Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in the aged population globally.1 In the UK, half of the total blind and partial sight registration results as a consequence of this condition.2
AMD is a complex multifactorial disease in that its development is due to a combination of causes including multiple genetic and environmental factors. It is usually sub-divided into dry (non-exudative) or wet (exudative or neovascular). Dry AMD occurs significantly more frequently and comprises 80-90 per cent of all cases.3
The incidence (of a disease for example) is defined as the number of new cases in a given population over an applied time frame.4 A recent study determined that there were approximately 150,000 new cases of patients with advanced AMD including geographical atrophy or neovascular AMD in the UK per year using population data from 2007 to 2009.2 The prevalence of these conditions (the total proportion or percentage of people in a population affected at a specific time) in the UK is 2.4 per cent of individuals aged 50 or over.5 This figure increases exponentially with age until 12.2 per cent are affected in the 80 years or greater age group.5
A significant increase in prevalence is predicted due to the increasing numbers of elderly (increasing by a third between 2009 and 2020).2 This means that with current treatment and eligibility criteria for wet AMD relevant numbers will continue to dramatically increase resulting in significant cost implications.
Variation in the prevalence of AMD related to ethnicity has also been shown by epidemiological studies indicating a greater occurrence in Caucasian populations compared to non-Caucasian.6 This may be due to underlying genetic and non-genetic influences.
Genetic factors of AMD
Different types of genetic studies have highlighted the association of several genetic variants (polymorphisms) in a number of genes with AMD.7 These variants are thought to contribute to at least 70 per cent of the total risk of developing the condition.7 One of these variants shown to have a strong association with AMD is in a gene for complement factor H (CFH).8 This compound has a role in a pathway known as the alternative complement cascade together with several other genes with variants more weakly associated with AMD. This is one of three pathways involved in the innate immune response, the non-specific fast acting aspect of the immune system. These pathways result in the formation of enzyme complexes (C3 convertases) that activate a protein (C3) triggering a single reaction chain culminating in amplification of the immune response.8
CFH has a key role in regulating the immune response by causing degradation of some of the complexes at different stages and inhibiting a positive feedback loop, hence dampening the resultant inflammation (Figure 1).9 Alteration to the gene coding for this compound results in a change to the protein’s chemical structure.8 CFH with the polymorphism associated with greater AMD risk is unable to bind as strongly to components of damaged retina (Bruch’s membrane). It is less efficient in controlling inflammation at the required site.10 The consequent inappropriate inflammatory response damages the individual’s own tissue and is thought to have a role in AMD development.
Non-genetic factors of AMD
Oxidative stress is thought to be another underlying factor in the pathogenesis of AMD.12 A consistent and significant association has been found between smoking which is known to cause oxidative damage and AMD. A number of reputable large-scale studies have shown that smokers have a significantly greater relative risk of developing AMD compared to non-smokers.13 Animal model studies have indicated that smoking may also result in the activation of the alternative complement pathway at the retina.10
Ultraviolet light and smoking result in the formation of intermediate chemicals called reactive oxidative species (ROS). These are also formed as by-products during metabolic processes. The high oxygen concentration and metabolic activity of the retina (such as in the mitochondria of retinal pigment epithelial cells) makes this tissue more prone to such changes. Oxidation by ROS can be inhibited by antioxidants. Usually there is a balance between ROS (which also have beneficial functions by influencing cell function and regulation) and antioxidants. If this homeostasis is tipped in favour of ROS activity, oxidative stress results.14 Uncontrolled these can cause tissue and DNA damage as well as cell damage and death (apoptosis).
