- Email: [email protected]
Retinal Pigment Epithelial Tear After Intravitreal Ranibizumab Treatment for Retinal Angiomatous Proliferation
Retinal Pigment Epithelial Tear After Intravitreal Ranibizumab Treatment for Retinal Angiomatous Proliferation HAN JOO CHO, HYOUNG SEOK KIM, SEUL GI YOO, JUNG IL HAN, YOUNG JU LEW, SUNG WON CHO, TAE GON LEE, AND JONG WOO KIM PURPOSE:
To evaluate the incidence and associated risk factors of retinal pigment epithelium (RPE) tears after intravitreal ranibizumab injection treatment for retinal angiomatous proliferation (RAP). DESIGN: Retrospective, observational case series. METHODS: Ninety-eight treatment-naı¨ve RAP eyes (86 patients) that received intravitreal ranibizumab injections were included. All patients were treated with an initial series of 3 monthly loading injections, followed by further injections as required. Baseline characteristics and features were evaluated as potential risk factors for RPE tearing. The visual and anatomic outcomes after treatment were evaluated at 12 months from baseline. RESULTS: RPE tears had developed in 8.2% (8) of the eyes by 12 months. Of these, all had pigment epithelium detachment (PED) at baseline, and the majority (7) had developed an RPE tear within 3 months. Multiple regression analysis showed that higher PED (odds ratio [OR] [ 1.411, 95% confidence interval [CI] [ 1.199–1.888, P [ .011) and thinner choroid (OR [ 0.815, 95% CI [ 0.719–0.912, P [ .023) were associated with a higher risk of RPE tearing. The mean best-corrected visual acuity of the patients with RPE tearing (0.56 ± 0.49 logarithm of the minimal angle of resolution [logMAR]) was significantly worse at 12 months than that of patients without RPE tearing (0.74 ± 0.55 logMAR, P [ .009) after treatment. CONCLUSIONS: RPE tears developed in 8.2% of eyes with RAP during the 12 months following ranibizumab injections. Higher PED height and thinner subfoveal choroidal thickness were associated with the development of RPE tears after ranibizumab treatment for RAP. (Am J Ophthalmol 2015;160(5):1000–1005. Ó 2015 by Elsevier Inc. All rights reserved.)
R
ETINAL ANGIOMATOUS PROLIFERATION (RAP) IS A
clinical entity generally categorized as a subtype of neovascular age-related macular degeneration (nAMD).1 RAP involves the proliferation of deep retinal capillaries; at later stages, this neovascularization progresses from subretinal to choroidal, with pigment epithelial detachment (PED).1 However, the origin of the neovascular process (intraretinal vs choroidal) remains controversial.2,3 The prevalence of RAP in newly diagnosed nAMD has been reported to be 5%–15%.4,5 A tear to the retinal pigment epithelium (RPE) is one of the more serious complications of nAMD.6 Although RPE tears can occur during the natural disease progression of nAMD, they are also seen after therapeutic interventions such as photodynamic therapy (PDT)7,8 or intravitreal injections with anti–vascular endothelial growth factor (VEGF) substances such as pegaptanib, bevacizumab, aflibercept, and ranibizumab.9–14 RPE tears after ranibizumab treatment have been reported in 2%–6% of eyes with nAMD, and in as much as 12%–25% of eyes with vascularized PED.13 When the fovea is involved in the RPE tear, visual prognosis is markedly poorer.15 In recent times, intravitreal injection of anti-VEGF drugs has been used extensively for the treatment of nAMD. Because RAP is considered to be a distinct subtype of nAMD, anti-VEGF injections are commonly used. However, owing to its relative infrequency, not much is known about RPE tearing following intravitreal anti-VEGF treatment for RAP. The purpose of this study was to identify the characteristics of RPE tearing after ranibizumab injections in RAP patients, the associated risk factors, and the prognosis.
METHODS WE PERFORMED A COMPUTERIZED SEARCH AND MEDICAL RE-
Supplemental Material available at AJO.com. Accepted for publication Jul 15, 2015. From the Department of Ophthalmology, Kim’s Eye Hospital, MyungGok Eye Research Institute, Konyang University College of Medicine, Seoul, South Korea. Inquiries to Han Joo Cho, Kim’s Eye Hospital, 156 4ga Yeoungdeungpodong, Yeoungdeungpo-gu, Seoul, South Korea; e-mail: chojoo@kimeye. com
1000
Ó
2015 BY
cord review for patients who had been diagnosed with RAP and treated with anti-VEGF injections (ranibizumab [Lucentis; Novartis Pharma AG, Basel, Switzerland]) between June 2012 and June 2014. All patients had been examined and treated at the Retina Center of Kim’s Eye Hospital at Konyang University College of Medicine. This study was approved by the Institutional Review Board
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.07.023
of Kim’s Eye Hospital, Konyang University College of Medicine. The study adhered to the tenets of the Declaration of Helsinki (IRB No A-2015-012). SUBJECTS:
The following inclusion criteria were used: (1) age >50 years; (2) confirmation of RAP using funduscopy, spectral-domain optical coherence tomography (SD OCT [Spectralis; Heidelberg Engineering, Heidelberg, Germany; and Spectral OCT/SLO; OTI Ophthalmic Technologies Inc, Miami, Florida, USA]), fluorescein angiography (FA), and indocyanine green angiography (ICGA) performed using a confocal laser scanning system (Spectralis HRAþOCT; Heidelberg Engineering) at the first visit; (3) treatment naı¨ve; (4) treatment with ranibizumab; and (5) a minimum follow-up period of 12 months. The diagnosis of RAP was based on the characteristic features of the condition, which include intraretinal hemorrhage, intraretinal vascular anastomoses, and PED with overlying cystic retinal edema, observed using OCT. In addition, the presence of retinal anastomotic feeder and drainage vessels on the FA or ICGA images, or of a ‘‘hot spot’’ corresponding to the neovascular lesion on the ICGA image, was also required in order for RAP to be diagnosed. Patients with RAP were classified as stage 1, 2, or 3 according to established grading criteria.1 The diagnosis and staging of RAP were evaluated by 2 independent investigators (H.J.C. and H.S.K.). When the evaluation was inconsistent, a senior investigator (T.G.L.) made the final decision. Exclusion criteria were as follows: (1) the presence of RPE tearing at baseline; (2) treatment using another antiVEGF agent (bevacizumab [Avastin; Genentech Inc, South San Francisco, California, USA]) or photodynamic therapy; (3) concomitant ocular diseases such as diabetic retinopathy, high myopia (more than 6 diopter spherical equivalent), vein or artery occlusion, or epiretinal membrane; and (4) trauma either during the study or in the contralateral eye, aphakia, or previous vitreoretinal surgery.
