Pathophysiology, screening and treatment of ROP: A multi-disciplinary perspective

Abstract

The population of infants at risk for retinopathy of prematurity (ROP) varies by world region; in countries with well developed neonatal intensive care services, the highest risk infants are those born at less than 28 weeks gestational age (GA) and less than 1 kg at birth, while, in regions where many aspects of neonatal intensive and ophthalmological care are not routinely available, more mature infants up to 2000 g at birth and 37 weeks GA are also at risk for severe ROP. Treatment options for both groups of patients include standard retinal laser photocoagulation or, more recently, intravitreal anti-VEGF drugs. In addition to detection and treatment of ROP, this review highlights new opportunities created by telemedicine, where screening and diagnosis of ROP in remote locations can be undertaken by non-ophthalmologists using digital fundus cameras. The ophthalmological care of the ROP infant is undertaken in the wider context of neonatal care and general wellbeing of the infant. Because of this context, this review takes a multi-disciplinary perspective with contributions from retinal vascular biologists, pediatric ophthalmologists, an epidemiologist and a neonatologist. This review highlights the latest insights regarding cellular and molecular mechanisms in the formation of the retinal vasculature in the human infant, pathogenesis of ROP, detection and treatment of severe ROP, the risks and benefits of anti-VEGF therapy, the identification of new therapies over the horizon, and the optimal neonatal care regimen for best ROP outcomes, and the benefits and pitfalls of telemedicine in the remote screening and diagnosis of ROP, all of which have the potential to improve ROP outcomes.

Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism

“…While hypoxia stimulates angiogenesis, excess oxygen suppresses VEGF and vascular growth. In preterm infants, supplemental oxygen exposure is a significant risk factor for retinopathy of prematurity, a disease associated with suppression of retinal vascular development (Chan-Ling et al, 2017; Hansen et al, 2017). As the now avascular neural retina matures, increasing its metabolic demands, VEGF is secreted by the hypoxic neuroglia giving rise to pathological neovascularization (Joyal et al, 2012, 2015; Pierce et al, 1995; Pierce et al, 1996; Scott et al, 2010; Sitaras et al, 2015; Stone et al, 1995; Weidemann et al, 2010).…”

Role of TLR4‐MAP4K4 signaling pathway in models of oxygen‐induced retinopathy

“…Premature infants are often exposed to a high oxygen environment, which disrupts the physiologic hypoxia in the developing retina and leads to abnormal structure and function of the retinal vasculature (1). Neovascularization (NV) occurs when there is an imbalance between the extent of retinal blood supply and the metabolic demands of the developing neurons (2). The newly formed blood vessels are leaky and may grow into the vitreous, leading to vision-threatening hemorrhage, scar formation, and tractional retinal detachment.…”

“…Anti-VEGF therapy is now considered as the first-line treatment for a number of retinal vascular disorders, especially in situations where laser treatment is ineffective (3,4). But there have been safety concerns about the potential side effects of anti-VEGF treatment of ROP in premature newborns (2). Anti-VEGF agents injected into the neonatal eye can enter the systemic circulation and compromise the development of the CNS or other organs (5,6).…”

“…Long-term ROP recurrence with anti-VEGF therapies has been reported (7,8), and in several clinical trials, the retinal avascular zone was found to last for a longer time in the treated eyes. Therefore, therapeutic options that can be used in conjunction with anti-VEGF monotherapy are highly desirable for ROP, and their future development will rely on further identifying the molecular basis and regulatory mechanisms of retinal aberrant angiogenesis (2).…”

“…In addition to the vascular lesions, inflammation is a key factor of ROP (2). Endothelial cells activated by ischemia can release inflammatory mediators such as cytokines and ligands for pattern recognition receptors (9).…”