Publications by authors named "Shenandoah Robinson"

90 Publications

Chorioamnionitis Precipitates Perinatal Alterations of Heme-Oxygenase-1 (HO-1) Homeostasis in the Developing Rat Brain.

Int J Mol Sci 2021 May 28;22(11). Epub 2021 May 28.

Department of Pediatrics, Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Chorioamnionitis (CHORIO), placental insufficiency, and preterm birth are well-known antecedents of perinatal brain injury (PBI). Heme-oxygenase-1 (HO-1) is an important inducible enzyme in oxidative and inflammatory conditions. In the brain, HO-1 and the iron regulatory receptor, transferrin receptor-1 (TfR1), are known to be involved in iron homeostasis, oxidative stress, and cellular adaptive mechanisms. However, the role of HO pathway in the pathophysiology of PBI has not been previously studied. In this study, we set out to define the ontogeny of the HO pathway in the brain and determine if CHORIO changed its normal developmental regulation. We also aimed to determine the role of HO-1/TfR1 in CHORIO-induced neuroinflammation and peripheral inflammation in a clinically relevant rat model of PBI. We show that HO-1, HO-2, and TfR1 expression are developmentally regulated in the brain during the perinatal period. CHORIO elevates HO-1 and TfR1 mRNA expression in utero and in the early postnatal period and results in sustained increase in HO-1/TfR1 ratios in the brain. This is associated with neuroinflammatory and peripheral immune phenotype supported by a significant increase in brain mononuclear cells and peripheral blood double negative T cells suggesting a role of HO-1/TfR1 pathway dysregulation in CHORIO-induced neuroinflammation.
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http://dx.doi.org/10.3390/ijms22115773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198804PMC
May 2021

Neonatal Subpial Hemorrhage: Clinical Factors, Neuroimaging, and Outcomes in a Quaternary Care Children's Center.

Pediatr Neurol 2021 Jul 28;120:52-58. Epub 2021 Apr 28.

Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland; Neurosciences Intensive Care Nursery, Johns Hopkins School of Medicine, Baltimore, Maryland. Electronic address:

Background: Subpial hemorrhages are underrecognized, underreported, and poorly understood. The spectrum of their clinical manifestations and consequences in neonates has not been fully described. Here, we describe the demographic, clinical, and radiographic characteristics of neonates with subpial hemorrhages.

Methods: We reviewed the medical records and neuroimaging studies of neonates with subpial hemorrhage who were admitted to our neonatal intensive care unit between September 2009 and December 2020.

Results: Of 114 neonates with intracranial hemorrhage, 31 (27%) had subpial hemorrhage. The majority of neonates in our cohort were male (68%) and born at term (55%). The most common imaging indication was apneas and/or seizures in 58%. Common comorbid conditions included cardiorespiratory failure (42%), hypoxic-ischemic encephalopathy (26%), and coagulopathy (23%). Subpial hemorrhages were multifocal in 45% of neonates, located in the temporal lobe in 45% of neonates, and tended to be larger in neonates with coagulopathy, birth trauma, or hydrocephalus requiring neurosurgical intervention. Subpial hemorrhage was associated with another type of intracranial bleed in 77% of cases and with arterial ischemic stroke in 16% of cases. Of 17 patients with more than one year of follow-up data, 14 (82%) have developmental delay and four (24%) have epilepsy. Of 14 patients with follow-up imaging, 10 (71%) had encephalomalacia subjacent to the subpial hemorrhage.

Conclusions: This is the largest cohort of neonates with subpial hemorrhages to date. Outcome data are limited by duration of follow-up and may be confounded by comorbid conditions and other concurrent hemorrhages. Further study is needed to define the spectrum of risk factors and expected neurological outcomes.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.04.011DOI Listing
July 2021

Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency.

J Neurosci Res 2021 Feb 20. Epub 2021 Feb 20.

Division of Pediatric Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.
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http://dx.doi.org/10.1002/jnr.24815DOI Listing
February 2021

Isolated and On Guard: Preparing Neonatal Intensive Care Unit Families for Life with Hydrocephalus.

Am J Perinatol 2021 Jan 17. Epub 2021 Jan 17.

Division of Pediatric Neurology, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina.

Objective:  This study was aimed to characterize the parent experience of caring for a child with posthemorrhagic hydrocephalus and to describe parent preferences for counseling in the neonatal period and beyond.

Study Design:  This was a qualitative interview study. Parents of infants born preterm with posthemorrhagic hydrocephalus completed semistructured interviews. Data were analyzed using a content analysis approach.

Results:  Thematic saturation was reached on parent communication preferences after 10 interviews. Parent experiences of infant hydrocephalus broadly fell into two time periods, the neonatal intensive care unit (NICU) and after NICU discharge. The themes of uncertainty, isolation, hypervigilance, and the need for advocacy were common to each phase.

Conclusion:  Parents expressed interest in the development of tiered NICU counseling tools that would provide evidence-based and family-centric information to (1) initiate connections with community and peer resources and (2) combat the isolation and hypervigilance that characterized their family experience of living with hydrocephalus.

Key Points: · Infants with posthemorrhagic hydrocephalus are at risk for adverse neurodevelopmental outcomes.. · The parent experience of caring for a child with posthemorrhagic hydrocephalus is not well-described. In this interview study, parents described uncertainty, isolation, and hypervigilance.. · These findings call for structured NICU counseling and longitudinal family supports after discharge..
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http://dx.doi.org/10.1055/s-0040-1722344DOI Listing
January 2021

Dual Myelomeningoceles in Twins: Case Report, Review, and Insights for Etiology.

Pediatr Neurosurg 2020 2;55(6):363-373. Epub 2020 Dec 2.

Division of Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Introduction: Despite folate supplementation, neural tube defects (NTDs) still occur in 0.5-1.0/1,000 pregnancies, with 30-50% not preventable with folate. Twinning has increased due to artificial fertilization and in itself predisposes to NTDs at a rate of 1.6/1,000. The contributions of genetic and environmental factors to myelomeningocele development remain poorly understood. Expression patterns of congenital pathologies in twins can sometimes provide etiological insight. Concordance of NTDs in twins is 0.03/1,000, with dual myelomeningocele reported in only 23 pairs, only one of which survived. We present the 24th pair, the 1st to maintain lower extremity motor function. We review all prior cases and discuss implications of twin concordance on the interplay of genetic and environmental influences. Case Report and Review: A new case of female monozygotic twins born to a well-nourished 24-year-old female is reported with details of perioperative care. Prenatal ultrasound showed L3-S4 and L5-S4 myelomeningoceles, Chiari II malformations, and ventriculomegaly. Copy number microarray was unrevealing. Each underwent uncomplicated repair on day of life 1, and ventriculoperitoneal shunt placement on days of life 10 and 16. Both had movement in the legs upon 6-week follow-up. All prior reported cases of concordant twin myelomeningoceles were abstracted and analyzed, revealing persistence of occurrence despite folate supplementation and a majority occurring in dizygotic pairs. The literature is also reviewed to summarize current knowledge of myelomeningocele pathophysiology as it relates to genetic and environmental influences.

