Age-related macular degeneration (AMD) is a complex disease and difficult to define. Since its first description by Holloway and Verhoeff in 1929 as a condition characterized by the loss of vision in older patients due to degenerative changes in the retina pigment epithelium (RPE) (1), the amount of knowledge about this disease, as well as the interest in finding an adequate therapy, has been increasing exponentially. Eighty years later, despite all the resources and efforts put forth to better understand the etiology and pathophysiology of AMD, many of its mechanisms remain elusive.

As life expectancy in developed countries and around the world has increased, AMD incidence has also risen to become the leading cause of vision loss among individuals aged 50 years or older (2, 3 and 4). It is believed that the annual incidence of some degree of AMD among patients 60 years or older reaches 40% to 50%. AMD-related disability and poor quality of life have become heavy socioeconomic burdens in industrialized countries (5, 6 and 7).

Although most AMD patients suffer the atrophic or “dry” form, the neovascular or “wet” form will be found in more than 10% of the cases. Wet AMD is characterized by deep choroidal neovascularization (CNV), subretinal fluid (SRF), subretinal hemorrhage (SRH), exudates, scarring, and severe visual loss (8, 9, 10 and 11). The natural history of the disease dictates that approximately 75% of the patients with subfoveal exudative lesions will become legally blind after 2 years (12,13). Population studies such as the Beaver Dam Eye Study demonstrated that approximately 10% to 20% of patients with the dry form of AMD will progress to the exudative form (especially if the patient’s retina exhibits large drusen [≥125 μm], soft indistinct drusen, retinal pigment epithelium abnormalities, or exudative and geographic lesions). This phenomenon of dry to wet progression was likely responsible for most of the estimated 1.2 million cases of visual loss due to AMD (14, 15 and 16) which occurred in the 1990s in the United States and may lead to 7 million by the year 2025, given that 4% of the wet AMD cases are classified as severe (17) (Fig. 32-1).

Although the etiology of the AMD is still largely unknown, there has been an improvement in understanding the pathophysiology of the disease. In a normal eye, the byproducts of photoreceptor metabolism are usually removed by the RPE cells (18). It is believed that the aging process slows down RPE metabolism, diminishing its phagocytosis and lysosomal capacity, and resulting in accumulation of cell debris, clinically seen as drusen (5,18 and 19). Over time, these changes gradually thicken Bruch’s membrane and make it more hydrophobic, impairing oxygen delivery to photoreceptors (19, 20 and 21). It is not clear why this aging process ends in cell loss and atrophy in dry AMD, while in the wet form it stimulates a choroidal neovascular response. What we do know is that the hypoxia induces a low-grade inflammatory cascade which ends in the production of several growth factors, including vascular endothelial growth factor (VEGF), found to have a key role in CNV pathogenesis (2,22). VEGF is a dimeric lipoprotein whose principal biological activity is to produce an increase in the vascularization of hypoxic
tissues (23,24). This is accomplished through several mechanisms: increase in the mitotic activity of vascular endothelial cells; increase in vascular permeability via leukocyte-mediated endothelial cell injury, formation of fenestrae and dissolution of tight junctions; and induction of activated endothelial cells to produce enzymes and metalloproteinases which digest the capillaries’ basement membrane, the surrounding ground substance, and Bruch’s membrane, thus forming spaces and breaks through which newly formed vessels pass into the subretinal space (2, 18, 23, 24, 25 and 26).

It has also been demonstrated by histological studies that a granulomatous inflammatory response to the degenerated Bruch’s membrane is additionally responsible for the formation of breaks (23, 24, 25, 26, 27, 28, 29 and 30). This is supported by the observation of lymphocyte and macrophage infiltration of Bruch’s membrane and accumulation of macrophages at the site of neovascularization in some animal models of laser-induced CNV (23, 24, 25, 26, 27, 28, 29 and 30). However, it is still unknown whether this inflammatory response is part of the aging process of the eye or if the macrophage and lymphocyte activation is necessary for the CNV process (23).

Once the CNV reaches the subretinal space, the visual impairment will be closely related to the lesion size, the amount of exudates, and thickness of the disciform fibrosis. Any therapeutic approach that helps to control or reduce the three pathways of VEGF action described earlier may result in the stabilization or improvement of visual acuity in patients with wet AMD (31,32).