Wusthoff Lab Publications

Abstract

To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pre-treatment maximal hourly seizure burden and total seizure duration with successful response to initial anti-seizure medication (ASM).Retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between 1/25/2017 and 10/9/2019. We evaluated a cohort of neonates born ≥36 weeks' gestation with moderate to severe HIE who underwent continuous electroencephalogram (EEG) monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1)pre-treatment maximal hourly seizure burden, (2)pre-treatment total seizure duration, (3)time from first seizure to initial ASM, and (4)successful response to initial ASM.Among 39 neonates meeting inclusion criteria, higher pre-treatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pre-treatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (RR 1.007, 95% CI 1.003-1.010).Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

View details for DOI 10.1016/j.jpeds.2024.113957

View details for PubMedID 38360261

Abstract

The survival of preterm infants has steadily improved thanks to advances in perinatal and neonatal intensive clinical care. The focus is now on finding ways to improve morbidities, especially neurological outcomes. Although antenatal steroids and magnesium for preterm infants have become routine therapies, studies have mainly demonstrated short-term benefits for antenatal steroid therapy but limited evidence for impact on long-term neurodevelopmental outcomes. Further advances in neuroprotective and neurorestorative therapies, improved neuromonitoring modalities to optimize recruitment in trials, and improved biomarkers to assess the response to treatment are essential. Among the most promising agents, multipotential stem cells, immunomodulation, and anti-inflammatory therapies can improve neural outcomes in preclinical studies and are the subject of considerable ongoing research. In the meantime, bundles of care protecting and nurturing the brain in the neonatal intensive care unit and beyond should be widely implemented in an effort to limit injury and promote neuroplasticity. IMPACT: With improved survival of preterm infants due to improved antenatal and neonatal care, our focus must now be to improve long-term neurological and neurodevelopmental outcomes. This review details the multifactorial pathogenesis of preterm brain injury and neuroprotective strategies in use at present, including antenatal care, seizure management and non-pharmacological NICU care. We discuss treatment strategies that are being evaluated as potential interventions to improve the neurodevelopmental outcomes of infants born prematurely.

View details for DOI 10.1038/s41390-023-02895-6

View details for PubMedID 38114609

View details for PubMedCentralID 7480736

Abstract

BACKGROUND AND OBJECTIVES: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin (Epo) or placebo for neonates with HIE treated with therapeutic hypothermia.METHODS: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at five one-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire cEEG recording was calculated using the arithmetic mean of the five EEG background ratings (normal=0; discontinuous=1; severely abnormal=2) as follows: "predominantly normal" (mean=0), "normal/discontinuous" (0

View details for DOI 10.1212/WNL.0000000000207744

View details for PubMedID 37816642

Abstract

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.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.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).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.

