Age-related Macular Degeneration – Review and Current Concepts
Figure 1: Fundus Photograph of the Left Eye of a Patient with Dry Age-related Macular Degeneration
Figure 2: Fundus Photograph of the Left Eye of a Patient with Exudative Age-related Macular Degeneration
Figure 3: Fundus Photograph of the Left Eye of a Patient with End-stage Age-related Macular Degeneration
Note large drusen and non-central geographic atrophy.
Note subretinal haemorrhage below an area of retinal pigment epithelium clumping.
over the next two decades, the number of people affected by ARMD is predicted to rise as well.
Impact on Society
ARMD proves to be a major public health concern, not only because of its current and predicted increased prevalence, but also because of the disabling impact it has on those suffering vision loss as a result of advanced ARMD. ARMD has a dramatic impact on the elderly in terms of daily living and overall quality of life.6,7
Not only are visual
impairments associated with difficulty with activities of daily living, but also with increased risk of depression and accidental injury.8,9 In addition, significant occupational impairment may result from even mild visual impairment. Furthermore, elderly patients with blinding disease have a higher likelihood of multiple sensory impairments.10,11
Risk Factors
Risk factors for the development of ARMD include advancing age, light skin pigmentation, hyperopia, family history, smoking, female gender, hypertension, hypercholesterolaemia and cardiovascular disease.12–19
A massive body of research has been undertaken in order to elucidate the genetic and environmental interplay that leads to the development of various stages and phenotypic variations of the disease. The atrophic form of the disease is characterised by macular RPE alterations, the accumulation of lipofuscin and drusen, retinal pigment epithelial atrophy and degeneration of segments of the choriocapillaris.23,24
Pathogenesis and Clinical Manifestations The pathogenic basis of ARMD is diverse and complex, depending on the stage of disease.20–22
(see Figure 1).
Evidenced by a central subretinal fibrosis known as a disciform scar.
Drusen are classified by size, with small drusen considered to be <64µm, intermediate drusen 64–124µm and large drusen >125µm.24 Larger drusen may give rise to areas of RPE detachment, sometimes referred to as a drusenoid pigment epithelial detachment (PED). Larger-sized drusen, larger number of drusen, confluence of drusen and presence of soft drusen have been noted to be associated with more advanced atrophic as well as exudative forms of ARMD.2,29 Clinically, patients with less-severe atrophic macular degeneration most often have few symptoms. However, with the presence of central geographic atrophy, patients can have severe vision loss and central scotoma (blind spot). Exudative (or wet) macular degeneration is characterised by formation of choroidal neovascular membrane, which occurs when fibrovascular tissue begins to grow from the choroid through Bruch’s membrane, thereby destroying the architecture of the overlying RPE and outer retina. Patients present with variable degrees of metamorphosia (perception of straight lines appearing wavy), decline in visual acuity, or scotoma. Clinically, examination reveals presence of intra-retinal or subretinal fluid; haemorrhage 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 neovascularisation 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 remains to be completely elucidated.30
It is thought that
Perhaps the earliest sign of the development of ARMD is the presence of macular drusen, or lipid-rich material with various amounts of collagen fibrils that accumulate at the level of the sub-RPE and Bruch’s membrane25
Pigment changes early in the disease consist of more focal areas of RPE hyperpigmentation and areas of non-contiguous, mottled depigmentation. Histologically, this represents atrophic areas of RPE overlying drusen deposits.26
As atrophic macular degeneration
progresses, extensive areas of RPE and retinal atrophy ensue, leading to the late stage known as geographic atrophy. This stage is characterised ultrastructurally by RPE loss and damaged photoreceptors in association with abnormal distribution of opsins in degenerating cells,27 overlying thinning of the neurosensory retina.28
with Segments of the choriocapillaris underlying the degenerating RPE also become atrophic. EUROPEAN OPHTHALMIC REVIEW
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
focal defects in Bruch’s membrane and oxidative stress may contribute to the pathophysiological development of choroidal neovascularisation. 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
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