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OBJECTIVE Pediatric intracranial aneurysms are rare. Most large series in the last 15 years reported on an average of only 39 patients. The authors sought to report their institutional experience with pediatric intracranial aneurysms from 1991 to 2021 and to compare pediatric patient and aneurysm characteristics with those of a contemporaneous adult cohort. METHODS Pediatric (≤ 18 years of age) and adult patients with one or more intracranial aneurysms were identified in a prospective database. Standard epidemiological features and outcomes of each pediatric patient were retrospectively recorded. These results were compared with those of adult aneurysm patients managed at a single institution over the same time period. RESULTS From a total of 4500 patients with 5150 intracranial aneurysms admitted over 30 years, there were 47 children with 53 aneurysms and 4453 adults with 5097 aneurysms; 53.2% of children and 36.4% of adults presented with a subarachnoid hemorrhage (SAH). Pediatric aneurysms were significantly more common in males, more likely giant (≥ 25 mm), and most frequently located in the middle cerebral artery. Overall, 85.1% of the pediatric patients had a modified Rankin Scale score ≤ 2 at the last follow-up (with a mean follow-up of 65.9 months), and the pediatric mortality rate was 10.6%; all 5 patients who died had an SAH. The recurrence rate of treated aneurysms was 6.7% (1/15) in the endovascular group but 0% (0/31) in the microsurgical group. No de novo aneurysms occurred in children (mean follow-up 5.5 years). CONCLUSIONS Pediatric intracranial aneurysms are significantly different from adult aneurysms in terms of sex, presentation, location, size, and outcomes. Future prospective studies will better characterize long-term aneurysm recurrence, rebleeds, and de novo aneurysm occurrences. The authors currently favor microsurgical over endovascular treatment for pediatric aneurysms.

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.

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.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.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.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.· 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..

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. 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. 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.

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.

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.

OBJECTIVESThe goal of this study was to evaluate clinical predictors of abnormal preoperative laboratory values in pediatric neurosurgical patients.METHODSData 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.RESULTSOf 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).CONCLUSIONSCritical 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.

Cotton balls are a versatile and efficient tool commonly used in neurosurgical procedures to absorb fluids and manipulate delicate tissues. However, the use of cotton balls is accompanied by the risk of accidental retention in the brain after surgery. Retained cotton balls can lead to dangerous immune responses and potential complications, such as adhesions and textilomas. In a previous study, we showed that ultrasound can be safely used to detect cotton balls in the operating area due to the distinct acoustic properties of cotton compared with the acoustic properties of surrounding tissue. In this study, we enhance the experimental setup using a 3D-printed custom depth box and a Butterfly IQ handheld ultrasound probe. Cotton balls were placed in variety of positions to evaluate size and depth detectability limits. Recorded images were then analyzed using a novel algorithm that implements recently released YOLOv4, a state-of-the-art, real-time object recognition system. As per the radiologists’ opinion, the algorithm was able to detect the cotton ball correctly 61% of the time, at approximately 32 FPS. The algorithm could accurately detect cotton balls up to 5mm in diameter, which corresponds to the size of surgical balls used by neurosurgeons, making the algorithm a promising candidate for regular intraoperative use.

Chronic pain is prevalent in adults with cerebral palsy. We aimed to explore associations between chronic pain and somatosensory, motor, cognitive, etiologic, and environmental factors in adults with cerebral palsy. This cross-sectional study enrolled 17 adult participants with cerebral palsy (mean age 31 years; 8 female; Gross Motor Functional Classification Status levels I-V) able to self-report and 10 neurotypical adult volunteers (mean age 34 years; 9 female). Participants reported pain characteristics, demographics, and affective factors. Physical examination included somatosensory and motor evaluation. Between-group comparisons used a ranksum test, and correlation analyses estimated effect size in terms of shared variance (ρ2). Individuals with cerebral palsy reported greater pain intensity, neuropathic qualities, and nociceptive qualities than control participants. Higher pain intensity was associated with female gender (ρ2 = 16%), anxiety/depression symptoms (ρ2 = 10%), and lower household income (ρ2 = 19%). It was also associated with better communicative ability (ρ2 = 21%), spinothalamic (sharp/temperature) sensory abnormalities (ρ2 = 33%), and a greater degree of prematurity (ρ2 = 17%). This study highlights similarity of chronic pain associations in people with cerebral palsy with patterns seen in other populations with chronic pain. Spinothalamic sensory abnormalities suggest central pain mechanisms.

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 FiO2 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.

OBJECTIVEBrain 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.METHODSThe 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.RESULTSTwenty-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).CONCLUSIONSIn 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.

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.

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 60 minutes via laparotomy. Shams underwent anesthesia and laparotomy for 60 min. 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.

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.

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.

Cell-based therapies hold significant promise for infants at risk for cerebral palsy (CP) from perinatal brain injury (PBI). PBI leading to CP results from multifaceted damage to neural cells. Complex developing neural networks are injured by neural cell damage plus unique perturbations in cell signaling. Given that cell-based therapies can simultaneously repair multiple injured neural components during critical neurodevelopmental windows, these interventions potentially offer efficacy for patients with CP. Currently, the use of cell-based interventions in infants at risk for CP is limited by critical gaps in knowledge. In this review, we will highlight key questions facing the field, including: Who are optimal candidates for treatment? What are the goals of therapeutic interventions? What are the best strategies for agent delivery, including timing, dosage, location, and type? And, how are short- and long-term efficacy reliably tracked? Challenges unique to treating PBI with cell-based therapies, and lessons learned from cell-based therapies in closely related neurological disorders in the mature central nervous system, will be reviewed. Our goal is to update pediatric specialists who may be counseling families about the current state of the field. Finally, we will evaluate how rigor can be increased in the field to ensure the safety and best interests of this vulnerable patient population.