View details for DOI 10.1002/cns3.6

View details for PubMedID 37842075

View details for PubMedCentralID PMC10572735

View details for DOI 10.1038/s41390-023-02775-z

View details for PubMedID 37573378

View details for PubMedCentralID 6477286

View details for DOI 10.1016/j.jpeds.2023.113442

View details for PubMedID 37100196

View details for DOI 10.1016/S2589-7500(23)00041-9

View details for PubMedID 36963906

View details for Web of Science ID 000995066100001

Abstract

To examine the association between CEEG use and discharge status, length of hospitalization, and health care cost in a critically ill pediatric population.Four thousand three hundred forty-eight critically ill children were identified from a US nationwide administrative health claims database; 212 (4.9%) of whom underwent CEEG during admissions (January 1, 2015-june 30, 2020). Discharge status, length of hospitalization, and health care cost were compared between patients with and without CEEG use. Multiple logistic regression analyzed the association between CEEG use and these outcomes, controlling for age and underlying neurologic diagnosis. Prespecified subgroups analysis was performed for children with seizures/status epilepticus, with altered mental status and with cardiac arrest.Compared with critically ill children without CEEG, those who underwent CEEG were likely to have shorter hospital stays than the median (OR = 0.66; 95% CI = 0.49-0.88; P = 0.004), and also total hospitalization costs were less likely to exceed the median (OR = 0.59; 95% CI = 0.45-0.79; P < 0.001). There was no difference in odds of favorable discharge status between those with and without CEEG (OR = 0.69; 95% CI = 0.41-1.08; P = 0.125). In the subgroup of children with seizures/status epilepticus, those with CEEG were less likely to have unfavorable discharge status, compared with those without CEEG (OR = 0.51; 95% CI = 0.27-0.89; P = 0.026).Among critically ill children, CEEG was associated with shorter stay and lower costs of hospitalization but was not associated with change of favorable discharge status except the subgroup with seizures/status epilepticus.

View details for DOI 10.1097/WNP.0000000000000993

View details for PubMedID 36893384

Abstract

OBJECTIVES: To assess variability in continuation of antiseizure medication (ASM) at discharge and to evaluate if continuation of ASM at discharge is associated with death or disability among infants with hypoxic-ischaemic encephalopathy (HIE) and seizures.DESIGN: Retrospective study of infants enrolled in three National Institute of Child Health and Human Development Neonatal Research Network Trials of therapeutic hypothermia.SETTING: 22 US centres.PATIENTS: Infants with HIE who survived to discharge and had clinical or electrographic seizures treated with ASM.EXPOSURES: ASM continued or discontinued at discharge.OUTCOMES: Death or moderate-to-severe disability at 18-22 months, using trial definitions. Multivariable logistic regression evaluated the association between continuation of ASM at discharge and the primary outcome, adjusting for severity of HIE, hypothermia trial treatment arm, use of electroencephalogram, discharge on gavage feeds, Apgar Score at 5min, birth year and centre.RESULTS: Of 302 infants included, 61% were continued on ASMs at discharge (range 13%-100% among 22 centres). Electroencephalogram use occurred in 92% of the cohort. Infants with severe HIE comprised 24% and 22% of those discharged with and without ASM, respectively. The risk of death or moderate-to-severe disability was greater for infants continued on ASM at discharge, compared with those infants discharged without ASM (44% vs 28%, adjusted OR 2.14; 95%CI 1.13 to 4.05).CONCLUSIONS: In infants with HIE and seizures, continuation of ASM at discharge varies substantially among centres and may be associated with a higher risk of death or disability at 18-22 months of age.

View details for DOI 10.1136/archdischild-2022-324612

View details for PubMedID 36732048

Abstract

The blooming of neonatal neurocritical care over the last decade reflects substantial advances in neuromonitoring and neuroprotection. The most commonly used brain monitoring tools in the neonatal intensive care unit (NICU) are amplitude integrated EEG (aEEG), full multichannel continuous EEG (cEEG), and near-infrared spectroscopy (NIRS). While some published guidelines address individual tools, there is no consensus on consistent, efficient, and beneficial use of these modalities in common NICU scenarios. This work reviews current evidence to assist decision making for best utilization of neuromonitoring modalities in neonates with encephalopathy or with possible seizures. Neuromonitoring approaches in extremely premature and critically ill neonates are discussed separately in the companion paper. IMPACT: Neuromonitoring techniques hold promise for improving neonatal care. For neonatal encephalopathy, aEEG can assist in screening for eligibility for therapeutic hypothermia, though should not be used to exclude otherwise eligible neonates. Continuous cEEG, aEEG and NIRS through rewarming can assist in prognostication. For neonates with possible seizures, cEEG is the gold standard for detection and diagnosis. If not available, aEEG as a screening tool is superior to clinical assessment alone. The use of seizure detection algorithms can help with timely seizures detection at the bedside.

