Polypoidal Choroidal Vasculopathy: Clinical Features and Genetic Predisposition

Polypoidal choroidal vasculopathy (PCV) was first described in the early 1980s and was originally thought to be a distinct abnormality of the choroidal vasculature found in the peripapillary area [1,2,3]. However, subsequent reports showed a broad clinical spectrum of PCV, and some authors suggested that PCV is a type of choroidal neovascularization (CNV) [4,5,6]. Hence, PCV is currently categorized as a phenotype of age-related macular degeneration (AMD), and most ophthalmologists believe that PCV is a type of CNV caused by AMD, although some reports suggested that some cases of PCV are indeed a distinct vascular abnormality of the choroidal vessels. PCV often shows several unique clinical manifestations which are apparently different from typical neovascular AMD (tAMD). For example, distinct polypoidal lesions are the most characteristic feature of PCV (fig. 1). PCV is often found in the extramacular area, whereas tAMD always exists within the macular area [7,8]. In addition, the natural course and response to treatment are often different between tAMD and PCV [9,10,11,12,13,14,15,16,17]. Moreover, recent genetic studies suggested a possible difference in the genetic background between tAMD and PCV [18,19,20,21,22,23,24,25], as well as the existence of heterogeneity among PCV cases [26,27]. Considering the accumulated knowledge about PCV, we now have to reconsider the rationale for understanding and treating this clinical entity. In this review article, the recent literature regarding PCV is first summarized to understand the clinical presentation of PCV, which can be divided into: (1) the common features between PCV and tAMD, and (2) some unique characteristics that are considered specific for PCV. Second, the possible genetic factors responsible for the phenotypes of PCV are introduced. Third, the optimal treatment strategies for PCV are discussed.

The age range of the patients in previous reports [13,28,29] was 21-93 years, and the mean was 68.4 years. PCV is more prevalent in Asian and African-American populations than Caucasians, which may cause the heterogeneity in the clinical features of AMD among the races. Previous studies reported that PCV accounts for 23.0-54.7% of patients with neovascular AMD in the Japanese [11,20,30], 49% in the Taiwanese [31], 22.3-24.5% in the Chinese [32,33] and 22.2-24.6% in the Korean populations [34,35], but in only about 8-13% of Caucasians [36]. African-Americans are also known to be susceptible to PCV, although no epidemiological study for black people has been reported to date. PCV is more prevalent in men than women in Asian populations (22-37% female), but the opposite is observed in Caucasians (52-65% female) [28]. It is also reported that PCV often affects African-American women. Bilateral cases were reported in 9-18% of Asians (Japanese) and 21-55% of Caucasians. The majority of PCVs (62-94%) are located in the macular area in Asian cohorts, but peripapillary PCV (fig. 2) was frequently observed (18-75%) in American and European cohorts [28]. Moreover, PCV can be located outside the posterior vascular arcade, which may cause peripheral exudative hemorrhagic chorioretinopathy [7,8]. In some PCV cases, a lesion beneath the macula and remote lesions are found simultaneously [37]. It is unknown why such ethnic variation exists in the epidemiology of PCV. Recent genetic studies suggested that some genetic factors may be associated with the clinical feature of PCV, which could be the reason for such ethnic variations in PCV.Several studies have determined the systemic and ocular risk factors of PCV. They reported that 41-45% of PCV patients had systemic hypertension [38,39,40]. Another report demonstrated that C-reactive protein levels were increased in patients with PCV [41]. Cigarette smoking is a potent risk factor for PCV [42], and a history of central serous chorioretinopathy was a significant risk factor for PCV [38].

In accordance with the literature, PCV is characterized by: (1) orange-red colored protrusions at the posterior pole of the retina (or sometimes at the peripheral retina), and/or (2) polypoidal lesions found by indocyanine green angiography (ICGA; fig. 1). However, polypoidal lesions may not be found due to hemorrhage blockage or insufficient image quality in some cases, which makes the diagnosis of PCV difficult. Such cases may be classified as ‘suspected of PCV' [43], but it is often very difficult to distinguish those cases from tAMD.

