Objective
To evaluate the therapeutic response of pigment epithelial detachment (PED) to anti–vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (nAMD), and identify predictive factors for PED resolution after treatment.
Design
Retrospective, interventional case series.
Methods
A total of 202 treatment-naïve nAMD eyes presenting PED at baseline were retrospectively included and analyzed. All patients were treated with an initial series of 3 monthly loading injections of ranibizumab or aflibercept, followed by additional injections as required.
Results
After 12 months of treatment, the mean PED height decreased from 453 ± 261 μm at baseline to 230 ± 142 μm ( P = .002), and the mean best-corrected visual acuity improved from 0.71 ± 0.41 logarithm of the minimal angle of resolution (Snellen equivalent, 20/102) to 0.60 ± 0.36 (20/79) ( P = .024). The proportion of complete PED resolution after treatment was 19.3% (39 eyes). Multivariate logistic regression analysis was used to find baseline characteristics associated with a higher chance of PED resolution, including lower PED height at baseline ( P = .018), polypoidal choroidal vasculopathy ( P = .015), or retinal angiomatous proliferation ( P = .010) compared to typical nAMD; serous PED ( P = .022) compared to fibrovascular PED; and aflibercept ( P = .039) compared to ranibizumab.
Conclusions
PEDs secondary to nAMD showed significant functional and anatomic improvement after intravitreal anti-VEGF injections over 12 months. However, the anti-VEGF treatment showed limited efficacy for the complete resolution of PED. The PED type, nAMD subtype, baseline PED height, and anti-VEGF drug type was associated with a higher probability of PED resolution after treatment.
Pigment epithelial detachment (PED) occurs in association with various retinal diseases, the most prevalent being neovascular age-related macular degeneration (nAMD). PED forms in nAMD cases when the retinal pigment epithelium (RPE) separates from the Bruch membrane owing to the presence of sub-RPE fluid, blood, fibrovascular membrane, or drusenoid material. PED occurs in up to 62% of eyes with evidence of advanced AMD by fluorescein angiography (FA).
Currently, the standard treatment for nAMD is intravitreal injection of anti–vascular endothelial growth factor (VEGF). However, PED is often resistant to anti-VEGF treatment. Recent studies have also reported that the presence of PED is a poor prognostic factor after anti-VEGF treatment in nAMD. Additionally, it has been reported that the presence of a PED itself is often a sign of disease progression in nAMD. However, the response of PED to anti-VEGF treatment has not been sufficiently reported. The purpose of the study was to identify therapeutic responses of PED to anti-VEGF treatment for nAMD during a 12-month period, and to identify predictive factors for PED resolution after treatment.
Methods
We conducted a computerized search and medical record review for patients who were newly diagnosed with nAMD and treated with anti-VEGF (ranibizumab [Lucentis; Genentech Inc, South San Francisco, California, USA] or aflibercept [Eylea; Bayer HealthCare, Berlin, Germany]) injections from May 2013 to September 2014. All patients were 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 of Kim’s Eye Hospital, Konyang University College of Medicine. All study conduct adhered to the tenets of the Declaration of Helsinki (IRB No. A-2015-031).
Subjects
Inclusion criteria included the following: (1) age >50 years; (2) confirmation of nAMD with funduscopy, spectral-domain optical coherence tomography (SDOCT [Spectralis; Heidelberg Engineering, Heidelberg, Germany and/or Spectral OCT/SLO; OTI Ophthalmic Technologies Inc, Miami, Florida, USA]), FA, and indocyanine angiography (ICGA), performed using a confocal laser scanning system (Spectralis HRA+OCT; Heidelberg Engineering) at the first visit; (3) no previous treatment; (4) PEDs with a minimum height of 200 μm at baseline, measured using OCT; (5) treatment with 1 type of anti-VEGF agent (aflibercept or ranibizumab); (6) a minimum follow-up period of 12 months.
