15

Type 3 Neovascularization—Retinal Angiomatous Proliferation

Anna C.S. Tan, MBBS, FRCSED; Kunal K. Dansingani, MA, FRCOphth; and K. Bailey Freund, MD

Type 3 neovascularization is a form of neovascular age-related macular degeneration (AMD) in which the proliferation of new vessels occurs predominantly within the neurosensory retina rather than in the subretinal or sub-retinal pigment epithelium (RPE) spaces.¹ Previously, other terms used to described this entity included retinal vascular anomalous complexes (RVAC),^2,3 retinal angiomatous proliferation (RAP),⁴ and occult choroidal neovascularization (CNV) with chorioretinal anastomosis (CRA).^5,6 Older age, White ethnicity, and hypertension, in addition to certain genetic markers, have been associated with the development of type 3 neovascularization.^7–9 Patients with unilateral type 3 neovascularization have a high risk of developing type 3 neovascularization in the contralateral eye (36% to 100% within 3 years).^10–12

PATHOGENESIS AND ORIGIN

Controversy exists regarding the origin and pathogenesis of type 3 neovascularization.^4,5,9 The first report of these retinal lesions described findings on fluorescein angiography (FA) in which an angiomatous lesion in the outer retina appeared to be fed by a more superficial, right-angled retinal arteriole and drained by a retinal venule.³ This angiomatous lesion also appeared to extend deep into the subretinal pigment epithelial space of an underlying pigment epithelial detachment (PED).^2,3 Further studies on vascularized PEDs found that a large percentage of PEDs that demonstrate findings of a “hot spot” on indocyanine green angiography (ICGA) have anastomoses with retinal vessels.⁶

Yannuzzi et al⁴ first proposed the term RAP. They hypothesized that the neovascular complexes originated within the retina and that their development and course could be classified into 3 stages: (1) proliferation of intraretinal capillaries from the deep retinal complex (41%), (2) growth of these vessels into the subretinal space (39%) and (3) the development of an associated underlying CNV that could be determined clinically or with angiography (20%).⁴ Contrary to this theory, Gass et al⁵ proposed that these lesions originated from occult subretinal pigment epithelium neovascularization that erodes through the RPE forming an occult CRA. To reconcile these conflicting theories, Freund et al¹ proposed the term type 3 neovascularization to refer to this predominantly intraretinal form of neovascularization, which is an extension of the anatomical classification of neovascularization that also includes type 1 (sub-RPE) neovascularization and type 2 (subretinal) neovascularization.¹ This classification scheme describes the lesion with respect to its predominant location within the retinal layers regardless of their origin. This description of type 3 neovascularization would include a spectrum of disease that includes (1) focal neovascular proliferation from the deep retinal layer (RAP) (Figure 15-1A), (2) intraretinal neovascular extension from an underlying occult type 1 neovascularization (CRA), or de novo breaks in Bruch’s membrane with neovascular infiltration into the retina (Figure 15-1B).¹

Anti-vascular endothelial growth factor (VEGF) levels have been shown to be higher in the aqueous humor of eyes with type 3 neovascularization compared to other forms of neovascular AMD.13 Furthermore, the fact that type 3 neovascularization responds well to intravitreal anti-VEGF injections suggests that upregulated VEGF is involved in its pathogenesis.^14–16 An upregulated VEGF production due to a hypoxic response of the retina from choroidal hypo-perfusion or the presence of a PED causing a physical separation of the photoreceptors in the retina from the choroid have been suggested as underlying mechanisms.^17–20 RPE hyperplasia with migration of RPE cells into retinal layers have been suggested as another possible factor that could incite an angiogenic response in vessels in the deep retina.^21,22,23

CLINICOPATHOLOGICAL STUDIES

Histology from excised submacular surgical specimens with type 3 neovascularization has shown that neovascularization was present within the retina and extended beneath the retina with the presence of reactive RPE hyperplasia, but without definite CNV.^24,25 However, the associated underlying choroidal vasculature was not excised in these specimens. Therefore, communication of this retinal neovascularization with the choroid could not be excluded. A few post-mortem histology specimens of type 3 neovascularization have shown the presence of intraretinal neovascularization without the presence of sub-neurosensory or sub-RPE neovascularization.^26,27 Another report of the post-mortem histology of a type 3 neovascularization showed extension of the neovascular complex from the outer retina into the sub-RPE space, abutting the elastic portion of Bruch’s membrane without any clear communication with the choroidal circulation.²⁸ Gass et al⁵ published a single post-mortem specimen showing the presence of a CRA associated with both a type 1 and type 2 neovascular network that seemed to communicate with the choroidal circulation. The limitations of histopathology are the small number of post-mortem specimens with intact retina and choroidal components and the lack of detailed longitudinal evidence regarding the origin and progression of type 3 lesions. Instead, sequential, multimodal, high-resolution imaging, which can accurately localize the neovascularization to specific layers of the retina during the origin and progression of type 3 neovascularization, has been used to study the pathogenesis of this disease.

