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Dandy-Walker malformation (DWM) is often sporadic, but there are a growing number of genetic disorders that have been associated with this condition. We present a female individual with a de novo variant in ABL1, c.734A>G (p.Y245), who was diagnosed prenatally with DWM. ABL1-related neurodevelopmental disorder was recently identified but brain malformations have not been well characterized to date. We reviewed the published literature and identified one additional individual with DWM and ABL1-related disorder, which suggests a possible association with this malformation., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Neonates with congenital heart disease (CHD) are at risk for adverse neurodevelopmental outcomes. This scoping review summarizes neuromonitoring methods in neonates with CHD. We identified 84 studies investigating the use of near-infrared spectroscopy (NIRS) (n = 37), electroencephalography (EEG) (n = 20), amplitude-integrated electroencephalography (aEEG) (n = 10), transcranial Doppler sonography (TCD) (n = 6), and multimodal monitoring (n = 11). NIRS was used to evaluate cerebral oxygenation, identify risk thresholds and adverse events in the intensive care unit (ICU), and outcomes. EEG was utilized to screen for seizures and to predict adverse outcomes. Studies of aEEG have focused on characterizing background patterns, detecting seizures, and outcomes. Studies of TCD have focused on correlation with short-term clinical outcomes. Multimodal monitoring studies characterized cerebral physiologic dynamics. Most of the studies were performed in single centers, had a limited number of neonates (range 3-183), demonstrated variability in neuromonitoring practices, and lacked standardized approaches to neurodevelopmental testing. We identified areas of improvement for future research: (1) large multicenter studies to evaluate developmental correlates of neuromonitoring practices; (2) guidelines to standardize neurodevelopmental testing methodologies; (3) research to address geographic variation in resource utilization; (4) integration and synchronization of multimodal monitoring; and (5) research to establish a standardized framework for neuromonitoring techniques across diverse settings. IMPACT: This scoping review summarizes the literature regarding neuromonitoring practices in neonates with congenital heart disease (CHD). The identification of low cerebral oxygenation thresholds with NIRS may be used to identify neonates at risk for adverse events in the ICU or adverse neurodevelopmental outcomes. Postoperative neuromonitoring with continuous EEG screening for subclinical seizures and status epilepticus, allow for early and appropriate therapy. Future studies should focus on enrolling larger multicenter cohorts of neonates with CHD with a standardized framework of neuromonitoring practices in this population. Postoperative neurodevelopmental testing should utilize standard assessments and testing intervals., (© 2024. The Author(s).)