Differential diagnoses of nAMD subtypes, including typical nAMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP), were made at baseline. Only patients whose ICGA revealed the presence of characteristic polypoidal structures at the border of the branching choroidal vascular networks were diagnosed as having PCV. RAP diagnoses were based on the characteristic features of the condition observed with OCT, which include intraretinal hemorrhage, intraretinal vascular anastomoses, and PED with overlying cystic retinal edema. In addition, the presence of retinal anastomotic feeder and drainage vessels on the FA or ICGA images, or of a “hot spot” corresponding to a neovascular lesion on the ICGA image, was also required to diagnose RAP.
The exclusion criteria were as follows: (1) evidence of end-stage AMD, such as central geographic atrophy or disciform scarring at baseline; (2) treatment with both aflibercept and ranibizumab (in the case of switching from ranibizumab to aflibercept or vice versa); (3) severe subretinal hemorrhage interfering with diagnosis or PED evaluation; (4) treatment combined with PDT; (5) other secondary choroidal neovascularization (CNV); (6) other concomitant ocular diseases, such as diabetic retinopathy, high myopia (more than spherical equivalent of 6 diopters), vein or artery occlusion; or (7) another ocular disease that could affect visual acuity.
Patient Assessment and Outcome Measures
When the patient had PED at baseline, the PED lesion was analyzed with FA, ICGA, and SDOCT with enhanced depth imaging (EDI) using a Spectralis SDOCT machine, as previously reported. An elevation of the RPE away from the Bruch membrane by any layer of choroidal neovascularization (CNV) is by definition a PED. However, to maintain the possibility of comparison with previous publications, only PEDs with a minimum height of 200 μm were defined as PEDs in this study. Maximal 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 19 or 31 horizontal lines [6 × 6-mm area]) with the EDI technique, such that the highest point of the PED was assessed.
PEDs were categorized as fibrovascular PED or serous PED according to FA/ICGA and SDOCT findings. Serous PED was identified by the presence of shading background fluorescence in the PED area in the early phase, followed by the gradual appearance of a circular zone of intensifying and irregular hyperfluorescent leakage. Additionally, only when the SDOCT findings showed homogenously hyporeflective sub-RPE space (optically empty) was the lesion categorized as serous PED. Fibrovascular PEDs were identified by areas of stippled hyperfluorescence and signs of leakage in the late phase of FA. If the SDOCT findings showed moderate hyperreflective material adherent to the surface or under the surface of the PEDs, this was also considered fibrovascular PED. Drusenoid PED was categorized as either fibrovascular or serous according to findings of neovascular components on FA/ICGA and SDOCT, as mentioned earlier. Resolution of PED after treatment was defined as a completely flattened PED without empty space between the RPE and Bruch membrane, including no CNV activity on SDOCT or FA/ICGA at 12 months. All measurements were estimated using Heidelberg Eye Explorer software (v. 5.6.4.0; Heidelberg Engineering). The categorization of PED and assessment of OCT images was performed by 2 retinal specialists (H.J.C. and H.S.K.), who were masked to the patient information. When the evaluations were inconsistent, the senior investigator (D.W.L.) made the final decision.
Intravitreal Anti–Vascular Endothelial Growth Factor Treatment
All patients were given a loading dose of 3 intravitreal anti-VEGF (ranibizumab 0.5 mg/0.05 mL or aflibercept 2 mg/0.05 mL) injections with a 1-month interval between treatments. Following the loading injections, additional injections were performed on an “as-needed” basis if any of the following conditions was observed: (1) visual deterioration of more than 2 lines (>0.2 logarithm of the minimal angle of resolution [logMAR]); (2) OCT evidence of intraretinal or subretinal fluid, or hemorrhage involving the macula, that had persisted for 1 month since the previous injection; (3) evidence of an active CNV lesion found on FA, ICGA, or OCT. All patients with nAMD were re-treated using the same criteria, regardless of whether they showed PED. Furthermore, we did not re-treat for residual PED when OCT, FA, or ICGA revealed no fluid or CNV activity. All patients were followed up for 12 months on a monthly basis after initial treatment. Follow-up examinations, including best-corrected visual acuity (BCVA) measurement, fundus photography, and SDOCT, were performed 3, 6, 9, and 12 months after the initial treatment visit. Additional FA, ICGA, and SDOCT examinations were performed whenever recurrence was suspected. In accordance with previous studies, where aflibercept was injected every 8 weeks during the maintenance phase, additional aflibercept was injected at 2-month intervals and ranibizumab was injected at 1-month intervals after the loading injection.
