Neovascular Phenotypes:RAP (Retinal angiomatous proliferation)



Rufino Silva, MD, PhD
Coimbra University Hospital. Faculty of Medicine. Coimbra. Portugal 




Over 100 years ago, Oller described for the first time the presence of anastomoses between the retinal and choroidal circulations in eyes with disciform scars(1).

Chorioretinal anastomoses were later described, associated with laser photocoagulation(2), radiotherapy(3), chorioretinal inflammatory diseases(4) and parafoveal telangiectasias(5).

Anatomopathological studies of these anastomoses were also undertaken in disciform scars resulting from late age-related macular degeneration (AMD)(6).

In 1992, Hartnett et al.(7) described nine cases of retinal neovascularization, to which they referred as “deep retinal vascular anomalous complex”.

In 2000, Slakter et al.(8) described chorioretinal anastomoses in eyes with pigment epithelial detachment and indocyanine green (ICG) hot spots.

In 2001, Yannuzzi et al. described chorioretinal anastomosis as neovascular proliferation with origin in the retina, and proposed the designation of RAP – retinal angiomatous proliferation(9).

Several authors(10-15) maintained the designation of chorioretinal anastomosis, proposing a choroidal origin for this clinical entity.

In 2008, Yannuzzi et al.(16) described 5 cases of RAP with the neovascular complex originating in the choroid instead of the retina, and proposed that RAP should be called type 3 neovascularization.

However, RAP is still the most common designation.




According to Yannuzzi et al.(9), the initial neovascularization process in RAP consists of 3 stages:

i) Stage I – Intraretinal neovascularization. This stage is mainly diagnosed when the second eye is already affected.

The presence of associated small retinal haemorrhages constitutes a very useful sign in early RAP diagnosis.

A small elevation of the inner/intermediate retina caused by angiomatous tissue may be observed under a slit lamp; this elevation may extend tangentially, assuming telangiectasic appearance.

In FA, the angiomatous complex is observed as a hyperfluorescent area in front of the RPE, identical to that occurring in classic choroidal and, more frequently occult neovascularization.

Dilated retinal vessels may perfuse and drain the intraretinal neovascularization (IRN) and form retino-retinal anastomoses. ICG may reveal a hot spot with staining and leakage.

ii) Stage II – Involvement of the subretinal space with localized neurosensory detachment of the retina, oedema and retinal haemorrhages at the edges may already be observed in fundus colour photography.

The angiomatous formation draining vein becomes visible, originating in the deep retina.

PED is observed in 94% of eyes; FA may reveal well-delimited hyperfluorescence in the diffuse leakage area associated with PED, identical to that occurring for a minimally classic choroidal neovascular membrane.

ICG clearly establishes stage II diagnosis as the presence of a hot spot with leakage, as well as a hyperfluorescent area associated with serous pigment epithelium detachment (SPED).

Leakage might not be revealed by FA, probably because fibrin from retinal exudates cannot be impregnated with fluorescein, contrary to what occurs with ICG(18).

FA is rarely useful in differential diagnosis between classic, occult or minimally classic membranes and stages I and II(9), contrary to ICG, where a slow-growing extra, juxta or subfoveal hot spot, sometimes asymptomatic, is observed in stages I and II.

Retino-retinal anastomoses may also be observed in stage II.

iii) Stage III – Choroidal neovascularization is clearly visible, sometimes with the appearance of vascularized PED.

According to Gass(13), RAP would progress in 5 stages instead of 3, easily identifiable by FA and ICG:

I) Pre-clinical stage – Atrophy of the outer retina, with retinal capillaries moving closer to a choroidal neovascular complex located below the RPE – type 1 choroidal neovascularization – and no clinical signs of chorioretinal anastomosis. ICG would be necessary to identify type 1 neovascularization.

II) Early clinical signs – Anastomosis between dilated capillaries of the deep retina and the choroidal neovascular complex is associated with small intraretinal haemorrhages, which would constitute the first clinical sign of chorioretinal anastomosis.

This stage may occur weeks or months before stage 3, where subretinal choroidal neovascularization is already observed.