Background: Prediction of outcomes in perinatal arterial ischemic stroke (PAIS) is challenging. We performed a systematic review and meta-analysis to determine whether infarct characteristics can predict outcomes in PAIS., Methods: A systematic search was conducted using five databases in January 2023. Studies were included if the sample included children with neonatal or presumed PAIS; if infarct size, location, or laterality was indicated; and if at least one motor, cognitive, or language outcome was reported. The level of evidence and risk of bias were evaluated using the Risk of Bias in Non-Randomized Studies of Interventions tool. Meta-analyses were conducted comparing infarct size or location with neurological outcomes when at least three studies could be analyzed., Results: Eighteen full-text articles were included in a systematic review with nine included in meta-analysis. Meta-analyses revealed that small strokes were associated with a lower risk of cerebral palsy/hemiplegia compared with large strokes (risk ratio [RR] = 0.263, P = 0.001) and a lower risk of epilepsy (RR = 0.182, P < 0.001). Middle cerebral artery (MCA) infarcts were not associated with a significantly different risk of cerebral palsy/hemiplegia compared with non-MCA strokes (RR = 1.220, P = 0.337). Bilateral infarcts were associated with a 48% risk of cerebral palsy/hemiplegia, a 26% risk of epilepsy, and a 58% risk of cognitive impairment., Conclusions: Larger stroke size was associated with worse outcomes across multiple domains. Widely heterogeneous reporting of infarct characteristics and outcomes limits the comparison of studies and the analysis of outcomes. More consistent reporting of infarct characteristics and outcomes will be important to advance research in this field., Competing Interests: Declaration of competing interest Dr. Lo receives research grant support from the NINDS and NICHD. Dr. Bridge receives research grant support from the National Institute of Mental Health, the Centers for Disease Control and Prevention, and the Patient-Centered Outcomes Research Institute; he is also a member of the Scientific Advisory Board of Clarigent Health. The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists., Competing Interests: Declaration of competing interest The authors report no conflict of interest or competing financial interests in relation to the work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fetal neurology encompasses the full spectrum of neonatal and child neurology presentations, with complex additional layers of diagnostic and prognostic challenges unique to the specific prenatal consultation. Diverse genetic and acquired etiologies with a range of potential outcomes may be encountered. Three clinical case presentations are discussed that highlight how postnatal phenotyping and longitudinal follow-up are essential to address the uncertainties that arise in utero, after birth, and in childhood, as well as to provide continuity of care., Competing Interests: Declaration of competing interest The authors have no conflicts of interest or funding relevant to this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Pediatric neurocritical care (PNCC) has emerged as a field to care for children at the intersection of critical illness and neurological dysfunction. PNCC fellowship programs evolved over the past decade to train physicians to fill this clinical need. We aimed to characterize PNCC fellowship training infrastructure and curriculum in the United States and Canada., Methods: Web-based survey of PNCC fellowship program leaders during November 2019 to January 2020., Results: There were 14 self-identified PNCC fellowship programs. The programs were supported by Child Neurology and/or Pediatric Critical Care Medicine divisions at tertiary/quaternary care institutions. Most programs accepted trainees who were board-eligible or board-certified in child neurology or pediatric critical care medicine. Clinical training consisted mostly of rotations providing PNCC consultation (n = 13) or as a provider on the pediatric intensive care unit-based neurointensive care team (n = 2). PNCC-specific didactics were delivered at most institutions (n = 13). All institutions provided training in electroencephalography use in the intensive care unit and declaration of death by neurological criteria (n = 14). Scholarly activity was supported by most programs, including protected time for research (n = 10)., Conclusions: We characterized PNCC fellowship training in the United States and Canada, which in this continuously evolving field, lays the foundation for exploring standardization of training going forward., Competing Interests: Declaration of competing interest Mark Wainwright reports board membership with Pediatric Neurocritical Care Research Group (PNCRG) and payment for participation in the Clinical Advisory Board of Sage Therapeutics. Sue Hong reports co-chair for the PNCRG Education Committee, grant from the NIH, and consulting fees from the Chicago Department of Public Health. Jennifer Erklauer reports a co-chair for the PNCRG Education Committee. Nicholas Abend reports grant funding by PCORI and Wolfson Foundation paid to his institution, book royalties paid by Demos Publishing, and payment for expert testimony. Kristin Guilliams reports board membership on the PNCRG and payment for expert testimony by Wiseman Ashworth Law Group for pediatric stroke expertise. Andrea Pardo reports grant funding by the Patrick G and Shirley W. Ryan Foundation, UCB Biosciences, NIH/NINDS, and NIH CSR paid to her institution. Jose Pineda reports board membership for the PNCRG, consulting fees from the NIH, honoraria from the American Board of Pediatrics, and participation in the NINDS Data Safety Monitoring Boards. Brian Appavu reports grants or contracts from the US Department of Defense, American Heart Association, and Innovators for Neuroscience in Kids Foundation and honoraria from Natus. Alexis Topjian reports grants from the NIH, payment for medical legal consulting, and participation in a Data Safety Monitoring Board for ESETT. Anne-Marie Guerguerian reports grants or contracts from the Canadian Institutes of Health Research and Garry Hurwitz Center for Brain and Mental Health, Health Outcomes, participating on the FAST Data Safety Monitoring Board, and leadership or fiduciary role for the Heart and Stroke Foundation of Canada and the American Heart Association., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The increase of intracellular Ca 2+ concentration, produced principally by its influx through the L-type Ca 2+ channels, is one of the major contributors to the ischemia-reperfusion injury. The inhibition of those channels in different experimental models was effective to ameliorate the post-ischemic damage. However, at a clinical level, the results were contradictory. Recent results of our group obtained in an ¨ ex vivo ¨ heart model demonstrated that a chemical derived from acetazolamide, the N-methylacetazolamide (NMA) protected the heart against ischemia-reperfusion injury, diminishing the infarct size and improving the post-ischemic recovery of myocardial function and mitochondrial dynamic. A significant inhibitory action on L-type Ca 2+ channels was also detected after NMA treatment, suggesting this action as responsible for the beneficial effects on myocardium exerted by this compound. Although these results were promising, the effectiveness of NMA in the treatment of ischemic heart disease in humans as well as the advantages or disadvantages in comparison to the classic calcium antagonists needs to be investigated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pardo, Díaz Zegarra, González Arbeláez, Aiello and Mosca.)