Discussion: Meticulous surgical and perioperative care allowed for early positive outcomes in each twin. However, etiopathogenesis remains elusive. In general, only of a minority of cases have underlying genetic lesions or clear environmental triggers. Concordance in monozygotic twins argues for a strong genetic influence; yet, literature review reveals a higher rate of concordant dizygotic twins. This, along with the observation of differing resultant phenotypes in monozygotic twins as seen in this case, prompts further investigation into nonfolate environmental influences. While efforts in genetic investigation should continue, the role of teratogens and exposures should not be minimized in research efforts, public health, and family counseling. Clinical genetic testing remains of limited utility in the majority of patients until more is known.
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http://dx.doi.org/10.1159/000511365DOI Listing
December 2020

Neonatal opioid exposure: public health crisis and novel neuroinflammatory disease.

Neural Regen Res 2021 Mar;16(3):430-432

Department of Pediatrics, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology, Kennedy Krieger Institute, Baltimore, MD; Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM; Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.

Substance use, specifically the use of prescription and non-prescription opioids among pregnant women, is a major public health issue and chief contributor to the opioid crisis. The prevalence of Neonatal Opioid Withdrawal Syndrome has risen 5-fold in the past decade, and is a well-recognized consequence of perinatal opioid exposure. By contrast, the long-term damage to the developing brain from opioid medications is just beginning to be recognized as a serious concern. Published data suggest that opioid exposure commencing in utero negatively affects the maturation of the neural-immune system, and trajectory of central nervous system development. Methadone induces peripheral immune hyper-reactivity, lasting structural and microstructural brain injury, and significant deficits in executive function and cognitive control in adult animals following in utero exposure. Thus, to address the cascading public health crisis stemming from the multitude of infants with in utero opioid exposure who will grow up with altered neurodevelopmental trajectories, rigorous preclinical, mechanistic studies are required. Such studies will define the long-term sequelae of prenatal opioid exposure in an effort to develop appropriate and targeted interventions. Specifically, the development of novel fluid, neuroimaging and biobehavioral biomarkers will be the most useful to aid in early identification and treatment of opioid exposed infants with the greatest risk of poor clinical outcomes. These studies will be essential to understand how in utero insults determine brain structure and function in adulthood, and what targeted interventions will be required to improve long-term outcomes in the countless children being born exposed to opioids each year.
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http://dx.doi.org/10.4103/1673-5374.293136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996018PMC
March 2021

Surgical considerations in Labrune syndrome.

Childs Nerv Syst 2021 05 12;37(5):1765-1770. Epub 2020 Aug 12.

Department of Neurosurgery, Division of Pediatric Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Purpose: Labrune syndrome (LS) is a rare white matter disease characterized by leukoencephalopathy with intracranial calcification and cysts (LCC). While the intracranial cyst characteristics of LS are for the most part stable, some may require surgical intervention when they develop associated hemorrhage and/or mass effect. To date, no review of the surgical outcomes of cyst decompression in LS has been performed.

Case Presentation: We report the case of a 16-year-old girl with LS who presented with progressive right hemiparesis from an enlarging hemorrhagic left thalamic cyst. The patient underwent frameless stereotactic cyst aspiration and Ommaya reservoir placement and her hemiparesis subsequently improved. Serial monitoring demonstrated stable decompression of the cyst.

Conclusions: The pathophysiology of LS is thought to be diffuse cerebral microangiopathy and it is thought that these microhemorrhages contribute to the formation of intracranial cysts as well as diffuse calcifications. Indications for surgical intervention in LS are not well established and the heterogeneity of lesions compels them to be managed on a case-by-case basis. Based on our literature review, surgery is the standard treatment of choice for patients with progressive symptoms and growing lesions on imaging studies, with outcomes favoring less-invasive stereotactic approaches with contingencies of reservoir placement when cysts recur.
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http://dx.doi.org/10.1007/s00381-020-04861-7DOI Listing
May 2021

Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity.

Front Pediatr 2020 26;8:272. Epub 2020 Jun 26.

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

The increased incidence of opioid use during pregnancy warrants investigation to reveal the impact of opioid exposure on the developing fetus. Exposure during critical periods of development could have enduring consequences for affected individuals. Particularly, evidence is mounting that developmental injury can result in immune priming, whereby subsequent immune activation elicits an exaggerated immune response. This maladaptive hypersensitivity to immune challenge perpetuates dysregulated inflammatory signaling and poor health outcomes. Utilizing an established preclinical rat model of perinatal methadone exposure, we sought to investigate the consequences of developmental opioid exposure on activation of peripheral blood mononuclear cells (PBMCs). We hypothesize that PBMCs from methadone-exposed rats would exhibit abnormal chemokine and cytokine expression at baseline, with exaggerated chemokine and cytokine production following immune stimulation compared to saline-exposed controls. On postnatal day (P) 7, pup PMBCs were isolated and cultured, pooling three pups per . Following 3 and 24 h, the supernatant from cultured PMBCs was collected and assessed for inflammatory cytokine and chemokine expression at baseline or lipopolysaccharide (LPS) stimulation using multiplex electrochemiluminescence. Following 3 and 24 h, baseline production of proinflammatory chemokine and cytokine levels were significantly increased in methadone PBMCs ( < 0.0001). Stimulation with LPS for 3 h resulted in increased tumor necrosis factor (TNF-α) and C-X-C motif chemokine ligand 1 (CXCL1) expression by 3.5-fold in PBMCs from methadone-exposed PBMCs compared to PBMCs from saline-exposed controls ( < 0.0001). Peripheral blood mononuclear cell hyperreactivity was still apparent at 24 h of LPS stimulation, evidenced by significantly increased TNF-α, CXCL1, interleukin 6 (IL-6), and IL-10 production by methadone PMBCs compared to saline control PBMCs ( < 0.0001). Together, we provide evidence of increased production of proinflammatory molecules from methadone PBMCs at baseline, in addition to sustained hyperreactivity relative to saline-exposed controls. Exaggerated peripheral immune responses exacerbate inflammatory signaling, with subsequent consequences on many organ systems throughout the body, such as the developing nervous system. Enhanced understanding of these inflammatory mechanisms will allow for appropriate therapeutic development for infants who were exposed to opioids during development. Furthermore, these data highlight the utility of this PBMC assay technique for future biomarker development to guide specific treatment for patients exposed to opioids during gestation.
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http://dx.doi.org/10.3389/fped.2020.00272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332770PMC
June 2020

Neonatal Hypoxic-Ischemic Encephalopathy Yields Permanent Deficits in Learning Acquisition: A Preclinical Touchscreen Assessment.