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.

OBJECTIVEMedically refractory spasticity and dystonia are often alleviated with intrathecal baclofen (ITB) administration through an indwelling catheter inserted in the lumbar spine. In patients with cerebral palsy, however, there is a high incidence of concomitant neuromuscular scoliosis. ITB placement may be technically challenging in those who have severe spinal deformity or who have undergone prior instrumented thoracolumbar fusion. Although prior reports have described drilling through the lumbar fusion mass with a high-speed bur, as well as IT catheter implantation at the foramen magnum or cervical spine, these approaches have notable limitations. To the authors' knowledge, this is the first report of ITB placement using cone beam CT (CBCT) image guidance to facilitate percutaneous IT catheterization.METHODSData were prospectively collected on patients treated between November 2012 and June 2014. In the interventional radiology suite, general anesthesia was induced and the patient was positioned prone. Imaging was performed to identify the optimal trajectory. Percutaneous puncture was performed at an entry site with image-guided placement of a sheathed needle. CBCT provided real-time 2D projections and 3D reconstructions for detailed volumetric imaging. A biopsy drill was passed through the sheath, and subsequently a Tuohy needle was advanced intrathecally. The catheter was threaded cephalad under fluoroscopic visualization. After tip localization and CSF flow were confirmed, the stylet was replaced, the external catheter tubing was wrapped sterilely in a dressing, and the patient was transported to the operating room. After lateral decubitus positioning of the patient, the IT catheter was exposed and connected to the distal abdominal tubing with typical pump placement.RESULTSOf 15 patients with Gross Motor Function Classification System Levels IV and V cerebral palsy and instrumented thoracolumbar fusion, 8 had predominantly spasticity, and 7 had mixed spasticity and dystonia. The mean age of patients was 20.1 years (range 13–27 years). Nine patients underwent initial catheter and pump placement, and 6 underwent catheter replacement. The procedure was technically successful, with accurate spinal catheter placement in all patients. The median hospital stay was 4 days (IQR 3–5 days). One patient had an early postoperative urinary tract infection. With a mean follow-up of 25.8 months (median 26, range 18–38 months), no CSF leakage or catheter failure occurred. One late infection due to Pseudomonas aeruginosa (requiring pump explantation) occurred at 4 months, probably secondary to recurrent urinary tract infections.CONCLUSIONSImage-guided CBCT navigation resulted in accurate percutaneous placement of the IT catheter for ITB pumps in patients with prior instrumented thoracolumbar fusion. The multimodality approach is an alternate technique that may be used for IT catheter insertion in patients with complex lumbar spine anatomy, extending the potential to provide safe, durable ITB therapy in this population.

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.

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 ex vivo 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 (p < 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 (p < 0.05). Early postnatal CXCR2 blockade also reduced microstructural abnormalities in white matter and hippocampus at P21 (p < 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.

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.

Traumatic brain injury (TBI) is a major public health issue, with recently increased awareness of the potential long-term sequelae of repetitive injury. Although TBI is common, objective diagnostic tools with sound neurobiological predictors of outcome are lacking. Indeed, such tools could help to identify those at risk for more severe outcomes after repetitive injury and improve understanding of biological underpinnings to provide important mechanistic insights. We tested the hypothesis that acute and subacute pathological injury, including the microgliosis that results from repeated mild closed head injury (rmCHI), is reflected in susceptibility-weighted magnetic resonance imaging and diffusion-tensor imaging microstructural abnormalities. Using a combination of high-resolution magnetic resonance imaging, stereology, and quantitative PCR, we studied the pathophysiology of male mice that sustained seven consecutive mild traumatic brain injuries over 9 days in acute (24 hr) and subacute (1 week) time periods. rmCHI induced focal cortical microhemorrhages and impaired axial diffusivity at 1 week postinjury. These microstructural abnormalities were associated with a significant increase in microglia. Notably, microgliosis was accompanied by a change in inflammatory microenvironment defined by robust spatiotemporal alterations in tumor necrosis factor-α receptor mRNA. Together these data contribute novel insight into the fundamental biological processes associated with repeated mild brain injury concomitant with subacute imaging abnormalities in a clinically relevant animal model of repeated mild TBI. These findings suggest new diagnostic techniques that can be used as biomarkers to guide the use of future protective or reparative interventions. © 2016 Wiley Periodicals, Inc.