RPE tears during treatment were identified using several imaging modalities: color fundus photograph, FA and/or ICGA images, and SDOCT. FA and/or ICGA images revealed hypofluorescence of the bare choroid, and all suspicious RPE tear–like lesions were confirmed by SDOCT; OCT showed interruption of the hyperreflective RPE layer, with elevation or scrolling of the torn RPE flap.
Statistical Analysis
SPSS software version 13.0 (SPSS Inc, Chicago, Illinois, USA) was used for all statistical analyses. Frequencies were compared between groups using χ 2 or Fisher exact tests. Analysis for continuous variable changes was performed using paired t tests. To investigate the baseline clinical characteristics related to the resolution of PED after anti-VEGF treatment, multivariate logistic regression analysis was performed. Forward and backward stepwise regressions were performed using the likelihood-ratio model, in which changes in the likelihood-ratio statistic based on the maximum partial likelihood estimates for the covariate were used for variable selection. A P value less than .05 was considered statistically significant, and all tests were 2-sided.
Results
Baseline Characteristics
A total of 442 eyes (426 patients) were newly diagnosed with nAMD at our institution and treated during the study period. Among them, 264 eyes (59.7%) presented with PED at baseline. Among the eyes with PED, 62 eyes were excluded for the following reasons: follow-up loss within 12 months (40 eyes), presence of severe subretinal hemorrhage at baseline (12 eyes), or treated with both ranibizumab and aflibercept (10 eyes). As a result, 202 eyes (181 patients) were enrolled in the study.
All patients were South Korean, and the average age for the entire study group was 69.7 ± 6.4 years. The mean baseline BCVA was 0.71 ± 0.41 (Snellen equivalent, 20/102). With regard to the CNV subtype, 105 of the 202 eyes (51.9%) were diagnosed as typical nAMD, 69 eyes (34.2%) were diagnosed as PCV, and 28 eyes (13.9%) were diagnosed as RAP. The mean maximal PED height was 453 ± 261 μm at baseline. Fibrovascular PED was found in 162 eyes (80.2%) and serous PED in 40 eyes (19.8%). The subjects’ clinical details are listed in Table 1 .
| Total (n = 202) | |
|---|---|
| Age (y) | 69.7 ± 6.4 |
| Sex, n (%) | |
| Male | 112 (55.4%) |
| Female | 90 (44.6%) |
| Mean baseline BCVA (logMAR) | 0.71 ± 0.41 (20/102) |
| Baseline BCVA (logMAR), n (%) | |
| <0.40 (20/40) | 39 (19.3%) |
| 0.40 (20/40) to 1.0 (20/200) | 119 (58.9%) |
| >1.0 (20/200) | 44 (21.8%) |
| nAMD subtype, n (%) | |
| Typical nAMD | 105 (51.9%) |
| PCV | 69 (34.2%) |
| RAP | 28 (13.9%) |
| Mean size of CNV (mm 2 ) | 1.9 ± 1.2 |
| Mean baseline central foveal thickness (μm) | 456 ± 196 |
| PED type, n (%) | |
| Fibrovascular PED | 162 (80.2%) |
| Serous PED | 40 (19.8%) |
| Maximal PED height at baseline (μm) | 453 ± 261 |
| PED location, n (%) a | |
| Subfoveal | 83 (41.1%) |
| Extrafoveal | 119 (58.9%) |
| Anti-VEGF agents of treatment, n (%) | |
| Ranibizumab | 131 (64.9%) |
| Aflibercept | 71 (35.1%) |
| Mean number of injections | 4.88 ± 1.22 |
a If any part of PED involved subfoveal area, the location of PED defined as subfoveal.
Subjects received a mean of 4.88 ± 1.22 intravitreal injections within 12 months (range, 3–10 injections). No complications were associated with injections, including endophthalmitis, traumatic lens injury, or retinal detachment. Furthermore, no patients developed systemic complications, such as cerebrovascular accident, because of the intravitreal anti-VEGF injections.
