Relationship Between Neonatal Brain Injury and Objective Measures of Head Trauma: A Case-Control Study.

BACKGROUND AND OBJECTIVES: Neonatal brain injury is a common and devastating diagnosis conferring lifelong challenges for children and families. The role of mechanical forces applied to the head, often referred to as "birth trauma," are often considered although evidence for this association is lacking. The objective of this study was to investigate the association between common types of neonatal brain injury and scalp swelling using a novel method to quantify scalp swelling as an unbiased proxy for mechanical forces applied to the head. METHODS: Case-control study using population-based, prospectively collected tertiary care center databases and healthy controls from the Human Connectome Development Project. Included were infants born 32-42 weeks gestational age and MRI in the first 9 days. Outcomes categories included healthy neonates, hypoxic ischemic encephalopathy (HIE) with or without brain injury, or stroke (ischemic or hemorrhagic). Volume of scalp swelling was objectively quantified by a novel imaging method blinded to brain injury. Variables included mode of delivery and use of instrumentation. Statistical tests included Kruskal-Wallis test, chi square, and multivariable and multinomial logistic regression. RESULTS: There were 309 infants included (55% male): 72 healthy controls, 77 HIE without brain injury on MRI, 78 HIE with brain injury, and 82 with stroke (60 ischemic, 22 hemorrhagic). Scalp swelling was present in 126 (40.8%, 95% confidence interval [CI] 35.2%-46.5%) with no difference in proportions between outcome groups. Compared to healthy controls, median volume was higher in those with HIE without brain injury (17.5 mL, 95% CI 6.8-28.2), HIE with brain injury (12.1 mL, 95% CI 5.5-18.6), but not ischemic stroke (4.7 mL, 95% CI -1.2-10.6) nor hemorrhagic stroke (8.3 mL, 95% CI -2.2-18.8). Scalp swelling was associated with instrumented delivery (OR 2.1, 95% CI 1.0-4.1), but not associated with increased odds of brain injury in those with HIE (OR 1.5, 95% CI 0.76-3.30). Scalp swelling measures were highly reliable (ICC = 0.97). DISCUSSION: "Birth trauma" quantified by scalp swelling volume was more common in infants with difficult deliveries, but not associated with greater odds of brain injury due to hypoxia or stroke. These results may help parents and practitioners to dissociate the appearance of trauma with the risk of brain injury.

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.

Identifying Genetic Susceptibility in Neonates With Hypoxic-Ischemic Encephalopathy: A Retrospective Case Series.

Neonatal hypoxic-ischemic encephalopathy is a clinical phenomenon that often results from perinatal asphyxia. To mitigate secondary neurologic injury, prompt initial assessment and diagnosis is needed to identify patients eligible for therapeutic hypothermia. However, occasionally neonates present with a clinical picture of hypoxic-ischemic encephalopathy without significant risk factors for perinatal asphyxia. We hypothesized that in patients with genetic abnormalities, the clinical manifestation of those abnormalities may overlap with hypoxic-ischemic encephalopathy criteria, potentially contributing to a causal misattribution. We reviewed 210 charts of infants meeting local protocol criteria for moderate to severe hypoxic-ischemic encephalopathy in neonatal intensive care units in Calgary, Alberta. All patients that met criteria for therapeutic hypothermia were eligible for the study. Data were collected surrounding pregnancy and birth histories, as well as any available genetic or metabolic testing including microarray, gene panels, whole-exome sequencing, and newborn metabolic screens. Twenty-eight patients had genetic testing such as microarray, whole-exome sequencing, or a gene panel, because of clinical suspicion. Ten of 28 patients had genetic mutations, including CDKL5, pyruvate dehydrogenase, CFTR, CYP21A2, ISY1, KIF1A, KCNQ2, SCN9A, MTFMT, and NPHP1. All patients lacked significant risk factors to support a moderate to severe hypoxic-ischemic encephalopathy diagnosis. Treatment was changed in 2 patients because of confirmed genetic etiology. This study demonstrates the importance of identifying genetic comorbidities as potential contributors to a hypoxic-ischemic encephalopathy phenotype in neonates. Early identification of clinical factors that support an alternate diagnosis should be considered when the patient's clinical picture is not typical of hypoxic-ischemic encephalopathy and could aid in both treatment decisions and outcome prognostication.