The PCV lesions usually appear as reddish or nonreddish pigment epithelial detachments (PEDs) and are occasionally accompanied by serous retinal detachment (SRD), subretinal hemorrhage, subretinal fibrinous material, hard exudates and drusens. The funduscopic findings at the initial visit may vary depending on when the patients visit the hospital. Although Uyama et al. [12] reported that about 83% (10 out of 12 cases) of PCV patients showed SRD at the first visit, Sho et al. [11] reported that about 52% of PCV patients showed SRD. In a recent report, Bessho et al. [13] observed SRD in 91% of the patients, and subretinal hemorrhage in 62% of the patients with PCV at the first examination. Previous studies have reported that polyp lesions are mostly present at the margin and inside the serosanguinous PED, which may present as a ‘notch sign' between the PED, including polyp lesions and connecting PED, which includes abnormal network vessels [11]. Two previous studies also reported that subretinal fibrinous material on the PED is often observed in PCV [44,45]. Retinal pigment epithelium (RPE) abnormalities (i.e. hyperplasia, atrophy) are frequently found overlying and around the lesions [11,13]. Microrips of the RPE and RPE tears could be found at the margins of the PEDs [46,47]. In some cases, multiple PEDs may span widely at the posterior pole of the retina, or more than 2 independent lesions could be found (i.e. one lesion at the macula and the other at the nasal retina) [48]. However, unlike tAMD, cases with no exudative changes are relatively common in PCV.

The visual acuity (VA) at the initial visit may vary depending on the degree of the exudative change. Those cases without subretinal hemorrhage and with no or slight SRD have good VA, whereas VA in those cases with severe exudative changes may be affected. However, the mean VA in PCV patients was generally better than in tAMD at baseline [49]. This is likely because PCV lesions remain under the RPE in the early stages, while tAMD occasionally develops CNV in the subretinal space (the so-called type 2 CNV), which may affect the sensory retina directly.

Unfortunately, fluorescein angiography (FA) is not an optimal tool to make a diagnosis of PCV, since FA is not sufficient to visualize the structures in the inner choroidal space where PCV likely exists. However, a ‘window defect' reflecting RPE atrophy is often observed, and the underlying polypoidal lesions may be found as ‘hyperfluorescent spots' by FA in certain PCV cases [28]. Subretinal fibrinous material, if it exists, can be observed as an expanding fluorescent leakage that may simulate the classic lesion of tAMD found by FA [44,45]. This appearance might be termed a ‘pseudoclassic CNV lesion', which is a characteristic of PCV (fig. 3).

In ICGA, PCV is typically characterized by distinct forms of choroidal vascular abnormalities, including characteristic polypoidal lesions with or without branching vascular networks (BVNs) of choroidal origin [50]. As described above, polyp lesions are mostly present at the margin and inside the PED, which may cause a ‘notch sign' between the PED, including polyp lesions and connecting PED, which includes the BVN. Clustered grape-like polypoidal lesions on ICGA were observed frequently (25-67%) in Asian populations [12,13,48]. It is very unique for PCV that some cases show pulsations of the polypoidal lesions in the early phase of ICGA [50,51,52]. Dilatation of choroidal vessels found in the early and middle phases of ICGA is another unique feature of PCV (fig. 4). Choroidal vascular hyperpermeability is often found in PCV by ICGA in the late phases, and is likely due to the staining of fibrinous materials which exist around the dilated choroidal vessels [53,54,55]. PCV cases show wide variation in their size, and the features of the BVN and polypoidal lesions. The Japanese Study Group of Polypoidal Choroidal Vasculopathy proposed that PCV with only BVN and no apparent polypoidal lesions may exist, and those cases are termed ‘suspected of PCV' [43]. However, those cases are often difficult to distinguish from tAMD. The variations of PCV in its presentation may be only due to the stage of the disease (more progressed disease should have larger lesions) [56], but evidence is accumulating which supports the existence of subtypes in PCV.