Background: Fetal neurology is a rapidly evolving field. Consultations aim to diagnose, prognosticate, and coordinate prenatal and perinatal management along with other specialists and counsel expectant parents. Practice parameters and guidelines are limited., Methods: A 48-question online survey was administered to child neurologists. Questions targeted current care practices and perceived priorities for the field., Results: Representatives from 43 institutions in the United States responded; 83% had prenatal diagnosis centers, and the majority performed on-site neuroimaging. The earliest gestational age for fetal magnetic resonance imaging was variable. Annual consultations ranged from <20 to >100 patients. Fewer than half (n = 17.40%) were subspecialty trained. Most respondents (n = 39.91%) were interested in participating in a collaborative registry and educational initiatives., Conclusions: The survey highlights heterogeneity in clinical practice. Large multisite and multidisciplinary collaborations are essential to gather data that inform outcomes for fetuses evaluated across institutions through registries as well as creation of guidelines and educational material., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ventricular assist devices (VADs) are increasingly used for end-stage heart failure in children. VAD-associated neurologic dysfunction, including stroke and intracranial hemorrhage, occurs in more than 20% of patients. Starting in 2019, we implemented a protocol to diagnose stroke in relation to VAD to facilitate treatment. A multidisciplinary approach was implemented including targeted education for providers. VAD goals, structured neurologic exam, and frequency of neuromonitoring were incorporated into daily rounds, tailored to patient's phase of recovery. A protocolized neurocritical team assessment was implemented. A VAD-specific stroke algorithm and order set were implemented to facilitate rapid neuroimaging. We performed a pre- and postimplementation analysis from 2015 to 2020. Forty-six patients had VADs placed, 25 preintervention, and 21 postintervention. We compared the number of patients evaluated for stroke, time to imaging, and documentation of last known normal exam. Preintervention, time to imaging was 7 hours, and documentation was inconsistent. Postintervention, time to imaging decreased to 2.8 hours ( p = 0.038) with universal documentation of last known normal ( p = 0.009). The use of head computerized tomographies decreased from 11 preintervention to three postintervention. Development of a VAD protocol decreased time to imaging for suspected stroke and reduced unnecessary imaging. Further studies are required to validate these data., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Background: More than half of children with pediatric acute liver failure (PALF) experience hepatic encephalopathy (HE), which is related to poor outcomes; however, HE is difficult to diagnose in children. The objective of this study was to evaluate if heart rate variability (HRV), a continuous measure of autonomic nervous system function, was related to the presence and severity of HE as well as clinical outcomes in children with PALF., Methods: We conducted a retrospective observational cohort study of 38 critically ill children with PALF to examine the association between HRV and HE severity and clinical outcome. HRV was estimated using the integer HRV (HRVi). Categorical variables were compared using the Fisher Exact test and continuous variables were compared using Kruskal-Wallis tests. Associations between grades of HE and minimum and median HRVi were evaluated with Pearson's correlation, with p values <0.05 considered significant., Results: A more negative median and minimum HRVi, indicating poorer autonomic nervous system function, was significantly associated with abnormal EEG findings, presence of HE, and poor outcomes (death or listing for transplant)., Conclusions: Heart rate variability may hold promise to predict outcomes in children with PALF, but these findings should be replicated in a larger sample., Impact: The findings of our study suggest that heart rate variability is associated with clinical outcomes in children with acute liver failure, a cohort for which prognostics are challenging, especially in young children and infants. Use of heart rate variability in the clinical setting may facilitate earlier detection of children with pediatric acute liver failure (PALF) at high risk for severe hepatic encephalopathy and poor outcomes. Identification of children with PALF at high risk of decompensation may assist clinicians in making decisions about liver transplantation, an important, but resource-limited, treatment of PALF., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

