Three-dimensional pattern of extraretinal neovascular development in retinopathy of prematurity

Abstract

Background: The application of three-dimensional (3D) visualization techniques to evaluate the earliest visible onset of abnormal retinal vascular development in preterm infants with retinopathy of prematurity (ROP), using bedside non-contact optical coherence tomography (OCT) imaging to characterize morphology and sequential structural changes of abnormal extraretinal neovascularization.

Methods: Thirty-one preterm infants undergoing routine ROP screening with written informed consent for research imaging were enrolled in this prospective observational study. We imaged the macula and temporal periphery of preterm infants using a handheld OCT system (Envisu 2300 or handheld swept-source research system). The scans obtained were segmented and, using enhanced ray casting, were converted to 3D volumes to which color filter was applied.

Results: Using colorized 3D visualization, we defined extraretinal neovascular structures as buds, bridging networks, and placoid lesions. We could longitudinally follow progression and regression of extraretinal neovascularization in stage 3 ROP after treatment in one infant over 12 weeks and document the appearance of early buds, and formation of florid neovascularization. From stages 2 to 3 ROP, we observed progression from sessile buds to a complex plaque that corresponded to stage 3 ROP on clinical examination. We demonstrated regression of neovascular complexes to small pre-retinal tufts after treatment with anti-VEGF.

Conclusions: The extension of OCT processing to include surface flattening and colorization that further improved structural analysis rendered better understanding of extraretinal tissue. Our ability to image similar areas in the same infant over multiple visits enabled us to study the evolution of these structural components and follow pathological vascular events longitudinally in development and regression after treatment. These methods can be applied to further study which are likely contribute to our understanding of the pathophysiology of neovascularization in ROP.

Keywords: 3D; OCT; Optical coherence tomography; ROP; Retinopathy of prematurity; Visualization.

Conflict of interest statement

Conflict of Interest: Dr. Toth receives royalties through her university from Alcon. Dr. Izatt has a patent and receives royalties from Leica Microsystems. No other authors have financial disclosures. No authors have a proprietary interest in the current study.

Figures

Figure 1:

Colorized three-dimensional (3D) and B-scan visualization of different types of buds (red arrows) found in stage 2 and above retinopathy of prematurity. a, b show dome-shaped, rounded sessile buds arising directly from the retinal surface and extending into the vitreous cavity. c, d show pedunculated buds that appear to arise on a thin delicate stalk at the lower end close to the retinal surface.

Figure 2:

En face view (a), three-dimensional (3D) volume (b), B-scan (c) and colorized 3D volume (d): of the neovascularization and avascular retina at the vascular-avascular junction. The 3D volume shows vascular elevations along dilated retinal blood vessels (red arrows) and bridging into extraretinal neovascular networks. The B-scans demonstrate avascular retina (dotted red line) and the vascular elevations (blue line) indicated on the en face and 3D view. Colorized 3D volume demonstrates the elevation of extraretinal tissue from the retinal surface with red indicating maximum elevation and blue indicating the retinal surface.

Figure 3:

Representative optical coherence tomography colorized three-dimensional (3D) volumes of a preterm infant with zone I stage 3 retinopathy of prematurity, prior to (a) and three weeks after (b) intravitreal bevacizumab injection. The yellow arrows in a indicating extraretinal neovascular tissue is seen regressing three weeks later.

Figure 4:

Colorized, three-dimensional, swept-source optical coherence tomography volumes of the posterior retina of a preterm infant with recurrent neovascularization over time. (a) 8 weeks after anti-VEGF at 41 weeks PMA residual tufts of neovascular tissue are visualized at the macula and along the superior arcade (yellow arrows) (b) at 43 weeks PMA shows increased vascular elevation, minimal change in the tufted lesion, and a mild increase in existing buds (yellow arrows) (c) at 45 weeks shows recurrent neovascularization. The number of buds increases dramatically (yellow arrows) and they are present over large and small blood vessels, appearing coalesced in parts of the superior arcade. The previously tufted area adjacent to the fovea developed into a placoid lesion with a prominent feeding vessel. The infant was treated with bevacizumab and follow-up imaging (d) was performed at 48 weeks showing interval regression in buds, placoid lesion and vascular elevation. All volumes are imaged with 100 b-scans per volume, except (c) which has 1,000 b-scans per volume.

Figure 5:

Colorized three-dimensional swept-source optical coherence tomography volumes of the temporal retina of a preterm infant followed over time. (a) at 33 weeks postmenstrual age (PMA) and stage 0 retinopathy of prematurity (ROP), the retina appears as a bland surface with no apparent extraretinal tissue or vessel elevation; (b) at 35 weeks PMA and stage 2 ROP, the retina appears similar to (a); (c) at 37 weeks PMA and stage 2 ROP shows the appearance of a single sessile bud; (d) represents another area of the temporal retina at 37 weeks, showing numerous small and large buds, both sessile and pedunculated type either found isolated or in clusters; ( e) at 39 weeks PMA and stage 3 ROP with pre-plus demonstrates vessel elevation and multiple buds coalescing to form a network and a placoid lesion; (f) at 40 weeks PMA and stage 3 ROP with pre-plus disease, demonstrates further increase in the elevation of the placoid lesion as indicated by the red color on the colorized volume, when compared to the previous week, along with vessel elevation and presence of multiple buds.

Figure 6:

Colorized three-dimensional (3D) swept-source optical coherence tomography volumes and B-scans of the temporal retina at a similar location (Supplementary figure 1) imaged at 37, 39 and 40 weeks PMA of a preterm infant. The white arrows in a,c,e, show buds followed over the three imaging timepoints. The buds are seen progressing from two small isolated sessile buds at 37 weeks to two pedunculated buds, clustered together, to nearly a bridging network at 40 weeks that appear to be more elevated when compared to the previous weeks. The yellow hollow arrows in b,d,f indicate the position of the buds on the 3D volume and their corresponding B-scan. The white line across the B-scan in (d) is an artifact from imaging. Imaging at 37 weeks (a, b) show the presence of early buds and extraretinal tissue at the ridge. The buds are mildly elevated at 39 weeks (c, d) with the presence of multiple sessile and pedunculated buds forming a network and moderately elevated early placoid lesion. Retinal vessel elevation is clearly evident and the retinal vessels are seen feeding into the extraretinal neovascular lesions in (d). Imaging at 40 weeks (e, f) shows further elevation of the extraretinal neovascular placoid lesion, with retinal vessels feeding into the placoid lesion and new posterior pedunculated buds when compared to 39 weeks.