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Background: Systemic inflammation amplifies neonatal hypoxic-ischemic (HI) brain injury. Azithromycin (AZ), an antibiotic with anti-inflammatory properties, improves sensorimotor function and reduces tissue damage after neonatal rat HI brain injury. The objective of this study was to determine if AZ is neuroprotective in two neonatal rat models of inflammation-amplified HI brain injury., Design/methods: Seven-day-old (P7) rats received injections of toll-like receptor agonists lipopolysaccharide (LPS) or Pam 3 Cys-Ser-(Lys) 4 (PAM) prior to right carotid ligation followed by 50 min (LPS + HI) or 60 min (PAM + HI) in 8% oxygen. Outcomes included contralateral forelimb function (forepaw placing; grip strength), survival, %Intact right hemisphere (brain damage), and a composite score incorporating these measures. We compared postnatal day 35 outcomes in controls and groups treated with three or five AZ doses. Then, we compared P21 outcomes when the first (of five) AZ doses were administered 1, 2, or 4 h after HI., Results: In both LPS + HI and PAM + HI models, AZ improved sensorimotor function, survival, brain tissue preservation, and composite scores. Benefits increased with five- vs. three-dose AZ and declined with longer initiation delay., Conclusions: Perinatal systemic infection is a common comorbidity of neonatal asphyxia brain injury and contributes to adverse outcomes. These data support further evaluation of AZ as a candidate treatment for neonatal neuroprotection., Impact: AZ treatment decreases sensorimotor impairment and severity of brain injury, and improves survival, after inflammation-amplified HI brain injury, and this can be achieved even with a 2 h delay in initiation. This neuroprotective benefit is seen in models of inflammation priming by both Gram-negative and Gram-positive infections. This extends our previous findings that AZ treatment is neuroprotective after HI brain injury in neonatal rats., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Single-center studies suggest that up to 30% of children undergoing extracorporeal membrane oxygenation have electrographic seizures. The aim of this study was to characterize seizure prevalence, seizure risk factors, and brain injury prevalence in the pediatric extracorporeal membrane oxygenation population at a tertiary care children's hospital., Methods: We performed a retrospective systematic review of medical records for 86 consecutive children (neonates to age 21 years) who received Neurology consults and continuous video electroencephalography while undergoing extracorporeal membrane oxygenation from November 2015 to September 2018., Results: Continuous video electroencephalography was initiated in 86 of 170 children who required extracorporeal membrane oxygenation (51%); median duration of continuous vodeo electroencephalography was four days. Nineteen of 86 had electroencephalography-confirmed seizures (22%). Sixteen of 19 had seizures within the first 48 hours on continuous video electroencephalography. Interictal epileptiform discharges were a significant risk factor for seizures; 89% of those with seizures versus 46% of those without had interictal epileptiform discharges (P < 0.001, Fisher's exact test). Children with seizures also had higher pericannulation lactate (median 6.7, interquartile range of 4.3 to 19.0 for those with, and median 4.0, interquartile range of 2.0 to 7.3 for those without; P = 0.02, Mann-Whitney U test). Seizures were associated with hemorrhage on neuroimaging (68% of children with seizures had intracranial hemorrhage versus 34% of those without, P = 0.01, chi-square test)., Conclusion: Approximately half the children undergoing extracorporeal membrane oxygenation received continuous video electroencephalography during the study period, and 22% had seizures. Interictal epileptiform discharges and elevated pre-extracorporeal membrane oxygenation lactate levels were risk factors for seizures; seizures were associated with intracranial hemorrhage., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Inflammation contributes to neonatal hypoxic-ischemic brain injury pathogenesis. We evaluated the neuroprotective efficacy of azithromycin, a safe, widely available antibiotic with anti-inflammatory properties, in a neonatal rodent hypoxic-ischemic brain injury model., Methods: Seven-day-old rats underwent right carotid artery ligation followed by 90-min 8% oxygen exposure; this procedure elicits quantifiable left forepaw functional impairment and right cerebral hemisphere damage. Sensorimotor function (vibrissae-stimulated forepaw placing, grip strength) and brain damage were compared in azithromycin- and saline-treated littermates 2-4 weeks later. Multiple treatment protocols were evaluated (variables included doses ranging from 15 to 45 mg/kg; treatment onset 15 min to 4 h post-hypoxia, and comparison of 1 vs. 3 injections)., Results: All azithromycin doses improved function and reduced brain damage; efficacy was dose dependent, and declined with increasing treatment delay. Three azithromycin injections, administered over 48 h, improved performance on both function measures and reduced brain damage more than a single dose., Conclusion: In this neonatal rodent model, azithromycin improved functional and neuropathology outcomes. If supported by confirmatory studies in complementary neonatal brain injury models, azithromycin could be an attractive candidate drug for repurposing and evaluation for neonatal neuroprotection in clinical trials.

Objectives: To describe survival and 3-month and 12-month neurobehavioral outcomes in children with preexisting neurobehavioral impairment enrolled in one of two parallel randomized clinical trials of targeted temperature management., Design: Secondary analysis of Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital and Out-of-Hospital trials data., Setting: Forty-one PICUs in the United States, Canada, and United Kingdom., Patients: Eighty-four participants (59 in-hospital cardiac arrest and 25 out-of-hospital cardiac arrest), 49 males, 35 females, mean age 4.6 years (SD, 5.36 yr), with precardiac arrest neurobehavioral impairment (Vineland Adaptive Behavior Scales, Second Edition composite score < 70). All required chest compressions for greater than or equal to 2 minutes, were comatose and required mechanical ventilation after return of circulation., Interventions: Neurobehavioral function was assessed using the Vineland Adaptive Behavior Scales, Second Edition at baseline (reflecting precardiac arrest status), and at 3 and 12 months postcardiac arrest, followed by on-site cognitive evaluation. Vineland Adaptive Behavior Scales, Second Edition norms are 100 (mean) ± 15 (SD); higher scores indicate better function. Analyses evaluated survival, changes in Vineland Adaptive Behavior Scales, Second Edition, and cognitive functioning., Measurements and Main Results: Twenty-eight of 84 (33%) survived to 12 months (in-hospital cardiac arrest, 19/59 (32%); out-of-hospital cardiac arrest, 9/25 [36%]). In-hospital cardiac arrest (but not out-of-hospital cardiac arrest) survival rate was significantly lower compared with the Therapeutic Hypothermia after Pediatric Cardiac Arrest group without precardiac arrest neurobehavioral impairment. Twenty-five survived with decrease in Vineland Adaptive Behavior Scales, Second Edition less than or equal to 15 (in-hospital cardiac arrest, 18/59 (31%); out-of-hospital cardiac arrest, 7/25 [28%]). At 3-months postcardiac arrest, mean Vineland Adaptive Behavior Scales, Second Edition scores declined significantly (-5; SD, 14; p < 0.05). At 12 months, Vineland Adaptive Behavior Scales, Second Edition declined after out-of-hospital cardiac arrest (-10; SD, 12; p < 0.05), but not in-hospital cardiac arrest (0; SD, 15); 43% (12/28) had unchanged or improved scores., Conclusions: This study demonstrates the feasibility, utility, and challenge of including this population in clinical neuroprotection trials. In children with preexisting neurobehavioral impairment, one-third survived to 12 months and their neurobehavioral outcomes varied broadly.

