This series of clinical cases of occult CNV schematically illustrate the polymorphic clinical features observed in routine clinical practice.

The clinical course is usually slow but progression is almost inevitable, either spontaneously or despite treatment, which always requires long-term observation.

Early lesions associated with little or no symptoms can frequently be detected in the fellow eye at a stage when

8treatment has a better chance of preserving satisfactory vision and even maintain reading.

After the initial phase of extension of the lesions, sometimes lasting several months or several years, they can be complicated by the appearance of classic choroidal neovascularization.

Lesions are still very sensitive to treatment at this stage.

The prognosis is much more guarded in the presence of serous pigment epithelium detachment, which carries a risk of hemorrhage and tears These complications are serious but can still respond favorably to treatment.

Advanced lesions with mixed and/or extensive choroidal neovascularization are even more severe due to fibrosis, alterations of the RPE, and severe photoreceptor disruption. However, stabilization or even considerable improvement can be achieved in some of these cases.

At the stage of atrophy of the outer retinal layers and RPE, treatment is intended to prevent extension of the lesions or massive hemorrhage.

Early diagnosis and detection of AMD therefore improve prognosis, and close observation of the fellow eye by repeated imaging can preserve vision.

Patients are not always aware of the risks related to poor follow-up at this early stage.

Described for the first time in 1994 as an active and progressive form of AMD, chorioretinal anastomoses

(CRA), constitute a unique entity among the various clinical forms of wet AMD (Coscas 1994, International Symposium on Fluorescein Angiography, Toronto). Chorioretinal anastomoses are active lesions and frequently involve both eyes.

They are different from the chronic anastomoses observed at the advanced stage of disciform scars, (Oeller,

1903).

Even from its early stages, CRA typically presents with the following signs:

▬Juxtafoveal retinal hemorrhage

▬An area of choroidal neovascularization (small and limited but clearly visible on fluorescein angiography and even more precisely on SLO-ICG angiography),

▬located within a pigment epithelium detachment

On SLO-ICG, a round Pigment Epithelium Detachment (PED) centered on the fovea can be detected in the early phases and gradually increases in size at the same rate as choroidal neovascularization and the anastomosis. The anastomosis between CNV and a retinal arteriole or veinule becomes increasingly visible in the late phase angiograms.

Chorioretinal anastomoses are relatively frequent, with a prevalence of 9% in our series of 200 consecutive cases of wet AMD.

Pathogenic Hypotheses

Choroidal origin

The theory that CRA originates from the choroidal circulation, originally suggested by the Créteil Group (Kuhn, 1995) and then by Slakter (1996), was also confirmed by Gass (2003).

Gass emphasized not only the importance of retinal hemorrhage as the first sign of this entity, but also that the origin of the choroidal neovascularization is located over a small area of atrophy of the RPE. He postulated that contact and subsequent anastomosis between CNV

and retinal vessels associated with the development of a serous PED.

Gass therefore concluded that the neovascularization associated with CRA is of “choroidal origin and subretinal localization”.

Retinal origin

A retinal origin for the neovascular proliferation has been suggested by other authors. The vascular proliferation, subsequently extends to the outer retina and then underneath the RPE. After it communicates with choroidal vessels, it is accompanied by a vascularized PED (Hartnett, 1996 and Yannuzzi, 2001 ).

The success of this latter hypothesis has led to the name retinal angiomatous proliferation” (RAP), which is widely used in the literature despite the unresolved controversy of its origin.

Until now, no case of early RAP followed throughout its natural history to the complete form of a vascularized PED with chorioretinal anastomosis has been well documented.

Type 3 neovascularization

The term “type 3 neovascularization” has been more recently proposed, indicating that the initial neovascularization may be derived from either:

▬The choroid or

▬Deep retinal capillaries,

with subsequent formation of anastomosis and intraretinal fluid (Freund, 2008, Yannuzzi, 2008).

Regardless of the initial subclinical stage, the symptomatic phase consists of:

▬Choroidal neovascularization,

▬Anastomoses with retinal vessels, and both

▬Subretinal and intraretinal neovascular proliferation.

The clinical pattern of CRA is as follows:

▬In the context of wet AMD,

▬With a vascularized PED,

▬Associated with high-risk soft drusen.

The lesion becomes bilateral and symmetrical in almost every case.

In most cases, biomicroscopic examination demonstrates one or more juxtafoveal retinal hemorrhages arising at the end of a retinal vessel near the fovea.

This retinal vessel has an abnormal course and (in contrast with adjacent vessels) becomes dilated and tortuous (Figure 1a, b, and c). Specifically, it appears to be disrupted as it plunges deeply towards the choroid, next to the hemorrhage, forming a right angle or an arch.

Its course and communications are often poorly visual-

ized by biomicroscopy.

9

Fluorescein Angiography

Fluorescein angiography may provide better visualization of the retinal vessels and the retino-choroidal anastomosis.

The deep neovascularization rapidly induces intense and localized leakage and hyper-fluorescence (hot spot) (Figure 2).

This hot spot is often initially partially masked by the retinal hemorrhage. Later, the progressive filling of the PED space with dye, does not allow visibility of the retino-choroidal anastomosis.

SLO-ICG Angiography

In contrast, SLO-ICG angiography allows precise analysis of the neovascularization and its communications with one or several retinal arterioles and/or venules (Figure 1b and c).

The site of the anastomosis is hyper-fluorescent and contrasts markedly against the dark background of the PED. There is no early leakage of the ICG dye and this leakage is only observed in the late phase of the angiogram (Figure 1b and c, and Figure 2).

Time-Domain OCT (Stratus*)

Time-Domain OCT (Stratus*) readily demonstrates:

▬The PED (usually optically empty), and

▬The intraretinal leakage

Exudative reactions are always marked with increased retinal thickness and particularly numerous and confluent cystoid spaces (Figure 2).