Recent studies have described the subclassification of PCV regarding the presence or absence of BVN (as feeder vessels for the polyp lesions) found by ICGA [57,58,59]. Thus, PCV with apparent BVN is called ‘type 1 PCV' or ‘polypoidal CNV', whereas the one with no or only faint BVN is called ‘type 2 PCV' or ‘typical PCV' (fig. 5). The presence or absence of BVN can usually be determined within 1 min starting from the injection of ICGA, but some cases are difficult to classify. Recent studies demonstrated that these 2 angiographic subtypes of PCV showed differences in their clinical course, genetic susceptibility and response to therapy. Type 1 PCV usually has larger lesion sizes due to the larger and more distinct BVN, smaller polyp size on ICGA, smaller choroidal thickness [57,58,59] and lower response to photodynamic therapy (PDT) as compared to type 2 PCV [60].

In most PCV cases, optical coherence tomography (OCT) revealed a sharply elevated PED with/without connecting lower PEDs, which may cause the so-called ‘tomographic notch sign' (fig. 4) [61]. Polypoidal lesions are likely to attach to the back surface of higher PEDs, and BVN present in the lower PED can be recognized as the ‘double layer sign' by high-resolution OCT. This sign represents the BVN invading into the space between the RPE and Bruch's membrane, which is commonly found in CNV due to tAMD. Because CNV in tAMD is thought to pass through Bruch's membrane and grow under (and often over) the RPE layer, at least 1 broken site of Bruch's membrane should be detected. Using OCT, suspected broken sites of Bruch's membrane are often observed in type 1 PCV at the origin of the BVN [57]. These findings suggest that PCV is a type of CNV. However, the ‘double layer sign' found in PCV may not necessarily mean the isolation of the RPE from Bruch's membrane. A recent study reported that the isolation between Bruch's membrane and the inner choroidal surface also exhibits a ‘double layer sign', which means that the BVN of the PCV may remain under Bruch's membrane with polypoidal lesions [57] (fig. 6). An increase in central choroidal thickness is frequently observed by high-resolution OCT with enhanced-depth imaging or by high-permeability OCT [62,63] (fig. 4). Several studies reported that the mean choroidal thickness of PCV patients was significantly larger than that of normal subjects [62,64,65,66]. This increase in choroidal thickness was reported to be associated with increased ocular perfusion pressure and an engorgement of the vortex vein [67,68]. It is interesting that central serous chorioretinopathy, known as a risk factor of PCV, also shows a remarkable increase in choroidal thickness [62,64].

Fundus autofluorescence studies performed for PCV have been recently reported. In the affected eyes with PCV, confluent hypoautofluorescence at the polypoidal lesions surrounded by a hyperautofluorescent ring was seen in 80.4% of PCV cases, and granular hypoautofluorescence at the BVN was seen in 98.9% of PCV cases. In addition, 42.4% of eyes with PCV showed hypoautofluorescence outside the macular area. In the unaffected fellow eyes, hypoautofluorescence was observed inside the macular area (58.1%) and in the entire fundus autofluorescence image (62.8%) in patients with PCV [69,70].

Histopathological studies of PCV using human specimens were conducted by obtaining subretinal tissues during vitreoretinal surgeries [55,71,72,73,74,75]. One report noted that polypoidal structures were located within Bruch's space. They were composed of clusters of dilated, thin-walled blood vessels surrounded by macrophages and fibrin material [71]. Kuroiwa et al. [72] reported that 4 of their 5 cases demonstrated large choroidal arterioles with an inner elastic layer; disruption of the inner elastic layer and arteriosclerotic changes of the vessels were identified. Increased deposition of basement membrane-like material, together with collagen fibers, arterioles and venules, can be found in excised specimens from patients with PCV, and arteriosclerosis was an important pathological feature [72]. Another histopathological examination revealed that the specimen consisted of a degenerated RPE-Bruch's membrane-choriocapillaris complex and an inner choroid. A tortuous, unusually dilated venule was present adjacent to an arteriole with marked sclerotic changes, appearing to form an arteriovenous crossing. These vessels seemed to represent native inner choroidal vessels, and had hemorrhage per diapedesis. Blood cells and fibrin filled the lumina of these vessels, and accumulated in the extravascular spaces, thus indicating vascular stasis [55]. Hyperpermeability and hemorrhage due to stasis of a dilated venule and an arteriole involved by sclerosis at the site where they crossed in the inner choroid might cause edema and degeneration of the tissue. A voluminous accumulation of blood cells and fibrin might generate an elevation of tissue pressure sufficient to displace the weakened lesion anteriorly. These results suggest that the polypoidal vessels in this case represent an abnormality in the inner choroidal vasculature. Another study reported positive immunohistochemical staining for vascular endothelial growth factor (VEGF) in the RPE and the vascular endothelial cells in the specimen, which suggested that the fibrovascular complex was a subretinal CNV [73]. In a recent study, hyalinization of the choroidal vessels and a massive exudation of fibrin and blood plasma with a change in the arteriosclerosis were observed in all of the specimens from PCV lesions. Some blood vessels were located above the RPE in 2 of the 5 eyes analyzed [74]. Immunohistochemically, CD68-positive cells were detected around the hyalinized vessels. There were no smooth muscle actin-positive cells in the vessels in the PCV. CD34 staining showed endothelial discontinuity. Vascular endothelial cells within the PCV specimens were immunonegative for VEGF. Hypoxia inducible factor-1-immunopositive inflammatory cells were located in the stroma of specimens [74].

