Age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is the leading cause of legal blindness in the industrialized world. AMD is characterized by accumulation of extracellular deposits, namely drusen, along with progressive degeneration of photoreceptors and adjacent tissues. AMD is a multifactorial disease encompassing a complex interplay between ageing, environmental risk factors and genetic susceptibility. Chronic inflammation, lipid deposition, oxidative stress and impaired extracellular matrix maintenance are strongly implicated in AMD pathogenesis. However, the exact interactions of pathophysiological events that culminate in drusen formation and the associated degeneration processes remain to be elucidated. Despite tremendous advances in clinical care and in unravelling pathophysiological mechanisms, the unmet medical need related to AMD remains substantial. Although there have been major breakthroughs in the treatment of exudative AMD, no efficacious treatment is yet available to prevent progressive irreversible photoreceptor degeneration, which leads to central vision loss. Compelling progress in high-resolution retinal imaging has enabled refined phenotyping of AMD in vivo. These insights, in combination with clinicopathological and genetic correlations, have underscored the heterogeneity of AMD. Hence, our current understanding promotes the view that AMD represents a disease spectrum comprising distinct phenotypes with different mechanisms of pathogenesis. Hence, tailoring therapeutics to specific phenotypes and stages may, in the future, be the key to preventing irreversible vision loss.

Fig. 1 |. Manifestations of AMD.

Age-related macular degeneration (AMD) affects the complex of photoreceptors, retinal pigment epithelium (RPE), Bruch’s membrane and the choriocapillaris, the innermost layer of the choroid. Schematic of normal retina–RPE–Bruch’s membrane choroid complex (part a). The early and intermediate stages of the disease are characterized by the deposition of extracellular debris, such as Drusen or basal linear deposits and subretinal drusenoid deposits, accompanied by pathological changes in the RPE, including the migration of RPE cells into the retina (parts b and c). Loss of the photoreceptors, RPE and choriocapillaris presumably begins in the early and/or intermediate stages (part c) and is definitive in geographic atrophy (GA; part d). The late stages of AMD are characterized by GA or by invasion of macular neovascularizations (MNV) into the outer retina, subretinal space or subRPE space (which is known as neovascular AMD; part e, left panel). The exudative stage becomes apparent when these new vessels leak or rupture, resulting in fluid accumulation and/or haemorrhages in the above-mentioned retinal spaces (part e, right panel).

Fig. 2 |. Annual incidence of AMD by 5-year age groups.

Estimated number of new cases each year and average annual incidence per 1,000 cases of age-related macular degeneration (AMD; including late AMD, geographic atrophy and neovascular AMD) by 5-year age groups in the white American population. Data from REF..

Fig. 3 |. Manifestations of AMD as observed on colour fundus photography.

a | Age-related macular degeneration (AMD) affects the centre of the macula. The square box highlights this area in a normal eye without pathological alterations. b | Early AMD with medium-sized drusen (yellowish deposits, arrowheads). c | Intermediate AMD with large drusen (arrowheads) and hyperpigmentation (arrows). d | Geographic atrophy (arrowheads). e | Neovascular AMD with haemorrhage (asterisks).

Fig. 4 |. Subretinal drusenoid deposits.

a | Near-infrared reflectance (NIR) image showing the location of the OCT scan (green line). b | Corresponding OCT scan. c | Magnified OCT image. The arrows indicate the structures that correlate with subretinal drusenoid deposits. The asterisks indicate the structures that typically correspond to drusen. Pseudodrusen seem to be located on top of a hyperreflective band whereas the drusen appear to be located beneath that same hyperreflective band (dashed line). Based on the assumption that the hyperreflective band represents the retinal pigment epithelium (RPE), it has been speculated that reticular pseudodrusen are located in the subretinal space, explaining the terminology ‘subretinal drusenoid deposits’ (SDD).

Fig. 5 |. Model of AMD pathogenesis.

