MASSIVE ADVANCING NONEXUDATIVE TYPE 1 CHOROIDAL NEOVASCULARIZATION IN CTRP5 LATE-ONSET RETINAL DEGENERATION: Longitudinal Findings on Multimodal Imaging and Implications for Age-Related Macular Degeneration

Abstract

Purpose: To describe longitudinal multimodal imaging findings of nonexudative choroidal neovascularization in CTRP5 late-onset retinal degeneration.

Methods: Four patients with CTRP5-positive late-onset retinal degeneration underwent repeated ophthalmoscopic examination and multimodal imaging. All four patients (two siblings and their cousins, from a pedigree described previously) had the heterozygous S163R mutation.

Results: All four patients demonstrated large subretinal lesions in the mid-peripheral retina of both eyes. The lesions were characterized by confluent hypercyanescence with hypocyanescent borders on indocyanine green angiography, faintly visible branching vascular networks with absent/minimal leakage on fluorescein angiography, Type 1 neovascularization on optical coherence tomography angiography, and absent retinal fluid, consistent with nonexudative choroidal neovascularization. The neovascular membranes enlarged substantially over time and the birth of new membranes was observed, but all lesions remained nonexudative/minimally exudative. Without treatment, all involved retinal areas remained free of atrophy and subretinal fibrosis.

Conclusion: We report the existence of massive advancing nonexudative Type 1 choroidal neovascularization in CTRP5 late-onset retinal degeneration. These findings have implications for age-related macular degeneration. They provide a monogenic model system for studying the mechanisms underlying the distinct events of choroidal neovascularization development, enlargement, progression to exudation, and atrophy in age-related macular degeneration. They suggest that choroidal hypoperfusion precedes neovascularization and that nonexudative neovascularization may protect against atrophy.

Figure 1.

Multimodal imaging of patient 1 (OD) at age 57 years, showing asymptomatic retinal hemorrhages outside the vascular arcades, at the inferonasal border of a large, dimly visible, subretinal lesion in the superotemporal mid-peripheral retina. Multimodal imaging of this lesion was consistent with a large non-exudative type 1 choroidal neovascular membrane. A. Color fundus photography; B-D. fluorescein angiography (early, mid, and late phases), showing a faintly visible, branching vascular network with minimal leakage; E-F. near-infrared reflectance and spectral domain optical coherence tomography, showing the double-layer sign, a subretinal hemorrhage at the border, and the absence of intraretinal or subretinal fluid.

Figure 2.

Multimodal imaging of patient 1 (OS) at age 61 years, showing asymptomatic retinal hemorrhages outside the vascular arcades, at the posterior border of a large, dimly visible, subretinal lesion in the mid-peripheral retina. Multimodal imaging of this lesion was consistent with a large non-exudative type 1 choroidal neovascular membrane. A. Color fundus photography; B-C. fluorescein angiography (early and late phases), showing a faintly visible, branching vascular network with minimal leakage; D-E indocyanine green angiography (early and late phases), showing a large hypercyanescent plaque with irregular but well-demarcated edges and a hypocyanescent border; F-G. near-infrared reflectance and spectral domain optical coherence tomography, showing the double-layer sign, a subretinal hemorrhage at the border, and the absence of intraretinal or subretinal fluid.

Figure 3.

Wide-field indocyanine green angiography (late phase) in patients 1–4 (both eyes), showing multiple hypercyanescent plaques (of varying sizes, from small to massive) with irregular but well-demarcated edges and hypocyanescent borders, consistent with type 1 choroidal neovascularization. The lesions appeared most commonly in the superotemporal and inferior mid-peripheral retina, with a high degree of symmetry present between both eyes of each patient.

Figure 4.

Enlargement over time in a choroidal neovascular lesion in patient 1 (OS). Tracked near-infrared reflectance and spectral domain optical coherence tomography (OCT) (C, D, G, H, K, L), together with OCT angiography (swept-source in 2018 and 2019) (A, E, I) and indocyanine green (ICG) angiography (late phase) (B, F, J), at ages 61 (A-D), 64 (E-H), and 65 (I-L), showing enlargement over time in the furthest extent of the double-layer sign on OCT and of the choroidal neovascularization on OCT angiography and ICG angiography.

Figure 5.

Multimodal imaging of patient 2 (OD) at age 55 years, consistent with non-exudative choroidal neovascular membrane. A-C. Fluorescein angiography (early, mid, and late phases); D. color fundus photography; E-G. indocyanine green angiography (early, mid, and late phases), showing a large hypercyanescent plaque with irregular but well-demarcated edges and a hypocyanescent border

Figure 6.

Enlargement and posterior extension over time in the choroidal neovascular lesions in both eyes of patient 1. Ultrawide-field indocyanine green angiography (late phase) at ages 61 (A) and 64 (B).

Figure 7.

Plots of change in square root of choroidal neovascular membrane area over time (A) and change in distance from fovea (B), for the four eyes with frequent longitudinal data, based on wide-field (102°) indocyanine green angiography. The square root area appeared to increase monotonically and at a relatively similar rate in all eyes, with a mean rate of 0.92 mm/year. The distance from the fovea appeared to decrease monotonically and at a relatively similar rate in all eyes, with a mean rate of 0.23 mm/year. The circles indicate participant 1 and the squares indicate participant 2 (OD filled and OS unfilled).