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Understanding Macular Degeneration

It is important for you to understand the different stages of Macular Degeneration, from its early stage beginnings of the dry form, which can be very mild at first. For some, this starts a progression to geographic atrophy, the end stage of the dry form. Then, in about one in seven people, abnormal blood vessel growth leads to the wet form of the disease, a more damaging, late stage Macular Degeneration which may lead to scar formations, called discaform scarring. For a more detailed description of these stages, you may call and ask for an excerpt of our last news journal, Vol. 4, No. 2, or go to our web site at: www.maculardegeneration.org and click on “age-related.”

It is important to understand these different stages of Macular Degeneration to help you better understand your own situation, what stage of the disease you may have, and help you better formulate questions for return visits to your doctor. Also from our last issue, we received many calls and letters from people thanking us for this new information — that they did not fully understand their dry Macular Degeneration could some day turn into wet. They also better understand why using the Amsler grid is so important, and why they should not “give up” in using this test. Calls also came from persons who have had the wet form of macular degeneration and did not fully understand that they could have more recurring episodes of abnormal blood vessel growth in the future, now also using the Amsler grid to be on the look-out for another potential problem.

If persons are diagnosed with the early form of Macular Degeneration, usually they are simply told that nothing can be done to reverse the situation or to halt its progression. Patients are often encouraged to take anti-oxidant vitamins, protect their eyes from the sun by wearing 100% UV protection sun-glasses, as well as a visor or hat to block out more of the sun’s rays, and to test themselves frequently using the Amsler grid.

Should any worsening of the disease from abnormal blood vessel growth under the retina occur, this Amsler grid chart is one way to test each eye individually to determine if there are any squiggly lines or distortions in the grid that were not there previously. These “new” squiggly lines or distortions in the grid may be a sign that abnormal blood vessels are starting to grow, thus turning from the dry form to the wet form.

As stated in our last news journal article, the progression of dry varies between individuals, with vision loss occurring more quickly in some than in others as the tissue in the macula degenerates. As it was also stated, when a person with dry Macular Degeneration loses most of their center vision, this central spot or degeneration is called geographic atrophy. This area of tissue in the center of the retina, which has degenerated, leaves the patient with a loss of most or all of the central vision.

One new study for patients with geographic atrophy is called the Guard Study. Patients in this study will be given a high concentration of an anti-oxidant called glutathione. By giving patients high concentrations of Thione, the anti-oxidant level in the patient’s blood will increase. Early findings suggest that the progression of geographic atrophy can be slowed down. Usually in geographic atrophy the monitoring of the progression is predictable, so its slowing or halting can be easily measured.

Early investigations looking at pharmacological agents that are not themselves anti-oxidants, but may help by stimulating their synthesis in the cells or that also protect with other mechanisms in cells, are also being studied. These “inducers” of anti-oxidants are at the early stages of research, but interestingly enough the help may come through food additives or foods like apples, broccoli, oranges, and other fruits and vegetables. Over the years many persons who have said they believed certain nutrients like lutein, zinc and the herb ginkgo biloba and others have helped slow their progression. Because there has not been a specific clinical trial for some of these agents, it will be difficult to predict who might benefit from them, or whether any of these agents actually helped at all, or if another factor helped slow the progression.

Obviously, more studies need to be done in these areas to get more definitive answers. Also, persons need to be aware that if they are taking certain vitamins and/or supplements they should keep in close contact with their doctor, especially if they are on several medications. The idea that “more is better” should be avoided. Large quantities of supplements may be harmful in certain circumstances and caution should be taken so as not to over do it with the quantity and varieties of supplements.

C.A.P.T. Trial

Another study for the dry form that you may have heard about is called the Complications of Age-related macular degeneration Prevention Trial (CAPT). In this trial, researchers in many centers across the United States are using a very light (sub-threshold) laser to burn in the particular pattern throughout the retina in the hope that the drusen can be affected and made to go away. The aim of this treatment is to protect or prevent the progression of vision loss or to keep the progression of the dry form from going to the wet form of macular degeneration. Early studies have shown that by doing this light laser treatment, drusen can be made to disappear. What is not known however is whether this outcome will actually slow the progression of Macular Degeneration. This is what needs further study.

