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Indocyanine Green Angiography: Guided Photodynamic Therapy for Polypoidal Choroidal Vasculopathy
Indocyanine Green Angiography: Guided Photodynamic Therapy for Polypoidal Choroidal Vasculopathy ATSUSHI OTANI, MANABU SASAHARA, YUKO YODOI, HIROKO AIKAWA, HIROSHI TAMURA, AKITAKA TSUJIKAWA, AND NAGAHISA YOSHIMURA ● PURPOSE:
To report the 12-month follow-up results of subfoveal polypoidal choroidal vasculopathy (PCV) patients treated with indocyanine green angiography (ICGA)-guided photodynamic therapy (PDT). ● DESIGN: Interventional, noncomparative cases series. ● METHODS: A retrospective analysis of the clinical and angiographic data related to 47 PCV eyes that were followed up for 12 months was carried out. The greatest linear dimension (GLD) for PDT was determined based on the ICGA findings. Optical coherence tomography (OCT) also was used to evaluate the therapeutic effects. ● RESULTS: The mean logarithm of the minimum angle of resolution visual acuity (VA; 0.58 ⴞ 0.37) significantly improved to 0.53 ⴞ 0.38 at three months (P ⴝ .04) and to 0.46 ⴞ 0.40 at 12 months (P ⴝ .02). The average ICGA GLD (2682.3 ⴞ 1026.9 mm) was significantly (P ⴝ .0001) smaller than the presumed fluorescein angiography (FA) GLD (4043.6 ⴞ 1914.8 mm). In more than 80% of cases, complete resolution of retinal exudative changes was observed. Although polypoidal vascular lesions disappeared in 82.2% of eyes, the branched vascular networks showed little change. The initial VA and GLD had little correlation with the VA outcome. ● CONCLUSIONS: ICGA-guided PDT reduces the size of laser exposure and is an effective treatment for PCV. Because PCV may appear as occult choroidal neovascularization (CNV) on FA, PCV should be diagnosed using ICGA before treatment because PCV may respond differently than CNV to appropriate treatment. (Am J Ophthalmol 2007;144:7–14. © 2007 by Elsevier Inc. All rights reserved.)
S
INCE IT WAS FIRST REPORTED IN BLACK WOMEN,1
polypoidal choroidal vasculopathy (PCV) is considered to be a distinct clinical entity that is characterized by the polypoidal appearance of vasculature that arises from interconnecting choroidal vessels.2– 4 Although PCV has been considered to be more common in nonwhite persons, a recent report suggests that 8% to 13% of white Accepted for publication Mar 11, 2007. From the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. Inquiries to Atsushi Otani, Department of Ophthalmology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan 606-8507; e-mail: [email protected] 0002-9394/07/$32.00 doi:10.1016/j.ajo.2007.03.014
©
2007 BY
patients with apparent exudative age-related macular degeneration (AMD) can be diagnosed as having PCV.5 Because PCV lesions originate from the choroidal vasculature and the vascular lesions progress beneath the retinal pigment epithelium (RPE), there are many clinical and pathologic similarities with AMD.2,6 – 8 Indeed, in many cases, it is difficult to distinguish PCV from AMD based on only fluorescein angiography (FA) results.5 Thus, indocyanine green angiography (ICGA) is critical for making the diagnosis of PCV.2,3 Despite these clinical and pathologic similarities, PCV has been reported to have a different clinical prognosis than type 1 or type 2 choroidal neovascularization (CNV). Furthermore, PCV may require a specific photodynamic therapy (PDT) treatment protocol.9,10 PDT has become the first choice for dealing with subfoveal CNV. However, several PDT-induced adverse effects, including temporary or irreversible changes of choroidal circulation, RPE damage, functional alternations of the neurosensory retina, and the induction of angiogenic factors, have been reported.11–15 The accurate and careful determination of the greatest linear dimension (GLD) may be important in avoiding these adverse effects. Indeed, massive hemorrhage after PDT has been reported in PCV patients.16,17 Herein, we report the 12-month follow-up results of subfoveal PCV patients who underwent ICGA- and OCT-guided PDT.
METHODS ● PATIENTS AND CLINICAL EVALUATION: A retrospective study of 47 eyes from 44 patients with PCV who were treated with PDT at Kyoto University Hospital between August 2004 and October 2005 was carried out. The analysis included the data for the 45 eyes that had at least 12 months of follow-up. All patients were assessed carefully; examinations included FA and ICGA using a scanning laser ophthalmoscope, HRA2 (Heidelberg Engineering, Dossenheim, Germany), and cross-sectional images obtained with optical coherence tomography (OCT; OCT3000, Humphrey Instruments, San Leandro, California, USA; or OCT Ophthalmoscope C7, Nidek, Gamagori, Japan). The OCT images were used to evaluate the exudative changes of the lesion, including intraretinal edema, subretinal fluid
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(SRF), serous or hemorrhagic pigment epithelial detachment (PED), and retinal or subretinal hemorrhage. OCT also was used to confirm the extension of the vascular lesions located in the sub-RPE space. The outcomes were analyzed every three months. The best-corrected visual acuity (VA) obtained by the Landort ring tests was converted into the logarithm of the minimum angle of resolution (logMAR) VA; a change of more than 0.2 in logMAR VA was considered to be significant. All images were examined independently by three ophthalmologists who judged the lesion changes (disappeared, decreased, or persisted/increased). The inclusion criteria for the PDT treatment were: 1) symptomatic PCV in patients more than 50 years of age, 2) the presence of subfoveal vascular lesions, 3) bestcorrected VA of 20/25 or worse, and 4) informed consent obtained from the patient. Exclusion criteria were: 1) any contraindications for FA, ICGA, or verteporfin, 2) presence of type II CNV, and 3) the presence of an RPE tear.
