Eyes with neovascular age-related macular degeneration (AMD) refractory to ranibizumab or bevacizumab have shown anatomical improvements with reduction in central foveal thickness (CFT),1–4 macular volume (MV),5 pigment epithelial detachment (PED) dimensions,3 and sometimes visual improvement3,6 after treatment with aflibercept. PEDs in AMD are frequently associated with choroidal neovascularization and a higher risk of severe vision loss.7 Quantitative volumetric algorithms using spectral-domain optical coherence tomography (SD-OCT) to measure change in the PED volume and area are more reproducible than subjective qualitative assessments in determining response to treatment and deciding when to retreat in eyes undergoing OCT-guided anti-vascular endothelial growth factor (VEGF) therapy.8
In this case series, we use an algorithm to quantify the volumetric changes in PED morphology in neovascular AMD eyes with a PED recalcitrant to prior bevacizumab or ranibizumab therapy that were transitioned to aflibercept.
Patients and Methods
The study is an interventional, noncomparative case series of consecutive patients with neovascular AMD who were switched from treatment with intravitreal ranibizumab or bevacizumab to intravitreal aflibercept for recalcitrant choroidal neovascularization secondary to AMD. Institutional review board approval was obtained. Patients required SD-OCT (Heidelberg Spectralis HRA+OCT, Heidelberg, Germany) documentation of persistent PED, subretinal fluid (SRF), intraretinal fluid (IRF), and/or sub– retinal pigment epithelium (RPE) fluid with adjacent SRF or IRF after at least 6 months of monthly anti-VEGF treatment. We excluded eyes with a history of anti-VEGF therapy less than 28 days prior, previous photodynamic therapy (PDT), significant subfoveal fibrosis (more than 50% of lesion), prior triamcinolone (less than 6 months), intraocular surgery (less than 2 months), history of vitrectomy, active intraocular inflammation, vitreous hemorrhage, subretinal hemorrhage involving at least 1 disc area of central fovea, previous RPE tear, or best corrected visual acuity (BCVA) of less than 20/40. Patients with idiopathic polypoidal choroidal vasculopathy (IPCV) and central serous retinopathy were also excluded.
Patients received a minimum of three monthly aflibercept injections. Afterwards, they were switched to a bimonthly interval if there was complete resolution of SRF or IRF or kept at an interval at which complete resolution fluid was maintained, based on a treat-and-extend approach. The treatment interval was guided by OCT and examination. Eyes were excluded if the PED extended outside the OCT image window at any point during follow up. Each eye served as its own historical control and was treated by the same physician using identical re-treatment criteria before and after conversion.
OCT imaging was performed using the standard (61-line) raster volume scan with 125 µm interscan spacing with eye tracking. The greatest basal diameter (GBD) and maximum height (MH) were measured directly using the built-in caliper tool. The volume of the PED was calculated using image data exported from the Heidelberg software to ImageJ (v1.47).9 In ImageJ, regions of interest (ROIs) were manually identified around the inner contours of the PED on each individual slice of the SD-OCT images. If multiple small PEDs were present, the largest contiguous PED was segmented. The width and height of each pixel was extracted from the Heidelberg OCT data. The number of pixels outlined by the ROI was exported and multiplied by the pixel dimensions to capture the area covered by the PED on each slice. This total area was then multiplied by the distance between B-scans to approximate the volume of the PED. This process is described in Figure 1. Data analysis was performed using paired, two-tailed t tests to compare values at baseline and at 18 months.
Illustration of stepwise approach to measure the pigment epithelial detachment volume using spectral-domain OCT scans.
Fifteen eyes were enrolled, of which four were excluded because the PED extended outside the OCT images. Eleven eyes of 10 patients (five male and five female; mean age: 80.7 ± 4.38 years) who had received an average of 25.7 ± 20.1 (range: six to 70) prior bevacizumab or ranibizumab injections over 26.6 ± 19.8 months (range: 12 to 63) were included. Four eyes (36.3%) had been previously treated with bevacizumab exclusively, one (9%) with ranibizumab exclusively, and six (54.5%) had been treated with both agents. Five patients were former smokers and five were nonsmokers. None had vitreomacular traction or an epiretinal membrane on baseline SD-OCT.
At baseline, BCVA was 0.37 ± 0.23 logMAR (range: 0.1 to 0.88) (average Snellen visual acuity of 20/47; range: 20/25 to 20/150). Mean PED GBD was 2,406 ± 942 µm (range: 1,212 to 4,392 µm), mean MH was 283 ± 158 µm (range: 110 to 600 µm), and mean PED volume was 0.687 ± 0.837 mm3. Baseline CFT was 339 ± 115 µm, and MV was 7.44 ± 1.35 mm3. At 18 months of follow-up, eyes on average had received 15.1 ± 2.47 (range: 12 to 19) aflibercept injections, mean BCVA remained stable at 0.38 ± 0.19 logMAR (range: 0.1 to 0.6; P = .8) (Snellen 20/48; range: 20/25 to 20/80). Mean PED volume improved to 0.562 ± 0.705 mm3 (P = .02), a decrease of 19% ± 12.3%. Mean MH improved to 207 ± 101 µm (range: 85 to 456 µm; P = .05), a 21% ± 22% reduction, and PED GBD increased to 2,570 ± 1279 µm (range: 459 to 5,074 µm; P = .32), a 6.1% ± 30% increase. CFT reduced to 318.4 ± 102.4 µm (P = .06), a 6.3% ± 11% decrease, and MV decreased to 7.3 ± 0.99 mm3 (P = .42), a 1.1% ± 12% reduction.