Aim: To inform design aspects of future trials by comparing 3 and 12-month neurobehavioural outcomes in children enrolled in Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-Of-Hospital and In-Hospital (THAPCA-OH, THAPCA-IH) trials., Methods: The THAPCA trials evaluated two targeted temperature management interventions (hypothermia, 32.0-34.0 °C; normothermia, 36.0-37.5 °C). Children, aged 2 days to <18 years, were enrolled from 2009-2015. Three and 12-month post-cardiac arrest (CA) outcomes included the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) (population mean = 100, SD = 15) and the pediatric cerebral performance category (PCPC) scale. Children without significant pre-existing neurodevelopmental deficits were included in primary outcome analyses. Among survivors, favorable 12-month outcome was defined as VABS-II ≥ 70., Results: VABS-II and PCPC were available at 3 and 12 months in 204 of 222 eligible survivors (THAPCA-OH, n = 82; THAPCA-IH, n = 122). Relative to THAPCA-IH, THAPCA-OH had significantly less pre-CA disability and significantly greater 12-month CA impairment, based on both VABS-II and PCPC. Correlations between 3 and 12-month VABS-II scores were strong for THAPCA-OH (r = 0.95) and THAPCA-IH (r = 0.72), and lower (p ≤ 0.001) in THAPCA-IH. Between time-points correlations were lower, but still significant in children <1 year at CA (p < 0.001). In both cohorts, 3-month VABS-II and PCPC categorical outcomes had high sensitivity (≥70%) for predicting favorable 12-month VABS-II outcomes, but specificity was lower for THAPCA-IH (68-89%) relative to THAPCA-OH (≥95%). Overall, 12-month diagnostic accuracy was ≥80% for both VABS-II and PCPC in both cohorts., Conclusions: In future paediatric cardiac arrest clinical trials that enroll similar cohorts, integration of 3-month neurobehavioral outcome measures should be considered., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To describe one-year cognitive and neurologic outcomes among extracorporeal cardiopulmonary resuscitation (ECPR) survivors enrolled in the Therapeutic Hypothermia after Paediatric Cardiac Arrest In-Hospital (THAPCA-IH) trial; and compare outcomes between survivors who received ECPR, later extracorporeal membrane oxygenation (ECMO), or no ECMO., Methods: All children recruited to THAPCA-IH were comatose post-arrest. Neurobehavioral function was assessed by caregivers using the Vineland Adaptive Behaviour Scales, 2nd edition (VABS-II) at pre-arrest baseline and 12 months post-arrest. Age-appropriate cognitive performance measures (Mullen Scales of Early Learning or Wechsler Abbreviated Scale of Intelligence) and neurologic examinations were obtained 12 months post-arrest. VABS-II and cognitive performance measures were transformed to standard scores (mean = 100, SD = 15) with higher scores representing better performance. Only children with broadly normal pre-arrest function (VABS-II ≥70) were included in this analysis., Results: One-year follow-up was attained for 127 survivors with pre-arrest VABS-II ≥70. Of these, 57 received ECPR, 14 received ECMO later in their course, and 56 did not receive ECMO. VABS-II assessments were completed at 12 months for 55 (96.5%) ECPR survivors, cognitive testing for 44 (77.2%) and neurologic examination for 47 (82.5%). At 12 months, 39 (70.9%) ECPR survivors had VABS-II scores ≥70. On cognitive testing, 24 (54.6%) had scores ≥70, and on neurologic examination, 28 (59.5%) had no/minimal to mild impairment. Cognitive and neurologic score distributions were similar between ECPR, later ECMO and no ECMO groups., Conclusions: Many ECPR survivors had favourable outcomes although impairments were common. ECPR survivors had similar outcomes to other survivors who were initially comatose post-arrest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: Although recent out-of-hospital cardiac arrest (CA) trials found no benefits of hypothermia versus normothermia targeted temperature management, preclinical models suggest earlier timing of hypothermia improves neuroprotective efficacy. This study investigated whether shorter time to goal temperature was associated with better one-year outcomes in the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital Trial., Methods: Patients were classified by tertiles of time to attain assigned goal temperature range (32-34°C or 36-37.5°C) following ROSC. Outcomes in the first tertile ("earlier") Group 1 were compared with second and third tertiles ("later") Group 2. Separate analyses were, additionally, completed for hypothermia and normothermia intervention groups. Three one-year outcomes were examined: survival; Vineland Adaptive Behavior Scale (VABS-II) score≥70; and decrease in VABS-II≤15 points from baseline., Results: In the entire cohort (n=281), median time from ROSC to goal temperature was 7.4 [IQR 6.2-9.7] hours: Group 1, 5.8 [IQR 5.2, 6.2] and Group 2, 8.8 [IQR 7.4, 10.4] h. Outcomes did not differ between these groups. For hypothermia subgroup, survival was lower in Group 1 than 2, [10/49(20%) versus 47/99(47%), p<0.002], with a trend toward fewer with VABS-II scores≥70 and change in VABS-II≤15 points (p=0.07-0.08). For normothermia subgroup, there was a trend toward higher survival in Group 1 than 2 [18/42(43%) versus 21/83(25%), p=0.065], but no differences in VABS-II-related measures. In multivariable logistic regression models, no difference in earlier and later groups or temperature intervention was observed., Conclusion: We found no evidence that earlier time to goal temperature was associated with better outcomes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Separate trials to evaluate therapeutic hypothermia after paediatric cardiac arrest for out-of-hospital and in-hospital settings reported no statistically significant differences in survival with favourable neurobehavioral outcome or safety compared to therapeutic normothermia. However, larger sample sizes might detect smaller clinical effects. Our aim was to pool data from identically conducted trials to approximately double the sample size of the individual trials yielding greater statistical power to compare outcomes., Methods: Combine individual patient data from two clinical trials set in forty-one paediatric intensive care units in USA, Canada and UK. Children aged at least 48 h up to 18 years old, who remained comatose after resuscitation, were randomized within 6 h of return of circulation to hypothermia or normothermia (target 33.0 °C or 36.8 °C). The primary outcome, survival 12 months post-arrest with Vineland Adaptive Behaviour Scales, Second Edition (VABS-II) score at least 70 (scored from 20 to 160, higher scores reflecting better function, population mean = 100, SD = 15), was evaluated among patients with pre-arrest scores ≥70., Results: 624 patients were randomized. Among 517 with pre-arrest VABS-II scores ≥70, the primary outcome did not significantly differ between hypothermia and normothermia groups (28% [75/271] and 26% [63/246], respectively; relative risk, 1.08; 95% confidence interval [CI], 0.81 to 1.42; p = 0.61). Among 602 evaluable patients, the change in VABS-II score from baseline to 12 months did not differ significantly between groups (p = 0.20), nor did, proportion of cases with declines no more than 15 points or improvement from baseline [22% (hypothermia) and 21% (normothermia)]. One-year survival did not differ significantly between hypothermia and normothermia groups (44% [138/317] and 38% [113/ 297], respectively; relative risk, 1.15; 95% CI, 0.95 to 1.38; p = 0.15). Incidences of blood-product use, infection, and serious cardiac arrhythmia adverse events, and 28-day mortality, did not differ between groups., Conclusions: Analysis of combined data from two paediatric cardiac arrest targeted temperature management trials including both in-hospital and out-of-hospital cases revealed that hypothermia, as compared with normothermia, did not confer a significant benefit in survival with favourable functional outcome at one year., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Importance: Little is known about neuropsychological outcomes of children who survived pediatric cardiac arrest (CA)., Objective: To describe the neuropsychological outcomes of CA survivors enrolled in the Therapeutic Hypothermia After Pediatric Cardiac Arrest In-Hospital (THAPCA-IH) and Out-of-Hospital (THAPCA-OH) trials and compare the results with the primary outcome measure for these trials., Design, Setting, and Participants: Secondary analysis of 222 CA survivors aged 1 to 18 years who received chest compressions for 2 minutes or more, remained comatose and required mechanical ventilation after return of circulation, and were enrolled in targeted temperature-management trials from 41 pediatric intensive care units. Data were collected from September 3, 2009, to February 3, 2016, and analyzed from March 10, 2017, to April 20, 2018., Main Outcomes and Measures: The Vineland Adaptive Behavior Scales, Second Edition (VABS-II), a standardized measure of neurobehavioral functioning based on caregiver report (age-corrected mean [SD] scores = 100 [15]), was used to evaluate pre-CA functioning within 24 hours after enrollment; VABS-II<70 indicated significant developmental delays; VABS-II and neuropsychological testing were completed 1 year after CA. Neuropsychological testing included the Mullen Scales of Early Learning (Mullen) for children younger than 6 years and the Wechsler Abbreviated Scale of Intelligence (WASI) and neuropsychological measures of attention, memory, processing speed, and executive functioning for older children., Results: Of 160 participants who completed neuropsychological testing, 96 (60.0%) were male; the median (interquartile range [IQR]) age was 2.5 years (1.3-6.1 years). Ninety-six (60.0%) were white, 41 (25.6%) were black, and 23 (14.4%) were of other/unknown race; 343 (21.2%) were Hispanic or Latino; 119 (74.4%) were non-Hispanic or Latino; and 7 (4.4%) were of unknown ethnicity. One hundred fourteen participants (71.2%) were classified as having favorable outcomes (VABS-II ≥70). Impairments (>2 SD below the mean for age) across neuropsychological measures ranged from 7% to 61%. Correlations between global cognitive and VABS-II scores were strong for younger children (Mullen, r = 0.69-0.87) but moderate for older children (r = 0.21-0.54 for the WASI). Of 111 children with favorable outcomes on VABS-II, 25.2% had global cognitive impairment and 30 of 35 older children (85.7%) had selective neuropsychological deficits., Conclusions and Relevance: In this prospectively evaluated cohort of pediatric CA survivors who were initially comatose, although 71.2% were classified as having favorable outcomes, significant neuropsychological deficits were identified in pediatric CA survivors who were classified as having favorable outcomes. The findings provide clinicians with a greater understanding of the spectrum of neuropsychological outcomes of pediatric CA survivors and the complex relationship between standardized caregiver-reported functional outcome measures incorporated in clinical trials and performance-based neuropsychological assessments.