(⫾ standard deviation [SD]). Details are shown in the Table. ● VISUAL OUTCOME:
The mean (⫾ SD) initial logMAR VA was 0.58 ⫾ 0.37. The mean logMAR VA improved to 0.53 ⫾ 0.38 at three months (P ⫽ .04, paired t test) and to 0.46 ⫾ 0.40 at 12 months (P ⫽ .02; Figure 2). At the three-month follow-up, the VA was decreased in three eyes, and the other 42 eyes had improved (10 eyes) or stabilized (32 eyes) VA. At the 12-month follow-up, six eyes had decreased VA, and 19 eyes had increased VA. Between the three- and 12-month follow-ups, 18 eyes had VA changes (11 eyes improved and seven eyes deteriorated); nine of the 11 eyes with increased VA received no retreatment during that period. By 12 months, multiple PDT was required in three of the 19 eyes with increased VA. ● SIZE OF GLD:
The average ICGA GLD in our series of patients was 2682.3 ⫾ 1026.9 m. The FA GLD of these eyes was 4043.6 ⫾ 1914.8 m; this was significantly larger than the ICGA GLD (P ⬍ .001, Mann–Whitney U test; Figure 3).
● DETERMINATION OF LESION SIZE: We calculated the GLD based on the analysis of FA or ICGA and OCT findings (Figure 1). The ICGA GLD was determined to cover the entire PCV vascular lesion, including polypoidal lesions and branching vascular network vessels (entire PCV vascular lesion). However, in contrast to the standard protocols,18 –21 FA GLD, PED, and lesions with blocked fluorescence were not included in determining the ICGA GLD.
● CLINICAL PICTURES AND ANGIOGRAPHIC FINDINGS: At 12-month follow-up, complete resolution of PED or SRF was observed in 82.9% and 95.1% of cases, respectively (Figure 4). Although polypoidal vascular lesions disappeared in 82.2% of eyes by 12 months, the branched vascular network showed little change. No case showed complete disappearance of network vasculature, and in most cases, PDT seemed to have little effect on the network vasculature. The recurrence of polypoidal lesions was observed in five cases (11.4%) between the three- and 12-month follow-ups. In most cases, the recurrence of PED and SRF was observed with the recurrence of polypoidal lesions. Interestingly, SRF also can recur without recurrence of the polypoidal lesion.
● PDT:
PDT with verteporfin (Visudyne, Novartis AG; Basel, Switzerland) was carried out according to the standard protocol except for determining the GLD. A 689-nm laser system (Carl Zeiss, Dublin, California, USA) was used and 50 J/mm2 energy was delivered with an 83-second exposure time. Every three months, retreatment was considered based on the angiography and OCT findings. The endpoint of treatment was the disappearance of macular exudative changes confirmed by OCT examination and the disappearance of polypoidal lesions on ICGA.
● LESION SIZE AND VA: Because the PCV lesion is located in the sub-RPE space, the FA findings of PCV lesions resemble those of occult CNV.22 In our series, 43 of 45 eyes showed occult CNV manifestations on FA. Without ICGA, these cases might have been diagnosed as occult CNV. The subgroup analysis of the Verteporfin in Photodynamic Therapy (VIP) trial suggested that PDT had a greater benefit for occult CNV in patients with either small lesion size (⬍4 MPS disk areas; 3600 m) or low initial VA (⬍20/50).18 To confirm whether this also applied to PCV, the visual outcome at 12 months was compared with the pre-PDT lesion size or VA. As shown in Figure 5, cases with lesion size larger than 3600 m (on FA GLD) had a good visual prognosis (VA stabilized or improved in 86.4%), which was not different from that of smaller cases (VA stabilized or improved in 87.0%).
● STATISTICAL ANALYSIS:
A paired t test was used to determine the significance of the difference in logMAR VA before and after PDT. Statistical analysis for the nonparametric data was carried out using the Wilcoxon signed-rank test and the Mann–Whitney U test.
RESULTS A RETROSPECTIVE ANALYSIS WAS CARRIED OUT OF 47 EYES
from 44 PCV patients. Two patients were excluded from the study because of incomplete examinations. The average age of the 45 patients was 73 years; there were 12 women and 33 men. All patients were of Japanese origin. The average number of PDT treatments was 1.22 ⫾ 0.47 8
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FIGURE 1. Angiographic and optical coherence tomography (OCT) findings of polypoidal choroidal vasculopathy (PCV) before and after photodynamic therapy (PDT). (Top left) The early phase of fluorescein angiography (FA). (Top right) Indocyanine green angiography (ICGA) results before PDT. Polypoidal vascular lesions and branched vascular networks clearly are detectable on ICGA, but not on FA. (Second row left) The red circle in the late-phase FA image indicates the FA-guided greatest linear dimension (GLD). (Second row right) In the late-phase ICGA image, the lesion of network vasculature is more prominent. The yellow circle indicates ICGA-guided GLD. (Third row) Vertical scan of OCT before PDT showing details of the lesion in the subretinal pigment epithelium space. The yellow arrow indicates the PCV vascular lesion (ICGA GLD) that does not include pigment epithelial detachment. The FA GLD is indicated by a red arrow. (Fourth row left) FA and ICGA images at three months after PDT. (Fourth row right) The aneurysmal components disappeared, leaving a residual nonspecific plaque on ICGA. (Bottom) Vertical OCT scan at three months after PDT.
