Purpose
To demonstrate the mechanism by which retinal pigment epithelium (RPE) tears occur in eyes with neovascular age-related macular degeneration (AMD) treated with intravitreal anti–vascular endothelial growth factor (VEGF) agents using spectral-domain optical coherence tomography (OCT).
Design
Retrospective observational case series.
Methods
OCT images of 8 eyes that developed RPE tears following the administration of intravitreal anti-VEGF agents for neovascular AMD were evaluated. Pretear and posttear images were compared in order to elucidate the mechanism by which RPE tears occur in this setting.
Results
In all eyes, pretear images revealed a vascularized pigment epithelial detachment (PED) containing hyperreflective material consistent with choroidal neovascularization (CNV). This CNV was adherent to the undersurface of the RPE and created contractile folds in the RPE contour. In 6 eyes, contractile neovascular tissue spanned the PED, causing outward bowing of the Bruch membrane and a peaked appearance to the overlying RPE monolayer. RPE tears occurred after the first anti-VEGF injection in 6 of 8 eyes. The posttear OCT images showed a discontinuity in the RPE with the CNV adherent to the retracted RPE. In all eyes, the RPE ruptured along a segment of bare RPE not in contact with the CNV or Bruch membrane.
Conclusions
Eyes with vascularized PEDs secondary to AMD may show specific OCT findings that increase the risk for RPE tear following intravitreal anti-VEGF injection. Rapid involution and contraction of neovascular tissue adherent to the undersurface of the RPE may impart a substantial contractile force that tears this already-strained tissue layer.
Although retinal pigment epithelium (RPE) tears can occur during the natural history of neovascular age-related macular degeneration (AMD), most RPE tears seen in clinical practice appear to be temporally associated with anti–vascular endothelial growth factor (VEGF) therapy in eyes with vascularized pigment epithelial detachments (PEDs). Risk factors for the development of an RPE tear following intravitreal anti-VEGF injection include maximal height, surface area, and greatest linear diameter of the baseline PED, as well as the associated presence of subretinal fluid or RPE folds.
Various mechanisms have been proposed for the development of RPE tears. Gass proposed that leakage from type 1 (sub-RPE) choroidal neovascularization (CNV) could increase hydrostatic pressure sufficient to tear the RPE. Bird implicated the RPE pumping mechanism as a major contributor to fluid accumulation within a PED and to the development of an RPE tear secondary to hydrostatic forces. Thermal contraction of CNV in the setting of laser photocoagulation was later proposed as another mechanism of tearing. More recently, various authors have attempted to explain the incidence of RPE tears in eyes shortly after treatment with intravitreal anti-VEGF therapy. Anti-VEGF therapy may cause contraction and fibrosis of the CNV, which rips the overlying RPE. Indeed, radial choroidal folds of the macula indicating traction have been documented prior to rupture of the RPE. Others have suggested that the intravitreal injection procedure could cause vitreomacular traction or rapid shifts in intraocular pressure resulting in an RPE tear. In this study, we used high-resolution spectral-domain optical coherence tomography (OCT) to provide insight into the causative mechanism of tears in the setting of anti-VEGF treatment.
Methods
This was a multicenter retrospective observational case series study that adhered to the tenets of the Declaration of Helsinki. Institutional Review Board (IRB) approval was obtained at Kaiser Permanente (IRB at Kaiser Permanente Medical Center, Woodland Hills, California, USA) and Vitreous-Retina-Macula Consultants (Western IRB, Olympia, Washington, USA). IRB approval is not granted for retrospective studies in Denmark. The authors in this study identified selected eyes with neovascular AMD that developed an RPE tear after intravitreal anti-VEGF injection and for which high-quality spectral-domain OCT scans were available. Images were analyzed before injection and after the tear had developed in each case.
The clinical histories, examination findings, and ancillary testing for these patients were collected, tabulated, and analyzed. Snellen visual acuity at baseline and at the last visit was collected for each patient. Ancillary testing included color photography, fluorescein angiography, and fundus autofluorescence imaging. Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) spectral-domain OCT, which provides high-resolution imaging of the details of the sub-RPE compartment, was employed in all eyes except for 1 pretear image obtained with the Cirrus 4000 spectral-domain OCT system (Carl Zeiss Meditec, Dublin, California, USA).
RPE tears were graded and analyzed according to the grading system published by Sarraf and associates. Briefly, tears were graded on a scale of 1-4 based on the greatest linear diameter of the tear in the vector direction of the tear and whether there was foveal involvement. Tears less than 200 μm in diameter were defined as grade 1, tears between 200 μm and 1 disc diameter were grade 2, and tears greater than 1 disc diameter were grade 3. When a grade 3 tear involved the fovea, it was classified as a grade 4 tear.
The spectral-domain OCT raster scans performed before and after the RPE tear were carefully analyzed to identify any findings illustrative of tear pathogenesis. Maximal PED height and subfoveal choroidal thickness were measured using the software installed by the respective OCT instruments’ manufacturers. The choroidal thickness in Case 3 could not be measured and was therefore not included.
