SUBFOVEAL CHOROIDAL THICKNESS CHANGES AFTER INTRAVITREAL RANIBIZUMAB AND PHOTODYNAMIC THERAPY FOR RETINAL ANGIOMATOUS PROLIFERATION ICHIRO MARUKO, MD, PHD,*† TOMOHIRO IIDA, MD, PHD,† HIROSHI OYAMADA, MD,* YUKINORI SUGANO, MD,* MASAAKI SAITO, MD, PHD,* TETSUJU SEKIRYU, MD, PHD* Purpose: To evaluate the subfoveal choroidal thickness changes after intravitreal ranibizumab and photodynamic therapy in patients with retinal angiomatous proliferation. Methods: Subfoveal choroidal thickness was retrospectively measured using enhanced depth imaging optical coherence tomography. Results: Thirty-two eyes of 26 patients (average age, 82 years) with newly diagnosed retinal angiomatous proliferation were examined. All eyes were treated with intravitreal ranibizumab and photodynamic therapy. In 14 eyes without recurrence over 6-month follow-up (average, 8.4 months), mean subfoveal choroidal thickness decreased from 198 mm at baseline to 169 mm (85.4%) at 3 months and to 173 mm (87.3%) at 6 months after treatment (P , 0.01 compared with baseline, respectively). In 18 eyes with recurrence over 3-month follow-up, mean subfoveal choroidal thickness decreased from 199 mm at baseline to 171 mm (85.9%) at 3 months after treatment and 176 mm (88.4%) even at recurrence (P , 0.01 compared with baseline, respectively). Conclusion: Subfoveal choroidal thickness after intravitreal ranibizumab and photodynamic therapy for retinal angiomatous proliferation decreased to approximately 85% compared with baseline by 3 months after treatment, and the trend persisted in eyes with or without recurrence during follow-up. This may indicate that choroidal changes are not associated with recurrence in retinal angiomatous proliferation. RETINA 35:648–654, 2015
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proliferation was first believed to originate from the intraretinal neovascularization as Yannuzzi et al1 reported, although it was recently suggested that the origin might involve preexisting or simultaneous proliferating choroidal neovascularization.3,4 Although the hypothesis is still controversial, the choroid in RAP is not fully understood. Spectral domain optical coherence tomography noninvasively detects morphologic changes in a variety of macular diseases. Spaide et al5 recently reported a new technique, enhanced depth imaging spectral domain optical coherence tomography (EDI-OCT), to evaluate the choroidal status. Chung et al6 and Koizumi et al7 reported that choroidal thickness in eyes with polypoidal choroidal vasculopathy (PCV) was thicker than in eyes with typical AMD. Recently, Kim et al8 and Yamazaki et al9 described that the choroid in RAP was thinner than typical AMD.
etinal angiomatous proliferation (RAP), which is one of the subtypes in neovascular age-related macular degeneration (AMD),1,2 is characterized as geriatric and often bilateral disease with poor natural course and frequent recurrence after treatment. Retinal angiomatous From the *Department of Ophthalmology, School of Medicine, Fukushima Medical University, Fukushima, Japan; and †Department of Ophthalmology, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan. None of the authors have any financial/conflicting interests to disclose. Designing and conducting of study (I.M. and T.I.); collection (I.M., H.O., and Y.S.); management, analysis, and interpretation of data (I.M., M.S., and T.S.); preparation and review (I.M. and T.I.); and approval of the manuscript (I.M., T.I., H.O., Y.S., M.S., and T.S.). Reprint requests: Ichiro Maruko, MD, PhD, Department of Ophthalmology, School of Medicine, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan; e-mail: [email protected]
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CHOROID AFTER IRI AND PDT FOR RAP MARUKO ET AL
In the treatment of RAP, several reports10–12 and we13–15 described the efficacy of combination therapy with anti-vascular endothelial growth factor agents and verteporfin (Visudyne; Novartis, Bulach, Switzerland) photodynamic therapy (PDT). However, no previous report has documented the choroidal changes after treatment and the choroidal contributions to recurrence in RAP. We previously reported that the choroidal thickness at PCV recurrence returned to the baseline level after choroidal thinning as a result of intravitreal ranibizumab and PDT using EDI-OCT.16,17 In this study, we retrospectively evaluated the central retinal thickness and the subfoveal choroidal thickness changes before and after intravitreal ranibizumab (Lucentis; Genentech, South San Francisco, CA) and PDT in RAP with or without recurrence. Methods Diagnosis The diagnostic criteria for RAP were proposed according to the classification of Yannuzzi et al.1 Definite cases had subretinal, intraretinal, or preretinal hemorrhages or retinal edema, dilated retinal vessels, retinal–retinal anastomosis, sudden termination of retinal vessels, a ring of lipid exudates and PED, and retinal choroidal anastomosis. We determined the vasogenic stage of RAP: Stage 1, intraretinal neovascularization; Stage 2, subretinal neovascularization; and Stage 3, choroidal neovascularization. Indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens or noncontact lens, and digital fluorescein angiography and indocyanine green angiography were performed to diagnose RAP. We used a digital imaging system with an infrared camera and a standard fundus camera (TRC-50 IX/IMAGEnet H1024 system; Topcon, Tokyo, Japan) and a confocal laser scanning system (HRA-2; Heidelberg Engineering, Heidelberg, Germany). The best-corrected visual acuity was measured with a Japanese standard decimal visual acuity chart and converted to the logarithm of the minimum angle of resolution (logMAR) scale for analysis. All eyes were examined with Spectralis OCT (Heidelberg Engineering). Judgment of recurrence was defined as the reappearance of exudative changes on OCT during the follow-up periods. We observed the choroid and measured the choroidal thickness (defined as the area between the outer RPE surface and the inner scleral surface) using EDIOCT,5 in which the Heidelberg Spectralis OCT device is positioned close to the eye to obtain an inverted image. Each section was obtained using eye tracking, and 100 scans were averaged to improve the signal-tonoise ratio. We measured the subfoveal choroidal
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thicknesses on the horizontal and vertical OCT lines passing through the center of the fovea. Treatment To treat RAP, we chose the combination therapy with intravitreal ranibizumab and PDT in this study. Patients were treated with PDT (6 mg/m2) according to the protocol of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy studies.15,16 Patients were treated 1 or 2 days before PDT with intravitreal ranibizumab (0.5 mg/0.05 mL) injected 3.5 to 4.0 mm posterior to the corneal limbus into the vitreous cavity using a 30-gauge needle after topical anesthesia was applied. Consecutive monthly intravitreal ranibizumab injections were administered for 3 months. The greatest linear dimension was measured on fluorescein angiography. The diameter of the PDT treatment spot size was the greatest linear dimension plus 1 mm. Recurrence of RAP was defined as the subretinal, intraretinal, or preretinal hemorrhage with exudative retinal edema with ophthalmoscope, fundus photograph, and/or OCT. If there is reappearance of RAP lesion on fluorescein angiography and indocyanine green angiography, we chose the combination therapy with intravitreal ranibizumab and PDT. If the exudative recurrence without apparent neovascularization on fluorescein angiography and indocyanine green angiography was observed, the rescue injection of ranibizumab performed as retreatment. Measurement of Retinal and Choroidal Thickness The subfoveal choroidal thicknesses were measured using EDI-OCT before intravitreal ranibizumab (baseline) and after PDT at 1, 3, and 6 months. Optical coherence tomography was performed at all visits. When the retreatment was needed, the subfoveal choroidal thickness was also measured at the point. The central retinal thickness including the retinal detachment was also measured at the same time. The measurements obtained from the OCT images represented the average of all the measurements performed by coauthors (I.M., H.O., and Y.S.) who were masked to the treatment status. The interexaminer differences were evaluated by intraclass correlation. The visual acquities are expressed as decimal equivalents and logMAR equivalents. The best-corrected visual acuity and the choroidal and retinal thicknesses were analyzed using the Wilcoxon signed-rank test. P # 0.05 was considered significant.