View details for DOI 10.1038/s41390-022-02393-1

View details for PubMedID 36476747

Abstract

An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo.Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models.Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo).In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia.In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

View details for DOI 10.1038/s41390-022-02398-w

View details for PubMedID 36470964

Abstract

Neonatal intensive care has expanded from cardiorespiratory care to a holistic approach emphasizing brain health. To best understand and monitor brain function and physiology in the neonatal intensive care unit (NICU), the most commonly used tools are amplitude-integrated EEG, full multichannel continuous EEG, and near-infrared spectroscopy. Each of these modalities has unique characteristics and functions. While some of these tools have been the subject of expert consensus statements or guidelines, there is no overarching agreement on the optimal approach to neuromonitoring in the NICU. This work reviews current evidence to assist decision making for the best utilization of these neuromonitoring tools to promote neuroprotective care in extremely premature infants and in critically ill neonates. Neuromonitoring approaches in neonatal encephalopathy and neonates with possible seizures are discussed separately in the companion paper. IMPACT: For extremely premature infants, NIRS monitoring has a potential role in individualized brain-oriented care, and selective use of aEEG and cEEG can assist in seizure detection and prognostication. For critically ill neonates, NIRS can monitor cerebral perfusion, oxygen delivery, and extraction associated with disease processes as well as respiratory and hypodynamic management. Selective use of aEEG and cEEG is important in those with a high risk of seizures and brain injury. Continuous multimodal monitoring as well as monitoring of sleep, sleep-wake cycling, and autonomic nervous system have a promising role in neonatal neurocritical care.

View details for DOI 10.1038/s41390-022-02392-2

View details for PubMedID 36434203

Abstract

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.

View details for DOI 10.1038/s41390-022-02295-2

View details for PubMedID 36195634

Abstract

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 (beta=-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.

View details for DOI 10.1016/j.pediatrneurol.2022.09.001

View details for PubMedID 36270133

Abstract

Electroencephalography (EEG) is a neurologic monitoring modality that allows for the identification of seizures and the understanding of cerebral function. Not only can EEG data provide real-time information about a patient's clinical status, but providers are increasingly using these results to understand short and long-term prognosis in critical illnesses. Adult studies have explored these associations for many years, and now the focus has turned to applying these concepts to the pediatric literature. The aim of this review is to characterize how EEG can be utilized clinically in pediatric intensive care settings and to highlight the current data available to understand EEG features in association with functional outcomes in children after critical illness. In the evaluation of seizures and seizure burden in children, there is abundant data to suggest that the presence of status epilepticus during illness is associated with poorer outcomes and a higher risk of mortality. There is also emerging evidence indicating that poorly organized EEG backgrounds, lack of normal sleep features and lack of electrographic reactivity to clinical exams portend worse outcomes in this population. Prognostication in pediatric critical illness must be informed by the comprehensive evaluation of a patient's clinical status but the utilization of EEG may help contribute to this assessment in a meaningful way.

View details for DOI 10.3390/children9091368

View details for PubMedID 36138677

Abstract

OBJECTIVE: To determine whether selection of treatment for children with infantile spasms (IS) varies by race/ethnicity.METHODS: The prospective US National Infantile Spasms Consortium database includes children with IS treated from 2012-2018. We examined the relationship between race/ethnicity and receipt of standard IS therapy (prednisolone, adrenocorticotropic hormone, vigabatrin), adjusting for demographic and clinical variables using logistic regression. Our primary outcome was treatment course, which considered therapy prescribed for the first and, when needed, the second IS treatment together.RESULTS: Of 555 children, 324 (58%) were Non-Hispanic white, 55 (10%) Non-Hispanic Black, 24 (4%) Non-Hispanic Asian, 80 (14%) Hispanic, and 72 (13%) Other/Unknown. Most (398, 72%) received a standard treatment course. Insurance type, geographic location, history of prematurity, prior seizures, developmental delay or regression, abnormal head circumference, hypsarrhythmia, and IS etiologies were associated with standard therapy. In adjusted models, Non-Hispanic Black children had lower odds of receiving a standard treatment course compared with Non-Hispanic white children (OR 0.42, 95% CI 0.20-0.89, p=0.02). Adjusted models also showed that children with public (vs. private) insurance had lower odds of receiving standard therapy for treatment 1 (OR 0.42, CI 0.21-0.84, p=0.01).INTERPRETATION: Non-Hispanic Black children were more often treated with non-standard IS therapies than Non-Hispanic white children. Likewise, children with public (vs. private) insurance were less likely to receive standard therapies. Investigating drivers of inequities, and understanding the impact of racism on treatment decisions, are critical next steps to improve care for patients with IS. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/ana.26363

