Polypoidal Choroidal Vasculopathy: A Subtype of Neovascular Age-Related Macular Degeneration

By Brian Lee, MD and Michael Ip, MD

Polypoidal choroidal vasculopathy (PCV) is a subtype of neovascular age-related macular degeneration (nAMD) that is sometimes less responsive to anti-vascular endothelial growth factor (anti-VEGF) monotherapy. However, combination treatment consisting of anti-VEGF and verteporfin photodynamic therapy (PDT) may improve outcomes.¹ PCV is characterized by aneurysmal polypoidal lesions that may be associated with a branching vascular network which is best observed with indocyanine green angiography (ICGA).² Although PCV has been reported to be more prevalent in Asian than Caucasian populations, it has been hypothesized that PCV is underdiagnosed in Caucasian populations because ICGA is not routinely performed.

PCV diagnosis is an important consideration in patients with nAMD who have a suboptimal response to anti-VEGF therapy, especially in patients with serosanguinous maculopathy. PCV should also be considered in the initial diagnosis of nAMD in Asian patients.

ICGA Diagnosis
ICGA is the gold standard for diagnosing PCV.² PCV, as defined in the EVEREST trial, is characterized by early subretinal ICGA hyperfluorescence within 5 minutes of dye injection and at least one of the following criteria³:

Nodular elevated appearance of the lesion on stereoscopic imaging.
Hypofluorescent halo around the lesion.
Abnormal vascular channel(s) supplying the lesion.
Pulsatile filling of the lesion.
Orange subretinal nodules corresponding to the hyperfluorescent areas on ICGA.
Massive submacular hemorrhage.

Noninvasive Diagnosis
Because ICGA is invasive and not performed as frequently as OCT imaging, OCT and color fundus photography diagnostic criteria have been established by the Asia-Pacific Ocular Imaging Society PCV Workgroup.² This Workgroup’s consensus nomenclature and non-ICGA diagnostic criteria are a combination of three OCT-based major criteria²:

Sub-retinal pigment epithelium (RPE) ring-like lesion.
En face OCT complex RPE elevation.
Sharp peaked pigment epithelial detachment (PED).

A combination of these three criteria has a high positive predictive value for PCV, but the absence of these findings does not exclude PCV.² Because a diagnosis of PCV is often considered only after patients have had a poor response to anti-VEGF treatment, and some of the key OCT findings disappear after anti-VEGF treatment, the baseline pre-treatment OCT should be examined for these features.

Treatment
The landmark EVEREST clinical trial compared standard fluence PDT alone, ranibizumab alone, and PDT in combination with ranibizumab. Polypoidal lesion regression was similar with combined treatment (77.8%) and PDT alone (71.4%) and was less effective with ranibizumab monotherapy (28.6%). However, visual acuity outcomes were similar among the three treatment groups (+10.9, +7.5, +9.2, respectively, for combination therapy, PDT and ranibizumab monotherapy).⁴

The PLANET clinical trial compared aflibercept monotherapy to aflibercept with rescue PDT. Rescue PDT was performed if the treating physician determined there was a suboptimal response to aflibercept at 12 weeks. This study showed similar rates of polypoidal lesion closure with aflibercept monotherapy (38.9%) and combination therapy (44.8%), as well as similar visual acuity improvement with monotherapy (+10.7 letters) and combination therapy (+10.8 letters).

The EVEREST II clinical trial showed that therapy consisting of prompt PDT in combination with ranibizumab correlates with higher rates of polypoidal lesion regression, better visual acuity and fewer anti-VEGF treatments compared to ranibizumab monotherapy.¹ In contrast to the PLANET clinical trial, in the EVEREST II trial a central reading center confirmed the diagnosis of PCV, which is important because PCV diagnosis can be challenging even with ICGA. In addition, PDT was performed at baseline in EVEREST II, rather than as rescue therapy per physician discretion in the PLANET trial.⁵ The median number of PDT treatments in the EVEREST II trial was 2, and the mean and median numbers of ranibizumab injections among patients in the combination treatment group were 8.1 and 6, respectively, compared to 12.6 and 12, respectively, in the monotherapy group. Visual acuity improvement was greater in the combination group (+9.6 letters) compared to the ranibizumab monotherapy group (+5.5 letters), as was the proportion with polypoidal lesion regression (56.6% and 26.7%, respectively).⁵

Summary
PCV is a subtype of nAMD that is less responsive to anti-VEGF monotherapy. Although ICGA is the gold standard for PCV diagnosis and management, OCT findings can provide high specificity (but low sensitivity) for PCV diagnosis. Combination therapy consisting of prompt PDT in combination with anti-VEGF may result in higher rates of PCV lesion regression, fewer anti-VEGF treatments and better vision compared to anti-VEGF monotherapy.

Reference(s):
1. Lim TH, Lai TYY, Takahashi K, et al. Comparison of ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: the EVEREST II randomized clinical trial. JAMA Ophthalmol. 2020;138(9):935-942. doi:10.1001/jamaophthalmol.2020.2443
2. Cheung CMG, Lai TYY, Teo K, et al. Polypoidal choroidal vasculopathy: consensus nomenclature and non–indocyanine green angiograph diagnostic criteria from the Asia-Pacific Ocular Imaging Society PCV Workgroup. Ophthalmology. 2021;128(3):443-452. doi:10.1016/j.ophtha.2020.08.006
3. Tan CS, Ngo WK, Chen JP, Tan NW, Lim TH, Group on behalf of the Everest Study. EVEREST study report 2: imaging and grading protocol, and baseline characteristics of a randomised controlled trial of polypoidal choroidal vasculopathy. Br J Ophthalmol. 2015;99(5):624-628. doi:10.1136/bjophthalmol-2014-305674
4. Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina. 2012;32(8):1453-1464. doi:10.1097/IAE.0b013e31824f91e8
5. Browning DJ. Adopting the results of Everest II into practice: a clearer view from a higher level study. JAMA Ophthalmol. 2017;135(11):1214-1215. doi:10.1001/jamaophthalmol.2017.3118

About our author(s):

	Dr. Lee is a Retina Fellow at UCLA Stein Eye Institute and Doheny Eye Institute.
	Dr. Ip is Professor of Ophthalmology at the David Geffen School of Medicine at UCLA.

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