How The Eye Works
The eye is like a camera. The eye focuses light and images from the outside world onto the retina. This is similar to a camera, in which lenses focus light and images onto the film. In the eye the CORNEA and LENS are responsible for focusing light to a pinpoint focus on the RETINA, which functions like the film of a camera.
The Retina and Macula
The retina is a tissue in the back of the eye. It is an extremely complex structure that contains millions of vision cells. The macula, an area if approximately ¼ inch in diameter, is the central part of the retina and is responsible for central or straight ahead vision. The term macular degeneration, therefore, implies a disease in which a degenerative or aging process affects the macula.
When rays of light enter the eye, they first pass through transparent structures-the cornea, the lens and the VITREOUS. The cornea and lens focus light rays onto the part of the macula called the FOVEA. It is this part of the macula that is responsible for very sharp straight ahead vision. Thus, if only a part of the macula is diseased, but the fovea is intact, vision can still be good. The fovea is different from the rest o f the retina, since it contains a very high concentration of extremely sensitive vision cells called CONES. Because of this, the fovea is the only area of the retina capable of 20/20 vision. Since the cones must have bright light to function normally, the fovea works best in daylight illumination. The rest of the retina, including the macula area outside of the fovea, has a lesser concentration of cones and also has another type of vision cell called RODS, which function better in dim illumination and are not capable of sharp central vision,
Behind the retina is another tissue called the CHOROID, which is a layer of normal blood vessels that brings circulation to the outer part of the retina. Between the retina and the choroid is a space called the subretinal space. In the wet form of age related macular degeneration, abnormal blood vessels from the choroid grow into the subretinal space. This growth of blood vessels leads to bleeding and scarring, which damages the sensitive rod and cone vision cells and subsequently results in a loss of central vision.
WHO GETS AGE RELATED MACULAR DEGENERATION?
Age-related macular degeneration (AMD) is the leading cause of central vision loss in persons over the age of 55 in the Western world. There are currently 14 million people in the United States with AMD, and as the baby-boomer population ages, 25million cases of AMD are expected by the year 2020.
The most important risk factor for developing AMD is increasing age. Two other risk factors are especially important: a family history of AMD and cigarette smoking. Many patients do not know if they have AMD in their family because their parents and grandparents may not have lived to be that old, and because AMD is a recently recognized disease. Other factors that increase the risk of developing AMD include high blood pressure, being female, chronic sunlight exposure, light colored skin pigmentation, obesity, and increased intake of fat, cholesterol, and store-bought packaged baked goods. On the other hand there are factors associated with decreased risk; some racial groups, particularly the black race have a much lower risk than Northern Europeans. People who have a higher intake of fish or nuts appear to have a lower risk of progression. There is less strong evidence to suggest that those with higher levels of serum carotenoids (lutein and Zeaxanthin),and an increased intake of fruit and dark green leafy vegetables have a lower risk of progressing to advanced forms of AMD. Recently, some reports have identified a gene mutation affecting control if immune function to be more common in patients with the later findings of age-related macular degeneration. The first change discovered occurs in a gene called Complement factor H, which is a molecule involved in controlling the immune system. Patients with variations In this gene may have increased activity of certain portions of the immune system. Since then other gene changes have been discovered that are either protective or high risk variants. Some of these genes appear to be important in Caucasians, while other genes are important for other groups as well.
Rarer forms of macular degeneration that are not age related may occur from other disorders. For example, in younger patients, infection myopia(near sightedness), and unknown factors may cause abnormal blood vessels to grow behind the retina. Although the process is similar to that seen in age related macular degeneration, in younger patients this disease has different causes and outcomes.
TYPES OF AGE RELATED MACULAR DEGENRATION
There are two basic types of age related macular degeneration: a “dry form” and “wet form”. The dry form of AMD is the most common form of AMD. In the dry form, yellow aging spots called DRUSEN begin to form underneath the macula. Drusen are formed, in part, from the build up of fatty materials including cholesterol. In most cases of dry AMD, the vision is usually not drastically affected. However, over the course of many years, patients with dry AMD may have a gradual thinning out of the rods and cones, resulting in a gradual loss of central vision. This may cause relatively mild symptoms, such as needing stronger light to read. Some patients develop atrophy (a withering or loss of cells) in the macula that can cause decreased central vision. The areas of atrophy that develop often have the shape of countries on a map and are called GEOGRAPHIC ATROPHY. At one time Geographic Atrophy accounted for about 10% of patients losing vision from AMD, but recently that proportion seems to be increasing.
