Choroidal hypoperfusion defects in retinopathy of prematurity: A new fluorescein angiographic finding

(Image Credit: AdobeStock/ondrooo)

Reviewed by Tianwei Ellen Zhou, MD, PhD

Choroidal insufficiency, characterized by various types of hypoperfusion patterns, is observed in patients with retinopathy of prematurity (ROP), according to Tianwei Ellen Zhou, MD, PhD, who was to present the data at the American Academy of Ophthalmology annual meeting in November in San Francisco, California.

Zhou also presented the data earlier this year at the annual meeting of the Canadian Ophthalmological Society in June in Québec City, Canada. She is a university lead at the Orbis Future Vision Leader program at Orbis Canada.

The retrospective case series involved infants with ROP who were treated with intravitreal bevacizumab or laser photocoagulation from 2011 to 2020 at the Hospital for Sick Children in Toronto, Canada.

“Conventionally, people think of ROP as an eye disease in the neonates, as its name suggests,” says Zhou, who is also an ophthalmology resident at the University of Toronto Department of Ophthalmology and Vision
Sciences in Canada. She notes that ROP remains the major ocular disorder of neonates worldwide.

“The traditional thinking is that only the retinal vessels are involved [in ROP], which would explain why anti-VEGF or laser therapies are used to treat it,” Zhou explains.

While the damages to the retinal vessels have been elucidated and well understood in ROP, the involvement of the choroid has not been thoroughly studied, prompting Zhou and her senior colleagues (Imaan Z. Kherani, MD; Nasrin N. Tehrani, MBBCh, MSc, FRCS Ed(Ophth), FRCSC; and Peter J. Kertes, MD, CM, FRCSC) to explore the impact on the choroid of ROP, says Zhou.

In previously published research, Zhou and colleagues used the oxygen-induced retinopathy (OIR) rodent model to study any possible impact on the choroid. They found that in the first postnatal week during OIR, choroidal degeneration commences and the choroid remains thin throughout the life of the OIR animals. Following the initial choroidal degeneration, there is an increase in the number of pleomorphic and dysfunctional retinal pigment epithelium (RPE) cells, as well as a gradual decline in photoreceptor population and function.¹

Given the findings that emerged in their research with an animal model, Zhou and colleagues sought to assess whether a similar impact on the choroid could be observed in neonates. They initially identified 118 patients with ROP and included those patients for whom intravenous fluorescein angiography (IVFA) had been conducted, leaving
79 patients. Three cases were excluded because of poor image quality and 2 were excluded because of severe phenotypes that precluded proper visualization of the choroid, leaving 74 cases for analysis.

“We use IVFA as imaging for all these patients [who] require treatments,” Zhou explains. “That is because IVFA allows us to document the treatment effects.”

The 74 infants with ROP had an average birth weight of 600.4 g and an average gestational age of 23.9 weeks. About 7 of 10 infants (69.4%) had zone 1, stage 3+ ROP, and the average age at which they underwent IVFA was 9.7 months. With respect to choroidal patterns, 64 eyes (86.5%) demonstrated multifocal areas of choroidal hypoperfusion. Four eyes showed central hypoperfusion (ie, the hypoperfused areas overlapping the macula), and 4 eyes demonstrated peripheral hypoperfusion (ie, hypoperfused areas outside of the macula). Only 2 eyes were deemed to have a normal choroidal pattern.

These study results suggest that choroidal involution is another component in OIR/ROP, according to Zhou.

“The choroid is the major blood supply to the photoreceptors, so if the choroid is thin, it cannot deliver enough oxygen and nutrients to the photoreceptors,” she says. “This is very problematic because starved photoreceptors cannot function properly, and that can impact the vision.”

Indeed, in a subsequent study, Zhou and Sylvain Chemtob, MD, described signs of premature aging in the RPE cells and photoreceptors in OIR rodents.

“By the time the OIR animals reached mid-adulthood, an equivalent to 50 years old in humans,” Zhou explains, “their RPE cells and photoreceptors were similar to those seen in patients with age-related macular degeneration. This prompted us to wonder if early insults to the choroid during infancy could precipitate a long-lasting impact throughout one’s adulthood.”²

Zhou notes her research with coinvestigators is groundbreaking because of the evidence of choroid insufficiency.

“This is the first time that choroidal insufficiency has been demonstrated in humans,” she says. “This clinical study confirms what we saw in an animal model. This is one of the handful of studies that documents choroidal hypoperfusion using IVFA in infants with ROP.”

Zhou notes she and her colleagues look forward to reading corroborating data from other researchers in the future.

“It may take time before more evidence emerges because the number of ROP patients is low compared [with the number of patients with] other retinal conditions, such as AMD or diabetic retinopathy,” Zhou says.

Because the doses of intravitreal anti-
VEGF medications used in patients with ROP are very low, it is very unlikely that anti-VEGF agents like bevacizumab and ranibizumab are affecting the choroid, says Zhou.

“After all, the OIR/ROP animals that exhibited choroidal thinning did not receive any anti-VEGF medication at all,” Zhou adds.

To date, this is the largest IVFA series that systematically describes choroidal hypoperfusion in ROP patients, notes Zhou.

“This study provided valuable clinical
data to support a finding first demonstrated in an animal model of ROP,” she concludes. “It also reminds us that ROP can be a
disease that affects both the retinal and choroidal vasculatures.”

Tianwei Ellen Zhou, MD, PhD

E: ellen.zhou@umontreal.ca

This article is based on a planned presentation made by Tianwei Ellen Zhou at the American Academy of Ophthalmology meeting in November in San Francisco, California, and at the annual meeting of the Canadian Ophthalmological Society in June in Québec City, Canada. Zhou has no relevant disclosures related to this content.

References:

1. Zhou TE, Rivera JC, Bhosle VK, et al. Choroidal involution is associated with a progressive degeneration of the outer retinal function in a model of retinopathy of prematurity: early role for IL-1β. Am J Pathol. 2016;186(12):3100-3116. doi:10.1016/j.ajpath.2016.08.004

2. Zhou TE, Zhu T, Rivera JC, et al. The inability of the choroid to revascularize in oxygen-induced retinopathy results from increased p53/miR-Let-7b activity. Am J Pathol. 2019;189(11):2340-2356. doi:10.1016/j.ajpath.2019.07.009