Northeast Wisconsin Retina Associates

CLINICAL CONDITIONS

MACULAR DEGENERATION

Macular degeneration is a generic term referring to deterioration of the macula and loss of central (detailed) vision. There are many forms of macular degeneration, however the substantial majority of cases are due to age-related macular degeneration (AMD). AMD is extremely common. In the United States, it is the most common cause of vision loss in individuals over the age of 60. AMD is a disease and not simply part of the normal aging process. Although AMD damages central vision, it usually does not affect peripheral vision. For example, a macular degeneration patient with significant vision loss could see the outline of a clock but not be able to discriminate the time. Fortunately, even in more advanced cases, AMD patients typically continue to maintain sufficient useful vision to take care of themselves although the ability to drive and read may have been lost. AMD occurs in two forms, which in layman’s terms are commonly referred to as dry and wet. Any patient with AMD first develops the dry form. Some patients subsequently progress to the wet form of the disease.

The incidence of AMD increases steadily with advancing age, as is the case with many degenerative conditions. It is significantly more common in patients of western and northern European descent. Smoking and uncontrolled high blood pressure are also risk factors, which unlike age and heritage, can be modified.

TWO FORMS OF AMD

As mentioned above, AMD occurs in two forms: dry and wet. Every AMD patient initially develops the dry form (also called early, nonexudative, atrophic, or non-neovascular). Some AMD patients progress to the wet form (also called advanced, exudative or neovascular). These forms of AMD behave quite differently.

Dry AMD

  • retina with dry AMD: drusen

    Dry AMD: Drusen

  • retina with dry AMD: atrophy

    Dry AMD: Atrophy

This form of macular degeneration progresses very slowly over years. Most patients notice only mild visual impairment such as some difficulty with fine print and/or the need for better lighting. Frequently, there also may be difficulty adjusting to different levels of illumination. The most common finding in patients with dry AMD is macular drusen. These yellowish deposits represent accumulated metabolic waste products from the photoreceptors (light sensitive nerve endings) of the macula. In a normal healthy macula, these waste products are removed by the body whereas in dry AMD, they accumulate slowly eventually resulting in damage to vision.

Occasionally, more serious vision loss can occur in dry AMD patients when a process of thinning of the macula takes place which is called atrophy. Although 90% of serious vision loss from AMD is due to the wet form, 10% occurs due to atrophy in patients with dry AMD.

Wet AMD

retina with wet AMD

Wet AMD

The wet form of AMD behaves very differently. In contrast to the dry form, it develops and progresses quickly, typically within a number of weeks or months. Without treatment, serious permanent loss of vision will usually result. In wet AMD, abnormal blood vessels form beneath the macula. As they grow, these abnormal blood vessels, called choroidal neovascularization (CNV), begin to leak fluid and often to bleed – hence the term wet. Patients affected by wet AMD usually notice the rapid development of blurred and/or distorted vision. Dim areas or blind spots in the central vision may also occur.

EVALUATION

In addition to a thorough ophthalmologic examination, evaluation of AMD patients often involves diagnostic testing including retinal photography, fluorescein angiography and OCT scanning (see above About Your Visit, Diagnostic Testing).

DRY AMD TREATMENT

For dry AMD, there is no specific treatment currently available although many patients at this stage have normal or near-normal vision. In an effort to reduce the risk of progression to wet AMD however, a number of interventions are helpful:

  1. Discontinue smoking. Smoking has clearly been demonstrated to have a significant negative impact on the course of macular degeneration dramatically increasing the risk of progressing from the dry form to the wet form. Cessation of smoking is therefore critical in any patient with macular degeneration.
  2. Control high blood pressure. Hypertension has also been shown to have a small negative impact on the course of macular degeneration. Control of high blood pressure is clearly in any patient’s best interest for a variety of reasons.
  3. Monitor vision regularly with an Amsler grid. This is an extremely simple means of periodically assessing the central vision of each eye and monitoring for the development of any loss of vision or distortion.
    The Amsler Grid
  4. Magnification aids and proper lighting. Any patient with visual impairment due to macular degeneration will benefit with appropriate lighting and in many cases, magnification aids. These aids must be tailored based on the patient’s level of impairment as well as the type of visual activities they are attempting to perform. In some cases, formal consultation with a low-vision specialist may be extremely helpful.
  5. Consider dietary supplementation with antioxidant vitamins and zinc. Large national clinical trials called the Age-Related Eye Disease Study (AREDS), and the second phase called AREDS2 have conclusively demonstrated the benefits of nutritional supplementation in macular degeneration patients. Please refer to the accompanying article, 'Nutritional Supplements and Macular Degeneration' (below), regarding the recommended vitamins and their dosages.