1 2 3 4 5 6 7 8 9 10 11 12 13
Recurrent Cases 1 2 3 4 5 6 7
No. Eye 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean ± SD
No. eye
87.8 80.8 94.9 79.1 83.6 82.1
F M M F M M
73.4 83.9 79.1 87.9 76.4 82.0 87.6 83.0
M F M F M F F
0.60 0.10 0.40 0.80 0.60 0.07 0.24 0.40 0.15 0.07 0.60 0.60 0.20 0.07 0.25
175 632 431 188 294 178 492 173 541 581 348 175 245 552 358 ± 175
3M
6M
Baseline
Baseline
1M
3M
6M
175 173 178 170 163 160 163 201 209 180 142 130 132 122 248 216 214 114 93 56 65 170 157 142 204 186 168 173 231 228 287 228 198 207 233 142 140 155 144 132 121 96 132 121 145 153 115 108 108 157 125 144 436 420 397 392 186 165 108 190 170 168 178 169 180 170 220 215 168 178 162 135 127 262 250 239 251 117 121 98 230 220 215 219 160 158 157 131 122 104 121 171 160 155 153 134 118 119 173 ± 35 163 ± 35 161 ± 47 198 ± 81 182 ± 82 169 ± 82 173 ± 83
Central Retinal Thickness* Recurrence Months
1M
3M
6M
Recurrence Baseline
1M
6M
Recurrence
F
6 11 6 6 6 11 10 7 9 9 9 7 7 14
630 218 295 600 578 478 230 373 232 235 453 302 281 307
232 139 207 227 175 254 187 175 NA 196 139 NA NA 204
217 127 139 183 198 173 168 166 155 181 139 175 191 144
— 135 — — — 199 150 146 147 137 188 NA NA 163
410 158 187 480 232 198 267 279 369 184 228 227 361 204
126 140 355 90 191 300 160 185 271 254 245 208 215 312
108 135 281 76 191 284 146 154 NA 226 243 NA NA 307
129 124 300 83 164 250 137 155 235 221 222 145 194 291
— 135 — — — 240 157 145 247 238 225 NA NA 291
116 144 302 94 167 244 155 165 240 228 240 144 206 287
F M F F
OS OS OS OS
2 2 2 2
1.00 0.40 0.30 0.16
(0.00) (0.40) (0.52) (0.80)
11 7 6 8
299 637 312 262
204 198 202 142
178 178 170 134
170 170 — 125
165 224 294 151
178 71 139 144
160 80 101 127
134 85 80 122
139 80 — 123
139 74 106 120
79.0
M
11
75.0
12 13 14 15
15 16 17 18
88.9 81.4 63.7 79.8
0.25 (0.59)
8.3
373 ± 149
Scar RAP(1) Other AMD Drusen Other AMD — — Drusen RAP(2) RAP Scar Scar Scar Scar
3M
(1.00) (0.22) (0.82) (0.62) (1.22) (1.00) (0.00) (0.70) (0.62) (−0.08) (1.05) (1.10) (0.30) (0.40)
F F
Fellow Eye
Subfoveal Choroidal Thickness†
0.10 0.60 0.15 0.24 0.06 0.10 1.00 0.20 0.24 1.20 0.09 0.08 0.50 0.40
86.8 81.9
80.7
— — — — — — — — — — — — — —
(0.22) (1.00) (0.40) (0.10) (0.22) (1.15) (0.62) (0.40) (0.82) (1.15) (0.22) (0.22) (0.70) (1.15) (0.60)
1M
3 2 2 2 3 2 2 2 2 2 2 2 1 2
M F F M F F M
Mean ± SD
1 2 2 3 2 2 2 1 2 3 2 2 2 2
Baseline
Subfoveal Choroidal Thickness†
OD OS OS OS OD OS OD OS OD OD OS OD OS OS
80.8 88.5 66.0 83.7 83.9 91.7 79.9
10
OS OS OD OD OD OD OS OS OS OD OD OS OD OD
BCVA (LogMAR) Age Gender Eye Stage at Baseline
1 2 3 4 5 6 7 8 9 10 11 12 13 14
8 9
Central Retinal Thickness*
BCVA (LogMAR) Age Gender Eye Stage at Baseline Recurrence
192 ± 168 ± 208 ± 102‡ 257 ± 93 34 24
199 ± 78
175 ± 171 ± 77 69
175 ± 71‡
Fellow Eye RAP(1) Scar RAP Drusen RAP(2) Drusen — — Scar — — — — Other AMD Scar Scar Scar High myopia
176 ± 67
*Retinal thickness including retinal detachment at the fovea. †Choroidal thickness measured using EDI-OCT. ‡Mean ± SD at 6 months after PDT includes the data in the eyes with recurrence at 6 months after PDT. (1) and (2), same cases that one eye had nonrecurrent case and the other eye had recurrent case; 1 M, 1 month after PDT; 3 M, 3 months after PDT; 6 M, 6 months after PDT; baseline, before treatment; drusen, multiple drusen without choroidal neovascularization; F, female; logMAR, logarithm of the minimum angle of resolution; M, male; NA, not available; Other AMD, other formation of AMD with previous treatment; PDT, photodynamic therapy with verteporfin; Scar, scar formation; SD, standard deviation.