In this study, a patient will have treatment only in one eye as the basis for a comparison. In some centers, patients have measured better vision on the eye that was treated. Interested candidates need to understand that treatment will only be performed in one eye since they will need to measure each eye’s rate of progression during the length of the study to learn what benefits this procedure may offer. Because of its category as a clinical trial, some patients who notice a difference in the treated eye may be frustrated by not being able to receive treatment in the other eye as well.

The Wet Form of Macular Degeneration

As we have outlined in our last two news journals, treatment for the wet form of Macular Degeneration is aimed at stopping the growth of abnormal blood vessels under the retina. Treatment, however, is not a cure. It is a way to hopefully halt or slow the progression. Additionally, as in conventional laser treatment, it may even cause damage to the healthy cells of the retina. One needs to remember that conventional laser treatment is a double-edged sword in which the use of the laser can help halt or prevent further vision loss, yet at the same time it can cause damage to the healthy portions of the retina. Studies have shown that those who do not receive conventional laser treatment continue to get worse and after 18 months usually show more severe deterioration than those who receive conventional laser treatment.

As we have also stated, these new blood vessels also grow towards the center from the sides of the eye. Conventional laser surgery is still the main treatment option and is used especially when these blood vessels are to the side of the macula, stopping these leaky blood vessels and sparing the vision in the center. When the laser is used in the center, despite damage to the macula, it has been shown that for some patients this approach yields better results than not treating these vessels, leading to significantly worse consequences than the damage of the small laser spot.

The other new treatment that you have heard about is sometimes called the Visudyne treatment, better known as photodynamic therapy or PDT. PDT is for the early stages of the wet form only and only for the classic type of neovascularizations (new vessels). For persons who have had the wet form for a long period of time, photodynamic therapy may not be of help unless he or she has had recent or new recurring blood vessel growth of the classic type.

Remember, if you have had wet Macular Degeneration in the past there is always a chance for a recurrence of blood vessel growth. There are two types of abnormal sub-retinal blood vessel growth: classic or occult. The classic type is well defined and easier to treat. The occult type is not very well defined and usually not treatable. If the doctors tell you that you have the wet form, ask what types of vessels are growing under your retina. Are they small or large? Are they classic or occult? Are they a combination of the above? Has the wet form caused a scar to form? Once these abnormal vessels reach their end point, a formation called a discaform scar is found in the center of vision. This is the end stage of the wet form of Macular Degeneration and unfortunately can no longer be treated. Again, even though someone has a discaform scar, they still should be on the lookout for future occurrences of abnormal vessel growth (50% of persons have reoccurring vessels within three years).

Combination Treatments

As we mentioned in our last news journal, photodynamic therapy is now a treatment option for persons with early stages of wet Macular Degeneration, especially those with classic neovascu-larization. Because blood vessels usually grow back, especially in the first year (approximately every 3 months), patients have to go back for a re-treatment. Clinical trials are now underway for combination treatments where photodynamic therapy is used in conjunction with anti-angiogensis drugs or steroids to stop vessel regrowth. These combination therapies are aimed at limiting the number of treatments for regrowth. It is interesting to note that patients who have had photodynamic therapy received approximately 4 treatments (averaging based on information from clinical trials). However, the second year patients did not need as many treatments, averaging 2 treatments instead of 4. Also, some patients who were in the initial clinical trials for PDT and are well into their third year have had no need for re-treatment. Researchers are not sure why these blood vessels are seeming to stop by this third year, but strong evidence shows no recurring growth at these later stages.

Other Approaches

Other approaches also being studied to thwart the growth of abnormal blood vessels, such as radiation therapy, are also borrowed from cancer research . The goal of radiation therapy, as with PDT, is to stop the progression of blood vessel growth under the retina. This approach has been tried and studied for many years now with somewhat limited success. Now that clinicians better understand just how much radiation is too much and that it could lead to radiation retinopathy or radiation optic retinopathy a year or two after treatment, people today receive smaller and safer amounts. Yet, are these amounts really enough to be effective? Currently several studies in progress suggest that some patients can benefit from a high dose of radiation without being harmed. More studies need to be done in order to understand which patients best fit this criterion.

