Demographics

The prevalence of PCV in presumed neovascular AMD was reported as 7.8% in US,¹ 4.0% in Belgian,²² 9.8% in Italian,²³ 8.2% in Greeek.²⁴ 23.0–54.7% in Japanese,²⁵ 22.3% in Chinese,²⁶ and 24.6%²⁷ in Korean populations. The prevalence varies with age.²⁸ In summary, PCV is more prevalent in blacks, Japanese and other Asians than in whites, while the incidence of AMD is very high in whites, and low in blacks. The incidence of both diseases is high in Asians.

Although early reports suggested that PCV was a condition predominantly of middle-aged women,¹¹ and that typically PCV presents one to two decades earlier than classical AMD, it is most commonly diagnosed in patients between the ages of 50 and 65.²⁹ However, the age of the subjects was reported with a mean of 66.1 ± 9.6 years in a Chinese population.²⁸ Caucasian patients usually present with PCV at an older age.³⁰ It has subsequently been established that PCV occurs in both genders (and more commonly in Asian men than women).²⁷ Although women are involved more often than men in some reports, more men still have manifestations of the disorder among Chinese patients.^26,28,30,31 PCV is usually a bilateral disease. The majority of the patients with evidence of PCV in one eye eventually develop similar lesions in the fellow eye.

The natural course of PCV is variable: it may be relatively stable or there may be repeated bleeding and leakage with vision loss and chorioretinal atrophy, with or without fibrotic scarring. Reddish-orange nodules alone, or nodules and small subretinal hemorrhage and absence of hard exudates, may still allow a benign clinical course and stable vision.^32,33

The association of PCV with other conditions is not certain. PCV with severe thrombocytopenia and massive hemorrhage has been reported,³⁴ and PCV has also been associated with sickle cell disease and irradiation.³⁵ Some experts believe it is advisable to screen PCV patients for hypertension and platelet count, but hypertension is common in older patients and is already monitored during medical visits, and the platelet data are not firmly established. The role of hereditary and environmental factors in its etiology is inconclusive and needs further study.

Clinical findings

Clinically, PCV is characterized by protruding orange-red elevated lesions, often with nodular elevations of the RPE, that can be seen during routine fundus examination using ophthalmoscopy and contact lens slit-lamp biomicroscopy. The nodular elevations of the RPE are easily visible by optical coherence tomography (OCT). PCV is also characterized by polypoidal lesions only observed when using ICGA. The lesions appear as polyp-like or grape-like clusters (Fig. 71.1).^11,15 The nodular lesions are associated with serous exudation and hemorrhage that may lead to detachment of the RPE and sometimes the neurosensory retina.³² Associated features are recurrent subretinal hemorrhage and vitreous hemorrhage (Fig. 71.2).

Fig. 71.1 (A) Color photograph of a 53-year-old male with blurred vision in the right eye for 2 years; visual acuity was 20/200. There are protruded orange–red elevated lesions (arrows) in the superior area of the macula. (B) Fluorescein angiogram of the same fundus showing occult choroidal neovascularization. (C) ICGA at 6 minutes 3 seconds reveals a branching vascular network in the central macula and polypoidal lesions with hypofluorescent halo (arrows) connecting to a branching vascular network (dashed arrows) and corresponding to the orange–red subretinal nodules.

Fig. 71.2 (A) Color photograph of a 65-year-old man with blurred vision for 18 months. There is a large area of a protruding orange–red elevated lesion on the temporal side of the fovea. (B) ICGA from the same fundus. (C) One month later the vision dropped to hand motions and the color photograph showed hemorrhagic retinal detachment inferior to the fovea. (D) One week later subretinal hemorrhages and bleeding into the vitreous cavity was demonstated on B-scan ultrasonography.

Polypoidal lesions are located mainly in the macular area, although this may be ascertainment bias since ICGA tends to look at that area. In one report, 69.5% polypoidal lesions were located in the macular area, 15% PCV lesions were located under the temporal retinal vascular arcade, and 4.5% PCV lesions were located peripapillary (within one disc diameter of the disc edge). PCV lesions were also located in the midperipheral area.²⁸

PCV lesions may be active or inactive (Fig. 71.3). PCV is considered as active if there is clinical, OCT or fluorescein angiography (FA) evidence of any one of the following: vision loss of 5 or more letters (ETDRS chart); subretinal fluid with or without intraretinal fluid; pigment epithelial detachment; subretinal hemorrhage; or fluorescein leakage (Box 71.1). There are currently no universally recognized criteria for defining disease activity in PCV; treatment should be initiated for active and symptomatic PCV and can be considered for active, asymptomatic PCV.¹²

Fig. 71.3 ICGA of a 73-year-old man with polypoidal choroidal vasculopathy and a 7-month history of decreased visual acuity in his left eye. There are two polyps in the macular region. The yellow arrowhead identifies an inactive polyp, while the red arrowhead points to an active polyp with surrounding hypofluorescence.