Neuroprotection care bundle implementation is associated with improved long-term neurodevelopmental outcomes in extremely premature infants.

OBJECTIVE: To study the impact of an evidence-based neuroprotection care (NPC) bundle on long-term neurodevelopmental impairment (NDI) in infants born extremely premature. STUDY DESIGN: An NPC bundle targeting predefined risk factors for acute brain injury in extremely preterm infants was implemented. We compared the incidence of composite outcome of death or severe neurodevelopmental impairment (sNDI) at 21 months adjusted age pre and post bundle implementation. RESULTS: Adjusting for confounding factors, NPC bundle implementation associated with a significant reduction in death or sNDI (aOR, 0.34; 95% CI 0.17-0.68; P = 0.002), mortality (aOR, 0.31; 95% CI (0.12-0.79); P = 0.015), sNDI (aOR, 0.37; 95% CI: 0.12-0.94; P = 0.039), any motor, language, or cognitive composite score <70 (aOR, 0.48; 95% CI: 0.26-0.90; P = 0.021). CONCLUSION: Implementation of NPC bundle targeting predefined risk factors is associated with a reduction in mortality or sNDI in extremely preterm infants.

Ageing is associated with maladaptive immune response and worse outcome after traumatic brain injury.

Traumatic brain injury is increasingly common in older individuals. Older age is one of the strongest predictors for poor prognosis after brain trauma, a phenomenon driven by the presence of extra-cranial comorbidities as well as pre-existent pathologies associated with cognitive impairment and brain volume loss (such as cerebrovascular disease or age-related neurodegeneration). Furthermore, ageing is associated with a dysregulated immune response, which includes attenuated responses to infection and vaccination, and a failure to resolve inflammation leading to chronic inflammatory states. In traumatic brain injury, where the immune response is imperative for the clearance of cellular debris and survey of the injured milieu, an appropriate self-limiting response is vital to promote recovery. Currently, our understanding of age-related factors that contribute to the outcome is limited; but a more complete understanding is essential for the development of tailored therapeutic strategies to mitigate the consequences of traumatic brain injury. Here we show greater functional deficits, white matter abnormalities and worse long-term outcomes in aged compared with young C57BL/6J mice after either moderate or severe traumatic brain injury. These effects are associated with altered systemic, meningeal and brain tissue immune response. Importantly, the impaired acute systemic immune response in the mice was similar to the findings observed in our clinical cohort. Traumatic brain-injured patient cohort over 70 years of age showed lower monocyte and lymphocyte counts compared with those under 45 years. In mice, traumatic brain injury was associated with alterations in peripheral immune subsets, which differed in aged compared with adult mice. There was a significant increase in transcription of immune and inflammatory genes in the meninges post-traumatic brain injury, including monocyte/leucocyte-recruiting chemokines. Immune cells were recruited to the region of the dural injury, with a significantly higher number of CD11b+ myeloid cells in aged compared with the adult mice. In brain tissue, when compared with the young adult mice, we observed a more pronounced and widespread reactive astrogliosis 1 month after trauma in aged mice, sustained by an early and persistent induction of proinflammatory astrocytic state. These findings provide important insights regarding age-related exacerbation of neurological damage after brain trauma.

Feeding during therapeutic hypothermia is safe and may improve outcomes in newborns with perinatal asphyxia.

