Retinal Angiomatous Proliferation in Age-Related Macular Degeneration
Gabriela E. Granella
Eric P. Jablon
INTRODUCTION
It is known that choroidal neovascularization (CNV) in age-related macular degeneration (AMD) may erode through the retinal pigment epithelium (RPE), infiltrate the neurosensory retina, and communicate with the retinal circulation in what has been referred to as a retinal-choroidal anastomosis (RCA). This is extremely common in the end stage of disciform disease (1). The reverse is also possible, as angiomatous proliferation originates from the retina and extends posteriorly into the subretinal space, eventually communicating in some cases with choroidal new vessels. This form of neovascular AMD, termed retinal angiomatous proliferation (RAP), can be confused with CNV. RAP begins in the deep retinal complex forming intraretinal neovascularization (IRN), which may subsequently progress to extend beneath the neurosensory retina, forming subretinal neovascularization (SRN) and a vascularized pigment epithelium detachment (PED). In the advanced stages of the process, there may be an RCA. Clinical features of RAP include intraretinal hemorrhages, cystoid macular edema (CME), and associated vascularized PED. Fluorescein angiography (FA) is useful in revealing the presence of the angiomatous intraretinal vascular complex and the extension of the associated PED. However, other diagnostic techniques, such as indocyanine green (ICG) angiography and optical coherence tomography (OCT), have now proven to be as useful—or even more—to demonstrate the presence of the RAP lesion.
HISTORY
Oeller (2), nearly 110 years ago, predicted the presence of retinal vascular communications in the predisciform stage of AMD in his classic, chorioretinal atlas. Later in 1985, Sorenson et al. (3) reported a communication between the retinal and choroidal circulation as a cause of recurrent CNV and eventual failure of thermal laser treatment. The retina itself was the source of the recurrent vascular ingrowth, which was subretinal rather than subpigment epithelial or CNV.
In 1992, Hartnett et al. (4), in a landmark article, were the first to describe retinal neovascularization as an early finding in neovascular AMD, preceding the disciform scarring stage of the disease. In a clinical and fluorescein angiographic description of 125 patients with neovascular AMD and an associated serous PED, they found nine patients (7.3%) to have retinal vascular abnormalities, which were described as “retinal angiomatous lesions.” Eight of these
nine eyes underwent thermal laser photocoagulation and eventually had recurrent CNV and progressive disciform scar formation. In 1995, Kuhn et al. (5) first clearly identified an RCA as a potential manifestation of this form of neovascular AMD. They specifically addressed the development of an RCA to an associated vascularized PED. Utilizing ICG angiography, this group found evidence for an RCA in 50 of 186—or 28%—of AMD patients with an associated vascularized PED. Indeed, they termed this form of neovascular AMD “retinal-choroidal anastomosis.” The outcome of laser photocoagulation treatment in these individuals was poor. Hartnett et al. (6), in a subsequent report in 1996 on 13 patients with this form of neovascular AMD and an associated serous PED, suggested that the neovascularization was in the deep retina; furthermore, an anastomosis connecting the retinal circulation to a deep retinal vascular abnormality was characteristic of the disorder. This subgroup of cases was termed “deep retinal vascular anomalous complex,” and the authors described other important associated macular abnormalities, including localized intraretinal hemorrhages and capillary telangiectasia. Support and validation of these clinical impressions were made possible by the work of Lafaut et al. (7). These investigators reported on clinical-pathologic correlations in six patients who had macular translocation surgery for this form of neovascular AMD. They found that IRN and SRN with detachment of the neurosensory retina were the most conspicuous findings. They also believed that the initiating vasogenic events were IRN and SRN, as reported by Slakter et al. (15).
nine eyes underwent thermal laser photocoagulation and eventually had recurrent CNV and progressive disciform scar formation. In 1995, Kuhn et al. (5) first clearly identified an RCA as a potential manifestation of this form of neovascular AMD. They specifically addressed the development of an RCA to an associated vascularized PED. Utilizing ICG angiography, this group found evidence for an RCA in 50 of 186—or 28%—of AMD patients with an associated vascularized PED. Indeed, they termed this form of neovascular AMD “retinal-choroidal anastomosis.” The outcome of laser photocoagulation treatment in these individuals was poor. Hartnett et al. (6), in a subsequent report in 1996 on 13 patients with this form of neovascular AMD and an associated serous PED, suggested that the neovascularization was in the deep retina; furthermore, an anastomosis connecting the retinal circulation to a deep retinal vascular abnormality was characteristic of the disorder. This subgroup of cases was termed “deep retinal vascular anomalous complex,” and the authors described other important associated macular abnormalities, including localized intraretinal hemorrhages and capillary telangiectasia. Support and validation of these clinical impressions were made possible by the work of Lafaut et al. (7). These investigators reported on clinical-pathologic correlations in six patients who had macular translocation surgery for this form of neovascular AMD. They found that IRN and SRN with detachment of the neurosensory retina were the most conspicuous findings. They also believed that the initiating vasogenic events were IRN and SRN, as reported by Slakter et al. (15).