Retinal photoreceptors and the retinal pigment epithelium (RPE) have a high concentration of phospholipids that are prone to oxidisation by ROS (as well as proteins and DNA). This results in the formation of abnormal oxidation products that are able to bind to surrounding protein. Their presence triggers the stimulation of increased macrophage activity as they are perceived by these cells as foreign. This cell type is involved in the innate immune response and releases various components that ultimately lead to inflammation and tissue damage.14,15 Macrophages can also present auto-antibiotics to T–cells to stimulate their production.14 This would be part of the adaptive or acquired immune response, the specific arm of the immune system. The role of this type of immunity in AMD is more theoretical, especially considering that there are no lymph glands within the eye, but has been supported by evidence from animal model studies.16
CFH usually binds to these oxidised phospholipids (significantly more so than with normal phospholipids) and regulates the resultant effects of oxidative stress such as the stimulation of macrophages and various inflammatory pathways.14 This binding ability of CFH of individuals with the at-risk genetic variant is considerably reduced.17
The function of the RPE is to maintain the photoreceptors by transporting nutrients, and removing metabolic waste products as well as old photoreceptor and RPE cells by phagocytosis.18 With increasing age this process becomes less efficient. Lipofuscin (lipoprotein aggregates) result from the phagocytosed contents. This is normally broken down by lysosomal enzymes within the RPE cell but accumulates to harmful levels as the efficacy of this reaction reduces. Toxic levels can result in the formation of ROS via lipid peroxidation and can result in further diminishing phagocytic function. This can ultimately result in RPE cell death.19 Lipofuscin has been found to stimulate injured RPE cells to secrete molecules called cytokines. Cytokines trigger the activation of various cells involved in the immune response potentiating the chronic inflammation associated with AMD.20
The effects of age on the metabolic processes can also result in the accumulation of extracellular metabolic products. These are known as drusen and are comprised of proteins (including components of the alternative complement pathway) and lipids that accumulate between the RPE and Bruch’s membrane (the acellular layer situated between the RPE and the choroid). They are visible as yellow retinal deposits during fundus examination. There are various types of drusen. At least one small, hard drusen is observed in most individuals in their 50s whereas large soft drusen (>125mm) with indistinct edges have a stronger association with advanced AMD development (Figure 2).21
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Many of the proteins involved in the alternative complement pathway have been found in drusen, supporting the theory of an inflammatory element contributing to AMD development.12 Oxidation aggregates have also been found in drusen, Bruch’s membrane, choroid and blood plasma of patients with AMD supporting the role of photo-oxidation and oxidative stress in this condition.
Antioxidant levels have been found to decrease with increasing age and this may be a contributory factor to the increase in prevalence of AMD with seniority. Certain antioxidants can be supplemented via dietary means. Patients with dry AMD may be advised regarding their diet and/or use of a multivitamin supplement if they are not doing so already. The AREDs study found that a supplement comprising vitamin C, vitamin E, beta-carotene, zinc and copper significantly reduced the progression rate and extent of visual loss of individuals with intermediate or advanced AMD over a given period of five years (Figure 3).22,23 It is important to check for contraindications. For example there is the link between high dose beta-carotene and the increased chance of lung cancer development in smokers so a supplement containing beta-carotene may not be advisable (consequently the manufacturers of many supplements on the market have taken this into account).22
Early AMD
The early stage of AMD is common but visual acuity is generally good (in the absence of co-pathology) and symptoms absent or mild. The features of early AMD are uniform regardless of whether it then develops into advanced dry or wet AMD. These include many small to a few medium soft drusen or abnormal pigmentary changes of the retinal pigment epithelium (RPE) that may include focal hyper and hypopigmentation.21 These changes alone do not usually impact retinal sensitivity.24
Fortunately only a small percentage of early AMD patients go on to develop the advanced form associated with significant visual loss.24 These individuals may develop either advanced dry or wet AMD.
Dry AMD
In dry AMD the number of soft drusen and pigmentary changes to the RPE may slowly progress (Figure 2). Coalescing of soft drusen can result in separation of the RPE from Bruch’s membrane. This leads to RPE cell apoptosis (cell death) and resultant RPE atrophy, depigmentation and loss of the dependent photoreceptors in this location.26 The area of RPE atrophy may gradually expand with development of clearly demarcated borders. This is geographic atrophy (GA) and a feature of advanced dry AMD. Regression of large, soft drusen present usually occurs prior to its development. GA initially develops in small areas around the fovea.1 It occurs in both eyes in over half of affected individuals often with symmetrical presentation.27
GA is also associated with thinning of the choroid with atrophy of the choriocapillaris increasing visibility of the larger choroidal blood vessels beneath, although ultimately these are also affected. Consequent reduction of retinal sensitivity corresponding to these atrophic zones results in visual field loss (paracentral scotomas).28 These areas may slowly increase in size and coalesce in conjunction with GA progression. As this occurs the likelihood of visual symptoms increases. These may include visual distortion (metamorphopsia), a symptom that may also occur with the onset of wet AMD.29 Patients may report difficulty with reading, especially in poor lighting conditions, (due to the scotomas and contrast sensitivity reduction) and increased illumination may help. Ocular adaptation may also be impaired when moving from dark to light areas and vice-versa and glare (from bright car headlights or sunlight for example) more noticeable.29,30
Tinted lenses may prove beneficial for use outdoors and even inside.29 Visual acuity may be unaffected as long as the fovea is spared.28
There is a small risk that individuals with GA may also develop choroidal neovascularisation (CNV). This is the abnormal growth of choroidal blood vessels (the hallmark of advanced wet AMD) in either the same or the other eye.20 These vessels develop from the choroidal blood circulation (choriocapillaris) and grow through defects in Bruch’s membrane into the sub-retinal space.