The molecular mechanisms responsible for the onset of disease, for the outcomes of the natural course, or any interventions, are not understood in PCV. Genetic association analysis was thought to be a useful tool to find those molecules which may be involved in the pathogenesis of this disease. For example, genetic variants in the complement factor H (CFH) gene on chromosome 1q32 [75,76,77,78,79] and in 2 tightly linked genes, age-related maculopathy susceptibility 2 (ARMS2), also known as LOC387715, and high-temperature requirement factor A1 (HTRA1) on 10q26 [80,81,82,83] are well known as major contributors to AMD. In particular, the single-nucleotide polymorphism (SNP) at rs1061170 (coding variant Y402H) in the CFH gene is presumed to have functional consequences consistent with AMD pathology [84]. However, the CFH Y402H variant shows apparent ethnic differences in its association with AMD because of the frequency of the risk allele (C allele); the risk allele frequency is 0.38 in Caucasians in the HapMap database [85], but it is 0.057 in the Japanese population and 0.067 in the Chinese population. Hence, CFH Y402H shows a strong association with AMD in Caucasians, but it was difficult to detect a positive association with Asian AMD cases owing to a limitation in statistical power [86,87,88,89]. Recently, large population studies and meta-analyses came to identify the CFH Y402H variant as a significant genetic risk factor in Asian AMD [20,90], although the susceptibility conferred by the Y402H variant may not translate across ethnic lines. However, other multiple CFH variants have been shown to be associated with AMD in Asians [89,91,92,93]. In particular, the CFH I62V variant was significantly associated with AMD (allelic OR = 1.85, 95% CI = 1.63-2.09) in a meta-analysis of Asian cohorts although no significant association of this SNP was established with AMD in Caucasian populations [91]. These reports suggested that variations in the CFH gene universally influence AMD susceptibility, but causal SNPs in the CFH region may vary among races.

Although limited information is available on the genetic basis of PCV, several studies demonstrated how genetics play an important role in the pathogenesis of PCV. The 2 major AMD susceptibility loci (CFH and ARMS2/HTRA1) have been shown to influence the risk of PCV [18,19,20,94,95,96,97,98,99,100]. In particular, SNPs in the ARMS2/ HTRA1 locus, rs10490924 (A69S) and rs11200638, are significantly associated with PCV [18,20,22,23,24]. Moreover, recent transgenic mouse studies demonstrated that the overexpression of HTRA1 displayed the cardinal features of PCV, including branching networks of choroidal vessels, polypoidal lesions and severe degeneration of the elastic laminae and tunica media of the choroidal vessels [101,102]. However, all genetic association studies showed a weaker association of ARMS2/HTRA1 with PCV than with tAMD, although the reasons were unknown (table 1). Those results raised the question whether other susceptible genes which are specific for PCV pathogenesis may exist. A previous report showed that coding variants of the elastin gene (rs2301995 and rs2856728) were associated with PCV, but not with tAMD [103]. However, two subsequent reports with larger cohorts showed the opposite results: the elastin gene polymorphism was associated with tAMD but not with PCV [22,104], which made the association of elastin gene variants with tAMD and PCV inconclusive. Those results might have occurred due to statistical type 1 and type 2 errors, but it is also possible that PCV is not a genetically homogeneous pathology. Another study reported that a missense variant at rs5882 in the cholesteryl ester transfer protein gene, a key regulator of high-density lipoprotein metabolism, was significantly associated with PCV (p = 2.73 × 10^-4), although it was not associated with tAMD [25]. The rs5882 GG genotype had a 3.53-fold (95% CI = 1.93-6.45) increased risk for PCV, and conferred a significantly lower serum high-density lipoprotein cholesterol level in PCV patients than the AA genotype (p = 0.048). On chromosome 9p21, which is well known to be associated with coronary artery disease and type 2 diabetes, rs10757278 was significantly associated with PCV (risk allele: A, allelic p = 0.014; OR = 1.44; 95% CI = 1.08-1.94), but was not associated with tAMD [105].