Front Pediatr 2020 5;8:289. Epub 2020 Jun 5.

Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Neonatal hypoxic-ischemic encephalopathy (HIE) remains a common problem world-wide for infants born at term. The impact of HIE on long-term outcomes, especially into adulthood, is not well-described. To facilitate identification of biobehavioral biomarkers utilizing a translational platform, we sought to investigate the impact of HIE on executive function and cognitive outcomes into adulthood utilizing a murine model of HIE. HIE mice (unilateral common carotid artery occlusion to induce ischemia, followed by hypoxia with a FiO of 0.08 for 45 min) and control mice were tested on discrimination and reversal touchscreen tasks (using their noses) shown to be sensitive to loss of basal ganglia or cortical function, respectively. We hypothesized that the HIE injury would result in deficits in reversal learning, revealing complex cognitive and executive functioning impairments. Following HIE, mice had a mild discrimination impairment as measured by incorrect responses but were able to learn the paradigm to similar levels as controls. During reversal, HIE mice required significantly more total trials, errors and correction trials across the paradigm. Analysis of specific stages showed that reversal impairments in HIE were driven by significant increases in all measured parameters during the late learning, striatal-mediated portion of the task. Together, these results support the concept that HIE occurring during the neonatal period results in abnormal neurodevelopment that persists into adulthood, which can impact efficient associated learning. Further, these data show that utilization of an established model of HIE coupled with touchscreen learning provides valuable information for screening therapeutic interventions that could mitigate these deficits to improve the long-term outcomes of this vulnerable population.
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http://dx.doi.org/10.3389/fped.2020.00289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291343PMC
June 2020

Principles of Medical and Surgical Treatment of Cerebral Palsy.

Neurol Clin 2020 05;38(2):397-416

Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA.

Cerebral palsy is the most common cause of childhood motor disability, affecting 2 to 3/1000 children worldwide. Clinical abnormalities in tone, posture, and movement are the result of brain dysgenesis or injury early in life, and impairment varies in type, distribution, and in severity. The underlying brain disorder may also lead to other associated neurologic and systemic impairments. Variability in functional impairments, which can change during development, necessitates an individualized treatment plan. Treatment options are primarily symptomatic and directed toward optimizing independence, function, and/or ease of care-while limiting side effects. New promising disease-preventing and modifying treatments are emerging.
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http://dx.doi.org/10.1016/j.ncl.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158771PMC
May 2020

Placenta and perinatal brain injury: the gateway to individualized therapeutics and precision neonatal medicine.

Pediatr Res 2020 04 14;87(5):807-808. Epub 2020 Feb 14.

Department of Neurology, Johns Hopkins Children's Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Wu and colleagues analyzed the placental pathology from a subset of the neonates in the NEATO trial who had reports available and correlated the placental pathology findings with outcomes. This study highlights the importance of placental pathology, and its potential to bring precision medicine to critically-ill neonates. Placental pathology will likely aid stratification of neonates for clinical trials and accelerate progress for neurorepair.
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http://dx.doi.org/10.1038/s41390-020-0807-8DOI Listing
April 2020

Early neurodevelopmental outcome in preterm posthemorrhagic ventricular dilatation and hydrocephalus: Neonatal ICU Network Neurobehavioral Scale and imaging predict 3-6-month motor quotients and Capute Scales.

J Neurosurg Pediatr 2019 Dec 20:1-11. Epub 2019 Dec 20.

7Neurology and Developmental Medicine and.

Objective: Brain injury remains a serious complication of prematurity. Almost half of infants with severe intraventricular hemorrhage (IVH) develop posthemorrhagic ventricular dilatation (PHVD) and 20% need surgery for posthemorrhagic hydrocephalus (PHH). This population is associated with an increased risk of later neurodevelopmental disability, but there is uncertainty about which radiological and examination features predict later disability. In this study the authors sought to devise and describe a novel combination of neurobehavioral examination and imaging for prediction of neurodevelopmental disability among preterm infants with PHVD and PHH.

Methods: The study patients were preterm infants (< 36 weeks gestation) with IVH and PHVD, with or without PHH. Ventricular index (VI), anterior horn width (AHW), thalamooccipital distance (TOD), ventricle/brain (V/B) ratio, and resistive indices (RIs) were recorded on the head ultrasound (HUS) just prior to surgery, or the HUS capturing the worst PHVD when surgery was not indicated. The posterior fossa was assessed with MRI. Neonatal ICU Network Neurobehavioral Scale (NNNS) examinations were performed at term age equivalent for each infant. A neurodevelopmental assessment using the Capute Scales (Capute Cognitive Adaptive Test [CAT] scores and Capute Clinical Linguistic Auditory Milestone Scale [CLAMS] scores) and a motor quotient (MQ) assessment were performed between 3 and 6 months of age corrected for degree of prematurity (corrected age). MQs < 50 reflect moderate to severe delays in early motor milestone attainment, CAT scores < 85 reflect delays in early visual and problem-solving abilities, and CLAMS scores < 85 reflect delays in early language.

Results: Twenty-one infants underwent assessments that included imaging and NNNS examinations, Capute Scales assessments, and MQs. NNNS nonoptimal reflexes (NOR) and hypertonicity subscores and AHW were associated with MQs < 50: NOR subscore OR 2.46 (95% CI 1.15-37.6, p = 0.034), hypertonicity subscore OR 1.68 (95% CI 1.04-3.78, p = 0.037), and AHW OR 1.13 (95% CI 1.01-1.39, p = 0.041). PVHI, cystic changes, and neurosurgical intervention were associated with CAT scores < 85: PVHI OR 9.2 (95% CI 1.2-73.2, p = 0.037); cystic changes OR 12.0 (95% CI 1.0-141.3, p = 0.048), and neurosurgical intervention OR 11.2 (95% CI 1.0-120.4, p = 0.046). Every 1-SD increase in the NOR subscore was associated with an increase in odds of a CAT score < 85, OR 4.0 (95% CI 1.0-15.0, p = 0.044). Worse NNNS NOR subscores were associated with early language delay: for a 1-SD increase in NOR subscore, there was an increase in the odds of a CLAMS score < 85, OR 19.5 (95% CI 1.3-303, p = 0.034).

Conclusions: In former preterm children with severe IVH and PHVD, neonatal neurological examination findings and imaging features are associated with delays at 3-6 months in motor milestones, visual and problem-solving abilities, and language.
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http://dx.doi.org/10.3171/2019.9.PEDS19438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305038PMC
December 2019

Prenatal opioid exposure: The next neonatal neuroinflammatory disease.