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TABLE. Clinical Background and 12 Months Results of ICGA-Guided PDT in Patients with PCV
Patient No.
Age (yrs)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Average
67 52 81 81 79 79 77 74 77 66 71 63 80 69 62 86 75 75 74 72 67 67 71 79 79 66 93 74 55 64 74 70 67 67 82 62 67 83 81 69 77 78 74 74 81 73
logMAR VA
GLD (m)
Gender
HT
DM
CVD
Before
3 Mos
12 Mos
FA
ICGA
PED
SRF
Polyp
M M M M M M M M M M F F M M M F M M M M M M M M M M F M F M F F M F M F F F M M M M M F M
– – – – – – – ⫹ ⫹ ⫹ – – – ⫹ – ⫹ – – ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ – – – – ⫹ – – – – – – ⫹ – ⫹ ⫹ ⫹ ⫹ – – –
⫹ – – – – – – ⫹ – – – – – – – – – – ⫹ ⫹ – – – – – – – – – – – – – – – – – – – ⫹ ⫹ – – – –
⫹ – – – – ⫹ – – – ⫹ – – ⫹ – – – – – – – – – – ⫹ ⫹ – – – – – – – – – – – – – ⫹ – – – – – –
0.70 0.30 0.52 0.70 0.52 0.40 1.00 0.52 1.70 0.22 0.30 0.15 1.15 0.40 0.40 0.15 0.52 0.70 1.15 0.70 0.70 1.00 0.70 0.22 0.70 0.82 0.40 1.40 0.22 0.15 1.15 0.22 0.40 0.40 0.30 0.10 0.30 0.52 1.15 0.30 1.05 0.30 0.22 0.82 0.40 0.58
1.00 0.22 0.30 0.70 0.82 0.30 0.82 0.30 1.30 0.30 0.10 0.15 1.30 0.05 0.10 0.22 0.30 0.70 1.22 1.00 0.82 1.00 0.52 0.22 0.70 0.70 0.40 1.15 0.30 0.10 0.82 0.05 0.30 0.52 0.40 0.05 0.30 0.70 1.15 0.30 1.00 0.22 0.15 0.40 0.22 0.53
0.70 0.10 0.40 0.40 0.82 0.52 1.05 0.15 1.00 0.10 ⫺0.08 0.52 1.30 0.05 ⫺0.08 0.30 0.30 0.30 1.22 1.00 0.70 0.70 1.22 0.70 0.70 0.52 0.40 1.30 0.82 0.00 0.82 0.30 0.15 0.52 0.05 ⫺0.08 0.15 0.22 1.15 0.05 0.40 0.10 0.10 0.10 0.10 0.45
2670 1440 1710 4530 7600 2400 8600 4320 5400 5500 3660 3264 9000 4900 3080 6000 4200 2600 3150 3600 2880 4050 6300 5600 4550 1750 4940 5400 1680 3500 2400 2170 3300 2400 4500 2700 2350 3620 7620 2000 2050 5590 2450 1070 5490 4044
3100 550 1000 1450 2400 2400 2150 1450 3100 3500 2000 1750 3800 3000 4200 3850 2950 1960 2880 1610 2880 3900 3500 3400 5000 1880 1650 5400 1680 2540 2400 2170 2500 2400 2230 2500 2350 2250 3900 1550 2050 5100 2450 2310 1900 2682
Di Di Di Di Di — NC De Di Di Di Re Di Di Di Di Di — Di Di — NC Di De Di Di Di Di Di Di — Re Di — — — — Di Di — — Di — — Re
Re Di Di Di — Di Di — — — Di Re Di Di Di Di Di Di Di Di De Di Di Di Di Di Di Di Re Di Di Re Di Di Di Di Di Di Di Di Di Di Di De Re
Di Di Di Di Di Di NC Di Di De Di Re Di Di De Re Di Di Di Di Di De De Di Di Di Re Di Di Di Di Re De Di Di Di Di De Di Di Di Di Di Di Re
FA Reading
Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ MC Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ MC Occ Occ Occ Occ Occ Occ Occ Occ
No. of PDT
1 1 2 1 3 2 2 2 2 1 2 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
CVD ⫽ cardiovascular disease; De ⫽ decreased; Di ⫽ dissapeared; DM ⫽ diabates; GLD ⫽ greatest linear dimension; HT ⫽ hypertension; ICGA ⫽ indocyanine green angiography; MC ⫽ minimally classic; NC ⫽ no change; Occ ⫽ occult choroidal neovascularization; PCV ⫽ polypoidal choroidal vasculopathy; PDT ⫽ photodynamic therapy; PED ⫽ pigment epithelial detachment; Polyp ⫽ polypoidal lesion by ICGA; Re ⫽ recurred; SRD ⫽ serous retinal detachment; VA ⫽ best-corrected visual acuity.
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FIGURE 3. Graph demonstrating the difference in the average indocyanine green angiography-guided greatest linear dimension (ICG-GLD) and fluorescein angiography-guided GLD (FA-GLD) in this series. The ICG-GLD was significantly smaller than the FA-GLD. FIGURE 2. Graphs demonstrating the logarithm of the minimum angle of resolution visual acuity (VA) outcome at (Top) three months and (Bottom) 12 months after photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV). Individual VA data from before and after PDT are plotted in the Left panel, and the average VA is compared in the Right panel. The average VA was increased significantly both at three and 12 months (paired t test).
Similarly, cases with a VA better than 20/50 had a good VA outcome at 12 months (VA stabilized or improved in 86.4%). As well, even among cases with larger lesions (⬎3600 m, FA-guided GLD), cases with a better than 20/50 VA had a better outcome.
