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.

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.

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.

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.

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.

Sex-dependent and chronic alterations in behavior and mitochondrial function in a rat model of pediatric mild traumatic brain injury.

OBJECTIVE: To determine if chronic changes in mitochondrial function occur following a mild traumatic brain injury in young rats. RESEARCH DESIGN: Closed-head, weight drop model was used to cause mTBI by applying rotational forces to the brain without surgery. Behavioral battery was used to assess multiple dimensions of impairment across time. Analysis of brain tissue carried out at three-weeks post-injury represents a chronic time point to complement previous work examining acute time points. METHODS AND PROCEDURES: Twenty-three male and 22 female rats one month of age were divided equally into sham and mTBI groups with the latter undergoing the weight drop. Multiple behavioral tests in combination with energetic (oxygen consumption), molecular (immunoblotting), and imaging (electron microscopy) characterization of brain mitochondria were performed. MAIN OUTCOMES AND RESULTS: Mitochondria isolated from sham juvenile female rats had higher basal oxygen consumption compared to juvenile male rats (514.875 ± 171.091 pmol/min vs. 267 ± 73.906 pmol/min, p < 0.0001). Chronic sex-dependent differences were observed in females after mTBI in basal (514.875 ± 171.091 pmol/min vs. 600.688 ± 124.422 pmol/min, p = 0.0264) and maximal oxygen consumption (298.938 ± 119.964 pmol/min vs. 403.281 ± 112.922 pmol/min, p = 0.0001) and proton leak (59.46 ± 7.807 vs. 84.32 ± 5.80 pmol/min, p = 0.0001). CONCLUSIONS: The juvenile rat brain displays sex differences in mitochondrial function at (1) baseline and (2) in long-term outcomes after mTBI. These results offer new insight into a potential mechanism for persistent, individualized impairments following pediatric mTBI.

Reducing the time interval between concussion and voluntary exercise restores motor impairment, short-term memory, and alterations to gene expression.

Despite the most common form of brain injury, there has been little progress in the prognosis and treatment of concussion/mild traumatic brain injury (mTBI). Current 'return-to-play' guidelines are conservative, deterring the initiation of physical and social activity until patients are asymptomatic; but the effects of post-injury exercise have not been adequately investigated. Therefore, this study examined the effects of voluntary exercise on concussion recovery. Using a translational rodent model of concussion, we examined the influence of exercise on injury-associated behaviours that comprise post-concussive syndrome (PCS) and gene expression changes (bdnf, dnmt1, Igf-1, pgc1-a, Tert) in prefrontal cortex and hippocampus. In addition, as we have previously demonstrated telomere length (TL) to be a reliable predictor of mTBI prognosis, TL was also examined. The results suggest that exercise initiated within 1-3 days post-concussion significantly improved motor and cognitive functioning, but had limited efficacy treating emotional impairments. What is more, when deprived of social interaction and exercise, a combination similar to clinical recommendations for rest until symptom resolution, animals did not recover and exhibited impairments similar to typical mTBI animals. Exercise aided in restoration of mTBI-induced modifications to gene expression in both brain regions. An inverse relationship between the exercise return interval and TL was identified, indicating greater recovery with acute exercise reinstatement. Although additional strategies may need to be employed for emotional functioning, these findings support re-evaluation of 'return-to-play' guidelines, suggesting that exercise is valuable for the treatment of concussion.

Diet, age, and prior injury status differentially alter behavioral outcomes following concussion in rats.

Mild traumatic brain injury (mTBI) or concussion affects a large portion of the population and although many of these individuals recover completely, a small subset of people experience lingering symptomology and poor outcomes. Little is known about the factors that affect individual susceptibility or resilience to poor outcomes after mTBI and there are currently no biomarkers to delineate mTBI diagnosis or prognosis. Based upon the growing literature associated with caloric intake and altered neurological aging and the ambiguous link between repetitive mTBI and progressive neurodegeneration, the current study was designed to examine the effect of a high fat diet (HFD), developmental age, and repetitive mTBI on behavioral outcomes following a mTBI. In addition, telomere length was examined before and after experimental mTBI. Sprague Dawley rats were maintained on a HFD or standard rat chow throughout life (including the prenatal period) and then experienced an mTBI/concussion at P30, P30 and P60, or only at P60. Behavioral outcomes were examined using a test battery that was administered between P61-P80 and included; beam-walking, open field, elevated plus maze, novel context mismatch, Morris water task, and forced swim task. Animals with a P30 mTBI often demonstrated lingering symptomology that was still present during testing at P80. Injuries at P30 and P60 rarely produced cumulative effects, and in some tests (i.e., beam walking), the first injury may have protected the brain from the second injury. Exposure to the high fat diet exacerbated many of the behavioral deficits associated with concussion. Finally, telomere length was shortened following mTBI and was influenced by the animal's dietary intake. Diet, age at the time of injury, and the number of prior concussion incidents differentially contribute to behavioral deficits and may help explain individual variations in susceptibility and resilience to poor outcomes following an mTBI.