OBJECTIVE Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for otherwise healthy full-term infants around the world. Currently, the primary treatment for infant TBI is supportive, as no targeted therapies exist to actively promote recovery. The developing infant brain, in particular, has a unique response to injury and the potential for repair, both of which vary with maturation. Targeted interventions and objective measures of therapeutic efficacy are needed in this special population. The authors hypothesized that MRI and serum biomarkers can be used to quantify outcomes following infantile TBI in a preclinical rat model and that the potential efficacy of the neuro-reparative agent erythropoietin (EPO) in promoting recovery can be tested using these biomarkers as surrogates for functional outcomes. METHODS With institutional approval, a controlled cortical impact (CCI) was delivered to postnatal Day (P)12 rats of both sexes (76 rats). On postinjury Day (PID)1, the 49 CCI rats designated for chronic studies were randomized to EPO (3000 U/kg/dose, CCI-EPO, 24 rats) or vehicle (CCI-veh, 25 rats) administered intraperitoneally on PID1–4, 6, and 8. Acute injury (PID3) was evaluated with an immunoassay of injured cortex and serum, and chronic injury (PID13–28) was evaluated with digitized gait analyses, MRI, and serum immunoassay. The CCI-veh and CCI-EPO rats were compared with shams (49 rats) primarily using 2-way ANOVA with Bonferroni post hoc correction. RESULTS Following CCI, there was 4.8% mortality and 55% of injured rats exhibited convulsions. Of the injured rats designated for chronic analyses, 8.1% developed leptomeningeal cyst–like lesions verified with MRI and were excluded from further study. On PID3, Western blot showed that EPO receptor expression was increased in the injured cortex (p = 0.008). These Western blots also showed elevated ipsilateral cortex calpain degradation products for αII-spectrin (αII-SDPs; p < 0.001), potassium chloride cotransporter 2 (KCC2-DPs; p = 0.037), and glial fibrillary acidic protein (GFAP-DPs; p = 0.002), as well as serum GFAP (serum GFAP-DPs; p = 0.001). In injured rats multiplex electrochemiluminescence analyses on PID3 revealed elevated serum tumor necrosis factor alpha (TNFα p = 0.01) and chemokine (CXC) ligand 1 (CXCL1). Chronically, that is, in PID13–16 CCI-veh rats, as compared with sham rats, gait deficits were demonstrated (p = 0.033) but then were reversed (p = 0.022) with EPO treatment. Diffusion tensor MRI of the ipsilateral and contralateral cortex and white matter in PID16–23 CCI-veh rats showed widespread injury and significant abnormalities of functional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD); MD, AD, and RD improved after EPO treatment. Chronically, P13–P28 CCI-veh rats also had elevated serum CXCL1 levels, which normalized in CCI-EPO rats. CONCLUSIONS Efficient translation of emerging neuro-reparative interventions dictates the use of age-appropriate preclinical models with human clinical trial–compatible biomarkers. In the present study, the authors showed that CCI produced chronic gait deficits in P12 rats that resolved with EPO treatment and that chronic imaging and serum biomarkers correlated with this improvement.

Introduction Preterm birth is a major cause of infant morbidity and long-term disability, and is associated with numerous central nervous system (CNS) deficits. Infants exposed to intrauterine inflammation, specifically chorioamnionitis, are at risk for very early preterm birth and neurological complications including cerebral palsy, epilepsy, and behavioral and cognitive deficits. However, placenta-brain axis abnormalities and their relationship to subsequent permanent CNS injury remain poorly defined. Methods Intrauterine injury was induced in rats on embryonic day 18 (E18) by transient systemic hypoxia-ischemia (TSHI) and intra-amniotic lipopolysaccharide (LPS) injection. Placenta, brain and serum were collected from E19 to postnatal day 0 (P0). Histology, TUNEL staining, western blot and multiplex immunoassays were used to quantify placental and brain abnormalities, and fetal serum cytokine levels. Results Prenatal TSHI + LPS caused acute and subacute placental injury hallmarked by inflammatory infiltrate, edema, hemorrhage and cell death along with placental increases in IL-1β and TNFα. TSHI + LPS increased a diverse array of circulating inflammatory proteins including IL-1β, TNFα, IL-6, IL-10, IL-4, IFNγ and CXCL1, both immediately after TSHI + LPS and in live born pups. CNS inflammation was characterized by increased CXCL1. Discussion Prenatal TSHI + LPS in rats induces placental injury and inflammation histologically consistent with chorioamnionitis, concomitant with elevated serum and CNS pro-inflammatory cytokines. This model accurately recapitulates key pathophysiological processes observed in extremely preterm infants including placental, fetal, and CNS inflammation. Further investigation into the mechanism of CNS injury following chorioamnionitis and the placental-brain axis will guide the use of future interventions.

Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies.

Introduction: 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. Objective: To evaluate the relationship between neonatal neurobehavioral findings on the NNNS and measures of ventricular dilation and associated brain injury on HUS and MRI. Materials and Methods: 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. Results: 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. Conclusion: 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.

Posthemorrhagic hydrocephalus of prematurity (PHHP) remains a global challenge. Early preterm infants (

Space-occupying lesions—including brain tumors, vein of Galen malformations, and arachnoid cysts—represent important intracranial mass lesions and share certain clinical features. Improvements in management in recent years have made the prognosis of these serious disorders considerably more favorable than in the past in selected cases. Still, very few children survive without unfavorable consequences, including hydrocephalus, intractable seizures, or significant developmental delay. Risks of interventions, such as anesthesia and blood loss, are tolerated better by infants older than 3 months, and definitive treatment may be deferred until later in infancy. Arachnoid cysts are an exception and can often be treated immediately with minimally invasive techniques.

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. 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. 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. 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.

