124
al.
(16)
re-evaluated the early stages of RAP lesions in
five eyes, using FA, ICG, td-OCT and fd-OCT, hav-
ing 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 underly-
ing occult type I CNV (originally occult chorioretinal
anastomoses)
iii)
De novo
breaks in Bruch’s membrane with neovas-
cular infiltration into the retina.
This new category, type 3 neovascularization, helps to
resolve the various conflicting theories and descrip-
tions 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 choroi-
dal origin of neovascularization but its unique charac-
teristic of two neovascular foci: one located in the deep
retina and the other at the choroidal level.
9. Treatment
RAP lesions were never included in randomized clini-
cal trials as a separate AMD subtype. All available
reports concerning treatment of RAP lesions using
different treatment modalities refer to non-random-
ized studies.
Thermal laser photocoagulation, surgical ablation,
PDT, intravitreal triamcinolone, intravitreal antian-
giogenic 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 mul-
tiple 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 subepi-
thelial fluid –, incorrect location or presence of multi-
ple afferent vessels. Slakter et al.
(8)
confirmed this poor
prognosis, particularly in serous PED cases. Occlusion
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 associ-
ated with increased VEGF and macrophage expres-
sion, ischemia and age-related macular alterations.
8. Pathogenesis
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 reti-
nal 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 bevaci-
zumab confirms the important role of VEGF in the
pathogenesis of RAP lesions.
According to Yannuzzi et al.
(9)
, the initial neovascu-
lar process in RAP occurs in the deep retina and con-
sists 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 sur-
gery, the retinal neovascular complex disappears and
no macular hole is left, which contradicts its retinal
origin.
It is clear that no definitive sequential histopathologi-
cal or imaging evidence exists to support intraretinal
versus choroidal origin of RAP lesions. Yannuzzi et
