**9. Macular neovascularization**

In the exudative form of AMD, the local production of vascular endothelial growth factor (VEGF) promotes the growth of choroidal neovascularization. These lesions were initially classified in: classic, occult, and variations (predominantly classic and minimally classic) based on their characteristics on FA.

Gass proposed [39] that the location of the neovascular membrane could be important to predict response to treatment and after the advent of OCT, an alternative classification was suggested:

#### **9.1 Type 1**

In this type the vessels are located in the sub-RPE space (**Figure 8**). It is the most common type of neovascularization in AMD. On FA, these lesions are depicted as occult or poorly defined CNV (choroidal neovascularization). Other FA terminologies are used to describe type 1 neovascular complex: vascularized RPE, vascularized PED or stippled hyperfluorescence. On indocyanine green angiography (ICG-A), this neovascular membrane appears as an area of low-intensity hyperfluorescence, known as plaque. On SD-OCT, it is possible to determine its location on a space bounded inferiorly by the hyperreflective remnants of Bruch membrane and superiorly by the hyperreflective RPE band. A new finding of the type 1 neovascularization was described by Spaide [40] recently. It was observed that when the RPE becomes elevated due to sub-RPE exudation, the neovessels adhere to the basal surface of the RPE. On Enhanced Depth Imaging (EDI) OCT, this is described as a hyperreflective material (supposed to be the neovascularization) lining the undersurface of the elevated RPE. This pattern may explain the vulnerability of type 1 neovascularization to RPE tears. This subgroup also includes polypoidal vasculopathy, which was recently renamed as aneurysmal type 1 neovascularization.

#### **Figure 8.**

*Type 1 neovascularization, also known as aneurysmal type 1 subretinal neovascular membrane. Inferiorly, OCT-B scan demonstrates PED with shallow subretinal fluid and intraretinal cystic degeneration. Superiorly, OCT-A slabs detect a branch vascular network ending in an aneurysm formation (yellow circle) located between the RPE and the Bruch's membrane.*

#### **9.2 Type 2**

It consists of a neovascular membrane that has perforated the RPE/Bruch membrane complex and is growing in the space between the neurosensory retina and the RPE [40]. On FA, these new vessels are commonly described as being classic or having a well-defined contour (**Figure 9**). Due to the attenuation of the choroidal fluorescence by the interjacent RPE promoting the formation of a dark background, the new vessels appear to fluoresce intensely. On the other hand, on ICG-A it may be challenging to identify the neovascular complex due to the intense hyperfluorescence of the background choroidal circulation. It is common to detect type 2 neovascularization along with type 1 vessels in exudative AMD. It is also possible that a type 2 neovascular complex regresses and turns into a type 1.

On OCT, it is possible to detect a disorganization of the overlying inner/outer segment junction in conjunction with intraretinal cystic spaces. Additionally, this exam identifies intraretinal rather than subretinal fluid.

#### **9.3 Type 3**

Type 3 neovascularization is the recent terminology for what once was known as Retinal Angiomatous Proliferation (RAP) and consists of an intraretinal neovascularization. Notable discussions happened regarding whether the origin of this neovascular complex was from the retinal circulation (as Yanuzzi suggested) or from the choroidal circulation (as suggested by Gass). Some studies support the

#### **Figure 9.**

*Type 2 neovascularization.* En face *OCT-A projection images of the neovascular complex with vessels both in the outer retina and the choriocapillaris (pink circles). Inferiorly, an OCT-B scan demonstrates the neovascular complex (arrowhead) located between the RPE and the neurosensory retina.*

#### **Figure 10.**

*Type 3 neovascularization. On the left, en face OCT-A slabs show the vascular lesion (pink circles) in the superficial and deep segments of the retina. The OCT-B scan, on the left, demonstrates the presence of intraretinal fluid, caused by the vascular lesion before treatment with anti-VEGF (arrowhead). On the right, en face OCT-A slabs still show the vascular lesion (orange circle), although the OCT-B scan, on the right, demonstrates resolution of fluid after the first injection of anti-VEGF (this type of neovascularization tends to respond well to treatment with anti-VEGF).*

theory that the origin of this neovascular complex can be from either circulation and may arise from both circulations at the same time as a Retinal-Choroidal Anastomosis (RCA) (**Figure 10**).

On OCT, it is characterized by large amounts of intraretinal fluid as well as a thin choroid. In this aspect it differs from types 1 and 2 neovascularization that have an associated thickened choroid. Another differential aspect, is that type 3 neovascularization leads more often to retinal atrophy due to damage to the external retina caused by its intraretinal origin and the thinner choroid [39, 41].

## **10. Outer retina atrophy**

Geographic Atrophy (GA) is a late-stage disease manifestation of nonneovascular AMD that generally progresses to severe central vision loss. It has traditionally been defined on color fundus photography as a sharply delineated circular or oval area of hypopigmentation or depigmentation in which choroidal vessels are visible. The size required for a lesion to be classified as GA varies with different studies, ranging from 175 μm to 430 μm in diameter.

Autofluorescence of these areas indicate them as hypoautofluorescent lesions, that may have a hyperautofluorescent rim, which is linked to acute suffering of the RPE. Atrophic areas typically demonstrate a late well-defined hyperfluorescence.

On OCT, as drusen regress, the overlying retinal layers undergo characteristic changes, while progressing to atrophy, that can be captured on OCT imaging. These changes, referred to as nascent GA in previous reports, include subsidence of the inner nuclear layer (INL) and outer plexiform layer (OPL), a hyporeflective wedgeshaped band within the Henle fiber layer (HFL), often accompanied by RPE disturbance, and increased signal hypertransmission into the choroid [42].

OCT-A shows significant impairment on the choriocapillaris flow in the zone immediately surrounding GA lesions. OCT-A seems to be able to give us information about the progression of atrophy, since the flow at the choriocapillary layer is diminished in the perifoveal region if compared to the parafoveal regions [43].

Previous studies have identified characteristic fundus features that are associated with a high risk for progression to GA [44]. Features related to a greater chance of developing GA are: large drusen volume, calcified drusen, intraretinal hyperreflective foci and SDD.

Spaide was one of the first to describe that outer retina atrophy could result from regression of SDD [45]. The outcomes of this study showed that, 43% of patients would eventually develop choroidal neovascularization after a period of two years and 43% would develop regression of SDD. Patients that had regression of SDD, had a decrease in the photoreceptor length, decrease in choroidal thickness and loss of ellipsoid band.

A score was proposed to better follow patients [28]. Among the scoring factors, there are: hyporeflective drusen, hyperreflective intraretinal foci, subretinal drusenoid deposits, and volume of large drusen. In order to generate the score, one point was assigned to each feature present in the study eye. The fellow eye was scored in a similar fashion. By adding the scores from both eyes, the total score (TS) is calculated. Category I is defined as a TS of 0, 1 or 2. Category II is defined as a TS of 3 or 4. Category III corresponds to a TS of 7 or 8. According to this score, in category I there was 0% chance to develop retinal atrophy; in category II there was a chance of 14,3%; in category III there was a chance of 47,5% and in category IV the chance was of 73%. The results allowed to conclude that patients in category I could be safely seen every 12 months, whereas patients in category II, III and IV could be seen every 6, 4 and 3 months, respectively [28, 43].