Recently, two studies demonstrated a difference in the association of the rs10490924 (A69S) variant in ARMS2 between the two angiographic phenotypes of PCV, type 1 PCV and type 2 PCV [27,58] (fig. 5). In those studies, no association of the ARMS2 A69S polymorphism with type 2 PCV was detected, whereas type 1 PCV showed a strong association with the ARMS2 A69S variant. Since the ARMS2 polymorphism is widely known to associate with AMD, their report indicates the existence of heterogenic susceptibility within PCV phenotypes, which may contribute to the different characteristics of PCV versus tAMD. This dissociation between the two angiographic phenotypes might suggest a correlation of ARMS2 with the formation of the BVN in PCV. In addition, this genetic heterogeneity in PCV may be a reason for the lower association of ARMS2/HTRA1 with PCV, including both phenotypes (types 1 and 2), than with tAMD.

Previous studies have reported that the natural course of PCV is favorable, since it often shows spontaneous regression [10,11,12,28]. However, on the other hand, it often causes severe hemorrhagic and exudative changes that result in a poor visual prognosis [12,13]. The clinical risk factors for a poor prognosis in PCV have been previously evaluated [11,12,13]. Bessho et al. [13] investigated the natural course of PCV in terms of the changes in the best-corrected VA (BCVA) after 12 months of observation, and found that the mean BCVA of PCV patients worsened significantly over the natural course. The clustered polypoidal choroidal lesions detected by ICGA were associated with a poor prognosis over the natural course. In this report, over 20% of PCV patients gained VAs of more than 0.2 logMAR, whereas about 50% of the patients lost their VA by more than 0.2 logMAR during the 12 months after the initial visit. The presence of serous PED is a suspected risk factor, whereas the presence of subretinal fibrinous material is a possible beneficial factor for the 12-month BCVA in PCV patients. Since polyp lesions are mostly present at the margin and inside the PED, and serous PED suggests strong infiltrating activity of the PCV [106], the accelerated infiltration from the polyp lesions into the subretinal pigment epithelial space may increase the tension on the PED flap, and thus cause PED microrips followed by acute decompression of the PED and increased blood flow in the polyp lesions. This then results in the rupture of these polyp lesions, and acute severe hemorrhage. In fact, PCV is often associated with systemic hypertension [38,39,40]. Subretinal fibrinous material, often observed on the PED in PCV patients, may be a beneficial factor for the visual prognosis over the natural course or after treatment [13,44,45]. Although the detailed mechanism of how this subretinal fibrinous material contributes to a better prognosis for PCV over its natural course is unknown, the involvement of an acute inflammatory pathway to produce this fibrinous material was suspected in certain cases of PCV [74,107,108], which often resolve spontaneously like common inflammatory conditions.

The clustered lesions found by ICGA induced a disadvantage to the visual outcome in PCV [12,13]. As a genetic risk factor, the risk alleles at rs10490924 and rs11200638 in the ARMS2/HTRA1 locus were reported to be significantly associated with a larger lesion size, a higher risk of vitreous hemorrhage, an earlier onset and a bilateral involvement, as compared to nonrisk allele holders in PCV cases [19,109,110,111].