The present study was a pre-registered direct replication of Ward et al.'s (2017) second experiment (OSF pre-registration found at: https://osf.io/5fq4r). This replication assigned both smartphone location (on desk, in pocket/bag, or outside of the testing room) and smartphone power (on, or off) for a total of six conditions. Participants completed an automated operation span (OSpan) task, a Cue-Dependent Go/No-Go task, and the smartphone attachment and dependency inventory. It was hypothesized that performance on an attention-demanding task (i.e., the OSpan task) would be worse for those in closer proximity to their smartphone (on desk) and that those with greater smartphone attachment and dependency would have a larger "brain drain" effect. Using the same tasks and conditions as in Ward et al.'s (2017) second experiment, the present study found that the "brain drain" effect did not replicate: there was no difference between smartphone location conditions on performance on either the o-span task or the go/no-go task. These findings demonstrate that the mere presence of one's smartphone may not be enough to affect cognitive performance. Understanding these effects is crucial in a time where smartphones are a basic necessity., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Hypoxic-ischemic injury (HII) is a major worldwide contributor of term neonatal mortality and long-term morbidity. At present, therapeutic hypothermia is the only therapy that has demonstrated efficacy in reducing severe disability or death in infants with moderate to severe encephalopathy. MRI and MRS performed during the first week of life are adequate to assess brain injury and offer prognosis. Patterns of injury will depend on the gestation age of the neonate, as well as the degree of hypotension., Competing Interests: Disclosures The authors have no disclosures., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: We evaluated changes in genetic testing for neonatal-onset epilepsy and associated short-term outcomes over an 8-year period among a cohort of patients in the neonatal intensive care unit (NICU) at a single institution before and after the introduction of sponsored genetic epilepsy testing in January 2018., Methods: Our primary outcome was a change in length of stay (LOS) after 2018. We also ascertained severity of illness with the Neonatal Sequential Organ Failure Assessment (nSOFA), type and result of genetic testing, turnaround time to molecular diagnosis (TAT), LOS, antiseizure medications (ASMs), and use of technology at discharge. We compared outcomes using nonparametric tests and difference-in-difference analysis., Results: Fifty-three infants with genetic testing were included; 20 infants were tested after 2018. A total of 4160 infants in the NICU without genetic testing were used as reference. In the genetic testing group, LOS was 25 days (interquartile range [IQR] 5, 49) pre-2018 and 19 days (IQR 6, 19) post-2018 (P < 0.001 when compared with the reference population in the difference-in-difference analysis). TAT decreased from 51 days to 17 days after 2018 (P = 0.003). ASM number decreased from 4 (IQR 2, 5) to 2 post-2018 (IQR 1, 3) (P = 0.02). Over the same time periods there was no significant change in birth weight, maximum nSOFA score, or technology dependence., Conclusions: In this cohort, changes in genetic testing for neonatal-onset epilepsy were associated with shorter LOS that was not explained by changes in severity of illness, birth weight, or the average LOS in the NICU over time. Validation of these results in a larger, multicenter sample size is warranted., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Our objective was to examine the effects of N-methylacetazolamide (NMA), a non‑carbonic anhydrase inhibitor, on ischemia-reperfusion injury. Isolated rat hearts were assigned to the following groups: 1) Non-ischemic control (NIC):110 min of perfusion and 2) Ischemic control (IC): 30 min of global ischemia and 60 min of reperfusion (R). Both groups were repeated in presence of NMA (5 μM), administered during the first 10 min of R. Infarct size (IS) was measured by TTC staining. Developed pressure (LVDP) and end-diastolic pressure (LVEDP) of the left ventricle were used to assess systolic and diastolic function, respectively. The content of P-Akt, P-PKCε, P-Drp1 and calcineurin Aβ were measured. In cardiomyocytes the L-type Ca 2+ current (ICaL) was recorded with the whole-cell configuration of patch-clamp technique. The addition of NMA to non-ischemic hearts decreased 15% the contractility. In ischemic hearts (IC group), NMA decreased IS (22 ± 2% vs 32 ± 2%, p < 0.05) and improved the post-ischemic recovery of myocardial function. At the end of R, LVDP was 54 ± 7% vs 18 ± 3% and LVEDP was 23 ± 8 vs. 55 ± 7 mmHg ¨p < 0.05¨. The level of P-Akt, P-PKCε and P-Drp1 increased and the expression of calcineurin Aβ decreased in NMA treated hearts. Peak ICaL density recorded at 0 mV was smaller in myocytes treated with NMA than in non-treated cells (-1.91 ± 0.15 pA/pF vs -2.32 ± 0.17 pA/pF, p < 0.05). These data suggest that NMA protects the myocardium against ischemia-reperfusion injury through an attenuation of mitochondrial fission by calcineurin/Akt/PKCε-dependent pathways associated to the decrease of ICaL current., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: A previously published, single-institution, case series suggested an association between topiramate administration in neonates and subsequent development of necrotizing enterocolitis (NEC). This contradicted our more extensive experiences using topiramate in this population. We therefore studied safety and tolerability of topiramate for treating refractory neonatal seizures, hypothesizing that the risk of developing NEC following topiramate exposure was low and that most infants tolerate topiramate., Methods: This multicenter retrospective cohort study included seventy-five neonates who received topiramate to treat seizures from January 2011 to October 2019 at three geographically diverse level IV neonatal intensive care units affiliated with pediatric tertiary hospitals. Data included demographics, birth history, seizure etiology, treatment response, side effects, and occurrence and details of NEC., Results: Three of seventy-five infants (4%) developed NEC following topiramate exposure. These infants did not differ in gestational age, birth weight, seizure etiology, postmenstrual age, weight when topiramate was initiated, or dosing of topiramate. Topiramate was well tolerated. Only three infants (4%) discontinued due to side effects. The most common side effect (20%) was weight loss (typically <5%). Topiramate was felt to be efficacious (61%). Most infants (72%) continued topiramate when discharged., Conclusions: Our multicenter, 75-infant study demonstrated that development of NEC after treatment with topiramate was rare (4%) and refutes prior literature suggesting an association. Topiramate was felt to be efficacious and was well tolerated. Although limited by retrospective design, study data are broadly applicable and support thoughtful use of topiramate as a safe, reasonable option for treating refractory neonatal seizures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Nonconvulsive seizures occur frequently in pediatric intensive care unit patients and can be impossible to detect clinically without electroencephalogram monitoring. Quantitative electroencephalography uses mathematical signal analysis to compress data, monitoring trends over time. Nonneurologists can identify seizures with quantitative electroencephalography, but data on its use in the clinical setting are limited., Local Problem: Bedside quantitative electroencephalography was implemented and nurses received education on its use for seizure detection. This quality improvement project aimed to describe the time between nurses' recognition of electrographic seizures and seizure treatment., Methods: Education was provided in phases over several months. Retrospective medical record review evaluated quantitative electroencephalograms and medication interventions from September 2019 through March 2020. A bedside form was used to measure nurses' use of quantitative electroencephalograms, change recognition, clinician notification, and seizure treatment. A nurse survey evaluated the education after implementation., Results: Data included 44 electroencephalograms from 30 pediatric intensive care unit patients aged 18 years or less with electroencephalogram monitoring durations of 4 hours or longer. Nurses monitored quantitative electroencephalograms in 73% of cases, documented at least 1 change in the quantitative electroencephalogram display in 28% of these cases, and contacted the neurocritical care team in 78% of cases in which they documented a change. Seizure treatment was initiated in response to the nursing call in 1 patient. Time to treatment was approximately 20 minutes., Conclusions: An education program for quantitative electroencephalogram interpretation by nurse providers is feasible yet complex, requiring multiple reeducation cycles., (©2022 American Association of Critical-Care Nurses.)