III) Proliferation of choroidal neovascularization over the RPE – subretinal neovascularization – type 2 CNV.

IV) Appearance of serous PED caused by activation of newly formed subepithelial vessels.

V) Mixed neovascularization – piggyback-type neovascularization, with two levels – type 1 and type 2 with cicatricial disciform lesion, making chorioretinal anastomosis visible.

Stage 3 in the Gass classification corresponds to stage I in the Yannuzzi classification, with stages 4 and 5 in the Gass classification corresponding to stages II and III, respectively.

Currently, the Yannuzzi classification is the most widely used.


Diagnosis of RAP


Clinical observation


The presence of small central macular haemorrhages, sometimes punctiform, associated with oedema in an eye with soft drusen, is highly suggestive of RAP in its initial stages (Fig 1).

The following lesions suggest RAP in AMD(8-17):

i) Small multiple haemorrhages, pre, intra or subretinal, normally not observed in macular neurosensory detachments with choroidal neovascularization.

ii) Tortuous, dilated retinal vessels, sometimes showing retino-retinal anastomoses (Fig. 2).

iii) Telangiectasias.

iv) Microaneurysms.

v) Sudden disappearance of a retinal vessel that appears to have moved deeper.

vi) Hard exudates around the retinal lesion (Fig. 1,3,4).

>> Figure 1 - RAP lesion

>> Figure 2 - ICG.

>> Figure 3 - RAP lesion.

>> Figure 4 - Bilateral RAP lesion.

>> Figure 5 - RAP lesion


Differential diagnosis


Differential diagnosis is mandatory for parafoveal telangiectasias, other forms of choroidal neovascularization and polypoidal choroidal vasculopathy.

Idiopathic parafoveal telangiectasia is a condition involving dilation of retinal capillaries located near the fovea, in one or both eyes.

RPE hyperplasia may also occur, with refractive punctiform deposits and macular leakage being observed in FA.

Migration of one or more venules to the deep retina may also be observed(5).

Anastomoses between retinal vessels and the choroidal circulation have been described, as well as new choroidal vessels.

The most significant differences are the fact that telangiectasias are not associated with serous PED, the RPE is healthier and choroidal neovascularization associated with parafoveal telangiectasias occurs less frequently(5,10).

Differential diagnosis should also be performed for other forms of choroidal neovascularization (CNV) with ICG hot spots (occult CNV) and polypoidal choroidal vasculopathy (PCV).

Small intraretinal haemorrhages, sometimes punctiform, in patients with soft drusen, are very typical in RAP, as are telangiectasias and retino-retinal anastomoses.

Retinal haemorrhages in PCV are normally larger, with round reddish-orange macular lesions being observed in the eye fundus.

OCT is also a useful differential diagnosis tool in RAP, PCV and occult membranes.

In RAP, intraretinal hyperreflectivity may be observed, corresponding to angiomatous proliferation associated with intraretinal fluid and/or RPE detachment.

In PCV, polyps appear in OCT as abrupt protrusions from the REP/Bruch’s membrane band, often associated with neurosensory detachment.


Natural progression


Natural history may be highly variable and probably similar to that of other CNV lesions.

However, many reports ascribe a poor prognosis to RAP lesions.

Kuhn et al.(12) studied 22 eyes and observed structural evolution towards classic membranes, signs of RPE rupture and fibrous scars in 36.4%, 4,6% and 31,8% of cases, respectively.

In functional terms, decrease in visual acuity occurred in 77% of cases. Final visual acuity (VA) values equal or inferior to 20/200 were observed in 14 eyes studied by Hartnett et al.(17).

In a retrospective and one-year study performed by Silva et al.(14) in 17 consecutive patients with RAP, a significant VA loss was observed in 69% of eyes and vision did not improve in any case(14).

Significant loss of vision was observed in the first 3 months after diagnosis; a trend towards stabilization was observed subsequently, with no significant differences in average VA being observed at 3, 6 and 12 months and at the end of the study (p>0.05).

