Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. 2287-2289 (doi:10.1542/peds.2006-0385)
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COMMENTARY

The Retina as a Window to the Brain in Vulnerable Neonates

Michael E. Msall, MD

University of Chicago Pritzker School of Medicine, Kennedy Mental Retardation Center, Comer Children's and LaRabida Children's Hospitals, Chicago, Illinois

Abbreviations: RLF, retrolental fibroplasia • ROP, retinopathy of prematurity • Cryo-ROP, Cryotherapy for Retinopathy of Prematurity Cooperative Group • IGF, insulin-like growth factor • PMA, postmenstrual age

Fifty years ago, Kinsey1 published the results of a cooperative study of what was then called retrolental fibroplasia (RLF) and the use of oxygen. Infants who weighed <1.5 kg and survived the first 48 hours were enrolled in this multicenter study. Of the 590 survivors who had an adequate eye examination, 533 infants had received curtailed oxygen and 53 had received routine oxygen. Of those infants who received routine oxygen, 38 (75%) had vascular changes of RLF (stage 1–3 retinopathy of prematurity [ROP]) and 12 (25%) had cicatricial RLF (stage 4–5 ROP). Among the 533 infants with curtailed oxygen, 178 had vascular changes (33%) of RLF and 35 (7%) had cicatricial RLF. This trial, sponsored by the National Society for the Prevention of Blindness and the National Institute of Neurologic Disease and Blindness, was notable for providing a multicenter clinical trial that halted the indiscriminate use of oxygen, which had been responsible for the blinding of thousands of children. This therapeutic misadventure had occurred because of medicine's ability to introduce the technology of supplemental oxygen in incubators without ways of measuring the physiologic impact on the preterm infant. At that time, there was no consistent ability to measure arterial blood gases, no uniform classification system for ROP, and limited opportunities for collaboration between neonatologists, ophthalmologists, neurodevelopmentalists, and epidemiologists.2–4 From this study, as well as the tort legal system that was quickly and vigorously pursued by the American Bar, a <40% restricted–supplemental oxygen policy was implemented in NICUs. In 1960, Avery5 demonstrated the down side of this restricted-oxygen era by showing that some infants with respiratory distress needed more oxygen than they had been receiving. Shortly thereafter, McDonald6 examined the 6- to 8-year follow-up of 1081 United Kingdom children who had weighed <1.8 kg and had been part of a Medical Research Council study. McDonald found that there was a correlation between spastic diplegic cerebral palsy syndrome and the duration of oxygen treatment in infants with respiratory distress syndrome. Those infants who received prolonged oxygen therapy had lower rates of diplegia, although the combination of respiratory distress syndrome and need for oxygen increased their risks for RLF.

Advances in neonatal medicine, developmental biology, and translational research have resulted in a new epidemic of ROP.7,8 This epidemic is associated with the increased survival of extremely low birth weight and extremely preterm infants, especially infants at the margins of viability (23–25 weeks' gestation).9–11 What is currently known is that the sickest and most immature infants have the highest risk for severe ROP and zone 1 ROP. In the Cryotherapy for Retinopathy of Prematurity (Cryo-ROP) multicenter study, infants who received cryosurgery had a decrease in unfavorable retinal structure from 44% to 26% (absolute risk reduction: 18%; 95% confidence interval: 9%–27%). However, the risk of unfavorable visual acuity in early childhood was reduced from 63% to 51% (absolute risk reduction: 12%; 95% confidence interval: 3%–21%). Overall, visual fields in the sighted eyes averaged 51° (SD: 11.8°) compared with control eyes, which averaged 58° (SD: 14.5°).12,13 However, it is in zone 1 disease that the limitations of cryosurgery were most apparent: 94% of treated infants and 88% of untreated infants had unfavorable functional vision as measured by Teller grating cards.14