Objective: Seizures are a common neonatal neurologic emergency. Many centers have developed pathways to optimize management. We evaluated neonatal seizure management pathways at level IV neonatal intensive care units (NICUs) in the United States to highlight areas of consensus and describe aspects of variability., Methods: We conducted a descriptive analysis of 11 neonatal seizure management pathways from level IV NICUs that specialize in neonatal neurocritical care including guidelines for electroencephalography (EEG) monitoring, antiseizure medication (ASM) choice, timing, and dose., Results: Study center NICUs had a median of 70 beds (interquartile range: 52-96). All sites had 24/7 conventional EEG initiation, monitoring, and review capability. Management pathways uniformly included prompt EEG confirmation of seizures. Most pathways included a provision for intravenous benzodiazepine administration if either EEG or loading of ASM was delayed. Phenobarbital 20 mg/kg IV was the first-line ASM in all pathways. Pathways included either fosphenytoin or levetiracetam as the second-line ASM with variable dosing. Third-line ASMs were most commonly fosphenytoin or levetiracetam, with alternatives including topiramate or lacosamide. All pathways provided escalation to continuous midazolam infusion with variable dosing for seizures refractory to initial medication trials. Three pathways also included lidocaine infusion. Nine pathways discussed ASM discontinuation after resolution of acute symptomatic seizures with variable timing., Conclusions: Despite a paucity of data from controlled trials regarding optimal neonatal seizure management, there are areas of broad agreement among institutional pathways. Areas of substantial heterogeneity that require further research include optimal second-line ASM, dosage, and timing of ASM discontinuation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Investigators from The Department of Comparative Medicine, from Yale School of Medicine report the effect of the ketogenic diet on the T cell immune function in mice exposed to influenza virus., Competing Interests: The author has declared that no competing interests exist., (Copyright: © 2020 The Author(s).)

