Age-related macular degeneration--emerging pathogenetic and therapeutic concepts

Abstract

Today, the average life expectancy in developed nations is over 80 years and climbing. And yet, the quality of life during those additional years is often significantly diminished by the effects of age-related, degenerative diseases, including age-related macular degeneration (AMD), the leading cause of blindness in the elderly worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a highly specialized region of the ocular retina responsible for fine visual acuity. Estimates gathered from the most recent World Health Organization (WHO) global eye disease survey conservatively indicate that 14 million persons are blind or severely visually impaired because of AMD. The disease has a tremendous impact on the physical and mental health of the geriatric population and their families and is becoming a major public health burden. Currently, there is neither a cure nor a means to prevent AMD. Palliative treatment options for the less prevalent, late-stage 'wet' form of the disease include anti-neovascular agents, photodynamic therapy and thermal laser. There are no current therapies for the more common 'dry' AMD, except for the use of antioxidants that delay progression in 20%-25% of eyes. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events, genetic factors, and biochemical processes associated with early AMD. Recently, compelling evidence has emerged that the innate immune system and, more specifically, uncontrolled regulation of the complement alternative pathway plays a central role in the pathobiology of AMD. The complement Factor H gene--which encodes the major inhibitor of the complement alternative pathway--is the first gene identified in multiple independent studies that confers a significant genetic risk for the development of AMD. The emergence of this new paradigm of AMD pathogenesis should hasten the development of novel diagnostic and therapeutic approaches for this disease that will dramatically improve the quality of our prolonged lifespan.

Figures

Figures 1–9

Figure 1: Normal macula of an elderly patient. The asterisk represents the location of the fovea, which lies directly in the visual axis. The macula (boxed area), which is adapted for high acuity vision, is located temporal to the optic nerve (arrow). It is approximately 6 mm in diameter and centered on the fovea. The vascular arcades are indicated by arrowheads. Figure 2: Ocular coherence tomogram (OCT) of a normal macula. The central area of depression (arrow) represents the fovea, corresponding to the asterisk depicted in Figure 1. Ret=retina. Figure 3: Color fundus photograph derived from an individual with early, dry age-related macular degeneration (AMD). Retinal pigment epithelium (RPE) pigment disruption is present in the macula (arrow) and numerous small (125 micron diameter), calcified drusen deposited primarily within the peri- and parafoveal regions. Smaller drusen are present in the foveal region (asterisk). Figures 8 and 9: Color fundus photograph from two patients with macular geographic atrophy (GA). The margins of the regions of RPE atrophy are clearly delineated. Choroidal blood vessels are more easily visualized in these regions of atrophy because of the loss and/or absence of the RPE pigment. A choroidal nevus (asterisk) is indicated in Figure 8. These eyes would be expected to have poor central vision due to the extensive atrophy.

Figures 10–18

Color fundus photograph (Figure 10), early fluorescein angiogram (Figure 11) and late fluorescein angiogram (Figure 12) from an individual with a classic choroidal neovascularization (CNV). Subretinal blood and fluid (arrowhead depicts edge) is clearly visible within the macular region in Figure 10. Note the lacey appearance of vessels (asterisk) in the early angiogram. Marked leakage of fluorescein (asterisk), with indistinct edges of hyperfluorescence (white area) is clearly visible in the late angiogram. Color fundus photograph (Figure 13), early fluorescein angiogram (Figure 14) and late fluorescein angiogram (Figure 15) from an individual with occult choroidal neovascularization. A single, small punctate region of hemorrhage (black arrow) and a ring of exudates (arrowhead depicts edge) that appears more indolent than that which typically occurs in classic choroidal neovascularization (CNV) (Figure 10) is visible in Figure 13. Note that there is minimal hyperfluorescence in the early phase of the angiogram, in contrast to that observed in the early stage of classic CNV. Speckled macular hyperfluorescence–-in contrast to the profuse leakage of fluorescein that occurs in classic lesions–-is visible in the late stage angiogram (Figure 15). Corresponding angiographic (Figure 16) and ocular coherence tomogram (OCT) images (Figure 17) from an individual with a macular pigment epithelial detachment (PED). A multilobulated, hyperfluorescent lesion with sharply demarcated borders (arrow) is clearly visible in the late stage angiogram depicted in Figure 16. The blister-like elevation of the retina and retinal pigment epithelial layer, which correlates with the PED shown in Figure 16, is appreciated on OCT in Figure 17. SRF=subretinal fluid; RET=retina. Figure 18: Color fundus photograph from an individual with end stage (cicatricial) exudative age-related macular degeneration (AMD). A large disciform scar (arrowhead) covering the macular region is distinctly visible.

Figure 19

Goldmann visual field simulating an individual with central visual loss. The physiological blind spot, which corresponds to the location of the optic nerve head, is depicted as a small dark oval. The larger, more irregular darkened region corresponds to a blind spot, or scotoma, caused by atrophy and/or scarring within the macula.

Figures 20–25

Light microscopic (Figures 20, 22–25) and schematic (Figure 21) images depicting the choroid-RPE-retina interface. A section showing the normal anatomical relationships of the macular choroid (Ch), retinal pigmented epithelium (RPE) and neural retina (R) is shown in Figure 20; the section passes directly through the foveal pit. The boxed region corresponds to that depicted in Figure 21, which compares the choriocapillaris-RPE interface in unaffected (top) and affected (bottom) individuals. The majority of early age-related macular degeneration (AMD)-associated extracellular lesions–-including drusen, basal laminar deposit (BLamD), and basal linear deposits (BLinD)–-form along this interface. Drusen (asterisks), which form between the RPE and Bruch’s membrane, are present in Figures 22 and 23. Extensive accumulations of BLamD (asterisks), which form between the RPE and its basal lamina, are depicted in Figure 24. Choroidal neovessels, located in both the sub-RPE and subretinal spaces (arrows) are shown in Figure 25. Arrowheads in Figures 23 and 24, Bruch’s membrane.

Figures 26–29

Transmission electron micrographs of the retinal pigment epithelium (RPE)-choroid interface in eyes of donors without (Figure 26) and with (Figures 27–29) a clinically documented history of age-related macular degeneration (AMD). A single druse (D) is shown in Figure 27; its location between the RPE basal lamina (arrowheads) and Bruch’s membrane (BM) is clearly indicated. BLamD (asterisk) accumulates between the basal surface of the RPE and its basal lamina (arrow), whereas BLinD is located within the innermost aspect of Bruch’s membrane (Figure 28). A patent choroidal neovessel (asterisk), lying between BM and a layer of BLamD (rectangle), is shown in Figure 29. RPE=retinal pigment epithelium; BM=Bruch’s membrane.