Targeted temperature management encompasses a range of clinical interventions to regulate systemic temperature, and includes both induction of varying degrees of hypothermia and fever prevention ("targeted normothermia"). Targeted temperature management plays a key role in the contemporary management of critically ill neonates and children with acute brain injury. Yet, many unanswered questions remain regarding optimal temperature management in pediatric neurocritical care. The introduction highlights experimental studies that have evaluated the neuroprotective efficacy of therapeutic hypothermia and explored possible mechanisms of action in several brain injury models. The next section focuses on three major clinical conditions in which therapeutic hypothermia has been evaluated in randomized controlled trials in pediatric populations: neonatal hypoxic-ischemic encephalopathy, postcardiac arrest encephalopathy, and traumatic brain injury. Clinical implications of targeted temperature management in pediatric neurocritical care are also discussed. The final section examines some of the factors that may underlie the limited neuroprotective efficacy of hypothermia that has been observed in several major pediatric clinical trials, and outlines important directions for future research., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: We assessed neuroactive medication use in critically ill children who require neurological consultation and evaluated the associations between administration of these medications and continuous electroencephalography (cEEG) utilization and seizure frequency., Methods: We evaluated exposure to sedatives, analgesics, anesthetics, and paralytics in consecutive patients (0 days to 18 years) for whom neurological consultation was requested in three intensive care units (ICUs) [neonatal (NICU), pediatric (PICU), and cardiothoracic (PCTU)]) at one children's hospital. We assessed cEEG usage and seizure incidence in relation to drug exposure., Results: From November 2015 to November 2016, 300 consecutive patients were evaluated (93 NICU, 139 PICU, and 68 PCTU). Ninety-seven (32%) were receiving ≥1 sedative infusion at the time of consultation [NICU 7 (8%), PICU 50(36%), PCTU 40 (58%%]; 91 (30%) received ≥1 paralytic agent within the preceding 24 hours. Continuous electroencephalography was performed more often for patients treated with sedative infusions (81 of 97 versus 133 of 203, P = 0.001) and paralytic medications (80 of 91 versus 134 of 209, P < 0.001) within 24 hours preceding consultation than those who were not. Sixty-eight of 214 (32%) had electrographic seizures (65 of 68 within initial 24 hours of monitoring); seizures were less common among patients who had received sedative infusions (18 of 81 versus 51 of 133, P = 0.014). In multivariable analysis of seizure likelihood, only younger age was associated with increased risk (P = 0.037)., Conclusions: Critically ill infants and children are frequently treated with sedatives, anesthetics, analgesics, and paralytics. Neuroactive medications limit bedside neurological assessments and, in this cohort, were associated with increased cEEG usage. Our data underscore the need to study the effect of these medications on clinical care and long-term outcomes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To implement a standardized approach to characterize neurologic outcomes among 12-month survivors in the Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) trials., Methods: Two multicenter trials enrolled children age 48 hours to 18 years who remained comatose after cardiac arrest (CA) occurring out-of-hospital (THAPCA-OH, NCT00878644) or in-hospital (THAPCA-IH, NCT00880087); patients were randomized to therapeutic hypothermia or therapeutic normothermia. The primary outcome, survival with favorable 12-month neurobehavioral outcome (Vineland Adaptive Behavior Scales [VABS-II]), did not differ between treatment groups in either trial. Neurologists examined 181 12-month survivors, described findings using the novel semi-quantitative Pediatric Resuscitation after Cardiac Arrest (PRCA) form, and rated findings in 6 domains; scores ranged from 0 (no deficits) to 21 (maximal deficits). PRCA scores were compared with 12-month VABS-II scores and cognitive scores., Results: Neurologic outcome PRCA scores were classified as no/minimal impairment, PRCA 0-3, 81/179 (45%); mild impairment, PRCA 4-7, 24/179 (13%); moderate impairment, PRCA 8-11, 15/179 (8%); severe impairment, PRCA 12-16, 20/179 (11%); profound impairment, PRCA 17-21, 39/179 (21%) (2/181 incomplete). VABS-II scores correlated strongly with PRCA category ( r = -0.88, p < 0.0001, Pearson correlation coefficient) and cognitive scores ( r = -0.72, p < 0.0001). Factors associated with poor outcomes included out-of-hospital CA, seizure recognition in the early postarrest period, and poor neurologic status at hospital discharge., Conclusion: The PRCA provides a robust method for depicting neurologic outcomes after acute encephalopathy caused by CA in children. It provides a global semiquantitative rating of neurologic impairment and domain-specific impairment. The strong correlation with well-established neurobehavioral outcome measures supports its validity over a broad age range and wide spectrum of outcomes., (© 2018 American Academy of Neurology.)

Aim: Children who remain comatose after in-hospital cardiac arrest (IH-CA) resuscitation are at risk for poor neurological outcome. We report results of detailed neurobehavioural testing in paediatric IH-CA survivors, initially comatose after return of circulation, and enrolled in THAPCA-IH, a clinical trial that evaluated two targeted temperature management interventions (hypothermia, 33.0 °C or normothermia, 36.8 °C; NCT00880087)., Methods: Children, aged 2 days to <18 years, were enrolled in THAPCA-IH from 2009 to 2015; primary trial outcome (survival with favorable neurobehavioural outcome) did not differ between groups. Pre-IH-CA neurobehavioural functioning, measured with the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) was evaluated soon after enrollment; this report includes only children with broadly normal pre-IH-CA scores (VABS-II composite scores ≥70; 269 enrolled). VABS-II was re-administered 3 and 12 months later. Cognitive testing was completed at 12 months., Results: Follow-ups were obtained on 125 of 135 eligible one-year survivors. Seventy-seven percent (96/125) had VABS-II scores ≥70 at 12 months; cognitive composites were ≥2SD of mean in 59%. VABS-II composite, domain, and most subdomain scores declined between pre-IH-CA and 3-month, and pre-IH-CA and 12-month assessments (composite means declined about 1 SD at 3 and 12 months, p < 0.005); 3 and 12-month scores were strongly correlated (r = 0.72, p < 0.001)., Conclusions: In paediatric IH-CA survivors at high risk for unfavorable outcomes, the majority demonstrated significant declines in neurobehavioural functioning, across multiple functional domains, with similar functioning at 3 and 12 months. About three-quarters attained VABS-II functional performance composite scores within the broadly normal range., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The mainstay of treatment of childhood epilepsy is to administer antiepileptic drugs (AEDs). This article provides an overview of the clinical approach to drug treatment of childhood epilepsy, focusing on general principles of therapy and properties of recently introduced medications. Initiation and cessation of therapy, adverse medication effects, drug interactions, indications for the various AEDs, and off-label use of AEDs are reviewed. The distinct challenges in treatment of epileptic spasms and neonatal seizures are addressed. Finally, ideas for the future of drug treatment of childhood epilepsy are presented, with particular attention to precision medicine., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: To describe the 1-year neurobehavioral outcome of survivors of cardiac arrest secondary to drowning, compared with other respiratory etiologies, in children enrolled in the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital (THAPCA-OH) trial., Methods: Exploratory analysis of survivors (ages 1-18 years) who received chest compressions for ≥2min, were comatose, and required mechanical ventilation after return of circulation (ROC). Participants recruited from 27 pediatric intensive care units in North America received targeted temperature management [therapeutic hypothermia (33°C) or therapeutic normothermia (36.8°C)] within 6h of ROC. Neurobehavioral outcomes included 1-year Vineland Adaptive Behavior Scales, Second Edition (VABS-II) total and domain scores and age-appropriate cognitive performance measures (Mullen Scales of Early Learning or Wechsler Abbreviated Scale of Intelligence)., Results: Sixty-six children with a respiratory etiology of cardiac arrest survived for 1-year; 60/66 had broadly normal premorbid functioning (VABS-II≥70). Follow up was obtained on 59/60 (30 with drowning etiology). VABS-II composite and domain scores declined significantly from premorbid scores in drowning and non-drowning groups (p<0.001), although declines were less pronounced for the drowning group. Seventy-two percent of children had well below average cognitive functioning at 1-year. Younger age, fewer doses of epinephrine, and drowning etiology were associated with better VABS-II composite scores. Demographic variables and treatment with hypothermia did not influence neurobehavioral outcomes., Conclusions: Risks for poor neurobehavioral outcomes were high for children who were comatose after out-of-hospital cardiac arrest due to respiratory etiologies; survivors of drowning had better outcomes than those with other respiratory etiologies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited., Methods: In a trial conducted at 37 children's hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest., Results: The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups., Conclusions: Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).