An enhanced home cage modulates hypothalamic CRH-ir labeling in juvenile rats, with and without sub-threshold febrile convulsions.

Pre and postnatal environments can have a profound impact on offspring development. This is especially true when considering the origin of neurological diseases, including epilepsy, a relatively common and chronic neurological condition, affecting 1-2% of the population. Previously, we have used maternal stress and an enhanced home cage (EHC) in an effort to identify potential factors in the early environment that may increase the risk for experiencing seizures. First, pregnant Long-Evans rats were exposed to a predator stress (PS). Then, at birth, litters were divided into standard cage (SC) and EHC groups until postnatal Day 14 (PD14) when a model of febrile convulsions was used to determine convulsion susceptibility of the various groups. Twenty-four hours later, pup brains were processed for immunohistochemical detection of corticotrophic releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus. Analysis of CRH immunoreactive (-ir) patterns revealed a buffering of CRH-ir in EHC reared offspring. Further, experiencing convulsions led to decreased CRH-ir. Our results support the concept that postnatal environmental influences affect neonatal programming and neurodevelopment of processes that could underlie seizure susceptibility, and that these effects can be modulated by EHC conditions.

Spatial MEG laterality maps for language: clinical applications in epilepsy.

Functional imaging is increasingly being used to provide a noninvasive alternative to intracarotid sodium amobarbitol testing (i.e., the Wada test). Although magnetoencephalography (MEG) has shown significant potential in this regard, the resultant output is often reduced to a simplified estimate of laterality. Such estimates belie the richness of functional imaging data and consequently limit the potential value. We present a novel approach that utilizes MEG data to compute "complex laterality vectors" and consequently "laterality maps" for a given function. Language function was examined in healthy controls and in people with epilepsy. When compared with traditional laterality index (LI) approaches, the resultant maps provided critical information about the magnitude and spatial characteristics of lateralized function. Specifically, it was possible to more clearly define low LI scores resulting from strong bilateral activation, high LI scores resulting from weak unilateral activation, and most importantly, the spatial distribution of lateralized activation. We argue that the laterality concept is better presented with the inherent spatial sensitivity of activation maps, rather than being collapsed into a one-dimensional index.

Prenatal transport stress, postnatal maternal behavior, and offspring sex differentially affect seizure susceptibility in young rats.

Epilepsy is a heterogeneous and chronic neurological condition of undefined etiology in the majority of cases. Similarly, the pathogenesis of the unprovoked seizures that lead to epilepsy is not known. We are interested in the factors that modify inherent seizure susceptibility, with a particular focus on those occurring during the prenatal and early postnatal periods. Female Sprague-Dawley rats were bred in-house or transported during pregnancy at one of two gestational days (G9 or G16). The effects of transport stress, maternal behavior, and offspring sex were then examined in terms of how they were related to provoked seizure susceptibility to kainic acid (KA) or a model of febrile convulsions (FCs) on postnatal day 14 (P14). We also examined the pattern of neuronal activation in the hippocampus and amygdala as indicated by the density of FosB protein immunoreactivity (FosB-ir). Results demonstrated only a small and inconsistent effect of transport alone, suggesting that the groups differed slightly prior to experimental manipulations. However, the influence of maternal behaviors such as licking and grooming (LG), arched back nursing (ABN), and dam-off time (DO) exerted a much stronger effect on the offspring. Dams designated as high LG gave birth to smaller litters, had pups that weighed less, had greater seizure susceptibility and severity, and had more FosB-ir neurons predominantly in the ventral hippocampus and the medial subnucleus of the amygdala (MeA). We also found a sex-dependent effect such that P14 males were smaller than their female littermates and had a greater seizure susceptibility and severity. Taken together, these results suggest an impact of prenatal and postnatal factors, as well as sex, on seizure susceptibility in young animals.

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.

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.

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.

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.

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.

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.

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.