Age-Related Macular Degeneration:

Past-Present-Future Treatment

by Edith S. Marks

The eye, probably one of the most exquisite organs in the body, can fit into your hand. It reveals the world to you in all its Technicolor splendor and fine detail. Those who possess good vision are hardly ever aware of its gifts; but when disease strikes, when the retina, finely tuned to transmit light messages to the brain for coherent sight, is damaged, the ensuing loss of vision can be devastating. Vatsal Doshi, MD, regards age-related macular degeneration (AMD) to be one of the most devastating retinal diseases for among those over age 65; it is the leading cause of blindness in the US. Doshi stressed that while several treatment options exist, tailoring treatment along with careful consideration of the patient’s other health issues is the main goal.

Macular degeneration is a disease process affecting only the central part of the retina. People who have lost vision in that region still possess intact peripheral vision. Age-related macular degeneration is the most common and the leading cause of vision loss in people over age 65 in the US. For some people, unfortunately, it is possible to have both glaucoma and macular degeneration, due possibly to the fact that both diseases primarily affect older people, as do other degenerative diseases.

It is helpful to review basic anatomy for a fuller comprehension of retinal disease. The retina, an extension of the brain, consists of a thin layer of nerve fibers lining the inner surface of the eye. It functions comparably to the film in a regular camera but it is far more complex. Basically, light rays entering through the pupil are converted to electrical signals. These signals are transferred to the brain via the optic nerve quite like an electrical cable transmitting electricity from one source to another.

The macula, the most central part of the retina, possesses the largest concentration of photoreceptors that are activated by light stimulation. The doctor dilating the eye can view the macula, a small section in the center of the retina that because it possesses more pigment such as lutein appears a bit darker. Lutein helps protect the macula from free-radical formation that damages the cells. Actually, the macula comprises a very small portion of the retina, but is one of the most crucial areas of the visual apparatus. It provides the vision for reading very small print, threading a fine needle, or viewing a street sign or a small bird atop a tree. The rest of the retina, the peripheral retina expands the reach of the visual field enlarging it to 50 to 60 degrees superiorly, 70º to 85º degrees inferiority, 60º nasally, and 90º to 100º temporally.

The retina is composed of many different layers, each providing a specific function. When one or more layers becomes partially or completely dysfunctional, vision problems ensue, for these layers are the seat of retinal disease. The outermost part of the retina comprises the photoreceptor apparatus, the cells that register the light signals. They are composed mainly of the rods, a bit more sluggish in responding to light perception and which are found in the periphery. The cones are more active registering signals rapidly. These are packed into the center of the macular, the area affected by AMD. Beneath the retina, the retinal pigment epithelium (RPE) layer is a support structure for the photoreceptors. Beyond the RPE, the Bruch membrane divides the retina from the choroid, a vascular structure of the retina that provides nutrients and oxygen necessary for the photoreceptors to function. The retinal ganglion cells, the important structure comprising the seat of glaucoma damage, receive information from the photoreceptors via a variety of intermediary connecting cells. In viewing the eye, the examiner can see only the gross retina, but not in detail as described above. However, new imaging instruments provide important details of the optic nerve.

Risk Factors

Most common are age and genetic variables. Researchers have found various genes indicating the links, and point to one especially: the complement factor, a molecule that plays a role in inflammation thought to also play a role in the mechanism for AMD. Doctors now believe that AMD runs in the family. A third risk factor is cigarette smoking. Possibly, diabetes and diet may be associated with macular degeneration, but these diseases are do not present as clear-cut evidence as do cardiovascular diseases such as high blood pressure and cholesterol. Doshi has not seen hard evidence linking diabetes to AMD, although the jury is still out. While at one point, sunlight was implicated, its effects are still undetermined. Nevertheless, doctors still do not advocate excessive exposure to the UV rays. To be on the safe side, Doshi recommends Polaroid sunglasses.

