Introduction

Neovascular age-related macular degeneration (nAMD), also known as “wet” or “exudative” AMD, is characterized by the abnormal formation of new choroidal vessels with growth under the retinal pigment epithelium (RPE) or in subretinal spaces, resulting in severe vision loss.¹ Polypoidal choroidal vasculopathy (PCV) features clinically distinguishable orange-reddish lesions beneath the RPE which are caused by dilation of abnormal choroidal vessels. PCV was first reported by Yannuzzi et al.² in 1990, yet there is still debate about whether PCV should be considered a subtype of nAMD or if they are completely distinct entities. Retinal angiomatous proliferation (RAP), a subtype of nAMD, is a pathology in which the vasogenic process of neovascularization starts from the retina to form choroidal neovascularization (CNV) and is strongly associated with soft drusen or reticular pseudodrusen at the macula.³ RAP tends to show bilateral involvement and is more common in older patients.³ The coexistence of PCV and typical nAMD has been reported in the literature, and although the combination of type 1 and type 3 AMD was also reported, the authors did not provide a detailed description of this case.^4,5,6,7,8

In this report, we describe a case of nAMD co-presenting with different types of lesions in a patient who responded to aflibercept treatment after developing tachyphylaxis to ranibizumab.

Discussion

Combinations of PCV and typical nAMD lesions in the same eye or one in each eye of the same patient have been reported in the literature.^4,5,6,7,8 However, the coexistence of PCV and RAP at the time of diagnosis has not been previously described. In a group of newly diagnosed 155 nAMD patients, Liu et al.⁴ found 3.2% of the cases had mixed lesions, all of them with PCV and typical CNV in the same eye. The authors considered this mixed presentation a third subtype of nAMD. In a series of 289 Japanese patients with PCV, RAP, and typical AMD, Maruko et al.⁵ found that 5.5% of the patients had combined lesions, all with PCV in one eye and typical AMD in the other eye. However, no combination of RAP and PCV was detected in these cases. Pereira et al.⁶ reported that 5.3% of their Brazilian nAMD patients had combined lesions with different types of each in one eye, but the combination of RAP and PCV in the same eye was not reported. In a study assessing the newly diagnosed subtypes of nAMD according to FA alone and FA + OCT images, the authors divided subtypes as type 1 (subRPE), type 2 (subretinal), type 3 (intraretinal), and mixed.⁷ PCV was considered type 1 and RAP as type 3. Using FA + OCT, mixed lesions were detected in 16.9% of 266 eyes and 15.5% of mixed lesions were a combination of type 1 and 3. However, they did not provide further details about the coexistence of PCV and RAP in the same patient or eye. One report included an 86-year-old female patient with unilateral RAP who developed PCV in the fellow eye three years after the initial diagnosis.⁸ Our patient had RAP and PCV in the same eye at the time of diagnosis and she may have presented in a early phase, enabling us to identify the RAP lesion. If the patient presented us later, progression towards the advanced stages might occured and we could have diagnosed as CNV instead of RAP.

Another issue that must be emphasized in our case is the development of tachyphylaxis. Binder⁹ differentiated tolerance from tachyphylaxis and pointed out that tachyphylaxis could occur in a short time when drugs were used repeatedly. There are several potential mechanisms for development of tachyphylaxis in nAMD, including the development of antibodies against anti-VEGF, change in lesion type or neovascular membrane structure, and other pathways of action used by anti-VEGF drugs.⁹ Another possible explanation could be upregulation of pro-angiogenic factors other than VEGF-A.⁹

Switching to other anti-VEGF drugs is one option for overcoming tachyphylaxis in nAMD treatment. Bevacizumab and ranibizumab have similar protein composition and sites of action. Aflibercept is shown to be effective in patients with large PEDs that were insufficiently responsive to multiple bevacizumab and ranibizumab injections.¹⁰ Because of the higher binding affinity of aflibercept, we decided to switch ranibizumab to aflibercept and achieved a favorable anatomical outcome.

In conclusion, this case study revealed that different types of lesions can be seen not only in the course of nAMD but also at initial diagnosis. ICGA and OCT are the most important tools to diagnose coexisting lesions when suspected clinically.