View details for PubMedID 35388521

View details for DOI 10.1161/CIRCGEN.121.003591

View details for PubMedID 35133172

View details for DOI 10.1056/NEJMc2112090

View details for PubMedID 35020984

Abstract

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.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.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.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.

View details for DOI 10.1016/j.pediatrneurol.2022.01.004

View details for PubMedID 35149302

Abstract

Introduction: Scalp high-frequency oscillations (HFOs, 80-250 Hz) are increasingly recognized as EEG markers of epileptic brain activity. It is, however, unclear what level of brain maturity is necessary to generate these oscillations. Many studies have reported the occurrence of scalp HFOs in children with a correlation between treatment success of epileptic seizures and the reduction of HFOs. More recent studies describe the reliable detection of HFOs on scalp EEG during the neonatal period.Methods: In the present study, continuous EEGs of 38 neonates at risk for seizures were analyzed visually for the scalp HFOs using 30 min of quiet sleep EEG. EEGs of 14 patients were of acceptable quality to analyze HFOs.Results: The average rate of HFOs was 0.34 ± 0.46/min. About 3.2% of HFOs occurred associated with epileptic spikes. HFOs were significantly more frequent in EEGs with abnormal vs. normal background activities (p = 0.005).Discussion: Neonatal brains are capable of generating HFOs. HFO could be a viable biomarker for neonates at risk of developing seizures. Our preliminary data suggest that HFOs mainly occur in those neonates who have altered background activity. Larger data sets are needed to conclude whether HFO occurrence is linked to seizure generation and whether this might predict the development of epilepsy.

View details for DOI 10.3389/fneur.2022.1048629

View details for PubMedID 36686542

Abstract

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.

View details for DOI 10.3390/children9010002

View details for PubMedID 35053627

Abstract

OBJECTIVE: To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease (CPD).STUDY DESIGN: The Neonatal Seizure Registry (NSR-1) is a multicenter, prospectively acquired cohort of neonates with clinical or EEG-confirmed seizures. CPD was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous electroencephalographic monitoring (cEEG) strategy, seizure characteristics, seizure management, and outcomes for neonates with and without CPD.RESULTS: We evaluated 83 neonates with CPD and 271 neonates without CPD. Neonates with CPD were more likely to have EEG-only seizures (40% vs. 21%, P <.001) and experience their first seizure later than those without CPD (174 vs. 21 hours of age, p<0.001), but they had similar seizure exposure (many-recurrent electrographic seizures 39% vs. 43%, p=0.27). Phenobarbital was the primary initial antiseizure medication (ASM) for both groups (90%), and both groups had similarly high rates of incomplete response to initial ASM administration (66% vs. 68%, p=0.75). Neonates with CPD were discharged from the hospital later (hazard ratio 0.34, 95%CI 0.25-0.45, p<0.001), although rates of in-hospital mortality were similar between the groups (hazard ratio 1.13, 95%CI 0.66-1.94, p=0.64).CONCLUSION: Neonates with and without CPD had a similarly high seizure exposure, but neonates with CPD 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 ASM. These data support guidelines recommending cEEG in neonates with CPD and indicate a need for optimized therapeutic strategies.

View details for DOI 10.1016/j.jpeds.2021.10.058

View details for PubMedID 34728234

Abstract

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.