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Nonrecurrent Cases
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Table 1. Baseline Characteristics and Changes in the Retinal and Choroidal Thicknesses After Combination Therapy With Intravitreal Ranibizumab and PDT for RAP
CHOROID AFTER IRI AND PDT FOR RAP MARUKO ET AL
Results Baseline Characteristics Thirty-two eyes of 26 patients (11 men and 15 women; average age, 81.7 years) with newly diagnosed RAP and over 6-month follow-ups were involved. Fifteen eyes of 11 patients were included in our previous study.15 The mean best-corrected visual acuity level at baseline was 0.27 (0.57 logMAR). We classified as 3 eyes with Stage 1, 25 eyes with Stage 2, and 4 eyes with Stage 3. In 20 patients with unilateral RAP, the fellow eyes showed scar formation in 10 eyes and multiple drusen without choroidal neovascularization in 4 eyes. In all 32 eyes, the mean subfoveal choroidal thickness was 199 ± 78 mm and the mean central retinal thickness was 366 ± 158 mm. In all 32 eyes with intravitreal ranibizumab and PDT, indocyanine green angiography 3 months after treatment showed no hot spot because of RAP lesion. Among all 32 eyes, 18 eyes (56.3%) needed the retreatment over 6-month followups. Fifteen eyes were performed with the recombination therapy, and residual three eyes were retreated with intravitreal ranibizumab injection. Baseline background characteristics data and retinal and choroidal thickness changes before and after treat-
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ment were summarized in Table 1. Intraclass correlation value for all measurements was 0.992 (95% confidence interval, 0.986–0.996), indicating high consistency. In 18 eyes with recurrence, average time was 8.3 (range, 6–14) months from initial treatment. Figures 1 and 2 were illustrated as the represent case in recurrent case. The mean subfoveal choroidal thickness significantly decreased from 199 ± 78 mm at baseline to 175 ± 77 mm by 1 month after PDT (n = 15, P , 0.01) and 171 ± 69 mm by 3 months after PDT (n = 18, P , 0.01). The mean subfoveal choroidal thickness at recurrence still showed the decrement (176 ± 67 mm, n = 18, P , 0.01, compared with baseline), which also unchanged from 3 months (n = 18, P = 0.15). The percentage changes of mean subfoveal choroidal thickness in recurrent cases are represented as circles in Figure 3. The mean central retinal thickness significantly decreased from 373 ± 149 mm at baseline to 192 ± 34 mm by 1 month after PDT (n = 15, P , 0.01) and 168 ± 24 mm by 3 months after PDT (n = 18, P , 0.01). The mean central retinal thickness at recurrence was 257 ± 93 mm, which increased 53% from 3 months after PDT (n = 18, P , 0.01). In 14 eyes without recurrence, the mean subfoveal choroidal thickness significantly decreased from 198 ±
Fig. 1. Case 15 of recurrent case. A representative RAP case of a 79-year-old woman. Top row: Gray-scale fundus photograph (FP), fluorescein angiography (FA), and indocyanine green angiography (ICGA) at baseline. Fundus photograph shows the multiple drusen and intraretinal hemorrhage. Fluorescein angiography shows the hyperfluorescence of active leakage at the fovea and cystoid macular edema. Indocyanine green angiography shows the RAP lesion with hyperfluorescence. Middle row: FP, FA, and ICGA 3 months after PDT. Fundus photograph shows no retinal hemorrhage. Fluorescein angiography indicates there is no leakage at the macula and a round-shape hypofluorescence corresponding to the irradiation area of PDT. Indocyanine green angiography also shows a round-shape hypofluorescence corresponding to the irradiation area of PDT and no hyperfluorescence from RAP lesion. Bottom row: At recurrence: FP, FA, and ICGA 8 months after PDT treatment. Fundus photograph shows the retinal swelling. Fluorescein angiography shows the hyperfluorescence of cystoid macular edema at the wider area compared with baseline. Indocyanine green angiography shows the larger RAP lesion with hyperfluorescence compared with baseline.
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Fig. 4. The percentage changes in the central retinal thickness and subfoveal choroidal thickness in recurrent cases after intravitreal ranibizumab and PDT. The filled triangles on the dashed line indicate the central retinal thickness changes, and the filled circles on the solid line indicate the subfoveal choroidal thickness changes. The central retinal thickness and subfoveal choroidal thickness changes are almost similar to Figure 3 until 3 months after PDT. The central retinal thickness increases at recurrence; however, the subfoveal choroidal thickness remains the thinner compared with baseline. Baseline, before treatment; 1 M, 1 month after PDT; 3 M, 3 months after PDT.
Fig. 2. Horizontal EDI-OCT images show changes in the choroidal thicknesses in the same case as in Figure 1. Each OCT image indicates baseline (top row), 1 month (second row), 3 months (third row), and 8 months (bottom row) at recurrence, respectively. The retinal edema disappears on 1 month after PDT. The subfoveal choroidal thickness has decreased 1 months and 3 months after treatment. The retinal edema reappears at recurrence; however, the choroidal thickness is almost the same as 3 months after PDT. Baseline, before treatment; 1 M, 1 month after PDT; 3 M, 3 months after PDT; 8 M, 8 months after PDT.
and it had remained either in eye with or without recurrence during follow-up. The visual prognosis in RAP if left untreated is poor. Also, responses to various forms of therapy, that is laser photocoagulation,18–21 surgical approach,22–24 transpupillary thermotherapy,25 and PDT,26–28 remain suboptimal. Although recent studies have reported promising short-term efficacy of anti-vascular endothelial growth factor injections,29–36 anti-vascular endothelial growth factor drugs are not enough to control the disease
81 mm at baseline to 182 ± 82 mm by 1 month after PDT (n = 14, P , 0.01), 169 ± 82 mm by 3 months after PDT (n = 14, P , 0.01), and 173 ± 83 mm by 6 months after PDT (n = 14, P , 0.01). The percentage changes of mean subfoveal choroidal thickness in nonrecurrent cases are represented as circles in Figure 4. The mean central retinal thickness significantly decreased from 358 ± 175 mm at baseline to 173 ± 35 mm by 1 month after PDT (n = 14, P , 0.01), 163 ± 35 mm by 3 months after PDT (n = 14, P , 0.01), and 161 ± 47 mm by 6 months after PDT (n = 14, P , 0.01). Discussion Subfoveal choroidal thickness in RAP with intravitreal ranibizumab and PDT decreased to 85% compared with baseline by 3 months after treatment,
Fig. 3. The percentage changes in the central retinal thickness and subfoveal choroidal thickness in all cases after intravitreal ranibizumab and PDT. The open triangles on the dashed line indicate the central retinal thickness changes, and the open circles on the solid line indicate the subfoveal choroidal thickness changes. The central retinal thickness decreases after treatment. The subfoveal choroidal thickness decreases to 85.1% at 3 months after treatment. Baseline, before treatment; 1 M, 1 month after PDT; 3 M, 3 months after PDT; 6 M, 6 months after PDT.
