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The onset and duration of hypoxic-ischemic (HI) insults rarely can be determined precisely in perinatal asphyxia. The need to establish the timing of HI insults will be critical for the successful application of evolving neuroprotective therapies that may be administered to the asphyxiated newborn. Diffusion-weighted magnetic resonance imaging has emerged as an imaging technique that can be used to identify HI brain injury before the detection of abnormalities by conventional magnetic resonance imaging. This case illustrates the early changes in diffusion-weighted and conventional magnetic resonance imaging studies and in quantitative values of the apparent diffusion coefficient in a unique case of neonatal asphyxia in which the onset and duration of the HI insult were known. [ABSTRACT FROM AUTHOR]

Background: Parents of neonates with seizures report persistent symptoms of depression, anxiety, and posttraumatic stress. We aimed to characterize the parent experience of caring for children impacted by neonatal seizures, including longitudinal assessment across childhood., Methods: This prospective, observational, multicenter study was conducted at Neonatal Seizure Registry (NSR) sites in partnership with the NSR Parent Advisory Panel. Parents completed surveys at discharge; 12, 18, and 24 months; and 3, 4, 5, 7, and 8 years. Surveys included demographic information and open-ended questions targeting parent experience. A conventional content analysis approach was used., Results: A total of 320 caregivers completed at least one open-ended question, with the majority of respondents at discharge (n = 142), 12 months (n = 169), 18 months (n = 208), and 24 months (n = 245). We identified the following three primary themes. (1) Personal Burden of Care: Parents experienced emotional distress, financial strain, physical demands, and fears for their child's unknown outcome; (2) Managing Day-to-Day Life: Parents described difficulties navigating their parenting role, including managing their child's challenging behaviors and understanding their child's needs amid neurodevelopmental impairment; (3) My Joys as a Parent: Parents valued bonding with their child, being a caregiver, and watching their child's personality grow., Conclusions: Parents of children impacted by neonatal seizures face persistent challenges, which are interwoven with the joys of being a parent. Our findings suggest that future interventions should promote resiliency, address caregivers' psychosocial needs longitudinally, and provide enhanced support for parents caring for children with medical complexity., Competing Interests: Declaration of Competing Interest Dr. Monica Lemmon receives funding from NIH (K23NS116453). Dr. Reneé Shellhaas receives royalties from UpToDate for authorship on topics related to neonatal seizures and serves as a consultant for the Epilepsy Study Consortium. Betsy Pilon is the Executive Director of Hope for HIE. The other authors have no disclosures to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Neonatal neurocritical care (NNCC) is a rapidly advancing field with limited fellowship training available in locally developed, non-accredited programs. A standardized survey aimed to understand the training backgrounds of individuals practicing NNCC, the structure of existing clinical NNCC services/training programs, and suggested clinical competencies for new graduates., Methods: We developed an anonymous survey electronically sent to members of societies related to NNCC. Using the survey results as a guide, we discuss a competence by design (CBD) curriculum as a complementary approach to traditional time-based training., Results: There were 82 responses to the survey from 30 countries; 95% of respondents were physicians. Thirty-one (42%) institutions reported having an NNCC service, 24 (29%) individuals reported formal NNCC training, 81% reported "significant variability" across NNCC training programs, and 88% were both in favor of standardizing training programs and pursuing formal accreditation for NNCC in the next 5 years., Conclusions: The survey results demonstrate international interest in standardizing NNCC training and development of an accreditation or certification process. We propose consideration of a CBD-type curriculum as a training approach to focus on the development of specific NNCC competencies, rather than assuming the acquisition of these competencies based on time as a surrogate., Impact: Continued growth and development in the field of NNCC has led to increasing need for training programs suited to meet the diverse needs of trainees from varied backgrounds. We present the results of an international survey that assessed the structure of existing training programs and the priority areas in which graduates must demonstrate competence, highlighting the combination of CBD and time-based training as one approach to address these recommendations. The survey results support interest in translating published training competencies, existing expertise, and infrastructure across centers into a standardized curriculum for NNCC including certification opportunities., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Neonatal encephalopathy (NE) continues to be a significant risk for death and disability. To address this risk, regional guidelines were developed with the support of a malpractice insurance patient safety organization. A NE registry was also established to include 14 centers representing around 50% of deliveries in the state of Massachusetts. The aim of this study was to identify areas of variation in practice that could benefit from quality improvement projects., Methods: This manuscript reports on the establishment of the registry and the primary findings to date., Results: From 2018 to 2020, 502 newborns with NE were evaluated for Therapeutic Hypothermia (TH), of which 246 (49%) received TH, representing a mean of 2.91 per 1000 live births. The study reports on prenatal characteristics, delivery room resuscitation, TH eligibility screening, and post-natal management of newborns with NE who did and did not receive TH., Conclusions: The registry has allowed for the identification of areas of variation in clinical practices, which have guided ongoing quality improvement projects. The authors advocate for the establishment of local and regional registries to standardize and improve NE patient care. They have made the registry data collection tools freely available for other centers to replicate this work., Impact: Malpractice insurance companies can take an active role in supporting clinicians in establishing clinical practice guidelines and regional registries. Establishing a collaborative regional neonatal encephalopathy (NE) registry is feasible. Data Collection tools for a NE registry have been made publicly available to be adopted and replicated by other groups. Establishing a regional NE registry allowed for the identification of gaps in knowledge, variations in practice, and the opportunity to advance care through quality improvement projects., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: Among neonates with acute symptomatic seizures, we evaluated whether inability to take full feeds at time of hospital discharge from neonatal seizure admission is associated with worse neurodevelopmental outcomes, after adjusting for relevant clinical variables., Methods: This prospective, 9-center study of the Neonatal Seizure Registry (NSR) assessed characteristics of infants with seizures including: evidence of brainstem injury on MRI, mode of feeding upon discharge, and developmental outcomes at 12, 18, and 24 months. Inability to take oral feeds was identified through review of medical records. Brainstem injury was identified through central review of neonatal MRIs. Developmental outcomes were assessed with the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) at 12, 18, and 24 months corrected age., Results: Among 276 infants, inability to achieve full oral feeds was associated with lower total WIDEA-FS scores (160.2±25.5 for full oral feeds vs. 121.8±42.9 for some/no oral feeds at 24 months, p<0.001). At 12 months, a G-tube was required for 23 of the 49 (47%) infants who did not achieve full oral feeds, compared with 2 of the 221 (1%) who took full feeds at discharge (p<0.001)., Conclusions: Inability to take full oral feeds upon hospital discharge is an objective clinical sign that can identify infants with acute symptomatic neonatal seizures who are at high risk for impaired development at 24 months., Competing Interests: Dr. Robers has no disclosures. Dr. Barks receives research support from NIH. Dr. Glass receives research support from NIH. Dr. Soul has no disclosures. Dr. Chang has no disclosures. Dr. Wusthoff has no disclosures. Dr. Chu receives research support from Biogen Inc, and from NIH. Dr. Massey has no disclosures. Dr. Abend has no disclosures. Dr. Lemmon receives research support from NIH (K23NS116453). Dr. Thomas receives research support through NIH and UCB. Dr. Guillet has no disclosures. Dr. Rogers has no disclosures. Dr. Franck has no disclosures. Mr. McCaffrey has no disclosures. Dr. Li has no disclosures. Dr. McCulloch has no disclosures. Dr. Shellhaas receives research support from NIH. She receives royalties from UpToDate for authorship of topics related to neonatal seizures, serves as a consultant for the Epilepsy Study Consortium and is president-elect of the Pediatric Epilepsy Research Foundation™.