View details for DOI 10.1016/j.siny.2021.101279

View details for PubMedID 34563467

View details for DOI 10.1097/WNP.0000000000000863

View details for PubMedID 34491940

Abstract

Neonatal encephalopathy (NE) describes the clinical syndrome of a newborn with abnormal brain function that may result from a variety of etiologies. HIE should be distinguished from neonatal encephalopathy due to other causes using data gathered from the history, physical and neurological exam, and further investigations. Identifying the underlying cause of encephalopathy has important treatment implications. This review outlines conditions that cause NE and may be mistaken for HIE, along with their distinguishing clinical features, pathophysiology, investigations, and treatments. NE due to brain malformations, vascular causes, neuromuscular causes, genetic conditions, neurogenetic disorders and inborn errors of metabolism, central nervous system (CNS) and systemic infections, and toxic/metabolic disturbances are discussed.

View details for DOI 10.1016/j.siny.2021.101272

View details for PubMedID 34417137

Abstract

BACKGROUND: Guidelines recommend evaluation for electrographic seizures in neonates and children at risk, including after cardiopulmonary bypass (CPB). Although initial research using screening electroencephalograms (EEGs) in infants after CPB found a 21% seizure incidence, more recent work reports seizure incidences ranging 3-12%. Deep hypothermic cardiac arrest was associated with increased seizure risk in prior reports but is uncommon at our institution and less widely used in contemporary practice. This study seeks to establish the incidence of seizures among infants following CPB in the absence of deep hypothermic cardiac arrest and to identify additional risk factors for seizures via a prediction model.METHODS: A retrospective chart review was completed of all consecutive infants≤3months who received screening EEG following CPB at a single center within a 2-year period during 2017-2019. Clinical and laboratory data were collected from the perioperative period. A prediction model for seizure risk was fit using a random forest algorithm, and receiver operator characteristics were assessed to classify predictions. Fisher's exact test and the logrank test were used to evaluate associations between clinical outcomes and EEG seizures.RESULTS: A total of 112 infants were included. Seizure incidence was 10.7%. Median time to first seizure was 28.1h (interquartile range 18.9-32.2h). The most important factors in predicting seizure risk from the random forest analysis included postoperative neuromuscular blockade, prematurity, delayed sternal closure, bypass time, and critical illness preoperatively. When variables captured during the EEG recording were included, abnormal postoperative neuroimaging and peak lactate were also highly predictive. Overall model accuracy was 90.2%; accounting for class imbalance, the model had excellent sensitivity and specificity (1.00 and 0.89, respectively).CONCLUSIONS: Seizure incidence was similar to recent estimates even in the absence of deep hypothermic cardiac arrest. By employing random forest analysis, we were able to identify novel risk factors for postoperative seizure in this population and generate a robust model of seizure risk. Further work to validate our model in an external population is needed.

View details for DOI 10.1007/s12028-021-01313-1

View details for PubMedID 34322828

Abstract

OBJECTIVE: Compare the effectiveness of initial treatment for infantile spasms.METHODS: The National Infantile Spasms Consortium prospectively followed children with new onset infantile spasms that began at age 2-24 months at 23 US centers (2012-2018). Freedom from treatment failure at 60 days required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. We managed treatment selection bias with propensity score weighting and within-center correlation with generalized estimating equations.RESULTS: Freedom from treatment failure rates were: ACTH 88/190 (46%), oral steroids 42/95 (44%), vigabatrin 32/87 (37%), and non-standard therapy 4/51 (8%). Changing from oral steroids to ACTH was not estimated to affect response (observed 44% estimated to change to 44% [95% CI 34-54]). Changing from non-standard therapy to ACTH would improve response from 8% to 39 [17-67]%, and to oral steroids from 8% to 38 [15-68]%. There were large but not statistically significant estimated effects of changing from vigabatrin to ACTH (29% to 42 [15-75]%), vigabatrin to oral steroids (29% to 42 [28-57]%), and non-standard therapy to vigabatrin (8% to 20 [6-50]%). Among children treated with vigabatrin, those with tuberous sclerosis complex (TSC) responded more often than others (62% vs 29%; p<0.05) CONCLUSION: Compared to non-standard therapy, ACTH and oral steroids are superior for initial treatment of infantile spasms. The estimated effectiveness of vigabatrin is between ACTH / oral steroids and non-standard therapy, though the sample was underpowered for statistical confidence. When used, vigabatrin worked best for TSC.CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for children with new onset infantile spasms, ACTH or oral steroids were superior to non-standard therapies.