Age-related macular degeneration (AMD) affects the complex of photoreceptors, retinal pigment epithelium, Bruch’s membrane (BrM) and the choroid. AMD is regarded as a multifactorial disease comprising a complex interplay between ageing, genetic susceptibility and environmental risk factors. AMD is hypothesized to develop as a consequence of disruption of the normal homeostatic mechanisms of the retina. In AMD, ageing changes coupled with chronic inflammation, altered lipid and lipoprotein deposition, increased oxidative stress and impaired extracellular matrix (ECM) maintenance lead to the formation of extracellular deposits, namely drusen and basal linear deposits (BLinD) in the BrM, which are the hallmark lesions of AMD.

Fig. 6 |. High-resolution OCT scans showing different stages of AMD.

a | Normal eye without age-related macular degeneration (AMD)-related pathological features. b | Eye with early AMD characterized by subtle elevations of the retinal pigment epithelium (RPE) and ellipsoid zone (EZ) of the photoreceptors corresponding to small or medium-sized drusen (arrows). c | Eye with intermediate AMD showing more pronounced elevations of the RPE, ellipsoid zone of the photoreceptors, and external limiting membrane, in the areas corresponding to large drusen (arrows). Note the small hyperreflective focus (small down arrow) on top of a large druse; this corresponds to hyperpigmentation and most likely reflects migrating RPE cells. d | Eye with geographic atrophy characterized by complete loss of outer retinal layers and the RPE (dashed bracket). e | Eye with neovascular AMD and exudation of fluid in the subretinal space (asterisk) and intraretinal space (arrows); the bracket indicates the extend of the macular neovascularization. BrM, Bruch’s membrane; EML, external limiting membrane; OCT, optical coherence tomography; ONL, outer nuclear layer; PR, photoreceptors. Part a adapted with permission from REF., Elsevier.

Fig. 7 |. Therapeutic effect of anti-VEGF treatment on exudative MNV.

a | Optical coherence tomography (OCT) scan in an eye of a patient at first diagnosis of exudative macular neovascularization (MNV). There is intraretinal fluid as a sign for exudation (arrows); in addition, there is a shallow elevation of the retinal pigment epithelium (RPE) (dashed bracket), which is presumably evoked by the MNV and subRPE fluid (asterisk). b | OCT scan in the same location after three monthly intravitreal anti-VEGF injections. There is no more intraretinal or subRPE fluid, although the subtle shallow elevation of the RPE indicates that the MNV is still present.

Fig. 8 |. Differential enlargement rates of GA.

Serial fundus autofluorescence images of eyes with geographic atrophy (GA). a | GA lesion with a progression rate of 1 mm²/year and only a few disseminated spots of increased fundus autofluorescence (FAF). b | A lesion with a progression rate of 2 mm²/year. In this eye, there is a widespread fine granular FAF signal surrounding the atrophic lesion. c | An eye with a trickling GA phenotype showing the fastest progression. The FAF signal is typically garish in the area of atrophy compared with the other GA subtypes, and the lesion is multilobular, surrounded by extensive reticular pseudodrusen. Copyright: adapted from REF..

Fig. 9 |. Exudative macular neovascularization in AMD.

a | Colour fundus photography. b | Near-infrared reflectance image; the green line indicates the location of the optical coherence tomography (OCT) scan. c | OCT scan (magnified) in an eye with intraretinal fluid (example areas indicated by arrows) as a sign of exudation. d | Fluorescein angiography (images taken serially within ~5 minutes) revealing a choroidal neovascularization (arrows) with leakage or exudation in the late phase as a sign of ‘activity’ (arrowhead). The characteristics are most compatible with a ‘type 2’ macular neovascularization (MNV) according to the Consensus on Neovascular AMD Nomenclature (CONAN) group. AMD, age-related macular degeneration.

Fig. 10 |. Non-exudative macular neovascularization.

a | There is a shallow irregular elevation of the retinal pigment epithelium (RPE), known as the SIRE sign, but no intraretinal or subretinal fluid on conventional optical coherence tomography (OCT). b | The OCT angiography scan at the same location as in part a shows flow between the RPE and the choroid (red signals; asterisks indicate the blood flow between the RPE and the choroid). c | Location of the OCT scan is indicated in the near-infrared reflectance image (green line). d and e | En face OCT angiography shows a large choroidal neovascularization (part d is a native OCT angiography en face image; part e shows the extent of choroidal neovascularization in red). Part a adapted from REF..