Background: Therapeutic hypothermia (TH) is standard of care for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE) but many survivors still suffer lifelong disabilities and benefits of TH for mild HIE are under active debate. Development of objective diagnostics, with sensitivity to mild HIE, are needed to select, guide, and assess response to treatment. The objective of this study was to determine if cerebral oxygen metabolism (CMRO 2 ) in the days after TH is associated with 18-month neurodevelopmental outcomes as the first step in evaluating CMRO 2 's potential as a diagnostic for HIE. Secondary objectives were to compare associations with clinical exams and characterise the relationship between CMRO 2 and temperature during TH., Methods: This was a prospective, multicentre, observational, cohort study of neonates clinically diagnosed with HIE and treated with TH recruited from the tertiary neonatal intensive care units (NICUs) of Boston Children's Hospital, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center between December 2015 and October 2019 with follow-up to 18 months. In total, 329 neonates ≥34 weeks gestational age admitted with perinatal asphyxia and suspected HIE were identified. 179 were approached, 103 enrolled, 73 received TH, and 64 were included. CMRO 2 was measured at the NICU bedside by frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS-DCS) during the late phases of hypothermia (C), rewarming (RW) and after return to normothermia (NT). Additional variables were body temperature and clinical neonatal encephalopathy (NE) scores, as well as findings from magnetic resonance imaging (MRI) and spectroscopy (MRS). Primary outcome was the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months, normed (SD) to 100 (15)., Findings: Data quality for 58 neonates was sufficient for analysis. CMRO 2 changed by 14.4% per °C (95% CI, 14.2-14.6) relative to its baseline at NT while cerebral tissue oxygen extraction fraction (cFTOE) changed by only 2.2% per °C (95% CI, 2.1-2.4) for net changes from C to NT of 91% and 8%, respectively. Follow-up data for 2 were incomplete, 33 declined and 1 died, leaving 22 participants (mean [SD] postnatal age, 19.1 [1.2] month; 11 female) with mild to moderate HIE (median [IQR] NE score, 4 [3-6]) and 21 (95%) with BSID-III scores >85 at 18 months. CMRO 2 at NT was positively associated with cognitive and motor composite scores (β (SE) = 4.49 (1.55) and 2.77 (1.00) BSID-III points per 10 -10  moL/dl × mm 2 /s, P = 0.009 and P = 0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes., Interpretation: Point of care measures of CMRO 2 in the NICU during C and RW showed dramatic changes and potential to assess individual response to TH. CMRO 2 following TH outperformed conventional clinical evaluations (NE score, cFTOE, and MRI/MRS) at predicting cognitive and motor outcomes at 18 months for mild to moderate HIE, providing a promising objective, physiologically-based diagnostic for HIE., Funding: This clinical study was funded by an NIH grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (R01HD076258)., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Outcomes of neonatal encephalopathy (NE) have improved since the widespread implementation of therapeutic hypothermia (TH) in high-resource settings. While TH for NE in term and near-term infants has proven beneficial, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. There is therefore a critical need to find additional pharmacological and non-pharmacological interventions that improve the outcomes for these children. There are many potential candidates; however, it is unclear whether these interventions have additional benefits when used with TH. Although primary and delayed (secondary) brain injury starting in the latent phase after HI are major contributors to neurodisability, the very late evolving effects of tertiary brain injury likely require different interventions targeting neurorestoration. Clinical trials of seizure management and neuroprotection bundles are needed, in addition to current trials combining erythropoietin, stem cells, and melatonin with TH. IMPACT: The widespread use of therapeutic hypothermia (TH) in the treatment of neonatal encephalopathy (NE) has reduced the associated morbidity and mortality. However, 30-50% of infants with moderate-to-severe NE treated with TH still suffer death or significant impairments. This review details the pathophysiology of NE along with the evidence for the use of TH and other beneficial neuroprotective strategies used in term infants. We also discuss treatment strategies undergoing evaluation at present as potential adjuvant treatments to TH in NE., (© 2022. The Author(s).)

Background: Neonatal seizures are common, but the impact of neonatal seizures on long-term neurologic outcome remains unclear. We addressed this question by analyzing data from an early-phase controlled trial of bumetanide to treat neonatal seizures., Methods: Neonatal seizure burden was calculated from continuous video-EEG data. Neurologic outcome was determined by standardized developmental tests and post-neonatal seizure recurrence., Results: Of 111 enrolled neonates, 43 were randomized to treatment or control groups. There were no differences in neurologic outcome between treatment and control groups. A subgroup analysis was performed for 84 neonates with acute perinatal brain injury (57 HIE, 18 stroke, 9 ICH), most of whom (70%) had neonatal seizures. There was a significant negative correlation between seizure burden and developmental scores (p<0.01). Associations between seizure burden and developmental scores were stronger in HIE and stroke groups compared with ICH (p<0.05)., Conclusion: Bumetanide showed no long-term beneficial or adverse effects, as expected based on treatment duration versus duration of neonatal seizures. For neonates with perinatal brain injury, higher neonatal seizure burden correlated significantly with worse developmental outcome, particularly for ischemic versus hemorrhagic brain injury. These data highlight the need for further investigation of the long-term effects of both neonatal seizure severity and etiology., Competing Interests: Conflict of interest disclosure: The authors report no conflicts of interest. Potential conflicts of interest: The authors have no conflicts of interest to report.

