Title: Childhood visual impairment and abnormalities of the optic disc: clinical phenotypes and associations with early-life and genetic factors
Funder: Department of Health and Social Care

Abstract: Background In the UK, around 1 child in 500 is visually impaired/blind. Half of this blindness is due to either congenital optic nerve disorders or cerebral visual impairment (CVI). The morphology of the optic disc (OD) and thickness of the retinal nerve fibre layer (RNFL) may vary in both these conditions and therefore visualization of the OD and measurement of the RNFL using optical coherence tomography (OCT) could be used as objective tools in diagnosis or monitoring, particularly in children who are too young to give accurate subjective measures of vision. However, neither normal OD morphology, nor its relationship with visual function, is well established in children. Children born prematurely are at high risk of visual impairment, most frequently due to cerebral white matter damage, which may reduce RNFL thickness and alter the appearance of the OD in children. Early identification of ophthalmic disease maximises visual, social and educational outcomes [1] and promising protective effects have been demonstrated for a number of neonatal interventions. Early diagnosis requires identifying at-risk individuals and environmental and genetic factors may have a role in this. Aims and methods I aim to clarify what is currently known about the normal paediatric OD and RNFL, and how this differs in prematurity, by systematic review of published evidence. I aim to determine the normal parameters of the paediatric OD and examine associations between this and visual function. I will also investigate the contribution of genetics and environment (e.g. early exposures such as prematurity and maternal smoking) to this phenotype. This will be achieved through analysis of data from 5000 children in the ALSPAC cohort study including retinal photographs taken at age 12 [2]. I aim to collect new data to investigate OD appearance and visual function in a cohort of 3-4 year-olds born prematurely, a high-risk group for visual impairment. I will also use OCT to measure RNFL thickness and will investigate the impact of brain injury and environmental factors, on OD measurements, RNFL and visual function. Potential benefits Characterisation of the limits of normality in the paediatric OD will immediately help clinicians to identify children with abnormal appearances. Detailed characterization of the OD phenotype will allow further work using existing Avon Longitudinal Study of Parents and children (ALSPAC) data, which will enable assessment of the predictability of this OD morphology and its heritability. This will allow identification of how much the environment contributes and therefore the potential to intervene. Improved understanding of how OD morphology and visual function are related will enable accurate information to be given to patients regarding the importance of abnormal findings. Identification of OD characteristics that are red flags' for visual impairment will be an objective measure for identifying children who may benefit from monitoring of visual function. This will facilitate early visual intervention, such as glasses, or patching. Objective measures are particularly helpful in young, or very disabled children, because vision assessment is limited by cooperation and often only advanced impairment can be detected with confidence. Identification of early life and maternal risk factors for an abnormal OD may identify modifiable factors, and will allow targeting of future testing programs and interventions to improve visual and social outcomes. A long-term goal will be to develop OD assessment into an early bedside assessment of brain injury in preterm infants and examine the diagnostic utility of RNFL thickness for the same purpose. For NHS patients, this would mean a more complete, early picture of a neonate's visual potential and potentially reduced exposure to expensive, invasive tests.

Lay abstract: Background, Aims and Methods Problems with the optic disc (part of the eye) are a leading reason for childhood blindness, but scientists and doctors don't really know what is normal in this area in children. Through this research I will summarise what we do know, identify normal and unusual appearances and their link with vision, and see if early-life, brain injuries or genes are related to how the back of the eye looks. Around 25,000 UK children have very poor vision, or are blind. Half of this blindness is brain- or optic nerve- related. The optic nerve is a path between the eyes and the brain. The end of this nerve is called the optic disc (OD) and can be seen by looking into the eye. The OD shape may change in both brain- and optic nerve- related blindness so it is useful in diagnosing and monitoring many eye conditions. Another part of the back of the eye that can change with poor vision is the retinal nerve fibre layer (RNFL). The RNFL can be seen using a photo-like scan called an OCT (optical coherence tomography), which can be done easily in most hospitals. In adults we know what a normal OD and RNFL look like, but in children we know much less. Knowing more about the OD and RNFL in children might help us understand more about why children go blind, and help us identify children who are high-risk early, so we can help these children see better. I will systematically survey all the research that describes what children's OD and RNFL look like, and if this is different in children born early. I will then look at OD measurements from 10,000 photos of children's OD, taken as part of a world- renowned study (ALSPAC). I will use the OD measurements and measures of vision to understand more about what the OD normally looks like and how an unusual looking OD is linked to functional vision. I will also see how an unusual-looking OD, or poor vision is linked to a child's genes, or things they are exposed to, like smoking in pregnancy. Finally, I will look at the OD of a sample of premature children (a group who are high-risk for poor vision) and will measure their RNFL. I will see how these things link with vision, by measuring how well they identify pictures and see colour and contrast. I will also look at how things the children are exposed to influence how the back of their eye looks. This will particularly include brain injury, which affects lots of premature infants and is a major cause of blindness. As the children are already part of a study, I will be able to use brain scans, taken when they were born and also gene data, linked to brain injury and background information about the children to see how the OD, RNFL and vision are affected. This will be a small study to help plan a larger study in very young babies. Patient and public involvement Parents of premature children have been involved in the design of the study and will continue to advise throughout. They will particularly be involved in decisions about the practical aspects of seeing children in research clinics and informed consent. They will also advise on the wording of patient information and reports. Dissemination I will present my findings to eye specialists internationally and will work with families and charities (e.g. Bliss) to get the findings of my research to the public. This will include Twitter and Facebook and an event organized with the help of parents. Impact My research could have an early impact on care for children, as eye surgeons will know more about what the OD and RNFL are like in children, and if changes are linked to vision. Doctors and parents will know more about things that put children at risk of poor vision and it might be possible to change some of these, or look out for children who are high-risk and treat any eye problems early, or include them in trials of new treatments.Long-term, with further work, it may be possible to use these simple measures to explain why children's ODs look the way they do and to develop eye examination into an early test to detect brain injury in preterm infants. If we can estimate early what their potential for vision could be, making changes at this point might help children to see better.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EYE