They are often present in two layers of the retina and are sometimes accompanied by subretinal fluid with subRPE detachment (PED) induced by the presence of deep choroidal neovascularization. In some cases, a hyperreflective band may be observed through the PED, suggestive of a fibrovascular tract.

Spectral-Domain OCT (Spectralis*)

The SD-OCT appearance of the lesion is very suggestive of the anatomical location with:

▬Localized disruption of the RPE, and

▬Hyper-reflective tissue derived from the choroid, bulging into the retina, which appears to correspond to the chorioretinal anastomosis.

Early stages of the disease can sometimes be detected during follow-up for the fellow eye. At this stage, a small and limited PED may be found. Within this PED, a localized zone of hyper-reflectivity is initially located underneath the RPE and then crosses the RPE band through a disruption. The lesion then extends towards and into the retinal tissue.

During progression, choroidal neovascularization may spread to invade the entire area of the PED (see Clinical

Cases, p. 282 to 300).

Complications

Extensive proliferations, retraction, or progression of this neovascularization can cause further complications such as:

▬RPE tears

▬Macular hemorrhages

▬Multiple anastomoses

Prognosis

Even without treatment the lesion may remain dormant for many months. But the natural history is always severe resulting in severe visual disability as the disease is almost always bilateral.

Treatment Modalities

Different treatment options have been proposed, but their results have remained largely disappointing.

Laser Photocoagulation

Thermal laser photocoagulation has been almost abandoned due to the high rate of neovascular recurrence and clinical relapse.

These recurrences are sometimes very severe and accom-

panied with hemorrhages and RPE tears.

9

The only cases with a chance of success are those eyes treated at a very early stage.

However, at this initial stage of minimal lesions associated with fairly good visual acuity, the benefit of treatment must be weighed against the high risk of complications, especially when more benign treatment modalities are available.

Anti-Angiogenic Therapy

Intravitreal injections of anti-VEGF appear to provide more favorable results, as demonstrated by several pilot studies.

Persistent lesions, relapses, and long-term recurrences are still frequent.

Nevertheless, these lesions appear to remain sensitive to on-going anti-VEGF injections, especially when treatment is initiated rapidly. Long-term follow up after treatment is therefore important.

Combined Therapy

PDT combined with other treatment modalities has also demonstrated useful results in CRA.

To date, only pilot studies have been reported.

These combination therapies require prolonged follow-up after treatment, and the long-term prognosis of these eyes remains guarded.

Photodynamic Therapy

This treatment can provide improvement in some cases, usually at an early stage, but it does not appear to provide reproducible results.

Several cases of RPE tears following PDT have been reported.

Cases of delayed treatment in advanced forms are especially associated with a high risk of spontaneous RPE tears.

Protection of the Fellow Eye

Prevention of vision loss therefore appears to be crucial. Prolonged follow-up with repeated comprehensive imaging of the fellow eye in patients already presenting with lesions in one eye is important.

Diagnostic imaging is therefore at least as important, if not more important, in this context than in all other forms of wet

AMD.

An 87-year-old monocular man with a history of central retinal artery occlusion in his right eye presented with recent, moderate loss of vision in his left eye.

This patient had a history of systemic cardiovascular disease with well-controlled hypertension. Coronary, popliteal, and iliac artery bypass grafts were well-toler- ated. VA: RE: LP - LE: 20/50.

Biomicroscopic Examination

Several disseminated soft drusen and a microscopic juxtafoveal hemorrhage at 5 o’clock (Figure 3a and b). Autofluorescence demonstrated a small territory of infe-

rior temporal juxtafoveal hyper-fluorescence.

9

Fluorescein Angiography

▬Late phase: progressive staining, close to the zone of intense fluorescein leakage, suggested progressive filling of a small PED (Figure 3b).

SLO-ICG Angiography

a): Early phase: hypo-fluorescent area suggestive of a PED. There was also a small, round, well-delineated, deep hyper-fluorescent lesion indicative of choroidal neovascularization. Retinal vessels were visualized but their terminations were fine and indistinct (Figure 3c).

The enlarged view clearly demonstrated the chorioretinal anastomosis with a direct communication between retinal vessels and the deeper choroidal neovascularization. There was also an end-to-end retino-retinal anastomosis between a retinal arteriole and a retinal venule (Figure 3d).

▬A small (200 microns) zone of early, intense hyperfluorescence, adjacent to the hemorrhage, was de-

tected but rapidly masked by fluorescein leakage

(Figure 3a).

▬The hyper-fluorescent area was located adjacent to the distal end of the retinal vessel, but the anastomosis was masked by fluorescein leakage.

b): Late phase: the edges of the dark and hypo-fluorescent PED were well-defined with hyper-fluorescent neovascularization contrasting against this dark background.

Suggested Diagnosis:

Initial stage of chorioretinal anastomosis with a small

serous PED, which had progressed over several weeks.

Horizontal cross-section

The RPE was raised with a moderately reflective cavity and a wavy contour, corresponding to the initial small PED. (Figure 4a).

A localized disruption of the RPE was observed adjacent to the PED, close to the center of the fovea. The CNV appeared to protrude through this disruption in the RPE and proliferate within the retina.

Abundant SRF was observed anterior to the RPE band.

Vertical cross-section

The vertical cross-section, centered directly on the angiographically hyper-fluorescent area, showed the same break in the RPE and unequivocally demonstrated protrusion of the CNV towards the retina (Figure 4b).

Anterior to the RPE, the cross-section showed increased retinal thickness with subretinal and intraretinal fluid. The outer retinal layers were clearly visible and only altered over the zone of protruding CNV. Numerous bright hyper-reflective spots were present.