Indocyanine green angiographic and optical coherence tomographic findings support classification of polypoidal choroidal vasculopathy into two types

Purpose: We assessed the characteristic indocyanine green angiographic (ICGA) and spectral domain optical coherence tomographic (SD-OCT) findings of two types of polypoidal choroidal vasculopathy (PCV), distinguishable by different filling patterns on ICGA. Methods: Thirty-one eyes with PCV were classified into types 1 and 2 based on ICGA findings of either the presence or absence of both a feeder and a draining vessel. Characteristic ICGA findings were evaluated for each type of PCV. Spectral domain optical coherence tomographic images of the 31 eyes were also used to compare the two types of PCV. Results: Both a feeder and a draining vessel were observed in 13 eyes (type 1). Eighteen eyes had neither feeder nor draining vessels (type 2). In PCV type 1, a break in the highly reflective line thought to be Bruch’s membrane was detected, corresponding to the feeder vessel in-growth site on SD-OCT. This line was straight. In PCV type 2, the highly reflective line exhibited irregular thickness and had highly reflective substances adhering to its lower portion. It curved downward and became increasingly obscure, ultimately disappearing at a point corresponding to the site at which network vessel filling began. The mean subfoveal choroidal thicknesses in eyes with PCV type 1 and PCV type 2 were 199 ± 65 and 288 ± 98 μm, respectively. Conclusions: Our observations support the existence of two distinct types of PCV. The first type represents choroidal neovascularization, whilst the second type involves choroidal vasculature abnormalities. Polypoidal choroidal vasculopathy (PCV) is now well known to be characterized by a branching vascular network and polypoidal lesions (Spaide et al. 1995) detectable by indocyanine green angiography (ICGA). However, as increasingly advanced genetic studies and imaging technologies become available, our understanding of the pathophysiology of PCV grows. In recent years, spectral domain optical coherence tomography (SD-OCT), including Enhanced Depth Imaging (EDI) OCT, has been used to investigate morphological alterations in eyes with PCV (Ojima et al. 2009; Ozawa et al. 2009; Freund et al. 2010; Chung et al. 2011; Koizumi et al. 2011; Miura et al. 2011). Despite these diagnostic advances, the pathogenesis of PCV remains controversial. Two different histopathological features have been described. One, as we reported previously (Nakashizuka et al. 2008), is related to arteriosclerotic changes of choroidal vessels (Okubo et al. 2002; Nakashizuka et al. 2008).The other corresponds to choroidal neovascularization (CNV) (Lafaut et al. 2000; Rosa et al. 2002; Terasaki et al. 2002). Vascular endothelial growth factor (VEGF) positivity in vascular endothelial cells of PCV was found in some studies (Terasaki et al. 2002; Matsuoka et al. 2004) but not in others (Nakajima et al. 2004; Nakashizuka et al. 2008). The aqueous VEGF level in eyes with PCV is reportedly higher than that in normal eyes but significantly lower than that in eyes with age-related macular degeneration (AMD) (Tong et al. 2006). Thus, uncertainty persists as to the role of humoral growth factors, and the consequences of inhibiting these factors, in PCV. Based on a recent study of the age-related maculopathy susceptibility gene 2 (ARMS-2), Tanaka et al. (2011a,b) suggested that PCV is divisible into two types. They divided their cohort of Japanese patients into 202 with typical PCV, that is, PCV in the narrow sense and 85 with polypoidal CNV. They found one variant of the ARMS-2 gene to be strongly associated with AMD. Typical PCV was not associated with the ARMS-2 variant. We previously reported the characteristic scanning laser ophthalmoscope indocyanine green angiographic (SLO-ICGA) findings of strictly defined PCV, that is, the type of PCV characterized by choroidal vasculature abnormalities (Yuzawa et al. 2005). Taking our SLO-ICGA (Yuzawa et al. 2005) and reported histopathological results (Nakajima et al. 2004) together, along with the findings of other studies (Lafaut et al. 2000; Okubo et al. 2002; Rosa et al. 2002; Terasaki et al. 2002; Matsuoka et al. 2004), we classified PCV into three groups (Yuzawa et al. 2005). The first was the aforementioned PCV in the narrow sense, which is caused by inner choroidal vessel abnormalities, not by CNV. The second, the polypoidal type, is CNV expanding rapidly under the retinal pigment epithelium (RPE), ultimately with polypoidal lesions developing at vessel termini. The third type, radiation-associated choroidal vasculopathy, is considered to be a complication of radiation (Spaide et al. 1999). Thus, PCV is classified mainly into choroidal vessel abnormalities and polypoidal CNV (Yuzawa 2012). In this study, we used both SLO-ICGA and SD-OCT findings to demonstrate differences between PCV in the narrow sense (hereafter, PCV type 2) and polypoidal CNV (hereafter, PCV