Object With the recent increasing interest in outcomes after repetitive mild traumatic brain injury (rmTBI; e.g., sports concussions), several models of rmTBI have been established. Characterizing these models in terms of behavioral and histopathological outcomes is vital to assess their clinical translatability. The purpose of this study is to provide an in-depth behavioral and histopathological phenotype of a clinically relevant model of rmTBI. Methods The authors used a previously published weight-drop model of rmTBI (7 injuries in 9 days) in 2- to 3-month-old mice that produces cognitive deficits without persistent loss of consciousness, seizures, gross structural imaging findings, or microscopic evidence of structural brain damage. Injured and sham-injured (anesthesia only) mice were subjected to a battery of behavioral testing, including tests of balance (rotarod), spatial memory (Morris water maze), anxiety (open field plus maze), and exploratory behavior (hole-board test). After behavioral testing, brains were assessed for histopathological outcomes, including brain volume and microglial and astrocyte immunolabeling. Results Compared with sham-injured mice, mice subjected to rmTBI showed increased exploratory behavior and had impaired balance and worse spatial memory that persisted up to 3 months after injury. Long-term behavioral deficits were associated with chronic increased astrocytosis and microgliosis but no volume changes. Conclusions The authors demonstrate that their rmTBI model results in a characteristic behavioral phenotype that correlates with the clinical syndrome of concussion and repetitive concussion. This model offers a platform from which to study therapeutic interventions for rmTBI.

Object While progesterone has been well studied in experimental models of adult traumatic brain injury (TBI), it has not been evaluated in pediatric models. The study of promising interventions in pediatric TBI is important because children have the highest public health burden of such injuries. Therapies that are beneficial in adults may not necessarily be effective in the pediatric population. The purpose of this study was to evaluate whether progesterone treatment improves outcomes in an experimental model of pediatric TBI. Methods The authors determined whether progesterone administered after controlled cortical impact (CCI) improves functional and histopathological outcomes in 4-week-old mice. Both male and female mice (58 mice total) were included in this study, as the majority of prior studies have used only male and/or reproductively senescent females. Mice were randomized to treatment with progesterone or vehicle and to CCI injury or sham injury. Motor (wire grip test) and memory (Morris water maze) testing were performed to determine the effect of progesterone on TBI. Lesion volume was also assessed. Results Compared with their vehicle-treated counterparts, the progesterone-treated CCI-injured male mice had improved motor performance (p < 0.001). In contrast, progesterone-treated CCI-injured female mice had a worse performance than their vehicle-treated counterparts (p = 0.001). Progesterone treatment had no effect on spatial memory performance or lesion volume in injured male or female mice. Conclusions These data suggest a sex-specific effect of progesterone treatment after CCI in adolescent mice and could inform clinical trials in children.

Recently, there has been increasing interest in outcomes after repetitive mild traumatic brain injury (rmTBI) (e.g., sports concussions). Although most of the scientific attention has focused on elite athlete populations, the sequelae of rmTBI in children and young adults have not been well studied. Prior TBI studies have suggested that developmental differences in response to injury, including differences in excitotoxicity and inflammation, could result in differences in functional and histopathological outcomes after injury. The purpose of this study is to compare outcomes in adolescent (5-week-old) versus adult (4-month-old) mice in a clinically relevant model of rmTBI. We hypothesized that functional and histopathological outcomes after rmTBI would differ in developing adolescent brains compared with mature adult brains. Male adolescent and adult (C57Bl/6) mice were subjected to a weight drop model of rmTBI (n = 10-16/group). Loss of consciousness (LOC) after each injury was measured. Functional outcomes were assessed including tests of balance (rotorod), spatial memory (Morris water maze), and impulsivity (elevated plus maze). After behavioral testing, brains were assessed for histopathological outcomes including microglial immunolabeling and N-methyl-d-aspartate (NMDA) receptor subunit expression. Injured adolescent mice had longer LOC than injured adult mice compared with their respective sham controls. Compared with sham mice, adolescent and adult mice subjected to rmTBI had impaired balance, increased impulsivity, and worse spatial memory that persisted up to 3 months after injury, and the effect of injury was worse in adolescent than in adult mice in terms of spatial memory. Three months after injury, adolescent and adult mice demonstrated increased ionized calcium binding adaptor 1 (IbA1) immunolabeling compared with sham controls. Compared with sham controls, NMDA receptor subtype 2B (NR2B) expression in the hippocampus was reduced by ∼20% in both adolescent and adult injured mice. The data suggest that injured adolescent mice may show a distinct pattern of functional deficits after injury that warrants further mechanistic studies.

Object Hydrocephalus remains a major public health problem. Conventional treatment has relied on extracranial shunting of CSF to another systemic site, but this approach is associated with a high rate of complications. Endoscopic third ventriculostomy (ETV) is a novel treatment for select forms of hydrocephalus that can eliminate the need for implantation of a lifelong ventricular shunt system. However, the indications for ETV are contested and its long-term effectiveness is not well established. Methods The authors selected 100 consecutive patients who underwent ETV for hydrocephalus beginning in 1994. Patients were enrolled and treated at a single institution by a single surgeon. The primary outcome was success of ETV, with success defined as no need for subsequent surgery for hydrocephalus. Results Ninety-five patients satisfied the inclusion criteria. The mean follow-up period was 5.1 years (median 4.7 years) with follow-up data available for as long as 17 years. Patients commonly presented with headache (85%), ataxia (34%), emesis (29%), and changes in vision (27%). The success rate for ETV was 75%. Twenty-one patients (22%) in the series had malfunctioning shunts preoperatively and 13 (62%) were successfully treated with ETV. Preoperative inferior bowing of the third ventricle floor on MRI was significantly associated with ETV success (p < 0.05). Conclusions Endoscopic third ventriculostomy is an effective and durable treatment for select patients with hydrocephalus. When successful, the procedure eliminates the lifelong complications associated with implanted ventricular shunts.

