Age-Related Macular Degeneration

Background

Age-related macular degeneration is the leading cause of legal blindness in patients over age 65 in the United States. It is estimated that, during the next five years, over one million Americans will go on to central blindness from macular degeneration.

Classification

There are two major forms of macular degeneration: atrophic (dry) and exudative (wet). 90% of all macular degeneration is the dry form but 90% of all legal blindness from macular degeneration is due to wet macular degeneration.

Atrophic (Dry) Macular Degeneration

Dry macular degeneration is generally characterized by a slow but progressive visual loss over the years. Often people will notes spots of blurred vision or distortion but this is generally not too bothersome unless it involves the center of the retina. Clinically this is characterized by yellow spots under the retina, called drusen, which are accumulations of metabolic waste products that indicate the overlying cells are not perfectly healthy. Areas of pigment clumping and atrophy (retinal thinning) are also found. Over time, large areas of thinning called geographic atrophy can cause severe visual loss.

Treatment

There is no effective treatment for atrophic macular degeneration. Once this degeneration has occurred, visual loss in that area is permanent. The Age-Related Eye Disease Study (AREDS) was released in 2001, and it showed that antioxidants, including beta-carotene, vitamin C, E, plus zinc slowed the rate of visual loss in patients who took them over a placebo. Patients with no degeneration or minimal degeneration did not benefit over the course of the study but this is likely due to the fact that their rate of visual loss with no or minimal disease over the course of the study was extremely small. It is generally our recommendation that, because the risks of antioxidant vitamins are small, patients with early signs of degeneration, especially those with a family history of the disease, take the vitamins anyway. Two dietary xanthophylls (lutein and zeaxanthin) that accumulate in macula and two omega-3 long-chain polyunsaturated fatty acids (LCPUFAs), docosahexaenoic acid and eicosapentaenoic acid, are currently being studied by the National Eye Institute in the AREDS-II Study.

Examinations

It is recommended that in addition to the vitamins, you monitor your vision daily with an Amsler grid. Patients should look at the grid with one eye at a time at a reading distance with your best reading correction. They should look at the central dot and make sure that all the lines appear straight and that all of the corners are visible while. Patients with some degeneration will have some abnormalities or areas where the line is distorted or even absent. Sudden changes from a baseline status could indicate bleeding or fluid leakage and require a dilated exam. General follow-up with dilated exam is recommended approximately twice a year depending on any other existing problems.

Exudative (Wet) Macular Degeneration

Although this accounts for only 10% of macular degeneration, it is responsible for the majority of legal blindness from the disease. It is characterized by a rapid visual loss as abnormal blood vessels grow underneath the retina and leak fluid and bleed. Over time, these vessels have associated scar tissue which can lead to permanent scar formation under the retina. Patients with dry macular degeneration have about a 1-5% chance per year of converting from the dry form to the wet form. Once wet macular degeneration has happened in one eye, the chance of it happening in the other is increased to approximately 5-10% per year.

Treatment

Although we have treatments for macular degeneration, it must be understood that these do not cure the disease or reverse visual loss in many cases. The goal of currently available treatments is to stop or reduce leakage and bleeding, and to minimize the size of the blind spot. However, outcomes are improving with newer medications such as ranibizumab (Lucentis) and many patients should at least stabilize with ranibizumab treatment. Generally, if exudative macular degeneration is left untreated, the blood vessels tend to grow which enlarges the blind spot, and the blood vessels continue to leak fluid and occasionally bleed. Scarring and permanent damage generally occurs to some extent in most patients. Once scarring has occurred, no currently available treatment will be effective.

Common Treatments

Ranibizumab (Lucentis)

Ranibizumab is an anti-VEGF antibody fragment that was derived from bevacizumab with the hope of improving retinal penetration. On June 30, 2006, it was approved by the FDA for treatment of exudative (wet) macular degeneration and it should be available in early July 2006. It is administered as a monthly intravitreal injection. Although patients may initially be hesitant to have an injection, it is a quick and painless procedure that only requires topical and subconjunctival anesthesia. Clinical trials have shown that around 95% of patients treated with ranibizumab maintain and 40% improve their vision over the course of therapy. This clearly is the most efficacious FDA-approved treatment to date and will become a first line therapy in many patients. Ranibizumab is covered by Medicare (AdminaStar Federal) in Indiana.

Bevacizumab (Avastin)

Bevacizumab is an anti-VEGF antibody that was originally approved by the FDA for treatment of colorectal cancer. Through pioneering work at the Bascom Palmer Eye institute in Miami, Dr. Phil Rosenfeld and colleagues have shown this to be a very effective treatment for exudative macular degeneration.

Bevacizumab has dramatically improved outcomes in exudative macular degeneration.

Even though this is considered an “off-label” use of the drug, there has been enough evidence of efficacy that it is now covered in Indiana by Medicare and most insurance carriers. Because of its significantly lower cost and less frequent administration, it is still a first line treatment in many patients.

Photodynamic Therapy

This laser treatment uses a light-sensitizing dye injected into a vein to more selectively destroy the vessels and spare the overlying retinal tissue. This is generally used for vessels that involve the direct center of the retina or fovea. The dye, called verteporfin (Visudyne), is infused into the patient's arm over a ten minute period. Five minutes later a laser is used to treat the vessels for an 83 seconds. Because this photosensitizing dye is injected into a patient's vein, the dye travels throughout their body and there are strict restrictions to avoid direct sunlight for five days. Like thermal laser, this treatment does not eliminate the original cause of the vessel growth. On average, patients need approximately three treatments during the first year, two during the second, and one during the third. Patients are seen on an every three month basis with repeat Fluorescein Angiograms. If there is leakage on the angiogram, the laser treatment is repeated. In rare cases where both eyes are affected by these vessels, a treatment can be performed sequentially with the same dye infusion.