Viola et al.(24) obtained also poor results: in 81% of cases, visual acuity had decreased by 2 ETDRS lines or worse by occasion of the 6-month examination. On final examination (6 - 44 months), 62% of study subjects showed subretinal fibrosis, with 56% showing chorioretinal anastomosis.




RAP was observed in 5 to 28% of new cases of occult exudative neovascularization (Table 1).

Kuhn et al.(12) and Axer-Siegel et al.(19) used SLO angiography, while Fernandes et al.(25) used videoangiography, which may explain the differences observed.

Using the ImageNet 1024 videoangiography system, our team observed a prevalence of 9.4% in a consecutive series of 563 patients(14).

Women appear to be more affected, corresponding from 64.7% to 71% of patients(8,12).

Patients with RAP are normally older than those showing occult membranes or membranes with classic components – average age of 79 vs. 76 years(6,8,9).

The average and median ages of a series of 108 patients studied by Yannuzzi et al.(9) were 80 and 81 years respectively.

Both eyes were similarly affected in 51.9% of patients, with RAP occurring in the second eye an average 15 months after appearing in the first eye.

At 3 years, both eyes were affected in 100% of patients(26,27).

Prevalence appears to be greater in hyperpigmented eyes(8,9,28).

>> Table 1: Percentage of RAP




Lafaut et al.(18) studied six “deep retinal vascular anomalous complex” lesion specimens from retinal translocation surgery in eyes studied with FA and ICG.

The deep vascular anomalous complex was located in front of the RPE, thus not representing choroidal neovascularization.

Nodular fibrovascular complexes surrounded by a ring of diffuse drusen – basal linear deposits under electron microscopy –, pigment epithelium and an amorphous fibrous material containing photoreceptor outer segment debris were observed.

The lesion was not covered by pigment epithelium; however, the latter was preserved around the lesion.

The amorphous material did not cover the retinal surface of the membrane, which adhered directly to the outer nuclear layer in 50% of cases.

Anastomoses between fibrovascular nodules and the choroidal circulation were only observed in cases showing isolated disciform scars.

Avascular fibrocellular membranes were observed on the inside of Bruch’s membrane and, in three cases, on the choroidal side of diffuse drusen.

Fibrin was present in affected retinas; choroidal anastomosis was not observed.

However, the latter possibility was not excluded, since the specimens studied may not have included the entire lesion.

Serous PED without CNV was observed in three cases. Gass et al.(13) described chorioretinal anastomosis and atrophy of the outer nuclear layer in a pre-clinical case, with outer retinal capillaries moving close to a choroidal neovascularization focus, having proposed a choroidal origin for RAP, instead of the retinal origin proposed by Yannuzzi.

In a histopathological study performed in nine neovascular lesions classed as RAP, Shimada et al.(29) found only intraretinal neovascularization in stage 2 cases.

In stage 3 cases, these authors found choroidal and intraretinal neovascularization; they concluded that their findings were in agreement with the classification proposed by Yannuzzi.

These authors observed expression of VEGF (in intraretinal neovascularization and in the RPE), CD68-positive macrophages (in the neovascularization area) and expression of hypoxia-inducing factors alpha 1 and alpha 2 (HIF 1 alpha and 2 alpha) in neovascular endothelial cells.

According to these authors, intraretinal neovascularization would appear before the occurrence of choroidal neovascularization and be associated with ischemia and increased expression of VEGF and inflammatory factors.

Monson et al.(30) described the histopathological characteristics of RAP in an 87-year-old woman.

The images obtained by fundus examination and fluorescein angiography were histopathologically consistent with a neovascular intraretinal angiomatous complex without subretinal pigment epithelial neovascularization.

Therefore, the origin of the neovascularization process (choroidal or retinal) is a controversial issue.

However, it is known that like in other forms on AMD-related choroidal neovascularization RAP lesions are associated with increased VEGF and macrophage expression, ischemia and age-related macular alterations.




The exact mechanism and origin of RAP are not yet known.

Kuhn et al.(12) studied the evolution of RAP in the second eye of two patients.