type 1). We performed simultaneous SLO-ICGA using eye-tracked Spectralis® HRA + OCT (Heidelberg Retina Angiograph plus OCT; Heidelberg Engineering GmbH, Heidelberg, Germany) in patients with PCV between June of 2008 and November of 2011. Thirty-one eyes of 31 patients which yielded clear images of the early phase of SLO-ICGA were selected. All patients had subretinal haemorrhage and/or serous retinal detachment and/or a haemorrhagic or serous RPE detachment (PED), as demonstrated by slit-lamp fundus examination. Occult CNV involving the macula was also seen on fluorescein angiography (FA) in all cases. Patients who had PCV and other concurrent fundus diseases, or who had undergone prior treatment for PCV, or who exhibited subretinal CNV on FA and/or SD-OCT were excluded from this study. For SLO-ICGA, indocyanine green dye (25 mg in 2 ml balanced saline) was injected into the cubital vein. Video angiography was recorded for 30 seconds starting from the time of dye injection, and consecutive photographs were then taken up to 1 min, and again at approximately 2.5, 5, 10 and 15 min. Indocyanine green angiographic findings in the 31 eyes were divided into two patterns: both a feeder and a draining vessel on SLO-ICGA (PCV type 1), and eyes with neither (PCV type 2). We also obtained simultaneous SD-OCT cross-sectional images, corresponding to either the in-growth site of the feeder vessel or the point at which the network vessel filling began on SLO. In addition, horizontal and vertical cross-sectional SLO-ICGA images were obtained at the fovea. We assessed the sites and filling states of the feeder and draining vessels, and the characteristics of the vessel networks. In eyes with PCV type 2, the filling, number and features of network vessels were evaluated. The subtraction method was employed to assess the images (Spaide et al. 1998). The subtraction image, obtained by subtracting the angiogram taken in the arteriovenous phase from that in the venous phase of SLO-ICGA, allows clear visualization of vessel filling. For both types of PCV, the largest diameter comprising a network of vessels plus polypoidal lesions was measured. We evaluated the pulsation and the presence of plaque, defined as a hyperfluorescent area observed in the late phase of SLO-ICGA (Guyer et al. 1996). For polypoidal lesions, the location and architecture were evaluated. The site on the SD-OCT image corresponding to either feeder vessel in-growth or the point at which the network vessel filling began was identified and subfoveal choroidal thickness was determined as the average of the measured thicknesses in the horizontal and vertical directions. The choroidal thickness under the fovea was scanned 100 times to improve the signal-to-noise ratio and the data obtained were averaged. Enhanced depth imaging was used in cases in which the choroidal thickness could not be measured. The choroidal thickness under the fovea was measured from the outer surface of the hyperreflective line corresponding to the RPE to the inner surface of the sclera. If pigment epithelium detachment was present, the highly reflective line thought to be Bruch’s membrane was used as the inner margin of the choroid instead of the RPE line. If Bruch’s membrane was not identified, the inner margin of the choroid was defined as the boundary. The 31 eyes were classified according to the SLO-ICGA findings. Thirteen eyes had both a feeder and a draining vessel (PCV type 1) whilst 18 eyes lacked both feeder and draining vessels, that is, showed only network vessels with polypoidal lesions (PCV type 2). The PCV type 1 group consisted of 13 eyes of 13 patients (nine males and four females, 55–82 years of age, 69.5 years on average) in which both a feeder and a draining vessel, connecting the network vessels to the polypoidal lesions, were detected. The feeder vessels were visible immediately after filling of the choroidal arterioles in these 13 eyes (1, 2). Fluorescence within the feeder vessels decreased rapidly and was obscured after a short time (1, 2). Very close to the feeder vessel, the draining vessel was observed as a gradually brightening fluorescent vessel and was visible for several minutes in all 13 eyes. In the subtraction images, the feeder vessel appeared black due to weakening of the venous phase fluorescence. The draining vessel appeared white due to the venous phase fluorescence in this vessel becoming stronger (1, 2). In these 13 eyes, a large number of vessels branched from the feeder vessels, and these branches constituted the networks (1, 2). Each network vessel was essentially straight and became thinner towards the periphery. The vessels were packed into a thin meshwork between relatively thick vessels branching from the feeder vessel. The shapes of the branching vascular networks were classified into two patterns. One type (eight eyes) was an umbrella-like pattern with vessels radiating from a feeder vessel, that is, spreading outward in a radial configuration (Fig. 1). The other