The typical US diet has >30% calories from fat; yet, typical laboratory diets contain 17% calories from fat. This disparity could confound the clinical relevance of findings in cerebral ischemia models. We compared outcomes after neonatal brain injury in offspring of rat dams fed standard low-fat chow (17% fat calories) or a higher fat diet (34% fat calories) from day 7 of pregnancy. On postnatal day 7, hypoxic-ischemic injury was induced by right carotid ligation, followed by 60, 75 or 90 min 8% oxygen exposure. Sensorimotor function, brain damage, and serum and brain fatty acid content were compared 1 to 4 weeks later. All lesioned animals developed left forepaw placing deficits; scores were worse in the high-fat groups (p < 0.0001, ANOVA). Similarly, reductions in left forepaw grip strength were more pronounced in the high-fat groups. Severity of right hemisphere damage increased with hypoxia-ischemia duration but did not differ between diet groups. Serum and brain docosahexaenoic acid fatty acid fractions were lower in high-fat progeny (p < 0.05, ANOVA). We speculate that the high-fat diet disrupted docosahexaenoic acid-dependent recovery mechanisms. These findings have significant implications both for refinement of neonatal brain injury models and for understanding the impact of maternal diet on neonatal neuroplasticity., (© The Author(s) 2016.)

Objectives: To analyze functional performance measures collected prospectively during the conduct of a clinical trial that enrolled children (up to age 18 yr old), resuscitated after out-of-hospital cardiac arrest, who were at high risk of poor outcomes., Design: Children with Glasgow Motor Scale score less than 5, within 6 hours of resuscitation, were enrolled in a clinical trial that compared two targeted temperature management interventions (THAPCA-OH, NCT00878644). The primary outcome, 12-month survival with Vineland Adaptive Behavior Scale, second edition, score greater or equal to 70, did not differ between groups., Setting: Thirty-eight North American PICUs., Participants: Two hundred ninety-five children were enrolled; 270 of 295 had baseline Vineland Adaptive Behavior Scale, second edition, scores greater or equal to 70; 87 of 270 survived 1 year., Interventions: Targeted temperatures were 33.0°C and 36.8°C for hypothermia and normothermia groups., Measurements and Main Results: Baseline measures included Vineland Adaptive Behavior Scale, second edition, Pediatric Cerebral Performance Category, and Pediatric Overall Performance Category. Pediatric Cerebral Performance Category and Pediatric Overall Performance Category were rescored at hospital discharges; all three were scored at 3 and 12 months. In survivors with baseline Vineland Adaptive Behavior Scale, second edition scores greater or equal to 70, we evaluated relationships of hospital discharge Pediatric Cerebral Performance Category with 3- and 12-month scores and between 3- and 12-month Vineland Adaptive Behavior Scale, second edition, scores. Hospital discharge Pediatric Cerebral Performance Category scores strongly predicted 3- and 12-month Pediatric Cerebral Performance Category (r = 0.82 and 0.79; p < 0.0001) and Vineland Adaptive Behavior Scale, second edition, scores (r = -0.81 and -0.77; p < 0.0001). Three-month Vineland Adaptive Behavior Scale, second edition, scores strongly predicted 12-month performance (r = 0.95; p < 0.0001). Hypothermia treatment did not alter these relationships., Conclusions: In comatose children, with Glasgow Motor Scale score less than 5 in the initial hours after out-of-hospital cardiac arrest resuscitation, function scores at hospital discharge and at 3 months predicted 12-month performance well in the majority of survivors.

Objective: To describe outcomes and complications in the drowning subgroup from the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital trial., Design: Exploratory post hoc cohort analysis., Setting: Twenty-four PICUs., Patients: Pediatric drowning cases., Interventions: Therapeutic hypothermia versus therapeutic normothermia., Measurements and Main Results: An exploratory study of pediatric drowning from the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital trial was conducted. Comatose patients aged more than 2 days and less than 18 years were randomized up to 6 hours following return-of-circulation to hypothermia (n = 46) or normothermia (n = 28). Outcomes assessed included 12-month survival with a Vineland Adaptive Behavior Scale score of greater than or equal to 70, 1-year survival rate, change in Vineland Adaptive Behavior Scale-II score from prearrest to 12 months, and select safety measures. Seventy-four drowning cases were randomized. In patients with prearrest Vineland Adaptive Behavior Scale-II greater than or equal to 70 (n = 65), there was no difference in 12-month survival with Vineland Adaptive Behavior Scale-II score of greater than or equal to 70 between hypothermia and normothermia groups (29% vs 17%; relative risk, 1.74; 95% CI, 0.61-4.95; p = 0.27). Among all evaluable patients (n = 68), the Vineland Adaptive Behavior Scale-II score change from baseline to 12 months did not differ (p = 0.46), and 1-year survival was similar (49% hypothermia vs 42%, normothermia; relative risk, 1.16; 95% CI, 0.68-1.99; p = 0.58). Hypothermia was associated with a higher prevalence of positive bacterial culture (any blood, urine, or respiratory sample; 67% vs 43%; p = 0.04); however, the rate per 100 days at risk did not differ (11.1 vs 8.4; p = 0.46). Cumulative incidence of blood product use, serious arrhythmias, and 28-day mortality were not different. Among patients with cardiopulmonary resuscitation durations more than 30 minutes or epinephrine doses greater than 4, none had favorable Pediatric Cerebral Performance Category outcomes (≤ 3)., Conclusions: In comatose survivors of out-of-hospital pediatric cardiac arrest due to drowning, hypothermia did not result in a statistically significant benefit in survival with good functional outcome or mortality at 1 year, as compared with normothermia. High risk of culture-proven bacterial infection was observed in both groups.