View details for DOI 10.1212/WNL.0000000000012511

View details for PubMedID 34266919

Abstract

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 ≥3days 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.

View details for DOI 10.1111/epi.16978

View details for PubMedID 34212365

Abstract

Engaging with ethical issues is central to the management of neonatal encephalopathy (NE). As treatment for these neonates evolves, new ethical issues will arise and many existing challenges will remain. We highlight three key ethical issues that arise in the care of neonates with NE treated with therapeutic hypothermia: facilitating shared decision making, understanding futility, and defining the boundaries between standard of care and research. Awareness of these issues will help clinicians counsel families in light of evolving treatments and outcomes.

View details for DOI 10.1016/j.siny.2021.101258

View details for PubMedID 34176763

View details for DOI 10.1038/s41390-021-01616-1

View details for PubMedID 34103677

Abstract

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.

View details for DOI 10.1001/jamaneurol.2021.1437

View details for PubMedID 34028496

View details for DOI 10.1212/WNL.0000000000012026

View details for PubMedID 33893199

View details for Web of Science ID 000729283603145

Abstract

Neonatal seizures present a unique diagnostic challenge with clinical manifestations often subtle or absent to the bedside observer. Seizures can be overdiagnosed in newborns with unusual paroxysmal movements and underdiagnosed in newborns without clinical signs of seizures. Electroclinical "uncoupling" also adds to diagnostic challenge. Reliable diagnosis requires additional tools; continuous electroencephalogram (EEG) monitoring is the gold standard for diagnosis of neonatal seizures. Certain high risk neonatal populations with known brain injury, such as stroke or hypoxic-ischemic encephalopathy, are most likely to benefit from continuous EEG. Studies have shown that risk stratification for continuous EEG has positive impact on care, including rapid and accurate diagnosis and treatment of neonatal seizures, which leads to reduced use of antiseizure medicines and length of hospital stay. This review describes common clinical manifestations of neonatal seizures, and clinical situations in which EEG monitoring to screen for seizures should be considered.

View details for DOI 10.1111/ped.14654

View details for PubMedID 33599034

Abstract

To characterize intracranial hemorrhage (ICH) as a seizure etiology in infants born at term and preterm. For term infants, to compare seizure severity and treatment response for multi-site vs single-site ICH and hypoxic-ischemic encephalopathy (HIE) with vs. without ICH.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 multi-site vs. single-site ICH and HIE with vs. without ICH.ICH was a more common seizure etiology in infants born preterm vs. term (27% vs. 10%, p<0.001). Most infants had subclinical seizures (74%) and an incomplete response to initial antiseizure medication (ASM) (68%). In infants born term, multi-site ICH was associated with more subclinical seizures than single-site ICH (93% vs. 66%, p=0.05) and an incomplete response to the initial ASM (100% vs. 66%, p=0.02). Status epilepticus was more common in HIE with ICH vs. HIE alone (38% vs. 17%, P = .05).Seizure severity was higher 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 multi-step treatment plan that considers early use of multiple ASMs, particularly with parenchymal and high-grade intraventricular hemorrhage and complicated ICH.