Background: Limited data exist regarding seizure burden, electroencephalogram (EEG) background, and associated outcomes in neonates with acute intracranial infections., Methods: This secondary analysis was from a prospective, multicenter study of neonates enrolled in the Neonatal Seizure Registry with seizures due to intracranial infection. Sites used continuous EEG monitoring per American Clinical Neurophysiology Society guidelines. High seizure burden was defined a priori as seven or more EEG-confirmed seizures. EEG background was categorized using standardized terminology. Primary outcome was neurodevelopment at 24-months corrected age using Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS). Secondary outcomes were postneonatal epilepsy and motor disability., Results: Twenty-seven of 303 neonates (8.9%) had seizures due to intracranial infection, including 16 (59.3%) bacterial, 5 (18.5%) viral, and 6 (22.2%) unknown. Twenty-three neonates (85%) had at least one subclinical seizure. Among 23 children with 24-month follow-up, the WIDEA-FS score was, on average, 23 points lower in children with high compared with low seizure burden (95% confidence interval, [-48.4, 2.1]; P = 0.07). After adjusting for gestational age, infection etiology, and presence of an additional potential acute seizure etiology, the effect size remained unchanged (β = -23.8, P = 0.09). EEG background was not significantly associated with WIDEA-FS score. All children with postneonatal epilepsy (n = 4) and motor disability (n = 5) had high seizure burden, although associations were not significant., Conclusion: High seizure burden may be associated with worse neurodevelopment in neonates with intracranial infection and seizures. EEG monitoring can provide useful management and prognostic information in this population., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Neurodevelopmental impairment is common in children with congenital heart disease (CHD), but postnatal variables explain only 30% of the variance in outcomes. To explore whether the antecedents for neurodevelopmental disabilities might begin in utero, we analyzed whether fetal brain volume predicted subsequent neurodevelopmental outcome in children with CHD., Methods: Fetuses with isolated CHD and sociodemographically comparable healthy control fetuses underwent fetal brain magnetic resonance imaging and 2-year neurodevelopmental evaluation with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) and the Adaptive Behavior Assessment System, Third Edition (ABAS-3). Hierarchical regression evaluated potential predictors of Bayley-III and ABAS-3 outcomes in the CHD group, including fetal total brain volume adjusted for gestational age and sex, sociodemographic characteristics, birth measures, and medical history., Results: The CHD group (n=52) had lower Bayley-III cognitive, language, and motor scores than the control group (n=26), but fetal brain volumes were similar. Within the CHD group, larger fetal total brain volume correlated with higher Bayley-III cognitive, language, and motor scores and ABAS-3 adaptive functioning scores ( r =0.32-0.47; all P <0.05), but this was not noted in the control group. Fetal brain volume predicted 10% to 21% of the variance in neurodevelopmental outcome measures in univariate analyses. Multivariable models that also included social class and postnatal factors explained 18% to 45% of the variance in outcome, depending on developmental domain. Moreover, in final multivariable models, fetal brain volume was the most consistent predictor of neurodevelopmental outcome across domains., Conclusions: Small fetal brain volume is a strong independent predictor of 2-year neurodevelopmental outcomes and may be an important imaging biomarker of future neurodevelopmental risk in CHD. Future studies are needed to support this hypothesis. Our findings support inclusion of fetal brain volume in risk stratification models and as a possible outcome in fetal neuroprotective intervention studies.

Background: Children with a history of acute provoked neonatal seizures are at high risk for disability, often requiring developmental services. The coronavirus disease 2019 (COVID-19) pandemic has led to widespread changes in how health care is delivered. Our objective was to determine the magnitude of service interruption of among children born between October 2014 and December 2017 and enrolled in the Neonatal Seizure Registry (NSR), a nine-center collaborative of pediatric centers in the United States., Methods: This is a prospective cohort study of children with acute provoked seizures with onset ≤44 weeks' gestation and evaluated at age three to six years. Parents of children enrolled in the NSR completed a survey about their child's access to developmental services between June 2020 and April 2021., Results: Among 144 children enrolled, 72 children (50%) were receiving developmental services at the time of assessment. Children receiving services were more likely to be male, born preterm, and have seizure etiology of infection or ischemic stroke. Of these children, 64 (89%) experienced a disruption in developmental services due to the pandemic, with the majority of families (n = 47, 73%) reporting that in-person services were no longer available., Conclusions: Half of children with acute provoked neonatal seizures were receiving developmental services at ages three to six years. The COVID-19 pandemic has led to widespread changes in delivery of developmental services. Disruptions in services have the potential to impact long-term outcomes for children who rely on specialized care programs to optimize mobility and learning., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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

