What You Should Know About Age-Related Macular Degeneration

What is age-related macular degeneration?
Many people, usually after age 65, develop a "wearing out," or degeneration of the macula as part of the aging process. We don't know why some people get these changes and others do not. There appears to be an increased risk of macular degeneration with increasing age, in cigarette smokers, and in those who have other family members affected by this disease. There are 15 million people in the United States affected by age-related macular degeneration, with over 1.6 million having the more severe wet type.

There are two basic types of age-related macular degeneration. The vast majority of people have the less severe dry type. The hallmark clinical finding of dry macular degeneration consists of small aging spots or drusen.

Normal Macula.		Dry macular degeneration with drusen (yellow spots).

Eyes with geographic atrophy, a variant of dry macular degeneration, develop a wearing away of the macular pigmented tissues. The atrophy causes discrete islands of blind spots. Vision is good unless the atrophy extends into the macular center.
 

Geographic atrophy just spares the macular center.		The atrophy gradually enlarged, causing loss of central vision.

Some patients with macular degeneration can develop a blister, which is called a pigment epithelial detachment. These blisters often cause blurriness or distortion. Various treatments have been attempted over the years without success. The blisters can remain stable, spontaneously flatten, or can go on to develop associated choroidal neovascularization.
 

Pigment epithelial detachment (outlined by arrows).		Fluorescein angiogram highlights the blister.

New blood vessels (choroidal neovascularization) grow beneath the macula in the more severe wet form.  These vessels cause the overlying macula to swell with fluid and blood which often causes permanent central vision loss.

		End-stage wet macular degeneration with macular hemorrhaging and scarring.

Choroidal neovascularization (CNVM) is invisible without a special test called fluorescein angiography. Fluorescein angiography is a photographic test, not involving x-rays, in which a colored vegetable dye is injected into an arm vein. A series of photographs are taken as the dye passes through the back of the eye. This allows us to better diagnose the presence and extent of the abnormal blood vessels and leakage in order to determine whether treatment can be offered. The abnormal blood vessels are classified as being well-defined (classic), poorly defined (minimally classic), or occult by how well the margins can be identified on angiography. The choice of treatment and the response to various therapies are often determined by how well-defined the lesion is.

Fluorescein angiography shows a white, well-defined CNVM (a red circle outlines the abnormal vessels).		Angiography shows a poorly-defined CNVM.  There is no distinct white lesion seen.

The goals of treatment are to prevent CNVM from developing in the first place (vitamin therapy), prevent CNVM from spreading into the macular center (laser photocoagulation), or limit the size of and leakage from the CNVM once it reaches the macular center (photodynamic therapy, Macugen, Lucentis, Avastin).

What are the symptoms of age-related macular degeneration?
Patients with mild dry degeneration usually notice minimal changes in their vision although there may be slow loss of reading vision over many years.  If the wet form develops, leakage and bleeding may involve the macular center causing symptoms such as distortion and vision loss. Patients never go completely blind since the part of the eye responsible for peripheral (side) vision is not affected by this disease.

Normal Vision.		Macular Degeneration.

Patients are often asked to check their central vision every day with an Amsler grid. This grid is a pattern that resembles a checkerboard. You will be asked to cover one eye and stare at a black dot in the center of the grid. While staring at the dot, you may notice that the straight lines in the pattern appear wavy to you. You may notice that some of the lines are missing. These may be signs of wet age-related macular degeneration. 
Click here to view a full-sized Amsler grid yourself.

Blurry areas and black spots.		Wavy or crooked lines.

How is age-related macular degeneration diagnosed?
The most important step in accurately diagnosing macular degeneration is a careful dilated eye examination by an eye doctor familiar with this disease. Further testing, including fluorescein angiography, may be necessary.

What treatments are available for age-related macular degeneration?

1) Preventive treatments.

• Nutritional supplements.  The Age-Related Eye Disease Study (AREDS), a large, randomized, multicenter prospective study sponsored by the National Eye Institute, found that taking supplements containing high levels of antioxidants and zinc significantly reduced the risk of advanced age-related macular degeneration. The nutrients are not a cure for age-related macular degeneration, nor will they restore vision already lost from the disease. However, they may play a key role in helping people at high risk for developing advanced age-related macular degeneration keep their vision. People who are at high risk for developing advanced age-related macular degeneration should consider taking the formulation used in the study and eating a diet high in vitamin C, vitamin E, zinc, and carotenoids. Your eye doctor will tell you if you would benefit from these supplements based on a dilated eye examination.
  
