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Retinal pigment epithelium apertures associated with subretinal fluid and acquired vitellifom lesions in non-neovascular age-related macular degeneration

Published:November 03, 2021DOI:https://doi.org/10.1016/j.jcjo.2021.09.013
      Classic features of non-neovascular age-related macular degeneration (AMD) include drusen, drusenoid retinal pigment epithelial (RPE) detachment, and RPE atrophy. More recent studies have shown that intra- and subretinal fluid also may complicate the non-neovascular form of AMD.
      • Hilely A
      • Au A
      • Freund KB
      • et al.
      Non-neovascular age-related macular degeneration with subretinal fluid.
      RPE aperture has been described as an atypical feature of eyes with non-neovascular AMD. Querques et al.
      • Querques G
      • Capuano V
      • Costanzo E
      • et al.
      Retinal pigment epithelium aperture: a previously unreported finding in the evolution of avascular pigment epithelium detachment.
      studied 10 eyes, most with drusenoid pigment epithelial detachment (PED) that developed such RPE defects. Similarly, Giannakaki-Zimmermann et al.
      • Giannakaki-Zimmermann H
      • Querques G
      • Munch IC
      • et al.
      Atypical retinal pigment epithelial defects with retained photoreceptor layers: a so far disregarded finding in age related macular degeneration.
      reported 7 eyes with apertures, of which 4 displayed drusenoid PED, whereas Yoshinaga et al.
      • Yoshinaga A
      • Ueda K
      • Terao R
      • Azuma K
      • Inoue T
      • Obata R.
      Clinical features of cases with retinal pigment epithelium aperture.
      studied 5 cases of RPE defect all associated with drusenoid PED.
      In this correspondence, we describe 7 cases of RPE aperture that developed in eyes with acquired vitelliform lesions and subretinal fluid in the absence of drusenoid PED at the time of presentation. In this retrospective case series, eyes with RPE aperture associated with subretinal fluid (SRF) secondary to non-neovascular AMD were captured. The study was approved by the institutional ethics committee and adhered to the tenets of Declaration of Helsinki. Inclusion criteria were age greater than 55 years, presence of classic features of non-neovascular AMD including macular drusen and/or outer retina and RPE atrophy associated with an RPE aperture, and the absence of macular neovascularization (MNV) with multimodal imaging including optical coherence tomography (OCT; Spectralis, Heidelberg Engineering, Heidelberg, Germany, or Avanti, Optovue, Calif.), OCT angiography (Spectralis, Heidelberg Engineering or Avanti), and fluorescein angiography (Heidelberg Retina Angiograph, Heidelberg Engineering). Eyes with retinochoroidal disorders other than AMD were excluded. RPE aperture was defined as an abrupt discontinuity of the RPE with a preserved overlying ellipsoid zone and external limiting membrane in the absence of retracted or scrolled RPE suggestive of an RPE tear.
      Seven eyes of 7 patients including 3 males and 4 females with an age range of 64–87 years were included. Table 1 summarizes the demographics and imaging findings. Best-corrected (Snellen) visual acuity was 20/32–20/100. Follow-up visits were available for 5 eyes. The visual acuity decreased in 3 eyes and remained stable in 2 other eyes. MNV was not detected at any of the baseline or follow-up visits.
      Table 1Patient Demographics and Imaging Characteristics of Eyes with RPE Defect Secondary to Non-neovascular AMD
      CaseAge, ySexIntravitreal injection before defectBCVA before defectBCVA at defectBCVA finalFollow-up after defect, moDrusenRPE atrophyIntraretinal HRFVitelliform depositionChoroidal thicknessFellow eye findings
      173FIVB20/10020/20024YesNoYesYes278Drusen, PED
      270MIVB20/10020/10020/20012YesNoYesYes290Drusen
      378MNo20/10020/1003YesYesYesYes299Drusen, PED, cRORA
      475FNo20/3220/4020/4012YesNoYesYes250None
      587MNo20/32YesYesYesYes268SRF, no MNV, iRORA
      685FNo20/40YesNoYesNo150Drusen, cRORA
      764FIVR20/3220/10020/40015YesNoYesYes352Drusen, PED
      RPE, retinal pigment epithelial; AMD, age-related macular degeneration; BCVA, best corrected visual acuity; HRF, hyper-reflective foci; F, female; M, male; IVB, intravitreal bevacizumab; PED, pigment epithelial detachment; cRORA, complete retinal pigment epithelium and outer retinal atrophy; SRF, subretinal fluid; MNV, macular neovascularisation; iRORA, incomplete retinal pigment epithelium and outer retinal atrophy; IVR, intravitreal ranibizumab.
      All 7 eyes presented with RPE aperture associated with SRF and an intact overlying ellipsoid zone and external limiting membrane (Fig. 1, Fig. 2). None of the eyes displayed evidence of macular hemorrhage or MNV with clinical examination or with OCT or OCTA imaging. All eyes displayed macular drusen and evidence of intraretinal hyper-reflective foci with OCT. Six of the 7 eyes showed evidence of associated acquired vitelliform lesions. Choroidal thickness ranged from 150 to 352 µm. Typical features of non-neovascular AMD were identified in 6 fellow eyes.
      Fig 1
      Fig. 1(A) Fundus autofluorescence, (B) spectral domain optical coherence tomography, and (C, D) optical coherence tomography angiography imaging 1 year before baseline presentation in a 70-year-old man showing subretinal vitelliform material without macular neovascularization and no evidence of a drusenoid pigment epithelial detachment. (E) Fundus autofluorescence and (F) optical coherence tomography images 1 year later (i. e. baseline presentation) showing the formation of an RPE aperture associated with subretinal fluid.
      Fig 2