CHOROID AFTER IRI AND PDT FOR RAP MARUKO ET AL
activity for long term. Finally, the efficacy of combination therapy with anti-vascular endothelial growth factor agents and PDT has been reported in the treatment of RAP.10–15 Especially, we chose the combination therapy with intravitreal ranibizumab and PDT as we reported that the combination therapy could archive the complete occlusion of the retinal–retinal anastomosis in RAP.15 However this combination was also plagued with recurrences. The recurrence rate was over 50% in this study. There was no study about the choroidal thickness change after treatment in RAP. We previously reported that the choroidal thickness at PCV recurrence returned to baseline because of choroidal thinning as a result of combination therapy of intravitreal ranibizumab and PDT using EDI-OCT,16,17 which might indicate that choroidal thickness changes after treatment reflect the activity of PCV. However, the subfoveal choroidal thickness in this study for RAP decreased 1 month after PDT, and it remained not only in eyes without recurrence but also in eyes with recurrence during follow-up. These results in RAP were different from the choroidal changes in PCV after PDT. This may reflect the difference between the pathogenesis of RAP and PCV. However, the central retinal thickness decreased to ,50% level from baseline to 3 months after initial treatment. However, there was over 50% increase in this parameter at recurrence from 3 months after PDT regardless of no change in choroidal thickness at the same time. This may indicate that the retinal exudation was independent of the choroidal changes of RAP in contrast of PCV. Thus, these results in this study may suggest that the disease activity in RAP depends on retinal exudation rather than choroidal exudation. Several reports described about the choroidal thickness before and after ranibizumab monotherapy. Manjunath et al37 mentioned that there was no difference, whereas Yamazaki et al38 noted that choroidal thickness decreased after treatment. In our previous study, we could not find the difference before and after treatment.39 These reports did not mention much about RAP because of a few cases. Recently, Kim et al8 and Yamazaki et al9 described that the choroid in RAP was thinner than typical AMD. Subfoveal choroidal thickness was 199 mm in this study. Although we cannot simply compare the results with other reports, it was thinner than our previous studies about PCV (269 mm)16 and typical AMD (227 mm).39 Intravitreal ranibizumab and PDT in this study made the choroid thin even for RAP with thinner choroid than other types of AMD. This might indicate that the intravitreal ranibizumab and PDT, especially PDT, furthermore reduced the choroidal thickness in RAP because of choroidal destruction including normal structure. Thus, we need a careful decision of the treat-
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ment option including intravitreal ranibizumab and PDT for RAP because we found no relationship between the recurrence and the choroidal thinning after treatment in this study, even if the combination therapy could archive the occlusion of the retinal–retinal anastomosis. Careful monitoring of choroidal thickness in patients with RAP after PDT is necessary in future. In conclusion, the subfoveal choroidal thickness reduced even in the event of recurrence after choroidal thinning as a result of intravitreal ranibizumab and PDT. This may indicate that choroidal changes are not associated with recurrence in RAP. This study had several weaknesses including its retrospective design. And also choroid was measured at subfovea only. As EDI-OCT needs to average 100 scans to reduce noise, we did not take the volumetric measurements in this study. However, we believe that these findings assist in understanding the pathogenic of RAP after treatment. Key words: choroidal thickness, retinal angiomatous proliferation, intravitreal ranibizumab, photodynamic therapy, recurrence, EDI-OCT. Acknowledgments This study followed the tenets of the Declaration of Helsinki. The Institutional Review Board at Fukushima Medical University School of Medicine approved OCT observation for eyes with macular and retinal disorders, the observational study for AMD at treatment and follow-up, and the retrospective comparative analysis performed in this study. References 1. Yannuzzi LA, Negrão S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2000;21:416–434. 2. Gross NE, Aizman A, Brucker A, et al. Nature and risk of neovascularization in the fellow eye of patients with unilateral retinal angiomatous proliferation. Retina 2005;25:713–718. 3. Freund KB, Ho IV, Barbazetto IA, et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina 2008;28:201–211. 4. Yannuzzi LA, Freund KB, Takahashi BS. Review of retinal angiomatous proliferation or type 3 neovascularization. Retina 2008;28:375–384. 5. Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. 6. Chung SE, Kang SW, Lee JH, Kim YT. Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology 2011;118:840–845. 7. Koizumi H, Yamagishi T, Yamazaki T, et al. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249:1123–1128.
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8. Kim JH, Kim JR, Kang SW, et al. Thinner choroid and greater drusen extent in retinal angiomatous proliferation than in typical exudative age-related macular degeneration. Am J Ophthalmol 2013;155:743–749; 749.e1–e2. 9. Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness in retinal angiomatous proliferation. Retina 2014;34:1316–1322. 10. Lo Giudice G, Gismondi M, De Belvis V, et al. Single-session photodynamic therapy combined with intravitreal bevacizumab for retinal angiomatous proliferation. Retina 2009;29:949–955. 11. Rouvas AA, Papakostas TD, Vavvas D, et al. Intravitreal ranibizumab, intravitreal ranibizumab with PDT, and intravitreal triamcinolone with PDT for the treatment of retinal angiomatous proliferation: a prospective study. Retina 2009;29:536–544. 12. Lee MY, Kim KS, Lee WK. Combination therapy of ranibizumab and photodynamic therapy for retinal angiomatous proliferation with serous pigment epithelial detachment in Korean patients: twelve-month results. Retina 2011;31:65–73. 13. Saito M, Shiragami C, Shiraga F, et al. Combined intravitreal bevacizumab and photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol 2008;146:935–941.e1. 14. Saito M, Shiragami C, Shiraga F, et al. Comparison of intravitreal triamcinolone acetonide with photodynamic therapy and intravitreal bevacizumab with photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol 2010;149: 472–481.e1. 15. Saito M, Iida T, Kano M. Combined intravitreal ranibizumab and photodynamic therapy for retinal angiomatous proliferation. Am J Ophthalmol 2012;153:504–514.e1. 16. Maruko I, Iida T, Sugano Y, et al. Subfoveal retinal and choroidal thickness after verteporfin photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2011;151:594–603. 17. Maruko I, Iida T, Oyamada H, et al. Choroidal thickness changes after intravitreal ranibizumab and photodynamic therapy in recurrent polypoidal choroidal vasculopathy. Am J Ophthalmol 2013;156:548–556. 18. Slakter JS, Yannuzzi LA, Schneider U, et al. Retinal choroidal anastomoses and occult choroidal neovascularization in agerelated macular degeneration. Ophthalmology 2000;107:742–754. 19. Bottoni F, Massacesi A, Cigada M, et al. Treatment of retinal angiomatous proliferation in age-related macular degeneration: a series of 104 cases of retinal angiomatous proliferation. Arch Ophthalmol 2005;123:1644–1650. 20. Johnson TM, Glaser BM. Focal laser ablation of retinal angiomatous proliferation. Retina 2006;26:765–772. 21. Krieglstein TR, Kampik A, Ulbig M. Intravitreal triamcinolone and laser photocoagulation for retinal angiomatous proliferation. Br J Ophthalmol 2006;90:1357–1360. 22. Borrillo JL, Sivalingam A, Martidis A, Federman JL. Surgical ablation of retinal angiomatous proliferation. Arch Ophthalmol 2003;121:558–561. 23. Sakimoto S, Gomi F, Sakaguchi H, Tano Y. Recurrent retinal angiomatous proliferation after surgical ablation. Am J Ophthalmol 2005;139:917–918.
