What is age-related macular degeneration (AMD)?

Age-related macular degeneraton (AMD) is a degenerative disease with a very high impact on the population, being the prime cause of legal blindness in people over 50 years of age. Furthermore, the incidence of AMD will continue to rise, since life-expectancy is ever greater, particularly in the developed countries.

30% of people of 70 years of age are affected by this disease in some form, while between 4-5% suffer from it in its more serious manifestations. If we add to this the fact that, until only a few years ago, almost nothing could be done to treat AMD, it is easy to understand the magnitude of this oustanding ophthalmological issue and the need to find an effective treatment in order to alleviate the suffering caused by the disease.


What types of age-related macular degeneration (AMD) exist?

There are many sub-types of the disease, but basically it takes two main forms: the wet or exudative type and the dry or atrophic type. Most cases of severe loss of vision are due to the wet forms of the disease, which give rise to hemorrhage and discharge in the layers of the retina, and in the most central part part of the retina; that is, the macula. Such hemorrhage is caused by small abnormal veins (the neovascular choroids) which invade the retina through its underlying layer (the choroids), and which finally destroy the delicate neural architecture of the macula (the most central part of the retina), leading to a loss of sight at the very centre of the visual field. This is the very fine and precise area of vision necessary for reading, face identification, driving, etc.. This disease in its final states does not cause blindness in the sense of total vision loss, but what remains is only peripheral vision – out of the corner of one’s eye - which is highly useful for walking properly without bumping into objects, but which is insufficient for the identification of finer details.
The disease in its dry form has a slower development and is less damaging; vision in small areas of the retinais gradually lost due to processes of cellular atrophy, which with time may coelesce and lead to loss of central vision.

First symptoms of AMD

One of the first symptoms of AMD may simply be a minor distorsion in the perception of straight lines (the horizon of the sea, a door frame, etc.). One may have a sensation of refraction, as of looking through water,or a small spot or opacity at the centre of one’s vision. On many occasions these symptoms may go unnoticed by patients, either because normal vision in one eye disguises the effects or because the patient ascribes them to other pathologies such as cataracts.
That is why it is highly recommendable, particularly for people of fifty years of age or over, to perform a simple test such as covering first one eye and then the other to check for good sight separately in either eye.

Revolutionary treatments for AMD

Over the years, and especially more recently, important scientific progress has been made in the treatment of the disease in its more serious forms, that is, its wet types, and these advances have revolutionized how it is dealt with as well as providing fresh hope for preserving the sight of our patients.

The first of these revolutionary measures was photodynamic therapy (consisting of a drug injected intravenously and activated in the affected veins by the application of a faint laser beam to the back of the eye). This enabled the disease to be treated when it affected the macula or centre of the retina, and was particularly beneficial for patients who until that time had had practically no alternative treatment. Nevertheless, its benefits were restricted to the alleviation of vision loss; in other words, loss of vision was still likely to occur, but at a slower rate than if the condition had gone untreated.This was no small improvement, but many of our patients still continued to experience progressive loss of vision.

The next revolution was the development of a treatment aimed directly at the activating mechanisms rather than attacking the tissue itself. The appearance of los antiangiogenic drugs enabled the “messenger” molecules to be inhibited. These are the molecules involved in the process of sending orders for the production of neovessels, so from the application of destructive treatments we were able to progress to the use of inhibitory treatments, thereby reducing undesired collateral effects.

This was the contribution of the first drug with these characteristics, pegaptanib sodium, which was administered directly every 6 weeks in the vitreous cavity; that is, by means of intra-ocular injections. Clinical trials also demonstrated a statistical improvement, although results still did not differ substantially from those obtained by photodynamic therapy: while the magnitude of vision loss could be palliated or reduced, many patients still continued to undergo loss.

Ranibizumab, the lastest revolution

At that time it seemed that the possibility of actually “gaining” vision was still utopian, except in a few cases. However, the results obtained with the next drug, ranibizumab, likewise administered intra-ocularly, and which had just been approved by the European Union, and therefore available in Spain, constituted the third and most significant revolution.

As soon as the results of the clinical trials with this drug were known, and for the first time in the history of treatment of age-related macular degeneration in its exudative or neovascular forms, the average number of cases of vision in patients treated in these trials began to rise.

The improvement from that time no longer consisted in the reduction of vision loss, but in the absence of vision loss, and even in many cases a definite recovery of sight. While previously only slight vision loss in between 60% and 70% of patients was considered to be a good result, this figure soon rose to 95%, and in 70% of cases no vision loss was recorded at all. At the conclusion of this research, vision levels in 40% of cases were held at above 20/40, which meant that 4 out of every 10 patients were able to drive, whereas at the beginning of the study only 1 out of every 10 could do so. Improvement was also achieved in 3 or more lines of vision in similar percentages, results which would have been unthinkable only a short time before.

These results were greatly welcomed by we in the ophthalmological community, who had grown accustomed to frustrationsin the treatment of AMD, and for many years had been testing different combinations in an attempt to improve the relative benefits obtained with photodynamic therapy and laser photocoagulation. However, despite the appearance of these results, we still had a long way to go before the drug became available, one or two years later.