Objective: We sought to characterize intracranial hemorrhage (ICH) as a seizure etiology in infants born term and preterm. For infants born term, we sought to compare seizure severity and treatment response for multisite vs single-site ICH and hypoxic-ischemic encephalopathy (HIE) with vs without ICH., Study Design: We studied 112 newborn infants with seizures attributed to ICH and 201 infants born at term with seizures attributed to HIE, using a cohort of consecutive infants with clinically diagnosed and/or electrographic seizures prospectively enrolled in the multicenter Neonatal Seizure Registry. We compared seizure severity and treatment response among infants with complicated ICH, defined as multisite vs single-site ICH and HIE with vs without ICH., Results: ICH was a more common seizure etiology in infants born preterm vs term (27% vs 10%, P < .001). Most infants had subclinical seizures (74%) and an incomplete response to initial antiseizure medication (ASM) (68%). In infants born term, multisite ICH was associated with more subclinical seizures than single-site ICH (93% vs 66%, P = .05) and an incomplete response to the initial ASM (100% vs 66%, P = .02). Status epilepticus was more common in HIE with ICH vs HIE alone (38% vs 17%, P = .05)., Conclusions: Seizure severity was greater and treatment response was lower among infants born term with complicated ICH. These data support the use of continuous video electroencephalogram monitoring to accurately detect seizures and a multistep treatment plan that considers early use of multiple ASMs, particularly with parenchymal and high-grade intraventricular hemorrhage and complicated ICH., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease., Study Design: The Neonatal Seizure Registry is a multicenter, prospectively acquired cohort of neonates with clinical or electroencephalographic (EEG)-confirmed seizures. Cardiopulmonary disease was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous EEG monitoring strategy, seizure characteristics, seizure management, and outcomes for neonates with and without cardiopulmonary disease., Results: We evaluated 83 neonates with cardiopulmonary disease and 271 neonates without cardiopulmonary disease. Neonates with cardiopulmonary disease were more likely to have EEG-only seizures (40% vs 21%, P < .001) and experience their first seizure later than those without cardiopulmonary disease (174 vs 21 hours of age, P < .001), but they had similar seizure exposure (many-recurrent electrographic seizures 39% vs 43%, P = .27). Phenobarbital was the primary initial antiseizure medication for both groups (90%), and both groups had similarly high rates of incomplete response to initial antiseizure medication administration (66% vs 68%, P = .75). Neonates with cardiopulmonary disease were discharged from the hospital later (hazard ratio 0.34, 95% CI 0.25-0.45, P < .001), although rates of in-hospital mortality were similar between the groups (hazard ratio 1.13, 95% CI 0.66-1.94, P = .64)., Conclusion: Neonates with and without cardiopulmonary disease had a similarly high seizure exposure, but neonates with cardiopulmonary disease were more likely to experience EEG-only seizures and had seizure onset later in the clinical course. Phenobarbital was the most common seizure treatment, but seizures were often refractory to initial antiseizure medication. These data support guidelines recommending continuous EEG in neonates with cardiopulmonary disease and indicate a need for optimized therapeutic strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Little is known about parent and family well-being after acute neonatal seizures. In thus study, we aimed to characterize parent mental health and family coping over the first two years after their child's neonatal seizures. Parents of 303 children with acute neonatal seizures from nine pediatric hospitals completed surveys at discharge and 12-, 18- and 24-months corrected age. Outcomes included parental anxiety, depression, quality of life, impact on the family, post-traumatic stress and post-traumatic growth. We used linear mixed effect regression models and multivariate analysis to examine relationships among predictors and outcomes. At the two-year timepoint, parents reported clinically significant anxiety (31.5%), depression (11.7%) and post-traumatic stress (23.7%). Parents reported moderately high quality of life and positive personal change over time despite ongoing challenges to family coping. Families of children with longer neonatal hospitalization, functional impairment, post-neonatal epilepsy, receiving developmental support services and families of color reported poorer parental mental health and family coping. Parents of color were more likely to report symptoms of post-traumatic stress and positive personal change. Clinicians caring for children with neonatal seizures should be aware of lasting risks to parent mental health and family coping. Universal screening would enable timely referral for support services to mitigate further risk to family well-being and child development.

Background: Parents of neonates with seizures are at risk of mental health symptoms due to the impact of illness on family life, prognostic uncertainty, and the emotional toll of hospitalization. A family-centered approach is the preferred model to mitigate these challenges. We aimed to identify strategies to promote family-centered care through an analysis of parent-offered advice to clinicians caring for neonates with seizures., Methods: This prospective, observational, and multicenter (Neonatal Seizure Registry) study enrolled parents of neonates with acute symptomatic seizures. Parents completed surveys about family well-being at 12, 18, and 24 months corrected gestational age. Parents were asked open-ended questions eliciting their advice to clinicians caring for neonates with seizures. Responses were analyzed using a conventional content analysis approach., Results: Among the 310 parents who completed surveys, 118 (38%) shared advice for clinicians. These parents were predominantly mothers (n = 103, 87%). Three overarching themes were identified. (1) Communicate information effectively: parents appreciate when clinicians offer transparent and balanced information in an accessible way. (2) Understand and validate parent experience: parents value clinicians who display empathy, compassion, and a commitment to parent-partnered clinical care. (3) Providesupportand resources: parents benefit from emotional support, education, connection with peers, and help navigating the health care system., Conclusions: Parents caring for neonates with seizures appreciate a family-centered approach in health care encounters, including skilled communication, understanding and validation of the parent experience, and provision of support and resources. Future interventions should focus on building structures to reinforce these priorities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To determine whether screening continuous EEG monitoring (cEEG) is associated with greater odds of treatment success for neonatal seizures., Methods: We included term neonates with acute symptomatic seizures enrolled in the Neonatal Seizure Registry (NSR), a prospective, multicenter cohort of neonates with seizures. We compared 2 cEEG approaches: (1) screening cEEG, initiated for indications of encephalopathy or paralysis without suspected clinical seizures; and (2) confirmatory cEEG, initiated for the indication of clinical events suspicious for seizures, either alone or in addition to other indications. The primary outcome was successful response to initial seizure treatment, defined as seizures resolved without recurrence within 30 minutes after initial loading dose of antiseizure medicine. Multivariable logistic regression analyses assessed the association between cEEG approach and successful seizure treatment., Results: Among 514 neonates included, 161 (31%) had screening cEEG and 353 (69%) had confirmatory cEEG. Neonates with screening cEEG had a higher proportion of successful initial seizure treatment than neonates with confirmatory cEEG (39% vs 18%; p < 0.0001). After adjusting for covariates, there remained a greater odds ratio (OR) for successful initial seizure treatment in the screening vs confirmatory cEEG groups (adjusted OR 2.44, 95% confidence interval 1.45-4.11, p = 0.0008)., Conclusions: These findings provide evidence from a large, contemporary cohort of neonates that a screening cEEG approach may improve odds of successful treatment of acute seizures., Classification of Evidence: This study provides Class III evidence that for neonates a screening cEEG approach, compared to a confirmatory EEG approach, increases the probability of successful treatment of acute seizures., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Neonatal encephalopathy (NE) is the most common etiology of acute neonatal seizures - about half of neonates treated with therapeutic hypothermia for NE have EEG-confirmed seizures. These seizures are best identified with continuous EEG monitoring, as clinical diagnosis leads to under-diagnosis of subclinical seizures and over-treatment of events that are not seizures. High seizure burden, especially status epilepticus, is thought to augment brain injury. Treatment, therefore, is aimed at minimizing seizure burden. Phenobarbital remains the mainstay of treatment, as it is more effective than levetiracetam and easier to administer than fosphenytoin. Emerging evidence suggests that, for many neonates, it is safe to discontinue the phenobarbital after acute seizures resolve and prior to hospital discharge., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: We aimed to evaluate early-life epilepsy incidence, seizure types, severity, risk factors, and treatments among survivors of acute neonatal seizures., Methods: Neonates with acute symptomatic seizures born 7/2015-3/2018 were prospectively enrolled at nine Neonatal Seizure Registry sites. One-hour EEG was recorded at age three months. Post-neonatal epilepsy and functional development (Warner Initial Developmental Evaluation of Adaptive and Functional Skills - WIDEA-FS) were assessed. Cox regression was used to assess epilepsy-free survival., Results: Among 282 infants, 37 (13%) had post-neonatal epilepsy by 24-months [median age of onset 7-months (IQR 3-14)]. Among those with post-neonatal epilepsy, 13/37 (35%) had infantile spasms and 12/37 (32%) had drug-resistant epilepsy. Most children with post-neonatal epilepsy had abnormal neurodevelopment at 24-months (WIDEA-FS >2SD below normal population mean for 81% of children with epilepsy vs 27% without epilepsy, RR 7.9, 95% CI 3.6-17.3). Infants with severely abnormal neonatal EEG background patterns were more likely to develop epilepsy than those with mild/moderate abnormalities (HR 3.7, 95% CI 1.9-5.9). Neonatal EEG with ≥3 days of seizures also predicted hazard of epilepsy (HR 2.9, 95% CI 1.4-5.9). In an adjusted model, days of neonatal EEG-confirmed seizures (HR 1.4 per day, 95% CI 1.2-1.6) and abnormal discharge examination (HR 3.9, 95% CI 1.9-7.8) were independently associated with time to epilepsy onset. Abnormal (vs. normal) three-month EEG was not associated with epilepsy., Significance: In this multicenter study, only 13% of infants with acute symptomatic neonatal seizures developed post-neonatal epilepsy by age 24-months. However, there was a high risk of severe neurodevelopmental impairment and drug-resistant seizures among children with post-neonatal epilepsy. Days of EEG-confirmed neonatal seizures was a potentially modifiable epilepsy risk factor. An EEG at three months was not clinically useful for predicting epilepsy. These practice changing findings have implications for family counseling, clinical follow-up planning, and future research to prevent post-neonatal epilepsy., (© 2021 International League Against Epilepsy.)