Objective: To determine the contemporary etiology, burden, and short-term outcomes of seizures in neonates monitored with continuous video-electroencephalogram (cEEG)., Study Design: We prospectively collected data from 426 consecutive neonates (56% male, 88% term) ≤44 weeks' postmenstrual age with clinically suspected seizures and/or electrographic seizures. Subjects were assessed between January 2013 and April 2015 at 7 US tertiary care pediatric centers following the guidelines of the American Clinical Neurophysiology Society for cEEG for at-risk neonates. Seizure etiology, burden, management, and outcome were determined by chart review by the use of a case report form designed at study onset., Results: The most common seizure etiologies were hypoxic-ischemic encephalopathy (38%), ischemic stroke (18%), and intracranial hemorrhage (11%). Seizure burden was high, with 59% having ≥7 electrographic seizures and 16% having status epilepticus; 52% received ≥2 antiseizure medications. During the neonatal admission, 17% died; 49% of survivors had abnormal neurologic examination at hospital discharge. In an adjusted analysis, high seizure burden was a significant risk factor for mortality, length of hospital stay, and abnormal neurological examination at discharge., Conclusions: In this large contemporary profile of consecutively enrolled newborns with seizures treated at centers that use cEEG per the guidelines of the American Clinical Neurophysiology Society, about one-half had high seizure burden, received ≥2 antiseizure medications, and/or died or had abnormal examination at discharge. Greater seizure burden was associated with increased morbidity and mortality. These findings underscore the importance of accurate determination of neonatal seizure frequency and etiology and a potential for improved outcome if seizure burden is reduced., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: This study examined 12-month neurobehavioral outcomes in children who survived out-of-hospital cardiac arrest (OH-CA), were comatose after resuscitation, and were enrolled in a clinical trial to evaluate targeted temperature management to hypothermia (33.0°C) or normothermia (36.8°C) (Therapeutic Hypothermia after Pediatric Cardiac Arrest, Out-of-Hopsital [THAPCA-OH]; NCT00878644)., Methods: Baseline functioning was assessed by caregiver responses on the Vineland Adaptive Behavior Scales-Second Edition (VABS-II) soon after OH-CA (based on functioning before OH-CA); children with broadly normal baseline functioning (VABS-II ≥70) were included in the THAPCA-OH primary outcome. VABS-II was completed again 12 months later. Then, face-to-face cognitive evaluations were completed. Analyses evaluated changes in VABS-II composite, domain, and subdomain scores and cognitive functioning at follow-up., Results: Ninety-six of 295 enrolled children were alive at 12 months; 87 of 96 had broadly normal baseline functioning (VABS-II ≥70). Follow-up was obtained on 85/87. Forty-two of 85 had VABS-II ≥70 at 12 months. VABS-II composite, domain, and subdomain scores declined significantly between baseline and 12-month follow-up (P < .001). Declines were greatest in older children. Most children displayed well below average cognitive functioning. Older age at cardiac arrest and higher baseline VABS-II scores were predictive of greater decline in neurobehavioral function. Treatment with hypothermia did not influence neurobehavioral outcomes., Conclusions: This is the largest study exploring long-term neurobehavioral outcomes in children surviving OH-CA who were comatose after resuscitation. Results revealed significant neurobehavioral morbidity across multiple functional domains, based both on caregiver reports and performance on objective cognitive measures, in survivors 1 year later., Competing Interests: Potential Conflict of Interest: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2016 by the American Academy of Pediatrics.)

Background: Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited., Methods: We conducted this trial of two targeted temperature interventions at 38 children's hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest., Results: A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality., Conclusions: In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

Objectives: The Therapeutic Hypothermia After Pediatric Cardiac Arrest trials will determine whether therapeutic hypothermia improves survival with good neurobehavioral outcome, as assessed by the Vineland Adaptive Behavior Scales Second Edition, in children resuscitated after cardiac arrest in the in-hospital and out-of-hospital settings. We describe the innovative efficacy outcome selection process during Therapeutic Hypothermia After Pediatric Cardiac Arrest protocol development., Design/setting: Consensus assessment of potential outcomes and evaluation timepoints., Interventions: None., Measurements and Main Results: We evaluated practical and technical advantages of several follow-up timepoints and continuous/categorical outcome variants. Simulations estimated power assuming varying hypothermia benefit on mortality and on neurobehavioral function among survivors. Twelve months after arrest was selected as the optimal assessment timepoint for pragmatic and clinical reasons. Change in Vineland Adaptive Behavior Scales Second Edition from prearrest level, measured as quasicontinuous with death and vegetative status being worst-possible levels, yielded optimal statistical power. However, clinicians preferred simpler multicategorical or binary outcomes because of easier interpretability and favored outcomes based solely on postarrest status because of concerns about accurate parental assessment of prearrest status and differing clinical impact of a given Vineland Adaptive Behavior Scales Second Edition change depending on prearrest status. Simulations found only modest power loss from categorizing or dichotomizing quasicontinuous outcomes because of high expected mortality. The primary outcome selected was survival with 12-month Vineland Adaptive Behavior Scales Second Edition no less than two SD below a reference population mean (70 points), necessarily evaluated only among children with prearrest Vineland Adaptive Behavior Scales Second Edition greater than or equal to 70. Two secondary efficacy outcomes, 12-month survival and quasicontinuous Vineland Adaptive Behavior Scales Second Edition change from prearrest level, will be evaluated among all randomized children, including those with compromised function prearrest., Conclusions: Extensive discussion of optimal efficacy assessment timing, and of the advantages versus drawbacks of incorporating prearrest status and using quasicontinuous versus simpler outcomes, was highly beneficial to the final Therapeutic Hypothermia After Pediatric Cardiac Arrest design. A relatively simple, binary primary outcome evaluated at 12 months was selected, with two secondary outcomes that address the potential disadvantages of primary outcome.

Objective: To describe the rationale, timeline, study design, and protocol overview of the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials., Design: Multicenter randomized controlled trials., Setting: Pediatric intensive care and cardiac ICUs in the United States and Canada., Patients: Children from 48 hours to 18 years old, who have return of circulation after cardiac arrest, who meet trial eligibility criteria, and whose guardians provide written consent., Interventions: Therapeutic hypothermia or therapeutic normothermia., Measurements and Main Results: From concept inception in 2002 until trial initiation in 2009, 7 years were required to plan and operationalize the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Two National Institute of Child Health and Human Development clinical trial planning grants (R21 and R34) supported feasibility assessment and protocol development. Two clinical research networks, Pediatric Emergency Care Applied Research Network and Collaborative Pediatric Critical Care Research Network, provided infrastructure resources. Two National Heart Lung Blood Institute U01 awards provided funding to conduct separate trials of in-hospital and out-of-hospital cardiac arrest. A pilot vanguard phase that included half the clinical sites began on March 9, 2009, and this was followed by full trial funding through 2015., Conclusions: Over a decade will have been required to plan, design, operationalize, and conduct the Therapeutic Hypothermia after Pediatric Cardiac Arrest trials. Details described in this report, such as participation of clinical research networks and clinical trial planning grants utilization, may be of utility for individuals who are planning investigator-initiated, federally supported clinical trials.

Background: In neonatal rats, early post-hypoxia-ischemia (HI) administration of the omega-3 fatty acid docosahexaenoic acid (DHA) improves sensorimotor function, but does not attenuate brain damage., Objective: To determine if DHA administration in addition to hypothermia, now standard care for neonatal asphyxial brain injury, attenuates post-HI damage and sensorimotor deficits., Methods: Seven-day-old (P7) rats underwent right carotid ligation followed by 90 min of 8% O2 exposure. Fifteen minutes later, pups received injections of DHA 2.5 mg/kg (complexed to 25% albumin) or equal volumes of albumin. After a 1-hour recovery, pups were cooled (3 h, 30°C). Sensorimotor and pathology outcomes were initially evaluated on P14. In subsequent experiments, sensorimotor function was evaluated on P14, P21, and P28; histopathology was assessed on P28., Results: At P14, left forepaw function scores (normal: 20/20) were near normal in DHA + hypothermia-treated animals (mean ± SD 19.7 ± 0.7 DHA + hypothermia vs. 12.7 ± 3.5 albumin + hypothermia, p < 0.0001) and brain damage was reduced (mean ± SD right hemisphere damage 38 ± 17% with DHA + hypothermia vs. 56 ± 15% with albumin + hypothermia, p = 0.003). Substantial improvements on three sensorimotor function measures and reduced brain damage were evident up to P28., Conclusion: Unlike post-HI treatment with DHA alone, treatment with DHA + hypothermia produced both sustained functional improvement and reduced brain damage after neonatal HI., (Copyright © 2013 S. Karger AG, Basel.)