ASSESSMENT AND OUTCOME MEASURES:
RPE tears were identified using 4 imaging modalities: color fundus photograph, FA and/or ICGA images, SD OCT, and autofluorescence images. FA and/or ICGA images revealed hypofluorescence of the bare choroid, and all suspicious RPE tear-like lesions were confirmed by SD OCT consisting of either 19 or 31 horizontal lines (6 3 6 mm area); OCT showed interruption of the hyperreflective RPE layer, with elevation or scrolling of the torn RPE flap.16 Increased depth of signals, corresponding to the bare choroid underlying the torn RPE, was frequently seen on OCT.9 When the patient had PED at baseline, PED height was defined as the vertical distance from the hyperreflective line of the Bruch membrane to the inner margin of the hyperreflective line of the RPE layer. All OCT scans were taken horizontally over the PED (consisting of either 19 or 31 horizontal lines [6 3 6 mm area]), such that the
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highest point of the PED was assessed. Subfoveal choroidal thickness was defined as the vertical distance from the hyperreflective line of the Bruch membrane to the hyperreflective line of the inner surface of the sclera on foveacentered SD OCT images. When the inner surface of the sclera was not visible on the conventional image, the OCT image was taken using an enhanced depth imaging (EDI) technique, a feature of the Spectralis SD OCT machine, as previously reported.17 Each section was obtained using eye tracking, and 100 scans were averaged in order to improve the signal-to-noise ratio. The lesion was defined as choroidal neovascularization (CNV) lesion included CNV and 1 or more of the following in or adjacent to the location of CNV: PED, blocked fluorescence, or hemorrhage. Hemorrhage was considered to be part of the lesion only when it was contiguous with the total neovascular lesion and the hemorrhage extended beyond the fluorescence of the underlying CNV on FA. The lesion size was measured manually by outlining the lesion on the FA image. All measurements were estimated using the Heidelberg Eye Explorer software (v. 5.6.4.0; Heidelberg Engineering) by 2 retinal specialists (H.J.C. and H.S.K.) who had been masked to patient information. As a measurement of functional outcome after treatment, the best-corrected visual acuity (BCVA) 12 months after treatment of patients with RPE tearing was compared with that of patients without RPE tearing. In addition, anatomic outcome, measured as central foveal thickness (defined as the vertical distance from the internal limiting membrane [ILM] to Bruch membrane on SD OCT images) after treatment was also compared between groups. In addition, the percentage of patients who had gained or lost more than 3 lines of vision since baseline was also assessed. INTRAVITREAL
RANIBIZUMAB TREATMENT: All patients had been given a loading dose of 3 intravitreal ranibizumab injections (0.5 mg/0.05 mL; Lucentis; Novartis Pharma AG, Basel, Switzerland) with a 1-month interval between treatments. Subsequent additional injections were given if any of the following conditions were observed: (1) visual deterioration of more than 2 lines (>0.2 logarithm of the minimal angle of resolution [logMAR]); (2) OCT evidence of persistent fluid or hemorrhage involving the macula for at least 1 month following the previous injection; (3) an increase in central foveal thickness of at least 100 mm on OCT; (4) evidence of an active RAP lesion found on FA, ICGA, or OCT. All patients were followed up on a monthly basis for 12 months after the initial treatment; the follow-up consisted of examinations such as fundus photography and SD OCT. Additional FA, ICGA, autofluorescence, and SD OCT examinations were performed whenever RAP recurred, or when RPE tears were suspected. The treatment was continued after occurrence of an RPE tear according to the retreatment criteria except when the patient strongly refused treatment.
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STATISTICAL ANALYSES:
SPSS software (version 13.0; SPSS, Inc, Chicago, Illinois, USA) was used for all statistical analyses. Frequencies were compared between treatment groups using either the x2 or Fisher exact test. Comparative statistical analyses were performed using unpaired t tests. A multivariate logistic regression analysis was performed using various baseline characteristics to identify risk factors for RPE tearing after treatment. Logistic regression models were tested using the Hosmer–Lemeshow test to ascertain the goodness of fit and forward and backward stepwise regression were performed using the likelihood-ratio model. The change in the likelihood ratio was used for variable selection, which was based on the maximum partial likelihood estimates for the covariate. All tests were 2-sided, and a P value <.05 was considered statistically significant.
RESULTS BASELINE CHARACTERISTICS:
A total of 109 eyes had been diagnosed with RAP and treated with intravitreal ranibizumab injections at our institution during the study period. Among these, 11 were excluded owing to followup loss. Finally, 98 eyes with RAP in 86 patients (45 men, 41 women; all South Korean) met the inclusion criteria and were enrolled in our study. The mean age of the subjects at their initial visit was 74.6 6 7.9 years, and the mean number of injections administered was 4.96 6 1.81 over 12 months. Table 1 outlines the clinical details of the patients included in the study. RPE tears had developed in 8 eyes (8.2%) after treatment during the 12-month follow-up period. All 8 of these eyes had shown PED at baseline. The majority of them (7 eyes) had developed the RPE tear during the period of the 3 monthly loading injections (within 3 months from baseline). RPE tears had developed in 2 eyes after the first injection, in 4 eyes after 2 injections, in 1 eye after 3 injections, and in 1 eye after 5 injections (Table 2). The Supplemental Figure (available at AJO.com) shows images taken from 1 representative case that had developed RPE tearing after intravitreal ranibizumab injections (Table 2, Patient 7). When the baseline characteristics were compared between the ‘‘RPE tearing’’ group (8 eyes) and the ‘‘no RPE tearing’’ group (90 eyes), there were several significant differences. The mean subfoveal choroidal thickness was smaller (P ¼ .021), the mean lesion size was greater (P ¼ .031), PED at baseline was more frequent (P ¼ .016), and the mean PED height was greater (P ¼ .003) in the ‘‘RPE tearing’’ group (Table 1). Other complications associated with intravitreal ranibizumab injections were observed in all subjects, including endophthalmitis, traumatic lens injury, retinal detachment, and systemic adverse events. 1002
RISK FACTORS ASSOCIATED WITH RETINAL PIGMENT EPITHELIUM TEARING AFTER INTRAVITREAL RANIBIZUMAB INJECTIONS: Among the baseline characteristics,
various parameters were considered possible predictive factors for RPE tearing after treatment; these were age, sex, baseline BCVA (logMAR), baseline central foveal thickness, baseline subfoveal choroidal thickness, lesion size, RAP stage (stage 1, 2, or 3), PED height, presence of reticular pseudodrusen, and number of injections. When the baseline data were analyzed using multivariate logistic regression, 2 factors were found to significantly increase the risk of RPE tearing; namely, thinner subfoveal choroid (odds ratio [OR] ¼ 0.815, 95% confidence interval [CI] ¼ 0.719–0.912, P ¼ .023) and higher PED (OR ¼ 1.411, 95% CI ¼ 1.199–1.888, P ¼ .011). VISUAL AND ANATOMIC OUTCOMES:
The BCVA of the group without RPE tearing had significantly improved after treatment—from 0.74 6 0.49 (20/109) at baseline to 0.56 6 0.44 (20/72) at 12 months (paired t test, P ¼ .012). However, the BCVA of the ‘‘RPE tearing’’ group showed no significant improvement after treatment: from 0.76 6 0.55 (20/115) at baseline to 0.74 6 0.56 (20/109) at 12 months (paired t test, P ¼ .672). Additionally, the BCVA at 12 months of the patients with RPE tearing was significantly worse than that of the patients without RPE tearing (0.56 6 0.44 [20/72] vs 0.74 6 0.56 [20/109], P ¼ .009). Among the patients with RPE tearing, only 1 (Patient 1; Table 2) had shown an improved BCVA of more than 3 _0.3 logMAR units), and 3 (Patients 5, 6, and 7; lines (> Table 2) had shown a worsened BCVA of more than 3 lines after treatment. The proportion of RPE-tearing patients with visual improvement (1 out of 8 eyes) was significantly lower than that of the patients without RPE tearing (35 out of 90 eyes; 38.9%; P ¼ .037 using Fisher exact test). Whereas there had been significant improvement to mean central foveal thickness in patients without RPE tearing after treatment—from 325 6 199 mm at baseline to 217 6 166 at 12 months (P ¼ .006) —there had been no statistical improvement to this value in the patients with RPE tearing: from 344 6 139 mm at baseline to 311 6 144 mm at 12 months (P ¼ .885). Moreover, the mean central foveal thickness of the ‘‘RPE tearing’’ group was significantly thicker at 12 months than that of the patients without RPE tearing (311 6 144 mm vs 217 6 166 mm, P ¼ .021).
