Elsevier

The Lancet

Volume 392, Issue 10153, 29 September–5 October 2018, Pages 1147-1159
The Lancet

Seminar
Age-related macular degeneration

https://doi.org/10.1016/S0140-6736(18)31550-2Get rights and content

Summary

Age-related macular degeneration is a leading cause of visual impairment and severe vision loss. Clinically, it is classified as early-stage (medium-sized drusen and retinal pigmentary changes) to late-stage (neovascular and atrophic). Age-related macular degeneration is a multifactorial disorder, with dysregulation in the complement, lipid, angiogenic, inflammatory, and extracellular matrix pathways implicated in its pathogenesis. More than 50 genetic susceptibility loci have been identified, of which the most important are in the CFH and ARMS2 genes. The major non-genetic risk factors are smoking and low dietary intake of antioxidants (zinc and carotenoids). Progression from early-stage to late-stage disease can be slowed with high-dose zinc and antioxidant vitamin supplements. Intravitreal anti-vascular endothelial growth factor therapy (eg, ranibizumab, aflibercept, or bevacizumab) is highly effective at treating neovascular age-related macular degeneration, and has markedly decreased the prevalence of visual impairment in populations worldwide. Currently, no proven therapies for atrophic disease are available, but several agents are being investigated in clinical trials. Future progress is likely to be from improved efforts in prevention and risk-factor modification, personalised medicine targeting specific pathways, newer anti-vascular endothelial growth factor agents or other agents, and regenerative therapies.

Introduction

Age-related macular degeneration (AMD) is a disease that affects the macular region of the retina, causing progressive loss of central vision.1, 2 Early-stage AMD includes clinical signs such as drusen and abnormalities of the retinal pigment epithelium. Late-stage AMD can be neovascular (also known as wet or exudative) or non-neovascular (known as atrophic, dry, or non-exudative). Late AMD results in loss of central visual acuity, leading to severe and permanent visual impairment and legal blindness, which has a major impact on quality of life and functional independence. By 2020, the number of people with AMD globally is expected to be around 200 million, increasing to nearly 300 million by 2040,3 thus posing a major public health problem with substantial socioeconomic implications. Although AMD remains the third leading cause of severe irreversible vision loss worldwide, legal blindness and visual impairment have decreased in incidence since the introduction of treatments targeting vascular endothelial growth factor (VEGF).1, 2, 4

Section snippets

Diagnosis, classification, and symptoms

AMD was traditionally diagnosed on the basis of clinical examination or assessment of colour fundus photographs. During the past two decades, spectral-domain optical coherence tomography and fundus autofluorescence imaging have been used to detect lesions, with improved resolution. Fluorescein angiography remains a useful modality to detect choroidal neovascularisation (to confirm the presence of neovascular AMD) and its location and activity (indicated by the extent of dye leakage). Optical

Epidemiology, prevalence, incidence, and risk factors

Three large, population-based studies—the Blue Mountains Eye Study (BMES), Beaver Dam Eye Study (BDES), and Rotterdam Study (RS)—have provided individual and pooled data on AMD prevalence and incidence in white populations.10

Many risk factors have been identified for AMD. Age is by far the strongest risk factor, with nearly all late AMD cases occurring in people older than 60 years. The estimated prevalence of late AMD in the three large population-based studies was 0·2% (10 of 4797

Implications of AMD

AMD has widespread effects on quality of life. Studies show that patients with AMD report greater life stress, lower satisfaction, lower activity levels, and increased depression than do similarly aged people without AMD.31 When treatment outcomes do not meet expectations, depression is prevalent, even among patients who have received anti-VEGF treatment.32 Reported health-related quality of life was similar or lower in patients with AMD than in those with other serious chronic health