  AREDS researchers found that people at high risk of developing advanced stages of macular degeneration lowered their risk by about 25 percent when treated with a high-dose combination of vitamin C (500 mg), vitamin E (400 IU), beta-carotene (15 mg), and zinc (as 80 mg zinc oxide), and copper ( 2mg cupric oxide which was also added to prevent a zinc-induced copper deficiency which may be associated with high levels of zinc supplementation). This treatment also reduced the risk of vision loss by about 19 percent.  The supplements did not provide any apparent benefit for those with either early macular degeneration (those with either several small drusen or a few medium-sized drusen in one or both eyes) or no macular degeneration.
  
  Some people with intermediate macular degeneration may wish to consider whether or not they wish to take large doses of the supplements for medical reasons. For example, beta-carotene has been shown to increase the risk of lung cancer among smokers.  Taking supplements with zinc may cause a copper deficiency. The study also found high zinc levels were associated with genitourinary tract problems. Patients may want to discuss the best combination of supplements to take with their primary care physician.
  
  Supplements based on the AREDS study include Ocuvite Preservision, Icaps AREDS formula, Viteyes, and Visvite.
  The value of other supplements, such as lutein and bilberry, are completely unknown since none have been adequately studied in randomized, prospective studies. They may be helpful, have no benefit, or might even prove to be harmful. The National Institutes of Health is currently sponsoring the AREDS 2, which will evaluate the benefits of oral supplementation with lutein (10 mg/day), zeaxanthin (2 mg/day), and omega-3 long-chain polyunsaturated fatty acids (1 gram/day).
  
  
• Life-style modifications.  Discontinuing smoking, weight loss, and regular exercise appear to be both good for your heart and your eyes.

2) Laser photocoagulation for wet age-related macular degeneration.

Choroidal neovascularization with surrounding hemorrhage.		Dry laser scar following successful laser photocoagulation surgery.

Laser surgery is performed in our office while you are awake and comfortable. The laser is used to seal the leaking vessels beneath the retina. The laser treatment usually takes less than 15 minutes to complete, and you can go home immediately following surgery. Arrangements for transportation should be made in advance since you may not be able to drive right away.

It takes several weeks to months before we can tell whether treatment has been successful. Patients usually require more than one laser surgery to control the macular leakage, often within the first month or two of treatment. Recurrences need to be promptly diagnosed and treated in order to maintain reading vision. For this reason, you will need to return for examinations every few weeks until the outcome is known. Although laser surgery decreases the risk of severe central vision loss by about 50%, some people will eventually lose reading vision.

3) Photodynamic therapy.
Laser photocoagulation surgery has traditionally been the standard treatment for patients with wet age-related macular degeneration and choroidal neovascularization outside the macular center. When choroidal neovascularization is beneath the center of the macula, laser not only destroys these abnormal vessels but also permanently damages the overlying retina. Patients are thus left with a dry scar but no central vision.

OCT scans before (top) and following (bottom) photodynamic therapy. The swollen, cystic appearing macula returns to its normal configuration following treatment.

4) Vascular Endothelial Growth Factor (VEGF) Inhibitors.
Scientists have recently identified a growth factor (Vascular Endothelial Growth Factor, or VEGF) that plays a major role in stimulating "neovascularization" or new blood vessel growth. VEGF causes the cells lining blood vessels (vascular endothelium) throughout the body to multiply and form new vessels. In the macula, VEGF may be produced by cells starved for oxygen. The VEGF then binds to the choroidal endothelial cells, which then proliferate and form choroidal neovascularization. Macugen and Lucentis are the two VEGF-inhibitors currently approved for ocular use. Avastin, another VEGF inhibitor approved for the treatment of colorectal cancer, is being evaluated as a treatment for choroidal neovascularization.

There are numerous other angiogenic inhibitor-like substances being investigated, including VEGF trap, short interfering RNA (SIRNA, Acuity Pharmaceuticals), and tyrosine kinase inhibitors.

• Macugen. Macugen (marketed by Eyetech and Pfizer Pharmaceuticals, www.macugen.com) is the first FDA-approved treatment that helps preserve vision by targeting this underlying cause for neovascular AMD. Macugen consists of a synthetic fragment of genetic material that specifically binds to the VEGF molecule and blocks it from stimulating the receptor on the surface of endothelial cells. Macugen is injected into the eye in a painless, in-office procedure, and then passes beneath the retina into the area where the abnormal blood vessels are growing. The injections are given every 6 weeks until the choroidal neovascularization regresses. Serious side effects occur in less than 1% of injections, including infection, retinal detachment, or cataract.
  
  Macugen was studied in 2 randomized, controlled, double-masked studies in patients with wet age-related macular degeneration, the VISION (VEGF Inhibition Study in Ocular Neovascularization) trial. The choroidal neovascularization included classic, occult, and mixed lesions up to 12 disc areas in size (a much broader group than in the photodynamic therapy studies). Patients were treated every 6 weeks for 48 weeks. Macugen reduced the risk of moderate vision loss (less than 3 lines of vision) in 70% compared to 55% of those receiving a sham injection. Severe vision loss (loss of at least 6 lines of vision) developed in 10% of eyes receiving Macugen compared to 22% of eyes receiving a sham injection. The risk of legal blindness (vision less than or equal to 20/200) was 38% with Macugen treatment compared to 56% of eyes receiving a sham injection. Although Macugen appeared to prevent vision loss, visual improvement was relatively uncommon. An improvement in at least 1 line of vision occurred in only 22% of treated eyes and 12% of eyes receiving a sham injection.
  