DISCUSSION IT HAS BEEN PROPOSED THAT RAP IS THE MANIFESTATION
of deep retinal-capillary proliferation, and that the later stages involve the progression from subretinal to choroidal neovascularization with PED formation.1,3 One recent investigation with SD OCT suggested that intraretinal (type 3) neovascularization may induce PED
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TABLE 1. Baseline Clinical Characteristics of Patients With Retinal Angiomatous Proliferation
Age (y 6 SD) Sex Male, n (%) Female, n (%) Mean of baseline BCVA (logMAR; Snellen equivalent) Baseline BCVA (logMAR; Snellen equivalent) <0.54 (20/70) 0.54 (20/70) to 1.0 (20/200) >1.0 (20/200) Mean central foveal thickness 6 SD (mm) Mean subfoveal choroidal thickness 6 SD (mm) Lesion location, n (%) Subfoveal Juxtafoveal Extrafoveal Mean lesion size 6 SD (mm2) Stage of RAP, n (%) Stage 1 Stage 2 Stage 3 Presence of PED, n (%) Mean PED height 6 SD (mm) Reticular pseudodrusen, n (%) Mean number of injections 6 SD
Total Eyes (n ¼ 98)
RPE Tear During Treatment (n ¼ 8)
No RPE Tear During Treatment (n ¼ 90)
P
74.6 6 7.9 (52–85)
77.1 6 4.2
74.3 6 6.6
.221a
52 (53.1%) 46 (46.9%) 0.75 6 0.52 (20/112)
3 (37.5%) 5 (62.5%) 0.76 6 0.55 (20/115)
49 (54.4%) 41 (45.6%) 0.74 6 0.49 (20/109)
.113b .626a
20 (20.4%) 47 (48.0%) 31 (31.6%) 327 6 166 141 6 55 (67–285)
1 (12.5%) 5 (62.5%) 2 (25.0%) 344 6 139 101 6 33
19 (21.1%) 42 (46.7%) 29 (32.2%) 325 6 199 147 6 61
.352c .717a .021a
13 (13.3%) 63 (64.2%) 22 (22.5%) 2.4 6 1.1
1 (12.5%) 4 (50.0%) 3 (37.5%) 2.9 6 1.3
12 (13.3%) 59 (65.6%) 19 (21.1%) 2.2 6 1.2
.511c .031a
9 (9.2%) 62 (63.3%) 27 (27.5%) 59 (60.2%) 221 6 144 60 (61.2%) 4.96 6 1.81
0 (0%) 4 (50.0%) 4 (50.0%) 8 (100%) 408 6 142 7 (87.5%) 4.52 6 1.43
9 (10.0%) 58 (64.4%) 23 (25.6%) 51 (56.7%) 197 6 112 53 (55.6%) 5.01 6 1.96
.323c .016b .003a .083b .550a
BCVA ¼ best-corrected visual acuity; logMAR ¼ logarithm of the minimal angle of resolution; PED ¼ pigment epithelial detachment; RAP ¼ retinal angiomatous proliferation; RPE ¼ retinal pigment epithelium; SD ¼ standard deviation. a P value by t test. b P value by x2 test. c P value by Fisher exact test.
by developing below the RPE layer, and that the type 3 neovascularization complex frequently localized at the apex of PED.18 Considering the neovascular process and development of PED in RAP, we hypothesized that there may be some difference between RAP and typical nAMD after anti-VEGF injection, with regard to incidence of RPE tearing and the response of PED. However, it transpired that the incidence of RPE tearing in our RAPonly cohort (8.2%) was similar to that of nAMD from previous reports (2.8%–14%).6,13,19 Recently, various investigations have proposed that contraction and/or fibrosis in choroidal neovascularization tissue after antiVEGF therapy can induce rips in the overlying RPE.20,21 Our results suggest that the mechanism of RPE tearing in RAP may be similar to that which has been proposed to occur in nAMD. Risk factors for the development of an RPE tear after intravitreal anti-VEGF treatment in nAMD have been
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reported. They include PED height, greatest linear dimension of the baseline PED, and PED surface area.15,22 Similarly to previous reports, all patients in our study who had developed RPE tearing had also presented with PED at baseline, and PED height was found to be a significant risk factor for the development of an RPE tear. A thinner subfoveal choroid is one of the characteristics of RAP when compared with typical nAMD,23 and thin choroid was another risk factor for RPE tearing in RAP patients in this study. It is not clear why thin choroid is associated with a higher risk of RPE tearing. However, several investigations have suggested a connection between thin choroid and RPE layer integrity. It has been reported that choroidal thickness is associated with ocular perfusion pressure,24 and that thin choroid may be associated with impaired choroidal blood flow.25 Hypoxic conditions may induce changes in the RPE extracellular matrix and in
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TABLE 2. Clinical Data of Retinal Angiomatous Proliferation Patients With a Retinal Pigment Epithelial Tear After Ranibizumab Treatment
Lesion Patient
1 2 3 4 5 6 7 8
Baseline
Number of Injections
Baseline Central
Baseline Subfoveal
Baseline
Foveal
Age/Sex
RAP Stage
Size (mm2)
Lesion Location
BCVA (Snellen)
BCVA at 12 Months
Before RPE Tear
Foveal Thickness (mm)
Choroidal Thickness (mm)
PED Height (mm)
Involvement of RPE Tear
Reticular Pseudodrusen
85/F 68/F 77/F 78/M 83/F 79/F 72/M 76/M
2 3 2 3 3 2 3 2
2.26 1.88 3.40 2.21 1.12 2.23 4.88 5.22
Extrafoveal Juxtafoveal Juxtafoveal Juxtafoveal Extrafoveal Extrafoveal Subfoveal Juxtafoveal
20/70 20/100 10/200 20/30 10/200 20/100 20/200 20/100
20/25 20/70 10/200 20/50 5/200 20/200 10/200 20/70
2 2 2 1 2 5 3 1
303 269 405 322 301 352 375 425
82 70 81 129 65 152 67 162
395 402 338 540 512 342 412 323
None None Yes None Yes Yes Yes None
Yes Yes Yes Yes Yes None Yes Yes
BCVA ¼ best-corrected visual acuity; PED ¼ pigment epithelial detachment; RAP ¼ retinal angiomatous proliferation; RPE ¼ retinal pigment epithelium.