type (five eyes) was a rake-like pattern with vessels extending from a feeder vessel, thereby resembling the teeth of a rake (Fig. 2). No pulsation was detected in the network vessels in any of these 13 eyes. Filling of the network vessels gradually became obscure, and plaque was prominent in the late phase in all 13 eyes (1, 2). All polypoidal lesions were at the termini of the network vessels and consisted of the dilatation of marginal tortuous network vessels. The polypoidal lesions followed the course of the marginal vessel in 11 of the 13 eyes, rather like an irregular string of beads (Fig. 1B). The largest diameters of the networks of vessels together with the polypoidal lesions ranged from 4250 to 7200 μm (mean 5513 ± 976 μm). Scanning Laser Ophthalmoscope Indocyanine Green Angiography (SLO-ICGA) of PCV type 1 showing an umbrella-like configuration of network vessels with 2 pigment epithelial detachments (PED). (A) At 22 seconds, the in-growth site of a feeder vessel is visible (white arrow). Many vessels can be seen to radiate from the feeder vessel. (B) At 29 seconds, a draining vessel is observed very close to the feeder vessel (yellow arrows). The network is composed of a large number of vessels. Polypoidal lesions are dilatations of marginal tortuous vessels (yellow arrowheads). The pattern is similar to that of choroidal neovascularization although there are numerous polyps at the periphery. (C) Subtraction image (A from B). The feeder vessel is black (black arrowheads) because at 29 seconds fluorescence in the feeder vessel has weakened markedly. The draining vessel appears white because only this vessel fluoresces in B (black arrows). (D) At 36 seconds, the draining vessel can still be seen. (E) At 634 seconds, plaque is surrounded by polypoidal lesions. (F) Spectral domain optical coherence tomographic showing a break in Bruch’s membrane and separation between the retinal pigment epithelium (RPE) and Bruch’s membrane. A break (black arrow) is observed in Bruch’s membrane corresponding to the in-growth site of the feeder vessel on SLO-ICGA (yellow arrow). Irregular of the RPE are observed corresponding to network vessels. Bruch’s membrane is straight. of Scanning laser ophthalmoscope indocyanine green angiographic (SLO-ICGA) of polypoidal choroidal vasculopathy type 1 showing a rake-like configuration of network vessels with a haemorrhagic (A) At seconds, the in-growth site of a feeder vessel is visible (white arrow). (B) At seconds, a draining vessel is observed very close to the feeder vessel (yellow arrow). The network is composed of a large number of vessels. Polypoidal lesions are dilatations of marginal tortuous vessels (yellow arrowheads). (C) Subtraction image (A from B). The feeder vessel is black (yellow arrow). The draining vessel appears white (yellow arrowheads). (D) At seconds, the draining vessel can still be seen. (E) At seconds, plaque is surrounded by polypoidal lesions. (F) Spectral domain optical coherence tomographic (SD-OCT) showing a break in Bruch’s membrane and separation between the retinal pigment epithelium and Bruch’s membrane. The line is thin and straight. substances the break in Bruch’s membrane (black arrow) on SD-OCT. The location of this break corresponds to the in-growth site of the feeder vessel on SLO-ICGA (yellow arrow). of The PCV type 2 in which feeder vessels not consisted of 18 eyes of 18 patients males and females, years of age, years on Filling of network vessels was observed in the choroidal venous phase on filling within network vessels in all 18 eyes. The networks were composed of a number of vessels showing dilatation and branching networks began to with the choroidal In the subtraction images, network vessels were still vessel filling was detected in network vessels in three eyes. All polypoidal lesions were at the of the networks for which was within the network Thirteen eyes had one the other The polypoidal lesions consisted of either a of numerous hyperfluorescent relatively large or large vessels with as vessels. was observed in of the 18 eyes Each polypoidal was of the The largest diameters of a vascular network together with polypoidal lesions ranged from to μm (mean ± significantly than that in type 1 PCV Indocyanine green angiography of polypoidal choroidal vasculopathy type 2 showing network vessels with (A) At seconds, network vessels (white and choroidal (yellow become (B) At seconds, filling of the network vessels can still be seen (black arrows). vessels and numerous dilatations of vessels. (C) Subtraction image (A from B). vessels are still (white vessel filling. (D) At 30 seconds, the network vessel can still be seen. (E) At seconds, plaque is (F) Spectral domain optical coherence tomographic showing separation between the retinal pigment epithelium (RPE) plus Bruch’s membrane on the one and the inner choroid on the The point by the black corresponds to the site at which network filling began on scanning laser ophthalmoscope indocyanine green angiographic (yellow arrow). The line thought to be the inner choroid irregular thickness with highly reflective substances adhering to its lower (black arrowheads). It downward towards the point network filling began (yellow A vessel appears to the between the RPE plus Bruch’s membrane and the inner choroid and to the RPE The RPE the point by the green is of Indocyanine green angiography of with polypoidal choroidal vasculopathy type 2 showing network vessels. (A) At seconds, network vessels become (white arrows). (B) At seconds, filling of the network vessels can still be seen (white arrows). vessels and (C) Subtraction image (A from B). vessels are still (white vessel filling. (D) At 30 seconds, the network vessel can still be seen. (E) At seconds, plaque is (F) Spectral domain optical coherence tomographic (SD-OCT) showing separation between the retinal pigment epithelium (RPE) plus Bruch’s membrane and the inner The point by the black on SD-OCT corresponds to the by the at which a network vessel to in the early phase of scanning laser ophthalmoscope indocyanine green The line thought to be the inner choroid irregular thickness with highly reflective substances adhering to its lower (black arrowheads). It downward towards the point network filling began (yellow A vessel appears to the between the RPE plus Bruch’s membrane and the inner choroid and to the RPE of In PCV type 1, a break in the highly reflective line thought to be Bruch’s corresponding to the in-growth site of the feeder vessel on was detected (1, 2). The line was thin and straight and lacked highly reflective substances adhering to its lower portion. Irregular of the RPE thick vessels of the network of vessels were also of the RPE to polypoidal lesions. In PCV type 2, the highly reflective line from that in PCV type the line was of irregular thickness with highly reflective substances adhering to its lower portion. the line was not straight. It curved downward and became increasingly obscure, ultimately disappearing at a point corresponding to the site at which the network vessel filling began. there were in this line. This pattern was observed in all 18 eyes with PCV type The RPE was in these 18 eyes, by a vessel corresponding to the network vessels A in the RPE at the site at which the network vessel filling began was observed in 10 of the 18 eyes. subfoveal choroidal thicknesses in eyes with type 1 and type 2 PCV were 199 ± 65 and 288 ± 98 μm, respectively. Thus, mean subfoveal choroidal thickness was significantly in type 2 than in type 1 PCV Characteristic SLO-ICGA findings of the presence of both a feeder vessel and an draining vessel were in 13 eyes with PCV type 1 in this study. vessels from the feeder vessel. et al. that PCV lesions be considered a of CNV. They observed in-growth sites of feeder vessels in of 22 eyes with PCV. studies have a choroidal and a et al. et al. et al. extending the break in Bruch’s membrane in CNV associated with AMD. In the study, vessels branching from the feeder vessel were essentially straight and became thinner towards the on ICGA. The network vessels umbrella-like or rake-like between these straight vessels showed and thereby networks. The umbrella-like configuration is similar to the characteristic findings of as demonstrated by whilst the rake-like configuration is similar to retinal neovascularization observed in et al. was reported to be a characteristic of CNV within Bruch’s membrane (Guyer et al. 1996). All lesions in the 13 eyes in our PCV type 1 group showed plaque in the late rapidly from numerous network vessels and this plaque on ICGA. Our results that the network vessels have the characteristics of CNV the Polypoidal lesions appeared to have been caused by the dilatation of marginal tortuous network vessels. classified subretinal CNV into two and The polypoidal type was as a growth pattern of vessels, not a in patients who be relatively to the of subretinal neovascularization because of their highly Characteristic SD-OCT findings in the study a corresponding to the in-growth site of the feeder vessel, in the line thought to be Bruch’s separation between the RPE and Bruch’s and irregular RPE corresponding to network vessels and polypoidal lesions. SD-OCT findings that network vessels branching from feeder vessels in Bruch’s between the RPE and Bruch’s become polypoidal vessels at the and then into the draining vessels close to feeder vessels. Taking the SLO-ICGA results of the study together with the aforementioned findings in the et al. et al. et al. 2004), we that the type of PCV which has a feeder vessel and a draining vessel as well as polypoidal lesions at network vessel termini in a configuration represents CNV with polyps under the RPE and is polypoidal CNV. the other the SLO-ICGA findings of PCV in the narrow sense (PCV type as in our (Yuzawa et al. are also branching networks to but with the choroidal in and network vessels is observed in the early The vessels, all of which within a branching network are in number and