Fundus fluorescein angiography (FA), the current gold standard for diagnosing neovascular AMD, is an invasive dye-based imaging modality that requires an intravenous administration of contrast followed by interval fundus photography for at least 10 minutes. FA generates two-dimensional images and provides dynamic information about retinal blood flow. Identification of various patterns of dye leakage, pooling, and staining can aid in the diagnosis of retinal and choroidal pathological lesions such as neovascularization. Though FA can readily identify the superficial retinal capillary plexus, this imaging modality poorly visualizes intraretinal structures such as the deep retinal capillary plexus and the choroid⁴ that give rise to neovascular complexes in AMD. In contrast to FA, indocyanine green angiography (ICGA) uses an intravenous dye that enables better visualization of the choroidal blood flow below the retinal pigment epithelium (RPE). During the early stages of neovascularization, however, ICGA may only reveal a hot spot or plaque of fluorescence that is used to infer the presence of an occult neovascular membrane since the morphology of the microvascular complex often cannot be seen. As opposed to FA and ICGA, optical coherence tomography angiography (OCTA) can detect blood flow at various depth-resolved levels of the retina and choroid using an en face platform and provides direct morphological identification of pathological microvascular lesions associated with all subtypes of neovascular AMD.^5,​6,​7

De Carlo et al⁸ sought to estimate the sensitivity and specificity of detecting choroidal neovascularization (CNV) using OCTA compared to the gold standard of FA. In this study, 30 eyes underwent OCTA and FA for suspected neovascularization on the same date of service. The angiograms were evaluated independently for the presence or absence of CNV. In this cohort, the specificity of neovascularization detection using OCTA compared to FA was high at 91% (20/22), but the sensitivity was low at 50% (4/8). Despite the relatively low sensitivity established in this study, the high specificity indicates that OCTA could potentially be performed as an adjunct to confirm the presence of a neovascular lesion when results from other methods are equivocal.

A study by Inoue et al⁹ compared FA and OCTA for the diagnosis of type 1 neovascularization and found comparable detection rates for neovascular AMD between 60 and 70% when either modality was used alone. Added advantages of OCTA included its improved capacity to identify the entire extent of the neovascular lesion and to identify the pattern of microvascular growth. The combined use of OCTA and OCT may provide the most practical and least invasive multimodal approach to best diagnose neovascular AMD.

OCTA imaging also enables quantitative analysis of neovascular complexes over time. Measurements such as area and density of the lesion obtained at baseline and following therapeutic injection may prove to be useful quantitative parameters of treatment response or failure. Other biomarkers of neovascular response are also being investigated including attenuation of the capillary fringe and the presence of flow void areas.¹⁰ The short acquisition time and noninvasive nature of OCTA may provide a more practical modality for sequential imaging in patients with AMD.

4.2 OCTA Features of Neovascular Age-Related Macular Degeneration

Three distinct lesion subtypes constitute the neovascular form of AMD and are best classified according to their spectral domain OCT (SD-OCT) features.¹¹ Type 1 neovascularization, the most common subtype of neovascular AMD,¹² is identified under the RPE and originates from the choriocapillaris. Type 2 neovascularization, by far the least common of the three entities, is also derived from the choriocapillaris but penetrates the RPE and is therefore located in the subretinal space. Type 3 neovascularization, previously termed retinal angiomatous proliferation (RAP), originates from the deep retinal capillary plexus and is localized in the outer retina. Mixed lesions with features of more than one subtype may also be encountered. Advancements in OCTA imaging will likely result in the development of similar classification criteria based on morphological features of each neovascular subtype.

4.2.1 Type 1 Neovascular Age-Related Macular Degeneration

Type 1 neovascularization, also referred to as occult CNV, originates from the choriocapillaris and is often associated with an overlying pigment epithelial detachment (PED). It is often difficult to detect an occult type 1 neovascular lesion especially when associated with a PED using standard multimodal imaging consisting of fundus photography, FA, ICGA, and SD-OCT. ▶ Fig. 4.1 illustrates the multimodal imaging findings (color fundus photography, SD-OCT, FA) of macular drusen associated with subretinal fluid, although FA failed to detect a neovascular lesion and only demonstrated staining of the nasal macular drusen. However, OCTA was performed and a treatment naïve type 1 neovascular lesion was subsequently identified. The characteristics of an early or treatment naïve type 1 lesion on OCTA have been described as a tangled web of fine vessels ( ▶ Fig. 4.1) or a round tuft of small-caliber capillaries in the absence of an associated dilated core feeder vessel.^{13,​14,​15} Roisman et al studied OCTA images of 11 patients with a diagnosis of neovascular AMD in one eye and asymptomatic, nonexudative AMD in the fellow eye.¹⁶ Each patient had previously undergone ICGA on both eyes and the presence of a macular plaque was identified in 3 of the 11 asymptomatic eyes. Subsequent OCTA imaging was able to clearly detect the type 1 neovascular lesion that corresponded to the macular plaques seen with ICGA. Further investigation is still needed to determine the clinical utility of OCTA to noninvasively identify an asymptomatic or early type 1 lesion and to determine the indication for initiation of anti–vascular endothelial growth factor (anti-VEGF) treatment.