While macular degeneration is a specific disease, the symptoms experienced may not be specific to AMD. For example, symptoms such as blurriness, distortion in central vision, and color change perception may be caused by a variety of different eye or other retinal problems. Typically, however, loss of central vision is the main feature of macular degeneration. The patient may be able to discern parts of an object such as the periphery of a clock, but the face, hands, and numbers of the clock will be obscured. Recognition of an individual by gait, voice, or other characteristics may be possible, but the person’s face will be a blanked out.

Of course, the hub of this condition lies with the retina, one of the most active tissues in the body, involving a constant turnover of the cells that results in a nonstop accumulation of waste products. In a healthy eye, cells designed to clear these products from the area proceed apace, but with AMD these products over time may accumulate forming deposits called drusen, which form beneath the retina. During the earlier stages, drusen may not cause a problem, but in later stages their accumulation damages the retina, stimulating the growth of weak and leaky abnormal blood vessels.

Drusen are not confined to the macular. For example, the area between vessels adjacent or around the macular may also harbor drusen, a condition called the familial form, but these may not cause much central vision loss. In general, however, drusen accumulate in greatest amount in the macular. During the intermediate stage there may be larger, more confluent drusen with associated pigment changes, but the patient may still have decent vision. The advanced stage is characterized by the loss of the retinal tissue that becomes very thin and atrophic (geographic atrophy), which may worsen the vision loss.

Usually, both eyes are affected by AMD, although the degree may not be symmetrical. One eye may initially experience more damage, but years later the other eye may catch up. The same may be true with glaucoma. Patients with glaucoma also may have one eye more affected by the disease and, depending upon the form, they often speak of one good eye and one bad eye; but in many cases, glaucoma affects both eyes equally. In the earlier stages, many patients may not have any symptoms, but by examining the back of the eye and the retina, your doctor may be able to detect potential problems. Therefore, doctors recommend a dilated eye exam to determine if the disease is present in order to initiate necessary treatment that in real time could prevent vision loss.

Macular degeneration is characterized by two forms: dry and wet. The dry form is called atrophic macular degeneration and the wet exudative macular degeneration. There is a distinction between the two as to the severity of the disease. In the past, the wet form has been viewed as the most difficult to treat and this is still partially true; however, both dry and wet forms can lead to severe vision loss. Although the wet form tends to be more acute, as the loss of vision may occur more rapidly compared with the dry form, years later, the dry form revs up. Both forms are equally insidious.

The dry form may eventually in some cases convert to wet form. Everybody starts out with the dry form, for the wet form usually does not develop spontaneously. One out of every seven people develops the wet form from the dry form. Dry macular degeneration is divided into three stages: early, intermediate, and advanced. In the early stage drusen are identified, but many patients may be asymptomatic and have good vision. With progression into the later stages, more symptoms manifest. As of now, the medical profession cannot predict who will develop the wet form, but as genetic information expands and produces a body of research, scientists in the near future may be able to identify patients at risk.

Dry Form: Treatment

An effective treatment for the dry form does not yet exist and doctors cannot prescribe any specific medication. However, vitamin therapy can help for those patients who are in the intermediate stage of the disease. A large NIH study (AREDS; Age-Related Eye Disease Study) revealed that patients with intermediate AMD who were taking a particular set of vitamin supplementation had a 25% reduction in the rate of vision loss, thereby reducing the chances of their conditions worsening. In the intermediate stages, doctors recommend AREDS vitamin supplements as a means for reducing an affected patient’s chance of vision loss. Since treating a person in the primary stage is vital, doctors suggest that patients with a family history of AMD should have eye examinations.

Wet Form

The wet form is characterized by abnormal blood vessels that grow underneath the retina. These aberrant vessels can leak fluid and blood into the retina, leading to a harmful condition and hampering the functioning of the retinal tissue. Other factors also occur with the wet form. The retinal pigment epithelium layer becomes elevated due to choroidal neovascularization, a condition whereby new blood vessels start growing in the choroid. Over time a disciform scar can result from this condition resulting from a breakdown of blood; and although the fluid is eventually absorbed, the scar may leave irrevocable damage. At this stage of the disease, treatment is not yet available to reverse the process or to regenerate retinal tissue.

