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Age-Related Macular Degeneration
An Update for the Non-Ophthalmologist

Macular degeneration is characterized by a loss of function in the portion of the eye responsible for central vision. Because central vision makes possible the detailed sight required for activities such as reading, driving and recognizing faces, macular degeneration may significantly diminish the ability to function independently in individuals who suffer from this disease. While some forms of macular degeneration result from hereditary diseases, most cases occur as part of the aging process and are known as age-related macular degeneration (AMD).

AMD is a leading cause of blindness in people over 55. AMD typically affects patients initially in one eye, with a high likelihood of it occurring in the second eye over time. Symptoms include blurred vision, difficulty seeing at a distance or doing detailed work – like sewing or reading fine print, blind spots developing in the middle of the field of vision, colors becoming hard to distinguish and distortion causing edges or lines to appear wavy. In addition to aging, risk factors include gender (women tend to be at greater risk than men), race (Caucasians are more likely to lose vision from AMD than African-Americans), smoking and a family history of the disease.

Approximately 15 million people in the United States have AMD, and more than 1.7 million Americans have the advanced form of AMD. Due to the aging baby boomer population, the National Eye Institute (NEI) estimates that advanced AMD prevalence will grow to 2.95 million by 2020. About 200,000 new cases of wet AMD are diagnosed each year in North America. Due to the rapid progression and severe, irreversible loss of central vision, early diagnosis and treatment is important for the successful management of wet AMD.

The Process of Macular Degeneration

While the exact cause of AMD is not known, the disease process begins when the transport of nutrients and waste products via the retinal pigment epithelial cells (RPE) begins to slow down, leading to the accumulation of waste products.

Types of AMD

There are two forms of AMD, dry (also called atrophic) and wet (neovascular). All cases of AMD begin as the dry form and, for unknown reasons, approximately 10 percent to 20 percent of these cases progress to the wet form. While both forms ultimately lead to loss of central vision, the degeneration occurs through different mechanisms and the course of the disease progression is different.

Dry AMD tends to progress more slowly than the wet form and is likely to cause severe loss of central vision or legal blindness in 15 percent to 20 percent of affected individuals. There are no treatments approved for dry AMD. In dry AMD, as the waste products build up, retinal cells near the drusen begin to die, leading to a loss of function in that area of the retina. In some cases, a large area of cells will die, creating a blind spot in central vision.

Approximately one in seven patients with dry AMD will develop the wet form. Wet AMD progresses more rapidly, and approximately 85 percent of affected individuals will advance to loss of central vision and be deemed legally blind. In wet AMD, the majority of damage to the retina occurs when new blood vessels begin to grow from the choroid up to the RPE and beneath the retina (a process known as choroidal neovascularization [CNV] or ocular angiogenesis). While the exact cause of CNV is not known, the current hypothesis is that new blood vessels are stimulated to grow due to the build-up of waste products associated with diminished transport via the RPE, reduction in oxygen concentration and inflammation. These new blood vessels are permeable, allowing blood and fluid to leak into the retina. This leakage may cause the retina to become swollen, impairing function of the retina and leading to poor or distorted central vision, as depicted below.

The Role of Angiogenisis in Wet AMD

In the 1990s the association between Vascular Endothelial Growth Factor (VEGF) levels and ocular diseases known to involve the growth of new blood vessels from the retina (ocular angiogenic diseases) was made. These studies found significantly higher VEGF levels in patients with ocular angiogenic disease compared to those patients without it.

In wet age-related macular degeneration, VEGF-A is believed to play a significant role in the formation of blood vessels that grow abnormally and leak beneath the macula. These blood vessels are fragile and can bleed and potentially cause distortion of the retina leading to deterioration of central vision.

Diagnosis

Due to the rapid progression and severe, irreversible loss of central vision associated with wet AMD, early diagnosis and treatment is important for the successful management of the disease. Drusen can be detected by ophthalmic examination prior to the development of AMD. A simple test, known as the Amsler grid, can be used to assess visual changes such as optical distortion or loss of vision.

The diagnosis of wet AMD generally requires Optical Coherence Tomography, Fluorescein Angiography, or Indocyanine Green Angiography.

Treatment Options

Several recent studies have indicated a strong link between nutrition and the development of macular degeneration. It has been scientifically demonstrated that people with diets high in fruits and vegetables (especially leafy green vegetables) have a lower incidence of macular degeneration. The Age-Related Eye Disease Study I (AREDS I) determined that a certain combination of vitamins can help slow the rate of progression from dry to wet macular degeneration in patients with certain forms of dry disease. The exact role of these vitamins is still controversial and a very large study, AREDS II, is currently fully enrolled and results will attempt clarify which combinations of vitamin nutrients are best in certain clinical situations (i.e., patient smokers versus non-smokers).

Currently, Lucentis™ (ranibizumab intravitreal injection), photodynamic therapy with Visudyne® (verteporfin) and Macugen® (pegaptanib sodium intravitreal injection) are approved in the United States for the treatment of wet AMD. Lucentis was approved by the Food and Drug Administration (FDA) for the treatment of neovascular (wet) age-related macular degeneration on June 30, 2006 and is the most recent addition to our armamentarium in the battle against wet AMD. Macugen® and photodynamic therapy only slowed the progression of visual deterioration seen in wet AMD. Lucentis on the other hand is the first FDA approved treatment which can not only effectively stabilize vision, but can actually improve vision in many patients. Avastin is an FDA approved treatment for colorectal cancer and has been used for the treatment of wet AMD “off-FDA label”. The efficacy of Avastin through intravitreal administration is currently being evaluated as part of a large National Eye Institute sponsored clinical trial. Anti-VEGF therapies and intravitreal injections are very well tolerated with a minimal side effect profile. There is, however, a theoretical concern that intravitreal Anti-VEGF therapies may slightly increase the incidence of stroke. The University of Chicago is involved in several major AMD clinical trials. For example, the HARBOR Study is evaluating various doses of Lucentis for wet AMD and retina specialists as well as patients eagerly await study results. Furthermore, data from a new anti-VEGF agent called “VEGF Trap” will be released in 2011 and there is hope that this new generation drug will allow vitreoretinal specialists to inject drug into the eye less frequently than our currently available therapies.

Pivotal Clinical Trials

Lucentis has been studied in two pivotal Phase III studies, including all subtypes of wet AMD. In these studies:

Future Directions

At the University of Chicago Section of Ophthalmology and Visual Science, numerous national clinical trials are underway to evaluate novel treatments for AMD, Diabetic Retininopathy, and Retinal Vein Occlusion. The VEGF Trap molecule is currently being investigated in clinical trials and holds great promise for the future treatment wet AMD. Sustained drug delivery of steroids for treating Retinal Vein Occlusions and Diabetic Macular Edema are underway as are clinical trials investigating the use of existing agents in various combinations to optimize outcomes in various vitreoretinal disorders.

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