Evidence is accumulating that PCV shows a better response to PDT than tAMD [14,15,112]. Most studies reported that the mean posttreatment VA was improved in PCV over a short-term follow-up (up to 1 year). In particular, most polypoidal lesions regressed by PDT whereas the BVN remains after PDT [113,114,115,116]. A recent multicenter randomized controlled trial revealed that polyp lesions disappeared in more than 70% of the PCV cases within 6 months after PDT [117]. However, several reports suggested some heterogeneity in the response to PDT among PCV patients [15,52]. Tamura et al. [45] reported better outcomes for PCV cases with subretinal fibrinous material adjacent to the polypoidal lesions treated with PDT. In accordance with the literature, PCV cases with grape-shaped polyp lesions showed poorer outcomes than other PCV cases. In view of the angiographic subtypes of PCV, type 1 PCV is considered to be more refractory to PDT than type 2 PCV [60]. Although the mean VA was improved and maintained up to 12 months after PDT in most reports [14,15,112,113,114,115,116,117,118,119], longer observational studies revealed that the merit of therapy was reduced 12 months after the initial PDT, mainly due to recurrences of the lesions [14,120,121,122]. Consequently, the improvement in the mean VA of the PCV patients was not significant anymore 30-36 months after the initial PDT [14,121,122]. Moreover, it could be below the baseline value 5 years after the treatment [123,124,125]. Persistent BVN may be the origin of new polypoidal lesions [126]. In a recent prospective cohort study, 56 out of 139 eyes (40%) in the tAMD cases and 52 out of 107 eyes (49%) in the PCV cases were recurrent during the 60 months of follow-up after the initial PDT [123]. In particular, 44 eyes (32%) in the tAMD and 27 eyes (25%) in the PCV cases were recurrent within 12 months after the initial resolution of the lesions obtained by PDT. The mean recurrence period during the 60 months of follow-up was 15.7 ± 13.5 months (mean ± SD) in the PCV group, which was significantly longer than in the tAMD group (8.6 ± 9.3 months). The mean VA was maintained for 60 months in the tAMD and PCV patients who showed no recurrence of their lesions.

Recently, genetic variants in the CFH gene have been tested to explain the response to PDT. In particular, the Y402H coding variant (rs1061170) in CFH is presumed to have functional consequences consistent with AMD pathology [84], and most studies were performed to determine whether CFH Y402H correlates with the outcome of PDT [127,128,129,130,131]. In tAMD, Brantley et al. [129] reported an association of the CFH Y402H variant with the visual outcome after PDT. In that study, the C allele was beneficial for the patients. Goverdhan et al. [131] also reported the positive association of CFH Y402H with the outcome of PDT in tAMD, but discovered the C allele as the risk allele for a better VA. On the other hand, other studies failed to demonstrate any association of this variant with the outcome of PDT [127,128,130]. In PCV cases, one study demonstrated that the SNPs rs1061170 (Y402H) and rs1410996 in the CFH region were significantly associated with an anatomical response to PDT [132]. Two studies found that the genotype at rs10490924 (A69S) in ARMS2 was significantly associated with the lesion size in PCV patients, as well as the visual outcome in tAMD and PCV patients 12 months after their first PDT [110,133]. Therefore, patients with more G alleles at rs10490924 showed better BCVA values until 12 months after their first PDT. Nakata et al. [134] reported that a variant at rs12603825 in the pigment epithelium-derived factor gene was associated with the recurrence-free period, and our own study revealed a significant association of the SNP at rs3173798 in the CD36 gene with the visual outcome of PDT in a dominant model. The presence of the C allele in rs3173798 was significantly associated with a poor response to PDT after multivariate logistic regression analysis with clinical pre-PDT parameters. The mean BCVA in the group with the TT genotype of rs3173798 was significantly improved over the 12 months of follow-up after the initial PDT [135].

