Neovascular Age-Related Macular

Degeneration

Choroidal Neovascularization

Choroidal neovascularization is a pathophysiologic process that produces specific structural alterations in the macular region that can be readily detected and evaluated with angiography. The new abnormal choroidal vessels proliferate along the inner aspect of Bruch’s membrane and penetrate through defects in Bruch’s membrane into the sub-RPE space (type 1 neovascularization) or subretinal space (type 2) [50]. The angiographic appearance of CNV varies according to the density, location, and maturity of these new vessels as well as the condition of the surrounding retina and RPE.

CNV and Fluorescein Angiography

that has added to our understanding of these angiographic findings. For example, it appears that actually the majority of eyes with occult CNV on the basis of fluorescein and ICG angiography have a fibrovascular PED [54].

It is not uncommon for both classic and occult CNV features to be present in one lesion. In this situation, the lesion is characterized in accordance with the relative area of each type of CNV. For example, if a lesion is 75% classic and 25% occult, it would be defined as being predominantly classic. Conversely, if the lesion is 25% classic and 75% occult, the lesion would be called predominantly occult. Lesions with classic CNV occupying less than 50% of the total area are referred to as minimally classic lesions. Historically, these descriptive terms were particularly useful in the era of photodynamic therapy for neovascular AMD as a reliable and reproducible way to classify lesions.

Categorization of CNV by classic and occult features on fluorescein angiography was originally introduced by the Macular Photocoagulation Study Group as a grading system for eyes enrolled in the Macular Photocoagulation Study [51]. The term “classic” CNV refers to a well-delineated, discrete focus of hyperfluorescence that manifests during the early phase of the filling sequence [51–53]. Although visualization of dye within the actual abnormal capillary network is possible, it is not mandatory for the diagnosis of classic CNV (Figs. 4.6 and 4.10). In contrast, the term “occult” CNV encompasses two hyperfluorescent patterns on fluorescein angiography: fibrovascular pigment epithelial detachments (PEDs) and late leakage of undetermined source (Figs. 4.1 and 4.5) [51–53]. The first pattern usually shows stippled hyperfluorescent dots in the early phase of the angiogram and a notched border. Pooling of dye within the PED occurs over the course of the angiogram and late-phase leakage may be observed around the margin of the PED. The second pattern is characterized by ill-defined late choroidal-based leakage in the absence of any identifiable classic CNV or fibrovascular PED in earlier phases of the angiogram. Interestingly, OCT examination has introduced valuable data

Pearl

Fluorescein angiography remains the gold standard angiograph test for the detection of CNV. ICG angiography may be useful in some cases of neovascular AMD or its variants.

CNV and Indocyanine Green

Angiography

In general, ICG angiography does not image classic CNV as dramatically as fluorescein angiography; it does not show prominent leakage likely due to the higher protein-binding affinity of ICG. Conversely, areas of occult CNV that appear very poorly defined on fluorescein angiography may be more well defined on ICG angiography (Fig. 4.5). In spite of this, there is still variability; certain areas of occult CNV appear as relatively large plaques of hyperfluorescence while others exhibit minimal hyperfluorescent abnormalities.

Clinically, ICG angiography is utilized with less frequency than fluorescein angiography, yet it remains very helpful for differentiating occult CNV secondary to neovascular AMD from three potential masqueraders in particular: retinal

Fig. 4.10 Classic choroidal neovascularization, before and after treatment. (a) Digital color fundus photograph from an eye with exudative age-related macular degeneration. (b) Digital fluorescein angiography demonstrates several areas of mottled hyperfluorescence as well as a more discreet small classic CNV. (c) OCT map at initial visit. (d) ETDRS map and thickness measurements from

initial visit. (e) OCT image from the initial visit (this is the same image as in Fig. 4.3). (f) OCT map after 2 injections of intravitreal ranibizumab. (g) ETDRS map and thickness measurements from the same visit. (h) OCT image from the same follow-up visit demonstrates resolution of much of the subretinal fluid, and disappearance of the subretinal hyper-reflective CNV

angiomatous proliferation (RAP), central serous chorioretinopathy (CSCR), and polypoidal choroidal vasculopathy (PCV). RAP lesions are characterized by a retinal-choroidal anastomosis and are considered a distinct subtype of neovascular AMD [55], also referred to as “type 3” neovascularization. RAP lesions are often more easily visualized with ICG angiography than fluorescein angiography [56]. While this may not be relevant with regard to anti-vascular endothelial growth factor (VEGF) therapy, which appears to be effective for RAP lesions [57], it supports the observation that thermal laser photocoagulation alone is unsuccessful as a long-term treatment strategy [58].