The dry form of AMD is a risk factor for the wet form. Although the wet form only develops in about 10 % of all of the vision that is lost from AMD. In the wet form of AMD, abnormal blood vessels begin to grow from the choroid, underneath the retina. These blood vessels, called CHOROIDAL NEOVASCULARIZATION or CNV, cause bleeding, leakage and scarring in the macula, resulting in rapid and severe loss of central vision.
SYMPTOMS OF AGE RELATED MACULAR DEGENERATION
Most patients with AMD have no visual symptoms and may not even know they have AMD until an eye doctor informs them. This lack of symptoms, particularly in the early forms, is the reason why all patients over the age of 55 should have an annual dilated eye examination to screen for AMD and other age related eye diseases. People with a family history of AMD, and those with ocular risk factors require more frequent and earlier exams.
The dry form of AMD causes visual symptoms very gradually over the course of many years to decades. Signs of these changes include needing brighter light to read, having a harder time following a line of print, or even developing a blank spot in the vision. The wet dorm, however, often results in a rapid change in central vision, usually causing acute decreased vision, distortion, or a blank spots. Patients may notice these visual distortions when looking at objects with straight edges, like the sides of a building, or the tile on their floor. They may be given an AMSLER GRID by their doctor to check this sensitive central area of the retina.
Most patients actually notice a problem with reading as their first symptom. Sometimes the patient does not notice a change until he or she covers the uninvolved eye. Still other times, the patient can be asymptomatic, and this condition in only discovered by an eye care professional. Usually, however, decreased vision or distortion are noted.
It is extremely important to note that even the most advanced forms of macular degeneration WILL NOT RESULT IN”TOTAL BLINDNESS”. AMD will only affect the central vision, leaving the side part of vision completely intact and functional.
EVALUATION FOR AGE RELATED MACULAR DEGENRATION
The eye care professional will examine the patient using various lenses and instruments to look for signs of AMD. The doctor will look for signs of both the dry and wet forms of AMD. When the doctor detects such changes, suspicious for wet AMD, the doctor may order a diagnostic test called a FLUORESCEIN ANGIOGRAM.
A Fluorescein angiography is a test where a fluorescent eye is injected into a vein in the arm. When the dye reaches the back of the eye, a rapid sequence of pictures is taken using a special FUNDUS camera. The film is then developed and areas of abnormal blood vessels (CNV) may be seen.
In newer imaging systems, special cameras are used which take digital pictures that are processed and stored on a computer. Pictures taken with film can’t be evaluated until the film is developed, but digital pictures are available immediately.
A newer from of retinal angiography, which uses a green dye and infrared light, may also be used in cases of wet AMD. It is called INDOCYANINE GREEN (ICG) ANGIOGRAPHY and allows the ophthalmologist to see into deeper layers of the retina and the CHOROID. These images cane be very useful in diagnosing and treating certain diseases of the retina where conventional fluorescein angiography may not reveal enough diagnostic information.
Another important test is OPTICAL COHERENCE TOMOGRAPHY or OCT. This test creates a cross section images of the macula. It is non invasive and can image microscopic changes in the retina. OCT does not require any injections and provides very useful information. OCT is one of the most important tests in following the progress a patient has with treatment.
PREVENTION OF AMD
Most of the research and development in AMD has been focused on the severe wet form (10 % of individuals) because it causes most vision loss. However, it is increasingly clear that preventive strategies for AMD are important, and that many individuals experience night vision, glare disability and reading disturbances before they develop severe eye disease.