Occult Vessels

Now that we better understand that photodynamic therapy and combination therapies may be the best treatment for classic neovascularization, what about patients who show only occult vessels? As we mentioned in our last news journal, a new procedure called transpupillary thermotherapy, or TTT for short, is being studied and even used by some clinics. In this approach, doctors are using a low-grade thermal energy to heat these occult vessels. Unlike the conventional laser, which damages the healthy tissues, this thermal energy seems to be safe. Its approach is that this thermal energy is used at safer levels over a longer period of time. Initial studies show that this low-grade energy will “cook” these occult vessels and stop their proliferation. Now a multi-center clinical trial has begun to study the further effects of TTT for occult neovascularization. Because TTT is still considered an “experimental therapy,” patients should be notified of its current status — that is, there is no medical proof that TTT should be used.

Gene Therapy

Only in the last two years have scientists and researchers working with new advances in technology begun a development of introducing new genes into human cells for the treatment of a disease. The approach can be to replace or remove a defective gene or to introduce a new gene that will stimulate the cell not to die but to begin to function properly again.

In order to do gene therapy, the abnormal genes must be identified. For Macular Degeneration there are genes that have been known and discovered, yet there are still many unidentified genes that probably cause the disease. Secondly, there has been significant progress in how to introduce the new gene into the retina. The new gene must be introduced into the retina via a virus called a vector, which delivers the new genetic information into these cells. This vector not only has to deliver the genetic information but it must do so for a long period of time. For someone with Macular Degeneration, this genetic information would need to be delivered for the rest of the person’s life.

Another difficult question involves controlling the amount of genetic materials once the vector is inside the cell - too little may have no effect and too much may harm the cell. This is a challenge requiring further investigation.

There are several types of gene therapy — one called gene replacement therapy involves the substitution of a healthy functioning gene for the defective gene that is not producing a certain required protein in the eye. Another approach is a genetic therapy that introduces a growth factor into the cell to keep the cell alive. A third type is replacing a gene that produces toxic chemicals with one that functions properly. There are also several other types of genetic therapies being done for other retina diseases besides Macular Degeneration. These therapies will help researchers understand how to intervene early in a variety of retinal diseases.

These gene replacement therapies are still not being performed in humans; however, scientists are getting closer to answering the question of when human trials can begin. Studies using animal models are now underway in several parts of the world.

Cell Transplantation

Over the last eight years there has been a lot of work on and attention paid to cell transplantation within the retina. Much of this research in its early stages failed to show what many of us were looking for - helping to regain lost vision. But there were many good lessons learned about working on the retina and now there is still hope towards the future in cell transplantation.

There are two main approaches in cell transplantation. One, prevention, catching the disease at its early stages to preserve tissue. Two, replacement, actually replace degenerated tissue.

Some of the problems involved in cell transplantation involve safety issues — including assurances that infections from the donor tissue do not transfer to the recipient. Secondly, the tissue historically that has been used is immature. Past studies indicate that immature cells (fetal cells) have been most successful. This creates ethical and moral dilemmas as well as logistical problems since the demand for immature tissue would far exceed its availability. Thirdly, recipient rejection would be another complication which would require the recipient to take immunosuppressive drugs (poorly tolerated by the elderly).

Preventive Model

One of the recent approaches that work under the preventative model is called macular translocation surgery. This surgery involves placing healthy RPE cells in the affected area of the macula, thereby sparing vision, in other words, by moving the retina on top of the healthy tissue and away from the diseased area. This surgery, which we have highlighted in past issues of Around the Edges, is still very invasive, still somewhat experimental, and only being performed in one or two centers in the U.S.

There were also initial studies done in trying to transplant tissue from a person’s own eye, that is from the side of the retina to its center where it is needed. Current studies for treatments for retinal disease do not include this method.

Another approach being researched to prevent loss of tissue involves introducing growth factors in the environment where the cells live, so that even though the cells are not functioning properly the growth factors will help “kick start” them again into working properly, thus preserving vision. Although this can be done in the laboratory, this is not a practical solution for patients to need to return for numerous injections of growth factor over a lifetime.

One final group has also tried another new approach by using cells in the sheath around nerve fibers in the body called Schwann cells. These sheaths around nerve fibers produce natural growth factor. If these natural growth factor manufacturing cells can be implanted into the diseased retina (where these cells do not normally exist), they may indeed preserve tissue. In early experiments, this approach seems promising in keeping tissues healthy and preventing them from degenerating.