Introduction: The NaKCl cotransporter NKCC1 facilitates intraneuronal chloride accumulation in the developing brain. Bumetanide (BUM), a clinically available diuretic, inhibits this chloride transporter and augments the antiepileptic effects of phenobarbital (PB) in neonatal rodents. In a neonatal cerebral hypoxia-ischemia (HI) model, elicited by right carotid ligation, followed by 90 min 8% O(2) exposure in 7-d-old (P7) rats, PB increases the neuroprotective efficacy of hypothermia (HT). We evaluated whether BUM influenced the neuroprotective efficacy of combination treatment with PB and HT., Methods: P7 rats underwent HI lesioning; 15 min later, all received PB (30 mg/kg), and 10 min later, half received BUM (10 mg/kg, PB-HT+BUM) and half received saline (PB-HT+SAL). One hour after HI, all were cooled (30 °C, 3 h). Contralateral forepaw sensorimotor function and brain damage were evaluated 1-4 wk later., Results: Forepaw functional measures were close to normal in the PB-HT+BUM group, whereas deficits persisted in PB-HT+SAL controls; there were corresponding reductions in right cerebral hemisphere damage (at P35, % damage: PB-HT+BUM, 21 ± 16 vs. 38 ± 20 in controls)., Discussion: These results provide evidence that NKCC1 inhibition amplifies PB bioactivity in the immature brain and suggest that coadministration of PB and BUM may represent a clinically feasible therapy to augment the neuroprotective efficacy of therapeutic HT in asphyxiated neonates.

Seizures are associated with adverse outcome in infants with hypoxic-ischemic encephalopathy. We hypothesized that early administration of the anticonvulsant phenobarbital after cerebral hypoxia ischemia could enhance the neuroprotective efficacy of delayed-onset hypothermia. We tested this hypothesis in a neonatal rodent model. Seven-d-old rats (n = 104) underwent right carotid ligation, followed by 90 min 8% O2 exposure; 15 min later, they received injections of phenobarbital (40 mg/kg) or saline. One or 3 h later, all were treated with hypothermia (30 degrees C, 3 h). Function and neuropathology were evaluated after 7 d (early outcomes) or 1 mo (late outcomes). Early outcome assessment demonstrated better sensorimotor performance and less cortical damage in phenobarbital-treated groups; there were no differences between groups in which the hypothermia delay was shortened from 3 to 1 h. Late outcome assessment confirmed sustained benefits of phenobarbital + hypothermia treatment; sensorimotor performance was better (persistent attenuation of contralateral forepaw placing deficits and absence of contralateral forepaw neglect); neuropathology scores were lower (median, phenobarbital 2 and saline 8.5, p < 0.05); and less ipsilateral cerebral hemisphere %Damage (mean +/- SD, 11 +/- 17 versus 28 +/- 22, p < 0.05). These results suggest that early posthypoxia-ischemia administration of phenobarbital may augment the neuroprotective efficacy of therapeutic hypothermia.

Objectives: : To describe a large multicenter cohort of pediatric cardiac arrest (CA) with return of circulation (ROC) from either the in-hospital (IH) or the out-of-hospital (OH) setting and to determine whether significant differences related to pre-event, arrest event, early postarrest event characteristics, and outcomes exist that would be critical in planning a clinical trial of therapeutic hypothermia (TH)., Design: : Retrospective cohort study., Setting: : Fifteen Pediatric Emergency Care Applied Research Network sites., Patients: : Patients aged 24 hours to 18 years with either IH or OH CA who had a history of at least 1 minute of chest compressions and ROC for at least 20 minutes were eligible., Interventions: : None., Measurements and Main Results: : A total of 491 patients met study entry criteria with 353 IH cases and 138 OH cases. Major differences between the IH and OH cohorts were observed for patient prearrest characteristics, arrest event initial rhythm described, and arrest medication use. Several postarrest interventions were used differently, however, the use of TH was similar (<5%) in both cohorts. During the 0-12-hour interval following ROC, OH cases had lower minimum temperature and pH, and higher maximum serum glucose recorded. Mortality was greater in the OH cohort (62% vs. 51%, p = 0.04) with the cause attributed to a neurologic indication much more frequent in the OH than in the IH cohort (69% vs. 20%; p < 0.01)., Conclusions: : For pediatric CA with ROC, several major differences exist between IH and OH cohorts. The finding that the etiology of death was attributed to neurologic indications much more frequently in OH arrests has important implications for future research. Investigators planning to evaluate the efficacy of new interventions, such as TH, should be aware that the IH and OH populations differ greatly and require independent clinical trials.

Medically refractory neonatal seizures represent a major therapeutic challenge in neonatal intensive care units. Conventional antiepileptic drugs demonstrate limited efficacy. Previous studies documented a high frequency of off-label drug therapy in neonates. We sought to determine if pediatric neurologists are recommending treatment of neonatal seizures with newer agents, despite a lack of information about their safety or efficacy in this population. Surveys were distributed at the 2007 Annual Meeting of the Child Neurology Society. Responses from 55 pediatric neurologists were analyzed. Seventy-three percent (40/55) recommended treatment of neonatal seizures with one or both of levetiracetam and topiramate; 47% (26/55) recommended levetiracetam; and 55% (30/55) recommended topiramate. Despite an absence of data on neonatal pharmacokinetics of either drug, neurologists made different dosing recommendations for these two drugs (P = 0.003, chi-square test). Respondents considered both agents to be efficacious in the majority of cases; adverse effects were recognized more frequently with topiramate. These results highlight the urgent need for rigorous clinical trials to understand the risks and benefits of new drug therapies for neonatal seizures.

This report describes a new experimental model to evaluate the effect of a recurrent systemic inflammatory challenge, after cerebral hypoxia-ischemia in immature mice, on the progression of brain injury. Treatment with a low dose of lipopolysaccharide (E. coli O55:B5, 0.2mg/kg for 3 days, then 0.1mg/kg for 2 days) daily for 5 days after unilateral cerebral hypoxia-ischemia (right carotid ligation followed by 35min in 10% O2) in 10-day-old mice resulted in increased right forebrain tissue damage (35.6% reduction in right hemisphere volume compared to 20.6% reduction in saline-injected controls), in bilateral reductions in corpus callosum area (by 12%) and myelin basic protein immunostaining (by 19%), and in suppression of injury-related right subventricular zone cellular proliferation. The post-hypoxic-ischemic lipopolysaccharide regimen that amplified brain injury was not associated with increased mortality, nor with changes in body temperature, weight gain or blood glucose concentrations. The results of the present study demonstrate that systemic inflammation influences the evolution of tissue injury after neonatal cerebral hypoxia-ischemia and may also impair potential recovery mechanisms.

Standardized approaches to the treatment of neonatal seizures remain undeveloped. We assessed the type and number of anticonvulsants selected, blood levels attained, and postdischarge anticonvulsant treatment of neonatal seizures among five neonatal intensive care units in the United States between 2000-2003. Almost all of the 480 neonates (94%) with seizures were treated, initially with phenobarbital (82%), lorazepam (9%), phenytoin (2%), other anticonvulsants (1%), or a combination of the first two drugs (6%). While the majority of neonates were treated with one drug (59%), the number of anticonvulsants varied (P<0.0001), as did the peak serum phenobarbital levels (P<0.0001). The majority (75%) of survivors received anticonvulsant treatment after discharge. These neonates were more likely to have had abnormal electroencephalography or brain imaging, or to have needed a second anticonvulsant, compared with neonates whose drug therapy was discontinued. Anticonvulsant therapy is used in the majority of neonates with seizures, mostly with phenobarbital, and treatment is continued beyond discharge. The observed wide therapeutic variability may reflect a lack of standardized diagnostic and treatment approaches, particularly for seizures refractory to initial phenobarbital therapy. Trials of anticonvulsants with long-term neurodevelopmental follow-up are needed to develop evidence-based treatment guidelines.