Brain Behav Immun 2020 02 22;84:45-58. Epub 2019 Nov 22.

Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, United States.

The rates of opioid use disorder during pregnancy have more than quadrupled in the last decade, resulting in numerous infants suffering exposure to opioids during the perinatal period, a critical period of central nervous system (CNS) development. Despite increasing use, the characterization and definition of the molecular and cellular mechanisms of the long-term neurodevelopmental impacts of opioid exposure commencing in utero remains incomplete. Thus, in consideration of the looming public health crisis stemming from the multitude of infants with prenatal opioid exposure entering school age, we undertook an investigation of the effects of perinatal methadone exposure in a novel preclinical model. Specifically, we examined the effects of opioids on the developing brain to elucidate mechanisms of putative neural cell injury, to identify diagnostic biomarkers and to guide clinical studies of outcome and follow-up. We hypothesized that methadone would induce a pronounced inflammatory profile in both dams and their pups, and be associated with immune system dysfunction, sustained CNS injury, and altered cognition and executive function into adulthood. This investigation was conducted using a combination of cellular, molecular, biochemical, and clinically translatable biomarker, imaging and cognitive assessment platforms. Data reveal that perinatal methadone exposure increases inflammatory cytokines in the neonatal peripheral circulation, and reprograms and primes the immune system through sustained peripheral immune hyperreactivity. In the brain, perinatal methadone exposure not only increases chemokines and cytokines throughout a crucial developmental period, but also alters microglia morphology consistent with activation, and upregulates TLR4 and MyD88 mRNA. This increase in neuroinflammation coincides with reduced myelin basic protein and altered neurofilament expression, as well as reduced structural coherence and significantly decreased fractional anisotropy on diffusion tensor imaging. In addition to this microstructural brain injury, adult rats exposed to methadone in the perinatal period have significant impairment in associative learning and executive control as assessed using touchscreen technology. Collectively, these data reveal a distinct systemic and neuroinflammatory signature associated with prenatal methadone exposure, suggestive of an altered CNS microenvironment, dysregulated developmental homeostasis, complex concurrent neural injury, and imaging and cognitive findings consistent with clinical literature. Further investigation is required to define appropriate therapies targeted at the neural injury and improve the long-term outcomes for this exceedingly vulnerable patient population.
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http://dx.doi.org/10.1016/j.bbi.2019.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010550PMC
February 2020

Fully automated, real-time, calibration-free, continuous noninvasive estimation of intracranial pressure in children.

J Neurosurg Pediatr 2019 Aug 23:1-11. Epub 2019 Aug 23.

1Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge.

Objective: In the search for a reliable, cooperation-independent, noninvasive alternative to invasive intracranial pressure (ICP) monitoring in children, various approaches have been proposed, but at the present time none are capable of providing fully automated, real-time, calibration-free, continuous and accurate ICP estimates. The authors investigated the feasibility and validity of simultaneously monitored arterial blood pressure (ABP) and middle cerebral artery (MCA) cerebral blood flow velocity (CBFV) waveforms to derive noninvasive ICP (nICP) estimates.

Methods: Invasive ICP and ABP recordings were collected from 12 pediatric and young adult patients (aged 2-25 years) undergoing such monitoring as part of routine clinical care. Additionally, simultaneous transcranial Doppler (TCD) ultrasonography-based MCA CBFV waveform measurements were performed at the bedside in dedicated data collection sessions. The ABP and MCA CBFV waveforms were analyzed in the context of a mathematical model, linking them to the cerebral vasculature's biophysical properties and ICP. The authors developed and automated a waveform preprocessing, signal-quality evaluation, and waveform-synchronization "pipeline" in order to test and objectively validate the algorithm's performance. To generate one nICP estimate, 60 beats of ABP and MCA CBFV waveform data were analyzed. Moving the 60-beat data window forward by one beat at a time (overlapping data windows) resulted in 39,480 ICP-to-nICP comparisons across a total of 44 data-collection sessions (studies). Moving the 60-beat data window forward by 60 beats at a time (nonoverlapping data windows) resulted in 722 paired ICP-to-nICP comparisons.

Results: Greater than 80% of all nICP estimates fell within ± 7 mm Hg of the reference measurement. Overall performance in the nonoverlapping data window approach gave a mean error (bias) of 1.0 mm Hg, standard deviation of the error (precision) of 5.1 mm Hg, and root-mean-square error of 5.2 mm Hg. The associated mean and median absolute errors were 4.2 mm Hg and 3.3 mm Hg, respectively. These results were contingent on ensuring adequate ABP and CBFV signal quality and required accurate hydrostatic pressure correction of the measured ABP waveform in relation to the elevation of the external auditory meatus. Notably, the procedure had no failed attempts at data collection, and all patients had adequate TCD data from at least one hemisphere. Last, an analysis of using study-by-study averaged nICP estimates to detect a measured ICP > 15 mm Hg resulted in an area under the receiver operating characteristic curve of 0.83, with a sensitivity of 71% and specificity of 86% for a detection threshold of nICP = 15 mm Hg.

Conclusions: This nICP estimation algorithm, based on ABP and bedside TCD CBFV waveform measurements, performs in a manner comparable to invasive ICP monitoring. These findings open the possibility for rational, point-of-care treatment decisions in pediatric patients with suspected raised ICP undergoing intensive care.
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http://dx.doi.org/10.3171/2019.5.PEDS19178DOI Listing
August 2019

Time to reconsider extended erythropoietin treatment for infantile traumatic brain injury?

Exp Neurol 2019 08 10;318:205-215. Epub 2019 May 10.

Division of Pediatric Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Pediatric traumatic brain injury (TBI) remains a leading cause of childhood morbidity and mortality worldwide. Most efforts to reduce the chronic impact of pediatric TBI involve prevention and minimization of secondary injury. Currently, no treatments are used in routine clinical care during the acute and subacute phases to actively repair injury to the developing brain. The endogenous pluripotent cytokine erythropoietin (EPO) holds promise as an emerging neuroreparative agent in perinatal brain injury (PBI). EPO signaling in the central nervous system (CNS) is essential for multiple stages of neurodevelopment, including the genesis, survival and differentiation of multiple lineages of neural cells. Postnatally, EPO signaling decreases markedly as the CNS matures. Importantly, high-dose, extended EPO regimens have shown efficacy in preclinical controlled cortical impact (CCI) models of infant TBI at two different, early ages by independent research groups. Specifically, extended high-dose EPO treatment after infantile CCI prevents long-term cognitive deficits in adult rats. Because of the striking differences in the molecular and cellular responses to both injury and recovery in the developing and mature CNS, and the excellent safety profile of EPO in infants and children, extended courses of EPO are currently in Phase III trials for neonates with PBI. Extended, high-dose EPO may also warrant testing for infants and young children with TBI.
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http://dx.doi.org/10.1016/j.expneurol.2019.05.004DOI Listing
August 2019

CXCR2 Blockade Mitigates Neural Cell Injury Following Preclinical Chorioamnionitis.