It was then that something else unexpected occured: a new drug made its appearance, bevacizumab, which is also an antiangiogenic drug, but this time developed for the treatment of metastatic colon cancer, and which would subsequently be used to treat macular degeneration. Bevacizumab is a molecule similar to ranibizumab but which was not designed for intra-ocular use. Its systemic endovenous use in patients suffering from cancer, and who were also affected by age-related macular degeneration, was observed to bring about improvements in this latter condition. These findings prompted the endovenous use of the drug in the treatment of AMD, notwithstanding the appreciable risk involved in terms of systemic secondary effects.

This treatment proved to be effective, but it entailed a high price as regards the risk of serious cardiovascular complications in patients of advanced age. These considerations led to the use of this medicine directly within the eye itself, similar to the way in which pegaptanib or ranibizumab are administered, even though it had not originally been developed for this purpose. Its early use in this regard was carried out with great caution, but was quickly and widely extended, since its benefits, which closely resembled those of ranibizumab, soon became evident, exceeding the results obtained from the use of other available drugs, in spite of its compassive or “off-label” use, different from that for which it had originally received approval.

While access to ranibizumab has been unavailable, the use of bevacizumab, despite its theoretical or potential risks, has proved to be unequalled in hundreds of our patients, and has led us to change completely our protocols for the treatment of this disease. However, subsequent to the approval of ranibizumab for intra-ocular use, it not longer makes sense to continue to use an unapproved experimental drug such as bevacizumab.

Antiangiogenic drugs, especially ranibizumab, have revolutionized the approach to tackling AMD, as well as providing our patients with a good possibility of avoiding total vision loss.

Although much progress has been made so far, there still remains a long way to go. The next step consists in developing drugs with similar results of effectiveness, but with safer means of administration, such as intra-vitreous injections every 6 months instead of each month as at present, or transescleral liberation drugs, which would thereby obviate intra-vitreous injections and their associated risks. Drugs of this nature, such as VEGF trap and bevasiranib, are currently being researched, and we are shortly to perform phase III clinical trials on these products.
Genetic advances in AMD

There has also been great progress recently in knowledge regarding AMD, its risk factors and genetic predisposition. Slight alterations in specific genes have been identified that enable people particularly susceptible to developing the disease to be identified, as well as advances in knowledge regarding trigger factors and the root cause of the disease. This genetic data is the first step towards a near future in which we are likely to be able to tackle this pathology by genetically modifying both the risk factors and protective factors involved.

Furthermore, the treatment envisaged in the near future will consist of modifying either the trigger factors or the risk factors, or on the other hand manipulation of protective factors by means of genetic intervention.

Although much remains to be done, much ore can be achieved than what might have been imagined just a few years ago. This research has also shown, for example, that smoking constitutes a much greater risk in patients with certain genetic sub-types, and may aggravate both prognosis and the consequences of the disease.

Preventing AMD with vitamins and antioxidants

A further important aspect of this disease is prevention. AMD has been associated with oxidative tissue stress. This is reflected by the fact that while age is the prime risk factor, smoking is the second and gives rise to a very high concentration of free radicals, which increase the oxidative state of the body. In other words, smoking leads to aging of the tissues.

Much has been said recently about antioxidants and vitamins. In Ophthalmology we are fortunate to have at our disposal data obtained from very well designed epidemiological clinical trials, which have indeed shown statistically that certain eating and lifestyle habits act as protectors and reduce the risk of either developing the disease or of increasing it.

One of these clinical trials, carried out in the United States, is known as AREDS (Age-related Eye Disease Study). It was designed for research into the natural course of AMD and its risk factors, and has involved studies on almost 5,000 patients since 1992. It has shown that vitamin and antioxidant supplements (Vitamin C, Vitamin E, beta-carotene, zinc and copper) reduce the risk of suffering from the disease in its most serious exudative forms by 25%, and can prevent loss of vision by 19%. The beneficial effects lasted for quite a long time after the conclusion of the study.

There is also growing evidence of the protective role played in this condition by lutein supplements, particularly by omega 3 unsaturated fatty acids (DHA/EPA). Knowledge is also being gained of the different mechanisms involved in both blood vessel cells and in platelets, by means of which the omega 3 fatty acids produce an antiangiogenic, neuroprotector and anti-inflammatory effect at the microvascular level.

Early detection of AMD

Another crucial aspect of the fight against vision loss caused by AMD is early detection. Medicine places great emphasis on this point, but it is especially important in those degenerative diseases for which there is no cure and in which successful treatment consists in aborting their progression.

We now have at our disposal a drug called ranibizumab, which is highly effective in arresting the serious exudative types of AMD. However, in order to attain good final vision it is extremely important not to begin at a stage of advanced deterioration. Treatment must be started as soon as possible, since in this way many of our patients can continue to read and drive normally, as well as enjoying personal independence despite suffering from a serious disease that until a short time ago was most likely to lead to considerable loss of vision.

Fortunately, this area of Ophthalmology has benefitted from many advances over a very short period of time, and this progress has dramatically changed the hopes and expectations of our patients. Although much remains to be done before we arrive at total prevention, erradicating the disease by acting upon the genetic agents and defects that cause it, we are now able to provide new forms of treatment which yield highly favourable results in terms of vision, and which far exceed merely palliative treatments, which was the case until only a short time ago.