DISCUSSION IN THIS STUDY, WE SHOWED THE EFFICACY OF ICGA-
guided PDT for treating symptomatic, subfoveal PCV. Similar to the previous reports,9,10,23–25 significant improvement in VA was observed at both three and 12 months after PDT, and more than 80% of patients had improved or stabilized VA. The GLD was determined based on the ICGA findings and included all of the vascular abnormalities, including polypoidal lesions and branching vascular networks. Unlike the standard protocol used in the VIP study, retinal hemorrhage and PED were not included as CNV lesions and were not necessarily treated in our series. In this setting, there was a concern regarding whether neovascular lesions that should be treated were hidden beneath the hemorrhage or PED. To minimize such occurrences, we also used OCT and searched carefully. Thus, in this VOL. 144, NO. 1
FIGURE 4. Graph demonstrating the effect of photodynamic therapy (PDT) on the retinal exudative changes and the polypoidal vascular lesions (polyp) at the time of the 12-month examination in patients with polypoidal choroidal vasculopathy (PCV). In most of the cases, these lesions disappeared or decreased by 12 months. PED ⴝ pigment epithelial detachment; SRF ⴝ subretinal fluid.
series, no hidden vascular lesions were detected after PDT. The mean ICGA GLD was significantly smaller than the FA GLD that would have been used based on the standard PDT protocol (Figure 3). Because the outcome of ICGA-guided PDT in our series was good, the smaller laser irradiation size that was used avoided the laser-
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induced problems and could be a benefit of ICGAguided PDT.26 –29 Polypoidal vascular lesions reacted dramatically to PDT. The polypoidal vascular lesions of 44 eyes disappeared or decreased in response to the first PDT. At 12 months, polypoidal vasculature was not detected by ICGA in 82.2% of cases. Secondary retinal exudative changes also disappeared or decreased after a single PDT treatment. Overall, 95.1% of SRF and 82.9% of PED completely disappeared at 12 months; these retinal changes probably resulted in a good visual outcome for the patients. In contrast, in most cases, the branching vascular networks of the PCV lesions did not change after PDT based on ICGA. There were no cases in which the branching vascular networks disappeared, and only in 23.8% of cases was there any decrease in the network vasculature. The dissociation in the clinical outcomes and the status of branching vascular networks suggests that the network vasculature has little role in the exudative retinal changes seen in PCV. If this is the case, the closure of branched vascular networks does not need to be a goal in PCV treatment. Further studies are needed to determine the role of the branching vascular networks in the development of the exudative changes seen in PCV. It has been shown that PDT produced greater treatment benefit in patients with classic or predominantly classic lesions than in those with minimally classic lesions or occult lesions.18,30 Because PCV lesions are located in the sub-RPE space, it is likely that PCV is diagnosed as being occult CNV when ICGA is not performed. Indeed, in this series, 43 of 45 cases were diagnosed as having occult CNV based on FA. If ICGA had not been carried out to diagnose PCV properly, the outcome of PDT would likely have been the same as is seen in occult CNV. However, as shown in this and other studies, in contrast to occult CNV, PCV treated by PDT has excellent outcomes. These observations indicate that although FA suggests occult CNV, care should be taken to diagnose PCV, because it is treated differently from occult CNV without PCV characteristics. Although PDT is the standard treatment method for patients with exudative AMD, there are several problems with this procedure, including PDT-induced closure of choriocapillaris and functional changes in the retina.26 –29 In addition, there have been recent reports of the frequent occurrence of retinal and subretinal hemorrhage after PDT in PCV cases.16,17 To perform PDT more efficiently and to produce minimal damage, several changes in the PDT procedure have been tested, including changing the power and duration of laser exposure,31 as well as combining PDT with corticosteroids or antiangiogenic drugs.32 ICGA-guided PDT is another potential strategy for treatment that is efficient and less harmful. Because our study was not a prospective one, we cannot determine whether PCV lesions for which ICGA had not
FIGURE 5. Graphs demonstrating the visual acuity (VA) outcomes after photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV) that were analyzed by pretreatment PDT lesion size or pretreatment VA. (Top) Eyes were divided into two groups based on the lesion size, >3600 m and <3600 m on fluorescein angiography greatest linear dimension (FA-GLD), and the VA outcome was compared at 12 months. (Middle) The eyes were divided into two groups based on VA before PDT (>20/50 and <20/50), and the VA outcome was compared at 12 months. (Bottom) The VA outcome also was compared by VA before PDT (>20/50 and <20/50) among patients with larger lesions based on FA-GLD (>3600 m).
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been performed and were treated as occult CNV would have a different result from PCV lesions treated with PDT. However, our data, as well as previous reports, clearly show
the benefit of this treatment for PCV without any major adverse effects. Further studies, including prospective ones, are needed.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN CONCEPTION AND design of study (A.O., N.Y.); analysis and interpretation (A.O., M.S., Y.Y., H.A., H.T., A.T., N.Y.); writing of the article (A.O.); critical revision of the article (A.O., A.T., N.Y.); final approval of the article (A.O., A.T., M.S., H.A., Y.Y., H.T., N.Y.); and data collection (A.O., M.S., Y.Y., H.A., H.T.). The Institutional Review Board at Kyoto University Graduate School of Medicine approved the study. A signed informed consent was not required by the Institutional Review Board for this retrospective review.
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Biosketch Atsushi Otani, MD, PhD, is an Assistant Professor of Ophthalmology at Kyoto University, Kyoto, Japan. He received MD and PhD at Kyoto University Graduate School of Medicine. In 2000 to 2003, Dr Otani was a research fellow at Dr Martin Friedlander’s lab of The Scripps Research Institute; La Jolla, California. His interests focus is on retinal diseases including macular diseases and retinal degeneration.