24. Shiragami C, Iida T, Nagayama D, et al. Recurrence after surgical ablation for retinal angiomatous proliferation. Retina 2007;27:198–203. 25. Kuroiwa S, Arai J, Gaun S, et al. Rapidly progressive scar formation after transpupillary thermotherapy in retinal angiomatous proliferation. Retina 2003;23:417–420. 26. Boscia F, Furino C, Sborgia L, et al. Photodynamic therapy for retinal angiomatous proliferations and pigment epithelium detachment. Am J Ophthalmol 2004;138:1077–1079. 27. Boscia F, Parodi MB, Furino C, et al. Photodynamic therapy with verteporfin for retinal angiomatous proliferation. Graefes Arch Clin Exp Ophthalmol 2006;244:1224–1232. 28. Silva RM, Cachulo ML, Figueira J, et al. Chorioretinal anastomosis and photodynamic therapy: a two-year follow-up study. Graefes Arch Clin Exp Ophthalmol 2007;245:1131–1139. 29. Meyerle CB, Freund KB, Iturralde D, et al. Intravitreal bevacizumab (Avastin) for retinal angiomatous proliferation. Retina 2007;27:451–457. 30. Costagliola C, Romano MR, dell’Omo R, et al. Intravitreal bevacizumab for the treatment of retinal angiomatous proliferation. Am J Ophthalmol 2007;144:449–451. 31. Joeres S, Heussen FM, Treziak T, et al. Bevacizumab (Avastin) treatment in patients with retinal angiomatous proliferation. Graefes Arch Clin Exp Ophthalmol 2007;245:1597–1602. 32. Lai TY, Chan WM, Liu DT, Lam DS. Ranibizumab for retinal angiomatous proliferation in neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2007;245: 1877–1880. 33. Ghazi NG, Knape RM, Kirk TQ, et al. Intravitreal bevacizumab (Avastin) treatment of retinal angiomatous proliferation. Retina 2008;28:689–695. 34. Bashshur ZF, Haddad ZA, Schakal A, et al. Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: a one-year prospective study. Am J Ophthalmol 2008;145:249–256. 35. Konstantinidis L, Mameletzi E, Mantel I, et al. Intravitreal ranibizumab (Lucentis) in the treatment of retinal angiomatous proliferation (RAP). Graefes Arch Clin Exp Ophthalmol 2009; 247:1165–1171. 36. Hemeida TS, Keane PA, Dustin L, et al. Long-term visual and anatomical outcomes following anti-VEGF monotherapy for retinal angiomatous proliferation. Br J Ophthalmol 2010;94:701–705. 37. Manjunath V, Goren J, Fujimoto JG, Duker JS. Analysis of choroidal thickness in age-related macular degeneration using spectral-domain optical coherence tomography. Am J Ophthalmol 2011;152:663–668. 38. Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S. Subfoveal choroidal thickness after ranibizumab therapy for neovascular age-related macular degeneration: 12-month results. Ophthalmology 2012;119:1621–1627. 39. Ogasawara M, Maruko I, Sugano Y, et al. Retinal and choroidal thickness changes following intravitreal ranibizumab injection for exudative age-related macular degeneration [in Japanese]. Nihon Ganka Gakkai Zasshi 2012;116:643–649.
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proliferation was first believed to originate from the intraretinal neovascularization as Yannuzzi et al1 reported, although it was recently suggested that the origin might involve preexisting or simultaneous proliferating choroidal neovascularization.3,4 Although the hypothesis is still controversial, the choroid in RAP is not fully understood. Spectral domain optical coherence tomography noninvasively detects morphologic changes in a variety of macular diseases. Spaide et al5 recently reported a new technique, enhanced depth imaging spectral domain optical coherence tomography (EDI-OCT), to evaluate the choroidal status. Chung et al6 and Koizumi et al7 reported that choroidal thickness in eyes with polypoidal choroidal vasculopathy (PCV) was thicker than in eyes with typical AMD. Recently, Kim et al8 and Yamazaki et al9 described that the choroid in RAP was thinner than typical AMD.
