Visuopathy of Prematurity - Is Retinopathy of Prematurity just the tip of the iceberg?

Preterm birth (birth<37 weeks of gestation) occurs in 15 million children per year (11%). ~1-2% are very preterm (VP; <32 weeks) or very low birth weight (VLBW; <1500 g). There have been improvements in VP/VLBW survival in high-income countries since the 1960s. In Europe only, over 1 million survivors have reached adulthood. ROP (Retinopathy of Prematurity) explains only a small proportion of visual dysfunction in children and adults born preterm. We propose that much of the visual dysfunction in very preterm/very low birth weight survivors can be attributed to the same, inflammation-related disease spectrum. In other words, we propose that ROP might be just the tip of the iceberg of an entity we call Visuopathy of Prematurity. We postulate the existence of a spectrum of inflammation-associated changes to the retina and choroid (both cellular and vasculogenetic) and to the visual pathways in the brain that should not be considered separate from ROP, but as an overarching, inflammation-initiated entity explaining the spectrum of visual dysfunction in preterm infants better than ROP alone. The proposed VOP paradigm includes evidence from experimental work, magnetic resonance imaging (MRI) and Optical Coherence Tomography (OCT). Taken together, the data supports the notion that sustained systemic inflammation in preterm newborns might contribute to a prolonged pathogenetic process that culminates in clinical VOP, and that explains the constellation of risk factors, imaging correlates, and clinical hallmarks in this entity. In this project, our objective is to confirm the existence of VOP. We will do this by searching and defining the VOP footprint via detailed in vivo imaging of retinal and choroideal tissue, automated analyses of retina applying AI (artificial intelligence) techniques, combined with electrophysiological testing of the retinal and cerebral visual axis and association with clinical outcomes.

The novelty of this project is the idea that visual problems of preterm infants are rooted in an entity we call Visuopathy of Prematurity (VOP) that has inflammation as a major etiological pathway and of which ROP is only the visible tip of the iceberg detectable by clinical examination. We have gathered an international team of experts that will define the VOP footprint, search for its (inflammatory) antecedents in the neonatal period, and simulate interventions with the ambition to find targets that can be modified to lower the incidence of VOP. We will apply state-of-the art AI-assisted imaging analyses and international population-based follow-up studies as well as computer simulations for intervention and objective functional studies applying neurophysiology. Furthermore, we will, in individuals with VOP, develop a brain plasticity training program. Our ambition is to pinpoint the site(s) of visual system lesion in this large group of patients, predict consequences of modifying risk factors on outcome and develop a strategy for brain plasticity training. Although ambitious, the qualifications of the cross-disciplinary international expert team that we have gathered, the complementarity of their competence, and the fact that data collections, feasibility studies and ethical approvals have already been performed and obtained prior to project start, will ensure the completion of the project and make success highly likely. Implementation of results from this project will decrease prevalence and personalize treatment of VOP, personalize rehabilitation of preterm birth survivors, and provide a tool for brain plasticity training. These are outcomes that have a clear relevance and large potential impact, and will benefit this extremely vulnerable patient population of preterm infants and, thereby, society.