Treatment

There have been heroic efforts to treat the wet form before it reaches the point of no return. Previously thermal lasers were used to apply heat energy to the abnormal blood vessels in order to shrink or disperse them. This treatment, however, created a problem of heating and damaging the normal healthy tissue. Since no other treatment was available, doctors continued to use this laser to prevent further loss of vision, but vision was not improved.

The second wave introduced laser photodynamic therapy. This treatment was a bit more selective. It involved injecting a medication into the bloodstream that migrated to the areas where the abnormal blood vessels grew. A light targeted just that area, activating the drug to shrink those blood vessels. This treatment tended to be a little bit more specific, yet the results were not ideal. Further vision loss was prevented, but patients did not gain any vision. For many years doctors were frustrated by the paucity of therapies available.

About seven years ago, for the wet form of the disease, doctors introduced medications that could be injected directly into the eye, and vision improved. The two most common medications used prior to last year were Lucentis and Avastin, both made by the drug company Genentech. These medications are antibodies to a factor called vascular endothelial growth factor (VEGF) that stimulates the abnormal leaky blood vessels in the eye. The medications carrying the antibody target the factor and reduce the leakiness of the neovascular blood vessels. Avastin was originally approved to treat colon cancer, but retina specialists believed there was good evidence to suggest that Avastin injected into the eye would treat the above condition. The specialists began to use Avastin off label. At the same time, the drug company tweaked Avastin to make it smaller and more specific for macular degeneration. The FDA approved Lucentis to specifically treat wet AMD. Both drugs are similar and work equally well. The big difference is cost. Lucentis sells for $2000 an injection, whereas Avastin is about $50. This disparity in price reflects the need to conduct studies to gain FDA approval for Avastin and then, of course, to market the product, all of which occurred with Lucentis.

Injections were originally given monthly for two years. Presently doctors are experimenting with different protocols to reduce the treatment burden. The consensus is that the patient may not need as many injections as originally anticipated. With each case the doctor evaluates the progress of the treatment and then, based on the patient’s responses, recommends the course of treatment. Doshi suggested that most patients don’t need monthly injections for a lifetime. Following a given period of time, intervals between injections can be increased to every 3 or 4 months. Some patients need only a few injections to get the desired results. Of course each case is evaluated as to the ideal course of treatment, but some patients will still need monthly injections for two years or more. Fortunately, insurance companies cover the costs of both of these medications.

While insurance companies are pushing for the use of generic products wherever possible, Doshi explained that generics in this case are not yet available, since the medication is a biological antibody, targeting a specific factor produced in the body, rendering it more difficult to develop one of comparable generic quality. Apparently, also, the patent for these drugs is longer than for the other types of medications.

After a period of 3 to 4 months, some patients with an acuity of 20/100 may with treatment register 20/30. These results are not uncommon, for in many cases of wet AMD the treatment is effective. As with any chronic disease, to maintain the goal, it becomes necessary to continue the injections. If treatment is aborted, most patients will revert to the presenting status. However, for a subset of patients, the initial treatments are sufficient to halt the progress of AMD and these patients become free of the ravages of the wet form without the need of additional injections. As with any chronic disease, trial and error usually determine the ideal treatment.

Because of the large cost difference and the fact that the FDA approved Lucentis for macular degeneration but not Avastin, the ophthalmological community decided to design a trial, the CATT, comparing both drugs. The result scientifically established that both medications work equally well. This study was cheered among the doctors and patients using the drugs.

New Medications

Late in November 2011, a new medication called Eylea was approved by the FDA. The target remains the same – VEGF – the molecule produced in the eye. The premise is that this new medication binds more strongly with VEGF and therefore its effects last longer. In the Eylea trial, after an initial monthly dosing patients received injections every two months and still retained a good response. Eylea is probably as effective as the medications now used. The advantage may be that it could reduce the number of injections needed.