Choroidal vascular hyperpermeability, reportedly a characteristic finding in central serous chorioretinopathy (CSC), might play a role in the pathogenesis of PCV. PCV with angioid streaks secondary to pseudoxanthoma elasticum has also been reported in one patient.^36,37

Some patients with PCV may develop CNV. PCV can induce ischemic changes, inflammation, sick RPE and breaks in Bruch’s membrane. These changes can contribute to the development of CNV, and fibrosis and scarring may ensue.³⁸

Angiographic features

PCV is better visualized by ICGA than by FA, because indocyanine green absorbs and emits near-infrared light, which readily penetrates the RPE, enhancing viewing of choroidal lesions. Also the binding affinity of indocyanine green to plasma proteins means that it does not leak from the choriocapillaris in the same way as fluorescein, so choroidal lesions are less obscured.³⁹ PCV primarily involves the inner choroidal vasculature.^22,40 In recent years ICGA has been accepted as the gold standard for the diagnosis of PCV, and as one of the specific criteria to distinguish PCV, retinal angiomatous proliferation, and typical AMD as types of neovascular AMD.³ The ICGA characteristics of PCV (summarized in Box 71.2) include: a branching network of inner choroidal vessels,^3,21,40–43 and nodular polypoidal aneurysms or dilations at the edge of these abnormal vessel networks, which correspond to orange subretinal nodules;^{3,11,20,31,32,40–42} and the presence of single or multiple focal nodular areas of hyperfluorescence (hypofluorescent halo, see Figure 71.1C) arising from the choroidal circulation within the first 6 minutes. Pulsation in polyps and/or associated vasculature has been less extensively reported and can be observed only using video ICGA.^44,45

ICGA should be considered to assist the diagnosis of PCV when routine ophthalmoscopic examination indicates a serosanguineous maculopathy with one of the following features: clinically visible orange–red subretinal nodules, spontaneous massive subretinal hemorrhage (if not so severe as to preclude all ICGA views), and in some cases with notched or hemorrhagic pigment epithelium detachment (PED), or a lack of response to anti-VEGF therapy. The total lesion area for PCV is the area of all polyps and the branching vascular network (BVN) as viewed by ICGA. This is important for laser and photodynamic treatment modalities.

Classification

PCV was classified by the Japanese Study Group on PCV.⁴² This panel of experts proposed three categories to subclassify PCV:¹²

Neovascular age-related macular degeneration

Some authors categorize PCV as a subtype of neovascular AMD.³ PCV has been considered to be part of or similar to AMD CNV due to similar features (Fig. 71.4A), elevated levels of vascular endothelial growth factor (VEGF), similar histology, and expression of growth factors and receptor antibodies. We view PCV as a distinct condition. It has been documented that the increased levels of VEGF in PCV are lower compared with AMD CNV or myopic CNV. The increase in VEGF levels in PCV is mild to moderate. The clinical features of the PCV are different from those of neovascular age-related macular degeneration. PCV is associated with polyp-like structures projecting from the plane of the inner choroid towards the outer retina or RPE, the RPE is mostly intact, while in neovascular AMD the neovascular tufts arising from the choroid may either invade and perforate Bruch’s membrane or grow throw defects in Bruch’s membrane and proliferate in either sub-RPE space (type I CNV) or in the subsensory retinal space (type II CNV).⁴⁶ The ingrowth of new vessels extending from the choroid into the sub-RPE space is the most important histopathologic change of occult CNV (Fig. 71.4B).

Fig. 71.4 (A) Color photograph of 72-year-old man with visual acuity 20/20. (B) ICGA demonstrates choroidal neovascularization (CNV) superior to fovea. (C) Optical coherence tomography (OCT) of the same fundus; the arrow points to the CNV component above the retinal pigment epithelium (RPE) band and the RPE band is broken. (D) Color photograph of 66-year-old woman with visual acuity 20/100, with orange–red subretinal nodules in the macular area (arrow). (E) ICGA of the same fundus showed polyps corresponding to the orange–red lesions. (F) OCT of the same fundus showed a detached RPE in a “bent back” form corresponding to the polypoidal lesion with subretinal fluid and a large area RPE detachment.

