Histology of Type 3 Macular Neovascularization and Microvascular Anomalies in Treated Age-Related Macular Degeneration

Berlin, Andreas; Cabral, Diogo; Chen, Ling; Messinger, Jeffrey D.; Balaratnasingam, Chandrakumar; Mendis, Randev; Ferrara, Daniela; Freund, K. Bailey; Curcio, Christine A.

doi:10.1016/j.xops.2023.100280

Cited by 8 publications

(11 citation statements)

References 74 publications

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“…We previously illustrated smooth transitions, within single histologic sections, between in-layer RPE to out-of-layer cells with abundant RPE organelles and without ultrastructural evidence of phagolysosomes indicating prior ingestion. 7,13 Ectopic RPE cells undergo molecular transdifferentiation, exhibiting gain of immune markers (CD68 and CD163) and loss of retinoid markers (RPE65 and CRALBP) at the same morphologic transitions. 6,14 We previously correlated histology to HRF through in vivo and ex vivo OCT imaging and found that appearance of clinical HRF may be preceded by RPE layer disturbance.…”

Section: Discussionmentioning

confidence: 99%

“…As described, 7 a White, pseudophakic woman in her 90's received comprehensive ophthalmologic examination and multimodal imaging during a 5-year follow-up. The patient presented in 2014 with exudative type 3 MNV secondary to AMD in the right eye.…”

Section: Clinical Coursementioning

confidence: 99%

“…Six of seven vascular lesions were confirmed by histology in these two treated eyes. 7,8 Clinical Image Capture and Analysis; Tissue Preparation for Cellular Analysis Detailed methods are found in the Supplemental Digital Content (see e.methods, http://links.lww. com/IAE/C34).…”

Section: Clinical Coursementioning

confidence: 99%

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Inflammatory Cell Activity in Treated Neovascular Age-Related Macular Degeneration

Berlin

Messinger

Ramtohul

et al. 2023

Retina

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Background: Imaging indicators of macular neovascularization (MNV) risk can help determine patient eligibility for new treatments for geographic atrophy secondary to age-related macular degeneration (AMD). Because type 1 MNV includes inflammation, we assessed by histology the distribution of cells with inflammatory potential in two fellow eyes with AMD. Methods: Two eyes of a white woman in her 90’s with type 3 MNV treated with anti-vascular endothelial growth factor were prepared for high-resolution histology. Eye-tracked spectral-domain optical coherence tomography (OCT) applied to the preserved donor eyes linked in vivo imaging to histology. Cells were enumerated in the intraretinal, subretinal and sub-retinal pigment epithelium (RPE)-basal lamina (BL) compartments on 199 glass slides. Cells with numerous organelles were considered to RPE-derived; cells with sparse RPE organelles were considered non-RPE phagocytes. Results: Both eyes had soft drusen and abundant SDD. In the retina and subretinal space, RPE-derived cells, including hyperreflective foci, were common (n=125, 73, respectively). Non-RPE phagocytes were infrequent (n=5 in both). Over drusen, RPE morphology transitioned smoothly from the age-normal layer towards the top, suggesting transdifferentiation. The sub-RPE-BL space had RPE-derived cells (n=87) and non-RPE phagocytes (n=49), including macrophages and giant cells. Conclusions: Numerous sub-RPE-BL cells of several types are consistent with the documented presence of pro-inflammatory lipids in drusen and aged Bruch’s membrane. The relatively compartmentalized abundance of infiltrating cells suggests that drusen contents are more inflammatory than SDD, perhaps reflecting their environments. Ectopic RPE occur frequently. Some manifest as hyperreflective foci. More cells may be visible as OCT technologies evolve.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Coursementioning

confidence: 99%

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Inflammatory Cell Activity in Treated Neovascular Age-Related Macular Degeneration

Berlin

Messinger

Ramtohul

et al. 2023

Retina

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“…11 Note that lesions such as perifoveal exudative vascular anomalous complex and deep retinal age-related microvascular anomalies, that can have overlapping features with T3 MNV, were excluded on the basis of OCT and/or OCT-A evidence of extension of the neovascular lesion through the RPE. 3…”