In childhood, the risk for seizures is greatest in the neonatal period. Currently used therapies have limited efficacy. Although the treatment of neonatal seizures has not significantly changed in the past several decades, there has been substantial progress in understanding developmental mechanisms that influence seizure generation and responsiveness to anticonvulsants. This review includes an overview of current approaches to the diagnosis and treatment of neonatal seizures, identifies some of the critical factors that have limited progress, and highlights recent insights about the pathophysiology of neonatal seizures that may provide the foundation for better treatment.

Periventricular white matter injury in premature infants is linked to chronic neurological dysfunction. Periventricular white matter injury is caused by many mechanisms including hypoxia-ischemia (HI). Animal models of HI in the neonatal rodent brain can replicate some important features of periventricular white matter injury. Most rodent studies have focused upon early cellular and tissue events following unilateral neonatal HI that is elicited by unilateral carotid artery ligation and followed by timed exposure to moderate hypoxia. Milder hypoxic-ischemic insults elicit preferential white matter injury. Little information is available about long-term cellular effects of unilateral HI. One month after unilateral neonatal hypoxia ischemia, we show that all the components for structural reorganization of the brain are present in moderately injured rats. These components in the injured side include extensive influx of neurites, axonal and dendritic growth cones, abundant immature synapses, and myelination of many small axons. Surprisingly, this neural recovery is often found in and adjacent to cysts that have the ultrastructural features of bone extracellular matrix. In contrast, brains with severe hypoxia ischemia one month after injury still undergo massive neuronal degeneration. While massive destruction of neurons and glia are striking events shortly after brain HI, neural cells re-express their intrinsic properties and attempt an anatomical recovery long after injury.

The chemokine macrophage inflammatory protein 1alpha (CCL3) is expressed by immune cells in the normal and injured perinatal brain. To determine whether the chemokine receptor CCR5 is a relevant target for CCL3 in the brain, we used RT-PCR and immunocytochemistry to assess changes in CCR5 expression and localization in developing normal and injured rat forebrain. CCR5 protein was expressed predominately by resting and activated microglia until 2 weeks of age. Neonatal hypoxia-ischemia increased CCR5 mRNA expression while causing CCR5 internalization, indicating receptor activation. These data implicate CCR5 in microglial recruitment and activation during brain development and after neonatal brain injury.

Neurogenesis persists throughout life in the rodent subventricular zone (SVZ) and increases in the adult after brain injury. In this study, postnatal day 7 (P7) rats underwent right carotid artery ligation followed by 8% O2 exposure for 90 min, a lesioning protocol that resulted in ipsilateral forebrain hypoxic-ischemic (HI) injury. The effects of HI injury on SVZ cell proliferation and neurogenesis were examined 1-3 wk later by morphometric measurement of dorsolateral SVZ size; by immunoassays to detect incorporation of bromodeoxyuridine (BrdU) in proliferating cells; and by immunoassays of doublecortin, a microtubule-associated protein expressed only by immature neurons. For determining the cell phenotypes of newly generated cells, tissue sections were double labeled with antibodies to BrdU and markers of mature neurons (neuronal nuclear protein), astrocytes (glial fibrillary acidic protein), or oligodendroglia (RIP). HI injury resulted in enlargement of the ipsilateral SVZ at P14-28 and a corresponding increase in BrdU cell numbers both in the ipsilateral SVZ and striatum at P21. HI injury also stimulated SVZ neurogenesis, based on increased doublecortin immunostaining in the SVZ ipsilateral to lesioning at P14-28. However, 4 wk after HI injury, in the lesioned striatum, although BrdU/glial fibrillary acidic protein and BrdU/RIP-labeled cells were identified, no BrdU/neuronal nuclear protein double-labeled cells were found. These results suggest that although acute neonatal HI injury stimulates SVZ proliferation and neurogenesis, there is inadequate trophic support for survival of newly generated neurons. Identification of the trophic factors that enhance maturation and survival of immature neurons could provide important clues for improving recovery after neonatal brain injury.

The mammalian forebrain subventricular zone (SVZ) contains stem cells capable of generating new neurons and glia. Recent studies indicate that acute brain injury is a potent stimulus for SVZ stem cell proliferation. To better understand mechanisms of the SVZ response to neonatal brain injury, we used a model that focuses on a unique mechanism of vulnerability of the immature CNS, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitotoxicity. We previously demonstrated that intracerebroventricular injection of the glutamate analog AMPA in rats at postnatal day 7 (P7) caused bilateral periventricular gray and white matter injury. We hypothesized that excitotoxic injury would stimulate cellular proliferation in the SVZ; we used the AMPA intracerebroventricular injection model to test this hypothesis. P7 rat pups received either left or right intracerebroventricular injections of S-AMPA (2.5 nmol). Normal and PBS-injected littermates were included as controls. On P8 or P14, serial coronal sections through the SVZ were collected; an immunohistochemical assay was performed with an antibody to the cell proliferation marker Ki-67. Bilateral Ki-67+ cells/SVZ were quantitated stereologically using the optical disector method. The median number of Ki-67+ cells/SVZ was increased in the SVZ of AMPA-injected rats relative to normal controls on both P8 and P14. To evaluate neurogenesis, we assayed the expression of doublecortin, a microtubular protein expressed only by immature neurons. From P8 to P14, there was a marked increase in doublecortin immunoreactive cells in the AMPA-injected SVZ. Many Ki-67+ nuclei were immediately surrounded by doublecortin staining. This study indicates that there is a proliferative response in the immature SVZ after an excitotoxic stimulus. Our findings suggest that some of these newly generated cells differentiate as immature neurons. This model may provide information about the mechanisms that regulate SVZ responses to neonatal brain injury.

Neurogenesis persists throughout life in the rodent subventricular zone (SVZ)-olfactory bulb pathway and increases in the adult after brain insults. The influence of neonatal injury on SVZ neural precursors is unknown. We examined the effects of hypoxia-ischemia (HI) on neonatal mouse SVZ cell proliferation and neurogenesis. Postnatal day 10 (P10) mice underwent right carotid artery ligation followed by 10% O2 exposure for 45 min. The SVZ area and hemispheric injury were quantified morphometrically 1-3 weeks later. Bromodeoxyuridine (BrdU) was used to label proliferating cells, and cell phenotypes of the progeny were identified by immunohistochemistry. HI significantly enlarged the ipsilateral SVZ at P18, P24, and P31, and increases in the SVZ area correlated directly with the degree of hemispheric damage. HI also stimulated cell proliferation and neurogenesis in the SVZ and peri-infarct striatum. Some newborn cells expressed a neuronal phenotype at P24, but not at P31, indicating that neurogenesis was short-lived. These results suggest that augmenting SVZ neuroblast recruitment and survival may improve neural repair after neonatal brain injury.

Background and Purpose: Critical factors influencing the neuroprotective efficacy of postischemic hypothermia include depth, duration, and time of onset of cooling. In clinical practice, there is an unavoidable lag between the hypoxic-ischemic (HI) insult and the opportunity to initiate cooling. We hypothesized that early administration of a neuroprotective agent in combination with later-onset cooling could represent an effective therapeutic intervention after neonatal HI. We evaluated whether treatment with topiramate, a clinically available anticonvulsant, increased the efficacy of delayed post-HI hypothermia in a neonatal rat stroke model., Methods: Postnatal day 7 (P7) rats underwent right carotid artery ligation followed by 1.5 hours of exposure to 8% oxygen. Fifteen minutes post-HI, animals received injections of topiramate (30 mg/kg) or PBS. Cooling was initiated 3 hours later ("delayed hypothermia") in all animals (3 hours, in 27 degrees C incubator). Functional outcome (forepaw response to vibrissae stimulation) and pathology (morphometric lesion measurements) were evaluated at P15 and P35., Results: Neither topiramate nor delayed hypothermia alone conferred protection in this protocol. Combined treatment with topiramate and delayed hypothermia improved both performance and pathological outcome in P15 and P35 rats compared with PBS-treated animals that underwent delayed hypothermia concurrently. At P15, functional measures were better in topiramate-treated animals (mean correct forepaw response 9.3/10 versus 4.8/10; P<0.001), and there was >50% reduction in tissue loss (P<0.001); trends were similar at P35., Conclusions: Our data provide the impetus for further evaluation of therapeutic approaches that combine drug therapy with delayed-onset cooling after neonatal HI brain injury.

