Age-related macular degeneration (AMD) is one of the most common causes of vision loss among adults over age 55 living in developed countries. It is caused by the breakdown of the macula, the central part of the retina located in the back of the eye. The macula allows people to see objects directly in front of them (called central vision), as well as fine visual details. People with AMD usually have blurred central vision, difficulty seeing details and colors, and they may notice distortion of straight lines.
The normal function of the macula and AMD is best understood accompanying a description of normal eye function. The eye is made up of many layers of different types of cells that all work together to send images from the environment to the brain, similar to the way a camera records images. When light enters the eye, it passes through the lens and lands on the retina, a very thin tissue, which lines the inside of the eye. The retina is made up of 10 different layers of specialized cells, which allow it to function similarly to film in a camera, by recording images. The macula is a small, yellow-pigmented area located in the center of the back of the eye on the retina. The macula contains blood vessels and nerve fibers. The retina contains many specialized cells called photoreceptors that sense light coming into the eye, convert light into electrical messages, and send them to the brain through the optic nerve. They allow the brain to perceive the environment.
The retina contains two types of photoreceptor cells: rod and cones. The rods are located primarily outside of the macula and they allow for peripheral (side) and night vision. Most of the photoreceptor cells inside the macula are the cone cells, which are responsible for perceiving color and viewing objects directly in front of the eye (central vision). If the macula is diseased, as in AMD, color and central vision are altered. There are two different types of AMD: dry AMD and wet AMD.
Approximately 90% of individuals with AMD have the dry form. This condition is sometimes referred to as nonexudative, atrophic, or drusenoid macular degeneration. In dry AMD, some of the layers of retinal cells (called retinal pigment epithelium, or RPE cells) near the macula begin to degenerate. The RPE is the insulating layer between the retinal and choroid layer, which contains blood vessels. The RPE acts as a protective shield against damaging chemicals and a filter for the nutrients that reach the retina from the choroid blood vessels. The RPE cells normally help remove waste products from the rods and cones. When the RPE cells are no longer able to provide this function, fatty deposits called drusen begin to accumulate, enlarge, and increase in number underneath the macula. The drusen formation can disrupt the cones and rods in the macula, causing them to degenerate, or atrophy (die). This usually leads to central and color vision defects for people with dry AMD. However, some people with drusen deposits have minimal or no vision loss, and require regular eye examinations to check for AMD. Dry AMD is sometimes called nonexudative, because even though fatty drusen deposits form in the eye, people do not have leakage of blood or other fluid (often called exudate) in the eye. Dry AMD symptoms remain stable or worsen slowly from early stages to intermediate or advanced stages of dry AMD. Advanced stages of AMD may result in vision loss. In addition, approximately 10% of people with dry AMD eventually develop wet AMD, the advanced stage of AMD.
Approximately 10% of patients with AMD have wet AMD that progressed from some stage of the dry form. This form of AMD is also called subretinal neovascularization, choroidal neovascularization, exudative form, or disciform degeneration. Wet AMD is caused by leakage of fluid and the formation of abnormal blood vessels (called neovascularization) in the choroid layer of the eye. The choroid is located underneath the retina and the macula, and it normally supplies them with nutrients and oxygen. When new, delicate blood vessels form, blood and fluid can leak from them. The formation of abnormal blood vessels underneath the macula leaks enough fluid to raise the macula up and away from the back of the eye and damages it. This causes central vision loss and distortion as the macula is pushed away from nearby retinal cells. Eventually a scar (called a disciform scar) can develop underneath the macula, resulting in severe and irreversible vision loss. Wet AMD does not have early or intermediate stages. It is considered advanced AMD and is more severe than dry AMD.
AMD is considered a complex disorder, caused by a combination of genetic and environmental factors. AMD exhibits multifactorial inheritance , and the many factors interact with one another and cause the condition. The aging process is one of the strongest risk factors for developing AMD. There is also genetic heterogeneity among different families with AMD, meaning that different genes can lead to the same or similar disease among different families. Overall, it has been estimated that siblings of individuals with AMD have four times the risk of developing AMD, compared to other individuals.