Until October 2001, there was no effective preventive treatment against new blood vessel growth or the severe form of dry AMD known as geographic atrophy. In October 2011 the results of the National Eye Institute’s (NEI) Age Related Eye Disease Study (AREDS) were released which proved that a high-dose vitamin and mineral formula significantly slowed the progression of moderate and advanced stage 3 and 4 disease. The vitamin formula consists of vitamin C 500 mg, vitamin E 400 IU, betacarotene 15 mg, Zinc 80 mg, and balance copper 2 mg. This formula decreased the progression of AMD BY about 25%, and AMD vision loss by about 20 % in patients who met the study entrance criteria of moderately advanced disease and were at future risk of developing severe AMD. This vitamin formula is called Ocuvite PreserVision and is produced by Bausch & Lomb. The AREDS study showed that this vitamin formula was safe to take but should be avoided boy smokers, because betacarotene can increase the risk of lung cancer development.
You will also went to watch your total vitamin E evidence that higher doses of vitamin E (above 400IU) may be harmful. Talk to your doctor about all of the supplements and the doses you are taking, especially with respect to betacarotene, vitamin E and Zinc. Two important studies have found that smokers should not take high doses of beta carotene. There is a version of Ocuvite PreserVision in capsule form that substitutes beta carotene with lutein and contains less Zinc. Lutein, Zeaxanthin, and omega-3 fatty acids are supplements that may be beneficial in slowing the progression of AMD prior to the advent of new blood vessel growth. The National Eye Institute is conducting the AREDS II clinical studies looking at the effects of these supplements in preventing advanced AMD.
TREATMENMT OF AMD
In the earlier stages of dry AMD, there is a build-up of material, drusen, in the macula. There may also be pigmentation changes as well. These early changes by themselves do not necessarily cause visual problems, but seem to increase the risk for further problems to occur. The first is that cells under the macula called retinal pigment epithelial cells, may start to die. Sometimes a few cells here and there may die without causing too much of a problem. In some patients, however, larger Zones of cells die to produce geographic atrophy. There is no treatment for geographic atrophy. Patients with early geographic atrophy may only require more light to be able to read. The second problem that may occur is the inappropriate growth of vessels under the macula, also called choroidal neovascularization, or wet AMD. Because the proportion of people living to advanced ages in increasing and because wet AMD is treatable, geographic atrophy is proving to be be an increasing problem for patients and doctors alike. Clinical trials assessing the safety and efficacy of drugs and procedures for dry AMD are beginning to emerge.
Over the past several decades hot LASER treatment was the only proven treatment for wet AMD. In hot laser therapy, a laser is used to cauterize the abnormal blood vessels growing underneath the retina. The surgeon uses the fluorescein angiogram or ICG as a map in determining where to apply the laser treatment. The angiogram helps identify the vessels and then the doctor tries to destroy the vessels with the laser. Unfortunately, hot laser therapy also burns through the overlying retina in order to cauterize the blood vessels beneath. In doing so, hot laser therapy creates a permanent blank spot in a person’s vision. Hot laser therapy continues to be used in some patients when the abnormal blood vessels are NOT growing directly underneath the center of the macula center of vision (fovea). However, experimental treatments are commonly used in these patients. The goal of laser treatment is to stabilize visual acuity and prevent it from getting worse. Only in certain situations is visual acuity improved following laser treatment.
The greatest reason for failure after hot laser treatment is that the blood vessels often grow back. Remember the body seems to want to grow the vessels as a normal healing response. While the hot laser may destroy the growing vessels, the body will often try to grow new vessels over time, and this occurs in at least 50 % of patients. If you undergo hot laser treatment, your doctor will be following you closely to look for any signs of the blood vessels growing back.
Photodynamic therapy with Visudyne (using cold laser therapy) was developed and approved by the Food and Drug Administration (FDA) for treating choroidal neovascularization (CNV) that lies directly underneath the center of vision (fovea). Cold laser treatment has been proven to be beneficial for all types of blood vessels that grow beneath the center of the macula if the vessels are small.
In cold laser treatment a light sensitive drug (Visudyne) is injected into the vein in your arm and travels with your circulation to the abnormal blood vessels underneath the retina. A cold laser is than aimed onto this area of your macula. The cold laser, unlike the hot laser, does not burn the retina. When the cold laser light hits the light sensitive drug in the abnormal blood vessels, it turns the drug on. Once the drug is turned “on”, it causes a chemical reaction to occur which leads to a blood clot forming in the blood vessels, closing them down.