Changes in Pigment Epithelial Detachment After Anti–Vascular Endothelial Growth Factor Treatment
The maximum PED height significantly decreased during the study period. The mean of the maximum PED height decreased from 453 ± 261 μm at baseline to 237 ± 161 μm at 3 months ( P = .003), 256 ± 177 μm at 6 months ( P = .009), 241 ± 190 μm at 9 months ( P = .011), and 230 ± 142 μm at 12 months ( P = .002) ( Figure 1 ). The proportion of complete resolution of PED was 16.8% (34 eyes) at 3 months, 21.8% (44 eyes) at 6 months, 20.8% (42 eyes) at 9 months, and 19.3% (39 eyes) at 12 months. This proportion tended to plateau after 3 months in spite of continuous treatment ( Figure 2 ). After 12 months of treatment, 51.5% of eyes (104 eyes) showed decreased PED heights greater than 50% from baseline, 11.4% (23 eyes) showed decreased PED height less than 50% from baseline, and 17.8% (36 eyes) showed increased PED height greater than baseline ( Table 2 ). The proportion of PED flattening and PED height greater than 50% decrease after treatment was highest at 6 months; however, no significant difference was found between each follow-up point ( Figure 2 ).
| Total (n = 202) | |
|---|---|
| Mean BCVA (logMAR) | 0.60 ± 0.36 |
| Change in mean BCVA from baseline (logMAR) | −0.11 |
| Mean central foveal thickness (μm) | 268 ± 171 |
| Change in mean central foveal thickness from baseline (μm) | −188 |
| Mean maximal PED height | 230 ± 142 |
| Mean maximal PED height changes from baseline (μm) | −223 |
| Change in PED height from baseline, n (%) | |
| Resolution of PED | 39 (19.3%) |
| Decrease in PED height more than 50% from baseline | 104 (51.5%) |
| Decrease in PED height less than 50% from baseline | 23 (11.4%) |
| Increase in PED height more than baseline | 36 (17.8%) |
| Development of RPE tear, n (%) | 20 (9.9%) |
| Ranibizumab | 11 (11/131 = 8.4%) |
| Aflibercept | 9 (9/71 = 12.7%) |
| Mean number of injections | |
| Ranibizumab | 5.04 ± 1.56 |
| Aflibercept | 4.71 ± 1.37 |
RPE tears developed in 20 eyes (9.9%): in 11 eyes after ranibizumab treatment (11 of 131 eyes; 8.4%) and in 9 eyes after aflibercept treatment (9 eyes out of 71 eyes; 12.7%). Although the incidence of RPE tears after aflibercept treatment was slightly higher than that after ranibizumab treatment, no significant difference was found between the 2 drugs ( P = .38, Table 2 ).
Visual Outcome and Pigment Epithelial Detachment Resolution
The mean BCVA of all subjects improved from 0.71 ± 0.41 (Snellen equivalent, 20/102) to 0.60 ± 0.36 (20/79) after 12 months of treatment ( P = .024). When comparing the visual outcomes between patients with and without PED resolution after 12 months of treatment (39 and 163 eyes, respectively), there was no significant difference in the baseline BCVA (0.65 ± 0.42 logMAR vs 0.73 ± 0.33 logMAR; P = .146). In addition, there was no significant difference in the mean injection number between patients with PED resolution (4.90 ± 1.33) and patients without PED resolution (5.07 ± 1.42) through 12 months from baseline ( P = .717). However, the mean BCVA from patients with PED resolution (39 eyes, 0.49 ± 0.35 logMAR; 20/61 Snellen) was significantly better than that of patients without PED resolution (163 eyes, 0.64 ± 0.32 logMAR; 20/87 Snellen) after 12 months of treatment ( P = .023).
Factors Predictive of Pigment Epithelial Detachment Resolution After Treatment
The univariate logistic regression analysis showed that nAMD subtype, PED type, baseline maximal PED height, and anti-VEGF type were associated with PED resolution after treatment ( Table 3 ). When the baseline data were analyzed using multivariate logistic regression, 4 factors were found to be significantly associated with higher chance of RPE resolution: nAMD subtype, PED type, baseline PED height, and anti-VEGF type.