      Fig. 2(A) Fundus autofluorescence, (B) fluorescein angiography, (C, D) en face optical coherence tomography angiography, and (E, F) spectral domain optical coherence tomography in a 75-year-old woman showing evidence of a retinal pigment epithelium aperture associated with an acquired vitelliform lesion in the absence of a drusenoid pigment epithelial detachment. No macular neovascularization is evident with (C) outer retinal and (D) choriocapillaris en face optical coherence tomography angiography slabs.
      Three patients presented with a history of prior intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. OCT and FA images were available for these 3 eyes before injections and before the development of an RPE aperture. Two of these 3 eyes displayed drusenoid PED with vitelliform material, and the other eye exhibited an acquired vitelliform lesion. None of these eyes had evidence of MNV before anti-VEGF injections.
      In this correspondence, we describe 7 eyes with RPE aperture associated with SRF and acquired vitelliform lesion (AVLs) in the setting of non-neovascular AMD. Drusenoid PED is an invariable association of aperture formation in prior studies
      • Querques G
      • Capuano V
      • Costanzo E
      • et al.
      Retinal pigment epithelium aperture: a previously unreported finding in the evolution of avascular pigment epithelium detachment.
      • Giannakaki-Zimmermann H
      • Querques G
      • Munch IC
      • et al.
      Atypical retinal pigment epithelial defects with retained photoreceptor layers: a so far disregarded finding in age related macular degeneration.
      • Yoshinaga A
      • Ueda K
      • Terao R
      • Azuma K
      • Inoue T
      • Obata R.
      Clinical features of cases with retinal pigment epithelium aperture.
      but was not observed at the time of baseline presentation in this study and was noted in 2 of 7 cases with prior images. MNV was absent in all eyes using multimodal imaging. From a total of 22 reported cases of RPE aperture in the literature, 19 were associated with drusenoid PED.
      • Querques G
      • Capuano V
      • Costanzo E
      • et al.
      Retinal pigment epithelium aperture: a previously unreported finding in the evolution of avascular pigment epithelium detachment.
      • Giannakaki-Zimmermann H
      • Querques G
      • Munch IC
      • et al.
      Atypical retinal pigment epithelial defects with retained photoreceptor layers: a so far disregarded finding in age related macular degeneration.
      • Yoshinaga A
      • Ueda K
      • Terao R
      • Azuma K
      • Inoue T
      • Obata R.
      Clinical features of cases with retinal pigment epithelium aperture.
      The exact mechanism of development of this characteristic RPE defect is not clear. Querques et al.
      • Querques G
      • Capuano V
      • Costanzo E
      • et al.
      Retinal pigment epithelium aperture: a previously unreported finding in the evolution of avascular pigment epithelium detachment.
      suggested that drusen regression in the context of drusenoid PED results in a sharply demarcated area of round RPE atrophy. In this study, AVL, not drusenoid PED, was the typical lesion type associated with the development of RPE aperture, although it is possible that drusenoid PED was present in these eyes predating patient baseline visits. AVL is a known risk factor for the development of RPE atrophy, similar to drusenoid PED, and is an indicator or biomarker of RPE impairment and disruption.
      • Jaffe GJ
      • Chakravarthy U
      • Freund KB
      • et al.
      Imaging features associated with progression to geographic atrophy in age-related macular degeneration: classification of atrophy meeting report 5.
      Subsequent development of RPE dehiscence therefore is not a surprising finding.
      RPE apertures should be differentiated from an RPE tear. RPE tears occur most commonly in eyes with neovascular AMD and large PEDs (>500 µm in height) after anti-VEGF therapy as a result of a combination of contractile and hydrostatic forces in the vascularized PED.
      • Nagiel A
      • Freund KB
      • Spaide RF
      • Munch IC
      • Larsen M SD
      Mechanism of retinal pigment epithelium tear formation following intravitreal anti-vascular endothelial growth factor therapy revealed by spectral-domain optical coherence tomography.
      ,
      • Sarraf D
      • Joseph A
      • Rahimy E.
      Retinal pigment epithelial tears in the era of intravitreal pharmacotherapy: risk factors, pathogenesis, prognosis and treatment (an American Ophthalmological Society thesis).
      Unlike apertures that typically develop near the apex of the PED, tears develop near the base of the PED, where the contractile forces are greatest. Non-neovascular fluid, acquired vitelliform lesions, and RPE apertures are all the result of RPE dysfunction and disruption. The greatest risk of decompensation of the RPE may relate to its separation distance from the underlying choroid that supports and nourishes the overlying pigmented layer. This may explain the propensity for non-neovascular fluid, AVLs, and apertures to develop at the apex of a large drusenoid PED. The presence of AVL alone, however, is a sign of RPE impairment and a risk factor for the development of RPE aperture and/or atrophy.

      Footnotes and Disclosure

      None of the authors has any conflict of interest in the subject matter of this paper. David Sarraf has received research grants from Amgen, Boehringer, Genentech, Heidelberg, Optovue, Regeneron, and Topcon and is a consultant for Amgen, Bayer, Genentech, Iveric Bio, Novartis, and Optovue and a paid speaker for Optovue.

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