In current terminology, it is known as RAP. It was first classified and named as a subset of AMD by Yannuzzi et al. (8) in 2001, who chose to name the condition RAP indicating the early appearance and origin of the neovascularization in the retina, the contiguous circumferential telangiectatic changes surrounding the core of new vessels, the development of IRN, the progression of new vessels into the subretinal space, and the variable as well as late onset of an RCA. In 2008, this form of neovascularization that originates from the retinal circulation has been demonstrated in a clinicopathologic correlation; Monson et al. (9) investigated the histopathologic features of RAP in an 87-year-old woman and reported an intraretinal angiomatous complex within the outer layer of the neurosensory retina overlaying a large PED with no CNV and no break in the Bruch’s membrane.
EPIDEMIOLOGY
Patients with RAP are similar clinically to patients with neovascular AMD from classic CNV or occult CNV (10). RAP has been estimated to account for 12% to 15% of newly diagnosed neovascular AMD (11) and is believed to have a different natural course and response to therapy compared with standard CNV (12). The patients with RAP tend to be female by a ratio of more than 2:1 and elderly at the time of initial diagnosis (80 years old). RAP is most frequently seen in Caucasians and uncommonly seen in Asians, and to date, it has not been described in Blacks. This racial predilection differentiates RAP from polypoidal CNV, which has a predisposition for pigmented races and the peripapillary area (13).
The initial lesion itself is always extrafoveal, presumably because of the perifoveal capillary-free zone, and it has never been reported to occur in the peripapillary area or peripheral fundus for reasons that are not known (14). Patients with RAP also exhibited a marked tendency toward bilateral and symmetric neovascular disease (15). In the study presented by Yannuzzi et al. (8), it was not possible to determine with reasonable assurance the presenting neovascular nature of bilateral cases with disciform disease in one eye. Patients who presented with unilateral RAP and subsequently developed neovascular changes in the fellow eye had an identical form of neovascular AMD without exception. Gross et al. (16) have reported that, in patients with unilateral RAP, a neovascular event in the fellow eye occurs at an annual and accumulative rate that far exceeds that for other forms of neovascular AMD, with a bilateral involvement in 100% of cases within 3 years. These findings, although considered well established, differ from those presented by Campa et al. (17) who showed that the incidence of RAP in the fellow eye is much lower (36.4% at 3 years) compared with previous report; however, these results have several limitations related to the retrospective nature and the small number of patients.
CLASSIFICATION
It was a long-held belief that all neovascularization in AMD originated from the choroidal circulation. In 2001, Yannuzzi et al. (8) challenged this traditional dogma based on the presumed origin and evolution of the neovascularized process. They believed that IRN originating from the inner retinal circulation produced a surrounding telangiectatic compensatory response to accommodate an increase in vascular perfusion, and they termed this variant “retinal angiomatous proliferation”. Thereafter, and due to a lingering uncertainty as to the origin of these lesions, Freund (11) has proposed naming this vascular lesion “type 3 neovascularization” to distinguish and emphasize the location of the neovascularization (intraretinal) independent of its origin.
Type 3 neovascularization (RAP) is now part of a logical extension of the original classification proposed by Gass (18) in his classic text on macular diseases. This classification is based upon the anatomic position of the abnormal vessels in relation to the monolayer RPE. Type 1 implies neovascularization located external or beneath the RPE. FA of eyes with these vessels commonly shows a pattern that is “poorly defined” with minimal leakage, also described as occult CNV. Type 2 neovascularization implies vessels that have penetrated the RPE layer to proliferate in the subneurosensory space. FA of this form of neovascularization will typically show a “well-defined” pattern with intense leakage, also referred to as classic CNV. The type 3 neovascularization
or RAP therefore indicates proliferating vessels within and below the retina itself. The origin of this neovascular subtype can be from either circulation and may originate from both circulations simultaneously in the form of an RCA. The presence of an RCA gives this entity many of its characteristic clinical, spectral-domain optical coherence tomography (SD-OCT), and angiographic features including intraretinal hemorrhages and CME. Type 3 lesions have been observed originating in areas with substantial photoreceptor loss that has brought the deep retinal vasculature in close proximity to the underlying RPE, Bruch’s membrane, and choriocapillaris. Typically, the angiogenic response occurs overlying a focal drusen/basal laminar deposit that may already be infiltrated by type 1 vessels. Presumably, loss of or erosion through the intervening RPE and an appropriate angiogenic milieu would allow the retinal and choroidal circulations to merge in the form of RCA with a continued proliferative response. As these lesions originate from both the retinal and choroidal circulations, they never originate within the foveal avascular zone.
