Integrated Visualization Highlighting Retinal Changes in Retinopathy of Prematurity From 3-Dimensional Optical Coherence Tomography Data

This cross-sectional study assesses results from 3-dimensional optical coherence tomography for 2 infants to find additional objective data that can aid the diagnosis of retinopathy of prematurity.

Key Points

Question

How does integrated 3-dimensional optical coherence tomography (OCT)–based visualization aid the diagnosis of retinopathy of prematurity (ROP)?

Findings

In this cross-sectional study, the integrated OCT visualization revealed, in addition to vascular dilation and tortuosity, thinner avascular retina, delayed development of the perifoveal vasculature, and extraretinal neovascularization in an infant with type 1 ROP and macular edema in an infant without ROP.

Meaning

Three-dimensional OCT provided additional objective data not visualized on ophthalmoscopic examination in eyes of 2 preterm infants, 1 with and 1 without ROP.

Abstract

Importance

Early diagnosis of plus disease is critical in the management of retinopathy of prematurity (ROP). However, there is substantial interexpert disagreement in the diagnosis of plus disease based on vascular changes alone. Information derived from optical coherence tomography (OCT) may help characterize the severity of vascular and structural abnormalities in ROP.

Objective

To describe integrated visualization of 3-dimensional (3-D) data from investigational swept-source OCT optimized to delineate retinal vascular and microanatomical features in eyes with and without ROP.

Design, Setting, and Participants

This cross-sectional, observational report of OCT was captured in the prospective Study of Eye Imaging in Preterm Infants (BabySTEPS) designed in July 2016 at the Duke Health Intensive Care Nursery. Between December 2018 and August 2019, 2 preterm infants born at 24 and 30 weeks’ gestation were enrolled, underwent ROP screening, and were imaged at those screening visits. Data at 36 weeks’ postmenstrual age were analyzed via this visualization developed between September 2020 and May 2021.

Main Outcomes and Measures

Superimposed en face retinal vascular shadow view (RVSV) montages and thickness maps were used along with OCT B-scans to evaluate retinal vasculature and cross-section in eyes with and without ROP.

Results

In the right eyes of 2 infants, 3-D data were integrated and visualized from investigational bedside OCT imaging at the posterior pole. In the infant who developed type 1 ROP, RVSV-OCT confirmed presence of dilated and tortuous posterior pole vessels, shunting, and incomplete perifoveal vascular development, resulting in a temporal notch of avascular retina in zone 1. The thickness map revealed irregular pockets of thickening and thinning, and integrated visualization outlined the demarcation between thicker vascularized retina and thinner avascular fovea and presence of extraretinal neovascularization overlying elevated vessels in the superior arcades. In the infant without ROP (stage 0), RVSV-OCT revealed no abnormal vascular findings at the posterior pole. The integrated visualization showed a dome-shaped retinal thickening at the fovea, which was confirmed as macular edema.

Conclusions and Relevance

In 2 preterm infants in BabySTEPS, 3-D visualization of OCT findings during the ongoing ROP disease process demonstrated supplemental information about the retinal vasculature and microanatomy that can be useful to clinicians. These additional details provided by OCT could be integrated into future ROP screening methods with artificial intelligence–based analytics.

Introduction

Retinopathy of prematurity (ROP) is caused by arrest of normal retinal vascular development and subsequent pathological neovascularization in preterm infants.¹ Indirect ophthalmoscopy is the gold standard for diagnosing and monitoring ROP, including evaluation of posterior pole blood vessels for abnormal dilation and tortuosity (ie, plus disease). However, ophthalmoscopy does not reveal changes in retinal microanatomy that may accompany these posterior pole vascular abnormalities.

The adaptation of bedside optical coherence tomography (OCT) to visualize infant retina has provided insights into in vivo development of the vascular and avascular retina, demonstrating subclinical features of ROP not visible on ophthalmoscopic examination.^1,2 Here we report a new method to simultaneously visualize 3-dimensional (3-D) vascular and retinal posterior pole structures in ROP captured with an investigational handheld, noncontact, swept-source OCT system.

