AGE-RELATED MACULAR DEGENERATION UPDATE: A REVIEW OF PATHOGENESIS, CLINICAL FINDINGS, AND TREATMENT

BY MARCO ZARBIN, MD, PhD, FACS

Supported in part by Research to Prevent Blindness, Inc. and the New Jersey Lions Eye Research Foundation.

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similar RPE melanin content, but differ in the degree of choroidal pigmentation.) Third, some inherited diseases (e.g., Sorsby's fundus dystrophy, some dominant late-onset retinal degenerations) resemble AMD pathologically with subRPE extracellular deposits and have some similar clinical features (e.g., problems with night vision and dark adaptation). Milam observed that degenerations associated with lipid/mineral deposits in Bruch's membrane are often autosomal dominant, and patients are often asymptomatic until adulthood. The diseases also feature loss of photoreceptors and RPE, choriocapillaris atrophy, and CNVs with fibrosis.

Fourth, Allikmets and coworkers found that mutations at the Stargardt's disease locus predispose heterozygous carriers to the nonexudative form of AMD: 26 (16%) of 167 individuals with AMD were heterozygous for mutations at the Stargardt's disease locus. There is some controversy over the significance of these data, however. ABCR, the Stargardt's disease gene, encodes a retinal rod photoreceptor protein (rim protein) that colocalizes with peripherin to the rod outer segment and may play a role in phototransduction.

Although lysosomal storage diseases, caused by "single gene" defects in metabolism, are characterized by accumulations of intracellular material, they do not resemble AMD. Thus, AMD may not be caused by a "single gene" defect, even if genes play a major role in determining susceptibility to the disease. Ongoing genetic studies should validate or refute the hypothesis that AMD is caused by more than one genetic abnormality.

2) Accumulation of intracellular material. Lipofuscin is present within RPE cells in childhood. Its presence is probably normal as may be the tendency for intraRPE lipofuscin content to increase with age. Of note, RPE lipofuscin content is greater in whites than in blacks. It is not clear whether the accumulation of intracellular debris represents the accumulation of normal substrate material that is not enzymatically degraded properly vs. abnormal substrate material, e.g., outer segments that have been oxidatively damaged before phagocytosis or outer segments that are abnormal due to an inherited abnormality such as a mutation in rim protein.

Outer segment material may be susceptible to oxidative damage for the following reasons. Photoreceptor outer segments are rich in polyunsaturated lipids. Most probably, lipofuscin is derived mainly from incompletely digested outer segments. Retinal oxygenation and light (especially short wavelength) exposure, potentiating free radical production (e.g., superoxide, hydroxyl free radical, and singlet oxygen), could increase lipofuscin production. The RPE contains many lysosomal enzymes (e.g., cathepsins, mannosidase, glucosaminidase, acid phosphatase, phospholipase) that permit digestion of the contents of phagolysosomes. Lipofuscin granules fuse with melanosomes to form complex granules. Macular RPE contains higher quantities of lipofuscin and complex granules than nonmacular RPE except at the fovea. Thus, environmental risk factors (e.g.,

Introduction. Age-related macular degeneration (AMD) is a condition(s) characterized by accumulation of membranous debris on both sides of the retinal pigment epithelium (RPE) basement membrane. Clinical manifestations of drusen, atrophy of the RPE/choriocapillaris, RPE detachment, and choroidal new vessel (CNV) formation occur after age 55 years. AMD is the most important cause of new cases of blindness in patients over 55 years of age. Usually, visual loss is confined to loss of central vision with preservation of peripheral vision. Decreased central vision results in loss of the ability to read, to drive, to recognize faces, and, in many cases, to live independently.

Thirty percent of patients over the age of 70 years have some clinical sign of AMD. Approximately 6 million Americans have the disease, and in fifty years, 20 million Americans will be affected by AMD. Over 80% of cases of severe visual loss result from the growth of abnormal blood vessels, CNVs, under the macula. Approximately 600,000 Americans have AMD-induced CNVs.