The second main use of ICG angiography is to differentiate occult CNV due to AMD from central serous chorioretinopathy (CSCR). In CSCR, the choroidal vessels appear dilated in the early filling phase of the angiogram. Mid-phase images usually show multifocal areas of choroidal vascular hyperpermeability, followed by silhouetting of the larger vessels in the late phase.

Finally, ICG angiography is often essential for making the diagnosis of PCV, which is a distinct abnormality of the choroidal vasculature that is more common in the Asian and African-American populations, though it can occur in Caucasians. PCV is characterized by three-dimensional,

branching, dilated inner choroidal vessels with reddish-orange, aneurismal projections at the terminal aspects of the lesion [59]. PCV commonly presents with variably sized serous or serosanguineous detachments of neurosensory retina and RPE detachments. The polypoidal lesions are usually located at the margin of the PED, may range in size, and may be accompanied by overlying RPE atrophy, RPE hyperplasia, and subretinal fibrosis (Fig. 4.7) [60]. In the early phase of the ICG angiogram, the polypoidal vessels may exhibit pulsations [61]. Thereafter, increasing choroidal vascular hyperpermeability is often detectable and in the late phase, ICG stains exudation in the inner choroid and retina due to its high affinity for fibrin [59].

Retinal Pigment Epithelial

Detachment

Although PEDs related to confluent drusen may occur in the setting of non-neovascular AMD [62], most PEDs are related to CNV. On fundus photography, these PEDs are kidney bean shaped with a “notch” that typically signifies the presence of an underlying occult CNV. Other findings that would suggest occult CNV include: blood or other exudative material within or adjacent to the PED, an irregular PED contour, and ill-defined late leakage or irregular, heterogeneous filling of the PED on fluorescein angiography. Adequate visualization of CNV on fluorescein angiography is often precluded by the melanin in the RPE and the intense hyperfluorescence within the PED that is due to rapidly accumulating dye. For this reason, the presence of a large PED has typically been an exclusion criterion in most studies of the treatment of neovascular AMD. In this situation, ICG angiography is a useful adjunct since it is not impeded by the presence of pigment or dye within a PED. With ICG, the full extent of the CNV within a notched PED can be readily distinguished. Similarly, in large PEDs without a notch, an underlying focus of CNV is often identified with ICG although not apparent on fluorescein angiography.

Analysis by EDI-OCT of the internal characteristics of fibrovascular PEDs secondary to

AMD has demonstrated that the CNV proliferates along the undersurface of the RPE detachment [63]. Contraction of the CNV has been associated with the formation of RPE tears, which may occur as part of the natural history of the disease [64, 65]. In addition, it is possible that anti-VEGF therapy may potentiate RPE tear formation in patients with fibrovascular PEDs [66, 67].

Tears of the RPE have a characteristic appearance on fundus photography and fluorescein angiography, although their size, location with respect to the foveola, and the associated visual acuity may vary [68]. Classically, there is a denuded area of exposed choroid adjacent to the dehisced RPE, which is scrolled back towards the CNV. The bare area is hyperfluorescent in the early phase of the angiogram due to a transmission window defect. Moreover, leakage from the underlying CNV may be visualized as the study progresses into the late phase, though the scrolled RPE may mask this hyperfluorescence to a certain degree. The scrolled RPE has been referred to as “doubly hypofluorescent” and “doubly autofluorescent” in light of what is essentially a vertical summation of pigment and lipofuscin, respectively. Based on OCT and autofluorescence imaging, it appears that the denuded area may eventually be repopulated by RPE cells that are devoid of melanin, with potential for visual recovery [69].

Retinal Vascular Contribution to the Exudative Process

Over the last decade, eyes with neovascular lesions that exhibit a retinal vascular anastomosis to CNV have received increasing attention in effort to better understand the anatomic structure of the anastomotic connection. This condition was first described by Hartnett and coworkers as deep retinal vascular anomalous complexes (RVAC) [70]. It was subsequently renamed retinal angiomatous proliferation (RAP) by Yannuzzi and colleagues [55]. Still later, Gass and colleagues [71] proposed that these eyes have a chorioretinal anastomosis with occult choroidal neovascularization (OCRA).