Results
Eight eyes of 8 patients that developed RPE tears shortly after intravitreal anti-VEGF injection for the treatment for neovascular AMD were included in this retrospective study. The relevant clinical data for each of these 8 eyes are summarized in the Table . The median patient age was 82 (standard deviation ± 6.5) years with a median pretear Snellen visual acuity of 20/65. All eyes received at least 1 anti-VEGF injection prior to the development of an RPE tear. In all but 2 cases, the tear developed after the first anti-VEGF injection. The anti-VEGF agent used in 6 patients was ranibizumab; the other 2 patients had received bevacizumab. The median visual acuity at the time of tear diagnosis was 20/75. There were 3 grade 2 tears, 4 grade 3 tears, and 1 grade 4 tear. The subfoveal choroidal thickness measured before and after tearing was comparable (pretear mean: 223.4 ± 116.5 μm; posttear mean: 232.5 ± 83.5 μm).
| Case # | Age | Sex | Pretear Visual Acuity | Posttear Visual Acuity | Pre-tear PED Height (μm) | Tear Grade | Anti-VEGF Agent | # of Pretear Injections | Presence of Folds | Bowing of Bruch Membrane |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 77 | M | 20/70 | 20/80 | 534 | 3 | Bevacizumab | 1 | + | − |
| 2 | 72 | M | 20/30 | 20/30 | 437 | 2 | Ranibizumab | 1 | + | − |
| 3 | 85 | M | 20/200 | 20/70 | 599 | 2 | Ranibizumab | 1 | + | + |
| 4 | 90 | F | 20/200 | 20/200 | 410 | 2 | Ranibizumab | 1 | + | + |
| 5 | 84 | F | 20/200 | 20/200 | 348 | 2 | Bevacizumab | 1 | + | + |
| 6 | 72 | F | 20/30 | 20/40 | 400 | 3 | Ranibizumab | 1 | + | + |
| 7 | 80 | M | 20/30 | 20/40 | 388 | 3 | Ranibizumab | 4 | + | + |
| 8 | 84 | F | 20/60 | 20/160 | 440 | 4 | Ranibizumab | 3 | + | + |
All eyes showed a vascularized PED (average maximal height for the 8 PEDs was 444.5 ± 82.5 μm; Table ) prior to the occurrence of the RPE tear. In all 8 cases, OCT sections through the PED demonstrated hyperreflective material adherent to the posterior surface of the RPE that appeared consistent with CNV. This tissue exhibited marked variability in thickness and in its distribution along the PED, but in every case there remained a segment of bare RPE not in contact with either the CNV or Bruch membrane. Evidence of CNV contraction, as demonstrated by wrinkles, folds, and irregularity of the adherent RPE, could be identified in all 8 eyes prior to the appearance of the RPE tear ( Figures 1 and 2 ). In 6 cases, scans showed the CNV extending across the undersurface of the PED with enough apparent contractile force to induce bowing of the Bruch membrane ( Figure 3 ). This outward bowing of Bruch created a lentiform optically empty cleft between Bruch and the band of CNV, and imparted a peaked appearance to the roof of the PED. The posttear OCTs demonstrated a retracted irregular RPE contour still in contact with the hyperreflective tissue on its undersurface. The rips occurred along a segment of bare RPE near the junction of attached and detached RPE. Below we provide brief clinical histories for 3 of the cases and highlight the characteristic pretear and posttear OCT findings of all 8 cases.
Report of Cases
Case 1
A 70-year-old man presented with a visual acuity of 20/70 and a vascularized PED in the right eye ( Figure 1 , Top). Spectral-domain OCT confirmed the presence of a highly elevated PED measuring 534 μm in maximal height ( Figure 1 , Upper middle). A hyperreflective CNV complex was noted on the undersurface of the PED with evidence of contraction and irregular folding of the RPE monolayer (arrow). In addition, subretinal fluid was present at the opposite edge of the PED. Intravitreal ranibizumab was administered, and after the first injection the patient presented with vision loss (visual acuity 20/80) attributable to a grade 3 RPE tear ( Figure 1 , Lower middle). Spectral-domain OCT confirmed the presence of an RPE tear and a retracted, irregular RPE segment still adherent to the CNV ( Figure 1 , Bottom).
Case 2
A 72-year-old man presented with a PED in the right eye and a visual acuity of 20/30 ( Figure 2 , Top). Spectral-domain OCT revealed a large PED 437 μm in maximal height with extensive CNV adherent to the irregular RPE monolayer suggestive of contraction ( Figure 2 , Upper middle). This sub-RPE CNV co-localized with areas of hyperfluorescence on indocyanine green angiography, supporting the notion that this hyperreflective material contained choroidal vessels. After 1 injection of ranibizumab, a grade 2 RPE tear formed, as revealed on fundus autofluorescence imaging ( Figure 2 , Lower left), and could be seen enlarging at follow-up 2 months later ( Figure 2 , Lower right). The vision remained stable at 20/30, and the posttear OCT revealed a collapsed PED with folded, retracted RPE still attached to the underlying CNV complex ( Figure 2 , Bottom).
Case 3
An 80-year-old man presented with a large vascularized PED in the left eye and visual acuity of 20/200. Spectral-domain OCT through the highly elevated PED (maximal height, 599 μm) showed extensive type 1 CNV extending across the undersurface of the RPE monolayer ( Figure 3 , Top left). The contractile force of the CNV is apparent in the irregular folding of the RPE, the peaked appearance of the PED apex, and the outward bowing of Bruch with an associated hyporeflective cleft (asterisk). A small amount of subretinal fluid was present. After 1 injection of ranibizumab, a grade 2 RPE tear formed at the junction of the attached and detached RPE with extensive folding in the retracted RPE ( Figure 3 , Top right).
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