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To report the 12-month follow-up results of subfoveal polypoidal choroidal vasculopathy (PCV) patients treated with indocyanine green angiography (ICGA)-guided photodynamic therapy (PDT). ● DESIGN: Interventional, noncomparative cases series. ● METHODS: A retrospective analysis of the clinical and angiographic data related to 47 PCV eyes that were followed up for 12 months was carried out. The greatest linear dimension (GLD) for PDT was determined based on the ICGA findings. Optical coherence tomography (OCT) also was used to evaluate the therapeutic effects. ● RESULTS: The mean logarithm of the minimum angle of resolution visual acuity (VA; 0.58 ⴞ 0.37) significantly improved to 0.53 ⴞ 0.38 at three months (P ⴝ .04) and to 0.46 ⴞ 0.40 at 12 months (P ⴝ .02). The average ICGA GLD (2682.3 ⴞ 1026.9 mm) was significantly (P ⴝ .0001) smaller than the presumed fluorescein angiography (FA) GLD (4043.6 ⴞ 1914.8 mm). In more than 80% of cases, complete resolution of retinal exudative changes was observed. Although polypoidal vascular lesions disappeared in 82.2% of eyes, the branched vascular networks showed little change. The initial VA and GLD had little correlation with the VA outcome. ● CONCLUSIONS: ICGA-guided PDT reduces the size of laser exposure and is an effective treatment for PCV. Because PCV may appear as occult choroidal neovascularization (CNV) on FA, PCV should be diagnosed using ICGA before treatment because PCV may respond differently than CNV to appropriate treatment. (Am J Ophthalmol 2007;144:7–14. © 2007 by Elsevier Inc. All rights reserved.)
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INCE IT WAS FIRST REPORTED IN BLACK WOMEN,1
polypoidal choroidal vasculopathy (PCV) is considered to be a distinct clinical entity that is characterized by the polypoidal appearance of vasculature that arises from interconnecting choroidal vessels.2– 4 Although PCV has been considered to be more common in nonwhite persons, a recent report suggests that 8% to 13% of white Accepted for publication Mar 11, 2007. From the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. Inquiries to Atsushi Otani, Department of Ophthalmology, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan 606-8507; e-mail: [email protected] 0002-9394/07/$32.00 doi:10.1016/j.ajo.2007.03.014
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2007 BY
patients with apparent exudative age-related macular degeneration (AMD) can be diagnosed as having PCV.5 Because PCV lesions originate from the choroidal vasculature and the vascular lesions progress beneath the retinal pigment epithelium (RPE), there are many clinical and pathologic similarities with AMD.2,6 – 8 Indeed, in many cases, it is difficult to distinguish PCV from AMD based on only fluorescein angiography (FA) results.5 Thus, indocyanine green angiography (ICGA) is critical for making the diagnosis of PCV.2,3 Despite these clinical and pathologic similarities, PCV has been reported to have a different clinical prognosis than type 1 or type 2 choroidal neovascularization (CNV). Furthermore, PCV may require a specific photodynamic therapy (PDT) treatment protocol.9,10 PDT has become the first choice for dealing with subfoveal CNV. However, several PDT-induced adverse effects, including temporary or irreversible changes of choroidal circulation, RPE damage, functional alternations of the neurosensory retina, and the induction of angiogenic factors, have been reported.11–15 The accurate and careful determination of the greatest linear dimension (GLD) may be important in avoiding these adverse effects. Indeed, massive hemorrhage after PDT has been reported in PCV patients.16,17 Herein, we report the 12-month follow-up results of subfoveal PCV patients who underwent ICGA- and OCT-guided PDT.
METHODS ● PATIENTS AND CLINICAL EVALUATION: A retrospective study of 47 eyes from 44 patients with PCV who were treated with PDT at Kyoto University Hospital between August 2004 and October 2005 was carried out. The analysis included the data for the 45 eyes that had at least 12 months of follow-up. All patients were assessed carefully; examinations included FA and ICGA using a scanning laser ophthalmoscope, HRA2 (Heidelberg Engineering, Dossenheim, Germany), and cross-sectional images obtained with optical coherence tomography (OCT; OCT3000, Humphrey Instruments, San Leandro, California, USA; or OCT Ophthalmoscope C7, Nidek, Gamagori, Japan). The OCT images were used to evaluate the exudative changes of the lesion, including intraretinal edema, subretinal fluid
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(SRF), serous or hemorrhagic pigment epithelial detachment (PED), and retinal or subretinal hemorrhage. OCT also was used to confirm the extension of the vascular lesions located in the sub-RPE space. The outcomes were analyzed every three months. The best-corrected visual acuity (VA) obtained by the Landort ring tests was converted into the logarithm of the minimum angle of resolution (logMAR) VA; a change of more than 0.2 in logMAR VA was considered to be significant. All images were examined independently by three ophthalmologists who judged the lesion changes (disappeared, decreased, or persisted/increased). The inclusion criteria for the PDT treatment were: 1) symptomatic PCV in patients more than 50 years of age, 2) the presence of subfoveal vascular lesions, 3) bestcorrected VA of 20/25 or worse, and 4) informed consent obtained from the patient. Exclusion criteria were: 1) any contraindications for FA, ICGA, or verteporfin, 2) presence of type II CNV, and 3) the presence of an RPE tear.