Object Although survival for extremely low gestational age newborns (ELGANs) has improved in the past 3 decades, these infants remain prone to complications of prematurity, including intraventricular hemorrhage (IVH). The authors reviewed the outcomes for an entire cohort of ELGANs who suffered severe IVH at their institution during the past 12 years to gain a better understanding of the natural history of IVH and frequency of ventriculoperitoneal (VP) shunt placement in this population. Methods Data from the neonatal ICU (NICU) database, neurosurgery operative log, and medical records were used to identify and follow up all ELGANs who suffered a severe IVH between 1997 and 2008. Trends between Period 1 (1997–2001) and Period 2 (2004–2008) were analyzed using the Pearson chi-square test. Results Between 1997 and 2008, 1335 ELGANs were admitted to the NICU at the authors' institution within 3 days of birth, and 111 (8.3%) of these infants suffered a severe IVH. Survival to 2 years, incidence of severe IVH, neonatal risk factors (gestational age, birth weight, and incidence of necrotizing enterocolitis), ventriculomegaly on cranial ultrasonography, and use of serial lumbar punctures for symptomatic hydrocephalus were all stable. Infants from Period 2 had a significantly lower incidence of bronchopulmonary dysplasia and sepsis than infants from Period 1 (both p < 0.001). All ELGANs with severe IVH and ventriculomegaly underwent long-term follow-up to identify shunt status at late follow-up. Twenty-two ELGANs (20%) with severe IVH required a temporary ventriculosubgaleal (VSG) shunt. Three infants with VSG shunts showed spontaneous hydrocephalus resolution, and 2 infants died of unrelated causes during the neonatal admission. The temporary VSG shunt complication rate was 20% (12% infection and 8% malfunction). Sixteen percent of all ELGANs (18 of 111) with severe IVH eventually required permanent ventricular shunt insertion. Six (35%) of 17 infants with a permanent VP shunt required at least 1 permanent shunt revision during the 1st year. The proportion of ELGANs with severe IVH who required a temporary VSG (35%) or permanent VP shunt (30%) during Period 1 decreased by more than 60% in Period 2 (10% [p = 0.005] and 8.3% [p = 0.009], respectively). Conclusions The authors report for the first time a marked reduction over the past 12 years in the proportion of ELGANs with severe IVH who required surgical intervention for hydrocephalus. Using the NICU database, the authors were able to identify and follow all ELGANs with severe IVH and ventriculomegaly. They speculate that the reduction in ventricular shunt rate results from improved neonatal medical care, including reduced infection, improved bronchopulmonary dysplasia, and postnatal steroid avoidance, which may aid innate repair mechanisms. Multicenter prospective trials and detailed analyses of NICU parameters of neonatal well-being are needed to understand how perinatal factors influence the propensity to require ventricular shunting.

Object Preterm infants are at risk for perinatal complications, including germinal matrix–intraventricular hemorrhage (IVH) and subsequent posthemorrhagic hydrocephalus (PHH). This review summarizes the current understanding of the epidemiology, pathophysiology, management, and outcomes of IVH and PHH in preterm infants. Methods The MEDLINE database was systematically searched using terms related to IVH, PHH, and relevant neurosurgical procedures to identify publications in the English medical literature. To complement information from the systematic search, pertinent articles were selected from the references of articles identified in the initial search. Results This review summarizes the current knowledge regarding the epidemiology and pathophysiology of IVH and PHH, primarily using evidence-based studies. Advances in obstetrics and neonatology over the past few decades have contributed to a marked improvement in the survival of preterm infants, and neurological morbidity is also starting to decrease. The incidence of IVH is declining, and the incidence of PHH will likely follow. Currently, approximately 15% of preterm infants who suffer severe IVH will require permanent CSF diversion. The clinical presentation and surgical management of symptomatic PHH with temporary ventricular reservoirs (ventricular access devices) and ventriculosubgaleal shunts and permanent ventriculoperitoneal shunts are discussed. Preterm infants who develop PHH that requires surgical treatment remain at high risk for other related neurological problems, including cerebral palsy, epilepsy, and cognitive and behavioral delay. This review highlights numerous opportunities for further study to improve the care of these children. Conclusions A better grasp of the pathophysiology of IVH is beginning to impact the incidence of IVH and PHH. Neonatologists conduct rigorous Class I and II studies to advance the outcomes of preterm infants. The need for well-designed multicenter trials is essential because of the declining incidence of IVH and PHH, variations in referral patterns, and neonatal ICU and neurosurgical management. Well-designed multicenter trials will eventually produce evidence to enable neurosurgeons to provide their smallest, most vulnerable patients with the best practices to minimize perioperative complications and permanent shunt dependence, and most importantly, optimize long-term neurodevelopmental outcomes.