the tight junctions between the RPE cells.26 Indeed, proteins of the RPE cell tight junction have been found to be decreased in hypoxic conditions using an animal model.27 Thus, a chronic hypoxic state caused by hypoperfusion derived from thin choroid may induce alteration or weakness in the RPE layer, which may in turn cause vulnerability to RPE-shearing forces after anti-VEGF injection. In addition, 1 case series involving 7 nAMD patients recently reported a tendency for decreased subfoveal choroidal thickness in eyes with RPE tearing, compared with the fellow eye with intact RPE.28 However, it is unclear whether thin choroid is a characteristic risk factor for RPE tear in RAP only, or whether it is also a risk factor in typical nAMD. Further studies are warranted to determine the mechanism of RPE tear development associated with thin choroid. An unfavorable visual prognosis has been reported in nAMD patients with RPE tears.19,20 This was in line with our own results from RAP patients. Both the BCVA and the central foveal thickness of the RPE tear patients at 12 months after treatment were significantly worse than those of the patients without RPE tearing. Currently, there is no modality or guideline available for treatment of patients with RPE tears occurring after intravitreal anti-VEGF injections. Therefore, antiVEGF treatment should be performed cautiously in RAP patients who have thin choroid or high PED height, with consideration to the possibility of subsequent RPE tear development. In addition, close monitoring of RAP patients and prompt therapeutic intervention
should be considered prior to the development of large PEDs. Our study had several limitations, including its retrospective nature. First, the sample size of RPE tear patients was relatively small and may have been insufficient for analysis. However, to the best of our knowledge, this study is the first report regarding RPE tears with an RAP-only cohort. Another limitation is that we did not classify type 1, 2, or 3 neovascularization. However, it is difficult to classify the type of neovascularization in advanced RAP cases, because there may be mixed lesion types and evidence of all neovascularization types present. A recent prospective study reported that RPE tearing was more frequent in eyes treated with high-dose (2 mg; 4 eyes out of 37) than standard-dose (0.5 mg) ranibizumab therapy (1 eye out of 37).20 This difference in tear incidence suggests an association between RPE tear development and anti-VEGF dose, or kinds of anti-VEGF drugs. This is the reason we excluded patients treated with other anti-VEGF agents. Future studies may allow for these variances in RPE tear development associated with different anti-VEGF drugs, or their doses. In conclusion, the incidence and clinical features of RPE tearing in RAP patients was similar to that seen in typical nAMD. High PED and thin subfoveal choroid were associated with the development of RPE tearing following intravitreal ranibizumab injections in RAP patients. Investigations into the precise mechanisms of RPE tearing after intravitreal anti-VEGF treatment, and its management, are warranted in the future.
FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. FINANCIAL DISCLOSURES: THE FOLLOWING AUTHORS HAVE NO financial disclosures: Han Joo Cho, Hyoung Seok Kim, Seul Gi Yoo, Jung Il Han, Young Ju Lew, Sung Won Cho, Tae Gon Lee, and Jong Woo Kim. All authors attest that they meet the current ICMJE criteria for authorship.
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16. Giovannini A, Amato G, Mariotti C, Scassellati-Sforzolini B. Optical coherence tomography in the assessment of retinal pigment epithelial tear. Retina 2000;20(1):37–40. 17. Shao L, Xu L, Chen CX, et al. Reproducibility of subfoveal choroidal thickness measurements with enhanced depth imaging by spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 2013;54(1):230–233. 18. Nagiel A, Sarraf D, Sadda SR, et al. Type 3 neovascularization: evolution, association with pigment epithelial detachment, and treatment response as revealed by spectral domain optical coherence tomography. Retina 2015;35(4): 638–647. 19. Doguizi S, Ozdek S. Pigment epithelial tears associated with anti-VEGF therapy: incidence, long-term visual outcome, and relationship with pigment epithelial detachment in age-related macular degeneration. Retina 2014;34(6): 1156–1162. 20. Sarraf D, Chan C, Rahimy E, Abraham P. Prospective evaluation of the incidence and risk factors for the development of RPE tears after high- and low-dose ranibizumab therapy. Retina 2013;33(8):1551–1557. 21. Nagiel A, Freund KB, Spaide RF, Munch IC, Larsen M, Sarraf D. Mechanism of retinal pigment epithelium tear formation following intravitreal anti-vascular endothelial growth factor therapy revealed by spectral-domain optical coherence tomography. Am J Ophthalmol 2013;156(5): 981–988. 22. Chan CK, Abraham P, Meyer CH, et al. Optical coherence tomography-measured pigment epithelial detachment height as a predictor for retinal pigment epithelial tears associated with intravitreal bevacizumab injections. Retina 2010;30(2): 203–211. 23. Kim JH, Kim JR, Kang SW, Kim SJ, Ha HS. Thinner choroid and greater drusen extent in retinal angiomatous proliferation than in typical exudative age-related macular degeneration. Am J Ophthalmol 2013;155(4):743–749. 24. Kim M, Kim SS, Kwon HJ, Koh HJ, Lee SC. Association between choroidal thickness and ocular perfusion pressure in young, healthy subjects: enhanced depth imaging optical coherence tomography study. Invest Ophthalmol Vis Sci 2012;53(12):7710–7717. 25. Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology 2014; 121(5):1079–1091. 26. Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells. J Cell Biochem 1999;74(1):135–143. 27. Rathnasamy G, Sivakumar V, Foulds WS, Ling EA, Kaur C. Vascular changes in the developing rat retina in response to hypoxia. Exp Eye Res 2015;130:73–86. 28. Bhavsar KV, Branchini L, Shah H, Regatieri CV, Duker JS. Choroidal thickness in retinal pigment epithelial tear as measured by spectral domain optical coherence tomography. Retina 2014;34(1):63–68.
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Biosketch Han Joo Cho, MD, graduated from the Yonsei University College of Medicine, Seoul, Korea in 2001. In 2006, he completed his residency at the Department of Ophthalmology of the same university. After a fellowship at the Kim’s Eye Hospital, Konyang University College of Medicine, Seoul, Korea, He has been a vitreoretinal surgeon at the same hospital since 2010. His primary areas of interest are vitreoretinal disorders and vitreous surgery.