Nutritional Supplements and Macular Degeneration

We continue to seek better treatment options for all AMD patients. This is a profound public health issue. AMD is the leading cause of legal blindness for patients over the age of 55 in the United States. Ideally, preventative treatments would be developed. The Age-Related Eye Disease Study (AREDS) was a national study which followed approximately 5,000 patients over the course of 12 years. AREDS was funded through the National Institutes of Health (NIH) and the National Eye Institute (NEI) and was not administered by pharmaceutical companies. AREDS sought to determine the potential benefits of dietary supplementation with antioxidants (vitamins A, C and E) and zinc. Specifically, AREDS researchers evaluated the long-term effect of these substances on the course of cataract formation (gradual loss of clarity of the lens of the eye) and most importantly AMD.

Questions addressed by AREDS:

  1. Do these supplements affect the development/progression of cataract? NO
  2. Do these supplements prevent the development of early/dry AMD in a patient with a normal, healthy macula? NO
  3. Do these supplements slow the progression of early/dry AMD once it is already present? NO
  4. Do these supplements alter the course of advanced/wet AMD once it has developed? NO
  5. Do these supplements diminish the risk of progression from dry to wet AMD? YES!!

Question #5 is actually the most significant since wet AMD can result in devastating, irreversible loss of vision. Dietary supplementation with antioxidants and zinc at the dosage levels prescribed in AREDS (see table below) reduced the risk of progression from dry to wet AMD by approximately 25%. This benefit was sustained over the 12-year course of the study. Treatment was extremely well tolerated throughout the course of AREDS without the occurrence of significant toxicities.

At the time AREDS was organized, the only readily available form of vitamin A was beta-carotene. Other forms of vitamin A (carotenoids) such as lutein and zeaxanthin were not included in AREDS and therefore no specific conclusions could be drawn regarding these substances at that time.

High dose zinc supplementation carries a theoretical risk of causing bone marrow suppression and anemia. To avoid this problem, a small amount of copper is also administered. No patients in AREDS experienced difficulty of this type.

Finally, care should be taken when using high dose vitamin supplementation. More is not necessarily better and significant toxicities can occur. There is also good evidence from other clinical studies that vitamin A supplementation in the form of beta-carotene in smokers may increase the risk for development of lung cancer. Beta-carotene should therefore be avoided in smokers.

AREDS was a landmark clinical study and although far from a cure for AMD, we are able to suggest a form of therapy which has the potential to diminish the risk of developing the wet form of AMD and associated severe visual loss.

Daily dosages administered in AREDS

Antioxidants:
Vitamin A (as beta-carotene)25,000 IU (15 mg)
Vitamin C500 mg
Vitamin E400 IU
Zinc (as zinc oxide)80 mg
Copper (as cupric oxide)2 mg*
* Zinc alone may lead to copper deficiency.

Many supplements of this general type have been on the market for years (examples include Ocuvite and ICAPS). Some preparations, including Ocuvite PreserVision, contain the AREDS formulation. All of the supplements are nonprescription and are available “over the counter.” The recommended dosage levels are relatively high, and though typically well-tolerated, if you choose to follow this course of therapy, you should inform your primary care physician.

Hoping to build on the success of AREDS, a follow-up study (AREDS2) was undertaken. AREDS2 was a six-year trial to test the benefits of substituting high doses of lutein and zeaxanthin for beta-carotene as well as adding omega-3 fatty acids (found in fish oil) to the original AREDS formulation. The study also tested the effect of lowering the zinc from 80 mg to 25 mg.

