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.
SeminarAge-related macular degeneration
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
References (139)
- et al.
Age-related macular degeneration
Lancet
(2008) - et al.
Age-related macular degeneration
Lancet
(2012) - et al.
Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis
Lancet Glob Health
(2014) - et al.
Causes of vision loss worldwide, 1990–2010: a systematic analysis
Lancet Glob Health
(2013) - et al.
Optical coherence tomography angiography in dry age-related macular degeneration
Surv Ophthalmol
(2018) - et al.
The application of optical coherence tomography angiography in retinal diseases
Surv Ophthalmol
(2017) - et al.
An international classification and grading system for age-related maculopathy and age-related macular degeneration
Surv Ophthalmol
(1995) - et al.
Clinical classification of age-related macular degeneration
Ophthalmology
(2013) - et al.
Validating the AREDS Simplified Severity Scale of age-related macular degeneration with 5- and 10-year incident data in a population-based sample
Ophthalmology
(2016) - et al.
Incidence and progression of geographic atrophy: observations from a population-based cohort
Ophthalmology
(2013)
Pseudodrusen and incidence of late age-related macular degeneration in fellow eyes in the comparison of age-related macular degeneration treatments trials
Ophthalmology
Reticular pseudodrusen: a risk factor for geographic atrophy in fellow eyes of individuals with unilateral choroidal neovascularization
Ophthalmology
Differentiating drusen: drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes
Prog Retin Eye Res
Risk factors for age-related macular degeneration: pooled findings from three continents
Ophthalmology
The incidence and progression of age-related macular degeneration over 15 years: the Blue Mountains Eye Study
Ophthalmology
Prevalence of age-related macular degeneration in Europe: the past and the future
Ophthalmology
Risk factors and biomarkers of age-related macular degeneration
Prog Retin Eye Res
Associations of cigarette smoking but not serum fatty acids with age-related macular degeneration in a Japanese population
Ophthalmology
Age-related macular degeneration and 5-year incidence of impaired activities of daily living
Maturitas
Cognitive impairment in age-related macular degeneration and geographic atrophy
Ophthalmology
Age-related macular degeneration and risk of degenerative dementia among the elderly in Taiwan: a population-based cohort study
Ophthalmology
Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy
Prog Retin Eye Res
A risk score for the prediction of advanced age-related macular degeneration: development and validation in 2 prospective cohorts
Ophthalmology
Risk models for progression to advanced age-related macular degeneration using demographic, environmental, genetic, and ocular factors
Ophthalmology
Prediction of age-related macular degeneration in the general population: the Three Continent AMD Consortium
Ophthalmology
Smoking, dietary betaine, methionine, and vitamin D in monozygotic twins with discordant macular degeneration: epigenetic implications
Ophthalmology
Distribution and composition of esterified and unesterified cholesterol in extra-macular drusen
Exp Eye Res
Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins
Prog Retin Eye Res
Retinal angiomatous proliferation
Surv Ophthalmol
Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians
Prog Retin Eye Res
Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study
Ophthalmology
Long-term effects of vitamins C and E, β-carotene, and zinc on age-related macular degeneration: AREDS report no. 35
Ophthalmology
Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration
Ophthalmology
Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results
Ophthalmology
Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial
Lancet
Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: results from the GEFAL noninferiority randomized trial
Ophthalmology
Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration
Ophthalmology
Prospective trial of treat-and-extend versus monthly dosing for neovascular age-related macular degeneration: TREX-AMD 1-year results
Ophthalmology
Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol
Ophthalmology
Safety and efficacy of conbercept in neovascular age-related macular degeneration: results from a 12-month randomized phase 2 study: AURORA study
Ophthalmology
Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: a randomized trial
Ophthalmology
Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration
Ophthalmology
Randomized trial to evaluate tandospirone in geographic atrophy secondary to age-related macular degeneration: the GATE study
Am J Ophthalmol
Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study
Ophthalmology
Intravitreal bevacizumab versus ranibizumab for treatment of neovascular age-related macular degeneration: findings from a Cochrane systematic review
Ophthalmology
Morphology and visual acuity in aflibercept and ranibizumab therapy for neovascular age-related macular degeneration in the VIEW trials
Ophthalmology
Ranibizumab or bevacizumab for neovascular age-related macular degeneration according to the Lucentis compared to Avastin study treat-and-extend protocol: two-year results
Ophthalmology
Two-year outcomes of “treat and extend” intravitreal therapy for neovascular age-related macular degeneration
Ophthalmology
A view of the current and future role of optical coherence tomography in the management of age-related macular degeneration
Eye (Lond)
Harmonizing the classification of age-related macular degeneration in the three-continent AMD consortium
Ophthalmic Epidemiol
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