Front Physiol 2019 2;10:324. Epub 2019 Apr 2.

Department of Pediatrics, School of Medicine, The University of New Mexico, Albuquerque, NM, United States.

Minimizing central nervous system (CNS) injury from preterm birth depends upon identification of the critical pathways that underlie essential neurodevelopmental and CNS pathophysiology. While chorioamnionitis (CHORIO), is a leading cause of preterm birth, the precise mechanism linking prenatal brain injury and long-term CNS injury is unknown. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its cognate receptor, CXCR2, are implicated in a variety of uterine and neuropathologies, however, their role in CNS injury associated with preterm birth is poorly defined. To evaluate the putative efficacy of CXCR2 blockade in neural repair secondary to CHORIO, we tested the hypothesis that transient postnatal CXCR2 antagonism would reduce neutrophil activation and mitigate cerebral microstructural injury in rats. To this end, a laparotomy was performed on embryonic day 18 (E18) in Sprague Dawley rats, with uterine arteries transiently occluded for 60 min, and lipopolysaccharide (LPS, 4 μg/sac) injected into each amniotic sac. SB225002, a CXCR2 antagonist (3 mg/kg), was administered intraperitoneally from postnatal day 1 (P1)-P5. Brains were collected on P7 and P21 and analyzed with western blot, immunohistochemistry and diffusion tensor imaging (DTI). Results demonstrate that transient CXCR2 blockade reduced cerebral neutrophil activation (myeloperoxidase expression/MPO) and mitigated connexin43 expression, indicative of reduced neuroinflammation at P7 ( < 0.05 for all). CXCR2 blockade also reduced alpha II-spectrin calpain-mediated cleavage, improved pNF/NF ratio, and minimized Iba1 and GFAP expression consistent with improved neuronal and axonal health and reduced gliosis at P21. Importantly, DTI revealed diffuse white matter injury and decreased microstructural integrity following CHORIO as indicated by lower fractional anisotropy (FA) and elevated radial diffusivity (RD) in major white matter tracts ( < 0.05). Early postnatal CXCR2 blockade also reduced microstructural abnormalities in white matter and hippocampus at P21 ( < 0.05). Together, these data indicate that transient postnatal blockade of CXCR2 ameliorates perinatal abnormalities in inflammatory signaling, and facilitates neural repair following CHORIO. Further characterization of neuroinflammatory signaling, specifically via CXCL1/CXCR2 through the placental-fetal-brain axis, may clarify stratification of brain injury following preterm birth, and improve use of targeted interventions in this highly vulnerable patient population.
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http://dx.doi.org/10.3389/fphys.2019.00324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454349PMC
April 2019

Preoperative laboratory testing before pediatric neurosurgery: an NSQIP-Pediatrics analysis.

J Neurosurg Pediatr 2019 04;24(1):92-103

1Division of Pediatric Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland; and.

Objectives: The goal of this study was to evaluate clinical predictors of abnormal preoperative laboratory values in pediatric neurosurgical patients.

Methods: Data obtained in children who underwent a neurosurgical operation were extracted from the prospective National Surgical Quality Improvement Program-Pediatrics (NSQIP-P, 2012-2013) registry. Multivariable logistic regression evaluated predictors of preoperative laboratory values that might require further evaluation (white blood cell count < 2000/μl, hematocrit < 24%, platelet count < 100,000/μl, international normalized ratio > 1.4, or partial thromboplastin time > 45 seconds) or a preoperative transfusion (within 48 hours prior to surgery). Variables screened included patient demographics; American Society of Anesthesiologists (ASA) physical designation classification; comorbidities; recent steroid use, chemotherapy, or radiation therapy; and admission type. Predictive score validation was performed using the NSQIP-P 2014 data.

Results: Of the 6556 patients aged greater than 2 years, 68.9% (n = 5089) underwent laboratory testing, but only 1.9% (n = 125) had a critical laboratory value. Predictors of a laboratory abnormality were ASA class III-V; diabetes mellitus; hematological, hypothrombotic, or oncological comorbidities; nutritional support; recent chemotherapy; systemic inflammatory response syndrome; and a nonelective hospital admission. These 9 variables were used to create a predictive score, with a single point assigned for each predictor. The prevalence of critical values in the validation population (NSQIP-P 2014) of patients greater than 2 years of age was 0.3% with a score of 0, 1.0% in those with a score of 1, 1.6% in those with a score of 2, and 6.2% in those with a score ≥ 3. Higher score was predictive of a critical value (OR 2.33, 95% CI 1.91-2.83, p < 0.001, C-statistic 0.76) and with the requirement of a perioperative transfusion (intraoperatively or within 72 hours postoperatively; OR 1.42, 95% CI 1.22-1.67, p < 0.001) in the validation population. Moreover, when the same score was applied to children aged 2 years or younger, a greater score was predictive of a critical value (OR 2.47, 95% CI 2.15-2.84, p < 0.001, C-statistic 0.76).

Conclusions: Critical laboratory values in pediatric neurosurgical patients are largely predicted by clinical characteristics, and abnormal preoperative laboratory results are rare in patients older than 2 years of age without comorbidities who are undergoing elective surgery. The NSQIP-P critical preoperative laboratory value scale is proposed to indicate patients with the highest odds of an abnormal value. The scale can assist with triaging preoperative testing based on the surgical risk, as determined by the treating surgeon and anesthesiologist.
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http://dx.doi.org/10.3171/2018.12.PEDS18441DOI Listing
April 2019

Chorioamnionitis in Rats Precipitates Extended Postnatal Inflammatory Lymphocyte Hyperreactivity.

Dev Neurosci 2019 Mar 28:1-11. Epub 2019 Mar 28.

Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA,

Preterm birth is an important cause of perinatal brain injury (PBI). Neurological injury in extremely preterm infants often begins in utero with chorioamnionitis (CHORIO) or inflammation/infection of the placenta and concomitant placental insufficiency. Studies in humans have shown dysregulated inflammatory signaling throughout the placental-fetal brain axis and altered peripheral immune responses in children born preterm with cerebral palsy (CP). We hypothesized that peripheral immune responses would be altered in our well-established rat model of CP. Specifically, we proposed that isolated peripheral blood mononuclear cells (PBMCs) would be hyperresponsive to a second hit of inflammation throughout an extended postnatal time course. Pregnant Sprague-Dawley dams underwent a laparotomy on embryonic day 18 (E18) with occlusion of the uterine arteries (for 60 min) followed by intra-amniotic injection of lipopolysaccharide (LPS, 4 μg/sac) to induce injury in utero. Shams underwent laparotomy only, with equivalent duration of anesthesia. Laparotomies were then closed, and the rat pups were born at E22. PBMCs were isolated from pups on postnatal day 7 (P7) and P21, and subsequently stimulated in vitro with LPS for 3 or 24 h. A secreted inflammatory profile analysis of conditioned media was performed using multiplex electrochemiluminescent immunoassays, and the composition of inflammatory cells was assayed with flow cytometry (FC). Results indicate that CHORIO PBMCs challenged with LPS are hyperreactive and secrete significantly more tumor necrosis factor α (TNFα) and C-X-C chemokine ligand 1 at P7. FC confirmed increased intracellular TNFα in CHORIO pups at P7 following LPS stimulation, in addition to increased numbers of CD11b/c immunopositive myeloid cells. Notably, TNFα secretion was sustained until P21, with increased interleukin 6, concomitant with increased expression of integrin β1, suggesting both sustained peripheral immune hyperreactivity and a heightened activation state. Taken together, these data indicate that in utero injury primes the immune system and augments enhanced inflammatory signaling. The insidious effects of primed peripheral immune cells may compound PBI secondary to CHORIO and/or placental insufficiency, and thereby render the brain susceptible to future chronic neurological disease. Further understanding of inflammatory mechanisms in PBI may yield clinically important biomarkers and facilitate individualized repair strategies and treatments.
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http://dx.doi.org/10.1159/000497273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765467PMC
March 2019

The Relationship Between Clinical Imaging and Neurobehavioral Assessment in Posthemorrhagic Ventricular Dilation of Prematurity.

Front Physiol 2019 11;10:64. Epub 2019 Feb 11.

Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, United States.

Neonatal intraventricular hemorrhage (IVH) and subsequent posthemorrhagic ventricular dilation and hydrocephalus of prematurity are associated with brain injury and neurodevelopmental impairment in the preterm population. Neuroimaging assesses cerebral injury and guides neurosurgical intervention; however, the relationship of head ultrasound (HUS) and magnetic resonance imaging (MRI) parameters to neonatal exams in this group has not been well described. The NICU Network Neurobehavioral Scale (NNNS) is a reproducible, highly reliable battery with motor and cognitive domain scores. To evaluate the relationship between neonatal neurobehavioral findings on the NNNS and measures of ventricular dilation and associated brain injury on HUS and MRI. Neonates with IVH and ventricular dilatation with and without posthemorrhagic hydrocephalus were enrolled. NNNS exams were performed at approximately term age equivalent. HUS indices were measured on the last HUS before initial neurosurgical procedure or that with worst ventriculomegaly if no intervention. The posterior fossa was assessed with MRI at term. Descriptive statistics including medians, interquartile ranges, means, and percentages were performed. Correlations were estimated using Pearson's method. 28 patients had NNNS and HUS, and 18 patients also had an MRI. Ventricle size measures for the cohort were significantly above normal. Motor and cognitive subscores on the NNNS exam varied from established baseline scores for postmenstrual age. Children who required neurosurgical intervention had higher ventricle/brain ratios and worse NNNS habituation scores. Ventricle sizes were modestly correlated with motor abnormalities (0.24-0.59); larger anterior horn width correlated with nonoptimal reflexes, hypertonicity and hypotonicity. Ventricle sizes were modestly correlated with cognitive scores (-0.44 to 0.27); larger ventricular index correlated with worse attention. Periventricular hemorrhagic infarction correlated with worse habituation. For this cohort of preterm infants with IVH, surgical intervention for posthemorrhagic hydrocephalus correlated with both larger degrees of ventriculomegaly and worse NNNS exams. Findings on both HUS and MRI correlated with motor and cognitive abnormalities on neonatal neurobehavioral exam, suggesting that larger neonatal ventricle sizes and white matter injury have detectable correlates on exam. The NNNS exam provides important additional information when assessing posthemorrhagic ventricular dilation and hydrocephalus of prematurity.
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http://dx.doi.org/10.3389/fphys.2019.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378306PMC
February 2019

Extended Combined Neonatal Treatment With Erythropoietin Plus Melatonin Prevents Posthemorrhagic Hydrocephalus of Prematurity in Rats.

Front Cell Neurosci 2018 25;12:322. Epub 2018 Sep 25.

Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM, United States.

Posthemorrhagic hydrocephalus of prematurity (PHHP) remains a global challenge. Early preterm infants (<32 weeks gestation), particularly those exposed to chorioamnionitis (CAM), are prone to intraventricular hemorrhage (IVH) and PHHP. We established an age-appropriate, preclinical model of PHHP with progressive macrocephaly and ventriculomegaly to test whether non-surgical neonatal treatment could modulate PHHP. We combined prenatal CAM and postnatal day 1 (P1, equivalent to 30 weeks human gestation) IVH in rats, and administered systemic erythropoietin (EPO) plus melatonin (MLT), or vehicle, from P2 to P10. CAM-IVH rats developed progressive macrocephaly through P21. Macrocephaly was accompanied by ventriculomegaly at P5 (histology), and P21 ( MRI). CAM-IVH rats showed impaired performance of cliff aversion, a neonatal neurodevelopmental test. Neonatal EPO+MLT treatment prevented macrocephaly and cliff aversion impairment, and significantly reduced ventriculomegaly. EPO+MLT treatment prevented matted or missing ependymal motile cilia observed in vehicle-treated CAM-IVH rats. EPO+MLT treatment also normalized ependymal yes-associated protein (YAP) mRNA levels, and reduced ependymal GFAP-immunolabeling. Vehicle-treated CAM-IVH rats exhibited loss of microstructural integrity on diffusion tensor imaging, which was normalized in EPO+MLT-treated CAM-IVH rats. In summary, combined prenatal systemic inflammation plus early postnatal IVH caused progressive macrocephaly, ventriculomegaly and delayed development of cliff aversion reminiscent of PHHP. Neonatal systemic EPO+MLT treatment prevented multiple hallmarks of PHHP, consistent with a clinically viable, non-surgical treatment strategy.
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http://dx.doi.org/10.3389/fncel.2018.00322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167494PMC
September 2018

Preterm neuroimaging and neurodevelopmental outcome: a focus on intraventricular hemorrhage, post-hemorrhagic hydrocephalus, and associated brain injury.

J Perinatol 2018 11 30;38(11):1431-1443. Epub 2018 Aug 30.

Neurosciences Intensive Care Nursery, The Johns Hopkins School of Medicine, Baltimore, MD, USA.