Genetics

AMD is a multifactorial disorder with a strong genetic component.40 Discovery of genetic loci associated with AMD was one of the first major successes to come from genome-wide association studies.40 Since then, large such studies have been done by international consortia for AMD.41, 42 By 2017, 52 common and rare variants at 34 genetic loci had been identified to be independently associated with late AMD on the basis of 16 144 cases of late AMD and 17 832 controls.43

The presence of very rare

Pathogenesis of AMD

The characteristic lesions of AMD are drusen, which are visible clinically in both the macula and retinal periphery. Colour fundus photography and clinical examination can be used to document drusen according to their size as hard (or small), medium (>63 μm), or large (>125 μm).54 Another form, compound drusen, can exist in the retinal periphery, but its implications are unclear.55 On histology and electron microscopy, drusen, particularly large drusen, correspond to basal linear deposits that

Prevention and delay of AMD progression

In the AREDS66 large multicentre clinical trial, treatment with a combined supplement containing high doses of zinc and antioxidants (ascorbic acid [vitamin C], vitamin E, β carotene, and copper) reduced the risk of progression to advanced AMD by around 25% (odds ratio 0·72, 95% CI 0·52–0·98) after an average 6·3-year follow-up. In the follow-up study (AREDS2),51, 67 in which the carotenoids lutein and zeaxanthin were added to the AREDS formula, people in the lowest quintile in terms of dietary

Anti-VEGF agents

Effective treatment for neovascular AMD is based on inhibition of the angiogenic protein VEGF, which is produced in the retina and induced by hypoxia and other conditions. VEGF increases retinal vascular permeability and promotes neovascularisation.73 The first anti-VEGF drug to be used in trials for neovascular AMD was pegaptanib sodium, an aptamer that binds VEGF165 and larger isoforms74 (table 2). Ranibizumab is an antibody fragment that also binds all VEGFA isoforms, and was used in the key

Treatment of atrophic AMD

Atrophic AMD (geographic atrophy) is estimated to account for 20% of legal blindness (20/200 [Snellen equivalent 6/60] or worse in the better eye) in the USA.118 When affecting the foveal centre, geographic atrophy typically impairs driving vision as well as the ability to read and to recognise faces. However, visual acuity does not correlate well with the extent of geographic atrophy because the fovea can be spared or surrounded for extended periods.13 Therefore, use of traditional visual

Alternative anti-VEGF therapies

The results of trials of newer anti-VEGF therapies, including intravitreal therapy with conbercept85 or brolucizumab,87, 123, 124 have been reported for neovascular AMD (table 2). The phase II trial85 of conbercept suggested similar or greater visual acuity gains and similar injection frequency to that of ranibizumab in the CATT study. Brolucizumab was non-inferior to ranibizumab in phase II trials, and showed a 1-month increase in the median time to post-baseline therapy, suggesting

Future directions

Practical therapeutic strategies for a complex disease such as AMD are likely to combine multiple factors, including diet, lifestyle, and improved pharmacological interventions, taking into account personalised genetic information.129 There is increasing interest in interventions to delay the progression from early to late stages of AMD. One area of research is high-dose statin therapy, shown in some small studies to be associated with drusen regression.130, 131 Given the high lipid content of

Conclusion

Over the past decade, major advances have been made in our understanding of the genetic basis of AMD, imaging of the pathological changes that occur, prevention of AMD progression through changes to nutrient intakes, and new therapeutic options in the form of anti-VEGF agents to treat neovascular AMD. As a result, legal blindness and visual impairment from AMD have substantially decreased in incidence. Current research is focused on developing new and longer-lasting agents for neovascular AMD

Search strategy and selection criteria

We systematically searched PubMed and Medline databases from Jan 1, 1980, to June 30, 2017, using the search terms “macular degeneration”, “choroidal neovascularisation”, “geographic atrophy”, “drusen”, “age-related maculopathy”, “AMD”, and “ARMD”. Relevant articles in English (or English translations) were retrieved and reviewed. Reference lists of reviews and original research articles were also searched to identify relevant studies.

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