In 1998, a family in which a unique form of AMD was passed from one generation to the next was discovered. Although most families with AMD do not display an obvious inheritance pattern, this particular family's pedigree showed an autosomal dominant form of AMD. Autosomal dominant refers to a specific type of inheritance in which only one allele (one copy of a gene pair) needs to have a mutation for the disease to develop. An affected person with an autosomal dominant condition thus has one allele with a mutation and one allele that functions properly. There is a 50% chance for this individual to pass on the allele with the mutation and a 50% chance to pass on the normal allele to each offspring. Genetic testing revealed that the autosomal dominant gene was located on chromosome 1q25-q31, in a locus now known as the ARMD1 gene locus. In 2004, possible AMD linkage evidence was discovered in four chromosomal regions: 1q31, 9p13, 10q26, and 17q25. In 1997, mutations in the gene for the retinal ATP-binding cassette transporter, also on chromosome one, were found in individuals diagnosed with AMD. However, as of 2005, it is clear that the retinal ABCR gene is not a major susceptibility gene for AMD.
In March 2005, the National Eye Institute (NEI) described the discovery of a gene for AMD in Caucasians. The genomes from AMD patients were screened by three separate research groups. All three groups discovered a commonly inherited variant of the same gene, called complement factor H (CFH). The CFH gene encodes a protein that regulates inflammation in the portion of the immune system that disposes of diseased and damaged cells. In some individuals with AMD, eye inflammation may trigger a biological process leading to AMD. This variation is in a region of CFH that binds the Creactive protein involved in inflammation. CFH functions as a brake on the immune system. The variation in CFH found in AMD causes the brake to be defective. The CFH gene is located on chromosome 1q25-31 in the ARMD1 locus that is repeatedly linked to AMD in family-based studies. Individuals with the variant gene have two to seven times the risk of macular degeneration, with the greatest risk in individuals with two copies of the variation. The CFH gene variation may account for a large percentage of risk for AMD, but is not an absolute determinant. Not all individuals with AMD have the CFH variant, and not all those with the variant have AMD. However, there is accumulating evidence that macular degeneration, much like atherosclerosis, is at least partly caused by inflammation.
It is also possible that although one particular gene may be the main cause of susceptibility for AMD, other genes or environmental factors may help alter the age of onset of symptoms or eye defects. Studies have revealed numerous risk factors for AMD, including:
- Heart disease
- High blood pressure
- Light skin and eye color
- Cigarette use
- High fat/high cholesterol diet
- Ultraviolet (UV) exposure (sunlight)
- Low levels of dietary antioxidant vitamins and minerals
- Female gender
The exact amount of risk associated with many of these factors is still undetermined, though studies have consistently found a strong association between AMD and smoking. Risk factors in combination with a family history of AMD place an individual at highest risk.
Among adults aged 55 and older, AMD is the leading cause of vision loss in developed countries. The risk of developing AMD increases with age, and is most commonly seen in adults during in the sixth and seventh decade. However, AMD has been reported in adults in the fourth decade. In developed countries, approximately one in 2,000 individuals is affected by AMD. By the age of 75, approximately 15% of people have early or mild forms of AMD, and approximately 7% have an advanced form of AMD. Although AMD occurs in both sexes, it is slightly more common in women.
The number of people affected with AMD is different in regions of the world and between ethnic groups. AMD is generally considered more common in Caucasians than in African Americans. Studies done in Japanese and other Asian populations have shown an increasing number of affected individuals.
The dry form of AMD is more common than the wet form of AMD. More than 85% of all intermediate and advanced cases of AMD have the dry form. Within the category of advanced AMD about two-thirds of AMD cases are the wet form. Almost all AMD-related vision loss results from advanced AMD, therefore the wet, advanced form of AMD leads to significantly more vision loss than the dry form, which has varying stages of development. Individuals who have advanced AMD in one eye are at very high risk of developing advanced AMD in the other eye.