Importance: Antiseizure medication (ASM) treatment duration for acute symptomatic neonatal seizures is variable. A randomized clinical trial of phenobarbital compared with placebo after resolution of acute symptomatic seizures closed early owing to low enrollment., Objective: To assess whether ASM discontinuation after resolution of acute symptomatic neonatal seizures and before hospital discharge is associated with functional neurodevelopment or risk of epilepsy at age 24 months., Design, Setting, and Participants: This comparative effectiveness study included 303 neonates with acute symptomatic seizures (282 with follow-up data and 270 with the primary outcome measure) from 9 US Neonatal Seizure Registry centers, born from July 2015 to March 2018. The centers all had level IV neonatal intensive care units and comprehensive pediatric epilepsy programs. Data were analyzed from June 2020 to February 2021., Exposures: The primary exposure was duration of ASM treatment dichotomized as ASM discontinued vs ASM maintained at the time of discharge from the neonatal seizure admission. To enhance causal association, each outcome risk was adjusted for propensity to receive ASM at discharge. Propensity for ASM maintenance was defined by a logistic regression model including seizure cause, gestational age, therapeutic hypothermia, worst electroencephalogram background, days of electroencephalogram seizures, and discharge examination (all P ≤ .10 in a joint model except cause, which was included for face validity)., Main Outcomes and Measures: Functional neurodevelopment was assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) at 24 months powered for propensity-adjusted noninferiority of early ASM discontinuation. Postneonatal epilepsy, a prespecified secondary outcome, was defined per International League Against Epilepsy criteria, determined by parent interview, and corroborated by medical records., Results: Most neonates (194 of 303 [64%]) had ASM maintained at the time of hospital discharge. Among 270 children evaluated at 24 months (mean [SD], 23.8 [0.7] months; 147 [54%] were male), the WIDEA-FS score was similar for the infants whose ASMs were discontinued (101 of 270 [37%]) compared with the infants with ASMs maintained (169 of 270 [63%]) at discharge (median score, 165 [interquartile range, 150-175] vs 161 [interquartile range, 129-174]; P = .09). The propensity-adjusted average difference was 4 points (90% CI, -3 to 11 points), which met the a priori noninferiority limit of -12 points. The epilepsy risk was similar (11% vs 14%; P = .49), with a propensity-adjusted odds ratio of 1.5 (95% CI, 0.7-3.4; P = .32)., Conclusions and Relevance: In this comparative effectiveness study, no difference was found in functional neurodevelopment or epilepsy at age 24 months among children whose ASM was discontinued vs maintained at hospital discharge after resolution of acute symptomatic neonatal seizures. These results support discontinuation of ASM prior to hospital discharge for most infants with acute symptomatic neonatal seizures.

Objective: In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard-therapy control group., Methods: A randomized, double-blind, dose-escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)-confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures., Results: Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post-SDA (both p < 0.01) compared with 2-hour baseline in treatment versus control groups with adjustment for seizure burden., Interpretation: Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327-340., (© 2020 American Neurological Association.)

Objective: Congenital heart disease (CHD) is associated with abnormal brain development in utero. We applied innovative fetal magnetic resonance imaging (MRI) techniques to determine whether reduced fetal cerebral substrate delivery impacts the brain globally, or in a region-specific pattern. Our novel design included two control groups, one with and the other without a family history of CHD, to explore the contribution of shared genes and/or fetal environment to brain development., Methods: From 2014 to 2018, we enrolled 179 pregnant women into 4 groups: "HLHS/TGA" fetuses with hypoplastic left heart syndrome (HLHS) or transposition of the great arteries (TGA), diagnoses with lowest fetal cerebral substrate delivery; "CHD-other," with other CHD diagnoses; "CHD-related," healthy with a CHD family history; and "optimal control," healthy without a family history. Two MRIs were obtained between 18 and 40 weeks gestation. Random effect regression models assessed group differences in brain volumes and relationships to hemodynamic variables., Results: HLHS/TGA (n = 24), CHD-other (50), and CHD-related (34) groups each had generally smaller brain volumes than the optimal controls (71). Compared with CHD-related, the HLHS/TGA group had smaller subplate (-13.3% [standard error = 4.3%], p < 0.01) and intermediate (-13.7% [4.3%], p < 0.01) zones, with a similar trend in ventricular zone (-7.1% [1.9%], p = 0.07). These volumetric reductions were associated with lower cerebral substrate delivery., Interpretation: Fetuses with CHD, especially those with lowest cerebral substrate delivery, show a region-specific pattern of small brain volumes and impaired brain growth before 32 weeks gestation. The brains of fetuses with CHD were more similar to those of CHD-related than optimal controls, suggesting genetic or environmental factors also contribute. ANN NEUROL 2021;89:143-157., (© 2020 American Neurological Association.)