Intraventricular hemorrhage in the setting of prematurity remains the most common cause of acquired hydrocephalus. Neonates with progressive post-hemorrhagic hydrocephalus are at risk for adverse neurodevelopmental outcomes. The goal of this review is to describe the distinct and often overlapping types of brain injury in the preterm neonate, with a focus on neonatal hydrocephalus, and to connect injury on imaging to neurodevelopmental outcome risk. Head ultrasound and magnetic resonance imaging findings are described separately. The current state of the literature is imprecise and we end the review with recommendations for future radiologic and neurodevelopmental research.
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http://dx.doi.org/10.1038/s41372-018-0209-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215507PMC
November 2018

Extended Erythropoietin Treatment Prevents Chronic Executive Functional and Microstructural Deficits Following Early Severe Traumatic Brain Injury in Rats.

Front Neurol 2018 19;9:451. Epub 2018 Jun 19.

Department of Pediatrics, University of New Mexico, Albuquerque, NM, United States.

Survivors of infant traumatic brain injury (TBI) are prone to chronic neurological deficits that impose lifelong individual and societal burdens. Translation of novel interventions to clinical trials is hampered in part by the lack of truly representative preclinical tests of cognition and corresponding biomarkers of functional outcomes. To address this gap, the ability of a high-dose, extended, post-injury regimen of erythropoietin (EPO, 3000U/kg/dose × 6d) to prevent chronic cognitive and imaging deficits was tested in a postnatal day 12 (P12) controlled-cortical impact (CCI) model in rats, using touchscreen operant chambers and regional analysis of diffusion tensor imaging (DTI). Results indicate that EPO prevents functional injury and MRI injury after infant TBI. Specifically, subacute DTI at P30 revealed widespread microstructural damage that is prevented by EPO. Assessment of visual discrimination on a touchscreen operant chamber platform demonstrated that all groups can perform visual discrimination. However, CCI rats treated with vehicle failed to pass reversal learning, and perseverated, in contrast to sham and CCI-EPO rats. Chronic DTI at P90 showed EPO treatment prevented contralateral white matter and ipsilateral lateral prefrontal cortex damage. This DTI improvement correlated with cognitive performance. Taken together, extended EPO treatment restores executive function and prevents microstructural brain abnormalities in adult rats with cognitive deficits in a translational preclinical model of infant TBI. Sophisticated testing with touchscreen operant chambers and regional DTI analyses may expedite translation and effective yield of interventions from preclinical studies to clinical trials. Collectively, these data support the use of EPO in clinical trials for human infants with TBI.
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http://dx.doi.org/10.3389/fneur.2018.00451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018393PMC
June 2018

A time for cocktails and inclusion.

Neural Regen Res 2018 Jun;13(6):987-988

Departments of Pediatrics and Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.

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http://dx.doi.org/10.4103/1673-5374.233440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022481PMC
June 2018

Repetitive Neonatal Erythropoietin and Melatonin Combinatorial Treatment Provides Sustained Repair of Functional Deficits in a Rat Model of Cerebral Palsy.

Front Neurol 2018 13;9:233. Epub 2018 Apr 13.

Pediatric Neurosurgery, Johns Hopkins University, Baltimore, MD, United States.

Cerebral palsy (CP) is the leading cause of motor impairment for children worldwide and results from perinatal brain injury (PBI). To test novel therapeutics to mitigate deficits from PBI, we developed a rat model of extreme preterm birth (<28 weeks of gestation) that mimics dual intrauterine injury from placental underperfusion and chorioamnionitis. We hypothesized that a sustained postnatal treatment regimen that combines the endogenous neuroreparative agents erythropoietin (EPO) and melatonin (MLT) would mitigate molecular, sensorimotor, and cognitive abnormalities in adults rats following prenatal injury. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague-Dawley rats. Uterine artery occlusion was performed for 60 min to induce placental insufficiency transient systemic hypoxia-ischemia, followed by intra-amniotic injections of lipopolysaccharide, and laparotomy closure. On postnatal day 1 (P1), approximately equivalent to 30 weeks of gestation, injured rats were randomized to an extended EPO + MLT treatment regimen, or vehicle (sterile saline) from P1 to P10. Behavioral assays were performed along an extended developmental time course ( = 6-29). Open field testing shows injured rats exhibit hypermobility and disinhibition and that combined neonatal EPO + MLT treatment repairs disinhibition in injured rats, while EPO alone does not. Furthermore, EPO + MLT normalizes hindlimb deficits, including reduced paw area and paw pressure at peak stance, and elevated percent shared stance after prenatal injury. Injured rats had fewer social interactions than shams, and EPO + MLT normalized social drive. Touchscreen operant chamber testing of visual discrimination and reversal shows that EPO + MLT at least partially normalizes theses complex cognitive tasks. Together, these data indicate EPO + MLT can potentially repair multiple sensorimotor, cognitive, and behavioral realms following PBI, using highly translatable and sophisticated developmental testing platforms.
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http://dx.doi.org/10.3389/fneur.2018.00233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908903PMC
April 2018

Bottom-of-sulcus focal cortical dysplasia presenting as epilepsia partialis continua multimodality characterization including 7T MRI.

Childs Nerv Syst 2018 06 14;34(6):1267-1269. Epub 2018 Feb 14.

Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 1800 Orleans Street, Zayed Tower, Room 4174, Baltimore, MD, 21287, USA.

Introduction: Bottom-of-sulcus focal cortical dysplasias are an under recognized, surgically treatable cause of focal epilepsy. Resection can dramatically reduce the seizure burden for children with refractory epilepsy, or eliminate seizures altogether.

Material And Methods: We report the case and present the results of multimodality evaluation of a 15-year-old young man who presented with long-standing partial epilepsy affecting his right leg, which over the years became refractory to therapy.

Results: High-resolution 3T MRI images acquired as a dedicated epilepsyprotocol were initially interpreted as unremarkable. On further review by an experienced specialist aware of clinical and electroencephalographic findings, a subtle focal cortical dysplasia was identified at the bottom of a sulcus near the medial aspect of the left precentral gyrus. After confirmation of the extent of the lesion with PET and ultra-high field 7T MRI, the patient underwent cortical mapping and focal resection and remains free of seizures.

Coclusions: This case emphasizes the need for a multidisciplinary approach to the evaluation of refractory focal epilepsy in children and highlights the potential role of ultra-high field 7T MRI in identifying the often subtle causative anatomic abnormalities.
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http://dx.doi.org/10.1007/s00381-018-3749-2DOI Listing
June 2018

Neonatal erythropoietin mitigates impaired gait, social interaction and diffusion tensor imaging abnormalities in a rat model of prenatal brain injury.

Exp Neurol 2018 04 26;302:1-13. Epub 2017 Dec 26.