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SUPPLEMENTAL FIGURE. A 72-year-old man with retinal angiomatous proliferation treated with intravitreal ranibizumab injections (Patient 7, Table 2). Color fundus photography (Top row, first image) showed multiple drusen, pigment epithelial detachment (PED), and fine retinal hemorrhage. Fluorescein angiography (FA) and indocyanine green angiography (ICGA; Top row, second and third images) revealed PED and a small hot spot representing an area of retinal anastomosis. Sectional spectral-domain optical coherence tomography (SD OCT) image (with the arrow seen on Top row, second image) showed PED and abnormal reflectivity lying over and under the PED. The subfoveal choroidal thickness was 67 mm (between arrowheads; Top row, fourth image). Five days after the third ranibizumab injection, the patient complained of decreased visual acuity. Color fundus photography (Second row, first image), FA (Second row, second image), and ICGA (Second row, third image) show increased PED size. FA shows leakage at the temporal edge of the PED, with passage of fluorescein into the subretinal space (Second row, second image; arrowhead). Both disruption of the RPE over the leakage area and corrugated folding of RPE layer (Second row, fourth image, arrowhead) are detectable on the SD OCT image (with the arrow seen on the Second row, second image). Two months after the final ranibizumab injection, a large RPE tear and bare choroid was found using fundus photography (Bottom row, first image), and SD OCT (Bottom row, second image). The images show the progression of the RPE tear and interruption of the hyperreflective RPE layer with elevation or scrolling of the torn RPE flap.
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RPE TEAR AND RETINAL ANGIOMATOUS PROLIFERATION
1005.e2
To evaluate the incidence and associated risk factors of retinal pigment epithelium (RPE) tears after intravitreal ranibizumab injection treatment for retinal angiomatous proliferation (RAP). DESIGN: Retrospective, observational case series. METHODS: Ninety-eight treatment-naı¨ve RAP eyes (86 patients) that received intravitreal ranibizumab injections were included. All patients were treated with an initial series of 3 monthly loading injections, followed by further injections as required. Baseline characteristics and features were evaluated as potential risk factors for RPE tearing. The visual and anatomic outcomes after treatment were evaluated at 12 months from baseline. RESULTS: RPE tears had developed in 8.2% (8) of the eyes by 12 months. Of these, all had pigment epithelium detachment (PED) at baseline, and the majority (7) had developed an RPE tear within 3 months. Multiple regression analysis showed that higher PED (odds ratio [OR] [ 1.411, 95% confidence interval [CI] [ 1.199–1.888, P [ .011) and thinner choroid (OR [ 0.815, 95% CI [ 0.719–0.912, P [ .023) were associated with a higher risk of RPE tearing. The mean best-corrected visual acuity of the patients with RPE tearing (0.56 ± 0.49 logarithm of the minimal angle of resolution [logMAR]) was significantly worse at 12 months than that of patients without RPE tearing (0.74 ± 0.55 logMAR, P [ .009) after treatment. CONCLUSIONS: RPE tears developed in 8.2% of eyes with RAP during the 12 months following ranibizumab injections. Higher PED height and thinner subfoveal choroidal thickness were associated with the development of RPE tears after ranibizumab treatment for RAP. (Am J Ophthalmol 2015;160(5):1000–1005. Ó 2015 by Elsevier Inc. All rights reserved.)
R
ETINAL ANGIOMATOUS PROLIFERATION (RAP) IS A
clinical entity generally categorized as a subtype of neovascular age-related macular degeneration (nAMD).1 RAP involves the proliferation of deep retinal capillaries; at later stages, this neovascularization progresses from subretinal to choroidal, with pigment epithelial detachment (PED).1 However, the origin of the neovascular process (intraretinal vs choroidal) remains controversial.2,3 The prevalence of RAP in newly diagnosed nAMD has been reported to be 5%–15%.4,5 A tear to the retinal pigment epithelium (RPE) is one of the more serious complications of nAMD.6 Although RPE tears can occur during the natural disease progression of nAMD, they are also seen after therapeutic interventions such as photodynamic therapy (PDT)7,8 or intravitreal injections with anti–vascular endothelial growth factor (VEGF) substances such as pegaptanib, bevacizumab, aflibercept, and ranibizumab.9–14 RPE tears after ranibizumab treatment have been reported in 2%–6% of eyes with nAMD, and in as much as 12%–25% of eyes with vascularized PED.13 When the fovea is involved in the RPE tear, visual prognosis is markedly poorer.15 In recent times, intravitreal injection of anti-VEGF drugs has been used extensively for the treatment of nAMD. Because RAP is considered to be a distinct subtype of nAMD, anti-VEGF injections are commonly used. However, owing to its relative infrequency, not much is known about RPE tearing following intravitreal anti-VEGF treatment for RAP. The purpose of this study was to identify the characteristics of RPE tearing after ranibizumab injections in RAP patients, the associated risk factors, and the prognosis.
METHODS WE PERFORMED A COMPUTERIZED SEARCH AND MEDICAL RE-
Supplemental Material available at AJO.com. Accepted for publication Jul 15, 2015. From the Department of Ophthalmology, Kim’s Eye Hospital, MyungGok Eye Research Institute, Konyang University College of Medicine, Seoul, South Korea. Inquiries to Han Joo Cho, Kim’s Eye Hospital, 156 4ga Yeoungdeungpodong, Yeoungdeungpo-gu, Seoul, South Korea; e-mail: chojoo@kimeye. com
1000
Ó
2015 BY
cord review for patients who had been diagnosed with RAP and treated with anti-VEGF injections (ranibizumab [Lucentis; Novartis Pharma AG, Basel, Switzerland]) between June 2012 and June 2014. All patients had been examined and treated at the Retina Center of Kim’s Eye Hospital at Konyang University College of Medicine. This study was approved by the Institutional Review Board
ELSEVIER INC. ALL
RIGHTS RESERVED.
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2015.07.023
of Kim’s Eye Hospital, Konyang University College of Medicine. The study adhered to the tenets of the Declaration of Helsinki (IRB No A-2015-012). SUBJECTS:
The following inclusion criteria were used: (1) age >50 years; (2) confirmation of RAP using funduscopy, spectral-domain optical coherence tomography (SD OCT [Spectralis; Heidelberg Engineering, Heidelberg, Germany; and Spectral OCT/SLO; OTI Ophthalmic Technologies Inc, Miami, Florida, USA]), fluorescein angiography (FA), and indocyanine green angiography (ICGA) performed using a confocal laser scanning system (Spectralis HRAþOCT; Heidelberg Engineering) at the first visit; (3) treatment naı¨ve; (4) treatment with ranibizumab; and (5) a minimum follow-up period of 12 months. The diagnosis of RAP was based on the characteristic features of the condition, which include intraretinal hemorrhage, intraretinal vascular anastomoses, and PED with overlying cystic retinal edema, observed using OCT. In addition, the presence of retinal anastomotic feeder and drainage vessels on the FA or ICGA images, or of a ‘‘hot spot’’ corresponding to the neovascular lesion on the ICGA image, was also required in order for RAP to be diagnosed. Patients with RAP were classified as stage 1, 2, or 3 according to established grading criteria.1 The diagnosis and staging of RAP were evaluated by 2 independent investigators (H.J.C. and H.S.K.). When the evaluation was inconsistent, a senior investigator (T.G.L.) made the final decision. Exclusion criteria were as follows: (1) the presence of RPE tearing at baseline; (2) treatment using another antiVEGF agent (bevacizumab [Avastin; Genentech Inc, South San Francisco, California, USA]) or photodynamic therapy; (3) concomitant ocular diseases such as diabetic retinopathy, high myopia (more than 6 diopter spherical equivalent), vein or artery occlusion, or epiretinal membrane; and (4) trauma either during the study or in the contralateral eye, aphakia, or previous vitreoretinal surgery.