OBJECTIVE: We assessed the impact of early enteral feeding introduction during therapeutic hypothermia on time to reach full enteral feeding (FEF) and other feeding related outcomes in infants born at ≥35 weeks gestational age and diagnosed with moderate to severe Hypoxic-Ischemic Encephalopathy. METHODS: A prospective cohort with historical control study, conducted on infants admitted to the Alberta Children's Hospital level III NICU in Calgary between January 2013 and December 2018. Infants were divided into 2 groups: (1) unfed group (UG), which was kept nil per os during the 72 h of therapeutic Hypothermia (TH), with subsequent introduction of feeding and gradual increase to FEF; (2) fed group (FG), which received feeding at 10 mL/kg/day during TH then increased gradually to FEF. Groups were compared for time to FEF and the type of milk they were being fed on discharge. Other gut related health risks such as NEC and sepsis were examined. RESULTS: During the study period, 146 infants received therapeutic hypothermia, of whom 75 in the UG and 71 in the FG. The FG compared to the UG received the first feed sooner after TH initiation (median 57 vs. 86.5 h, p < .001), reached FEF earlier (median 6 vs. 8 days, p = .012), had a higher rate of being fully fed in the first week of life (70 vs. 53%, p < .035), was kept NPO for shorter duration (median 2 vs. 4 days, p < .001), and had a higher rate of breast milk feeding at discharge (41 vs. 13%, p < .001). There were no cases of necrotizing enterocolitis or late onset sepsis in either group during the hospital stay. CONCLUSION: Minimal enteral feeding during therapeutic hypothermia appears to be safe and leads to a shorter time to FEF and higher rates of breast milk feeding at discharge.

Pearls & Oy-sters: Cerebral Abscess Secondary to Pulmonary Arteriovenous Malformation in Hereditary Hemorrhagic Telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant condition that is linked to a myriad of neurologic complications arising from vascular malformations of the brain, spinal cord, and lungs. Our case describes a previously healthy 3-year-old male who presented to hospital with fever of unknown origin and was found to have a brain abscess stemming from a pulmonary arteriovenous malformation (PAVM). This etiology was identified after a period of diagnostic delay; the medical team was suspicious for a proximal embolic source due to the presence of multiple tiny infarcts seen on MRI of the brain, but transthoracic echocardiogram and head and neck angiogram were unremarkable. Fortunately, an enhanced CT of the chest was performed, identifying a moderately sized PAVM. PAVMs are associated with intracranial abscesses due to shunting and loss of the normal filtering effects of the lung capillary bed. Impaired pulmonary filtration can permit paradoxical thromboemboli and septic microemboli to enter systemic circulation, predisposing patients with PAVMs to cerebral abscess and ischemic stroke. Screening for PAVMs with contrast-enhanced echocardiogram or enhanced CT of the chest may be considered in patients with cryptogenic brain abscess or recurrent embolic stroke of unknown origin. PAVMs are often associated with hereditary hemorrhagic telangiectasia (HHT). As many features of HHT have delayed clinical manifestation, genetic testing for HHT should be considered in all people with PAVM, even in the absence of other clinical features. In our case, genetic testing returned positive, confirming a new diagnosis of HHT type 1.

Impact of outreach education program on outcomes of neonates with hypoxic ischemic encephalopathy.

AIM: To evaluate the impact of outreach education targeting neuroprotection on outcomes of outborn infants with moderate-to-severe hypoxic ischemic encephalopathy (HIE). METHODS: A retrospective cohort study of infants admitted with moderate-to-severe HIE was conducted following the implementation of outreach education in January 2016. Key interventions were early identification and referral of infants with encephalopathy utilizing telemedicine and a centralized communication system, hands-on simulation, and interactive case discussion and dissemination of clinical management guidelines and educational resources. The association between the intervention and a composite outcome of death and/or severe brain injury on brain magnetic resonance imaging (MRI) was tested controlling for the confounding factors. RESULTS: Of 165 neonates, 37 (22.4%) died and/or had a severe brain injury. This outcome decreased from 35% (27/77) to 11% (10/88) following the implementation of outreach education (P<0.001). Eligible infants not undergoing therapeutic hypothermia within 6 hours from birth decreased from 19.5% (15/77) to 4.5% (4/88). The use of inotropes decreased from 49.3% (38/77) to 19.6% (13/88). Any core temperature below 33°C was recorded for 20/53 (38%) before and 16/78 (21%) after, while those within the target range of 33°C to 34°C at admission to a tertiary care facility increased from (15/53) 28% to (51/88) 58%. Outreach education was independently associated with decreased composite outcome of death and/or severe brain injury on MRI (adjusted odds ratio 0.2; 95% confidence interval 0.07 to 0.52). CONCLUSION: Outreach education targeting neuroprotection for infants with moderate-to-severe HIE was associated with a reduction in death and/or severe brain injury.