Fetal MRI is the modality of choice to study supratentorial brain malformations. To accurately interpret the MRI, the radiologist needs to understand the normal sequence of events that occurs during prenatal brain development; this includes familiarity with the processes of hemispheric cleavage, formation of interhemispheric commissures, neuro-glial proliferation and migration, and cortical folding. Disruption of these processes results in malformations observed on fetal MRI including holoprosencephaly, callosal agenesis, heterotopic gray matter, lissencephaly and other malformations of cortical development (focal cortical dysplasia, polymicrogyria). The radiologist should also be familiar with findings that have high association with specific conditions affecting the central nervous system or other organ systems. This review summarizes and illustrates common patterns of supratentorial brain malformations and emphasizes aspects that are important to patient care.

Background: Neonatal seizures are associated with death and neurological morbidity; however, little is known about how neonates with seizures die., Methods: This was a prospective, observational cohort study of neonates with seizures treated at seven sites of the Neonatal Seizure Registry. We characterized the mode of death, evaluated the association between infant characteristics and mode of death, and evaluated predictors of death or transfer to hospice., Results: We enrolled 611 consecutive neonates with seizures, and 90 neonates (15%) died before hospital discharge at a median age of 11 days (range: 1 to 163 days); 32 (36%) died in the first postnatal week. An additional 19 neonates (3%) were transferred to hospice. The most common mode of in-hospital death was death after extubation amidst concerns for poor neurological prognosis, in the absence of life-threatening physiologic instability (n = 43, 48%). Only one infant died while actively receiving cardiopulmonary resuscitation. In an adjusted analysis, premature birth (odds ratio: 3.06, 95% confidence interval 1.59 to 5.90) and high seizure burden (odds ratio: 4.33, 95% confidence interval 1.88 to 9.95) were associated with increased odds of death or transfer to hospice., Conclusion: In a cohort of neonates with seizures, death occurred predominantly after decisions to withdraw or withhold life-sustaining intervention(s). Future work should characterize how these decisions occur and develop optimized approaches to support families and clinicians caring for newborns with seizures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Objective: To characterize and determine risk factors for key dimensions of well-being at hospital discharge in families of neonates with acute symptomatic seizures., Study Design: This prospective, observational cohort study enrolled 144 parent-infant dyads among neonates with acute symptomatic seizures from 9 pediatric hospitals in the Neonatal Seizure Registry. One parent per family completed a discharge survey, which included measures of anxiety and depression, health-related quality of life, and impact on the family. Multivariable regression analyses adjusted for site were constructed to examine parent and infant characteristics associated with well-being., Results: At discharge, 54% of parents reported symptoms of anxiety and 32% reported symptoms of depression. Parents of infants with hypoxic-ischemic encephalopathy reported more depression and worse quality of life than parents of infants with other seizure etiologies. Parental quality of life was also lower with greater infant age at discharge. A higher level of maternal education was associated with greater impact on the family. All these differences were medium to large effect sizes, ranging from 0.52 to 0.78., Conclusions: Symptoms of anxiety and depression are common in parents of infants with neonatal seizures, and several parent and infant characteristics are associated with poorer parental quality of life and family well-being. These findings are a call to action to improve mental health screening and services for parents of infants with neonatal seizures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To use novel optical techniques to measure perioperative cerebral hemodynamics of diverse congenital heart disease (CHD) groups (two-ventricle, d-transposition of the great arteries [TGA], and single ventricle [SV]) and (1) compare CHD groups with healthy controls preoperatively and (2) compare preoperative and postoperative values within each CHD group., Methods: Frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy were used to measure cerebral oxygen saturation, cerebral blood volume, cerebral blood flow index, cerebral oxygen extraction fraction (OEF, calculated using arterial oxygen saturation and cerebral oxygen saturation), and an index of cerebral metabolic rate of oxygen consumption in control and CHD neonates. Preoperative CHD measures were compared with controls. Preoperative and postoperative measures were compared within each CHD group., Results: In total, 31 CHD neonates (7 two-ventricle, 11 TGA, 13 SV) and 13 controls were included. Only neonates with SV CHD displayed significantly lower preoperative cerebral blood flow index (P < .04) than controls. TGA and SV groups displayed greater OEF (P < .05) during the preoperative period compared with controls. Compared with the preoperative state, postoperative neonates with TGA had a greater arterial oxygen saturation with lower OEF., Conclusions: Differences in cerebral hemodynamics and oxygen metabolism were observed in diverse CHD groups compared with controls. Increased OEF appears to be a compensatory mechanism in neonates with TGA and SV. Studies are needed to understand the relationship of these metrics to outcome and their potential to guide interventions to improve outcome., (Copyright © 2019. Published by Elsevier Inc.)

Mabry syndrome is a glycophosphatidylinositol (GPI) deficiency characterized by intellectual disability, distinctive facial features, intractable seizures, and hyperphosphatasia. We expand the phenotypic spectrum of inherited GPI deficiencies with novel bi-allelic phosphatidylinositol glycan anchor biosynthesis class O (PIGO) variants in a neonate who presented with intractable epilepsy and complex gastrointestinal and urogenital malformations., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: To evaluate the feasibility of a protocol using combined magnetic resonance imaging (MRI), clinical data, and electroencephalogram (EEG) to identify neonates with mild neonatal encephalopathy (NE) treated with therapeutic hypothermia (TH) who are eligible for "early exit"., Methods: Retrospective chart review of TH cases at a single Level III NICU over a 5-year period was used to describe the demographic, clinical, and outcome data in neonates that received early exit in contrast to 72 hour TH treatment., Results: Two hundred and eight TH cases, including 18 early exit cases (9%) and 9 cases (4%) evaluated for early exit with MRI but continued on 72 hours of TH, were identified. Early exit and 72 hour treatment groups did not differ in demographics or cord gas measures, although early exit neonates had a shorter length of stay (p < 0.05). Consistent with the early exit protocol, no early exit infants had evidence of moderate or severe encephalopathy on EEG or evidence of hypoxic ischemic injury on MRI at 24 hours of life. Neurology follow up between age 1 and 18 months was available for 10 early exit infants, 8 of whom had a normal examination., Conclusions: Early MRI at 24 hours of age, alongside clinical and EEG criteria, is feasible as part of a protocol to identify neonates eligible for early exit from therapeutic hypothermia.

Neonatal brain injury (NBI) remains a major contributor to neonatal mortality and long-term neurodevelopmental morbidity. Although therapeutic hypothermia is the only proven treatment to minimize brain injury caused by neonatal encephalopathy in term neonates, it provides incomplete neuroprotection. There are no specific drugs yet proven to prevent NBI in preterm neonates. This review discusses the scientific and emerging clinical trial data for several neuroprotective drugs in development, examining potential efficacy and safety concerns. Drugs with the highest likelihood of success and closest to clinical application include erythropoietin for term and preterm neonates and antenatal magnesium for preterm neonates., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population.

