increasing age, oxidative stress, inflammation, genetics, mitochondrial factors, ischemia, and environmental contributors [2, 3]. AMD is characterized by angiogenesis, drusen formation, and local complementary and inflammatory responses [4]. The inciting event of dry AMD, however, still remains to be determined. Dry AMD involves changes in the photoreceptor cells, retinal pigment epithelium (RPE), and choroid, but it is still unclear where the initial change takes place. Theories suggest that there may be a primary dysfunction of the photoreceptor cells, or that a defective RPE may lead to photoreceptor cell damage. Fairly recently, however, choroidal changes have also been discovered to be associated with the occurrence of dry AMD, an area that is still being explored with great interest [5–9].
Classification of AMD
Clinically, AMD is classified into three categories: early, intermediate, and late AMD. Normal aging may involve the formation of a few drusen, less than 63 μm in size, between the RPE and Bruch’s membrane, which have not been shown to increase the risk of development of AMD [10]. Drusen consist of hydrophobic extracellular focal deposits of lipofuscin, photoreceptor debris, and inflammatory components [11, 12]. Early AMD is characterized by drusen between 63 and 125 µm in size with no pigmentary changes. Pigmentary abnormalities, due to RPE alterations, or larger-sized drusen, at greater than 125 µm, indicate progression to intermediate AMD [13]. Overall, drusen size is an important predictive marker, as small drusen less than 63 µm are unlikely to progress to late AMD [13]. The risk of developing late AMD increases with increasing drusen size [14]. The development of neovascularization and/or geographic atrophy (GA) defines late AMD. GA, still under the umbrella of dry AMD, is characterized by subretinal drusen and loss of photoreceptors, RPE, and choriocapillaris (CC). Atrophy is usually confined to a particular region, hence the term “geographic atrophy,” and often a clear-cut boundary between affected RPE and adjacent normal, unaffected RPE may be visualized. GA has also been associated with outer retinal changes and atrophy and alteration of choroidal vessels [15, 16]. The presence of neovascularization in late AMD is often referred to as exudative, or wet, AMD.
Overall, both wet AMD and dry AMD are associated with poor visual outcomes. While wet AMD accounts for only 10% of patients with AMD, it is the reason for 90% of AMD-related blindness. The advent of intravitreal anti-vascular endothelial growth factor (VEGF) injections has revolutionized the treatment of wet AMD, greatly improving visual outcomes [17, 18]. However, it has been questioned whether anti-VEGF injections result in the progression to outer retinal and macular atrophy [9, 19].
Multimodal Imaging of AMD
Prior to the introduction of fundus autofluorescence, color fundus photography was the gold standard for evaluation of AMD [20, 21]. More recently, fundus autofluorescence has been used in the evaluation of patients with dry AMD, and especially to measure and to prognosticate macular atrophy [22, 23]. However, the paradigm is slowly shifting in the favor of optical coherence tomography (OCT) [20, 24]. OCT has been used to qualitatively evaluate for dry AMD, as well as to measure drusen volume, which is associated with risk of progression of dry AMD [25]. It can also be used to evaluate the characteristics of drusen that are associated with a higher risk of progression to advanced dry AMD, as well as exudative AMD [26, 27]. Moreover, OCT can also be used to look for reticular pseudodrusen (RPD), which have been associated with a higher risk of choroidal atrophy and of progression of AMD [28–30]. The en face image generated after a volumetric scan can be used to delineate areas of atrophy, with sub-RPE illumination serving to highlight the area of atrophy [31, 32].
More recently, OCT angiography (OCTA) has also been used in the evaluation of patients with AMD. The changes seen on OCTA in the various stages of the disease are described below.
OCTA of Early and Intermediate AMD
The early and intermediate phases of AMD are characterized by drusen and/or RPE and CC changes. The location of drusen above the CC, between Bruch’s membrane and the RPE, has led to speculation that overlying RPE and outer retinal changes occur due to nutrient deprivation. Drusen may form a type of barrier that interferes with the diffusion of oxygen and nutrients supplied by the CC. Furthermore, studies have suggested that certain sites are more prone to drusen formation due to prior changes in vascular dynamics. CC dysfunction, indicating insufficient choroidal perfusion, may guide and dictate the area of drusen formation. Indeed, FA and indocyanine green angiography show prolonged choroidal filling in dry AMD, suggesting underlying microvascular deficiency. However, it remains a matter of debate whether these vascular changes cause or result from drusen formation.
Fig. 1. SD-OCT and OCTA images of a 77-year-old male with dry AMD. a The structural OCT B-scan highlights three drusen lesions (yellow arrows). b On the corresponding en face OCTA image of the CC, loss of flow (yellow arrows) is seen under these three lesions. c Note that the corresponding regions on the OCT intensity en face do not suggest pronounced signal attenuation, confirming that the dark areas of no flow on the OCTA are indeed CC loss, as opposed to shadowing.
OCT has allowed for some light to be shed on the structural CC changes involved in disease progression. Drusen, RPE changes, and outer retinal alterations have been well visualized, especially with enhanced depth imaging OCT [33] and high-resolution spectral-domain (SD) OCT. This technology has allowed for the quantification and automated detection of drusen and choroidal and outer retinal structural changes [34, 35]. For example, choroidal thinning has been shown to correlate