PURA-Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum.

BACKGROUND AND OBJECTIVES: Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. METHODS: Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. RESULTS: A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. DISCUSSION: The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Training in neonatal neurocritical care: a proposal for a hybrid model of competence by design and time-based methods.

BACKGROUND: Neonatal neurocritical care (NNCC) is a rapidly advancing field with limited fellowship training available in locally developed, non-accredited programs. A standardized survey aimed to understand the training backgrounds of individuals practicing NNCC, the structure of existing clinical NNCC services/training programs, and suggested clinical competencies for new graduates. METHODS: We developed an anonymous survey electronically sent to members of societies related to NNCC. Using the survey results as a guide, we discuss a competence by design (CBD) curriculum as a complementary approach to traditional time-based training. RESULTS: There were 82 responses to the survey from 30 countries; 95% of respondents were physicians. Thirty-one (42%) institutions reported having an NNCC service, 24 (29%) individuals reported formal NNCC training, 81% reported "significant variability" across NNCC training programs, and 88% were both in favor of standardizing training programs and pursuing formal accreditation for NNCC in the next 5 years. CONCLUSIONS: The survey results demonstrate international interest in standardizing NNCC training and development of an accreditation or certification process. We propose consideration of a CBD-type curriculum as a training approach to focus on the development of specific NNCC competencies, rather than assuming the acquisition of these competencies based on time as a surrogate. IMPACT: Continued growth and development in the field of NNCC has led to increasing need for training programs suited to meet the diverse needs of trainees from varied backgrounds. We present the results of an international survey that assessed the structure of existing training programs and the priority areas in which graduates must demonstrate competence, highlighting the combination of CBD and time-based training as one approach to address these recommendations. The survey results support interest in translating published training competencies, existing expertise, and infrastructure across centers into a standardized curriculum for NNCC including certification opportunities.

Cord Blood Cytokine Levels Correlate With Types of Placental Pathology in Extremely Preterm Infants.

Background: Placental abnormalities are associated with inflammation and have been linked to brain injury in preterm infants. We studied the relationship between placental pathology and the temporal profiles of cytokine levels in extremely pre-term infants. Study Design: We prospectively enrolled 55 extremely preterm infants born between June 2017 and July 2018. Levels of 27 cytokines were measured in blood drawn from the umbilical artery at birth and from infants at 1-3 and 21-28 days of life. Placental pathology was grouped as normal (N), inflammation (I), vasculopathy (V), or combined vasculopathy and inflammation (V+I). Results: Complete data was available from 42 patients. Cord blood median levels of cytokines differed between groups with the highest levels observed in group V+I as compared to groups N, I and V for the following: Eotaxin (p = 0.038), G-CSF (p = 0.023), IFN-γ (p = 0.002), IL-1ra (p < 0.001), IL-4 (p = 0.005), IL-8 (p = 0.010), MCP-1 (p = 0.011), and TNFα (p = 0.002). Post-hoc analysis revealed sex differences between and within the placental pathology groups. Conclusion: Specific types of placental pathology may be associated with differential cytokine profiles in extremely pre-term infants. Sampling from cord blood may help assess the pathological status of the placenta and potentially infer outcome risks for the infant.

Metabolic acidosis rather than hypo/hypercapnia in the first 72 hours of life associated with intraventricular hemorrhage in preterm neonates.