Section: Inclusion/exclusion Criteriamentioning

confidence: 99%

“…1,2 Accompanied by activated Müller glia, the neovascular complex extends posteriorly through a defect in the retinal pigment epithelium (RPE) and causes exudation. 3,4 Type 3 macular neovascularization can be associated with various morphologic alterations and typically develops over a large druse or drusenoid pigment epithelium detachment (dPED). 5,6 Sacconi et al 7 recently showed that nascent geographic atrophy, which is an optical coherence tomography (OCT) sign preceding the development of drusen associated atrophy, was observed in 22.7% of eyes before T3 MNV development.…”

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confidence: 99%

From drusen to type 3 macular neovascularization

Bousquet,

Santina,

Corradetti

et al. 2023

Retina

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Purpose: To investigate the imaging features preceding the occurrence of type 3 (T3) macular neovascularization (MNV) using tracked spectral-domain optical coherence tomography (SD-OCT). Method: From a cohort of eyes with T3 MNV and ≥ 12 months of prior tracked SD-OCT, T3 lesions that developed above soft drusen were selected for OCT analysis. Retinal imaging findings at the location where type T3 MNV occurred were analyzed at each follow-up until the onset of T3 MNV. The following OCT parameters were assessed: drusen size (height and width), outer nuclear layer (ONL)/ Henle fiber layer (HFL) thickness at the drusen apex, and the presence of intraretinal hyperreflective foci (HRF), retinal pigment epithelium (RPE) disruption, incomplete RPE and outer retina atrophy (iRORA), and complete RORA (cRORA). Results: From a cohort of 31 eyes with T3 MNV, T3 lesions developed above soft drusen in 20 eyes (64.5%). Drusen showed progressive growth (p<0.001) associated with ONL/HFL (p<0.001) thinning prior to T3 MNV. The following OCT features were identified preceding the occurrence of T3 MNV, typically at the apex of the drusenoid lesion: disruption of the external limiting membrane (ELM)/ellipsoid zone (EZ) and/or the RPE, HRF, and iRORA/cRORA. Conclusion: Our results demonstrate specific anatomic alterations preceding the occurrence of T3 MNV that most commonly originates above soft drusen. Drusen growth, reduced ONL/HFL thickness, and RPE atrophy at the drusen apex precede the development of T3 MNV. Identifying these OCT features should warrant close monitoring for identification of T3 MNV which can benefit from prompt intravitreal anti-VEGF therapy.

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The potential key role of choroidal non-perfusion and rod degeneration in the pathogenesis of macular neovascularization type 3

Haj Najeeb,

Schmidt-Erfurth

2024

Eye

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Macular neovascularization type 3 (MNV3) is a multifactorial disease with distinct epidemiological, clinical, pathomorphological and topographical characteristics. This review of the literature discusses the latest experimental and clinical outcomes that could explain the pathogenesis of retinal neovascularization. Although patients with MNV3 are usually older than those with MNV1 or 2, their lesions do not coexist with, precede, or follow other types in the same eye. The regional distribution of MNV3 lesions is characterized as confined to the parafoveal macula without any involvement of the rod-free foveal area. Focal outer retinal atrophy and choroidal non-perfusion are the main structural features that occur prior to the development of retinal neovascularization. Also, histological and experimental studies of MNV3 and other non-neovascular age-related macular degeneration diseases complicated with MNV3-like lesions strongly suggest rod degeneration contributes to the pathogenesis. Therefore, the retinal neovascularization in MNV3 has a different pathogenesis from the choroidal neovascularization in MNV1 and 2 and emerging evidence indicates that choroidal non-prefusion and rod degeneration play a key role in the pathogenesis of MNV3. Accordingly, we suggest a sequence of pathological events that start with choroidal non-perfusion due to advanced age followed by hypoxia of the outer retina at the parafoveal area. This induces a remarkable degeneration of rods that triggers the growth of retinal neovascularization due to the imbalance of the angiogenic factors in the outer retina.

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Histology of Type 3 Macular Neovascularization and Microvascular Anomalies in Treated Age-Related Macular Degeneration

Cited by 8 publications

References 74 publications

Inflammatory Cell Activity in Treated Neovascular Age-Related Macular Degeneration

Inflammatory Cell Activity in Treated Neovascular Age-Related Macular Degeneration

From drusen to type 3 macular neovascularization

The potential key role of choroidal non-perfusion and rod degeneration in the pathogenesis of macular neovascularization type 3

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