etinal angiomatous proliferation (RAP), which is one of the subtypes in neovascular age-related macular degeneration (AMD),1,2 is characterized as geriatric and often bilateral disease with poor natural course and frequent recurrence after treatment. Retinal angiomatous From the *Department of Ophthalmology, School of Medicine, Fukushima Medical University, Fukushima, Japan; and †Department of Ophthalmology, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan. None of the authors have any financial/conflicting interests to disclose. Designing and conducting of study (I.M. and T.I.); collection (I.M., H.O., and Y.S.); management, analysis, and interpretation of data (I.M., M.S., and T.S.); preparation and review (I.M. and T.I.); and approval of the manuscript (I.M., T.I., H.O., Y.S., M.S., and T.S.). Reprint requests: Ichiro Maruko, MD, PhD, Department of Ophthalmology, School of Medicine, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan; e-mail: [email protected]
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CHOROID AFTER IRI AND PDT FOR RAP MARUKO ET AL
In the treatment of RAP, several reports10–12 and we13–15 described the efficacy of combination therapy with anti-vascular endothelial growth factor agents and verteporfin (Visudyne; Novartis, Bulach, Switzerland) photodynamic therapy (PDT). However, no previous report has documented the choroidal changes after treatment and the choroidal contributions to recurrence in RAP. We previously reported that the choroidal thickness at PCV recurrence returned to the baseline level after choroidal thinning as a result of intravitreal ranibizumab and PDT using EDI-OCT.16,17 In this study, we retrospectively evaluated the central retinal thickness and the subfoveal choroidal thickness changes before and after intravitreal ranibizumab (Lucentis; Genentech, South San Francisco, CA) and PDT in RAP with or without recurrence. Methods Diagnosis The diagnostic criteria for RAP were proposed according to the classification of Yannuzzi et al.1 Definite cases had subretinal, intraretinal, or preretinal hemorrhages or retinal edema, dilated retinal vessels, retinal–retinal anastomosis, sudden termination of retinal vessels, a ring of lipid exudates and PED, and retinal choroidal anastomosis. We determined the vasogenic stage of RAP: Stage 1, intraretinal neovascularization; Stage 2, subretinal neovascularization; and Stage 3, choroidal neovascularization. Indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens or noncontact lens, and digital fluorescein angiography and indocyanine green angiography were performed to diagnose RAP. We used a digital imaging system with an infrared camera and a standard fundus camera (TRC-50 IX/IMAGEnet H1024 system; Topcon, Tokyo, Japan) and a confocal laser scanning system (HRA-2; Heidelberg Engineering, Heidelberg, Germany). The best-corrected visual acuity was measured with a Japanese standard decimal visual acuity chart and converted to the logarithm of the minimum angle of resolution (logMAR) scale for analysis. All eyes were examined with Spectralis OCT (Heidelberg Engineering). Judgment of recurrence was defined as the reappearance of exudative changes on OCT during the follow-up periods. We observed the choroid and measured the choroidal thickness (defined as the area between the outer RPE surface and the inner scleral surface) using EDIOCT,5 in which the Heidelberg Spectralis OCT device is positioned close to the eye to obtain an inverted image. Each section was obtained using eye tracking, and 100 scans were averaged to improve the signal-tonoise ratio. We measured the subfoveal choroidal
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thicknesses on the horizontal and vertical OCT lines passing through the center of the fovea. Treatment To treat RAP, we chose the combination therapy with intravitreal ranibizumab and PDT in this study. Patients were treated with PDT (6 mg/m2) according to the protocol of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy studies.15,16 Patients were treated 1 or 2 days before PDT with intravitreal ranibizumab (0.5 mg/0.05 mL) injected 3.5 to 4.0 mm posterior to the corneal limbus into the vitreous cavity using a 30-gauge needle after topical anesthesia was applied. Consecutive monthly intravitreal ranibizumab injections were administered for 3 months. The greatest linear dimension was measured on fluorescein angiography. The diameter of the PDT treatment spot size was the greatest linear dimension plus 1 mm. Recurrence of RAP was defined as the subretinal, intraretinal, or preretinal hemorrhage with exudative retinal edema with ophthalmoscope, fundus photograph, and/or OCT. If there is reappearance of RAP lesion on fluorescein angiography and indocyanine green angiography, we chose the combination therapy with intravitreal ranibizumab and PDT. If the exudative recurrence without apparent neovascularization on fluorescein angiography and indocyanine green angiography was observed, the rescue injection of ranibizumab performed as retreatment. Measurement of Retinal and Choroidal Thickness The subfoveal choroidal thicknesses were measured using EDI-OCT before intravitreal ranibizumab (baseline) and after PDT at 1, 3, and 6 months. Optical coherence tomography was performed at all visits. When the retreatment was needed, the subfoveal choroidal thickness was also measured at the point. The central retinal thickness including the retinal detachment was also measured at the same time. The measurements obtained from the OCT images represented the average of all the measurements performed by coauthors (I.M., H.O., and Y.S.) who were masked to the treatment status. The interexaminer differences were evaluated by intraclass correlation. The visual acquities are expressed as decimal equivalents and logMAR equivalents. The best-corrected visual acuity and the choroidal and retinal thicknesses were analyzed using the Wilcoxon signed-rank test. P # 0.05 was considered significant.
1 2 3 4 5 6 7 8 9 10 11 12 13
Recurrent Cases 1 2 3 4 5 6 7
No. Eye 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Mean ± SD
No. eye
87.8 80.8 94.9 79.1 83.6 82.1
F M M F M M
73.4 83.9 79.1 87.9 76.4 82.0 87.6 83.0
M F M F M F F
0.60 0.10 0.40 0.80 0.60 0.07 0.24 0.40 0.15 0.07 0.60 0.60 0.20 0.07 0.25
175 632 431 188 294 178 492 173 541 581 348 175 245 552 358 ± 175
3M
6M
Baseline
Baseline
1M
3M
6M
175 173 178 170 163 160 163 201 209 180 142 130 132 122 248 216 214 114 93 56 65 170 157 142 204 186 168 173 231 228 287 228 198 207 233 142 140 155 144 132 121 96 132 121 145 153 115 108 108 157 125 144 436 420 397 392 186 165 108 190 170 168 178 169 180 170 220 215 168 178 162 135 127 262 250 239 251 117 121 98 230 220 215 219 160 158 157 131 122 104 121 171 160 155 153 134 118 119 173 ± 35 163 ± 35 161 ± 47 198 ± 81 182 ± 82 169 ± 82 173 ± 83
Central Retinal Thickness* Recurrence Months
1M
3M
6M
Recurrence Baseline
1M
6M
Recurrence
F
6 11 6 6 6 11 10 7 9 9 9 7 7 14
630 218 295 600 578 478 230 373 232 235 453 302 281 307
232 139 207 227 175 254 187 175 NA 196 139 NA NA 204
217 127 139 183 198 173 168 166 155 181 139 175 191 144
— 135 — — — 199 150 146 147 137 188 NA NA 163
410 158 187 480 232 198 267 279 369 184 228 227 361 204
126 140 355 90 191 300 160 185 271 254 245 208 215 312
108 135 281 76 191 284 146 154 NA 226 243 NA NA 307
129 124 300 83 164 250 137 155 235 221 222 145 194 291
— 135 — — — 240 157 145 247 238 225 NA NA 291
116 144 302 94 167 244 155 165 240 228 240 144 206 287
F M F F
OS OS OS OS
2 2 2 2
1.00 0.40 0.30 0.16
(0.00) (0.40) (0.52) (0.80)
11 7 6 8
299 637 312 262
204 198 202 142
178 178 170 134
170 170 — 125
165 224 294 151
178 71 139 144
160 80 101 127
134 85 80 122
139 80 — 123
139 74 106 120
79.0
M
11
75.0
12 13 14 15
15 16 17 18
88.9 81.4 63.7 79.8
0.25 (0.59)
8.3
373 ± 149
Scar RAP(1) Other AMD Drusen Other AMD — — Drusen RAP(2) RAP Scar Scar Scar Scar
3M
(1.00) (0.22) (0.82) (0.62) (1.22) (1.00) (0.00) (0.70) (0.62) (−0.08) (1.05) (1.10) (0.30) (0.40)
F F
Fellow Eye
Subfoveal Choroidal Thickness†
0.10 0.60 0.15 0.24 0.06 0.10 1.00 0.20 0.24 1.20 0.09 0.08 0.50 0.40
86.8 81.9
80.7
— — — — — — — — — — — — — —
(0.22) (1.00) (0.40) (0.10) (0.22) (1.15) (0.62) (0.40) (0.82) (1.15) (0.22) (0.22) (0.70) (1.15) (0.60)
1M
3 2 2 2 3 2 2 2 2 2 2 2 1 2
M F F M F F M
Mean ± SD
1 2 2 3 2 2 2 1 2 3 2 2 2 2
Baseline
Subfoveal Choroidal Thickness†
OD OS OS OS OD OS OD OS OD OD OS OD OS OS
80.8 88.5 66.0 83.7 83.9 91.7 79.9
10
OS OS OD OD OD OD OS OS OS OD OD OS OD OD
BCVA (LogMAR) Age Gender Eye Stage at Baseline
1 2 3 4 5 6 7 8 9 10 11 12 13 14
8 9
Central Retinal Thickness*
BCVA (LogMAR) Age Gender Eye Stage at Baseline Recurrence
192 ± 168 ± 208 ± 102‡ 257 ± 93 34 24
199 ± 78
175 ± 171 ± 77 69
175 ± 71‡
Fellow Eye RAP(1) Scar RAP Drusen RAP(2) Drusen — — Scar — — — — Other AMD Scar Scar Scar High myopia
176 ± 67
*Retinal thickness including retinal detachment at the fovea. †Choroidal thickness measured using EDI-OCT. ‡Mean ± SD at 6 months after PDT includes the data in the eyes with recurrence at 6 months after PDT. (1) and (2), same cases that one eye had nonrecurrent case and the other eye had recurrent case; 1 M, 1 month after PDT; 3 M, 3 months after PDT; 6 M, 6 months after PDT; baseline, before treatment; drusen, multiple drusen without choroidal neovascularization; F, female; logMAR, logarithm of the minimum angle of resolution; M, male; NA, not available; Other AMD, other formation of AMD with previous treatment; PDT, photodynamic therapy with verteporfin; Scar, scar formation; SD, standard deviation.