AIM: Safe limits of arterial partial pressure of carbon dioxide (PaCO2) and acidosis in premature infants are not well defined. Both respiratory and systemic illness along with center-specific ventilation strategies contribute to PaCO2 fluctuations and acid-base imbalances during the critical time period of first 72 h of life. This study evaluated the association between early blood gas parameters and intraventricular hemorrhage (IVH) in preterm infants. METHODS: This retrospective observational study included neonates with a gestational age (GA) of ≤29 wks, who had at least 7 blood gas analysis done within the first 72 h of life. By adjusting for known variables that predispose to IVH, multivariable logistic regression analysis was used to study the association of PaCO2 and acid-base measures with the risk of IVH. RESULTS: Between 2013-2016, among 272 neonates who met inclusion criteria and were assessed for IVH on cranial ultrasound within first week of life, 101 neonates [mean GA of 25 ± 1.5 wks] had IVH and 171 neonates [mean GA of 25 ± 1.6 wks] had normal scans. After adjustment for confounding variables, higher values of maximum lactate (OR = 1.18, 95% CI = 1.1-1.3, p < .0001) and maximum base deficit (OR = 1.19, 95% CI = 1.1-1.2, p < .0001) within 72 h of life increased the likelihood of any grade of IVH. However, time-weighted average PaCO2, maximum and minimum PaCO2 had no statistically significant effect on the risk of IVH. The relationship remained unchanged even when moderate-severe IVH was considered as the primary outcome. CONCLUSION: Severe metabolic acidosis rather than hypo/hypercapnia during the first 72 h of life was associated with higher odds of IVH in infants born at ≤29 wks of gestation. Future studies determining levels of PaCO2 that is safe for premature brain would need to control for the metabolic component of acidosis.

Neuroinflammation and Precision Medicine in Pediatric Neurocritical Care: Multi-Modal Monitoring of Immunometabolic Dysfunction.

The understanding of molecular biology in neurocritical care (NCC) is expanding rapidly and recognizing the important contribution of neuroinflammation, specifically changes in immunometabolism, towards pathological disease processes encountered across all illnesses in the NCC. Additionally, the importance of individualized inflammatory responses has been emphasized, acknowledging that not all individuals have the same mechanisms contributing towards their presentation. By understanding cellular processes that drive disease, we can make better personalized therapy decisions to improve patient outcomes. While the understanding of these cellular processes is evolving, the ability to measure such cellular responses at bedside to make acute care decisions is lacking. In this overview, we review cellular mechanisms involved in pathological neuroinflammation with a focus on immunometabolic dysfunction and review non-invasive bedside tools that have the potential to measure indirect and direct markers of shifts in cellular metabolism related to neuroinflammation. These tools include near-infrared spectroscopy, transcranial doppler, elastography, electroencephalography, magnetic resonance imaging and spectroscopy, and cytokine analysis. Additionally, we review the importance of genetic testing in providing information about unique metabolic profiles to guide individualized interpretation of bedside data. Together in tandem, these modalities have the potential to provide real time information and guide more informed treatment decisions.

Neuroprotection Care Bundle Implementation to Decrease Acute Brain Injury in Preterm Infants.

BACKGROUND: We assessed the impact of an evidence-based neuroprotection care bundle on the risk of brain injury in extremely preterm infants. METHODS: We implemented a neuroprotection care bundle consisting of a combination of neuroprotection interventions such as minimal handling, midline head position, deferred cord clamping, and protocolization of hemodynamic and respiratory managements. These interventions targeted risk factors for acute brain injury in extremely preterm infants (born at gestational age less than 29 weeks) during the first three days of birth. Implementation occurred in a stepwise manner, including care bundle development by a multidisciplinary care team based on previous evidence and experience, standardization of outcome assessment tools, and education. We compared the incidence of the composite outcome of acute preterm brain injury or death preimplementation and postimplementation. RESULTS: Neuroprotection care bundle implementation associated with a significant reduction in acute brain injury risk factors such as the use of inotropes (24% before, 7% after, P value < 0.001) and fluid boluses (37% before, 19% after, P value < 0.001), pneumothorax (5% before, 2% after, P value = 0.002), and opioid use (19% before, 7% after, P value < 0.001). Adjusting for confounding factors, the neuroprotection care bundle significantly reduced death or severe brain injury (adjusted odds ratio, 0.34; 95% confidence interval, 0.20 to 0.59; P value < 0.001) and severe brain injury (adjusted odds ratio, 0.31; 95% confidence interval, 0.17 to 0.58; P < 0.001). CONCLUSIONS: Implementation of neuroprotection care bundle targeting predefined risk factors is feasible and effective in reducing acute brain injury in extremely preterm infants.