Daily dosages administered in AREDS2

Antioxidants:
Vitamin A (carotenoids)
Lutein80 mg
Zeaxanthin2 mg
Vitamin C500 mg
Vitamin E400 IU
Omega-3 fatty acids
DHA350 mg
EPA650 mg
Zinc (as zinc oxide)25 mg
Copper (as cupric oxide)2 mg

The results of AREDS2 were published in May 2013. The benefit of the AREDS2 formulation was no different than the original AREDS formulation (AREDS2 = AREDS). Because of the concerns regarding lung cancer and beta-carotene supplementation noted above, patients who smoke should certainly use the AREDS2 formulation. Nonsmokers can continue with the original AREDS supplement or switch to AREDS2.

WET AMD Treatment

Fortunately, over the last few years, major advances have been made in the understanding and treatment of wet AMD. One of the key chemical mediators which results in the growth of abnormal blood vessels (CNV) beneath the macula is called vascular endothelial growth factor (VEGF). Drugs have been developed to block the effect of VEGF and have found a variety of applications in medicine – from treating certain cancers to eye diseases including AMD. Since 2006, injection of anti-VEGF medications into the eye has become the mainstay of therapy for wet AMD. (See discussion regarding Surgical Procedures: Intraocular Injection of Medications.) Anti-VEGF drugs permit stabilization (prevention of further vision loss) in the substantial majority of wet AMD patients. In 30 to 40% of patients, measurable and often significant improvement/recovery of vision can be achieved. This has represented a revolutionary advance from previous treatment options. Currently, three medications (Avastin®, Lucentis® and Eylea®) are commonly used in the treatment of wet AMD.

As with any treatment, there are certain inherent limitations. In the case of anti-VEGF medication therapy, patients and their families should understand that wet AMD is a chronic disease – just like diabetes or hypertension. Although the current treatment modalities often prove to be highly successful, no cure is available. Most patients with wet AMD will require ongoing treatment at varying frequencies over the long term. On the other hand, the dramatic advances in the treatment of wet AMD over the past several years has allowed many of our patients to maintain a much higher level of independence and quality of life than with previous treatment options.

Prior to 2006, the mainstay of treatment for wet AMD had been laser treatments including, laser photocoagulation and more recently, photodynamic therapy (PDT). These remain additional weapons in the treatment arsenal for macular degeneration, however are much less commonly used since the advent of the current era of medication therapy.

Anti-VEGF Drugs

Since 2006, we have been in a new era in the treatment of the wet form of age-related macular degeneration (AMD). It is now well-established that a chemical called vascular endothelial growth factor (VEGF) is one of the main mediators responsible for the growth of leaky blood vessels beneath the macula causing the loss of vision that occurs in the wet form of AMD. VEGF has other functions in the body. For example, in the case of some cancers, it is responsible for causing blood vessels to grow into and nourish the tumor. “Designer” drugs have been created to block the effects of VEGF and have now become the mainstay in the treatment of patients with wet AMD as well as other diseases. These medications are called “anti-VEGF drugs” and have revolutionized treatment of AMD.

The first anti-VEGF drug introduced for treating wet AMD was Macugen® ­(pegaptanib). Like all such drugs for treating AMD, it is administered by periodic injection into the eye Surgical Procedures: Intraocular Injection of Medications. There are several active forms of VEGF in the eye and Macugen was designed to block only one. Ultimately, this drug was found to be about equal in efficacy to the laser treatment which had been the mainstay of therapy for wet AMD since its introduction in the year 2000 (photodynamic therapy with Visudyne or “PDT”). Most patients treated with Macugen continued to lose vision over time despite ongoing therapy.

Macugen has been supplanted by two other drugs that block all forms of VEGF in the eye and provide a significantly better response with many patients actually experiencing measurable improvement in their vision.