Following 18 months of aflibercept, correlation of PED volume with PED height decreased (r = 0.866 to 0.404), while correlation with PED width was relatively unchanged (r = 0.858 to 0.843).
PED involution and contraction that occurs with anti-VEGF therapy has been likened to a wound healing response, whereby the growth stimulus to the vascular component has been removed, allowing the inflammatory and fibrotic elements to predominate.10,11
Unique to this investigation, we analyze the volumetric outcomes of PED using data from individual OCT raster scans in patients with PEDs refractory to treatment with bevacizumab or ranibizumab 18 months after switching them to aflibercept. During 18 months of follow-up, PED volume decreased by 19%, height decreased by 21%, and GBD increased by 6.8%, suggesting a flattening of the PED while preserving the BCVA.
Ferrone et al12 graded PEDs based on a subjective 0-to-3 grading scale and reported that patients switched to aflibercept displayed a significant decrease in subjective PED size (range: 0.73 to 0.62; P = .008) measured on a 0-to-3 scale. Patel et al13 reported improvement of three eyes with serous PEDs and SRF who responded to intravitreal aflibercept after being recalcitrant to prior bevacizumab and/or ranibizumab therapy, and Yamashita reported similar results in three eyes with PED associated with IPCV.14
Rahimy et al15 recently reported that chronic fibrovascular multilayered PEDs develop in eyes with exudative AMD receiving serial intravitreal anti-VEGF injections through a sequential layering of hyperreflective bands beneath the RPE and their propensity to fill more of the sub-RPE compartment of the fibrovascular PED. Beneath the fusiform complex, formation of a hyporeflective cavity, the pre-choroidal cleft, between the deeper fibrous component and the underlying hyperreflective choroid has been reported to be indicative of horizontal contraction by the multilayered tissue complex. Such OCT morphology was seen in several eyes in our series and could explain why a reduction in height but not diameter was seen in some of our patients (Figure 2). The correlation between PED volume and height decreased after treatment with aflibercept due to flattening of PED, suggesting that PED height alone may not be an accurate measure of PED morphology and PED volume is more indicative of response to therapy.
A 78-year-old woman with neovascular age-related macular degeneration and persistent pigment epithelial detachment (PED) despite 19 prior ranibizumab injections over 20 months before transitioning to aflibercept. After 15 aflibercept injections, there was a significant reduction in PED volume from 2.95 mm3 to 2.46 mm3. PED height reduced from 600 µm to 219 µm, and diameter increased from 4,392 µm to 5,074 µm, demonstrating a flattening of the PED. Central foveal thickness remained stable from 366 µm to 371 µm, and macular volume reduced from 8.29 mm3 to 7.99 mm3. BCVA was preserved at 20/40.
The limitations of this study are its retrospective nature and small cohort size. Larger sample sizes would allow for more power in determining significance for factors such as PED MH and GBD. In addition, the PEDs that were excluded for extending outside the OCT window tended to be larger than average, and they may have a less favorable response to anti-VEGF treatment.
In summary, in a subset of patients with refractory exudative AMD who were transitioned to aflibercept after prior treatment with bevacizumab and ranibizumab, there was a significant anatomic improvement in PED morphology while preserving visual acuity.
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- Kumar N, Marsiglia M, Mrejen S, et al. Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina. 2013;33(8):1605–1612. doi:10.1097/IAE.0b013e31828e8551 [CrossRef]
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- Chang AA, Li H, Broadhead GK, et al. Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration. Ophthalmology. 2014;121(1):188–192. doi:10.1016/j.ophtha.2013.08.035 [CrossRef]
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- Penha FM, Gregori G, Garcia Filho CA, et al. Quantitative changes in retinal pigment epithelial detachments as a predictor for retreatment with anti-VEGF therapy. Retina. 2013;33(3):459–466. doi:10.1097/IAE.0b013e31827d2657 [CrossRef]
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- Grossniklaus HE, Ling JX, Wallace TM, et al. Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis. 2002;8: 119–126.
- Schlingemann RO. Role of growth factors and the wound healing response in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2004;242(1):91–101. doi:10.1007/s00417-003-0828-0 [CrossRef]
- Ferrone PJ, Anwar F, Naysan J, et al. Early initial clinical experience with intravitreal aflibercept for wet age-related macular degeneration. Br J Ophthalmol. 2014;98(Suppl 1):i17–21. doi:10.1136/bjophthalmol-2013-304474 [CrossRef]
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- Rahimy E, Freund KB, Larsen M, et al. Multilayered pigment epithelial detachment in neovascular age-related macular degeneration. Retina. 2014;34(7):1289–1295. doi:10.1097/IAE.0000000000000130 [CrossRef]