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Wet AMD
Alternatively, early AMD may progress to wet AMD. The risk of dry AMD progressing to wet over a given five years is between 14 per cent and 20 per cent.31 Visual loss in the wet form tends to be sudden and dramatic in contrast to the slow and gradual deterioration associated with dry AMD. Oxidation by UV light and ageing are also thought have a role in development of the wet form of AMD.32 Accumulation of the metabolic by-products mentioned previously together with activation of the complement pathway may trigger a cascade of inflammatory processes resulting in the over-secretion of a growth factor called vascular endothelial growth factor (VEGF) by the RPE.32,33
The uncontrolled expression of VEGF in wet AMD may also be caused by hypoxia in these individuals. Choroidal capillaries are sparse and reduced in size in wet AMD compromising blood supply. This change, together with age-related thickening of Bruch’s membrane results in hypoxia.29,32.
VEGF binds to specific receptors and its action with that of a number of other growth factors and enzymes stimulates the growth of immature vessels (choroidal neovascular membrane) in an attempt to reduce the hypoxia. These are fragile and fluid leakage or bleeding may occur underneath or within the retina. This results in sub-retinal and intra-retinal fluid accumulation or haemorrhages respectively and elevation and detachment of the RPE and/or neurosensory retina. If untreated neovascularisation can result in the development of fibrovascular (disciform) scarring. This is the final stage of wet AMD and nearly always involves the fovea.34 Resultant atrophy of the RPE and photoreceptors causes a central scotoma that significantly impairs the patient’s vision. A pink annulus can initially form around the active CNV. This indicates that blood is being diverted from the choroidal circulation to the CNV. As the CNV becomes inactive, this ring becomes atrophied and tends to dramatically increase in size over subsequent years significantly expanding the original scotoma.34
Conclusion
With an ageing population AMD is becoming more prevalent. Necessary progress is being made in the understanding of the numerous factors underlying this complex and common disease. What causes some people to go on to develop advanced AMD and why do some develop choroidal neovascularisation whereas geographical atrophy is observed in others? It is thought that oxidative stress and the immune system play roles together with inflammation and that modifiable factors have an influence, but the full story is not yet known (Figure 1).
A recent study has shown that the various genetic variants may each contribute to different stages of AMD, with some having a role in promoting the transitions from either the early to intermediate, intermediate to the advanced form (either CNV or GA) or both. Their analysis also took into account various non-genetic factors.35 They found variants in the genes CFH, ARMS2 (whose function is currently unknown) and the protein C3 in the alternative complement pathway had a role both in the progression of intermediate to large drusen and from large drusen to either CNV or GA.35
There are currently a number of tests available which test for various polymorphisms associated with the genes most strongly associated with AMD. Although people may be more ready to change modifiable factors in their lifestyle (diet, smoking, body mass index) if necessary to potentially reduce their risk or at least slow disease progression, there is currently no specific treatment currently available for dry AMD. Taking this into account, how would individuals react to a high-risk diagnosis following genetic testing and what management is required? Would there be a need for additional care such as counselling?36
As optometrists our role involves informing the patient about their condition. This includes advice on diet, supplementation, ocular protection with sunglasses when necessary and other modifying factors such as smoking. Communication about self-monitoring and the action to take when necessary is also important. The need for regular eye examinations should also be made clear. Unfortunately there is no current medical treatment for the dry form but prompt referral to the correct service (via fast track service if available) is mandatory to increase the likelihood of wet AMD treatment being successful.
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? Louise Stainer is a hospital optometrist at Optegra Eye Hospital, Birmingham