a larger image if it were flat on a plane tangent to the posterior pole of the eye. The size of this ‘‘straightened’’ image can be calculated as follows:
The average eye has a diameter of 24.07 mm, creating a radius of 12.035 mm. The angle subtended by a circular segment 5.5 mm in length is (see Fig. 1.4):
Fig. 1.4 The top eye shows the arc subtended by the ‘‘straightened’’ image covering the entire macula; the bottom eye shows the object that would create the macular image. Note
that the eye’s nodal point is situated 17 mm in front of the retina