The Pediatric Neurotrauma Age Paradox: The Younger the Research Animal the Better, the Younger the Child the Worse?

Background: Pediatric neurotrauma is the leading cause of death and disability in children in developed nations. Age is a controversial factor in pediatric neurotrauma. The inverse prognostic relationship between pediatric and adult patients adds to the controversy: while older children have better functional outcomes e.g. higher Frankel Grade scores for spinal cord injury, and higher Glasgow Outcome Scale-Extended scores for brain injury, the opposite is typically reported for adult patients. Yet in pre-clinical neuroscience, current focus is on the higher regenerative ability of the neonatal and infancy period vs. adult animals. Thus, this age paradox of the brain/spinal cord between injured animal models and injured children is important, as it may determine whether experimental therapies developed using animal models can be translated into clinic and exert significantly beneficial effects on pediatric neurotrauma patients.

Objective: This study was done to characterize the prognostic effects of age in neonatal/infantile animal models of neurotrauma vs. in pediatric neurotrauma studies, to inform future animal studies that investigate pediatric neurotrauma pathophysiology and outcomes.

Methods: A search was performed using four health science databases (Embase, Pubmed, Scopus, Web of Science) and two clinical databases (ClinicalTrials.gov, Cochrane Library). Studies were screened against predefined inclusion criteria, namely that 1) it be pediatric-focused, or include neonatal/infantile animal models of neurotrauma, and 2) it examines age as a deterministic factor in injury outcome. A PRISMA checklist-based protocol was used for evaluating pediatric clinical studies, and an ARRIVE checklist-based protocol was used for evaluating animal injury studies for inclusion.

Results/Conclusion: While structural factors that are common to both the pediatric nervous system and infantile animal models contribute to their enhanced neuroplasticity and functional restoration, several biophysical and behavioral mechanisms appear to be behind this age paradox. These results suggest that pre-clinical studies require a more multi-faceted approach to studying pediatric neurotrauma.