Neonatal hypoxic-ischemic (HI) white matter injury is a major contributor to chronic neurological dysfunction. Immature oligodendrocytes (OLGs) are highly vulnerable to HI injury. As little is known about in vivo OLG repair mechanisms in neonates, we studied whether new OLGs are generated after HI injury in P7 rats. Rats received daily BrdU injections at P12-14 or P21-22 and sacrificed at P14 to study the level of cell proliferation or at P35 to permit dividing OLG precursors to differentiate. In P14 HI-injured animals, the number of BrdU+ cells in the injured hemisphere is consistently greater than controls. At P35, sections were double-labeled for BrdU and markers for OLGs, astrocytes, and microglia. Double-labeled BrdU+/myelin basic protein+ and BrdU+/carbonic anhydrase+ OLGs are abundant in the injured striatum, corpus callosum, and the infarct core. Quantitative studies show four times as many OLGs are generated from P21-35 in HI corpora callosa than controls. Surprisingly, the infarct core contains many newly generated OLGs in addition to hypertrophied astrocytes and activated microglia. These glia and non-CNS cells may stimulate OLG progenitor proliferation or induce their migration. At P35, astrogliosis and microgliosis are dramatic ipsilaterally but only a few microglia and some astrocytes are BrdU+. This finding indicates microglial and astrocytic hyperplasia occurs shortly after HI but before the P21 BrdU injections. Although the neonatal brain undergoes massive cell death and atrophy the first week after injury, it retains the potential to generate new OLGs up to 4 weeks after injury within and surrounding the infarct., (Copyright 2004 Wiley-Liss, Inc.)

Conflicting data have emerged regarding the role of complement activation in the pathophysiology of cerebral ischemia. On the basis of considerable evidence implicating inflammatory mediators in the progression of neonatal brain injury, we evaluated the contribution of complement activation to cerebral hypoxic-ischemic (HI) injury in the neonatal rat. To elicit unilateral forebrain HI injury, 7-d-old rats underwent right carotid ligation followed by 1.5-2 hr of exposure to 8% oxygen. Using immunoprecipitation and Western blot assays, we determined that HI induces local complement cascade activation as early as 8 hr post-HI; there was an eightfold increase in the activation fragment inactivated C3b at 16 hr. With immunofluorescence assays and confocal microscopy, both C3 and C9 were localized to injured neurons 16 and 24 hr post-HI. To investigate the contribution of systemic complement to brain injury, we administered the complement-depleting agent cobra venom factor (CVF) 24 hr before HI lesioning and evaluated both acute HI-induced complement deposition and the extent of resulting tissue injury 5 d after lesioning. CVF depleted both systemic and brain C3 by the time of surgery and reduced infarct size. Analysis of lesioned, CVF-treated animals demonstrated minimal neuronal C3 deposition but no reduction in C9 deposition. C3-immunoreactive microglia were identified in injured areas. These results indicate that complement activation contributes to HI injury in neonatal rat brain, systemic administration of CVF does not eliminate complement deposition within injured brain, and microglia may represent an important local source of C3 after acute brain injury.

Chemokines are small, soluble proteins that regulate leukocyte migration, adhesion, and proliferation. Recent evidence suggests that chemokine receptors are expressed in the central nervous system and that their functions extend beyond their roles in inflammation. Specific chemokines and their receptors are implicated in cerebellar development. In this study, we evaluated the expression of beta-chemokine receptor CCR1 in the immature and adult rat cerebellum and report striking developmental changes in CCR1 expression. Reverse transcriptase polymerase chain reaction assays of cerebellum revealed moderate increases in CCR1 mRNA expression from postnatal day (P) 3 to adulthood. Light and confocal microscopy were used to evaluate developmental changes in the neuroanatomical and cell-specific distribution of CCR1 immunoreactivity. CCR1 immunoreactivity was detected as early as P3 and peaked between P7 and P21. The predominant CCR1-immunoreactive neuronal cell types included granule cells of the internal granular layer, Purkinje cells, Golgi cells, and molecular layer interneurons; Bergmann glia, astrocytes, and resting microglia also expressed CCR1. In contrast, granule cells in the external germinal layer, descending granule cells, and activated microglia rarely expressed CCR1. We also evaluated the expression of the CCR1 ligand macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3). Two cell populations expressed MIP-1alpha: physiologically activated microglia in white matter (P7-P14) and Purkinje cells (P7-adult). MIP-1alpha-positive cells were frequently located near the processes and cell bodies of CCR1-immunoreactive cells, during times of neuronal and glial maturation (second and third postnatal weeks). These findings provide support for the hypothesis that CCR1 plays a role in postnatal cerebellar development., (Copyright 2003 Wiley-Liss, Inc.)

Background and Purpose: Macrophage inflammatory protein (MIP)-1alpha is a well-characterized monocyte chemoattractant; its role in regulating monocyte and microglial recruitment and activation in the injured neonatal brain is unknown. We evaluated the impact of acute hypoxic-ischemic (HI) brain injury on the expression of MIP-1alpha in neonatal rat brain., Methods: To elicit forebrain ischemic injury, 7-day-old (P7) rats underwent right carotid ligation, followed by 2.5 hours of 8% oxygen exposure. We used an enzyme-linked immunosorbent assay and immunohistochemistry to detect MIP-1alpha; double-labeling immunofluorescence assays were analyzed with confocal microscopy to identify cellular sources of MIP-1alpha. Immunocytochemistry assays were also used to detect 2 MIP-1alpha receptors, CCR1 and CCR5., Results: We found marked increases in tissue concentrations of MIP-1alpha in the HI cerebral hemisphere, peaking from 8 to 72 hours after lesioning. Immunocytochemistry assays revealed that MIP-1alpha was constitutively expressed in physiologically activated microglia; from 8 to 120 hours after lesioning, MIP-1alpha immunoreactive monocytes and microglia accumulated in the lesion territory. In immunoreactive cells, MIP-1alpha was diffusely distributed throughout the cytoplasm at early post-HI time intervals; by 72 hours, MIP-1alpha immunoreactivity was typically concentrated adjacent to the nucleus, a pattern indicative of active MIP-1alpha production. In P7 to P12 brain, many cells expressed MIP-1alpha receptors; both CCR1 and CCR5 immunoreactivity were localized to endothelium and ependyma; CCR1-immunoreactive astrocytes and neurons and CCR5-immunoreactive microglia were also identified., Conclusions: These data implicate MIP-1alpha as a mediator of the complex and sustained inflammatory response initiated by perinatal HI braininjury.

Neonatal periventricular white matter injury is a major contributor to chronic neurologic dysfunction. In a neonatal rat stroke model, myelin basic protein (MBP) immunostaining reveals acute periventricular white matter injury. Yet, the extent to which myelin proteins can recover after neonatal hypoxic-ischemic injury is unknown. We developed a quantitative method to correlate the severity of the hypoxic-ischemic insult with the magnitude of loss of MBP immunostaining. Seven-day-old (P7) rats underwent right carotid ligation, followed by exposure to 8% oxygen for 1, 1.5, 2, or 2.5 h. On both P12 and P21, white matter integrity was evaluated by densitometric analysis of MBP immunostaining, and the amount of tissue injury was evaluated by morphometric measurements of cerebral hemisphere areas. The most severe hypoxic-ischemic insults (2.5 h) elicited marked reductions in MBP immunostaining ipsilaterally on both P12 and P21. In contrast, in mildly lesioned animals (1.5 h), MBP immunostaining was reduced ipsilaterally on P12, but 2 wk after lesioning, on P21, there was a substantial restoration of MBP immunostaining. The restoration in MBP immunostaining could reflect either functional recovery of injured oligodendroglia or proliferation and maturation of oligodendroglial precursors. Our data demonstrate that quantitative measurement of MBP immunostaining provides a sensitive indicator of acute oligodendroglial injury. Most importantly, we show that in this neonatal rodent stroke model, restoration of myelin proteins occurs after moderate, but not after more severe, cerebral hypoxia-ischemia.