Department of Pediatrics, University of New Mexico School of Medicine, University of New Mexico, Albuquerque, NM, United States; Department of Neurosciences, University of New Mexico School of Medicine, University of New Mexico, Albuquerque, NM, United States.

Children who are born preterm are at risk for encephalopathy of prematurity, a leading cause of cerebral palsy, cognitive delay and behavioral disorders. Current interventions are limited and none have been shown to reverse cognitive and behavioral impairments, a primary determinant of poor quality of life for these children. Moreover, the mechanisms of perinatal brain injury that result in functional deficits and imaging abnormalities in the mature brain are poorly defined, limiting the potential to target interventions to those who may benefit most. To determine whether impairments are reversible after a prenatal insult, we investigated a spectrum of functional deficits and diffusion tensor imaging (DTI) abnormalities in young adult animals. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) would induce multiple functional deficits concomitant with reduced microstructural white and gray matter integrity, and tested whether these abnormalities could be ameliorated using postnatal erythropoietin (EPO), an emerging neurorestorative intervention. On embryonic day 18 uterine arteries were transiently occluded for 60min via laparotomy. Shams underwent anesthesia and laparotomy for 60min. Pups were born and TSHI pups were randomized to receive EPO or vehicle via intraperitoneal injection on postnatal days 1 to 5. Gait, social interaction, olfaction and open field testing was performed from postnatal day 25-35 before brains underwent ex vivo DTI to measure fractional anisotropy, axial diffusivity and radial diffusivity. Prenatal TSHI injury causes hyperactivity, impaired gait and poor social interaction in young adult rats that mimic the spectrum of deficits observed in children born preterm. Collectively, these data show for the first time in a model of encephalopathy of prematurity that postnatal EPO treatment mitigates impairments in social interaction, in addition to gait deficits. EPO also normalizes TSHI-induced microstructural abnormalities in fractional anisotropy and radial diffusivity in multiple regions, consistent with improved structural integrity and recovery of myelination. Taken together, these results show behavioral and memory deficits from perinatal brain injury are reversible. Furthermore, resolution of DTI abnormalities may predict responsiveness to emerging interventions, and serve as a biomarker of CNS injury and recovery.
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http://dx.doi.org/10.1016/j.expneurol.2017.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849508PMC
April 2018

Advanced Pediatric Neurosonography Techniques: Contrast-Enhanced Ultrasonography, Elastography, and Beyond.

J Neuroimaging 2018 03 27;28(2):150-157. Epub 2017 Dec 27.

Division of Pediatric Radiology and Pediatric Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD.

Recent technical advances in neurosonography continue broadening the diagnostic utility, sensitivity, and specificity of ultrasound for detecting intracranial abnormalities bed side. The clinical and functional applications of neurosonography have significantly expanded since the 1980s when transcranial Doppler sonography first allowed anatomic and hemodynamic delineation of the intracranial vessels through the thin temporal skull. In the past few years, contrast-enhanced ultrasonography, elastography, 3D/4D reconstruction tools, and high-resolution microvessel imaging techniques have further enhanced the diagnostic significance of neurosonography. Given these advances, a thorough familiarity with these new techniques and devices is crucial for a successful clinical application allowing improved patient care. It is essential that future neurosonography studies compare these advanced techniques against the current "gold standard" computed tomography and magnetic resonance imaging to assure the accuracy of their diagnostic potential. This review will provide a comprehensive update on currently available advanced neurosonography techniques.
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http://dx.doi.org/10.1111/jon.12492DOI Listing
March 2018

Preclinical chorioamnionitis dysregulates CXCL1/CXCR2 signaling throughout the placental-fetal-brain axis.

Exp Neurol 2018 03 5;301(Pt B):110-119. Epub 2017 Nov 5.

Department of Pediatrics, University of New Mexico School of Medicine, Albuquerque, NM, United States; Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM, United States. Electronic address:

In the United States, perinatal brain injury (PBI) is a major cause of infant mortality and childhood disability. For a large proportion of infants with PBI, central nervous system (CNS) injury begins in utero with inflammation (chorioamnionitis/CHORIO) and/or hypoxia-ischemia. While studies show CHORIO contributes to preterm CNS injury and is also a common independent risk factor for brain injury in term infants, the molecular mechanisms mediating inflammation in the placental-fetal-brain axis that result in PBI remain a gap in knowledge. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been clinically implicated in CHORIO and in mature CNS injury, although their specific role in PBI pathophysiology is poorly defined. Given CXCL1/CXCR2 signaling is essential to neural cell development and neutrophil recruitment, a key pathological hallmark of CHORIO, we hypothesized CHORIO would upregulate CXCL1/CXCR2 expression in the placenta and fetal circulation, concomitant with increased CXCL1/CXCR2 signaling in the developing brain, immune cell activation, neutrophilia, and microstructural PBI. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague Dawley rats to induce CHORIO. Specifically, uterine arteries were occluded for 60min to induce placental transient systemic hypoxia-ischemia (TSHI), followed by intra-amniotic injection of lipopolysaccharide (LPS). Pups were born at E22. Placentae, serum and brain were collected along an extended time course from E19 to postnatal day (P)15 and analyzed using multiplex electrochemiluminescence (MECI), Western blot, qPCR, flow cytometry (FC) and diffusion tensor imaging (DTI). Results demonstrate that compared to sham, CHORIO increases placental CXCL1 and CXCR2 mRNA levels, concomitant with increased CXCR2 neutrophils. Interestingly, pup serum CXCL1 expression in CHORIO parallels this increase, with sustained elevation through P15. Analyses of CHORIO brains reveal similarly increased CXCL1/CXCR2 expression through P7, together with increased neutrophilia, microgliosis and peripheral macrophages. Similar to the placenta, cerebral neutrophilia was defined by increased CXCR2 surface expression and elevated myeloperoxidase expression (MPO), consistent with immune cell activation. Evaluation of microstructural brain injury at P15 with DTI reveals aberrant microstructural integrity in the callosal and capsular white matter, with reduced fractional anisotropy in superficial and deep layers of overlying cortex. In summary, using an established model of CHORIO that exhibits mature CNS deficits mimicking those of preterm survivors, we show CHORIO induces injury throughout the placental-fetal-brain axis with a CXCL1/CXCR2 inflammatory signature, neutrophilia, and microstructural abnormalities. These data are concomitant with abnormal cerebral CXCL1/CXCR2 expression, and support temporal aberrations in CXCL1/CXCR2 and neutrophil dynamics in the placental-fetal-brain axis following CHORIO. These investigations define novel targets for directed therapies for infants at high risk for PBI.
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http://dx.doi.org/10.1016/j.expneurol.2017.11.002DOI Listing
March 2018
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