  There are no study results comparing Macugen to photodynamic therapy, although both appear to be fairly similar in their efficacy. Combining photodynamic therapy with intravitreal steroids is probably more effective than Macugen alone. Lucentis also appears to be more effective than Macugen. The future role of Macugen therapy is therefore uncertain. It might prove to be most useful for patients who fail to respond to Lucentis or photodyamic therapy with intravitreal steroids..
  
  
• Lucentis. Genentech has produced an antibody fragment, Lucentis (also known as AMD-Fab or rhuFab), that binds to VEGF and prevents it from interacting with the VEGF receptor on the surface of endothelial cells. Lucentis is injected into the eye in a painless, in-office procedure, and then passes beneath the retina into the area where the abnormal blood vessels are growing. The injections are given every 4 weeks for at least a year or two. There are numerous clinical studies in progress, including the FOCUS and ANCHOR trials for predominantly classic choroidal neovasculariation and the MARINA trial for minimally classic or occult choroidal neovascularization. Lucentis appears to be superior to both photodynamic therapy and Macugen for maintaining and improving vision for a broad-spectrum of eyes with wet age-related macular degeneration. Approximately 90 to 95% of patients treated with Lucentis maintained or improved vision (< 3 lines of vision loss) compared to 62 to 68% of those treated with photodynamic therapy. After 12 months, vision improved by about 1 to 2 lines in patients treated with Lucentis compared to a loss of about 2 lines in patients treated with photodynamic therapy. Vision was at least 20/40 in about one-third of patients receiving Lucentis compared to only 3 to 11% of those who received photodynamic therapy. Unfortunately, patients appear to require monthly intraocular injections for at least a year or two for best visual results.
  
  
• Avastin. Avastin (bevacizumab) is an anti-VEGF compound currently approved for treating colorectal cancer. Its chemical structure is very similar to Lucentis. There is very promising and preliminary data suggesting that injecting very tiny amounts of Avastin into the eye appears to be as effective as Lucentis in treating wet age-related macular degeneration. The cost per treatment is a fraction of other available therapies, including photodynamic therapy and Macugen. Before Avastin can be broadly recommended, however, there needs to be more experience to better determine its safety and efficacy.
  
  

5) Subretinal surgery.
Using advanced microsurgical techniques, hemorrhage and abnormal blood vessels growing beneath the macula can be removed. Unfortunately these techniques can benefit only a small minority of patients with age-related macular degeneration and carry a risk of major complications such as retinal detachment and total blindness. The Submacular Surgery Trial, the definitive National Eye Institute sponsored study, unfortunately failed to show any significant benefits for these techniques.

6) Investigational treatments.
Although there have been great strides over recent years in treating macular degeneration, we are still far from being able to prevent macular degeneration from developing in the first place, as well as treating choroidal neovascularization once it develops. There are a multitude of new treatments being investigated, although we will not know if they are helpful or harmful until the ongoing clinical studies are completed. Some of the treatments currently under investigation include the following:

• Transpupillary thermotherapy (TTT).  This treatment uses a low-intensity laser spot to gently heat choroidal neovascularization. TTT appears to cause less secondary retinal damage and vision loss, while hopefully also being able to close the underlying choroidal neovascularization. Unfortunately, preliminary data from the Transpupillary Thermotherapy for Choroidal Neovascularization (TTT4CNV), a large, randomized prospective study, failed to show significant beneft in preventing moderate vision loss.
  
  
• Implantable Miniature Telescope (IMT). The Implantable Miniature Telescope, a tiny lens inserted in the eye during a cataract-like operation, may help reduce central visual impairment. Acting like a telescope, this device will enlarge images by about 2 to 3 times, making it easier for those who have already permanently lost central vision to recognize images at distance. One-year efficacy data from a prospective, multicenter trial showed patients had a mean improvement of over 3 lines of vision in both distance and near best-corrected acuity in the study eye.
  
  Unfortunately, on a recent 10-3 vote, the Food and Drug Administration's Ophthalmic Devices Panel recommended that the IMT be found "not approvable." The panel decision was based on unresolved safety concerns regarding possible corneal damage in addition to uncertainty regarding the efficacy of the device. The final FDA decision is still pending.
  
  
• Other treatments being investigated include translocation surgery and radiation therapy, although results to date have been unimpressive. Steroid injections (Retaane [Anecortave acetate]) or implants (Retisert) are also being evaluated.