OCT findings (Fig. 71.4C and F) can assist in understanding the differences in the retinal structures that are affected by these two clinical entities and also may help in the differential diagnosis of PCV and neovascular AMD.¹³

Central serous chorioretinopathy

Central serous chorioretinopathy (CSC) is characterized by accumulation of transparent fluid and round, serous detachment of the macular retina. It has been thought to be due to a focal leakage from one or more defects at the level of the RPE, which allow serous fluid from the choriocapillaris to diffuse into the subretinal space. It has been hypothesized that a protracted disturbance in the microcirculation of the choriocapillaris leads to leakage of fluid into the sub-RPE space. A combination of choroidal hyperpermeability and impaired RPE function leads to pooling of fluid in the sub-RPE space with eventual leakage through the RPE into the subretinal space. ICGA has expanded our knowledge of CSC. A consistent finding is the hyperpermeability of the choroid during ICGA in CSC. The multifocal choroid hyperfluorescence patches in the ICG demonstrate multifocal choroid vascular hyperpermeable areas.⁴¹

PCV masquerading as CSC has been reported. In CSC with persistent and/or recurrent exudation, a myriad of retinal pigment epithelial changes may evolve that make it difficult to differentiate it from PCV. In such patients, ICGA may be useful in differentiating these two entities. An accurate clinical diagnosis is important since CSC and PCV differ in terms of their risk factors, natural course, visual prognosis and treatment.⁴⁷

Thermal laser photocoagulation

Laser photocoagulation has been suggested to be beneficial, albeit it with short-term follow-up. The greatest benefit may be for extrafoveal PCV.⁴⁸ In some studies that analyzed reported vision outcomes, ICGA-guided laser photocoagulation was successful in stabilizing or improving vision in 55–100% of eyes; however, vision loss occurred in 13–45% of eyes.^31,48–50 Photocoagulation of the whole lesion, compared with polyps only, appears to be more efficacious.⁴⁹

Photodynamic therapy

Verteporfin photodynamic therapy (PDT) causes regression or resolution of polyps by its angio-occlusive mechanism of action. It has been shown to achieve complete occlusion of polyps and resolution of exudative changes after less than three treatments, restricts loss of letters on the ETDRS chart to less than 15, or improved vision in 80–100% of patients after 1 year.^51,52 For treatment-naïve patients the entire PCV lesion as indicated by ICGA (polyps plus the BVN) should be treated.

Common complications reported with verteporfin-PDT therapy are subretinal hemorrhage, recurrence of PCV with leakage from the BVN, and fibrous scarring. Subretinal hemorrhage is common and can lead to vitreous hemorrhage and consequently a poor outcome.^51,52 Larger lesion size and a leaking vascular net⁵¹ are risk factors for bleeding after PDT.

Anti-VEGF therapy

Recent studies have demonstrated that anti-VEGF agents are useful in the treatment of CNV in neovascular AMD. Since increased VEGF levels have been observed in PCV patients,^45, anti-VEGF therapy might be theoretically beneficial for treating PCV. It was shown that intravitreal anti-VEGF helped in resolving the macular edema, polypoidal complexes decreased in 4/12 (33%) eyes by intravitreal ranibizumab,⁵³ and 1/11 (9.09%) eyes by intravitreal bevacizumab.⁵⁴

Combination therapy

EVEREST is a multicenter, double-masked, ICGA-guided randomized controlled trial studying patients with symptomatic PCV. Eyes were treated with verteporfin PDT monotherapy, 0.5 mg ranibizumab monotherapy or a combination of these treatments. Both combination therapy and verteporfin PDT monotherapy were superior to ranibizumab monotherapy in achieving complete polyp regression at month 6. Improvements in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) also favored combination therapy.¹²

The authors of a recent relatively large comparative case series reported that with combination verteporfin PDT plus bevacizumab there were better early BCVA outcomes than with verteporfin PDT alone (P = 0.0016 for the difference between treatments in mean BCVA change from baseline at 3 months and P = 0.048 at 12 months).⁵² Combination therapy also decreased the rate of PDT-related hemorrhages compared with verteporfin PDT monotherapy (3/61 [4.9%] vs 15/85 [17.6%], respectively), but did not impact the resolution and recurrence of lesions.⁵⁵

These trials support the selection of ICGA-guided verteporfin PDT with or without combination with ranibizumab as standard preferred treatment options.