Avastin (bevacizumab) is an antibody that combines with and inactivates VEGF. It was originally developed for treating certain malignancies (the primary use at present is in the treatment of advanced stages of colon cancer) and is given intravenously for this purpose.

Lucentis (ranibizumab) is a modified fragment of the Avastin molecule. Both drugs are made by the same company – Genentech. Although Avastin was already in existence, Genentech chose to test Lucentis but not Avastin in the treatment of wet AMD. Avastin was thought to be too large to penetrate through the macula after injection into the eye, however this was never actually tested and ultimately proved to be incorrect.

Lucentis was subjected to safety and efficacy studies as well as clinical trials. It received FDA approval and became available for use at the end of the summer 2006. Before Lucentis became available, however, worldwide enthusiasm among retina specialists had developed for Avastin based on impressive results reported with its use in treating wet AMD. Widespread use of Avastin has occurred since the fall of 2005. In most cases, both drugs are effective in stabilizing vision and in many cases, significant measurable improvement in vision can also occur.

In early 2011, the results of a large clinical trial providing a direct comparison between Avastin and Lucentis were published. This study, the Comparison of Age-Related Macular Degeneration Treatments Trial (CATT), demonstrated equivalent efficacy between the two drugs.

At the end of 2011, a third drug called Eylea (aflibercept) received FDA approval. This drug was evaluated in large clinical trials in both the US and Europe. Side-by-side comparison studies with Lucentis documented equivalent efficacy between the two drugs. In many patients, Eylea can be administered less frequently, which can be a significant benefit.

Comparison of anti-VEGF medications

AvastinLucentisEylea
FDA-approved for wet AMDnoyesyes
Reimbursable through Medicareyesyesyes
Track record with regard to safety/efficacy thru clinical trialsyesyesyes
Frequency of administration (weeks)4-644-8
Potential for stabilizing visionGoodGoodGood
Cost per dose$$$$$$$$$

FDA-approved uses and “Off-Label” Status

Based upon results of clinical trials demonstrating safety and efficacy, the Food and Drug Administration (FDA) may approve a drug to be marketed for the treatment of a specific condition. This only occurs when the manufacturer actively pursues the costly and lengthy approval process. As a condition for such approval, the manufacturer produces a “label” explaining the indications, risk and benefits for use.

Once a device or medication is approved by the FDA and brought to market, physicians may use it “off-label” for other purposes if they are well-informed about the product, base its use on firm scientific method and sound medical evidence, and maintain appropriate records. For years, retinal specialists have been using anti-VEGF medications “off-label” to treat a variety of serious, potentially blinding retinal/macular conditions. This has proven to be both safe and effective and is currently considered “standard of care.”

Expectations regarding treatment

The main goal of treatment with anti-VEGF medications for eye disease is to prevent further loss of vision. As mentioned above, the most common indication for treatment is the wet form of age-related macular degeneration (wet AMD). Although some patients may have significant improvement in vision, this occurs in only a minority (approximately 35%). Even with ongoing therapy, treatment may not ultimately prevent further loss of vision caused by the underlying disease process.

As with any treatment, there are certain inherent limitations. In the case of anti-VEGF medication therapy for eye disease, patients and their families should understand that conditions such as age-related macular degeneration (AMD) are chronic diseases. Although our newer treatment modalities often prove to be highly successful, no cure is available. The vast majority of patients will require ongoing treatment at varying frequencies over the long term. On the other hand, the dramatic advances provided by anti-VEGF medications over the past several years have allowed many of our patients to maintain a much higher level of independence and quality of life as compared with previous treatment options.

Summary

Currently, there are three very similar drugs which offer great hope in the treatment of wet AMD. As mentioned above, a significant number of patients receiving these treatments experience measurable improvement in vision – rather than only stabilizing or slowing the rate of deterioration. Of course, none of these represent a cure for wet AMD nor does the typical patient regain completely normal vision. Clearly, economic considerations remain a significant component in the decision-making process for some patients due to the high cost of Lucentis and Eylea. As described previously, all three drugs have now been subjected to extensive clinical use and, to the best of our knowledge, have proven to be both safe and effective.

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