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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.

Recently, it has been discovered that a receptor gene called the toll-like receptor 3 (TLR3), which causes cell death, may be a trigger for geographic atrophy. Geographic atrophy is a significant cause of visual loss and affects about 900,000 Americans.

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. It has been estimated that 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.

Treatments

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 bevacizumab (Avastin). Many patients should at least stabilize with these treatments. 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

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. 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. In our experience, results are very comparable to ranibizumab (see below).

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. We have used this medication extensively in our clinic since 2005.

Ranibizumab (Lucentis)

Ranibizumab is an anti-VEGF antibody fragment that was derived from bevacizumab with the hope of improving retinal penetration. Based on two randomized clinical trials (ANCHOR and MARINA), it was approved by the FDA for treatment of exudative (wet) macular degeneration and became available in 2006. Like bevacibumab, it is administered as a monthly intravitreal injection. 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 considered a first line therapy in some patients. Ranibizumab is covered by Medicare (AdminaStar Federal) in Indiana.

Lucentis vs. Avastin

With the availability of two excellent anti-VEGF agents, a common question posed to physicians is which agent (Avastin or Lucentis) is “better.” The National Eye Institute is currently sponsoring a randomized study comparing the two drugs, but results may be years away. Based on our experience, the drugs appear equivalent in terms of clinical response. Both have been extremely well-tolerated with no known systemic side effects, which is most likely attributable to the very low intraocular doses and route of administration. The biggest difference between the two agents is cost. The cost per dose (in a form ready for intraocular injection), is approximately ten times higher for Lucentis than it is for Avastin. Because there seems to be no difference in efficacy and a major difference in cost, we treat most patients with Avastin. The decision to continue treatment, switch to another agent, or combine with photodynamic therapy is based on the patient's clinical response.

PrONTO Study and Implications for Today's Practices

With different agents and different dosing schedules, it is clear that one protocol may not be optimal for all patients. Dr. Philip Rosenfeld, from the Bascom Palmer Eye Institute in Miami, designed the Prospective OCT imaging of patients with Neovascular AMD Treated with IntraOcular Lucentis (PrONTO) study to prospectively evaluate variable dosing of ranibizumab using OCT. Patients with wet AMD received 3 monthly injections with Lucentis (ranibizumab) and then only as needed, using predetermined criteria. The average number of injections at the 12-month time point was 5.6. An average gain in visual acuity of 9.3 letters was noted at 12 months -- better than the results of the MARINA trial. And in results similar to those of the MARINA trial at 12 months, 95% of patients maintained visual acuity (less than 15-letter loss) and 35% of patients gained 3 or more lines. Dr. Rosenfeld noted a tendency for OCT to show return of fluid before loss of vision, allowing re-treatment with ranibizumab without loss of vision.

For most patients, I currently use the following schedule:

  • 3-4 monthly injections with Avastin (sometimes Lucentis). OCTs done to determine response
  • Supplemental fluorescein angiography to determine leakage on some visits

Once lesion becomes “dry” dosing can be less frequent. There are numerous strategies for maintenance and one single protocol will not be ideal for all patients.

  • The phase 3 studies (ANCHOR and MARINA) required indefinite monthly dosing. This is rarely done in clinical practice.
  • In the “Skip and Extend” regimen, if two consecutive visits show no fluid and stable vision, the injection is skipped and the patient returns in a month. As long as fluid does not recur, visits are gradually spaced out usually to a maximum of six months.
  • In the “Treat and Extend” regimen, if two consecutive visits show no fluid and stable vision, an injection is given and the patient returns in 6 weeks. As long as fluid does not recur, the patient receives another injection and returns in two months. This typically continues up to a maximum of six months.
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 was previously used as a first-line therapy until injections replaced it. Recently, it has regained popularity as part of combination treatments with injections (combination therapy), and with injections and steroids (triple therapy).

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.

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. Two to four milligrams are injected through the white part of the eye directly into the vitreous cavity. 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.

Other Treatments

With the arrival of newer injections, pegaptanib sodium (Macugen) and thermal laser are now rarely used. Surgical treatments for macular degeneration occasionally receive media attention, but there is no proven surgery for macular degeneration.

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.