Functional magnetic resonance imaging study of working memory several years after pediatric concussion.

PRIMARY OBJECTIVE: The neurophysiological effects of pediatric concussion several years after injury remain inadequately characterized. The objective of this study was to determine if a history of concussion was associated with BOLD response differences during an n-back working memory task in youth. RESEARCH DESIGN: Observational, cross-sectional. METHODS AND PROCEDURES: Participants include 52 children and adolescents (M = 15.1 years, 95%CI = 14.4-15.8, range = 9-19) with past concussion (n = 33) or orthopedic injury (OI; n = 19). Mean time since injury was 2.5 years (95%CI = 2.0-3.0). Measures included postconcussion symptom ratings, neuropsychological testing, and blood-oxygen-dependent-level (BOLD) functional magnetic resonance imaging (fMRI) during an n-back working memory task. MAIN OUTCOMES AND RESULTS: Groups did not differ on accuracy or speed during the three n-back conditions. They also did not differ in BOLD signal change for the 1- vs. 0-back or 2- vs. 0-back contrasts (controlling for task performance). CONCLUSIONS: This study does not support group differences in BOLD response during an n-back working memory task in youth who are on average 2.5 years post-concussion. The findings are encouraging from the perspective of understanding recovery after pediatric concussion.

Efficacy of Melatonin in Children With Postconcussive Symptoms: A Randomized Clinical Trial.

BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8-18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of -21 (95% confidence interval [CI]: -16 to -27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, -2 [95% CI: -13 to 6]; 10 mg melatonin, 4 [95% CI: -7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS.

Sleep Parameters and Overnight Urinary Melatonin Production in Children With Persistent Post-concussion Symptoms.

BACKGROUND: Sleep disturbance is common after a mild traumatic brain injury (mTBI) in children, yet its biology is poorly understood. We aimed to explore sleep-related problems (SRPs), sleep-activity patterns, and endogenous melatonin production in children with different recovery trajectories following mTBI. We hypothesized that children with delayed recovery would have more SRPs and abnormal sleep-activity patterns, which would correlate with lower overnight melatonin production. METHODS: In this prospective controlled cohort study, we enrolled 83 children with persistent symptoms, 26 children who had clinically recovered following mTBI, and 25 healthy controls. SRPs were evaluated using the sleep subscale of the Post-Concussion Symptom Inventory. Sleep actigraphy was performed for five to seven days at 37 (S.D. 7) days post-injury. Health-related quality of life and mood disturbance was assessed using the Child Health Questionnaire and the Behavior Assessment System for Children, respectively. Endogenous melatonin production was assessed using overnight urine collection. RESULTS: The groups were similar in age (13.9 [S.D. 2.6] years) and sex (52% female). Regression analysis demonstrated increased SRP in the symptomatic group (9.0; 95% confidence interval: 7.6, 11.1) compared with the recovered group (1.6; 95% confidence interval: 1.0, 2.4) and controls (2.0; 95% confidence intervals: 1.2, 3.2). Actigraphy parameters and urinary melatonin levels were not significantly different between groups. Neither SRPs nor actigraphy parameters correlated with anxiety and depression scores. CONCLUSIONS: Although children with persistent post-concussion symptoms reported more SRPs, this was not related to actigraphy sleep parameters or melatonin production. Further research is warranted to understand the pathophysiology of post-traumatic sleep disturbance.

Acute and Persistent Alterations of Cerebellar Inflammatory Networks and Glial Activation in a Rat Model of Pediatric Mild Traumatic Brain Injury.