Purpose: Conventional video-EEG monitoring is required to diagnose seizures accurately in neonates. This tool is resource-intense and has limited availability in many centers. Seizure prediction models could help allocate resources by improving efficiency in which conventional video-EEG monitoring is used to detect subclinical seizures. The aim of this retrospective study was to create a neonate-specific seizure prediction model using clinical characteristics and EEG background findings., Methods: We conducted a 3-year retrospective study of all consecutive neonates who underwent conventional video-EEG monitoring at a tertiary care pediatric hospital. Variables including age, EEG indication, high-risk clinical characteristics, and EEG background informed seizure prediction models based on a multivariable logistic regression model. A Cox proportional hazard regression model was used to construct time to first EEG seizure., Results: Prediction models with clinical variables or background EEG features alone versus combined clinical and background EEG features were created from 210 neonates who met inclusion criteria. The combined clinical and EEG model had a higher area under the curve for combined sensitivity and specificity to 83.0% when compared to the clinical model (76.4%) or EEG model (66.2%). The same trend of higher sensitivity of the combined model was found for time to seizure outcome., Conclusions: While both clinical and EEG background features were predictive of neonatal seizures, the combination improved overall prediction of seizure occurrence and prediction of time to first seizure as compared with prediction models based solely on clinical or EEG features alone. With prospective validation, this model may improve efficiency of patient-oriented EEG monitoring.

It was highlighted that the original article [1] contained a typographical error in the Results section. Subject 17 was incorrectly cited as Subject 1. This Correction article shows the revised statement. The original article has been updated.

In a prospective cohort of 534 neonates with acute symptomatic seizures, 66% had incomplete response to the initial loading dose of antiseizure medication (ASM). Treatment response did not differ by gestational age, sex, medication, or dose. The risk of incomplete response was highest for seizures due to intracranial hemorrhage and lowest for hypoxic-ischemic encephalopathy, although the difference was not significant after adjusting for high seizure burden and therapeutic hypothermia treatment. Future trial design may test ASMs in neonates with all acute symptomatic seizure etiologies and could target neonates with seizures refractory to an initial ASM., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Background: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity)., Methods: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes., Results: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances., Conclusions: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.

While cardiorespiratory monitoring is standard for newborns in the NICU, monitoring of brain hemodynamics and oxygenation is usually sporadic and targeted to newborns with suspected or confirmed neurologic disorders. This is unfortunate, since critically ill newborns, both preterm and term-born, are at high risk of brain injury and would benefit from improved techniques for continuous monitoring of brain hemodynamics and oxygenation, in addition to monitoring of systemic hemodynamics and oxygenation. Near-infrared spectroscopy (NIRS) and, to a lesser extent, Doppler ultrasound are techniques that have been used in research and increasingly for clinical purposes to measure and monitor brain hemodynamics and oxygenation in newborns. NIRS monitoring can be useful for detection of diverse pathologic conditions that occur frequently in very preterm newborns and in selected populations of term newborns at risk for brain injury related to disturbances of systemic hemodynamics. This chapter reviews the current state of the art with regard to brain-monitoring techniques and the research directed at this important area, and it concludes with suggestions for the use of currently available tools to manage newborns at high risk of neurologic injury from disturbances in brain hemodynamics and oxygenation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Acute symptomatic seizures caused by either diffuse or focal perinatal hypoxic-ischemic insults and intracranial hemorrhage in term newborns make up the large majority of all neonatal seizures. Acute seizures are one of the most common neurological disorders in term newborns who require admission to the neonatal intensive care unit. Despite elucidation of seizure pathogenesis in this population using animal models, treatment is limited by a lack of good evidence-based guidelines because of a paucity of rigorously conducted clinical trials or prospective studies in human newborns. A result of this knowledge gap is that management, particularly drug choice, is guided by clinical experience rather than by data informing drug efficacy and safety. This review summarizes the common etiologies and pathogenesis of acute symptomatic seizures, and the current data informing their treatment, including potential novel drugs, together with a suggested treatment algorithm., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Muscular dystrophy-dystroglycanopathy type A (MDDGA3), one of a group of diseases collectively known as congenital muscular dystrophies, is an alpha-dystroglycanopathy with characteristic brain and ocular abnormalities. We report the case of a 9-month-old boy with developmental delay whose family sought evaluation for esotropia. Subsequent examination, imaging, and testing revealed significant motor and cognitive delay, marked weakness with appendicular spasticity, and a diffuse brain malformation. In addition, the patient had poor visual acuity, nystagmus, optic nerve hypoplasia, bilateral retinal dysplasia and retinal dragging with a large vertical angle kappa, and an avascular peripheral retina. Genetic testing revealed two known heterozygous mutations in the POMGnT1 gene confirming MDDGA3. He was treated with botulinum toxin injections for his strabismus and continues to be followed, with planned laser ablation of the peripheral avascular retina., (Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Background: While therapeutic hypothermia (TH) is an effective neuroprotective therapy for neonatal hypoxic-ischemic encephalopathy, TH has not been demonstrated to improve outcome in other pediatric populations. Patients with acquired or congenital heart disease (CHD) are at high risk of both cardiac arrest and neurodevelopmental impairments, and therapies are needed to improve neurologic outcome. The primary goal of our study was to compare safety/efficacy outcomes in post-arrest CHD patients treated with TH versus controls not treated with TH., Methods: Patients with CHD treated during the first 18 months after initiation of a post-arrest TH protocol (temperature goal: 33.5 °C) were compared to historical and contemporary post-arrest controls not treated with TH. Post-arrest data, including temperature, safety measures (e.g. arrhythmia, bleeding), neurodiagnostic data (EEG, neuroimaging), and survival were compared., Results: Thirty arrest episodes treated with TH and 51 control arrest episodes were included. The groups did not differ in age, duration of arrest, post-arrest lactate, or use of ECMO-CPR. The TH group's post-arrest temperature was significantly lower than control's (33.6 ± 0.2 °C vs 34.7 ± 0.5 °C, p < 0.001). There was no difference between the groups in safety/efficacy measures, including arrhythmia, infections, chest-tube output, or neuroimaging abnormalities, nor in hospital survival (TH 61.5% vs control 59.1%, p = NS). Significantly more controls had seizures than TH patients (26.1% vs. 4.0%, p = 0.04). Almost all seizures were subclinical and occurred more than 24 h post-arrest., Conclusion: Our data show that pediatric CHD patients who suffer cardiac arrest can be treated effectively and safely with TH, which may decrease the incidence of seizures., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder with variable expressivity in heterozygous females. While liver function testing is often abnormal in patients with OTCD, liver failure is uncommon on presentation. A 13-month-old female with no significant past medical history presented with irritability, right arm weakness, and decreased appetite. Initial workup revealed hepatic dysfunction with an INR of 3.4, ammonia level of 75 μmol/L, and abnormal brain MRI with gyral edema with restricted diffusion, and patchy signal abnormality in basal ganglia. The MRI findings led to a putative diagnosis of acute disseminated encephalomyelitis prompting corticosteroid treatment. As steroid treatment was begun, she developed significant hepatocellular dysfunction with ALT 2,222 U/L, AST 630 U/L, prolonged INR, and elevated ammonia (213 μmol/L). Neurologic signs resolved and her ammonia level decreased (43 μmol/L) without further intervention; however, she had ongoing acute liver failure with coagulopathy and episodic irritability, managed as seronegative autoimmune hepatitis with partial response to corticosteroid therapy. At 18 months of age she presented with severe irritability with markedly increased ammonia (417 μmol/L). Plasma amino acids obtained several days prior to this acute episode demonstrated elevation in glutamine (2,725 μmol/L) and alanine (1,459 μmol/L). Biochemical testing demonstrated elevation of urine orotic acid (>240.6 mmol/mol creatinine). Genetic testing confirmed a heterozygous nonsense mutation in the OTC gene (c.958C>T, R320X). After treatment with ammonia scavengers and a protein-restricted diet, hepatic function normalized and irritability resolved. The diagnosis of a urea cycle disorder should be considered in patients with unexplained hepatic dysfunction.