Replacement Model

For many people who already have Macular Degeneration, the great hope, yet a much more difficult and complicated solution, is that new cells can be transplanted into the retina where there are no longer any cells functioning. These light sensitive cells called photoreceptor cells must not only lay flat on the host retina, but must make many intricate connections in order to have functional vision. If the connections are not made, even though the cells still remain healthy, a person would not regain any vision.

One group has tried to take sheets of immature cells and transplant them into a host retina. This approach is fairly new, and it is too early to tell its success.

A second group has transplanted mature retinal cells into animals and has had some initial success in getting the cells to connect properly.

A third group has a new approach in helping to replace poor RPE cells in the retina by taking pigment cells from the iris (the colored part of the eye) and replicating them by growing more cells in the laboratory and then inserting them into the damaged pigment layer in the retina. These pigment cells have some of the same qualities as the pigment cells needed in the retina to keep the tissue healthy. This particular study, being done in Japan, has not yet published data on its findings. To date, we do not know if the final outcome will be useful.

A fourth group is researching in conjunction with a new biotech company how to take a donor eye and use the tissue, while keeping out infection and preventing any problems, yet multiply itself many times. If successful, this approach will be able to help tens of thousands of people from only one donor eye.

The most likely hope of cell transplantation is in the new area of stem cell therapy. Stem cells, which can be found in a matured state (thereby not having to use fetal tissue), may be a way to get a breakthrough in this area of retinal cell transplantation. Progress has been made in finding stem cells that can be used in the retina, although there are many factors that need to be studied in understanding how or if these cells will work.

At present, all of these studies are precursors to having human eye (retinal) transplants for prevention or replacement. Many of these studies are steps in the positive direction and now with the use of animal models, they can be tested for safety and effectiveness before going into the human realm.

Artificial Vision — Implantable Devices

There have been media reports over the last year or so which lead persons to believe that a chip could bring vision to Stevie Wonder and many blind people. The area of implantable devices is making progress. This may not mean help within the next five years, but soon after, it could mean breakthroughs for those who are blind. There are several groups around the world studying artificial vision which include a retinal chip, a chip on the surface of the retina, or a chip on the underside or sub-retinal space, as well as others who have continued to work on electrode implants in different layers of the visual cortex of the brain. These devices called visual neuroprosthetics may not bring 20/20 vision to people; however, they may give blind persons a way to function independently whether traveling around the city or even seeing enlarged words on a computer screen.

Despite media reports on the progress of retina chips, there still is a lot of work to be done in getting a retina chip to work properly for a human to gain vision. Some of the problems include getting the chip to stay in place for a long period of time (as you can imagine there may be some people who would need a retina chip for 30, 40, or 50 years). Secondly, being able to have a complex array of electrodes lined up and functioning with inner connection to the retina has still not been developed.

Other complications can occur as well. The body may detect the chip and cause the retina to form a scar (common in many eye conditions). There have been other scientists who have been working for many years on the idea of stimulating the surface of the visual cortex in the brain in order to get a response such as a flash of light from an electrode. Last year Dr. Dobelle from the Dobelle Institute made the news with a blind patient that he had been working with for over 22 years in stimulating the visual cortex with limited success. Other groups including the University of Utah are taking a similar approach but using other stimulating methods deeper within the tissue of the brain with much less energy and current to stimulate the visual cortex. They worked diligently in studying how many actual pixels or electrodes need to be stimulated in order for someone to function with ambulatory vision. Results so far look very promising although much work still needs to be done. In order to move some of this technology from the laboratory into the clinic and use in human trials, the National Institutes of Health have helped to fund the launching of a company called Second Sight located in California which hopefully will drive this technology into the market place much quicker, bringing more positive and quick results for many.

It is important for people with Macular Degenration to understand that those individuals with good remaining peripheral vision would have much greater visual capacity than the vision provided by these new technologies. However, these implants in conjunction with special camera-like glasses could provide someone with macular degeneration the capability to read in the future.

For more information on clinical trails offered for Macular Degeneration patients, visit The Foundation's website at www.blindness.org/disease/clinictrial_detail.asp?id=13&type=2


For more information on Macular Degeneration,
visit The Foundation Fighting Blindness at www.FightBlindnesss.org
or e-mail us at MDInfo@blindness.org.

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