ASSESSMENT AND OUTCOME MEASURES:
RPE tears were identified using 4 imaging modalities: color fundus photograph, FA and/or ICGA images, SD OCT, and autofluorescence images. FA and/or ICGA images revealed hypofluorescence of the bare choroid, and all suspicious RPE tear-like lesions were confirmed by SD OCT consisting of either 19 or 31 horizontal lines (6 3 6 mm area); OCT showed interruption of the hyperreflective RPE layer, with elevation or scrolling of the torn RPE flap.16 Increased depth of signals, corresponding to the bare choroid underlying the torn RPE, was frequently seen on OCT.9 When the patient had PED at baseline, PED height was defined as the vertical distance from the hyperreflective line of the Bruch membrane to the inner margin of the hyperreflective line of the RPE layer. All OCT scans were taken horizontally over the PED (consisting of either 19 or 31 horizontal lines [6 3 6 mm area]), such that the
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highest point of the PED was assessed. Subfoveal choroidal thickness was defined as the vertical distance from the hyperreflective line of the Bruch membrane to the hyperreflective line of the inner surface of the sclera on foveacentered SD OCT images. When the inner surface of the sclera was not visible on the conventional image, the OCT image was taken using an enhanced depth imaging (EDI) technique, a feature of the Spectralis SD OCT machine, as previously reported.17 Each section was obtained using eye tracking, and 100 scans were averaged in order to improve the signal-to-noise ratio. The lesion was defined as choroidal neovascularization (CNV) lesion included CNV and 1 or more of the following in or adjacent to the location of CNV: PED, blocked fluorescence, or hemorrhage. Hemorrhage was considered to be part of the lesion only when it was contiguous with the total neovascular lesion and the hemorrhage extended beyond the fluorescence of the underlying CNV on FA. The lesion size was measured manually by outlining the lesion on the FA image. All measurements were estimated using the Heidelberg Eye Explorer software (v. 5.6.4.0; Heidelberg Engineering) by 2 retinal specialists (H.J.C. and H.S.K.) who had been masked to patient information. As a measurement of functional outcome after treatment, the best-corrected visual acuity (BCVA) 12 months after treatment of patients with RPE tearing was compared with that of patients without RPE tearing. In addition, anatomic outcome, measured as central foveal thickness (defined as the vertical distance from the internal limiting membrane [ILM] to Bruch membrane on SD OCT images) after treatment was also compared between groups. In addition, the percentage of patients who had gained or lost more than 3 lines of vision since baseline was also assessed. INTRAVITREAL
RANIBIZUMAB TREATMENT: All patients had been given a loading dose of 3 intravitreal ranibizumab injections (0.5 mg/0.05 mL; Lucentis; Novartis Pharma AG, Basel, Switzerland) with a 1-month interval between treatments. Subsequent additional injections were given if any of the following conditions were observed: (1) visual deterioration of more than 2 lines (>0.2 logarithm of the minimal angle of resolution [logMAR]); (2) OCT evidence of persistent fluid or hemorrhage involving the macula for at least 1 month following the previous injection; (3) an increase in central foveal thickness of at least 100 mm on OCT; (4) evidence of an active RAP lesion found on FA, ICGA, or OCT. All patients were followed up on a monthly basis for 12 months after the initial treatment; the follow-up consisted of examinations such as fundus photography and SD OCT. Additional FA, ICGA, autofluorescence, and SD OCT examinations were performed whenever RAP recurred, or when RPE tears were suspected. The treatment was continued after occurrence of an RPE tear according to the retreatment criteria except when the patient strongly refused treatment.
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STATISTICAL ANALYSES:
SPSS software (version 13.0; SPSS, Inc, Chicago, Illinois, USA) was used for all statistical analyses. Frequencies were compared between treatment groups using either the x2 or Fisher exact test. Comparative statistical analyses were performed using unpaired t tests. A multivariate logistic regression analysis was performed using various baseline characteristics to identify risk factors for RPE tearing after treatment. Logistic regression models were tested using the Hosmer–Lemeshow test to ascertain the goodness of fit and forward and backward stepwise regression were performed using the likelihood-ratio model. The change in the likelihood ratio was used for variable selection, which was based on the maximum partial likelihood estimates for the covariate. All tests were 2-sided, and a P value <.05 was considered statistically significant.