Chronic type 1 neovascularization has been noted to exhibit a markedly different morphology compared to early type 1 lesions. The older lesions consist of large, mature vascular complexes with vessels branching from a core trunk composed of one or more large dilated feeder vessels ( ▶ Fig. 4.2).^{5,​13,​17} This pattern of neovascular growth has been described as a “seafan” or “medusa” morphology. Some researchers have proposed that the dilated core feeder vessels may be the result of chronic anti-VEGF therapy and become more resistant as their endothelial cells acquire protective overlying pericytes. The finer branching vessels at the fringe are primarily composed of unprotected endothelial cells and are therefore more responsive to anti-VEGF therapy.^{5,​13,​18,​19} In his seminal paper, Spaide noted the distinction between angiogenesis and arteriogenesis in order to explain the vascular abnormalization associated with chronically treated type 1 neovascular complexes.¹³ He theorized that anti-VEGF treatment leads to the closing of smaller pericyte-poor vessels within the neovascular complex, which results in increased vascular resistance within the lesion. The persistent pericyte-rich vessels remain perfused, however, and are subsequently exposed to higher flow rates and intraluminal pressure, creating a stimulus for arteriogenesis and increased vessel caliber. Cycles of pruning and regrowth of pericyte-poor vessels within a chronic type 1 lesion in response to repeated anti-VEGF therapy causes the mature pericyte-rich core vessels to progressively enlarge. In the setting of prolonged anti-VEGF therapy, this process can result in the evolution of a neovascular lesion toward subretinal fibrosis.^20,​21

OCTA can also be used to identify type 1 lesions in their late or fibrotic stage. In eyes with subretinal fibrosis complicating neovascular AMD, OCTA often detects blood flow related to recalcitrant vessels located within the fibrotic scar.²² The vessels in these fibrotic complexes can appear large and dilated with or without vascular loops and interconnecting capillaries, but typically consist of predominantly mature vessels without an associated dense capillary plexus ( ▶ Fig. 4.3). This pattern of neovascular growth has been described as a “dead tree” morphology. The majority of fibrotic lesions also have large flow void areas within the choriocapillaris surrounding the lesion.^17,​22 At this stage, OCTA is most useful in determining whether the fibrotic vessels are active or inactive. A proposed set of criteria for evaluating the activity of a neovascular lesion will be discussed later in this chapter.

4.2.2 Type 2 Neovascular Age-Related Macular Degeneration

Type 2 neovascularization, also termed classic CNV (using FA criteria), originates from the choriocapillaris but is located above the RPE in the subretinal space. It is the least common subtype of neovascular AMD occurring in only about 9 to 17% of cases.^12,​23 Classic type 2 membranes present as well-defined areas of hyperfluorescence in early FA frames, while late frames demonstrate leakage of dye from the lesion. OCTA images of affected eyes illustrate high-flow vessels above the RPE in the outer retina as well as in the choriocapillaris. The morphology of type 2 lesions has been described as “medusa-shaped” or “glomerulus-shaped,”²⁴ although the clinical utility of identifying these patterns remains uncertain. These lesions are characterized by oval or globular structures consisting of high-flow vessels entwined with a dense network of finer vessels. Flow void areas are usually seen surrounding the lesion when segmented at both the outer retina and the choriocapillaris. A large feeder vessel is typically identified and may represent the main vessel responsible for piercing through the RPE to give rise to the neovascular complex located in the subretinal space ( ▶ Fig. 4.4). In rare cases, it is possible to distinguish the afferent and efferent branches that supply and drain the lesion.²⁵ Concurrent subretinal fluid can also be appreciated with OCTA co-registered B-scans in cases of type 2 neovascularization.

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