Elsevier

The Lancet

Volume 379, Issue 9827, 5–11 May 2012, Pages 1728-1738
The Lancet

Series
Age-related macular degeneration

https://doi.org/10.1016/S0140-6736(12)60282-7Get rights and content

Summary

Age-related macular degeneration is a major cause of blindness worldwide. With ageing populations in many countries, more than 20% might have the disorder. Advanced age-related macular degeneration, including neovascular age-related macular degeneration (wet) and geographic atrophy (late dry), is associated with substantial, progressive visual impairment. Major risk factors include cigarette smoking, nutritional factors, cardiovascular diseases, and genetic markers, including genes regulating complement, lipid, angiogenic, and extracellular matrix pathways. Some studies have suggested a declining prevalence of age-related macular degeneration, perhaps due to reduced exposure to modifiable risk factors. Accurate diagnosis combines clinical examination and investigations, including retinal photography, angiography, and optical coherence tomography. Dietary anti-oxidant supplementation slows progression of the disease. Treatment for neovascular age-related macular degeneration incorporates intraocular injections of anti-VEGF agents, occasionally combined with other modalities. Evidence suggests that two commonly used anti-VEGF therapies, ranibizumab and bevacizumab, have similar efficacy, but possible differences in systemic safety are difficult to assess. Future treatments include inhibition of other angiogenic factors, and regenerative and topical therapies.

Introduction

Age-related macular degeneration is a progressive chronic disease of the central retina and a leading cause of vision loss worldwide. Most visual loss occurs in the late stages of the disease due to one of two processes: neovascular (“wet”) age-related macular degeneration and geographic atrophy (“late dry”). In neovascular age-related macular degeneration, choroidal neovascularisation breaks through to the neural retina, leaking fluid, lipids, and blood, and leading to fibrous scarring. In geographic atrophy, progressive atrophy of the retinal pigment epithelium, choriocapillaris, and photoreceptors occurs. Most severe visual loss from age-related macular degeneration is caused by the these advanced forms of the disease.

A decade ago, age-related macular degeneration was largely untreatable. However, new pharmaceuticals based on suppression of vascular endothelial growth factor (VEGF) have substantially changed the management of the disease.1, 2, 3 In 2006, landmark clinical trials showed that monthly intravitreal injections of ranibizumab (Lucentis, Genentech/Novartis) prevented vision loss in nearly 95% of patients, and significantly improved vision in 40%. Recent population-based data have shown that legal blindness attributable to age-related macular degeneration has been reduced by 50% in some countries since the introduction of VEGF antagonists.4 Another drug, bevacizumab (Avastin, Genentech), originally developed for systemic treatment of colon cancer and related to the parent ranibizumab molecule, is now widely used as an off-label alternative. Intravitreal bevacizumab is popular because its efficacy seems to be similar to that of ranibizumab but is substantially cheaper. In 2011, an important head-to-head trial5 showed that bevacizumab and ranibizumab have equivalent efficacy over a 1-year period. In addition to treatment, major advances have been made in understanding the epidemiology, risk factors, and genetics of age-related macular degeneration.

Section snippets

Prevalence and incidence

There have been many epidemiological studies on age-related macular degeneration in the past 30 years. In a meta-analysis6 of population-based studies in white people aged 40 years and older, the prevalence of early age-related macular degeneration was estimated to be 6·8% and late age-related macular degeneration 1·5%.

Epidemiological data in other ethnic groups have been reported. Results from the Baltimore Eye Study7 showed that late age-related macular degeneration was nine to ten times more

Genetics

For several years there has been strong evidence for genetic influences on the development of age-related macular degeneration, supported by familial aggregation, segregation, linkage, and twin studies (appendix).

Since 2005, several genetic loci have been associated with age-related macular degeneration, including two major loci in the complement factor H (CFH) gene on 1q32 and the ARMS2/HTRA1 locus on the 10q26 gene cluster (see appendix). Other confirmed genes in the complement pathway

Pathogenesis

Several biological pathways have been implicated in the pathogenesis of age-related macular degeneration. These include senescence, shown by lipofuscin accumulation in retinal pigment epithelium cells, choroidal ischaemia, and oxidative damage.38 More recently, attention has been focused on the function of VEGF in light of its role as a therapeutic target.39 VEGF is a key regulator of angiogenesis, and withdrawal or interference with its function leads to cessation of vascular growth and

Clinical features and classification

Patients with early age-related macular degeneration are usually asymptomatic, and present clinically with yellowish drusen seen underneath the retinal pigment epithelium, with areas of mottled retinal pigment epithelium hyperpigmentation and hypopigmentation.

Patients usually develop rapid visual loss when neovascular age-related macular degeneration occurs. Typically, patients describe sudden worsening of central vision with distortion of straight lines (metamorphopsia) or a dark patch in

Retinal imaging

Major advances have occurred in retinal imaging for the management of age-related macular degeneration. Traditionally, fundus fluorescein angiography (FFA) is done. It is an invasive investigation in which a yellow dye (fluorescein) is intravenously injected with sequential photographs taken to assess choroidal and retinal blood flow. In neovascular age-related macular degeneration, leakage of dye (hyperfluorescence) into the retinal tissues is noted.46, 47 This leakage is classified by

Prevention

One strategy for prevention of age-related macular degeneration is based on modification of nutrient intake. Studies show increased intake of the macular carotenoids lutein and zeaxanthin and foods rich in these nutrients (eg, spinach and collard greens) are associated with a decreased risk of neovascular age-related macular degeneration.55 Dietary analyses of the observational component of the AREDS study56 also showed that lutein and zeaxanthin reduced age-related macular degeneration risk.

In

Laser photocoagulation

In the 1980s, the Macular Photocoagulation Study46, 47 reported favourable outcomes for direct laser photocoagulation in a proportion (about 20%) of eyes with small classic extrafoveal and juxtafoveal choroidal neovascularisation lesions, but poorer visual outcomes for subfoveal choroidal neovascularisation lesions.46, 47 Treatment with laser in these selected patients was effective in reducing long-term severe visual loss, but was limited by lack of vision gain and high recurrence rates (50%),

New research

Progress has been made in the improvement of screening methods to detect age-related macular degeneration. Recently, a system for automated detection of early age-related macular degeneration signs from retinal photographs has been described, with sensitivity and specificity rates of 75%.71 Further development of such systems might facilitate community screening.

Much research has focused on improved anti-VEGF treatment protocols that reduce the burden of monthly intravitreal injections,

Conclusion

Age-related macular degeneration is a major cause of visual impairment in older adults. No effective preventive drug therapies exist although nutritional and behavioural modifications can reduce progression to advanced age-related macular degeneration. This disorder is heritable and up to 20 genes are associated with age-related macular degeneration. However, the disease is complex and environmental factors also have a role. Advances have been made in disease detection allowing for earlier

Search strategy and selection criteria

We searched the Cochrane Library, Medline, and Embase for articles published between 1980 and 2011. We used the search terms “age-related macular degeneration” and “age-related maculopathy” in combination with the following terms: “prevalence”, “incidence”, “risk factors”, “pathogenesis”, “gene”, “diagnosis”, “screening”, “imaging”, “treatment”, and “therapy”. We largely selected publications in the past 5 years, but did not exclude commonly referenced and highly regarded older publications. We

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