Neonatal seizures constitute the most frequent presenting neurologic sign encountered in the neonatal intensive care unit. Despite limited efficacy and safety data, phenobarbital continues to be used near-universally as the first-line anti-seizure drug (ASD) in neonates. The choice of second-line ASDs varies by provider and institution, and is still not supported by sufficient scientific evidence. In this review, we discuss the available evidence supporting the efficacy, mechanism of action, potential adverse effects, key pharmacokinetic characteristics such as interaction with therapeutic hypothermia, logistical issues, and rationale for use of neonatal ASDs. We describe the widely used neonatal ASDs, namely phenobarbital, phenytoin, midazolam, and levetiracetam, in addition to potential ASDs, including lidocaine, topiramate, and bumetanide., (Copyright © 2017. Published by Elsevier Ltd.)

Objective: Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures., Methods: Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis., Results: Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations ( p = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, p = 0.01)., Conclusions: Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis., (© 2017 American Academy of Neurology.)

Background: The purpose of this study was to characterize seizures among preterm neonates enrolled in the Neonatal Seizure Registry, a prospective cohort of consecutive neonates with seizures at seven pediatric centers that follow the American Clinical Neurophysiology Society's neonatal electroencephalography monitoring guideline., Study Design: Of 611 enrolled neonates with seizures, 92 (15%) were born preterm. Seizure characteristics were evaluated by gestational age at birth for extremely preterm (<28 weeks, N = 18), very preterm (28 to <32 weeks, N = 18), and moderate to late preterm (32 to <37 weeks, N = 56) and compared with term neonates., Results: Hypoxic-ischemic encephalopathy (33%) and intracranial hemorrhage (27%) accounted for the etiology in more than half of preterm neonates. Hypothermia therapy was utilized in 15 moderate to late preterm subjects with encephalopathy. The presence of subclinical seizures, monotherapy treatment failure, and distribution of seizure burden (including status epilepticus) was similar in preterm and term neonates. However, exclusively subclinical seizures occurred more often in preterm than term neonates (24% vs 14%). Phenobarbital was the most common initial medication for all gestational age groups, and failure to respond to an initial loading dose was 63% in both preterm and term neonates. Mortality was similar among the three preterm gestational age groups; however, preterm mortality was more than twice that of term infants (35% vs 15%)., Conclusions: Subclinical seizures were more common and mortality was higher for preterm than term neonates. These data underscore the importance of electroencephalographic monitoring and the potential for improved management in preterm neonates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Deep anesthesia in adults may be associated with electroencephalographic (EEG) suppression and higher rates of postoperative complications. Little is known about the impact of anesthetic depth on short- or long-term outcomes in pediatrics. Brain activity monitoring may complement clinical signs of anesthetic depth. This prospective observational study aimed to assess the frequency and degree of profound EEG suppression using multichannel EEG in children during sevoflurane general anesthesia., Methods: Children aged 0-40 months who required general anesthesia for elective surgery were included. Continuous EEG recordings were performed starting from when anesthesia began and until recovery. Discontinuity was defined as EEG amplitude <25 uV, lasting ≥2 s, and observed in all electrodes across the scalp. Frequency, duration, and inter-event interval of discontinuity events were measured. Relationships between discontinuity events and postnatal age, endtidal sevoflurane concentration (etSEVO), and multiple clinical parameters were analyzed., Results: Discontinuity events were observed in 35/68 children, with a median duration of 10 s (95%CI: 8-12) and a median of 4 events per patient (95%CI: 2-7). Children who had discontinuity events were younger (5.5 months, 95%CI: 3.6-6.5) compared to children who did not have discontinuity events (10.2 months, 95%CI: 6.1-14); (difference between medians, 4.7 months, 95%CI: 2.3-8, P = 0.0002). Younger infants exhibited a higher number of discontinuity events, and the incidence decreased with postnatal age (r 68 = -0.53, P < 0.0001). The majority of discontinuity events were observed during the first 30 min of anesthesia (66.4% total events), where etSEVO was >3%. Few discontinuity events were observed during maintenance and none during emergence. Blood pressure, heart rate, tissue oxygen saturation, and endtidal CO 2 partial pressure did not change during these events., Conclusions: Electroencephalographic monitoring may complement clinical signs in providing information about brain homeostasis during general anesthesia. The impact of discontinuity events on immediate and long-term outcomes merits further study., (© 2017 John Wiley & Sons Ltd.)

We aimed to define determinants of duration of treatment for acute symptomatic neonatal seizures in a contemporary multicenter observational cohort study. After adjustment for potential confounders, only study site and seizure etiology remained significantly associated with the chance of continuing antiseizure medication after discharge to home., (Copyright © 2016 Elsevier Inc. All rights reserved.)