View details for DOI 10.1016/j.jpeds.2021.11.012

View details for PubMedID 34780777

Abstract

Continuous EEG (cEEG) is a fundamental neurodiagnostic tool in the care of critically ill neonates and is increasingly recommended. cEEG enhances prognostication via assessment of the background brain activity, plays a role in predicting which neonates are at risk for seizures when combined with clinical factors, and allows for accurate diagnosis and management of neonatal seizures. Continuous EEG is the gold standard method for diagnosis of neonatal seizures and should be used for detection of seizures in high-risk clinical conditions, differential diagnosis of paroxysmal events, and assessment of response to treatment. High costs associated with cEEG are a limiting factor in its widespread implementation. Centralized remote cEEG interpretation, automated seizure detection, and pre-natal EEG are potential future applications of this neurodiagnostic tool.

View details for DOI 10.3389/fped.2021.768670

View details for PubMedID 34805053

Abstract

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.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.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.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.

View details for DOI 10.1016/j.pediatrneurol.2021.07.013

View details for PubMedID 34509000

View details for DOI 10.1177/1833358318794501

View details for Web of Science ID 000599908600007

View details for DOI 10.1097/WNP.0000000000000806

View details for PubMedID 33475321

Abstract

Access to paediatric neurology care is complex, resulting in significant wait times and negative patient outcomes. The goal of the American Academy of Pediatrics National Coordinating Center for Epilepsy's project, Access Improvement and Management of Epilepsy with Telehealth (AIM-ET), was to identify access and management challenges in the deployment of telehealth technology. AIM-ET organised four paediatric neurology teams to partner with primary-care providers (PCP) and their multidisciplinary teams. Telehealth visits were conducted for paediatric epilepsy patients. A post-visit survey assessed access and satisfaction with the telehealth visit compared to an in-person visit. Pre/post surveys completed by PCPs and neurologists captured telehealth visit feasibility, functionality and provider satisfaction. A provider focus group assessed facilitators and barriers to telehealth. Sixty-one unique patients completed 75 telehealth visits. Paired t-test analysis demonstrated that telehealth enhanced access to epilepsy care. It reduced self-reported out-of-pocket costs (p<0.001), missed school hours (p<0.001) and missed work hours (p<0.001), with 94% equal parent/caregiver satisfaction. Focus groups indicated developing and maintaining partnerships, institutional infrastructure and education as facilitators and barriers to telehealth. Telehealth shortened travelling distance, reduced expenses and time missed from school and work. Further, it provides significant opportunity in an era when coronavirus disease 2019 limits in-person clinics.

View details for DOI 10.1177/1357633X20969531

View details for PubMedID 33183129

View details for DOI 10.1016/j.pediatrneurol.2020.08.014

View details for PubMedID 33069006

Abstract

OBJECTIVE: Neonates with seizures have a high risk of mortality and neurological morbidity. We aimed to describe the experience of parents caring for neonates with seizures.DESIGN: This prospective, observational and multicentre (Neonatal Seizure Registry) study enrolled parents of neonates with acute symptomatic seizures. At the time of hospital discharge, parents answered six open-ended response questions that targeted their experience. Responses were analysed using a conventional content analysis approach.RESULTS: 144 parents completed the open-ended questions (732 total comments). Four themes were identified. Sources of strength: families valued medical team consensus, opportunities to contribute to their child's care and bonding with their infant. Uncertainty: parents reported three primary types of uncertainty, all of which caused distress: (1) the daily uncertainty of the intensive care experience; (2) concerns about their child's uncertain future and (3) lack of consensus between members of the medical team. Adapting family life: parents described the many ways in which they anticipated their infant's condition would lead to adaptations in their family life, including adjusting their family's lifestyle, parenting approach and routine. Many parents described financial and work challenges due to caring for a child with medical needs. Emotional and physical toll: parents reported experiencing anxiety, fear, stress, helplessness and loss of sleep.CONCLUSIONS: Parents of neonates with seizures face challenges as they adapt to and find meaning in their role as a parent of a child with medical needs. Future interventions should target facilitating parent involvement in clinical and developmental care, improving team consensus and reducing the burden associated with prognostic uncertainty.