or RAP therefore indicates proliferating vessels within and below the retina itself. The origin of this neovascular subtype can be from either circulation and may originate from both circulations simultaneously in the form of an RCA. The presence of an RCA gives this entity many of its characteristic clinical, spectral-domain optical coherence tomography (SD-OCT), and angiographic features including intraretinal hemorrhages and CME. Type 3 lesions have been observed originating in areas with substantial photoreceptor loss that has brought the deep retinal vasculature in close proximity to the underlying RPE, Bruch’s membrane, and choriocapillaris. Typically, the angiogenic response occurs overlying a focal drusen/basal laminar deposit that may already be infiltrated by type 1 vessels. Presumably, loss of or erosion through the intervening RPE and an appropriate angiogenic milieu would allow the retinal and choroidal circulations to merge in the form of RCA with a continued proliferative response. As these lesions originate from both the retinal and choroidal circulations, they never originate within the foveal avascular zone.
A three-stage classification was proposed to characterize the clinical manifestations and progressive changes. The clinical appearance of the earliest manifestations was termed “stage I” (Fig. 8.1). As these vessels evolved, they appeared to extend beneath the neurosensory retina to become SRN termed “stage II” (Fig. 8.2A and B) and eventually merged with the choroidal circulation proliferating beneath the RPE as CNV, or stage III, to form an RCA (Fig. 8.3). The original interpretation of this angiogenic sequence was based on reports of atypical forms of neovascularization in AMD (4,5,13), particularly with the use of combined FA and ICG angiography and the first-generation OCT imaging system (OCT-1, Carl Zeiss, Meditec, Inc., Dublin, CA, USA) available at that time (19).
Stage I: Intraretinal Neovascularization
Capillary proliferation within the retina, originating from the deep capillary plexus in the paramacular area, is the earliest manifestation detected in any patient with RAP. In this stage, there is usually a nodular mass of angiomatous tissue in the middle and inner retina. As this lesion progresses, there is a predominantly vertical extension of the IRN to the anterior and posterior boundaries of the retina. The neovascularization also may show a lateral extension of the vessels in an irregular stellate configuration. This is characterized by projections of capillaries tangentially and obliquely from the primary neovascularized area, resembling the appearance of a sea urchin. One or more prominently dilated perfusing arterioles or draining venules could be seen early in this stage, communicating with the core of the IRN. Evidence also demonstrates a retinal-retinal anastomosis (RRA). Some medium-sized capillaries projecting from the core of angiomatous proliferation have been noted to communicate with the larger, dilated inner retinal vessels. A few intraretinal hemorrhages and intraretinal edema could be seen clinically surrounding the IRN. The FA reveals a focal area of intraretinal staining with an indistinct border corresponding to the IRN and surrounding intraretinal edema. ICG reveals a focal area of intense hyperfluorescence within the retina or a so-called hot spot at the site of the IRN. Matsumoto et al. (20) showed with SD-OCT the origin of the IRN in nine eyes with untreated RAP. Retinal edema was always observed around the IRN in eyes with stage I. The frequency of retinal edema around the IRN and the low incidence of serous retinal detachment (SRD) suggest the intraretinal origin of neovascularization in RAP. The IRN was outside the avascular fovea in all eyes and appeared as a highly reflective mass that originated at the outer plexiform layer (OPL) and extended to the deeper retinal layers. In eyes at stage I, the highly reflective mass at the OPL corresponding to IRN disappeared, but drusenoid PED remained unchanged after repeated intravitreal bevacizumab (IVB) in SD-OCT, which lends further support to the postulation of intraretinal origin of RAP. The disruption of the RPE beneath the IRN is often seen in stage I. Although Freund et al. (11) interpreted the disrupted RPE as intraretinal invasion of CNV in early-stage RAP, it may reflect the drusenoid PED with attached IRN.
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