and in the and arteriovenous of abnormalities corresponding to polypoidal lesions similar in to network vessels and numerous dilatations of vessels. pulsation is seen in both the network and polypoidal lesions. has also been observed in not eyes with PCV in the narrow sense (PCV type 2). In our prior study (Nakashizuka et al. 2008), characteristic features of PCV type 2 were to vessels Bruch’s membrane. vessels are observed the characteristic is is thought to from an in and is an essentially arteriosclerotic not Vascular endothelial cells were for VEGF in our study (Nakashizuka et al. 2008). from the SLO-ICGA findings and the results of studies (Okubo et al. 2002; et al. we that the of this type of PCV is choroidal vascular abnormalities. Spectral domain optical coherence tomographic (SD-OCT) findings in PCV type 2 also to from of PCV type Nakashizuka et al. from our group used to for and demonstrated vascular in vessels, was in vessels in the study. of cells from vessel results in vessel from the results of histopathological vessels the RPE to an in due to the presence of several vessels and in to from these vessels within the In we found mean subfoveal choroidal thickness to be significantly in eyes with PCV type 2 than in with type The choroid is reportedly thick in PCV whilst relatively thin in et al. 2011; Koizumi et al. 2011). The presence of vessels and the in our studies is thought to from the choroid in PCV type RPE in type 2 PCV be to decreased at the point at which network vessel filling is the in the highly reflective line in cases of PCV type 2, observed on which we to be Bruch’s membrane. The line is straight in PCV type In the line in PCV type 2 is of irregular thickness with highly reflective substances adhering to its lower and downward and increasingly obscure, ultimately disappearing at a point corresponding to the site at which network vessel filling are in this line. The aforementioned studies showed vessels to be Bruch’s membrane in PCV type Our that with to be polypoidal lesions. the network vessels and which from the of to the endothelial of choroidal vessels. findings to the line showing irregular thickness with highly reflective substances adhering to its lower portion. The vessels and from the RPE plus Bruch’s membrane on SD-OCT. the line which we to be Bruch’s membrane not in be Bruch’s membrane at instead the inner in PCV type et al. reported that PCV corresponds to polypoidal CNV (PCV type 1) in our The ICGA and SD-OCT findings of polypoidal CNV classified according to our are similar to reported by et al. are between the hyperreflective RPE and Bruch’s membrane plus the inner In some observed three highly reflective that is, the from Bruch’s and inner choroid was seen as a highly Our histopathological results have the to be under Bruch’s membrane in PCV type 2 (Nakashizuka et al. 2008). Bruch’s membrane from the inner We that the hyperreflective line which we considered to be Bruch’s membrane in be the inner choroid on SD-OCT in PCV type The study of et al. showed that the inner choroid can as a hyperreflective line. This on our is based on Bruch’s membrane becoming due to of choroidal vessels, whilst the inner choroid remains in Our SD-OCT images the PCV to be between a of the RPE plus Bruch’s and the inner is to our SD-OCT findings. The largest diameter of a vascular network together with polypoidal lesions in eyes with type 2 PCV was significantly than that in type 1 PCV. et al. that PCV with vascular lesions 2 PCV also Okubo et al. classified PCV into two groups based on and and showed that eyes with lesions of short had changes in the and This group of eyes the as our type 2 PCV. Tanaka et al. showed the which is a gene for to be related to polypoidal CNV but not to PCV in the narrow sense (PCV type 2). The showed of the gene to be genetic for retinal whilst of two other and were associated with the of et al. nor was associated with PCV in the narrow In recent study, et al. suggested to be associated with both the features and to of and typical PCV. In a very recent study, the the of of 36 with PCV and et al. 2012). They found the of two to between PCV and AMD. They that a be associated with differences in genetic susceptibility to PCV typical as well as also the of PCV to genetic differences differences between PCV types 1 and PCV reported in is considered to be polypoidal PCV in the narrow sense (PCV type 2) is very in studies of because the number of patients with PCV is et al. In recent years, and or in have been used for the treatment of PCV. However, on the type of PCV. of the two types of PCV is to be for both and It is also that the types of PCV and choroidal patients who not from to be identified, an in our Polypoidal choroidal vasculopathy has been the of because was first identified three et al. diagnostic and treatment are to of the of this group of our of the and of different types of PCV we be to our patients with results were at a of the of This study was in by the on and The of and of