Unfortunately, for the advanced dry form, a similar treatment does not yet exist. This is the next frontier in the battle to reverse the incursions of the dry form. Fortunately, there are 10 to 12 different trials in progress examining the effects of newer medications. Some of the investigations, as with glaucoma trials, are examining newer strategies involving stem cells, transplanting retinal tissue, and different types of complement inhibitors. Hopefully, in the next 5 to 10 years, a new medication for treating the advanced dry form will be making headlines.

Nutrition

The vitamins suggested for AMD consist of A, C, E, copper, and zinc. These were the vitamins that were studied in the AREDS. In addition, there is additional evidence that lutein, omega-3s, and zeaxanthin also are helpful. Doshi and other retinologists usually recommend AREDS vitamin therapy either at the initial or the intermediate stage of diagnosis. At this stage the diagnosis is based on an evaluation of the size and number of drusen and pigment changes, despite the fact the patient may not complain of much visual loss.

The colorful fruits and vegetables rich in beta-carotene, lutein, and zeaxanthin such as carrots; summer and winter squash; corn; the deep green vegetables, including kale, collards, bok choi, and spinach; yellow fruits; and all the berries, especially blueberries, are examples of products beneficial to eye health.

Wouldn’t it be easy to inject these vitamins directly into the eye? Alas, at this stage, this technology is not available, but eating these fruits and vegetables nourishes the body, and the blood reaching the eye deposits nutrients to it. The AREDS formula provides high doses, some of which apparently reach the eye, but other formulas of comparable strength are acceptable.

There are studies in progress to determine if these vitamins are helpful for other eye diseases, but lack of current evidence obviates recommending them for patients with glaucoma or other retinal diseases. Nevertheless, Doshi thinks that taken appropriately, these eye vitamins are not likely to be harmful for non-AMD patients. In general, Doshi does recommend taking a recognized multivitamin known to have beneficial effects for general health.

Also, the AREDS2 trial is in progress. This study examines additional vitamin supplements such as lutein, zeaxanthin, and omega-3s. Those results will probably be available in a few years, but retinologists realize that patients are purchasing the AREDS2 supplements right now. Be sure to read the label to ascertain that lutein, zeaxanthin, and omega-3s are included. A prescription is not needed; the AREDS2 formula is available over the counter. Of course, in the supplement industry, as soon as a formula receives any publicity, many companies develop their own versions.

Low Vision Assistance

for those patients where treatment no longer can retard the advance of the disease, ophthalmologists recommend a low vision evaluation with the goal to maintain independence and ability to perform activities that patients have been accustomed to – in other words, continue with individual lifestyles. Ophthalmologists now routinely recommend visiting a low vision specialist, preferably an optometrist who can prescribe the tools needed for optimal functioning. These may range from magnifiers, stands, computers, large-print books and newspapers, and many other devices.

One device approved by the FDA is a telescope that can be implanted into the eye. Some patients with AMD who have not had cataract surgery may qualify for this new treatment. It consists of performing a cataract operation and, rather than a normal intraocular lens, a telescope the size of a pea is implanted. The image seen is magnified. This is an exciting area. Although Doshi hasn’t seen patients who have had this treatment, he expects that in the next few years this form of implantation may become more common and available. Go to the New York Eye and Ear Infirmary website and other websites for more information, or search online for “implanted telescopes” and find the entire history of the process from beginning to FDA approval. Of course, with any new device, further explorations in this field will become available.

References

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Dr. Vatsal Doshi
225 Millburn Ave, Suite 206
Millburn, NJ 07041

973-467-2020

vdoshi77@gmail.com

Edith S. Marks

Author: Coping With Glaucoma and Glaucoma: Patient to Patient

edithmarks@nyc.rr.com