These authors assumed the existence of two asymmetrical membranes, a smaller retinal membrane – the angiomatous anomaly – over a larger membrane – the choroidal membrane, secondary to failure of a diseased pigment epithelium, unable to modulate and inhibit neovascular factors.

Pigment epithelial decompensation might also lead to deposition of materials in the subretinal space, under the basal lamina, and consequent thickening of Bruch’s membrane, which would decrease inner retinal oxygenation.

The presence of serous PED might increase hypoxia by moving the retina even further from the choroid(17).

Choriocapillaris atrophy and hypoxia may lead to intense neovascular activity, with reactive synthesis of growth factors, such as VEGF(31).

Overexpression of VEGF is sufficient to produce IRN and subretinal neovascular membranes (SRN) in animal and human models(31,32).

The relatively good response of these lesions to ranibizumab and bevacizumab confirms the important role of VEGF in the pathogenesis of RAP lesions.

According to Yannuzzi et al.(9), the initial neovascular process in RAP occurs in the deep retina and consists of 3 stages.

Gass(13) contested a retinal origin for anastomosis, with basis on the following facts:

i) no communication between retinal vessels and the choroid was found in surgical specimens;

ii) the location of vascular anomalous complexes on the outer nuclear layer of atrophic retinas is more compatible with a choroidal origin hypothesis;

iii) although the macular retina is not excised in surgery, the retinal neovascular complex disappears and no macular hole is left, which contradicts its retinal origin.

It is clear that no definitive sequential histopathological or imaging evidence exists to support intraretinal versus choroidal origin of RAP lesions.

Yannuzzi et al.(16) re-evaluated the early stages of RAP lesions in five eyes, using FA, ICG, td-OCT and fd-OCT, having concluded that the initial lesion may have its origin not only in deep retinal capillaries but also in the choroid.

They described RAP disease as “type 3 neovascularization”, a type of neovascularization with preference for the retina, displaying the following manifestations(16):

i) Focal neovascular proliferation from the deep retinal layer (originally RAP)

ii) Intraretinal neovascular extension from underlying occult type I CNV (originally occult chorioretinal anastomoses)

iii) De novo breaks in Bruch’s membrane with neovascular infiltration into the retina.

This new category, type 3 neovascularization, helps to resolve the various conflicting theories and descriptions of RAP lesion origin: neovascularization in RAP may originate not only from deep retinal capillaries but also from the choroid.

However, the main issue regarding RAP lesions is not the intraretinal or choroidal origin of neovascularization but its unique characteristic of two neovascular foci: one located in the deep retina and the other at the choroidal level.




RAP lesions were never included in randomized clinical trials as a separate AMD subtype.

All available reports concerning treatment of RAP lesions using different treatment modalities refer to non-randomized studies.

Thermal laser photocoagulation, surgical ablation, PDT, intravitreal triamcinolone, intravitreal antiangiogenic drugs and combined treatments have been used for treating RAP lesions.

Thermal laser – Kuhn et al.(12) photocoagulated hot spots in 28 eyes with “occlusion” in 25% of cases, including one eye with recurrence.

No occlusion occurred in the remaining 75% of cases, despite multiple treatment sessions. Treatment caused tearing of the pigment epithelium in 45% of cases and visual acuity decreased in 86% of eyes.

The low success rate observed might have been related to several factors, such as inadequate laser penetration – given serous PED height or absorption of radiation by the subepithelial fluid –, incorrect location or presence of multiple afferent vessels.

Slakter et al.(8) confirmed this poor prognosis, particularly in serous PED cases.

Occlusion was not possible in 86% of eyes and progressive disciform evolution was observed.

In a series of 108 eyes with RAP, Bottoni et al.(33) achieved full obliteration of chorioretinal anastomosis in 57.1% of cases classed as stage 1, according to Yannuzzi.

Clinical experience shows that some extrafoveal stage 1 lesions (Yannuzzi classification) are amenable to laser photocoagulation(34).

However, the risk of complications needs to be evaluated(11) and careful follow-up is mandatory, given the high rates of persistence and recurrence.