RESULTS BASELINE CHARACTERISTICS:
A total of 109 eyes had been diagnosed with RAP and treated with intravitreal ranibizumab injections at our institution during the study period. Among these, 11 were excluded owing to followup loss. Finally, 98 eyes with RAP in 86 patients (45 men, 41 women; all South Korean) met the inclusion criteria and were enrolled in our study. The mean age of the subjects at their initial visit was 74.6 6 7.9 years, and the mean number of injections administered was 4.96 6 1.81 over 12 months. Table 1 outlines the clinical details of the patients included in the study. RPE tears had developed in 8 eyes (8.2%) after treatment during the 12-month follow-up period. All 8 of these eyes had shown PED at baseline. The majority of them (7 eyes) had developed the RPE tear during the period of the 3 monthly loading injections (within 3 months from baseline). RPE tears had developed in 2 eyes after the first injection, in 4 eyes after 2 injections, in 1 eye after 3 injections, and in 1 eye after 5 injections (Table 2). The Supplemental Figure (available at AJO.com) shows images taken from 1 representative case that had developed RPE tearing after intravitreal ranibizumab injections (Table 2, Patient 7). When the baseline characteristics were compared between the ‘‘RPE tearing’’ group (8 eyes) and the ‘‘no RPE tearing’’ group (90 eyes), there were several significant differences. The mean subfoveal choroidal thickness was smaller (P ¼ .021), the mean lesion size was greater (P ¼ .031), PED at baseline was more frequent (P ¼ .016), and the mean PED height was greater (P ¼ .003) in the ‘‘RPE tearing’’ group (Table 1). Other complications associated with intravitreal ranibizumab injections were observed in all subjects, including endophthalmitis, traumatic lens injury, retinal detachment, and systemic adverse events. 1002
RISK FACTORS ASSOCIATED WITH RETINAL PIGMENT EPITHELIUM TEARING AFTER INTRAVITREAL RANIBIZUMAB INJECTIONS: Among the baseline characteristics,
various parameters were considered possible predictive factors for RPE tearing after treatment; these were age, sex, baseline BCVA (logMAR), baseline central foveal thickness, baseline subfoveal choroidal thickness, lesion size, RAP stage (stage 1, 2, or 3), PED height, presence of reticular pseudodrusen, and number of injections. When the baseline data were analyzed using multivariate logistic regression, 2 factors were found to significantly increase the risk of RPE tearing; namely, thinner subfoveal choroid (odds ratio [OR] ¼ 0.815, 95% confidence interval [CI] ¼ 0.719–0.912, P ¼ .023) and higher PED (OR ¼ 1.411, 95% CI ¼ 1.199–1.888, P ¼ .011). VISUAL AND ANATOMIC OUTCOMES:
The BCVA of the group without RPE tearing had significantly improved after treatment—from 0.74 6 0.49 (20/109) at baseline to 0.56 6 0.44 (20/72) at 12 months (paired t test, P ¼ .012). However, the BCVA of the ‘‘RPE tearing’’ group showed no significant improvement after treatment: from 0.76 6 0.55 (20/115) at baseline to 0.74 6 0.56 (20/109) at 12 months (paired t test, P ¼ .672). Additionally, the BCVA at 12 months of the patients with RPE tearing was significantly worse than that of the patients without RPE tearing (0.56 6 0.44 [20/72] vs 0.74 6 0.56 [20/109], P ¼ .009). Among the patients with RPE tearing, only 1 (Patient 1; Table 2) had shown an improved BCVA of more than 3 _0.3 logMAR units), and 3 (Patients 5, 6, and 7; lines (> Table 2) had shown a worsened BCVA of more than 3 lines after treatment. The proportion of RPE-tearing patients with visual improvement (1 out of 8 eyes) was significantly lower than that of the patients without RPE tearing (35 out of 90 eyes; 38.9%; P ¼ .037 using Fisher exact test). Whereas there had been significant improvement to mean central foveal thickness in patients without RPE tearing after treatment—from 325 6 199 mm at baseline to 217 6 166 at 12 months (P ¼ .006) —there had been no statistical improvement to this value in the patients with RPE tearing: from 344 6 139 mm at baseline to 311 6 144 mm at 12 months (P ¼ .885). Moreover, the mean central foveal thickness of the ‘‘RPE tearing’’ group was significantly thicker at 12 months than that of the patients without RPE tearing (311 6 144 mm vs 217 6 166 mm, P ¼ .021).
DISCUSSION IT HAS BEEN PROPOSED THAT RAP IS THE MANIFESTATION
of deep retinal-capillary proliferation, and that the later stages involve the progression from subretinal to choroidal neovascularization with PED formation.1,3 One recent investigation with SD OCT suggested that intraretinal (type 3) neovascularization may induce PED
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TABLE 1. Baseline Clinical Characteristics of Patients With Retinal Angiomatous Proliferation
Age (y 6 SD) Sex Male, n (%) Female, n (%) Mean of baseline BCVA (logMAR; Snellen equivalent) Baseline BCVA (logMAR; Snellen equivalent) <0.54 (20/70) 0.54 (20/70) to 1.0 (20/200) >1.0 (20/200) Mean central foveal thickness 6 SD (mm) Mean subfoveal choroidal thickness 6 SD (mm) Lesion location, n (%) Subfoveal Juxtafoveal Extrafoveal Mean lesion size 6 SD (mm2) Stage of RAP, n (%) Stage 1 Stage 2 Stage 3 Presence of PED, n (%) Mean PED height 6 SD (mm) Reticular pseudodrusen, n (%) Mean number of injections 6 SD
Total Eyes (n ¼ 98)
RPE Tear During Treatment (n ¼ 8)
No RPE Tear During Treatment (n ¼ 90)
P
74.6 6 7.9 (52–85)
77.1 6 4.2
74.3 6 6.6
.221a
52 (53.1%) 46 (46.9%) 0.75 6 0.52 (20/112)
3 (37.5%) 5 (62.5%) 0.76 6 0.55 (20/115)
49 (54.4%) 41 (45.6%) 0.74 6 0.49 (20/109)
.113b .626a
20 (20.4%) 47 (48.0%) 31 (31.6%) 327 6 166 141 6 55 (67–285)
1 (12.5%) 5 (62.5%) 2 (25.0%) 344 6 139 101 6 33
19 (21.1%) 42 (46.7%) 29 (32.2%) 325 6 199 147 6 61
.352c .717a .021a
13 (13.3%) 63 (64.2%) 22 (22.5%) 2.4 6 1.1
1 (12.5%) 4 (50.0%) 3 (37.5%) 2.9 6 1.3
12 (13.3%) 59 (65.6%) 19 (21.1%) 2.2 6 1.2
.511c .031a
9 (9.2%) 62 (63.3%) 27 (27.5%) 59 (60.2%) 221 6 144 60 (61.2%) 4.96 6 1.81
0 (0%) 4 (50.0%) 4 (50.0%) 8 (100%) 408 6 142 7 (87.5%) 4.52 6 1.43
9 (10.0%) 58 (64.4%) 23 (25.6%) 51 (56.7%) 197 6 112 53 (55.6%) 5.01 6 1.96
.323c .016b .003a .083b .550a
BCVA ¼ best-corrected visual acuity; logMAR ¼ logarithm of the minimal angle of resolution; PED ¼ pigment epithelial detachment; RAP ¼ retinal angiomatous proliferation; RPE ¼ retinal pigment epithelium; SD ¼ standard deviation. a P value by t test. b P value by x2 test. c P value by Fisher exact test.