Objective: To determine whether the use of rapid sequence magnetic resonance imaging (rsMRI) is associated with improved efficiency of care when managing infants with suspected neonatal onset seizures., Methods: We conducted a preintervention and postintervention study of the use of rsMRI in term infants with suspected neonatal onset seizures without evidence of hypoxic ischemic encephalopathy. Study patients were collected from a contemporary cohort from 2016 to 2017 and were compared with a historical cohort from 2014. The primary outcome was hospital length of stay. Secondary outcomes included use of other imaging modalities (head ultrasound, computed tomography [CT], and MRI), use of antiseizure medications at the time of discharge, and cost of hospitalization. Continuous variables were compared using the Mann-Whitney U test and categorical variables using the Fisher's exact or χ 2 tests. A two-tailed P < 0.05 was considered statistically significant., Results: Ninety-five patients met inclusion criteria, 47 in the preintervention and 48 in the postintervention group. Incorporation of the protocol-guided rsMRI in the evaluation of patients with neonatal seizures was associated with decreased use of CT scans (34% vs 10%, P = 0.007) and full MRIs (85% vs 62%, P = 0.019). Use of head ultrasound, length of stay, and costs were not different between groups., Conclusions: In patients with neonatal seizures, rsMRI was not associated with a reduced hospital length of stay. The use of rsMRI resulted in fewer neonates receiving CT scans during their hospitalization. rsMRI may hasten the identification of stroke or hemorrhage in neonates with seizures., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Emerging data suggest that pediatric traumatic brain injury (TBI) is associated with impaired developmental plasticity and poorer neuropsychological outcomes than adults with similar head injuries. Unlike adult mild TBI (mTBI), the effects of mTBI on white matter (WM) microstructure and vascular supply are not well understood in the pediatric population. The cerebral vasculature plays an important role providing necessary nutrients and removing waste. To address this critical element, we examined the microstructure of the corpus callosum (CC) following pediatric mTBI using diffusion tensor magnetic resonance imaging (DTI), and investigated myelin, oligodendrocytes, and vasculature of WM with immunohistochemistry (IHC). We hypothesized that pediatric mTBI leads to abnormal WM microstructure and impacts the vasculature within the CC, and that these alterations to WM vasculature contribute to the long-term altered microstructure. We induced in mice a closed-head injury (CHI) mTBI at post-natal day (P) 14; then at 4, 14, and 60 days post-injury (DPI) mice were sacrificed for analysis. We observed persistent changes in apparent diffusion coefficient (ADC) within the ipsilateral CC following mTBI, indicating microstructural changes, but surprisingly changes in myelin and oligodendrocyte densities were minimal. However, vascular features of the ipsilateral CC such as vessel density, length, and number of junctions were persistently altered following mTBI. Correlative analysis showed a strong inverse relationship between ADC and vessel density at 60 DPI, suggesting increased vessel density following mTBI may restrict WM diffusion characteristics. Our findings suggest that WM vasculature contributes to the long-term microstructural changes within the ipsilateral CC following mTBI.

Competing Interests: There are no conflicts of interest.

Concussion or mild traumatic brain injury (mTBI) is often accompanied by long-term behavioral and neuropsychological deficits. Emerging data suggest that these deficits can be exacerbated following repeated injuries. However, despite the overwhelming prevalence of mTBI in children due to falls and sports-related activities, the effects of mTBI on white matter (WM) structure and its development in children have not been extensively examined. Moreover, the effect of repeated mTBI (rmTBI) on developing WM has not yet been studied, despite the possibility of exacerbated outcomes with repeat injuries. To address this knowledge gap, we investigated the long-term effects of single (s)mTBI and rmTBI on the WM in the pediatric brain, focusing on the anterior commissure (AC), a WM structure distant to the injury site, using diffusion tensor imaging (DTI) and immunohistochemistry (IHC). We hypothesized that smTBI and rmTBI to the developing mouse brain would lead to abnormalities in microstructural integrity and impaired oligodendrocyte (OL) development. We used a postnatal day 14 Ascl1-CreER: ccGFP mouse closed head injury (CHI) model with a bilateral repeated injury. We demonstrate that smTBI and rmTBI differentially lead to myelin-related diffusion changes in the WM and to abnormal OL development in the AC, which are accompanied by behavioral deficits 2 months after the initial injury. Our results suggest that mTBIs elicit long-term behavioral alterations and OL-associated WM dysregulation in the developing brain. These findings warrant additional research into the development of WM and OL as key components of pediatric TBI pathology and potential therapeutic targets., (© 2018 S. Karger AG, Basel.)

White matter injury (WMI) of prematurity is associated with a spectrum of neurological disorders ranging from mild cognitive and behavioral deficits to cerebral palsy. Translational studies have implicated impaired oligodendrocyte development after hypoxia as the primary cause of WMI, but the underlying mechanisms remain poorly understood. The goal of this study was to identify alterations in the expression of oligodendrocyte precursor cell transcription factors in a mouse model of transient mild global hypoxia. Postnatal day (P) 7 mouse pups were exposed to hypoxia (7.5% O 2 ) for 60minutes. We compared oligodendrocyte differentiation and subsequent myelin formation between hypoxia and sham animals at P9, P14 and P28 by examining the expression of key transcription factor regulators of oligodendrocyte differentiation (Ascl1, Olig1, Olig2, and Nkx2.2), as well as APC, a mature oligodendrocyte marker, in the major white matter regions including the corpus callosum, external capsule and anterior commissure. We also examined the effect on myelin formation by examining two myelin specific protein constituents, myelin associated glycoprotein (MAG) and myelin basic protein (MBP), in white matter tracts and whole brain lysate respectively. We found that transient hypoxia at P7 altered the expression of Ascl1, Olig1 and Nkx2.2, resulting in delayed myelination in the external capsule. In addition, our study showed that oligodendrocyte progenitor cells specified several days prior to a hypoxic event are more susceptible to maturation arrest than those specified shortly prior to hypoxia. Our results suggest that alterations of Ascl1, Olig1 and Nkx2.2 underlie impaired oligodendrocyte differentiation and deficient myelination in WMI. These transcription factors are potential therapeutic targets for the treatment of WMI in preterm infants., (Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.)