Photodynamic therapy (PDT) is an FDA-approved treatment for choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). The primary study in this disease was called the TAP (Treatment of AMD with Photodynamic therapy) study. This was published in the journal Archives of Ophthalmology in 2001 and data have been collected up to 5 years. The major results of the study are summarized in the following graph which shows a decrease in visual loss over five years. Similar to conventional thermal laser, retreatments are usually needed with the average patient receiving 6-7 treatments over five years.

Comparison of Visudyne and placebo showing greater preservation of vision in the Visudyne group compared to placebo over 5 years. Note that both groups of patients tended to lose vision, but lost significantly less if they were treated.

• Year 1 - 3.5 treatments
• Year 2 - 2.3 treatments
• Year 3 - 1.1 treatments
• Year 4 - 0.4 treatments
• Year 5 - 0.1 treatments

What Side Effects Can Occur with PDT and Visudyne?

By far, most patients tolerate this procedure without any problems. The most common reported side effects (Visudyne vs. placebo) were visual disturbance (22% vs. 16%), back pain (2.5% vs. 0%), infusion-related problem (16% vs. 6%), photosensitivity (4% vs. 0%), and allergic reactions (2% vs. 4%).

The two most specific problems were back pain and photosensitivity. Back pain can be reduced by having patients drink a couple extra glasses of water before the procedure. Photosensitivity can be avoided by staying out of direct sunlight for the full 5 day period.

Triamcinolone Acetate (Kenalog)

Triamcinolone Acetate is a long-acting anti-inflammatory steroid which is used in wet macular degeneration for its action against blood vessel growth and retinal swelling. Four milligrams are injected through the white part of the eye directly into the vitreous cavity. Topical and subconjunctival anesthesia make this a quick and painless procedure. The drug lasts in the eye for three months on average. Patients are followed monthly to monitor intraocular pressure which may rise after this injection. This typically works best in combination with other treatments such as PDT laser.

Other Treatments

These treatments are useful in certain situations, but have been replaced by newer and more effective treatments noted above.

Pegaptanib Sodium (Macugen)

Pegaptanib sodium was the first FDA-approved anti-VEGF treatment for wet AMD. It is administered by directly injection into the vitreous cavity every six weeks. Although most patients are initially hesitant, it is a quick and painless procedure that only requires topical and subconjunctival anesthesia. The average patient lost 9.4 letters on an eye chart with treatment versus 17 letters without Macugen. With the success shown by bevacizumab (Avastin) and the new FDA approval of ranibizumab (Lucentis), Macugen is being used less frequently. It is however, also being evaluated as a maintenance therapy after initial control of the lesion by other treatments, as well as for treatment in other neovascular conditions.

Graph comparing patients treated with Macugen [yellow top line] and those with sham treatment [purple bottom line] over the course of two years. Note that on average, all patients lost vision, but patients treated with Macugen were more likely to retain visual acuity and the benefit extended over two years.

Thermal Laser

Thermal laser uses a laser to burn and coagulate blood vessels under the retinas. Drops are used to anesthetize the eye and the laser is used to burn the vessels. The advantage of this technique is that it has been around for many years and is relatively easy on the patient. It does not impose any restrictions post-operatively. The primary disadvantage is that the overlying retina is also burned and coagulated in the process. This is generally reserved for well-defined vessels that are present in areas away from the fovea. Because the inciting cause of the blood vessel growth is not cured by the laser, there is up to a 50% recurrence rate. However, well-designed clinical studies show that patients’ vision does better with treatment compared to without.

Surgical Treatments

Recently there has been press about surgical treatments for macular degeneration. As of now, there is no accepted proven method of intraocular surgery for macular degeneration that gives an outcome any better than natural history alone. The submacular surgery trial is a National Institute of Health sponsored study that is evaluating whether or not surgically removing the blood vessels underneath the retina is a viable option. My past experience, including experience gained with patients as part of this clinical trial, make me feel that this will have very limited application. Another recent press release from Duke University showed that, in very special circumstances, a surgery called a macular translocation can be performed. This was a limited study on eight patients who had failed photodynamic therapy. Two major surgeries later, some patients had better vision and some patients were worse. The statistical significance of this with only eight patients was not there. This is clearly in an experimental stage and, at the most recent American Academy of Ophthalmology meeting, it was stated that this should not be done in the general community until this technique is perfected and then proven to be helpful in a large study with many patients.

Other Ocular Conditions

Even though some patients will say that "nothing can be done" and question why they need to be seen, it is important to identify treatable and preventable causes of visual loss. Patients with macular degeneration and impaired central vision could certainly also have glaucoma which could take away peripheral vision. Cataracts can occur and, even in cases of severe macular degeneration, cataract surgery has been shown to improve the quality of life by increasing the amount of light getting to the retina and improving peripheral vision.

Low Vision Aids

A patient with macular degeneration generally requires more light and more magnification to be able to see. At certain levels of degeneration no amount of magnification will help. Often things in early stages, like handheld magnifiers with or without lights, can be very helpful. When the degeneration gets more severe, things like reading machines (closed circuit TVs) can be helpful. There are resources where patients can buy watches that speak and things like large button phones and playing cards with large symbols and numbers. If you are interested in this, feel free to contact our office for assistance in locating a source close to you.