Encephalopathy of prematurity (EoP) is a term that encompasses the central nervous system (CNS) abnormalities associated with preterm birth. To best advance translational objectives and uncover new therapeutic strategies for brain injury associated with preterm birth, preclinical models of EoP must include similar mechanisms of prenatal global injury observed in humans and involve multiple components of the maternal-placental-fetal system. Ideally, models should produce a similar spectrum of functional deficits in the mature animal and recapitulate multiple aspects of the pathophysiology. To mimic human systemic placental perfusion defects, placental underperfusion and/or chorioamnionitis associated with pathogen-induced inflammation in early preterm birth, we developed a model of prenatal transient systemic hypoxia-ischemia (TSHI) combined with intra-amniotic lipopolysaccharide (LPS). In pregnant Sprague Dawley rats, TSHI via uterine artery occlusion on embryonic day 18 (E18) induces a graded placental underperfusion defect associated with increasing CNS damage in the fetus. When combined with intra-amniotic LPS injections, placental inflammation is increased and CNS damage is compounded with associated white matter, gait and imaging abnormalities. Prenatal TSHI and TSHI+LPS prenatal insults meet several of the criteria of an EoP model including recapitulating the intrauterine insult, causing loss of neurons, oligodendrocytes and axons, loss of subplate, and functional deficits in adult animals that mimic those observed in children born extremely preterm. Moreover, this model allows for the dissection of inflammation induced by divergent injury types.

Object Nonaccidental head trauma (NAHT) is a major cause of death in infants. During the current economic recession, the authors noticed an anecdotal increase in infants with NAHT without an increase in the overall number of infants admitted with traumatic injuries. An analysis was performed to determine whether there was an association between economic recession and NAHT. Methods With Institutional Review Board approval, the trauma database was searched for NAHT in infants 0–2 years old during nonrecession (December 2001 to November 2007) and recession (December 2007 to June 2010) periods. Incidence is reported as infants with NAHT per month summarized over time periods. Continuous variables were compared using Mann-Whitney U-tests, and proportions were compared using the Fisher exact test. Results Six hundred thirty-nine infant traumas were observed during the study time period. From the nonrecession to the recession period, there was an 8.2% reduction in all traumas (458 in 72 months [6.4 /month] vs 181 in 31 months [5.8/month]) and a 3.5% reduction in accidental head traumas (142 in 72 months [2.0/month] vs 59 in 31 months [1.9/month]). Nonaccidental head trauma accounted for 14.6% of all traumas (93/639). The median patient age was 4.0 months and 52% were boys. There were no significant differences in the representative counties of referral or demographics between nonrecession and recession populations (all p > 0.05). The monthly incidence rates of NAHT doubled from nonrecession to recession periods (50 in 72 months [0.7/month] vs 43 in 31 months [1.4/month]; p = 0.01). During this recession, at least 1 NAHT was reported in 68% of the months compared with 44% of the months during the nonrecession period (p = 0.03). The severity of NAHTs also increased, with a greater proportion of deaths (11.6% vs 4%, respectively; p = 0.16) and severe brain injury (Glasgow Coma Scale score ≤ 8: 19.5% vs 4%, respectively; p = 0.06) during the recession. Conclusions In the context of an overall reduction in head trauma, the significant increase in the incidence of NAHT appears coincident with economic recession. Although the cause is likely multifactorial, a full analysis of the basis of this increase is beyond the scope of this study. This study highlights the need to protect vulnerable infants during challenging economic times.

Hippocampal recording using depth electrodes is indicated in a small subgroup of patients with medically intractable seizures. There are several conventional techniques for implantation of hippocampal depth electrodes. We describe a new method for hippocampal depth electrode placement using an image-guided endoscopic transoccipital route. This technique is simple and effective, eliminating several drawbacks of conventional techniques.One silicone-injected cadaver head was used. A rigid endoscope sheath was inserted through a transoccipital corridor into the atrium of the lateral ventricle and then advanced to the temporal horn. Each of the hemispheres was cannulated. The hippocampus was identified visually, and a depth electrode was inserted into the substance of the hippocampus along its long axis under direct vision.In both hemispheres we were able to successfully implant the depth electrode within the hippocampus. The advantages of our technique over conventional approaches are (1) there is no need for frame-based stereotaxy, thus reducing operating time and patient discomfort, (2) the electrodes are inserted into the hippocampus under direct endoscopic visualization, reducing the chance of injury to vascular structures, (3) there is no need to insert a larger cannula into the hippocampus before placement of the electrodes, reducing trauma to the hippocampus, and (4) the number of electrodes within the hippocampus can be assessed at the end of the procedure, reducing malposition.We believe that image-guided endoscopic transoccipital hippocampal depth electrode placement can be performed with precision equal or superior to conventional techniques but without their major disadvantages.

Object In recent years there has been an increased incidence of golf-associated head injuries in children and adolescents. At the authors' institution, they have identified a unique pattern of head injury associated with a swinging golf club. In this study, the authors highlight the mechanism of this injury and report their experience treating it. Methods The authors reviewed the database of Rainbow Babies and Children's Hospital Trauma Center and performed a retrospective analysis of golf injuries recorded over a 10-year period (January 2000–April 2010). They identified 13 children (9 boys and 4 girls) who sustained head injuries in golfing accidents. All patients were 10 years of age or younger. The medical charts were reviewed and follow-up interviews were conducted to better delineate the details of the injuries. Results Injuries included 13 depressed skull fractures, 7 epidural hematomas, and 1 cerebral contusion. All 13 patients sustained their injuries after being struck in the head by a golf club. Seven sustained injuries on the follow-through of the initial swing and 3 sustained injuries on the backswing. All but one patient required neurosurgical intervention. Five patients developed neurological sequelae. None of the children had prior experience with golf equipment. All but one injury occurred in the child's own backyard. There was no direct supervision by an adult in any of the cases. Conclusions Golfing can lead to serious head injuries in children. The authors noticed a unique pattern of golf-related head injuries, previously not described, that they have termed the “swing-ding.” This golf club–inflicted injury occurs when a child stands too close to a swinging golfer and is struck in the head, subsequently sustaining a comminuted depressed skull fracture in the frontal or temporal region, with or without further intracranial injury. The study suggests that a lack of adult supervision, minimal previous golf experience, and proximity of the child to the swinging golfer are all implicated in this head injury pattern.