Methods

This cross-sectional, observation report follows Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. Infants with written informed parental consent were enrolled and imaged between December 2018 and August 2019 under a prospective study of eye imaging in preterm infants (BabySTEPS) approved by the Duke University Health System institutional review board in July 2016 and registered with ClinicalTrials.gov (NCT02887157). The study adheres to guidelines of the Health Insurance Portability and Accountability Act and tenets of the Declaration of Helsinki. Parents were not given any incentive or compensation for participation in this study.

The infants’ eyes were pharmacologically dilated for standard-of-care clinical examination for ROP performed by 1 of 2 expert pediatric ophthalmologists who also recorded detailed ophthalmoscopic findings for this study. On the day of ROP screening, we performed research OCT imaging at bedside without sedation or use of an eyelid speculum.³ The investigational swept-source OCT system featured a 200-kHz, 1060-nm centered laser (Axsun Technologies) with a 700-g handheld, noncontact probe. We captured anisotropic 10 × 10–mm OCT volumes with 950 A-scans per B-scan, 256 B-scans per volume, and 2 B-scans acquired at each lateral location on the slow axis to allow for averaging in postprocessing.^4,5

For 3-D visualization, we incorporated en face OCT images extracted from a narrow axial window bracketed around the retinal pigment epithelium (retinal vessel shadow view [RVSV-OCT])⁶ and thickness maps generated using software optimized for automatic segmentation (DOCTRAP version 66.2). We extracted the internal limiting membrane and Bruch membrane segmentation from OCT volumes. The thickness of each A-scan location across all B-scans was calculated and standardized to 1001 × 1001–pixel matrix maps. Color intensity for thickness values was previously developed in a larger data set.^7,8,9 Because they originated from the same data volume, the RVSV-OCT and thickness maps could be manually superimposed as shown in Figure 1. Data were analyzed via this visualization developed between September 2020 and May 2021.

Figure 1. Information Extracted From Bedside Optical Coherence Tomography (OCT) Performed at 36 Weeks’ Postmenstrual Age on 2 Preterm Infants Born at 24 and 30 Weeks.

Infant 1 (A and B) developed type 1 (treatment-indicated) retinopathy of prematurity (ROP). A, OCT images showed dilated and tortuous posterior pole vessels with shunting (white arrowhead) and the vascular-avascular junction in zone 1 (black arrowheads) on the retinal vessel shadow view (RVSV-OCT). B, Images showed an avascular retina, indicated by the demarcation between the thicker vascularized retina and the thinner avascular fovea, pockets of diffuse retinal thinning, and the presence of extraretinal neovascular tissue overlying the elevated vessels in the superior arcade (black arrowhead) on the retinal thickness maps (inset) superimposed on RVSV-OCT. OCT images from infant 2 (C and D) without ROP showed a dome-shaped retinal thickening representing macular edema and no abnormal vascular findings on the thickness map (inset) superimposed on RVSV-OCT. En face RVSV-OCT images were extracted from data bracketed around the retinal pigment epithelium (A and C). The green (superior arcade) and yellow (foveal) lines indicate the location of the B-scans and the asterisks the location of the fovea (A and C). The color scale for the retinal thickness map is the same in B and D (insets); however, the transparency of the thickness map was increased in D to optimize visualization in print when superimposed on as in D.

Results

In the right eyes of 2 infants born at 24 and 30 weeks’ gestation and imaged at 36 weeks’ postmenstrual age, we highlight distinct retinal microanatomy for 1 infant who developed type 1 (treatment-indicated) ROP and another without ROP (stage 0). On clinical examination, infant 1 showed immature vascularization into anterior zone 1, with stage 2 ROP, preplus disease with shunting, and no hemorrhage and was treated with bevacizumab 3 days later. Infant 2 showed immature vascularization into anterior zone 2 and normal appearance of the posterior pole vessels with stage 0 ROP. Both infants were graded as having questionable macular edema on clinical examination.

In infant 1, RVSV-OCT confirmed the presence of dilated and tortuous posterior pole vessels, shunting from arterioles to arterioles and arterioles to venules, and incomplete perifoveal vascular development resulting in a temporal notch of avascular retina in zone 1 (Figure 1A). The thickness map (Figure 1B, inset) showed irregular retinal thickening and thinning across the retina. Together, RVSV-OCT and the superimposed thickness map provided a coherent overview of demarcation between thicker vascularized retina and thinner avascular fovea and presence of extremely thick sites of extraretinal neovascularization overlying elevated vessels in the superior arcades (Figure 1B).