Unfortunately, in photodynamic therapy, the blood vessels have a tendency to “open up again”. The body appears to want to grow the vessels in macular degeneration. Usually, when the vessels regrow, a repeat cold laser treatment is performed. The average patient requires approximately 3 to 4 cold laser treatments in the first year. Thus, PDT should be thought of as a series of treatments rather than just a single one. Your doctor will determine, at regular intervals, whether this therapy needs to be repeated. The goal of photodynamic therapy is not to make the vision better, BUT to decrease the rate at which the vision gets worse. In most cases, we expect that the vision may continue to get worse even if cold laser therapy is performed. REMEMBER! PDT will only slow the rate of worsening of the vision.
Pharmacological Therapy (Drug Therapy)
Vascular Endothelial Growth Facto (VEGF) is a molecule that binds to blood vessel cells and tells them to start growing. VEGF has and tells them to start growing. VEGF has been implicated as a cause of abnormal blood vessel growth in wet AMD.
Macugen is a drug that blocks only one type of VEGF from binding to the blood vessel’s cell, resulting in a decreased ability of the cell to grow. Macugen is given as an injection into the eye every 6 weeks, which is about 9 times a year. Phase III studies of Macugen for wet AMD demonstrated that it significantly decreased the rate of vision loss and was relatively safe. Macugen’s main effect was to stabilize the vision, similar to photodynamic therapy with Visudyne. Vision improvement occurred in very few patients, and most patients continued to lose vision. The injection procedure is associated with a small risk of injection, retinal detachment and cataract formation.
Generation developed an antibody fragment that binds to all types of VEGF. Lucentis has been studied in several large multi centered trials. The vision responses from Lucentis treatment have been very good showing a 95 % stabilization in vision. Instead of joust slowing the rate of vision loss, approximately 25 % of patients treated with Lucentis gained vision. Most of the rest had stable vision.
Lucentis is administered as an injection into the eye. The injections are given monthly at first, but it is often possible, by using OCT guidance, to use the drug less frequently.
Lucentis blocks VEGF, but so does another drug developed by Genentech- Avastin. This drug was originally developed to treat cancer. When used in the eye the dose of Avastin is quite low. Because the dose of Avastin is low the cost is correspondingly low. Avastin is approved by the FDA, but for cancer treatment. In the eye Avastin use is considered to be off-label. We do not know if Lucentis or Avastin is better. Both drugs appear to work quite well in the eye.
Photodynamic Therapy and Intervitreal Triamcinolone
A number of other studies have begun which combine photodynamic therapy, as described above, with the injection of a corticosteroid, Triamcinolone or dexamethasone, into the vitreous cavity. The corticosteroid acts as reduce the inflammation associated with the new blood vessel growth and reduces leakage from the abnormal vessels as well. In early pilot trials, patients treated with this combination therapy demonstrated improved visual and anatomical results. This treatement not only holds the promise of improving upon theeffects of the currently available therapy, but also points toward the concept of combining multiple forms of treatment to generate a synergistic effect, and better visual outcome.
Surgical management of macular degeneration involves either physically removing the abnormal blood vessels from under the retina (submacular surgery) or moving the central part of the retina away from the area of blood vessel growth (macular translocation). The Submacular Surgery Trial (SST) found that surgical removal of blood vessels was not effective in the treatment of choroidal neovascularization secondary to age related macular degeneration. Some centers have investigated an approach where the retina is rotated to a new location (macular translocation surgery). Although this surgery has not been clinically proven, it is a treatment option for a minority of patients with wet AMD.
Recently, the media has publicized both retinal and retinal pigment epithelial transplantation, which have been performed on a very small number of human subjects. There have also implanted in patients who are blind that appear to restore a VERY LIMITED degree of light vision. Many of these patients could not determine if a light was on or off. These patients do not have good vision, by any means. It is important to exphasize these are extremely experimental techniques that have not yet demonstrated a positive effect on patients and which are likely several years away from public availability if they are successful.