(⫾ standard deviation [SD]). Details are shown in the Table. ● VISUAL OUTCOME:
The mean (⫾ SD) initial logMAR VA was 0.58 ⫾ 0.37. The mean logMAR VA improved to 0.53 ⫾ 0.38 at three months (P ⫽ .04, paired t test) and to 0.46 ⫾ 0.40 at 12 months (P ⫽ .02; Figure 2). At the three-month follow-up, the VA was decreased in three eyes, and the other 42 eyes had improved (10 eyes) or stabilized (32 eyes) VA. At the 12-month follow-up, six eyes had decreased VA, and 19 eyes had increased VA. Between the three- and 12-month follow-ups, 18 eyes had VA changes (11 eyes improved and seven eyes deteriorated); nine of the 11 eyes with increased VA received no retreatment during that period. By 12 months, multiple PDT was required in three of the 19 eyes with increased VA. ● SIZE OF GLD:
The average ICGA GLD in our series of patients was 2682.3 ⫾ 1026.9 m. The FA GLD of these eyes was 4043.6 ⫾ 1914.8 m; this was significantly larger than the ICGA GLD (P ⬍ .001, Mann–Whitney U test; Figure 3).
● DETERMINATION OF LESION SIZE: We calculated the GLD based on the analysis of FA or ICGA and OCT findings (Figure 1). The ICGA GLD was determined to cover the entire PCV vascular lesion, including polypoidal lesions and branching vascular network vessels (entire PCV vascular lesion). However, in contrast to the standard protocols,18 –21 FA GLD, PED, and lesions with blocked fluorescence were not included in determining the ICGA GLD.
● CLINICAL PICTURES AND ANGIOGRAPHIC FINDINGS: At 12-month follow-up, complete resolution of PED or SRF was observed in 82.9% and 95.1% of cases, respectively (Figure 4). Although polypoidal vascular lesions disappeared in 82.2% of eyes by 12 months, the branched vascular network showed little change. No case showed complete disappearance of network vasculature, and in most cases, PDT seemed to have little effect on the network vasculature. The recurrence of polypoidal lesions was observed in five cases (11.4%) between the three- and 12-month follow-ups. In most cases, the recurrence of PED and SRF was observed with the recurrence of polypoidal lesions. Interestingly, SRF also can recur without recurrence of the polypoidal lesion.
● PDT:
PDT with verteporfin (Visudyne, Novartis AG; Basel, Switzerland) was carried out according to the standard protocol except for determining the GLD. A 689-nm laser system (Carl Zeiss, Dublin, California, USA) was used and 50 J/mm2 energy was delivered with an 83-second exposure time. Every three months, retreatment was considered based on the angiography and OCT findings. The endpoint of treatment was the disappearance of macular exudative changes confirmed by OCT examination and the disappearance of polypoidal lesions on ICGA.
● LESION SIZE AND VA: Because the PCV lesion is located in the sub-RPE space, the FA findings of PCV lesions resemble those of occult CNV.22 In our series, 43 of 45 eyes showed occult CNV manifestations on FA. Without ICGA, these cases might have been diagnosed as occult CNV. The subgroup analysis of the Verteporfin in Photodynamic Therapy (VIP) trial suggested that PDT had a greater benefit for occult CNV in patients with either small lesion size (⬍4 MPS disk areas; 3600 m) or low initial VA (⬍20/50).18 To confirm whether this also applied to PCV, the visual outcome at 12 months was compared with the pre-PDT lesion size or VA. As shown in Figure 5, cases with lesion size larger than 3600 m (on FA GLD) had a good visual prognosis (VA stabilized or improved in 86.4%), which was not different from that of smaller cases (VA stabilized or improved in 87.0%).
● STATISTICAL ANALYSIS:
A paired t test was used to determine the significance of the difference in logMAR VA before and after PDT. Statistical analysis for the nonparametric data was carried out using the Wilcoxon signed-rank test and the Mann–Whitney U test.
RESULTS A RETROSPECTIVE ANALYSIS WAS CARRIED OUT OF 47 EYES
from 44 PCV patients. Two patients were excluded from the study because of incomplete examinations. The average age of the 45 patients was 73 years; there were 12 women and 33 men. All patients were of Japanese origin. The average number of PDT treatments was 1.22 ⫾ 0.47 8
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FIGURE 1. Angiographic and optical coherence tomography (OCT) findings of polypoidal choroidal vasculopathy (PCV) before and after photodynamic therapy (PDT). (Top left) The early phase of fluorescein angiography (FA). (Top right) Indocyanine green angiography (ICGA) results before PDT. Polypoidal vascular lesions and branched vascular networks clearly are detectable on ICGA, but not on FA. (Second row left) The red circle in the late-phase FA image indicates the FA-guided greatest linear dimension (GLD). (Second row right) In the late-phase ICGA image, the lesion of network vasculature is more prominent. The yellow circle indicates ICGA-guided GLD. (Third row) Vertical scan of OCT before PDT showing details of the lesion in the subretinal pigment epithelium space. The yellow arrow indicates the PCV vascular lesion (ICGA GLD) that does not include pigment epithelial detachment. The FA GLD is indicated by a red arrow. (Fourth row left) FA and ICGA images at three months after PDT. (Fourth row right) The aneurysmal components disappeared, leaving a residual nonspecific plaque on ICGA. (Bottom) Vertical OCT scan at three months after PDT.
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TABLE. Clinical Background and 12 Months Results of ICGA-Guided PDT in Patients with PCV
Patient No.