In infant 2, RVSV-OCT revealed retinal vascular development beyond the macula and no shunting or vascular tortuosity (Figure 1C). The thickness map (Figure 1D, inset) demonstrated uniformed areas of thickening near the optic nerve and another smooth dome-shaped area of thickening. The integrated RVSV-OCT and thickness map visualization demonstrated absence of extraretinal neovascularization, helped localize the uniformed thickening to the arcade vessels near the optic nerve, and showed dome-shaped retinal thickening to the macula, representing macular edema (Figure 1D), a common finding in preterm infants.⁵ In both infants, findings are detailed in OCT B-scans (Figure 2), which lack the integrated overview of Figure 1.

Figure 2. Optical Coherence Tomography B-Scans in the Fovea and Superior Arcade of the Eyes of 2 Preterm Infants Born at 24 and 30 Weeks.

B-scans from infant 1 showed a thin, underdeveloped fovea (A), elevation of superior arcade vessel (white arrowhead) between 2 neovascular buds, and the presence of more extensive extraretinal neovascularization (black arrowhead) (B). B-scans from infant 2 showed cystoid spaces in the inner nuclear layer at the fovea, persistent inner retinal layers (C), and a lack of abnormal findings (ie, elevated vessels or extraretinal neovascularization) across the superior arcade (D). Asterisks indicate the locations of the foveal center.

Discussion

Merging RVSV-OCT images and retinal thickness maps, we visualized retinal vasculature and microanatomy and oriented for the user the location of ROP pathology. By removing choroidal patterns, RVSV-OCT highlighted vessel dilation and tortuosity. Retinal thickness maps, along with B-scans, revealed thinner avascular retina, delayed development of the perifoveal vasculature, and extraretinal neovascularization in infant 1 and macular edema in infant 2. This multimodal visualization of OCT findings in type 1 ROP can supplement a clinician’s perspective on retinal microanatomy during an ongoing disease process and may thereby enhance clinical management of ROP.

Although some of these visualization components such as thickness maps are available in conventional tabletop systems for adult care, adult retinal vascular disease is not treated based on grading of the dilation and tortuosity of retinal vasculature, unlike ROP. An infant with ROP is not a miniature adult, but rather a patient with a developing retina and unique morphological characteristics relevant to ROP progression and need for treatment. We postulate that visualization methods designed for preterm infant eyes as demonstrated in this Brief Report may address ROP better than an adaptation of methods developed for adult retinopathies. Furthermore, integration of these visualization components is revolutionary in infant care and may be adapted to other OCT devices in the future.

We have reported vascular characteristics using spectral-domain OCT in preterm infants with no disease, preplus disease, and plus disease and developed a Vascular Abnormality Score on OCT to quantify severity, based predominantly on cross-sectional data.¹⁰ As stated in that study, the primary goal of imaging was the macula, which limited capture of the arcades. Since then, we have modified OCT speed, the imaging protocol, and image processing with the goal of acquiring scans that provide sufficient information for the diagnosis of plus disease.⁶ The visualization reported here, by providing integrated data on the relative location of abnormalities of retinal tissue, retinal vasculature, and extraretinal neovascularization, improves researchers’ understanding of pathology based on OCT morphology and reveals indicators and associations that may be helpful in categorizing plus disease.^6,11

Conventionally, presence of plus disease in the posterior pole is an important indication for treatment in ROP.¹¹ However, there is substantial interexpert disagreement about the diagnosis of plus disease based on visualizing vascular changes alone, as preplus disease and plus disease represent a continuum of vascular abnormalities.^11,12 In this report, we demonstrate in 2 preterm infants an example of a method to visualize retinal thickness changes on OCT that are not typically visualized during ophthalmoscopic examination. Along with vascular dilation and tortuosity, this method may provide additional objective data to help characterize the severity of vascular abnormalities and identify eyes in need of treatment. Further study of longitudinal OCT findings in infants may increase understanding of ongoing changes in retinal microanatomy within the continuum of retinal vascular abnormalities.⁵

Supplement.

Members of the BabySTEPS group