Signs and symptoms
AMD causes no pain. In some cases, AMD advances so slowly that affected individuals may not notice much change in their vision. In other cases, the disease progresses fast and may lead to a loss of vision in both eyes. One of the most common signs of early AMD is drusen, which is yellow deposits under the retina, most common in individuals over the age of 60. Drusen can be detected during a comprehensive dilated eye exam. Individuals with early AMD have several small drusen to a few medium-sized drusen. At this stage, there are no other symptoms and no vision loss. Individuals with intermediate AMD have many medium-sized drusen to one or more large drusen. The most common symptom at this stage is a blurred area in the central field of vision. Increased light may be necessary for reading and other tasks. Individuals with advanced AMD have drusen along with a degeneration of light-sensitive cells and supporting tissue in the central retinal area. A blurred spot in the central field of vision gets larger and darker over time. There is difficulty reading and recognizing objects from afar. As the AMD progresses, functional vision may be entirely lost in both eyes. AMD may also cause decreased color vision. Vision loss from dry AMD in only one eye may make it harder to notice changes in overall vision, as the other eye compensates.
While the majority of people with AMD maintain their peripheral vision, the severity of symptoms is dependent on the type of AMD. Wet AMD and advanced dry AMD are associated with the most symptoms. Wet AMD may cause straight lines to have a wavy appearance. The degree of change of visual acuity and other symptoms that can be seen by an eye exam increases over time. Individuals with dry AMD usually develop decreased visual acuity very slowly over a period of many years. Detectable changes are small from year to year, and central vision is partially retained. However, individuals with wet AMD usually have symptoms that precipitate quickly and have a greater risk of developing severe central vision loss in as little as a two-month period. Individuals with dry AMD may suddenly develop wet AMD without undergoing progressive stages of dry AMD.
A variety of tests is used to diagnose AMD. The visual acuity test measures the smallest letters an individual can read with one eye on a standardized chart at a distance of 20 ft (6 m). The refraction test involves the same standardized eye chart, but requires the patient to focus through a refraction lens to determine the amount of correction needed for optimum visual acuity. The pupillary reflex test examines the ability of the pupil to constrict or dilate in the presence or absence of bright light. The slit lamp examination is also known as biomicroscopy. A high-intensity light source is focused to shine as a slit on the anterior portion of the eye. The eyes are examined with a microscope designed for the eye called a biomicroscope. The eyes may be temporarily stained with an orange-colored dye called fluorescein to help visualize the structures of the eye. Examination of the posterior portion of the eye involves dilating the pupils with specialized eye drops before examination. Retinal photography can then be performed. Fluorescein angiography, or retinal photography, uses fluorescein dye injected into a vein of the arm and a special camera to analyze and photograph the retina, choroid, and associated blood vessels. This examination can be used to visualize the changes in vasculature associated with wet AMD. Tonometry
measures the pressure levels inside the eye. Color testing assesses the functioning of the cone cells in recognizing colors. Standardized pictures made up of dots of different colors are arranged in specific patterns and used to determine color recognition. The Amsler grid test uses a printed paper grid to test for decreased central vision, distorted vision, or blind spots.
As of 2005, genetic testing for genes associated with AMD is not recommended. The utility of such tests would be minimal at best, because there is no information available on how to interpret test results as applies to an individual's likelihood of developing AMD. Individuals with AMD are encouraged to monitor changes in their own vision through the use of an Amsler grid.
