Prediction Models for Neurocognitive Outcome of Mild Traumatic Brain Injury in Children: A Systematic Review.

Mild traumatic brain injury (mTBI) is highly prevalent in children. Recent literature suggests that children with mTBI are at considerable risk of persisting neurocognitive deficits, threatening post-injury child development. Nevertheless, clinical tools for early identification of children at risk are currently not available. This systematic review aims to describe the available literature on neurocognitive outcome prediction models in children with mTBI. Findings are highly relevant for early identification of children at risk of persistent neurocognitive deficits, allowing targeted treatment of these children to optimize recovery. The electronic literature search was conducted in PubMed, EMBASE, CINAHL, Cochrane, PsychINFO and Web of Science on February 9, 2022. We included all studies with multi-variate models for neurocognitive outcome based on original data from only children (age <18 years) with mTBI. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, two authors independently performed data extraction and risk of bias analysis using the Prediction model Risk of Bias Assessment Tool (PROBAST). This systematic review identified eight original studies (nine articles) reporting prediction models for neurocognitive outcome, representing a total of 1033 children diagnosed with mTBI (mean age at injury = 10.5 years, 37.6% girls). Neurocognitive outcome assessment took place between 1 month and 7 years post-injury. Models were identified with significant predictive value for the following outcomes: memory, working memory, inhibition, processing speed, and general neurocognitive functioning. Prediction performance of these models varied greatly between weak and substantial (R2 = 10.0%-54.7%). The best performing model was based on demographic and pre-morbid risk factors in conjunction with a subacute neurocognitive screening to predict the presence of a deficit in general neurocognitive functioning at 12 months post-injury. This systematic review reflects the absence of robust prediction models for neurocognitive outcome of children with mTBI. The findings indicate that demographic factors, pre-morbid factors as well as acute and subacute clinical factors have relevance for neurocognitive outcome. Based on the available evidence, evaluation of demographic and pre-morbid risk factors in conjunction with a subacute neurocognitive screening may have the best potential to predict neurocognitive outcome in children with mTBI. The findings underline the importance of future research contributing to early identification of children at risk of persisting neurocognitive deficits.

Resting-state network organisation in children with traumatic brain injury.

Children with traumatic brain injury are at risk of neurocognitive and behavioural impairment. Although there is evidence for abnormal brain activity in resting-state networks after TBI, the role of resting-state network organisation in paediatric TBI outcome remains poorly understood. This study is the first to investigate the impact of paediatric TBI on resting-state network organisation using graph theory, and its relevance for functional outcome. Participants were 8-14 years and included children with (i) mild TBI and risk factors for complicated TBI (mildRF+, n = 20), (ii) moderate/severe TBI (n = 15), and (iii) trauma control injuries (n = 27). Children underwent resting-state functional magnetic resonance imaging (fMRI), neurocognitive testing, and behavioural assessment at 2.8 years post-injury. Graph theory was applied to fMRI timeseries to evaluate the impact of TBI on global and local organisation of the resting-state network, and relevance for neurocognitive and behavioural functioning. Children with TBI showed atypical global network organisation as compared to the trauma control group, reflected by lower modularity (mildRF + TBI and moderate/severe TBI), higher smallworldness (mildRF + TBI) and lower assortativity (moderate/severe TBI ps < .04, Cohen's ds: > .6). Regarding local network organisation, the relative importance of hub regions in the network did not differ between groups. Regression analyses showed relationships between global as well as local network parameters with neurocognitive functioning (i.e., working memory, memory encoding; R2 = 23.3 - 38.5%) and behavioural functioning (i.e., externalising problems, R2 = 36.1%). Findings indicate the impact of TBI on global functional network organisation, and the relevance of both global and local network organisation for long-term neurocognitive and behavioural outcome after paediatric TBI. The results suggest potential prognostic value of resting-state network organisation for outcome after paediatric TBI.

Towards PErsonalised PRognosis for children with traumatic brain injury: the PEPR study protocol.

INTRODUCTION: Traumatic brain injury (TBI) in children can be associated with poor outcome in crucial functional domains, including motor, neurocognitive and behavioural functioning. However, outcome varies between patients and is mediated by complex interplay between demographic factors, premorbid functioning and (sub)acute clinical characteristics. At present, methods to understand let alone predict outcome on the basis of these variables are lacking, which contributes to unnecessary follow-up as well as undetected impairments in children. Therefore, this study aims to develop prognostic models for the individual outcome of children with TBI in a range of important developmental domains. In addition, the potential added value of advanced neuroimaging data and the use of machine learning algorithms in the development of prognostic models will be assessed. METHODS AND ANALYSIS: 210 children aged 4-18 years diagnosed with mild-to-severe TBI will be prospectively recruited from a research network of Dutch hospitals. They will be matched 2:1 to a control group of neurologically healthy children (n=105). Predictors in the model will include demographic, premorbid and clinical measures prospectively registered from the TBI hospital admission onwards as well as MRI metrics assessed at 1 month post-injury. Outcome measures of the prognostic models are (1) motor functioning, (2) intelligence, (3) behavioural functioning and (4) school performance, all assessed at 6 months post-injury. ETHICS AND DISSEMINATION: Ethics has been obtained from the Medical Ethical Board of the Amsterdam UMC (location AMC). Findings of our multicentre prospective study will enable clinicians to identify TBI children at risk and aim towards a personalised prognosis. Lastly, findings will be submitted for publication in open access, international and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL71283.018.19 and NL9051.