Object Surgery for medically intractable epilepsy secondary to unihemispheric pathology has evolved from more aggressive hemispherectomy to less aggressive variations of hemispherotomy. The authors propose a novel minimally invasive endoscopic hemispherotomy that should give results comparable to conventional open craniotomy and microsurgery. Methods Endoscopic transventricular hemispherotomy was performed in 5 silicon-injected cadaveric heads in the authors' minimally invasive neurosurgery laboratory. The lateral ventricle was accessed endoscopically through a frontal and occipital bur hole. White matter disconnections were performed to unroof the temporal horn and to disconnect the frontobasal region, corpus callosum, and fornix. Results Using an endoscopic transventricular approach, all white matter disconnections were successfully performed in all 5 cadavers. Conclusions The authors have demonstrated the feasibility of endoscopic transventricular hemispherotomy in a cadaveric model. The technique is simple and could be useful in a subgroup of patients with parenchymal volume loss and ventriculomegaly.

Epilepsy associated with preterm birth is often refractory to anticonvulsants. Children who are born preterm are also prone to cognitive delay and behavioral problems. Brains from these children often show diffuse abnormalities in cerebral circuitry that is likely caused by disrupted development during critical stages of cortical formation. To test the hypothesis that prenatal injury impairs the developmental switch of gamma-amino butyric acid (GABA)ergic synapses from excitatory to inhibitory, thereby disrupting cortical circuit formation and predisposing to epilepsy, we used immunohistochemistry to compare the expression of cation-chloride transporters that developmentally regulate postsynaptic GABAergic discharges in postmortem cerebral samples from infants born preterm with known white matter injury (n = 11) with that of controls with minimal white matter gliosis (n = 7). Controls showed the expected developmental expression of cation-chloride transporters NKCC1 and KCC2 and ofcalretinin, a marker of a GABAergic neuronal subpopulation. Samples from infants with white matter damage showed a significant loss of expression of both NKCC1 and KCC2 in subplate and white matter. By contrast, there were no significant differences in total cell number or glutamate transporter VGLUT1 expression. Together, these novel findings suggest a molecular mechanism involved in the disruption of a critical stage of cerebral circuit development after brain injury from preterm birth that may predispose to epilepsy.

Object Trauma secondary to car surfing is a unique mechanism of head and spinal injury in children and adolescents. In this study, the authors present their experience with neurological injuries resulting from car surfing and describe the growing national trend of car-surfing injuries and the increasing portrayal of this activity in the media. Methods A retrospective study of the Rainbow Babies and Children's Hospital trauma database was conducted to identify all cases of neurological injuries secondary to car surfing. Between January 1995 and December 2008, 7 patients ≤ 16 years of age, including 6 boys and 1 girl, were identified. The charts of these patients were reviewed. National data on car-surfing fatalities over the same time period in children and adolescents 10–20 years of age were obtained from the National Highway Traffic Safety Administration, and these data were analyzed for national trends in car-surfing fatalities. Results All 7 children with injuries due to car surfing suffered traumatic head injuries. Three patients fell from the back of the moving vehicle, 2 fell from the hood, 1 fell from the side of the vehicle, and 1 patient sustained head injuries after intentionally jumping off the moving vehicle. All 7 children suffered intracranial bleeding, and 4 had associated skull fractures. One patient underwent craniotomy to evacuate an acute subdural hematoma. The other 6 patients required nonoperative treatment. Four patients had permanent neurological problems. National statistics have shown a steady rise in car-surfing fatality rates since 2000, especially in California, Florida, and Texas. Conclusions Car surfing is an unusual but serious mechanism of neurological injury in children and adolescents. Despite its dangers, car surfing is becoming a more common pastime in the pediatric population. National statistics have shown a steady rise in car-surfing fatalities since 2000. This national rise in fatalities chronologically overlaps with the introduction of media depictions of the activity since 1995. Increased awareness of the dangers of car surfing may help prevent future head injuries.

Object The increase in the prevalence of nonsynostotic occipital deformational plagiocephaly in infants, which resulted from the American Academy of Pediatrics' 1992 recommendation to have healthy infants sleep supine, has been accompanied by significant controversy in diagnosis and management. The controversy was exacerbated by the 1998 FDA classification of cranial orthotic devices as Class II devices requiring premarket notification, and the subsequent increase in treatment-associated costs. Methods Two independent reviews of the literature were conducted to clarify the objective evidence available within the context of pediatric craniofacial knowledge. Results . Although deformational plagiocephaly is not a life-threatening problem, it is a source of disfigurement for children that may be detrimental to their well-being. Current methods for quantifying the degree of disfigurement have limited interrater reliability, and no prospective randomized controlled trials comparing the efficacy of cranial orthoses to repositioning and physical therapy protocols have been published. Despite this lack of Class I evidence, cranial orthoses are routinely and effectively used to treat persistent severe deformational plagiocephaly. The need for the current FDA regulations has not been supported by clinical experience and reported complications. Conclusions This review resulted in the following recommendations: 1) more parental education is needed to minimize the development and progression of deformational plagiocephaly; 2) mild deformity can be treated with repositioning and physical therapy protocols; and 3) severe deformity is likely to be corrected more quickly and effectively with cranial orthosis (when used during the appropriate period of infancy) than with repositioning and physical therapy. The available data do not support the need for FDA classification for cranial orthoses as Class II devices requiring premarket notification. Removal of the regulations, which centralized production of the orthoses to larger companies and markedly increased charges, will probably eliminate much of the controversy and parental anxiety generated by marketing strategies.

