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LONG-TERM FOLLOW-UP OF RETINAL PIGMENT EPITHELIUM RESTORATION AFTER A TRIPLE TEAR

Zahid, Sarwar, MD*; Dolz Marco, Rosa, MD, PhD†,‡; Freund, K. Bailey, MD*,†,‡,§

Retinal Cases and Brief Reports: January 2019 - Volume 13 - Issue 1 - p 5–9
doi: 10.1097/ICB.0000000000000530
Case Report

Purpose: To demonstrate longitudinal multimodal imaging findings in a case of neovascular age-related macular degeneration presenting with multiple retinal pigment epithelium (RPE) tears showing progressive RPE restoration.

Methods: Observational clinical case report.

Results: A 79-year-old woman diagnosed with neovascular age-related macular degeneration developed 3 consecutive RPE tears in her right eye during the course of treatment with intravitreal anti–vascular endothelial growth factor therapy. The RPE tears initially appeared hypoautofluorescent on fundus autofluorescence. Spectral domain optical coherence tomography showed contractile folds of the RPE with adjacent subretinal fluid and overlying ellipsoid zone disruption. Over an 8-year follow-up period, the RPE defects progressively resolved with a return of patchy fundus autofluorescence. Eye-tracked spectral domain optical coherence tomography showed gradual restoration of the RPE band defects over an enlarging Type 1 neovascular lesion.

Conclusion: Some RPE tears may show observable remodeling and restoration over time. These changes may be followed longitudinally with multimodal imaging, including eye-tracked spectral domain optical coherence tomography and fundus autofluorescence.

Using a multimodal imaging approach, the authors show retinal pigment epithelium restoration after a triple retinal pigment epithelium tear in an eye with neovascular age-related macular degeneration receiving continuous intravitreal anti–vascular endothelial growth factor therapy over an 8-year follow-up.

*Department of Ophthalmology, New York University Langone Medical Center, New York, New York;

Vitreous Retina Macula Consultants of New York, New York, New York;

LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, New York; and

§Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York.

Reprint requests: K. Bailey Freund, MD, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, 5th Floor, New York, NY 10022; e-mail: kbfnyf@aol.com

Supported by The Macula Foundation, Inc.

K. B. Freund: Consultant to Optovue (Fremont, CA), Genentech (South San Francisco, CA), Optos (Marlborough, MA), Bayer HealthCare (Müllerstr, Berlin), and Heidelberg Engineering (Franklin, MA) (honorarium for each). R. Dolz Marco: Research grants from Alcon, Bayer, Heidelberg Engineering, Novartis, Roche, and Thea. The remaining author has no financial/conflicting interests to disclose.

Retinal pigment epithelium (RPE) tears may occur in eyes with vascularized pigment epithelial detachment (PED) secondary to neovascular age-related macular degeneration (NVAMD).1 Retinal pigment epithelium tears may occur spontaneously or in association with treatments such as anti–vascular endothelial growth factor (anti-VEGF) therapy, thermal laser photocoagulation, and photodynamic therapy.2 Previous work has also shown the development of multiple tears in the same eye. Although some studies have shown the incidence of RPE tears associated with anti-VEGF treatment to be as high as 12% to 20%,1,3 a more recent report of 407 treatment-naive eyes reported an incidence of 7.9% at 12 months after the initiation of intravitreal anti-VEGF therapy with ranibizumab. These authors found a high risk (27%) of RPE tear in eyes with fibrovascular PEDs and a much lower risk (2.3%) in eyes with polypoidal choroidal vasculopathy.4 Larger size and height of vascularized PEDs have both been shown to convey an increased risk of RPE tears.5,6 The visual prognosis for eyes developing RPE tears depends primarily on the extent of foveal involvement.3 Continued anti-VEGF therapy after an RPE tear may help with maintenance of visual acuity.4 Previous studies have shown that RPE defects after a tear may show gradual restoration of the RPE band on spectral domain optical coherence tomography (SD-OCT) over time with partial normalization of fundus autofluorescence (FAF) within the affected area.2

Herein, we report the long-term follow-up of a patient presenting with 3 consecutive RPE tears related to Type 1 neovascularization occurring in the setting of NVAMD. Multimodal imaging showed gradual remodeling and restoration of the RPE defects. To our knowledge, this is the first report to include a quantitative FAF analysis of these changes. We review possible mechanisms related to the healing process.

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Case Report

A 79-year-old white woman with a history of NVAMD in both eyes presented to our practice with central metamorphopsia in her right eye. She had a history of open-angle glaucoma in the left eye controlled with topical brimonidine and dorzolamide. She had been treated elsewhere with a single intravitreal bevacizumab injection in her right eye 1 week before presentation. Her best-corrected visual acuity was 20/60 in her right eye and 20/30 in her left eye. The anterior segments of both eyes were unremarkable. Funduscopic examination of the right eye showed a small RPE tear inferior to the fovea (arrowheads) (Figure 1A). Spectral domain optical coherence tomography (Heidelberg Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany) demonstrated contractile folds of the RPE band inferior to the fovea. There was overlying ellipsoid zone disruption and adjacent subretinal fluid occurring in association with Type 1 neovascularization (Figure 1C). The initial PED measured 426 microns in height and 2,917 microns in width on SD-OCT. Fundus autofluorescence (Topcon TRC-50XF; Topcon America, Paramus, NJ) showed the area of the RPE tear as an area of homogeneous hypoautofluorescence (Figure 1B). She returned 4 weeks later (best-corrected visual acuity: 20/100) and was noted to have a second RPE tear superior to the fovea (Figure 1, D–F). She received a second intravitreal bevacizumab injection (1.25 mg/0.05 mL) at that time. Fluorescein angiography (Topcon TRC-50XF; Topcon America) showed hyperfluorescence in areas of RPE loss with central irregular hypofluorescence and hyperfluorescence corresponding to the redundant RPE and Type 1 neovascular lesion (Figure 1E). She returned again 4 weeks later and was noted to have a third RPE tear nasal to the fovea (arrowheads) (Figure 1, G–I). Although these three areas were distinct RPE tears, their locations circumferentially surrounding the initial PED suggested that they were part of a continuous process.