Treatment and management
There is no universal cure for either type of AMD. Some individuals with wet AMD can prevent further progression of damage with laser photocoagulation therapy. Light rays are focused by a thermal laser to burn off abnormal blood vessels forming beneath the macula, preventing further leakage of blood and fluid. Some normal tissue is also affected. Previously lost vision is not restored with this treatment. Only a small percentage of wet AMD cases can be treated with laser surgery. Laser surgery is most effective if the abnormal blood vessels have developed away from the fovea, the central part of the macula. Laser photocoagulation treatments do not prevent future abnormal blood vessels from forming, and are not effective for dry AMD. In 2000, the FDA approved the use of a light-activated drug called Visudyne (verteporfin). Visudyne is injected into the bloodstream via a vein in the arm. It circulates through the body to the eyes, specifically attaching to the abnormal AMD blood vessels present under the macula. When light rays from a non-thermal laser hit these blood vessels, the Visudyne is activated to produce a chemical reaction that destroys the abnormal vessels, causing very little damage to nearby healthy tissues. If the abnormal blood vessels re-grow, the procedure is repeated. While this therapy does not cure AMD, it is useful in managing specific problem areas and reducing further vision loss.
There is no specific treatment for dry macular degeneration; laser therapy is not useful. Once dry AMD reaches the advanced stage, no form of treatment can prevent vision loss. The National Eye Institute's Age-Related Eye Disease Study (AREDS) reported that taking a high-dose antioxidant and zinc supplement significantly reduced the risk of advanced AMD and vision loss. The specific daily quantities reported were 500 mg vitamin C, 400 I.U. vitamin E, 15 mg beta-carotene (equivalent to 25,000 I.U. vitamin A), and 80 mg zinc oxide. Two milligrams of copper in the form of cupric oxide was added to the formulation to prevent a condition called copper deficiency anemia, associated with high levels of zinc intake. Supplementation is indicated in individuals with intermediate AMD in one or both eyes, or advanced AMD in one, but not the other eye. The AREDS reported that supplementation did not keep individuals with early AMD from progressing to an intermediate stage.
In December 2004, the FDA approved Macugen drug treatment. This treatment attacks a growth factor protein involved in abnormal blood vessel growth in the eye. Macugen was developed by Eyetech Pharmaceuticals and Pfizer, and is administered through injections directly into the eye every six weeks. In previous clinical trials with Macugen, some patients experienced slower rates of vision loss, or restored vision. There are other drugs currently in clinical trials that have not yet been approved by the FDA. Avastin has a mechanism of action similar to Macugen, but is administered by intravenous injection into a vein in the arm. In 2005, Avastin had FDA approval for treatment of colorectal cancer , but not for macular degeneration. The FDA has issued a caution that Avastin has been shown to increase the risk of stroke and heart attack. Another drug in clinical trials is Retaane, which attacks enzymes involved in abnormal blood vessel growth. Retaane would not be administered with a needle and treatments would be every six months. In October 2000, it was reported that a medication called Iloprost, over a six-month time period, caused improvements in visual acuity, daily living activities, and overall quality of life for individuals with dry AMD. Follow-up research is being done to investigate the safety and usefulness of these medications.
In 2005, multiple future therapies are being investigated. Radiation treatment to destroy abnormal blood vessels and implantable telescopes to improve vision are being tested. Japan developed a method of blood filtration called rheopheresis to remove harmful proteins and fatty acids to treat the dry form of AMD. This technique has not been approved by the FDA in the United States, but is being used in Canada and Europe.
Low-vision devices are available to help improve AMD vision difficulties by using magnifying lenses and bright lights. Some low-vision aids shift images to the periphery for clearer vision. There are many different types of low-vision devices that can help to overcome vision impairment and live independently.
Most individuals with mild dry macular degeneration will never develop disabling central vision loss. However, there is no current method of predicting which individuals will progress to an advanced stage of AMD. AMD can cause the loss of central vision only and cannot cause peripheral vision loss. However, loss of central vision may interfere with many activities of daily life and significantly impact its quality. An individual with advanced AMD may become functionally blind, so that reading, driving, recognizing faces, and many other common activities become impossible. The prognosis depends on the stage of the disease and type. Mild forms of dry AMD have a better prognosis than advanced dry or wet AMD. As symptoms progress, individuals with AMD become at higher risk for psychological distress due to decreasing quality of life and independence. The prognosis improves if low-vision devices and support groups are utilized to improve the quality of life.
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Maria Basile, PhD
Pamela J. Nutting, MS, CGC