Why Do We Still Rely on Ophthalmoscopy to Diagnose Retinopathy of Prematurity?

There was a time not that long ago when there was equipoise as to whether optical coherence tomography (OCT) could complement the clinical examination in a meaningful way and whether it justified the time and expense for practices focused on adult patients with retinal conditions. In 2018, OCT has become standard equipment and has a critical role in the diagnosis and monitoring of many vitreoretinal diseases. The recent development of OCT angiography (OCTA) may further enhance clinical care. Management paradigms based on OCT have become standard of care for neovascular age-related macular degeneration and diabetic macular edema, 2 of the leading causes of blindness and vision impairment in adults. However, OCT has yet to become mainstream in the management of pediatric vitreoretinal diseases. Even in the most common pediatric retinal disease, retinopathy of prematurity (ROP), the use of imaging technologies generally and OCT and OCTA in particular lags behind adult diseases, despite compelling evidence that these technologies could improve our clinical care.^1,2

Clinical trials have defined the severity of disease at which treatment benefits outweigh the risks for patients with ROP.³ However, we know that (1) expert examiners often disagree on disease severity and treatment decisions for the same patient,^3,4 (2) even with standard of care management some babies progress to retinal detachment and blindness, and (3) visual outcomes are variable after ROP resolution even in those patients who have good anatomic (ophthalmoscopic) outcomes.³ Optical coherence tomography has the potential to help us better understand and potentially improve all 3 of these challenges. First, recent studies have demonstrated that there are structural changes on OCT that correlate with severe ROP.^5,6 These studies suggest that objective OCT-based biomarkers of disease severity could be used to diagnose zone, stage, and the presence of plus disease and to monitor disease progression. Second, OCT and OCTA could identify the earliest structural and angiographic signs preceding disease progression to advanced stages of ROP, such as early vitreoretinal traction preceding retinal detachment, potentially leading to earlier intervention.^6,7 Third, we have learned in the last few years that the foveal contour and foveal avascular zone fails to develop normally in severe ROP, which correlates with reduce visual acuity, and cystoid macular edema develops in some preterm infants with ROP for unclear reasons; neither of these is fully understood or can be observed or studied ophthalmoscopically.²

To better understand the role OCT may play in the diagnosis and treatment of ROP, we need more studies like the one performed by Zepeda et al⁸ in this issue of JAMA Ophthalmology. In this study, the authors used a Bioptigen portable OCT (Leica) and prospectively evaluated a cohort of patients during routine ROP screening, focusing on changes in the vitreous. As motivation, the authors highlight the role that the vitreous plays in severe ROP and suggest that the OCT may be able to detect vitreous organization and traction leading to retinal detachment analogously to other proliferative retinopathies. In the cohort of 65 patients (209 examinations), the authors found unilateral associations between vitreous bands (hyper-reflective lines in the vitreous) and the presence of cystoid macular edema and epiretinal membranes. Interestingly, however, the vitreous findings were not associated with overall ROP severity, plus disease, or type 1 ROP (requiring treatment), and there were no retinal detachments in this small cohort of patients.

Like many novel studies, the findings in Zepeda et al⁸ raise as many questions as they answer. Fundamentally, when evaluating the importance of a new finding, such as linear reflections from the vitreous, we have to ask the following questions: Is the finding (1) reproducible, (2) normal or abnormal, and (3) clinically relevant (if abnormal)? First, the authors demonstrated that the interpretation of the images is fairly consistent between masked examiners, but it would be helpful in future studies to explore how dependent the finding is on factors such as signal quality, dilation, and imaging technique. Second, as the authors point out, there is a dearth of experience for what constitutes normal vitreous OCT findings in the studied population. To bolster the case for the importance of these findings, it would be helpful to study a number of normal neonates to demonstrate the absence of the same findings in eyes without ROP. Third, it is intriguing that this finding had no correlation with vitreous haze on examination, stage 3 ROP, or plus disease; this is a negative finding that, as the authors recommend, clearly calls for more contemplation and subsequent study. It may also be helpful to standardize the timing of the examination based on postmenstrual age (because ROP evolves in a fairly predictable course over time), as well as the specific region of imaging on the retina. The finding of hyaloidal organization would presumably be most apparent and relevant in association with higher stages of disease, which are typically not captured on a macular scan. The association of vitreous bands with epiretinal membranes and cystoid macular edema is also interesting and bears further study. It is plausible that these eyes may have something different about them that highlights the vitreous organization more than eyes without epiretinal membranes or cystoid macular edema, even if the relationship is not causal. Thus, the article generates a number of testable hypotheses for future studies.

It remains possible to provide the standard of care for ROP without OCT, but perhaps the time is right for a new standard of care in treatment of children with retinal disease. Barely more than a decade ago, the relatively rapid adoption of OCT into standard clinical practice for adults coincided with the development of vascular endothelial growth factor antagonists. Together, OCT-based management paradigms continue to evolve for the most common retinal diseases in adults, and have made both OCT and vascular endothelial growth factor antagonists indispensable to caring for our patients. It may take a similar therapeutic transition in ROP to clearly demonstrate how the additional structural and angiographic detail from OCT and OCTA can lead to novel (and/or earlier) therapeutic interventions that result in improved anatomic and visual outcomes for these patients. All things considered, it seems clear that the routine use of OCT in ROP could (1) provide more objective disease staging, (2) improve the sensitivity of detection and quantification of stage 3 disease and earlier detection of the tractional changes leading to retinal detachment, and (3) illustrate subclinical structural and angiographic changes that may lead to an improved understanding of ROP pathophysiology. For now, more studies like Zepeda et al⁸ are needed to determine not only how OCT provides a more complete view of the vitreoretinal interface changes in ROP but ultimately how this information translates into improved outcomes for these infants.