The authors conducted a multiinstitutional, retrospective analysis to better define outcome and prognostic indicators for temporal lobe epilepsy surgery for suspected mesial temporal sclerosis (MTS) in young children.Data were collected for all children undergoing temporal resections at four epilepsy centers over approximately 10 years. Children with a histopathological diagnosis of neoplasm were excluded. Forty-nine patients (28 boys and 21 girls) were included in the study. Their mean age at surgery was 9.1 years (range 1.25-13.9 years). The mean age at seizure onset was 3.2 years (range birth-10 years). Histopathological examination demonstrated MTS in 26 cases, gliosis in nine, dysplasia in five, gliosis with dysplasia in four, and nonspecific or normal findings in five. Forty-one anterior temporal lobectomies (nine tailored) and eight selective amygdalohippocam-pectomies were performed (28 left side, 21 right side). Twenty-nine children (59.2%) underwent invasive monitoring. Operative complications included extraaxial hematomas (two cases), cerebrospinal fluid leaks (two cases), and hydrocephalus (one case), each in children undergoing invasive monitoring. The mean duration of follow up was 26.4 months (range 5-74 months) overall and 23.9 months (range 6-74 months) for the Engel Class I subgroup. Outcomes at the most recent follow-up examination were categorized as Engel Class I-II in 31 (63.3%) of 49 children overall, 20 (76.9%) of 26 children with confirmed MTS, four (36.4%) of 11 children with gliosis, and four (57.1%) of seven children with dysplasia. All patients who underwent selective amygdalohippocampectomies had confirmed MTS and Engel Class I outcomes. Patients with more than one seizure type (p = 0.048) or moderate to severe developmental delay (p = 0.03) had significantly worse outcomes (Engel Class III or IV). Age at seizure onset, age at surgery, and duration of seizure disorder were not significantly related to outcome. There was a trend for bilateral or extratemporal findings on electroencephalography (EEG) (p = 0.157), high preoperative seizure frequency (p = 0.097), and magnetic resonance (MR) imaging findings inconsistent with MTS (p = 0.142) to be associated with worse outcome, although it did not reach statistical significance. In only 12 (46.1%) of the 26 patients with confirmed MTS was the condition prospectively diagnosed on preoperative MR imaging.Younger children with temporal lobe epilepsy have satisfying surgical outcomes, particularly when MTS is present. Magnetic resonance imaging may not be as sensitive in detecting MTS in children as in older patients. Negative predictors identified include multiple seizure types and preoperative developmental delay. Multifocal or bilateral EEG findings, high preoperative seizure frequency, and MR imaging findings inconsistent with MTS also independently suggested worse outcome.

Increasing evidence indicates that fetal metabolic stress may result in a variety of post-natal perturbations during brain development. The goal of the study was to determine the duration of hypoxia/ischemia that would elicit a demonstrable regional depression of metabolism in the fetal brain and further to examine several end-points to determine if the metabolic stress affects the developing brain. The uterine artery and uterine branch of the ovarian artery were occluded with aneurysm clamps for a period of 45 min, the clips removed and the metabolites in five regions of the perinatal brain were measured at 0, 2 and 6 h of reflow. Regional P-creatine, ATP and glucose levels were significantly depleted at the end of the 45 min occlusion. The levels of glycogen and glutamate at the end of the occlusion indicated a decreasing trend which was not significant. The concentration of citrate remained essentially unchanged at the end of the occlusion. To ensure that the insult was not lethal to the tissue, the recovery of the metabolites was examined at 2 and 6 h of reflow and generally the concentrations of the high-energy phosphates and glucose were normal or near-normal by 6 h of reperfusion in the five regions of the brain examined. The changes in the metabolites indicate that 45 min of hypoxia/ischemia is an appropriate model for studying neonatal development after fetal metabolic stress.

Tuberous sclerosis complex is a genetic disorder characterized by the development of hamartomas in multiple organs including the brain, skin, eye, kidney, and heart. Neurological features include seizures and mental retardation. Cortical tubers and subependymal nodules are the characteristic intracranial lesions of tuberous sclerosis. Subependymal giant cell astrocytomas, typically located adjacent to the foramen of Monro, can enlarge and cause symptomatic ventricular obstruction. The authors describe the case of a 3-year-old boy with a history of tuberous sclerosis and retinal lesions who presented with an enlarging enhancing pineal region mass. Via an infratentorial supracerebellar approach, the mass was removed using both the operative microscope and a rigid neuroendoscope. Pathological examination showed a giant cell astrocytoma. To the authors' knowledge, this is the first reported case of tuberous sclerosis associated with a giant cell astrocytoma of the pineal region. Diagnostic considerations are discussed.