Despite advances in maternal fetal medicine and respiratory, nutritional, and ophthalmologic care, understanding modifiable factors in causal pathways involved in those infants who go on to require intervention for threshold ROP is necessary. An important reason for this perspective was provided in the secondary outcome of longer-term functional status in the Cryo-ROP study.15 This analysis included both the 1063 children from the 5-center extended natural history cohort and 223 from the randomized cohort wherein children with threshold ROP were randomly assigned to receive cryosurgery. Examination of the functional status at the age of 5.5 years among children in the natural history cohort of the Cryo-ROP trial demonstrated that factors that led to decreasing the severity of ROP were associated with enhanced developmental skills in mobility, self-care, continency, and communicative-social cognitive skills. Among the 134 children with favorable visual acuity at 5.5 years, 25% had self-care, 22% had communicative-social cognitive, 5% had motor, and 5% had continency functional limitations. Among the 82 children with unfavorable visual acuity status, self-care disability occurred in 77%, communicative-social cognitive disability in 66%, continency disability in 50%, and motor disability in 43% (P < .001).

It is in this light that the article by Löfqvist et al16 (in this issue of Pediatrics) is important. In this prospective study of extremely preterm births (median gestational age: 27.6 weeks; median birth weight: 935 g), the authors examined the relationship between retinal vascular growth inhibition as measured by ROP stage, brain growth as measured by sequential head circumference, and serum insulin-like growth factor 1 (IGF-1), a protein that affects the production of vascular endothelial growth factor.14 Key findings were that the infants who did not develop ROP had the least inhibition of head growth between birth and 31 weeks' postmenstrual age (PMA). Those with the most severe inhibition of head circumference had the highest rate of ROP in zone 1 and the most severe form of ROP. If a child at 31 weeks' PMA had a decrement of head circumference of 0.5 SD less than that of another child of the same gestational age, the risk of proliferative ROP doubled (ie, increased by 97%). At 31 weeks' PMA, the probability of developing severe (stage 3 or higher) is 5 times greater if mean head circumference is below –2.5 SD (<1st percentile) compared with ≥2.5 SD (>1st percentile). Specifically, an extremely preterm infant whose head circumference was <1st percentile at 31 weeks' PMA had an almost 1 in 3 chance of developing stage 3 ROP compared with 1 in 16 with a head circumference above the 1st percentile using appropriate neonatal growth charts. This occurred in a setting where the mean serum levels of IGF-1 and head circumference z score were highly correlated. It is important to note that infants with ROP and without ROP had similar protein and caloric intake.

It is to be pointed out that the research design was an observational study with a sample size of 58. However, multiple repeated measures with meticulous attention to standardized measures of growth, plotting of growth on appropriate updated charts, and systematic collection of serum IGF concurrent with ROP classification decreases the threat that these observations are merely a chance occurrence. However, this study needs confirmation as well as a priori definitions of nutritional practices and other caregiving practices that reflect current care of extremely preterm infants in other countries including the United States.

The lesson from the Löfqvist et al16 study is that ROP is not only a disorder of retinal vascular development but also a disorder of the neural retina. In the past, our ability to examine brain structure and function has been limited by our inability to understand pathways of risk and resiliency in the underdeveloped brain. Using a tape measure for brain growth is an easily obtained noninvasive assessment. Understanding the proliferate retinal switch may not only facilitate a better approach to ROP and its management but also help us understand the importance of this neurovascular switch on brain vulnerability. In this respect systematically neuroimaging children with severe ROP is essential if we are to understand this linkage. By developing models that allow us to understand the dynamics of brain and retinal growth, we can begin to see that the retinal eye is a window to the brain. We can then begin to realize the historic promise of neonatal medicine: to intervene based on principles of developmental biology, to do no harm, and to ensure long-term survival without disability.


   ACKNOWLEDGMENTS
 
Jennifer J. Park provided critical review and technical support.


   FOOTNOTES
 
Accepted Feb 7, 2006.

Address correspondence to Michael E. Msall MD, University of Chicago Pritzker School of Medicine, Kennedy Mental Retardation Center, Comer Children's and LaRabida Children's Hospitals, 5841 S Maryland Ave, MC0900, Chicago, IL 60637. E-mail: mmsall{at}peds.bsd.uchicago.edu

The author has indicated he has no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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