Posterior Segment Age-related Macular Degeneration
Figure 3: Fundus Photograph of the Left Eye of a Patient with End-stage Age-related Macular Degeneration
Subsequently, genome-wide linkage analysis led to the identification of several candidate genes.36,37
and 16 have been identified by several genome-wide scans.38
Complement factor H polymporphism variant on choromosome 1 has a significant association with various stages of ARMD.39–41 Interestingly, this resides within a binding site for cross-reactive protein and is an important regulator of various aspects of the complement cascade. The polymorphism is significantly associated with both neovascular ARMD and geographic atrophy, as well as conferring a higher risk of bilateral disease. More recently, an additional locus on chromosome 10q LOC387715 that confers an independent risk of ARMD has been identified.42
The apparent
importance of genes involved in the complement cascade has led to further studies and identification of several additional candidate genes, including complement component 2.43
Evidenced by a central subretinal fibrosis known as a disciform scar.
retina. Patients present with variable degrees of metamorphopsia (perception of straight lines appearing wavy), decline in visual acuity, or scotoma. Clinically, examination reveals presence of intra-retinal or subretinal fluid; hemorrhage at any layer (pre-, intra-, or subretinal or sub-RPE); RPE detachment; and/or presence of lipid (see Figure 2). The end-result of untreated neovascularization is fibrotic scar formation, known as a disciform scar, with permanent central vision loss (see Figure 3). Fluorescein angiography, indocyanine green angiography, and optical coherence tomography (OCT) imaging are used to aid in the diagnosis of exudative ARMD.
The specific cascade of events that leads to this wet form of ARMD is complex and continues to be completely elucidated.30
It is thought that
focal defects in Bruch’s membrane and oxidative stress may contribute to the pathophysiologic development of choroidal neovascularization. Furthermore, upregulation of pro-angiogenic factors such as VEGF and platelet-derived growth factor (PDGF) or the downregulation of anti- angiogenic factors such as pigment epithelial-derived growth factor (PEDF) or endostatin are known to play a major role in the process, and now serve as possible therapeutic targets in the management of exudative ARMD.31,32
Although several biologic predispositions are known to exist and continue to be uncovered, the risk and development of ARMD has a highly complex and multifactorial etiology. As we begin to further understand the pathogenesis of the disease more clearly, there appears to be a variety of genetic risk factors that are then modified by environmental risk factors to result in a final common pathway with variable ocular manifestations and phenotypic expression.
Therapy
Dry (Atrophic) Age-related Macular Degeneration Current therapy of atrophic ARMD revolves around vitamin supplementation to reduce progression. This is compounded with the patient’s overall risk assessment, patient education, avoidance of cigarette smoking, regular follow-up examination schedule, and home monitoring by the patient for new metamorphopsia or scotoma with the aid of an Amsler grid.
The Age-Related Eye Disease Study (AREDS) developed a grading scale for macular degeneration and evaluated the benefit of zinc and antioxidant therapy for preventing vision loss in various stages of AMD.44,45
Thus, the major event seems to be a disruption in the balance of pro-angiogenic and anti-angiogenic factors. The initiating event in this process remains elusive and is likely diverse. Many soluble factors such as VEGF, hypoxia-inducible factor (HIF), fibroblast growth factor (FGF), PDGF, insulin-like growth factor (IGF) and many others have been shown to have pro-angiogenic properties.30–33
Additionally, there is
recent evidence showing that drusen or their components may have some pro-angiogenic effects.34
Genetic Factors
Recently, genetic factors have been investigated, and several candidate susceptibility polymorphisms have been identified. An association with variation in fibulin 5 was demonstrated in patients with ARMD.35
98
Patients with intermediate ARMD (defined as a few intermediate or at least one large drusen, or non-central geographic atrophy) or unilateral advanced ARMD (vision loss secondary to ARMD in one eye) were found to benefit from a supplement of antioxidants (500mg vitamin C, 400IU vitamin E, 15mg beta carotene), and zinc (80mg zinc oxide and 2mg cupric oxide to prevent zinc-induced anemia). Results from AREDS showed that those with intermediate or unilateral advanced ARMD who received the above combination of supplements had a 25% risk reduction in the progression to advanced AMD as well as a 19% risk reduction in rates of moderate vision loss (loss of three or more lines of visual acuity) at five years. AREDS 2 is currently under way examining the possible added benefit of lutein, zeaxanthin and omega 3 fatty acids on ARMD progression.
Wet (Exudative) Age-related Macular Degeneration Neovascular ARMD has been a historically challenging disease to treat. Early treatment modalities included laser photocoagulation to well- defined areas of extrafoveal or juxtafoveal choroidal neovascularization. Subfoveal lesions were poor candidates for laser photocoagulation, given
US OPHTHALMIC REVIEW Polymorphisms on chromosomes 1, 2, 3, 10,
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