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Nonrecurrent Cases
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Table 1. Baseline Characteristics and Changes in the Retinal and Choroidal Thicknesses After Combination Therapy With Intravitreal Ranibizumab and PDT for RAP
CHOROID AFTER IRI AND PDT FOR RAP MARUKO ET AL
Results Baseline Characteristics Thirty-two eyes of 26 patients (11 men and 15 women; average age, 81.7 years) with newly diagnosed RAP and over 6-month follow-ups were involved. Fifteen eyes of 11 patients were included in our previous study.15 The mean best-corrected visual acuity level at baseline was 0.27 (0.57 logMAR). We classified as 3 eyes with Stage 1, 25 eyes with Stage 2, and 4 eyes with Stage 3. In 20 patients with unilateral RAP, the fellow eyes showed scar formation in 10 eyes and multiple drusen without choroidal neovascularization in 4 eyes. In all 32 eyes, the mean subfoveal choroidal thickness was 199 ± 78 mm and the mean central retinal thickness was 366 ± 158 mm. In all 32 eyes with intravitreal ranibizumab and PDT, indocyanine green angiography 3 months after treatment showed no hot spot because of RAP lesion. Among all 32 eyes, 18 eyes (56.3%) needed the retreatment over 6-month followups. Fifteen eyes were performed with the recombination therapy, and residual three eyes were retreated with intravitreal ranibizumab injection. Baseline background characteristics data and retinal and choroidal thickness changes before and after treat-
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ment were summarized in Table 1. Intraclass correlation value for all measurements was 0.992 (95% confidence interval, 0.986–0.996), indicating high consistency. In 18 eyes with recurrence, average time was 8.3 (range, 6–14) months from initial treatment. Figures 1 and 2 were illustrated as the represent case in recurrent case. The mean subfoveal choroidal thickness significantly decreased from 199 ± 78 mm at baseline to 175 ± 77 mm by 1 month after PDT (n = 15, P , 0.01) and 171 ± 69 mm by 3 months after PDT (n = 18, P , 0.01). The mean subfoveal choroidal thickness at recurrence still showed the decrement (176 ± 67 mm, n = 18, P , 0.01, compared with baseline), which also unchanged from 3 months (n = 18, P = 0.15). The percentage changes of mean subfoveal choroidal thickness in recurrent cases are represented as circles in Figure 3. The mean central retinal thickness significantly decreased from 373 ± 149 mm at baseline to 192 ± 34 mm by 1 month after PDT (n = 15, P , 0.01) and 168 ± 24 mm by 3 months after PDT (n = 18, P , 0.01). The mean central retinal thickness at recurrence was 257 ± 93 mm, which increased 53% from 3 months after PDT (n = 18, P , 0.01). In 14 eyes without recurrence, the mean subfoveal choroidal thickness significantly decreased from 198 ±
Fig. 1. Case 15 of recurrent case. A representative RAP case of a 79-year-old woman. Top row: Gray-scale fundus photograph (FP), fluorescein angiography (FA), and indocyanine green angiography (ICGA) at baseline. Fundus photograph shows the multiple drusen and intraretinal hemorrhage. Fluorescein angiography shows the hyperfluorescence of active leakage at the fovea and cystoid macular edema. Indocyanine green angiography shows the RAP lesion with hyperfluorescence. Middle row: FP, FA, and ICGA 3 months after PDT. Fundus photograph shows no retinal hemorrhage. Fluorescein angiography indicates there is no leakage at the macula and a round-shape hypofluorescence corresponding to the irradiation area of PDT. Indocyanine green angiography also shows a round-shape hypofluorescence corresponding to the irradiation area of PDT and no hyperfluorescence from RAP lesion. Bottom row: At recurrence: FP, FA, and ICGA 8 months after PDT treatment. Fundus photograph shows the retinal swelling. Fluorescein angiography shows the hyperfluorescence of cystoid macular edema at the wider area compared with baseline. Indocyanine green angiography shows the larger RAP lesion with hyperfluorescence compared with baseline.
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Fig. 4. The percentage changes in the central retinal thickness and subfoveal choroidal thickness in recurrent cases after intravitreal ranibizumab and PDT. The filled triangles on the dashed line indicate the central retinal thickness changes, and the filled circles on the solid line indicate the subfoveal choroidal thickness changes. The central retinal thickness and subfoveal choroidal thickness changes are almost similar to Figure 3 until 3 months after PDT. The central retinal thickness increases at recurrence; however, the subfoveal choroidal thickness remains the thinner compared with baseline. Baseline, before treatment; 1 M, 1 month after PDT; 3 M, 3 months after PDT.