by developing below the RPE layer, and that the type 3 neovascularization complex frequently localized at the apex of PED.18 Considering the neovascular process and development of PED in RAP, we hypothesized that there may be some difference between RAP and typical nAMD after anti-VEGF injection, with regard to incidence of RPE tearing and the response of PED. However, it transpired that the incidence of RPE tearing in our RAPonly cohort (8.2%) was similar to that of nAMD from previous reports (2.8%–14%).6,13,19 Recently, various investigations have proposed that contraction and/or fibrosis in choroidal neovascularization tissue after antiVEGF therapy can induce rips in the overlying RPE.20,21 Our results suggest that the mechanism of RPE tearing in RAP may be similar to that which has been proposed to occur in nAMD. Risk factors for the development of an RPE tear after intravitreal anti-VEGF treatment in nAMD have been
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reported. They include PED height, greatest linear dimension of the baseline PED, and PED surface area.15,22 Similarly to previous reports, all patients in our study who had developed RPE tearing had also presented with PED at baseline, and PED height was found to be a significant risk factor for the development of an RPE tear. A thinner subfoveal choroid is one of the characteristics of RAP when compared with typical nAMD,23 and thin choroid was another risk factor for RPE tearing in RAP patients in this study. It is not clear why thin choroid is associated with a higher risk of RPE tearing. However, several investigations have suggested a connection between thin choroid and RPE layer integrity. It has been reported that choroidal thickness is associated with ocular perfusion pressure,24 and that thin choroid may be associated with impaired choroidal blood flow.25 Hypoxic conditions may induce changes in the RPE extracellular matrix and in
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TABLE 2. Clinical Data of Retinal Angiomatous Proliferation Patients With a Retinal Pigment Epithelial Tear After Ranibizumab Treatment
Lesion Patient
1 2 3 4 5 6 7 8
Baseline
Number of Injections
Baseline Central
Baseline Subfoveal
Baseline
Foveal
Age/Sex
RAP Stage
Size (mm2)
Lesion Location
BCVA (Snellen)
BCVA at 12 Months
Before RPE Tear
Foveal Thickness (mm)
Choroidal Thickness (mm)
PED Height (mm)
Involvement of RPE Tear
Reticular Pseudodrusen
85/F 68/F 77/F 78/M 83/F 79/F 72/M 76/M
2 3 2 3 3 2 3 2
2.26 1.88 3.40 2.21 1.12 2.23 4.88 5.22
Extrafoveal Juxtafoveal Juxtafoveal Juxtafoveal Extrafoveal Extrafoveal Subfoveal Juxtafoveal
20/70 20/100 10/200 20/30 10/200 20/100 20/200 20/100
20/25 20/70 10/200 20/50 5/200 20/200 10/200 20/70
2 2 2 1 2 5 3 1
303 269 405 322 301 352 375 425
82 70 81 129 65 152 67 162
395 402 338 540 512 342 412 323
None None Yes None Yes Yes Yes None
Yes Yes Yes Yes Yes None Yes Yes
BCVA ¼ best-corrected visual acuity; PED ¼ pigment epithelial detachment; RAP ¼ retinal angiomatous proliferation; RPE ¼ retinal pigment epithelium.
the tight junctions between the RPE cells.26 Indeed, proteins of the RPE cell tight junction have been found to be decreased in hypoxic conditions using an animal model.27 Thus, a chronic hypoxic state caused by hypoperfusion derived from thin choroid may induce alteration or weakness in the RPE layer, which may in turn cause vulnerability to RPE-shearing forces after anti-VEGF injection. In addition, 1 case series involving 7 nAMD patients recently reported a tendency for decreased subfoveal choroidal thickness in eyes with RPE tearing, compared with the fellow eye with intact RPE.28 However, it is unclear whether thin choroid is a characteristic risk factor for RPE tear in RAP only, or whether it is also a risk factor in typical nAMD. Further studies are warranted to determine the mechanism of RPE tear development associated with thin choroid. An unfavorable visual prognosis has been reported in nAMD patients with RPE tears.19,20 This was in line with our own results from RAP patients. Both the BCVA and the central foveal thickness of the RPE tear patients at 12 months after treatment were significantly worse than those of the patients without RPE tearing. Currently, there is no modality or guideline available for treatment of patients with RPE tears occurring after intravitreal anti-VEGF injections. Therefore, antiVEGF treatment should be performed cautiously in RAP patients who have thin choroid or high PED height, with consideration to the possibility of subsequent RPE tear development. In addition, close monitoring of RAP patients and prompt therapeutic intervention
should be considered prior to the development of large PEDs. Our study had several limitations, including its retrospective nature. First, the sample size of RPE tear patients was relatively small and may have been insufficient for analysis. However, to the best of our knowledge, this study is the first report regarding RPE tears with an RAP-only cohort. Another limitation is that we did not classify type 1, 2, or 3 neovascularization. However, it is difficult to classify the type of neovascularization in advanced RAP cases, because there may be mixed lesion types and evidence of all neovascularization types present. A recent prospective study reported that RPE tearing was more frequent in eyes treated with high-dose (2 mg; 4 eyes out of 37) than standard-dose (0.5 mg) ranibizumab therapy (1 eye out of 37).20 This difference in tear incidence suggests an association between RPE tear development and anti-VEGF dose, or kinds of anti-VEGF drugs. This is the reason we excluded patients treated with other anti-VEGF agents. Future studies may allow for these variances in RPE tear development associated with different anti-VEGF drugs, or their doses. In conclusion, the incidence and clinical features of RPE tearing in RAP patients was similar to that seen in typical nAMD. High PED and thin subfoveal choroid were associated with the development of RPE tearing following intravitreal ranibizumab injections in RAP patients. Investigations into the precise mechanisms of RPE tearing after intravitreal anti-VEGF treatment, and its management, are warranted in the future.
FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. FINANCIAL DISCLOSURES: THE FOLLOWING AUTHORS HAVE NO financial disclosures: Han Joo Cho, Hyoung Seok Kim, Seul Gi Yoo, Jung Il Han, Young Ju Lew, Sung Won Cho, Tae Gon Lee, and Jong Woo Kim. All authors attest that they meet the current ICMJE criteria for authorship.
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Biosketch Han Joo Cho, MD, graduated from the Yonsei University College of Medicine, Seoul, Korea in 2001. In 2006, he completed his residency at the Department of Ophthalmology of the same university. After a fellowship at the Kim’s Eye Hospital, Konyang University College of Medicine, Seoul, Korea, He has been a vitreoretinal surgeon at the same hospital since 2010. His primary areas of interest are vitreoretinal disorders and vitreous surgery.
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SUPPLEMENTAL FIGURE. A 72-year-old man with retinal angiomatous proliferation treated with intravitreal ranibizumab injections (Patient 7, Table 2). Color fundus photography (Top row, first image) showed multiple drusen, pigment epithelial detachment (PED), and fine retinal hemorrhage. Fluorescein angiography (FA) and indocyanine green angiography (ICGA; Top row, second and third images) revealed PED and a small hot spot representing an area of retinal anastomosis. Sectional spectral-domain optical coherence tomography (SD OCT) image (with the arrow seen on Top row, second image) showed PED and abnormal reflectivity lying over and under the PED. The subfoveal choroidal thickness was 67 mm (between arrowheads; Top row, fourth image). Five days after the third ranibizumab injection, the patient complained of decreased visual acuity. Color fundus photography (Second row, first image), FA (Second row, second image), and ICGA (Second row, third image) show increased PED size. FA shows leakage at the temporal edge of the PED, with passage of fluorescein into the subretinal space (Second row, second image; arrowhead). Both disruption of the RPE over the leakage area and corrugated folding of RPE layer (Second row, fourth image, arrowhead) are detectable on the SD OCT image (with the arrow seen on the Second row, second image). Two months after the final ranibizumab injection, a large RPE tear and bare choroid was found using fundus photography (Bottom row, first image), and SD OCT (Bottom row, second image). The images show the progression of the RPE tear and interruption of the hyperreflective RPE layer with elevation or scrolling of the torn RPE flap.
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