Age (yrs)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Average
67 52 81 81 79 79 77 74 77 66 71 63 80 69 62 86 75 75 74 72 67 67 71 79 79 66 93 74 55 64 74 70 67 67 82 62 67 83 81 69 77 78 74 74 81 73
logMAR VA
GLD (m)
Gender
HT
DM
CVD
Before
3 Mos
12 Mos
FA
ICGA
PED
SRF
Polyp
M M M M M M M M M M F F M M M F M M M M M M M M M M F M F M F F M F M F F F M M M M M F M
– – – – – – – ⫹ ⫹ ⫹ – – – ⫹ – ⫹ – – ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ – – – – ⫹ – – – – – – ⫹ – ⫹ ⫹ ⫹ ⫹ – – –
⫹ – – – – – – ⫹ – – – – – – – – – – ⫹ ⫹ – – – – – – – – – – – – – – – – – – – ⫹ ⫹ – – – –
⫹ – – – – ⫹ – – – ⫹ – – ⫹ – – – – – – – – – – ⫹ ⫹ – – – – – – – – – – – – – ⫹ – – – – – –
0.70 0.30 0.52 0.70 0.52 0.40 1.00 0.52 1.70 0.22 0.30 0.15 1.15 0.40 0.40 0.15 0.52 0.70 1.15 0.70 0.70 1.00 0.70 0.22 0.70 0.82 0.40 1.40 0.22 0.15 1.15 0.22 0.40 0.40 0.30 0.10 0.30 0.52 1.15 0.30 1.05 0.30 0.22 0.82 0.40 0.58
1.00 0.22 0.30 0.70 0.82 0.30 0.82 0.30 1.30 0.30 0.10 0.15 1.30 0.05 0.10 0.22 0.30 0.70 1.22 1.00 0.82 1.00 0.52 0.22 0.70 0.70 0.40 1.15 0.30 0.10 0.82 0.05 0.30 0.52 0.40 0.05 0.30 0.70 1.15 0.30 1.00 0.22 0.15 0.40 0.22 0.53
0.70 0.10 0.40 0.40 0.82 0.52 1.05 0.15 1.00 0.10 ⫺0.08 0.52 1.30 0.05 ⫺0.08 0.30 0.30 0.30 1.22 1.00 0.70 0.70 1.22 0.70 0.70 0.52 0.40 1.30 0.82 0.00 0.82 0.30 0.15 0.52 0.05 ⫺0.08 0.15 0.22 1.15 0.05 0.40 0.10 0.10 0.10 0.10 0.45
2670 1440 1710 4530 7600 2400 8600 4320 5400 5500 3660 3264 9000 4900 3080 6000 4200 2600 3150 3600 2880 4050 6300 5600 4550 1750 4940 5400 1680 3500 2400 2170 3300 2400 4500 2700 2350 3620 7620 2000 2050 5590 2450 1070 5490 4044
3100 550 1000 1450 2400 2400 2150 1450 3100 3500 2000 1750 3800 3000 4200 3850 2950 1960 2880 1610 2880 3900 3500 3400 5000 1880 1650 5400 1680 2540 2400 2170 2500 2400 2230 2500 2350 2250 3900 1550 2050 5100 2450 2310 1900 2682
Di Di Di Di Di — NC De Di Di Di Re Di Di Di Di Di — Di Di — NC Di De Di Di Di Di Di Di — Re Di — — — — Di Di — — Di — — Re
Re Di Di Di — Di Di — — — Di Re Di Di Di Di Di Di Di Di De Di Di Di Di Di Di Di Re Di Di Re Di Di Di Di Di Di Di Di Di Di Di De Re
Di Di Di Di Di Di NC Di Di De Di Re Di Di De Re Di Di Di Di Di De De Di Di Di Re Di Di Di Di Re De Di Di Di Di De Di Di Di Di Di Di Re
FA Reading
Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ MC Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ Occ MC Occ Occ Occ Occ Occ Occ Occ Occ
No. of PDT
1 1 2 1 3 2 2 2 2 1 2 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1
CVD ⫽ cardiovascular disease; De ⫽ decreased; Di ⫽ dissapeared; DM ⫽ diabates; GLD ⫽ greatest linear dimension; HT ⫽ hypertension; ICGA ⫽ indocyanine green angiography; MC ⫽ minimally classic; NC ⫽ no change; Occ ⫽ occult choroidal neovascularization; PCV ⫽ polypoidal choroidal vasculopathy; PDT ⫽ photodynamic therapy; PED ⫽ pigment epithelial detachment; Polyp ⫽ polypoidal lesion by ICGA; Re ⫽ recurred; SRD ⫽ serous retinal detachment; VA ⫽ best-corrected visual acuity.
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FIGURE 3. Graph demonstrating the difference in the average indocyanine green angiography-guided greatest linear dimension (ICG-GLD) and fluorescein angiography-guided GLD (FA-GLD) in this series. The ICG-GLD was significantly smaller than the FA-GLD. FIGURE 2. Graphs demonstrating the logarithm of the minimum angle of resolution visual acuity (VA) outcome at (Top) three months and (Bottom) 12 months after photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV). Individual VA data from before and after PDT are plotted in the Left panel, and the average VA is compared in the Right panel. The average VA was increased significantly both at three and 12 months (paired t test).
Similarly, cases with a VA better than 20/50 had a good VA outcome at 12 months (VA stabilized or improved in 86.4%). As well, even among cases with larger lesions (⬎3600 m, FA-guided GLD), cases with a better than 20/50 VA had a better outcome.