Fig. 2. Horizontal EDI-OCT images show changes in the choroidal thicknesses in the same case as in Figure 1. Each OCT image indicates baseline (top row), 1 month (second row), 3 months (third row), and 8 months (bottom row) at recurrence, respectively. The retinal edema disappears on 1 month after PDT. The subfoveal choroidal thickness has decreased 1 months and 3 months after treatment. The retinal edema reappears at recurrence; however, the choroidal thickness is almost the same as 3 months after PDT. Baseline, before treatment; 1 M, 1 month after PDT; 3 M, 3 months after PDT; 8 M, 8 months after PDT.
and it had remained either in eye with or without recurrence during follow-up. The visual prognosis in RAP if left untreated is poor. Also, responses to various forms of therapy, that is laser photocoagulation,18–21 surgical approach,22–24 transpupillary thermotherapy,25 and PDT,26–28 remain suboptimal. Although recent studies have reported promising short-term efficacy of anti-vascular endothelial growth factor injections,29–36 anti-vascular endothelial growth factor drugs are not enough to control the disease
81 mm at baseline to 182 ± 82 mm by 1 month after PDT (n = 14, P , 0.01), 169 ± 82 mm by 3 months after PDT (n = 14, P , 0.01), and 173 ± 83 mm by 6 months after PDT (n = 14, P , 0.01). The percentage changes of mean subfoveal choroidal thickness in nonrecurrent cases are represented as circles in Figure 4. The mean central retinal thickness significantly decreased from 358 ± 175 mm at baseline to 173 ± 35 mm by 1 month after PDT (n = 14, P , 0.01), 163 ± 35 mm by 3 months after PDT (n = 14, P , 0.01), and 161 ± 47 mm by 6 months after PDT (n = 14, P , 0.01). Discussion Subfoveal choroidal thickness in RAP with intravitreal ranibizumab and PDT decreased to 85% compared with baseline by 3 months after treatment,
Fig. 3. The percentage changes in the central retinal thickness and subfoveal choroidal thickness in all cases after intravitreal ranibizumab and PDT. The open triangles on the dashed line indicate the central retinal thickness changes, and the open circles on the solid line indicate the subfoveal choroidal thickness changes. The central retinal thickness decreases after treatment. The subfoveal choroidal thickness decreases to 85.1% at 3 months after treatment. Baseline, before treatment; 1 M, 1 month after PDT; 3 M, 3 months after PDT; 6 M, 6 months after PDT.
CHOROID AFTER IRI AND PDT FOR RAP MARUKO ET AL
activity for long term. Finally, the efficacy of combination therapy with anti-vascular endothelial growth factor agents and PDT has been reported in the treatment of RAP.10–15 Especially, we chose the combination therapy with intravitreal ranibizumab and PDT as we reported that the combination therapy could archive the complete occlusion of the retinal–retinal anastomosis in RAP.15 However this combination was also plagued with recurrences. The recurrence rate was over 50% in this study. There was no study about the choroidal thickness change after treatment in RAP. We previously reported that the choroidal thickness at PCV recurrence returned to baseline because of choroidal thinning as a result of combination therapy of intravitreal ranibizumab and PDT using EDI-OCT,16,17 which might indicate that choroidal thickness changes after treatment reflect the activity of PCV. However, the subfoveal choroidal thickness in this study for RAP decreased 1 month after PDT, and it remained not only in eyes without recurrence but also in eyes with recurrence during follow-up. These results in RAP were different from the choroidal changes in PCV after PDT. This may reflect the difference between the pathogenesis of RAP and PCV. However, the central retinal thickness decreased to ,50% level from baseline to 3 months after initial treatment. However, there was over 50% increase in this parameter at recurrence from 3 months after PDT regardless of no change in choroidal thickness at the same time. This may indicate that the retinal exudation was independent of the choroidal changes of RAP in contrast of PCV. Thus, these results in this study may suggest that the disease activity in RAP depends on retinal exudation rather than choroidal exudation. Several reports described about the choroidal thickness before and after ranibizumab monotherapy. Manjunath et al37 mentioned that there was no difference, whereas Yamazaki et al38 noted that choroidal thickness decreased after treatment. In our previous study, we could not find the difference before and after treatment.39 These reports did not mention much about RAP because of a few cases. Recently, Kim et al8 and Yamazaki et al9 described that the choroid in RAP was thinner than typical AMD. Subfoveal choroidal thickness was 199 mm in this study. Although we cannot simply compare the results with other reports, it was thinner than our previous studies about PCV (269 mm)16 and typical AMD (227 mm).39 Intravitreal ranibizumab and PDT in this study made the choroid thin even for RAP with thinner choroid than other types of AMD. This might indicate that the intravitreal ranibizumab and PDT, especially PDT, furthermore reduced the choroidal thickness in RAP because of choroidal destruction including normal structure. Thus, we need a careful decision of the treat-
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ment option including intravitreal ranibizumab and PDT for RAP because we found no relationship between the recurrence and the choroidal thinning after treatment in this study, even if the combination therapy could archive the occlusion of the retinal–retinal anastomosis. Careful monitoring of choroidal thickness in patients with RAP after PDT is necessary in future. In conclusion, the subfoveal choroidal thickness reduced even in the event of recurrence after choroidal thinning as a result of intravitreal ranibizumab and PDT. This may indicate that choroidal changes are not associated with recurrence in RAP. This study had several weaknesses including its retrospective design. And also choroid was measured at subfovea only. As EDI-OCT needs to average 100 scans to reduce noise, we did not take the volumetric measurements in this study. However, we believe that these findings assist in understanding the pathogenic of RAP after treatment. Key words: choroidal thickness, retinal angiomatous proliferation, intravitreal ranibizumab, photodynamic therapy, recurrence, EDI-OCT. Acknowledgments This study followed the tenets of the Declaration of Helsinki. The Institutional Review Board at Fukushima Medical University School of Medicine approved OCT observation for eyes with macular and retinal disorders, the observational study for AMD at treatment and follow-up, and the retrospective comparative analysis performed in this study. References 1. Yannuzzi LA, Negrão S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina 2000;21:416–434. 2. Gross NE, Aizman A, Brucker A, et al. Nature and risk of neovascularization in the fellow eye of patients with unilateral retinal angiomatous proliferation. Retina 2005;25:713–718. 3. Freund KB, Ho IV, Barbazetto IA, et al. Type 3 neovascularization: the expanded spectrum of retinal angiomatous proliferation. Retina 2008;28:201–211. 4. Yannuzzi LA, Freund KB, Takahashi BS. Review of retinal angiomatous proliferation or type 3 neovascularization. Retina 2008;28:375–384. 5. Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. 6. Chung SE, Kang SW, Lee JH, Kim YT. Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology 2011;118:840–845. 7. Koizumi H, Yamagishi T, Yamazaki T, et al. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249:1123–1128.
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