View details for DOI 10.1136/archdischild-2019-318612

View details for PubMedID 32503792

View details for Web of Science ID 000536058004299

View details for Web of Science ID 000536058005071

Abstract

Pediatric neurology patients frequently use integrative medicine; however, providers may feel uncomfortable or unfamiliar with these therapies. Child neurologist attitudes toward integrative medicine and educational needs in integrative medicine have not been assessed. A national, anonymous survey was distributed to Child Neurology residents (n=294) and program directors (n=71) to assess attitudes toward specific integrative medicine modalities, practices in discussing integrative medicine with patients, and perceived need for a curriculum on integrative medicine; 61 (17%) partially and 53 (15%) fully completed the survey. Comparative analyses applied chi-square and independent t tests. Qualitative content analysis was performed on free text responses. Most providers surveyed consider mind and body practices safe (93% of respondents) and effective (84%), but have concerns about the safety of chiropractic manipulation (56% felt this was harmful), and the efficacy of homeopathy (none considered this effective). Few inquire about patient integrative medicine use regularly. Child Neurology residents are interested in further education on this topic.

View details for DOI 10.1177/0883073820925285

View details for PubMedID 32468894

Abstract

To characterize and determine risk factors for key dimensions of well-being at hospital discharge in families of neonates with acute symptomatic seizures.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.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.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.

View details for DOI 10.1016/j.jpeds.2020.02.024

View details for PubMedID 32446494

View details for DOI 10.1038/s41390-020-01143-5

View details for PubMedID 32916680

Abstract

 The aim of the study is to model amplitude-integrated electroencephalography (aEEG) utility to diagnose seizures in common clinical scenarios. Using reported neonatal seizure prevalence and aEEG sensitivities and specificities, likelihood ratios (LRs) and post-test probabilities were calculated to quantify aEEG utility to diagnose seizures in three typical clinical scenarios. Prevalence data supported pretest probabilities for neonatal seizures of 0.4 in neonatal hypoxic ischemic encephalopathy (HIE), 0.27 in bacterial meningitis, and 0.05 in extreme prematurity. Reported sensitivity of 85% and specificity of 90% for seizures with expert aEEG interpretation yielded a positive likelihood ratio (LR+) of 8.7 and a negative likelihood ratio (LR-) of 0.17. Reported sensitivity of 65% and specificity of 70% with intermediate interpretation yielded LR+ 2.17 and LR- 0.5. Reported sensitivity of 40% and sensitivity of 50% with inexperienced interpretation gave LR+ 0.8 and LR- 1.2. These translate the ability to move pretest to post-test probability highly dependent on user expertise. For HIE, a pretest probability of seizure of 0.4 moves to a post-test probability of 0.85 when aEEG is positive for seizures by expert interpretation, and down to 0.1 when aEEG is negative. In contrast, no useful information was gained between pretest and post-test probability by aEEG interpreted as negative or positive for seizure at the inexperienced user level. Similarly, in the models of meningitis or extreme prematurity, incremental information gained from aEEG ranged widely based on interpreter experience. aEEG is most useful to screen for neonatal seizures when used in conditions with high seizure prevalence, and when interpretation has a sensitivity and specificity as reported for expert users. In contrast, aEEG can become negligible in providing meaningful clinical information when applied in conditions having lower seizure prevalence or when interpretation has low accuracy. Appropriate patient selection and high quality interpretation are essential for aEEG utility in neonatal seizure detection.· aEEG utility for neonatal seizure screening relies on patient selection and quality interpretation.. · Utility of aEEG is highest with high seizure prevalence and expert interpretation.. · Utility of aEEG can be negligible with lower seizure prevalence or low accuracy interpretation..

View details for DOI 10.1055/s-0040-1721711

View details for PubMedID 33321530