DISCUSSION IN THIS STUDY, WE SHOWED THE EFFICACY OF ICGA-
guided PDT for treating symptomatic, subfoveal PCV. Similar to the previous reports,9,10,23–25 significant improvement in VA was observed at both three and 12 months after PDT, and more than 80% of patients had improved or stabilized VA. The GLD was determined based on the ICGA findings and included all of the vascular abnormalities, including polypoidal lesions and branching vascular networks. Unlike the standard protocol used in the VIP study, retinal hemorrhage and PED were not included as CNV lesions and were not necessarily treated in our series. In this setting, there was a concern regarding whether neovascular lesions that should be treated were hidden beneath the hemorrhage or PED. To minimize such occurrences, we also used OCT and searched carefully. Thus, in this VOL. 144, NO. 1
FIGURE 4. Graph demonstrating the effect of photodynamic therapy (PDT) on the retinal exudative changes and the polypoidal vascular lesions (polyp) at the time of the 12-month examination in patients with polypoidal choroidal vasculopathy (PCV). In most of the cases, these lesions disappeared or decreased by 12 months. PED ⴝ pigment epithelial detachment; SRF ⴝ subretinal fluid.
series, no hidden vascular lesions were detected after PDT. The mean ICGA GLD was significantly smaller than the FA GLD that would have been used based on the standard PDT protocol (Figure 3). Because the outcome of ICGA-guided PDT in our series was good, the smaller laser irradiation size that was used avoided the laser-
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induced problems and could be a benefit of ICGAguided PDT.26 –29 Polypoidal vascular lesions reacted dramatically to PDT. The polypoidal vascular lesions of 44 eyes disappeared or decreased in response to the first PDT. At 12 months, polypoidal vasculature was not detected by ICGA in 82.2% of cases. Secondary retinal exudative changes also disappeared or decreased after a single PDT treatment. Overall, 95.1% of SRF and 82.9% of PED completely disappeared at 12 months; these retinal changes probably resulted in a good visual outcome for the patients. In contrast, in most cases, the branching vascular networks of the PCV lesions did not change after PDT based on ICGA. There were no cases in which the branching vascular networks disappeared, and only in 23.8% of cases was there any decrease in the network vasculature. The dissociation in the clinical outcomes and the status of branching vascular networks suggests that the network vasculature has little role in the exudative retinal changes seen in PCV. If this is the case, the closure of branched vascular networks does not need to be a goal in PCV treatment. Further studies are needed to determine the role of the branching vascular networks in the development of the exudative changes seen in PCV. It has been shown that PDT produced greater treatment benefit in patients with classic or predominantly classic lesions than in those with minimally classic lesions or occult lesions.18,30 Because PCV lesions are located in the sub-RPE space, it is likely that PCV is diagnosed as being occult CNV when ICGA is not performed. Indeed, in this series, 43 of 45 cases were diagnosed as having occult CNV based on FA. If ICGA had not been carried out to diagnose PCV properly, the outcome of PDT would likely have been the same as is seen in occult CNV. However, as shown in this and other studies, in contrast to occult CNV, PCV treated by PDT has excellent outcomes. These observations indicate that although FA suggests occult CNV, care should be taken to diagnose PCV, because it is treated differently from occult CNV without PCV characteristics. Although PDT is the standard treatment method for patients with exudative AMD, there are several problems with this procedure, including PDT-induced closure of choriocapillaris and functional changes in the retina.26 –29 In addition, there have been recent reports of the frequent occurrence of retinal and subretinal hemorrhage after PDT in PCV cases.16,17 To perform PDT more efficiently and to produce minimal damage, several changes in the PDT procedure have been tested, including changing the power and duration of laser exposure,31 as well as combining PDT with corticosteroids or antiangiogenic drugs.32 ICGA-guided PDT is another potential strategy for treatment that is efficient and less harmful. Because our study was not a prospective one, we cannot determine whether PCV lesions for which ICGA had not
FIGURE 5. Graphs demonstrating the visual acuity (VA) outcomes after photodynamic therapy (PDT) for polypoidal choroidal vasculopathy (PCV) that were analyzed by pretreatment PDT lesion size or pretreatment VA. (Top) Eyes were divided into two groups based on the lesion size, >3600 m and <3600 m on fluorescein angiography greatest linear dimension (FA-GLD), and the VA outcome was compared at 12 months. (Middle) The eyes were divided into two groups based on VA before PDT (>20/50 and <20/50), and the VA outcome was compared at 12 months. (Bottom) The VA outcome also was compared by VA before PDT (>20/50 and <20/50) among patients with larger lesions based on FA-GLD (>3600 m).
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been performed and were treated as occult CNV would have a different result from PCV lesions treated with PDT. However, our data, as well as previous reports, clearly show
the benefit of this treatment for PCV without any major adverse effects. Further studies, including prospective ones, are needed.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FINANCIAL CONFLICT OF INTEREST. INVOLVED IN CONCEPTION AND design of study (A.O., N.Y.); analysis and interpretation (A.O., M.S., Y.Y., H.A., H.T., A.T., N.Y.); writing of the article (A.O.); critical revision of the article (A.O., A.T., N.Y.); final approval of the article (A.O., A.T., M.S., H.A., Y.Y., H.T., N.Y.); and data collection (A.O., M.S., Y.Y., H.A., H.T.). The Institutional Review Board at Kyoto University Graduate School of Medicine approved the study. A signed informed consent was not required by the Institutional Review Board for this retrospective review.
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Biosketch Atsushi Otani, MD, PhD, is an Assistant Professor of Ophthalmology at Kyoto University, Kyoto, Japan. He received MD and PhD at Kyoto University Graduate School of Medicine. In 2000 to 2003, Dr Otani was a research fellow at Dr Martin Friedlander’s lab of The Scripps Research Institute; La Jolla, California. His interests focus is on retinal diseases including macular diseases and retinal degeneration.
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