Fig. 1

Fig. 1

Over the course of several months, SD-OCT showed gradual restoration of the RPE band in all 3 areas (Figure 2). Clinical examination continued to show hypopigmentation in the areas of the previous RPE defects (Figure 3A). There was an incomplete return of FAF in the areas (Figure 3C) that remained relatively hypoautofluorescent when compared with similar areas in the fellow eye (Figure 3D). Quantitative FAF confirmed an overall reduction in FAF throughout the macula compared with the left eye, particularly in the areas corresponding to the previous RPE defects (Figure 3, E and F). However, some areas appeared to have recovered a normal level of FAF. In particular, using the Delori pattern overlay, the quantitative FAF values for the fovea were 59.27 in the right eye and 51.30 in the left eye. The quadrants surrounding the fovea in the right eye demonstrated a lower average autofluorescence (parafoveal 4 quadrant average: 113.16; inner 8 quadrant average: 180.54) compared with the left eye (parafoveal 4 quadrant average: 170.32; inner 8 quadrant average: 267.25).

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Over the course of 92 months, she was treated with 2 intravitreal injections of bevacizumab (1.25 mg/0.05 mL) and 64 injections of ranibizumab (0.5 mg/0.05 mL). Her best-corrected visual acuity initially improved to 20/40 and then later to 20/30 after cataract extraction and intraocular lens placement.

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Discussion

Several pathophysiologic mechanisms have been proposed to explain the development of RPE tears in eyes with NVAMD. In addition to hydrostatic forces acting inward, contraction of neovascular tissue adherent to the undersurface of the RPE monolayer may produce a horizontal shearing force that contributes to the occurrence of a tear.7 This latter hypothesis is supported by the development of RPE tears immediately after the initiation of anti-VEGF therapy, as was seen in our patient.1 The initial PED was large in height and width, which was consistent with size parameters that conveyed the increased risk of RPE tears in previous studies.5,6 A potential mechanism for the development of the three RPE tears in this patient is that they may all have been part of the same pathophysiologic process. Because the focus of the neovascularization was centrally located within the PED, it is possible that the triple RPE tear resulted from equal contractile shearing forces directed in all directions circumferentially; the breaks increased with continued anti-VEGF therapy and stopped only after the contractile forces were relieved. There are concerns that continued treatment of eyes with RPE tears might cause additional contraction of neovascular tissue producing further distortion of the overlying retina. However, previous studies have shown a visual benefit for continued anti-VEGF treatment in eyes with fovea-sparing RPE tears. Sarraf et al1 report that eyes in which anti-VEGF injections were withheld after an RPE tear had worse visual outcomes compared with those in which treatment was continued. The benefit of continued treatment in eyes with foveal-involving RPE tears is less certain.4

Given the known risk of progressive vision loss from untreated NVAMD and8,9 a goal of at least maintaining visual acuity with further treatment, we elected to continue anti-VEGF treatment in our patient. Interestingly, she developed a third foveal-sparing RPE tear after a second injection. Fortunately, she maintained excellent visual acuity with ongoing intravitreal anti-VEGF therapy.

The spectrum of clinical outcomes after an RPE tear is highly variable, ranging from minimal visual consequences to catastrophic submacular hemorrhages leading to fibrovascular scarring or even hemorrhagic retinal detachment. Although there have been reports describing histological analysis of surgically excised neovascular membranes from eyes having had spontaneous RPE tears,10,11 we are not aware of any clinicopathologic descriptions showing RPE restoration after an RPE tear. Thus, the exact mechanism of RPE healing is currently unknown. Based on clinical and imaging observations, a variety of RPE healing processes have been described, including RPE repopulation, RPE migration, and RPE hyperplasia. One study used SD-OCT and FAF to show examples of all three of these phenomena, including an eye showing complete self-healing after a small RPE tear.12 In our case, there appeared to be complete restoration of the hyperreflective RPE band on SD-OCT with partial normalization of FAF seen in the three distinct areas of RPE disruption. Quantitative FAF showed that these areas of presumed RPE repopulation had reduced levels of FAF compared with corresponding regions of the patient's fellow eye which had more mild nonneovascular findings (Figure 3). We did not feel that the observed FAF patterns in our case allowed us to draw meaningful conclusions regarding the precise nature of the RPE healing process that occurred.

Interestingly, structural optical coherence tomography in our patient appeared to show that the restoration of the hyperreflective RPE band developed on the surface of an enlarging Type 1 neovascular membrane. This Type 1 lesion showed its most rapid growth during the first 10 months after the occurrence of the 3 RPE tears. The lesion continued to grow slowly over an extended 7-year follow-up. During this time, the eye received continuous anti-VEGF injections approximately every 6 weeks.

In summary, our report shows the value of a multimodal imaging approach, including eye-tracked structural optical coherence tomography and FAF for documenting and studying the unusual occurrence of RPE restoration after a triple RPE tear. In future studies, serial quantitative FAF may facilitate a better understanding of whether the repair process is driven by RPE repopulation, RPE migration, or RPE hyperplasia. We hypothesize that continuous VEGF suppression may have helped to control the underlying Type 1 neovascular process, thereby facilitating RPE restoration.

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References

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Keywords:

age-related macular degeneration; multimodal imaging; retinal pigment epithelium migration; retinal pigment epithelium repopulation; retinal pigment epithelium tear; neovascularization

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