What is the macula? The macula is a specialized area of the retina that is ~5500 µm in diameter, comparable to the size of the head of a nail, and contains two or more layers of ganglion cells. The fovea is ~1500 µm in diameter and is a central depression in the macula. The fovea contains the foveal avascular zone, which is ~500 µm in diameter, and the central foveola, which is ~350 µm in diameter. Macula lutea ("yellow spot" in Latin) derives its name from the presence of a high concentration of yellow pigments, primarily carotenoids, in the foveola. These pigments (mainly lutein and zeaxanthin) have antioxidant activity, filter out photic damage-causing blue light, and may be derived from the plasma. The foveola contains specialized photoreceptors. Photons are captured by the photoreceptor outer segment, a columnar structure consisting of stacks of membranous discs containing the photopigments. The foveola provides high acuity (20/10-20/20) vision necessary for reading, sewing, performing surgery, etc. The extrafoveolar part of the macula provides less sharp vision, ranging from 20/40-20/200.

For photoreceptors to function properly, they must be in intimate contact with the RPE. The photoreceptors and RPE exchange nutrients and other materials. The choroid is a vascular layer of the eye wall interposed between the sclera and RPE, and its capillaries, termed the choriocapillaris, provide the blood supply to the RPE and photoreceptors. The RPE is separated from the choriocapillaris by a thin layer of collagenous connective tissue called Bruch's membrane. Bruch's membrane is composed of an inner and outer collagenous zone separated by an elastic lamina. The basement membranes of the RPE and choriocapillaris line the inner and outer aspect of Bruch's membrane, respectively.

When the macula malfunctions, people experience blurring or darkness in the center of their visual field. AMD affects both distance and near vision, but it results in total blindness only rarely. The condition may hardly be noticeable in its early stages. Sometimes only one eye loses vision while the other eye retains good vision for many years. Some common ways vision loss is detected are: words on a page look blurred; a dark or empty area appears in the center of vision; straight lines look distorted.

What is the cause of AMD? Research has focused on the role of genetics, light exposure, and oxidative damage in developing AMD. Twin studies indicate that there is a definite genetic component to the disease (see below). The environment of the photoreceptor-RPE interface is rich in oxygen and polyunsaturated lipids. Normal metabolic processes and possible photochemical damage from ultraviolet and high energy visible light can lead to the formation of free radicals and singlet oxygen that initiate lipid peroxidation. In contrast to normal, shed outer segments, the products of these lipoperoxidation reactions are metabolized poorly by the RPE lysosomal enzymes, and this indigestible material accumulates within the RPE, causes cell damage, and accumulates within Bruch's membrane where it may also cause cell damage by altering the permeability properties of Bruch's membrane.

Histological changes in AMD and a hypothetical pathogenic sequence of events. Hogan championed the notion that AMD arises from abnormalities in the RPE. A hypothetical pathogenic sequence of events consistent with known data is: 1) RPE dysfunction; 2) accumulation of intracellular material in the RPE; 3) abnormal accumulation of extracellular material; 4) change in Bruch's membrane composition; 5) change in Bruch's membrane permeability to nutrients; and 6) response of the RPE to metabolic distress.

1) RPE dysfunction. Abnormal accumulation of intracellular material could be a cause as well as a consequence of RPE dysfunction. The material could be the product of incomplete or aberrant metabolism (e.g., phagolysosomes) and/or metabolic renewal (autophagic vacuoles). RPE dysfunction might be precipitated by an inherited susceptibility and/or environmental exposure.

Bird and others have pointed out that the incidence of AMD is increasing independently of the increasing mean age of the population. This finding is most consistent with environmental factors causing AMD.

Evidence for an inherited predisposition to AMD is as follows. First, there is a high concordance for disease in twin studies, and there is a higher risk of AMD among first degree relatives of affected persons. Second, the prevalence appears to be much higher in whites than in blacks. (Of note, blacks and whites have