Typical clinical features of type 3 neovascularization include the presence of intraretinal hemorrhages, lipid exudation, intraretinal cystoid macula edema, and telangiectatic vessels that may form retinal-retinal anastomoses (Figures 15-2 and 15-3).^4,9,29 In the absence of concurrent CNV, large subretinal hemorrhages and subretinal fluid are uncommon in the early stages of type 3 neovascularization. Drusenoid or serous PEDs, soft drusen, and reticular pseudodrusen are other commonly associated findings (see Figure 15-2).^10,29 Type 3 lesions typically develop in the perifoveal and extrafoveal regions, but spare the foveal avascular zone (see Figures 15-2 and 15-3).^4,9 They are rarely seen in the peripheral retina past the vascular arcades.⁹ Fundus autofluorescence initially shows focal areas of hyper-autofluorescence that become hypo-autofluorescent during the development of the type 3 lesion (see Figure 15-2).³⁰ Other focal areas of hypo-autofluorescence that occur correspond to areas of intraretinal hemorrhage and atrophy (see Figure 15-2).

Following the description of type 3 neovascularization, early studies that used FA and ICGA alone to diagnose these lesions showed them to account for 20% to 25% of all occult CNV^31,32 cases, and 12% to 15% of all lesions occurring in neovascular AMD.^33,34 A more recent study in which highly trained masked graders used the combination of FA and spectral domain (SD) optical coherence tomography (OCT) to determine the presenting lesion type in a cohort of newly diagnosed White patients with neovascular AMD found the incidence of type 3 neovascularization to be 34.2%.³⁴ FA findings include early focal leakage, the presence of retinal-retinal anastomoses with feeder vessels that may turn abruptly toward the RPE, and increasing leakage that in the later phases may show a petalloid pattern of cystoid macula edema (see Figures 15-2 and 15-3).^3,29,34 ICGA findings most commonly include the presence of a hyper-fluorescent “hot spot” (see Figure 15-3).²⁹ Other patterns of hyper-fluorescence, however, have been reported such as irregular, circular, multifocal, and combined patterns.³⁵ Another study of early type 3 neovascularization showed that focal hyper-fluorescence on FA and ICGA corresponded to the intraretinal vascular neovascular complex that was fed by a single retinal arteriole.³⁶ There was no angiographic evidence of a CRA or underlying type 1 or type 2 neovascularization.³⁶ Delayed choroidal filling in both the early and late phases of ICGA have been reported in eyes with type 3 neovascularization compared to normal controls.²⁰

The combined use of high-resolution OCT with FA has shown that as many as 34% of all newly diagnosed neovascular AMD eyes of White patients may manifest type 3 lesions.34 Features on OCT typical of type 3 neovascularization include a focal, linear, hyper-reflective intraretinal lesion occurring in areas of localized outer retinal disruption (see Figure 15-2).^22,34 In many cases, the intraretinal neovascular component may appear to be adherent to the underlying RPE with a common presence of an underlying RPE defect and variable elevation of the RPE layer (see Figure 15-2).^20,34 An associated PED has been reported in 86% to 93% of all eyes with type 3 neovascularization. This PED can be drusenoid (see Figure 15-2), serous or consist of mixed components.^22,35 Surrounding intraretinal cystic changes and the presence of intraretinal hyper-reflective foci are common findings (see Figure 15-2).^20,23,36 These lesions correspond to a feeder vessel with an area of surrounding focal leakage seen on the early phase of the FA and a “hot spot” seen on ICGA (see Figure 15-2).^23,36 Eyes with type 3 neovascularization have also been found to have a thinner subfoveal choroid compared to normal controls and eyes with other lesion types occurring in neovascular AMD.^37,38

Retrospective analysis of consecutive eye-tracked SD-OCT scans in patients with initial unilateral type 3 neovascularization, who subsequently developed type 3 neovascularization in the contralateral eye, showed the presence of precursor hyper-reflective foci above the external limiting membrane that migrated further into the inner retina during the development of focal RPE atrophy (Figure 15-4).^22,30 These hyper-reflective foci corresponded to pigment seen on color fundus photographs. Small, localized RPE elevations with focal RPE disruption associated with thinning of the ellipsoid zone and outer nuclear layer reduced the distance between the RPE and outer plexiform layer (see Figure 15-4).³⁰ These changes preceded the development of intraretinal edema and the typical type 3 neovascular features described previously (see Figure 15-4).^22,30

FEATURES OF TYPE 3 NEOVASCULARIZATION ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY

Cross-sectional SD-OCTA imaging enables visualization of a discrete, linear, high-flow structure that extends from the middle retinal layers across the outer nuclear layer (which is usually devoid of flow signals) to reach the RPE layer (Figures 15-4 and 15-5). This high-flow structure corresponds to the hyper-reflective structure seen on structural SD-OCT and the point of leakage seen on FA and ICGA (see Figure 15-5). In our series of eyes with type 3 neovascularization, 13 (57%) of 23 cases showed extension of this flow signal through the RPE layer (see Figure 15-5) into the sub-RPE space; in 3 (13%) eyes the high-flow signal was confined to the retina above the RPE (Figure 15-6), and in 2 (9%) eyes with treated inactive disease, there was an absence of the high-flow signal. These high-flow signals did not seem to extend into the subretinal or sub-RPE spaces (see Figure 15-5). We also observed that, although most of the hyper-reflective signals seen on structural OCT corresponded to flow signals seen on cross-sectional OCTA, there were some hyper-reflective foci that did not have a corresponding flow signal (see Figure 15-5). We hypothesize that these may represent migrating intraretinal RPE cells that are involved in the pathogenesis of type 3 neovascularization, and are separate structures from the intraretinal neovascularization itself.

Stay updated, free articles. Join our Telegram channel

Join