Following a traumatic brain injury (TBI), inflammation is a well-documented but poorly understood phenomenon, especially at later time-points (i.e., beyond 72 h) and in brain areas outside the cortex. The cerebellum, important for motor and cognitive functioning, represents an area of the brain equally affected by TBI that is seldom evaluated despite its potential involvement in persistent deficits after injury. In the context of TBI and inflammation, most studies focus on severe TBI in adult males, with fewer studies on pediatric mild TBI in both sexes. Our study addresses this gap by profiling neurological function and cerebellar inflammation over time in the juvenile male and female rat brain following a mild, closed-head weight-drop injury (mTBI). At 24 h, 72 h, 7 days, and 21 days post-mTBI, animals were subjected to behavioral testing to evaluate TBI effects over time. Alongside behavioral deficits up to 7 days post-injury, inflammatory profiling by multi-plex enzyme-linked immunosorbent assay (ELISA) revealed increased inflammatory markers, including CXCL1, interleukin (IL)-5, and vascular endothelial growth factor alpha (VEGFα), in plasma at 24-72 h and in the cerebellum at 72 h post-injury. Network analysis of cytokines also showed increased inter-relationships between multiple mediators at all time-points, emphasizing the persistent and dynamic changes to inflammatory patterns after mTBI. Transcript levels of microglia/macrophage activation markers, including Iba1 and CX3CR1, were significantly elevated at 7 days post-TBI in both sexes, and at 21 days in females, suggesting activation of immune cells in the cerebellum. When examining the protein expression of GFAP and CX3CR1, a significant increase in CX3CR1 was noted in males at 21 days but not in females. Characterizing the evolution of cerebellar inflammation in pediatric mTBI provides insight into potential mechanisms of persistent changes that could contribute to neurological dysfunction.

Neuro-Inflammation in Pediatric Traumatic Brain Injury-from Mechanisms to Inflammatory Networks.

Compared to traumatic brain injury (TBI) in the adult population, pediatric TBI has received less research attention, despite its potential long-term impact on the lives of many children around the world. After numerous clinical trials and preclinical research studies examining various secondary mechanisms of injury, no definitive treatment has been found for pediatric TBIs of any severity. With the advent of high-throughput and high-resolution molecular biology and imaging techniques, inflammation has become an appealing target, due to its mixed effects on outcome, depending on the time point examined. In this review, we outline key mechanisms of inflammation, the contribution and interactions of the peripheral and CNS-based immune cells, and highlight knowledge gaps pertaining to inflammation in pediatric TBI. We also introduce the application of network analysis to leverage growing multivariate and non-linear inflammation data sets with the goal to gain a more comprehensive view of inflammation and develop prognostic and treatment tools in pediatric TBI.

Microstructural neuroimaging of white matter tracts in persistent post-concussion syndrome: A prospective controlled cohort study.

INTRODUCTION: Children with mild traumatic brain injury (mTBI) typically recover quickly, however approximately 15% experience persistent post-concussive symptoms (PPCS) past 3 months. The microstructural pathology associated with underlying persistent symptoms is poorly understood but is suggested to involve axonal injury to white matter tracts. Diffusion tensor imaging (DTI) can be used to visualize and characterize damage to white matter microstructure of the brain. OBJECTIVE: We aimed to investigate white matter microstructure in children with persistent concussive symptoms as compared to typically developing controls, alongside evaluating differences in white matter changes over time and how this relates to symptom recovery. METHODS: The current study is a prospective, longitudinal, controlled cohort study of children with mTBI. 104 children aged 8 to 18 years with a mTBI (72 symptomatic; 32 asymptomatic) were recruited from the Alberta Children's Hospital and compared to 20 healthy controls. Microstructural evidence of white matter injury was evaluated using DTI one month post injury and repeated 4 to 6 weeks later. Primary outcomes included fractional anisotropy and mean diffusivity of the corticospinal tracts, uncinate fasciculi, and motor fibers of the corpus callosum. Post-concussive symptoms were also measured using the Post-Concussion Symptom Inventory (PCSI) taken at both time points. RESULTS: Fractional anisotropy of the left uncinate fasciculi was lower in symptomatic children compared to controls (F(2,119) = 3.582, p = 0.031). No other significant differences were observed. CONCLUSIONS: Our findings provide evidence of microstructural injury following mTBI in children with ongoing post-concussive symptoms one month post injury. The changes were persistent 4-6 weeks later. Further longitudinal studies of white matter microstructure in PPCS will be helpful to clarify whether these white matter alterations resolve over time.