This chapter reviews age-related macular degeneration and other conditions that cause choroidal neovascularization.
Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world in people over 50 years. It is estimated that among North Americans, 11 million (85%–90% of all AMD patients) currently have “dry” (nonneovascular, or non-exudative) AMD and 1.5 million people (10%–15% of all AMD patients) have “wet” (neovascular) AMD. An estimated 71,000 new cases of neovascular AMD develop each year in North America.
Normal aging results in a spectrum of changes in the macula, many clinically undetected, that affect the outer retina, retinal pigment epithelium (RPE), Bruch membrane, and choriocapillaris:
Photoreceptors are reduced in density and distribution.
Ultrastructural changes in the pigment epithelium include loss of melanin granules, formation of lipofuscin granules, and accumulation of residual bodies.
Basal laminar/linear deposits accumulate; these deposits consist of granular, lipid-rich material and widely spaced collagen fibers collecting between the plasma membrane of the RPE cell and the inner collagenous layer of Bruch membrane on either side of the basement membrane of the RPE (Fig 4-1; discussed later in the chapter).
Progressive involutional changes occur in the choriocapillaris.
All of these changes represent aging and may not be part of AMD. Abnormalities associated with AMD that are not necessarily part of normal aging may be classified as nonneovascular or neovascular.
Figure 4-1 Schematic illustration of basal laminar deposits and basal linear deposits that result in a thickened inner collagenous layer of Bruch membrane. RPE = retinal pigment epithelium.
(Illustration by Christine Gralapp.)
Population-based studies have demonstrated that of the risk factors for AMD, age is the first and foremost; in resource-rich countries, 10% of people over the age of 65 years and 25% over the age of 75 years have AMD. Additional risk factors include female sex, hypertension, hypercholesterolemia, cardiovascular disease, higher waist-to-hip ratio in men, positive family history, cigarette smoking, elevated levels of C-reactive protein and other inflammatory markers, hyperopia, and light iris color. Of modifiable risk factors, cigarette smoking has been consistently demonstrated to be most significant. Racial origin is another important risk factor. The 10-year longitudinal Multi-Ethnic Study of Atherosclerosis (MESA) found that the prevalence of AMD was highest in whites (5.4%) and lowest in African Americans (2.4%); prevalence was intermediate in Hispanics (4.2%) and Asians (4.6%).
Klein R, Klein BE, Knudtson MD, et al. Prevalence of age-related macular degeneration in 4 racial/ethnic groups in the multi-ethnic study of atherosclerosis. Ophthalmology. 2006;113(3):373–380.
Genetics and AMD
The etiology of AMD remains poorly understood. Development of the disorder involves interplay between genetic predisposition and other risk factors. A recent genome-wide association study of 43,000 people identified 52 genetic variants, both common and rare, located on the 34 loci associated with AMD. These genes harbor mutations that affect various biochemical pathways, including the complement cascade, lipid transport and metabolism (eg, APOE), modulation of the extracellular collagen matrix (eg, COL8A1, COL10A1, TIMP3), clearance of all-trans-retinaldehyde from photoreceptors (ABCA4), and angiogenesis (eg, MMP9, VEGFA). The alternate complement pathway includes the highest number of known AMD risk alleles, including CFH, CFI, C2/CFB, C3, and C7.
The 2 major susceptibility genes for AMD are CFH (1q31), which codes for complement factor H, and ARMS2 (10q26), for which the gene product and function are poorly understood. ARMS2/HTRA1 and MMP20 are associated with choroidal neovascularization (CNV) lesion size. The CFH Y402H mutation confers a 4.6-fold increased risk for AMD when heterozygous and a 7.4-fold increased risk when homozygous. The ARMS2 A69S mutation confers a 2.7-fold increased risk for AMD when heterozygous and an 8.2-fold increased risk when homozygous. When both genes are homozygous for the aforementioned mutations in an individual, the risk for AMD is increased to 50-fold.
Genetic testing is available for AMD and usually includes testing for many of the known risk alleles. However, the interpretation and usefulness of the results remain controversial, because unhealthy lifestyles increase AMD risk regardless of the AMD risk genotype. The risk models used either are poorly validated or add little information to the risks that can already be estimated from clinical findings and assessment of the patient’s risk factors (eg, smoking history, family history). The American Academy of Ophthalmology’s official recommendation is to defer genetic testing for complex disorders such as AMD until replicable studies have confirmed the value of such testing for prognostication or response to therapy. Pharmacogenomic testing is also possible; it aims to predict the optimal pharmacologic or nutritional-supplement interventions for a given patient. Evidence to support this approach is only beginning to emerge, and validation studies are lacking. However, this is a fast-moving area of research, and progression to useful testing is likely.
AAO Retina/Vitreous PPP Panel, Hoskins Center for Quality Eye Care. Preferred Practice Pattern® Guidelines. Age-Related Macular Degeneration. San Francisco: American Academy of Ophthalmology; 2015. Available at: www.aao.org/ppp.
Frisch LG, Igl W, Bailey JN, et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants. Nat Genet. 2016:48(2):134–143.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.