Age-related Macular Degeneration (AMD)
In industrialized countries, Age-related Macular Degeneration (AMD) is the leading cause of severe and irreversible loss of vision in subjects over the age of 65. This diseases affects the central part of the retina, known as the macula, which is responsible for high-resolution vision.
A recent research project, which encompassed three studies carried out on different countries and with a large sample population, has found AMD to be present in 0.2% of the population between the ages of 55 and 64, and 13% of the population over the age of 85 (Smith 2001). Due to increasing life expectancies and the rarity of AMD in people of African descent (Friedman 1999, EDPRG 2004), this pathology predominantly affects industrialized countries, especially in the West.
AMD is generally classified as follows: initial, and advanced (neovascular or exudative – wet AMD – and atrophic), to indicate different and progressively more severe stages, including increasing loss of vision, of this disease. Patients with early AMD have lesions on the retina, such as drusen, and areas affected by pigmentary alterations (mostly hyperpigmentation), but almost always maintain a good level of visual acuity. Advanced or neovascular AMD leads to severe loss of vision, and the formation of a central scotoma (missing area of vision) leading to neovascularization in the vicinity of or at the centre of the macula. These newly-formed blood vessels come almost exclusively from the choroid and cause the formation of a fibrovascular scar that destroys the central retina. The other advanced form of AMD is known as atrophic AMD (so-called central geographic atrophy), with atrophic changes in the retina and the choriocapillaris in the macula. Less frequently, geographic atrophy can lead to the sudden and complete loss of vision. Most available treatments aim to prevent or cure neovascular AMD, but as of yet there are no proven treatments for geographic atrophy.
Currently known risk factors, in addition to age, include: cigarette smoke (smokers are 3 times more at risk than non-smokers), family history (the risk is 4 time higher in family members of AMD patients), gender (higher prevalence in women), race and ethnicity (higher prevalence in Caucasians), refractive error (for every diopter of hyperiomia, the risk of developing AMD increases by 5%), iris colour (eyes with melanin-rich, well-pigmented dark irises seem to be more protected from light-induced oxidative damage), cataracts (subjects with a history of cataract surgery have a statistically significant higher risk of development or progression of advanced AMD), high blood pressure, alcohol consumption, and exposure to sunlight.
Macular degeneration is diagnosed through an evaluation of the subjective symptoms reported by the patient, the observation of characteristic lesions during the ophthalmoscopic examination of the ocular fundus, and through proven imaging techniques such as fluoroangiography (FAG), idocyanine green angiography (ICG) and optical coherence tomography (OCT). Each one of these methods makes it possible to identify the specific characteristics of each lesion type, their characterization, and their monitoring over time. They are this also extremely useful in assessing the efficacy of the chosen treatment.
The main symptoms of macular degeneration include distorted vision (metamorphopsia), a central scotoma (missing area of vision), reduced visual acuity (often associated with altered colour perception), and often the perception of objects as smaller than they really are (micropsia).
Distorted vision is often the first and most alarming symptom of macular degeneration; it can also be a warning bell for the re-activation of an existing lesions in macular degeneration patients. It is thus useful for patients affected by initial AMD to take a self-administered Amsler Test (Fig.1), an easily performed examination that can pinpoint the onset of these symptoms and monitor them over time.
The exam consists of placing a grid 30 cm from the test subject’s eyes. The test subject must then look at the grid wearing their best corrective eyewear for reading. After covering one eye with their hand, the test subject must look at the black dot in the centre of the grid. If the surrounding lines look wavy, deformed, or discontinuous, the test subject must immediately consult their ophthalmologist.
Treatment of Age-related Macular Degeneration
Prevention is without a doubt the first step in the treatment of macular diseases. The AREDS (Age-Related Eye Disease Study) has highlighted the efficacy of high doses of anti-oxidants and zinc in reducing the risk of advanced AMD in patients with drusen in both eyes, or affected by advanced AMD in only one eye.
For some years now we have witnessed the increasing use of anti-angiogenic drugs in the treatment of these morbid forms. These drugs act by inhibiting VEGF (Vascular Endothelial Growth Factor), a growth factor behind the development of the neovases responsible for the most advanced and aggressive forms of the disease, thus preventing its growth. There are currently three drugs that have been approved and reimbursed by international clinical trials: Pegaptanib (Macugen®), Ranibizumab (Lucentis®) and Aflibercept (Eylea®).
Pegaptanib sodium is an aptamer with three-dimensional conformation that binds with high affinity and specificity to the isoform 165 of VEGF inhibiting its activity.
Ranibizumab is a fragment of intravitreally administered monoclonal antibody also able to bind to all isoforms of VEGF in extracellular space.
Aflibercept, the latest anti-VEGF, is a soluble fusion protein obtained by combining encoding DNA sequences in the second domain of the human receptor VEGF 1 (VEGFR1) and the third domain of the human receptor VEGF 2 (VEGFR2), both merged with the constant region of human IgG1. Eylea acts as a soluble "trap" receptor, which binds VEGF-A and PlGF with a greater affinity than its natural receptors and can therefore inhibit the binding and activation of these receptors with VEGF, preventing neovascularization of the retina and choroid, as well as the formation of edema.
Avastin (Bevacizumab) is the monoclonal antibody molecule from which comes the smallest fragment of Ranibizumab. This substance antagonizes all biologically active isoforms of VEGF and is currently used for neovascular DMLE, even if with off-label procedure that can only be carried out in public hospitals.
Photodynamic therapy was one of the first therapies used to treat neovascular AMD, and it continues to be used to this day, particularly for treating classical forms and chorodial neovascularization in subjects affected by high myopia. This method is based on the selective destruction of walls of the newly-formed vessel through the photochemical activation of a substance injected into the system, theVerteporfin(Visudyne ®).
Photocoagulative thermal laser therapy
This therapy is used only for the treatment of certain forms of macular degeneration, intended solely when the lesion appears to be located outside the central part of the macula (neovascularization and extrafoveal).
In recent years, certain surgical techniques have been used on patients with exudative macular degeneration, particularly macular translocation and submacular surgery.
Due to the high risk associated with these techniques, and the difficulty of the surgical procedures, they are unlikely to enter into widespread use for the treatment of these pathologies, even if future trials conducted on selected patients were to demonstrate their benefits more convincingly.