Neovascular age-related macular degeneration

Aimee V. Chappelow, MD and Andrew P. Schachat, MD

DISEASE PREVALENCE AND INFLUENCE

Age-related macular degeneration (AMD) is the leading cause of severe, irreversible vision loss in individuals over the age of 50 years in western societies. Advanced AMD affects an estimated 14 million people worldwide, and as the population ages, the number of individuals with AMD in the USA is expected to increase from 1.75 million in 2000 to 2.95 million in 2020.1 Choroidal neovascularization (CNV) is the hallmark of “wet” or “exudative” AMD, and is responsible for approximately 90% of cases of severe vision loss due to AMD.

RISK FACTORS

As the nomenclature implies, the prevalence of early and advanced AMD increases with age, from 14.4% in people aged 55–64 years to 36.8% in those older than 75 years.2 Other systemic risk factors associated with development of AMD include cigarette smoking, Caucasian race, systemic hypertension,3 elevated serum cholesterol, greater exposure to visible light, and prior history of ischemic stroke.4 Analysis of demographic data collected from the 4757 Age-Related Eye Disease Study (AREDS) participants confirmed smoking and Caucasian race as risk factors associated with progression from intermediate to advanced AMD.5 More recently, a role for genetics has been implicated. Homozygosity for a specific polymorphism in the gene for complement factor H has been shown to increase the risk for the development of AMD by a factor of 7.4.6 Other single nucleotide polymorphisms have been associated not only with an increased risk of progression of AMD, but also with a lower likelihood of response to treatment with antioxidants and zinc (the current standard of care for dry or nonexudative AMD).7

A number of studies have assessed the risk for development of CNV in the fellow eye in patients with unilateral neovascular AMD. Risk factors for development of CNV in the fellow eye include the presence of large drusen (>63 µm), five or more soft drusen, focal retinal pigment epithelial (RPE) hyperpigmentation, and definite systemic hypertension.8 The Macular Photocoagulation Study (MPS) reported a 5-year cumulative incidence rate of neovascular AMD ranging from 7% (if an eye had none of the aforementioned risk factors) to 87% (if all four risk factors were present).9 The rate of development of CNV in the fellow eye at 1 year ranges from 4 to 12% in various studies.8 The average age at which neovascular AMD develops is 75 years; given a life expectancy of at least an additional 5–10 years, a significant number of patients will develop bilateral neovascular AMD.

ETIOLOGY/PATHOGENESIS

To date, no single etiology has been identified as causative of neovascular AMD. However, it is thought that the same inflammatory processes that lead to drusen formation also help create a cellular and molecular milieu for CNV.10 Proposed theories to explain the stimulus for such inflammatory processes include excessive oxidative stress,

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dietary deficiency, light exposure, and autoimmune mechanisms. Further the drusen itself, composed of cellular remnants of degenerating RPE, serves as a chronic inflammatory stimulus. Many inflammatory mediators, including neutrophils, macrophages, mast cells, and activated microglia, are capable of producing and releasing proangiogenic factors. Through a complex interplay between numerous cellular mediators, stimulation of neovascularization occurs with either a net increase in proangiogenic molecules (transforming growth factor-α (TGF-α), TGF-β, the angiopoietins, and members of the vascular endothelial growth factor (VEGF) family) or a net decrease in antiangiogenic molecules (pigment epithelium-derived factor (PEDF), thrombospondin, and angiostatin). Local hypoxia may also play a role in upregulating VEGF and other growth factors via a separate pathway mediated by hypoxia-inducible factor-1a (HIF-1a).11

The VEGF family of proangiogenic factors comprises VEGF-A (often referred to simply as VEGF), VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF)-1 and -2. The biologically active secreted form of VEGF-A is a homodimer that binds VEGF receptor (VEGFR)-1 and VEGFR-2 on vascular endothelial cells, inducing intracellular tyrosine kinase pathways. Multiple biologically active forms of VEGF-A are generated by alternative messenger RNA splicing and proteolytic cleavage. VEGF-A has been detected in elevated levels in both the excised CNV membranes12 and vitreous of patients with CNV,13 and is integral to the growth and maintenance of CNV. As such, it has become a popular and effective target for pharmacotherapy in AMD.

Macroscopically, CNV is a neovascular proliferation that grows through breaks in Bruch’s membrane and progresses laterally between the RPE and Bruch’s membrane. The endothelial cells that make up this neovascular tuft lack normal barrier function, and thus tend to leak fluid, protein, and lipid, which may precipitate within the retina. Further, increased vascular fragility can lead to hemorrhage. Grossniklaus and Gass14 proposed two different histologic types of subretinal neovascular membranes: type 1 (located beneath the RPE) and type 2 (between the retina and the RPE). Clinical characteristics that distinguished patients with type 2 CNV were younger patient age (<50 years), normal fellow eye, and fundus appearance characterized by a subretinal pigmented halo or pigmented plaque in the area of the lesion and sharply defined borders. Type 1 versus type 2 CNV might have importance during consideration of surgery to remove CNV, but in the pharmacotherapy era the differentiation seems to these authors to be moot.

NATURAL HISTORY

CNV is classified based upon clinical (subfoveal, juxtafoveal, or extrafoveal) and angiographic (classic, occult, predominantly classic, or minimally classic) criteria (Table 18.1). Attempts to define the natural history of each lesion subgroup have been largely achieved by pooling data from fellow eyes in treatment trials rather than through true observational series. Meta-analyses are limited by diversity of reporting formats among individual studies and general paucity of long-term follow-up. With these caveats in mind, the following generalizations can be made.