Parents often ask neonatologists and neurologists to determine neurologic prognosis in the preterm and term infant after neonatal brain injury. Prognostication in these populations remains rather full of uncertainties. Knowledge of available diagnostic tests and their limitations allows the clinician to synthesize the most likely outcomes after neurologic injury. In this review, we describe the diagnostic tools available to the clinician, active areas of research, and challenges in neurologic prognostication of the neonate., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Investigators from the Accident Vasculaire Cérébral de nouveau-né (AVCnn) Study Group, a multicenter registry in France, examined outcomes at 7 years of age in children previously identified with neonatal arterial ischemic stroke (NAIS).

Researchers from Johns Hopkins School of Medicine report a pilot observational study investigating the influence of hemodynamic management in 28 neonates with hypoxic ischemic injury (HIE).

Investigators from Washington University St. Louis studied the impact of electroencephalographic monitoring of neonates with Hypoxic Ischemic Encephalopathy (HIE) and their degree of MRI injury and neurodevelopmental outcomes when increasing seizure burden was present.

The aim was to study the mitochondrial Ca(2+) handling of mitochondria isolated from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) hearts and to establish a possible correlation with systolic blood pressure (SBP). Mitochondrial swelling after Ca(2+) addition, Ca(2+)-retention capacity (CRC) by calcium green method, and membrane potential (ΔΨm) were assessed. SBP was 124±1 (WKY) and 235±6mmHg (SHR). CRC, Ca(2+) response and ΔΨm were lower in SHR than WKY mitochondria. The conclusion is: the more depolarized state of SHR than WKY mitochondria results in an abnormal Ca(2+) handling and this event is closely associated with the SBP., (Copyright © 2014 © Elsevier B.V. and Mitochondria Research Society. Published by Elsevier B.V. All rights reserved.)

Mild traumatic brain injury (mTBI) is an increasing public health concern as repetitive injuries can exacerbate existing neuropathology and result in increased neurologic deficits. In contrast to other models of repeated mTBI (rmTBI), our study focused on long-term white-matter abnormalities after bilateral mTBIs induced 7 days apart. A controlled cortical impact (CCI) was used to induce an initial mTBI to the right cortex of Single and rmTBI Sprague Dawley rats, followed by a second injury to the left cortex of rmTBI animals. Shams received only a craniectomy. Ex vivo diffusion tensor imaging (DTI), transmission electron microscopy (TEM), and histology were performed on the anterior corpus callosum at 60 days after injury. The rmTBI animals showed a significant bilateral increase in radial diffusivity (myelin), while only modest changes in axial diffusivity (axonal) were seen between the groups. Further, the rmTBI group showed an increased g-ratio and axon caliber in addition to myelin sheath abnormalities using TEM. Our DTI results indicate ongoing myelin changes, while the TEM data show continuing axonal changes at 60 days after rmTBI. These data suggest that bilateral rmTBI induced 7 days apart leads to progressive alterations in white matter that are not observed after a single mTBI.

Object: The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models., Methods: In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT)., Results: In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival., Conclusions: Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone.

Patients with Duchenne muscular dystrophy (DMD) lose ambulation by age 12. Long-term steroids have lengthened ambulation by 2-5 years. Ischial weight-bearing knee ankle foot orthoses prolong ambulation for 2-3 years. We report the outcome of the ambulatory status of a patient with DMD treated with daily steroid therapy and orthoses. This male patient was diagnosed with DMD at age of 2. He has been treated with daily steroids since age 7 years. He lost the ability to arise from the floor and walk up steps at age 14 and lost ambulation by age 16. He was fitted with orthoses at age 16 following surgical correction of his lower extremity contractures and regained independent ambulation. At age 20, he was able to stand independently in his orthoses and take steps with moderate support. We conclude that a combination of daily steroids and orthoses prolongs ambulation beyond that of the natural history DMD., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Cellular abnormalities in amyotrophic lateral sclerosis (ALS) are not limited to motor neurons. Astrocyte dysfunction also occurs in human ALS and transgenic rodents expressing mutant human SOD1 protein (SOD1(G93A)). Here we investigated focal enrichment of normal astrocytes using transplantation of lineage-restricted astrocyte precursors, called glial-restricted precursors (GRPs). We transplanted GRPs around cervical spinal cord respiratory motor neuron pools, the principal cells whose dysfunction precipitates death in ALS. GRPs survived in diseased tissue, differentiated efficiently into astrocytes and reduced microgliosis in the cervical spinal cords of SOD1(G93A) rats. GRPs also extended survival and disease duration, attenuated motor neuron loss and slowed declines in forelimb motor and respiratory physiological functions. Neuroprotection was mediated in part by the primary astrocyte glutamate transporter GLT1. These findings indicate the feasibility and efficacy of transplantation-based astrocyte replacement and show that targeted multisegmental cell delivery to the cervical spinal cord is a promising therapeutic strategy for slowing focal motor neuron loss associated with ALS.

Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.

The focus of most neurodegenerative disease studies has been on neuronal death in particular subpopulations of the central nervous system. The associated response of glial populations has been ascribed the term "reactive astrocytosis." This has been defined as the proliferation of astrocytes accompanied by cellular hypertrophy and changes in gene expression following injury to the central nervous system. Yet the significance of that response to disease course is debated. In both human ALS and in the SOD1G93A mouse model of ALS, reactive astrocytosis is a hallmark of the disease--particularly at endstage. The brain also harbors immature progenitors which have the capacity for differentiation into both glial and neuronal lineages. We examined whether glial progenitors in the adult spinal cord of SOD1G93A mice become activated and contribute the astroglial response observed in this model. We found that the glial progenitor proteoglycan NG2 is increased in parallel with GFAP during the symptomatic phase of the disease and that there is a differential in vitro response of SOD1G93A glial progenitors to inflammatory cytokines when compared to wildtype mouse glial progenitors. This response was accompanied by the proliferation of glial progenitors but not mature GFAP+ astrocytes, through the translocation of the transcription factor Olig2 from the nucleus to the cytoplasm-resulting in astrocyte differentiation. These data suggest that adult glial progenitors from SOD1G93A mice differentially respond to inflammatory cytokines and contribute to the observed reactive astrocytosis observed in SOD1G93A mouse lumbar spinal cord., (Copyright (c) 2007 Wiley-Liss, Inc.)

Mutations in the superoxide dismutase 1 (SOD1) gene are associated with familial amyotrophic lateral sclerosis (ALS), and the SOD1(G93A) transgenic mouse has been widely used as one animal model for studies of this neurodegenerative disorder. Recently, several reports have shown that abnormalities in neuronal development in other models of neurodegeneration occur much earlier than previously thought. To study the role of mutant SOD1 in glial progenitor biology, we immortalized glial restricted precursors (GRIPs) derived from mouse E11.5 neural tubes of wild-type and SOD1(G93A) mutant mice. Immunocytochemistry using cell lineage markers shows that these cell lines can be maintained as glial progenitors, because they continue to express A2B5, with very low levels of glial fibrillary acidic protein (astrocyte), betaIII-tubulin (neuron), and undetected GalC (oligodendrocyte) markers. RT-PCR and immunoblot analyses indicate that the chemokine receptor CXCR4 is reduced in SOD1(G93A) GRIPs. Subsequently, SOD1(G93A) GRIPs are unable to respond to SDF1alpha to activate ERK1/2 enzymes and the transcription factor CREB. This may be one pathway leading to a reduction in SOD1(G93A) cell migration. These data indicate that the abnormalities in SOD1(G93A) glial progenitor expression of CXCR4 and its mediated signaling and function occur during spinal cord development and highlight nonneuronal (glial) abnormalities in this ALS model., (Copyright 2007 Wiley-Liss, Inc.)

Recent studies have highlighted the role of astrocytes in the development of motor neuron disease in animal models. The astrocyte glutamate transporter GLT1 is responsible for a significant portion of glutamate transport from the synaptic cleft; regulating synaptic transmission and preventing glutamate excitotoxicity. While previous studies have demonstrated reductions in GLT1 with SOD1-mediated disease progression, it is not well established whether a reduction in this astrocyte-specific transporter alters the pathobiology of motor neuron degeneration in the SOD1(G93A) mouse. In order to address this possible astrocyte-specific influence, we crossed the SOD1(G93A) mouse line with a mouse heterozygous for GLT1 (GLT1+/-) exhibiting a significant reduction in transporter protein. Mice that carried both the SOD1 mutation and a reduced amount of GLT1 (SOD1(G93A)/GLT1+/-) exhibited an increase in the rate of motor decline accompanied by earlier motor neuron loss when compared with SOD1(G93A) mice. A modest reduction in survival was also noted in these mice. Dramatic losses of the GLT1 protein and reduced glutamate transport in the lumbar spinal cords of the SOD1(G93A)/GLT1+/- animals were also observed. GLT1 was not significantly changed in cortices from these animals suggesting that the effect of mutant SOD1 on GLT1 production/function was largely targeted to spinal cord rather than cortical astrocytes. This study suggests that astrocytes, and the astrocyte glutamate transporter GLT1, play a role in modifying disease progression and motor neuron loss in this model.