The intravitreal injection of anti-VEGF agents is currently the primary treatment for exudative AMD. Studies from Western countries have reported significantly better visual outcomes with monthly intravitreal injections of ranibizumab (IVR) than PDT in exudative AMD patients [136,137], but these studies did not distinguish between the phenotypes of AMD, and the effects of anti-VEGF therapy for PCV may differ from those for tAMD. Overall, the effects of IVR monotherapy against PCV are currently contentious, and no consensus has been reached to date. Some studies reported that the polypoidal lesions of PCV were barely resolved by anti-VEGF monotherapy, which might explain the limited efficacy of IVR against PCV [138,139,140]. However, Song et al. [141] reported that IVR without PDT for PCV in Korean patients resulted in significant visual and anatomical improvements over a 1-year follow-up period, and other reports suggested that the disappearance of the polypoidal lesions occurred at a high rate in PCV cases after anti-VEGF monotherapy [74,142,143]. A recent review suggested an overall improvement of the VA of PCV patients using IVR [144], and a most recent multicenter randomized controlled trial (LAPTOP study) revealed that IVR monotherapy achieved a significantly better visual prognosis than PDT monotherapy in PCV patients [145]. However, Matsumiya et al. [16,17] reported that the degree of improvement in the VA in PCV patients was lower than that of tAMD patients treated by anti-VEGF monotherapy. Some reports demonstrated that several pretreatment factors influenced the outcome of IVR [16,17,146], which might be useful to predict the visual and anatomical consequences for PCV patients who undergo IVR.

Although very little has been studied about the genetic factors associated with the outcome of IVR in PCV patients [147], a number of recent studies assessed the possible genetic factors associated with the outcome of IVR in tAMD patients [147,148,149,150,151,152,153,154,155,156,157,158,159,160]. Most studies focused on the SNPs in the CFH, ARMS2 and VEGF-A genes, since these genes were reported to be associated with the pathogenesis of exudative AMD, but a consistent conclusion has not been made to date (tables 2, 3). In particular, CFH Y402H was the most studied SNP and many reports demonstrated that the C allele in CFH Y402H was associated with the reduced response to anti-VEGF therapy [151,154,155]. Since the C allele in CFH Y402H is known to be a risk allele for the incidence of exudative AMD, C allele-rich cases likely have more active lesions than the others, and hence those cases are likely more refractory to the treatment. A recent meta-analysis demonstrated the association of CFH Y402H with the visual outcome of IVR in Caucasians (the CC genotype showed a decreased response to anti-VEGF therapy compared to the TT genotype) [148]. However, more recent reports described that the C allele was beneficial for the posttreatment BCVA in British and Korean populations over shorter (3 and 6 months) follow-up periods [152,158]. The risk/benefit effects of CFH Y402H regarding the treatment outcome might be changed by the proportion of AMD phenotypes at baseline or by the duration of the follow-up period. Moreover, the association of CFH Y402H with the outcome of IVR might be different between Caucasians and Asians, since the frequency of the C allele is very low in Asian populations [90]. Although Chang et al. [158] and Yamashiro et al. [147] reported a relatively better visual outcome (though not significantly better) in the C-rich genotypes than the others for CFH Y402H in the Asian populations, additional meta-analyses will be required to conclude the association of CFH Y402H with the visual outcome of IVR in Asians, particularly in PCV cases.

Recently, a multicenter randomized controlled trial (EVEREST study) was conducted to compare the effects of PDT monotherapy, IVR monotherapy and their combination (PDT + IVR) in patients with PCV. It reported that all therapies resulted in improvements of the patients' VAs 6 months after treatment [117]. In addition, PDT monotherapy and combination therapy achieved a significantly higher proportion of patients with complete polyp regression (more than 70%) at 6 months than IVR monotherapy (less than 30%). Similar results were reported in other studies with different populations [113,116,139,143,146,161]. Considering the results from recent publications, combination therapy is likely the most effective modality for treating PCV. However, the cost-effectiveness of combination therapy should be carefully assessed, and a strategy to select the appropriate candidates for this therapy should be established because of its expense.

In the future, it will be important to evaluate the long-term results of each modality with a large number of subjects to determine the efficacy and durability of this therapy, particularly in PCV patients.

As described above, PCV is a unique phenotype of AMD which should be handled with a different strategy from tAMD. In particular, the effects of various treatment modalities may be different between tAMD and PCV, which necessitate further investigation to determine the correct indications for PDT, anti-VEGF therapy and combination therapy for PCV. Moreover, genetic association analyses may disclose the difference in the pathogenesis between tAMD and PCV, and may indicate how to choose the appropriate interventions for each PCV patient.

The authors report no conflicts of interest.