Surgical ablation – Borrillo et al.(35) performed vitrectomy with detachment of the posterior hyaloid face, surgical section of afferent arterioles and draining veins and membrane excision in 4 eyes with RAP and PED – stage II – with resolution of intraretinal oedema, collapse of the PED after 7-10 days and increased average visual acuity (20/200 pre-operative vs. 20/70).

Shimada et al.(36) excised the neovascular complex in 9 eyes from 8 patients – stages II and III.

VA remained stable in the post-operative period; however, significant destruction of the RPE and the choriocapillaris occurred in patients with serous PED.

The authors concluded that surgery may stabilise VA in stage III but is not indicated in stage II.

Surgical section of the afferent vessel associated with intravitreal injection of triamcinolone was performed in one eye, with resolution of exudation and visual acuity of 20/320 at 6 months(37).

Nakata M et al.(38) found surgical ablation (even combined with PDT) not useful for the treatment of RAP lesions, given the high frequency of reperfusion from retinal inflow vessels associated with this procedure.

Shiragami C et al.(39) observed recurrence of RAP lesions in all 7 cases treated, 2 to 13 months after surgical ablation.

Surgical ablation of RAP is no more recommended for RAP lesions, considering the better outcomes achieved with other treatment modalities, such as antiangiogenic drugs.

Photodynamic therapy alone or associated with triamcinolone acetate.

In studies of photodynamic therapy in monkeys with neovascular complexes and chorioretinal anastomosis, occlusion of the complex was observed, but not of anastomoses.

Anastomoses would be responsible for neovascular complex repermeabilization(40).

Kusserow et al.(41) treated 6 eyes with predominantly classic membranes and chorioretinal anastomosis without success.

No improvements in VA were observed for any of the treated eyes. Membranes continued to grow; no post-treatment hyperfluorescence was observed in FA.

Stabilization or improvement in visual acuity was observed after PDT in 73.3% of eyes (<3 lines loss) at 12 months, which represent better outcomes compared to natural evolution(14).

However, significant VA decline was observed in the second year, mainly due to recurrence(15).

Boscia et al.(42) treated 13 eyes with PDT, having concluded that PDT would only be useful in cases where serous PED represents less than 50% of the lesion.

In 2006, these authors referred that early treatment of eyes with smaller lesions using PDT with verteporfin potentially led to a beneficial effect on vision, whereas it might worsen the natural progression of larger lesions, with most eyes undergoing enlargement, disciform transformation or RPE tear(43).

Reported short-term results of non-randomized studies on RAP lesions treated with PDT and IVTA(44,45,46) revealed apparently better VA outcomes and/or a reduced number of treatment sessions compared to PDT alone. However, recurrences were also frequent(47,48).

Krebs I. et al.(49) found no significant differences between the PDT monotherapy group and the combined PDT and Intravitreal Triamcinolone (IVTA) group regarding evolution of distance VA, retinal thickness and lesion size, having concluded that new therapeutic strategies might be required in RAP lesions, probably including therapy with antiangiogenic agents.

Antiangiogenic agents: Similarly to what occurs in classic and occult lesions, intravitreal antiangiogenic drugs appear to lead to better outcomes in the treatment of RAP lesions than PDT alone.

Treatment with ranibizumab(50,51) and bevacizumab(52,53) has shown very promising results up to 12 months, with treated eyes displaying significant functional and anatomical improvements and no apparent short-term safety concerns.

Improved VA and short-term oedema reduction or elimination, were also observed in combined treatments using PDT and ranibizumab(54) or bevacizumab(55,56).

Information from clinical trials suggests that the response of RAP lesions to CNV treatments may be similar to that of other variants of neovascular AMD(57).

The superiority of combined treatment with PDT and ranibizumab or bevacizumab has not yet been demonstrated.

Longer follow-up will be necessary to evaluate whether the well-known tendency for recurrence observed with PDT and entailing VA decline is also observed with antiangiogenic drug monotherapies or combined treatment with PDT.


>> References


Last revision: October 2011 by Rufino Silva