Bio


https://med.stanford.edu/wusthoff-lab.html

Academic Appointments


Administrative Appointments


  • Director of Neurocritical Care, Lucile Packard Children's Hospital Stanford (2019 - Present)
  • Neurology Director, LPCH Neuro NICU, Lucile Packard Children's Hospital (2013 - Present)

Professional Education


  • Board Certification: American Board of Psychiatry and Neurology, Neurology with Special Qualifications in Child Neurology (2009)
  • Internship: Children's Hospital of Oakland (2006) CA
  • Medical Education: University of California at San Francisco School of Medicine (2004) CA
  • Fellowship: Children's Hospital of Philadelphia Child Neurology (2010) PA
  • Board Certification: American Board of Psychiatry and Neurology, Epilepsy (2014)
  • Board Certification: American Board of Pediatrics, Pediatrics (2009)
  • Residency: Children's Hospital of Oakland (2009) CA

Current Research and Scholarly Interests


My projects focus on clinical research in newborns with, or at risk, for brain injury. I use EEG in at-risk neonates to better understand the underlying pathophysiology of risk factors that may lead to worse outcomes. I am particularly interested in neonatal seizures and how they may exacerbate perinatal brain injury with a goal to identify treatments that might protect the vulnerable brain. I am also interested in EEG in other pediatric populations, as well as medical ethics and global health.

Clinical Trials


  • Neonatal Seizure Registry - Developmental Functional EValuation Recruiting

    The NSR-DEV study is a longitudinal cohort study of around 280 Neonatal Seizure Registry participants that aims to evaluate childhood outcomes after acute symptomatic neonatal seizures, as well as examine risk factors for developmental disabilities and whether these are modified by parent well-being.

    View full details

  • High-dose Erythropoietin for Asphyxia and Encephalopathy Not Recruiting

    Hypoxic-ischemic encephalopathy (HIE) occurs when a baby gets reduced blood flow and oxygen to the brain near the time of birth. This results in death or neurologic disabilities including cerebral palsy and cognitive impairment in up to half of affected infants. This clinical trial will determine if the drug erythropoietin (Epo) added to hypothermia (usual therapy) will improve outcomes for infants suffering from HIE.

    Stanford is currently not accepting patients for this trial.

    View full details

2023-24 Courses


All Publications


  • Seizure Control in Neonates Undergoing Screening vs Confirmatory EEG Monitoring. Neurology Wusthoff, C. J., Sundaram, V., Abend, N. S., Massey, S. L., Lemmon, M. E., Thomas, C., McCulloch, C. E., Chang, T., Soul, J. S., Chu, C. J., Rogers, E. E., Bonifacio, S. L., Cilio, M. R., Glass, H. C., Shellhaas, R. A., Neonatal Seizure Registry Group 2021

    Abstract

    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 two 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 anti-seizure 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% versus 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% CI: 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.

    View details for DOI 10.1212/WNL.0000000000012293

    View details for PubMedID 34078719

  • Relationship of Neonatal Seizure Burden Prior to Treatment and Response to Initial Anti-Seizure Medication. The Journal of pediatrics Numis, A. L., Glass, H. C., Comstock, B. A., Gonzalez, F., Maitre, N. L., Massey, S. L., Mayock, D. E., Mietzsch, U., Natarajan, N., Sokol, G. M., Bonifacio, S., Van Meurs, K., Thomas, C., Ahmad, K., Heagerty, P., Juul, S. E., Wu, Y. W., Wusthoff, C. J. 2024: 113957

    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

  • Neuroprotective therapies in the NICU in preterm infants: present and future (Neonatal Neurocritical Care Series). Pediatric research Molloy, E. J., El-Dib, M., Soul, J., Juul, S., Gunn, A. J., Bender, M., Gonzalez, F., Bearer, C., Wu, Y., Robertson, N. J., Cotton, M., Branagan, A., Hurley, T., Tan, S., Laptook, A., Austin, T., Mohammad, K., Rogers, E., Luyt, K., Wintermark, P., Bonifacio, S. L. 2023

    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

  • Association of EEG Background and Neurodevelopmental Outcome in Neonates With Hypoxic-Ischemic Encephalopathy Receiving Hypothermia. Neurology Glass, H. C., Numis, A. L., Comstock, B. A., Gonzalez, F. F., Mietzsch, U., Bonifacio, S. L., Massey, S., Thomas, C., Natarajan, N., Mayock, D. E., Sokol, G. M., Van Meurs, K. P., Ahmad, K. A., Maitre, N., Heagerty, P. J., Juul, S. E., Wu, Y. W., Wusthoff, C. J. 2023

    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

  • Feeding and developmental outcomes after neonatal seizures-A prospective observational study. Annals of the Child Neurology Society Roberts, K. H., Barks, J. D., Glass, H. C., Soul, J. S., Chang, T., Wusthoff, C. J., Chu, C. J., Massey, S. L., Abend, N. S., Lemmon, M. E., Thomas, C., Guillet, R., Rogers, E. E., Franck, L. S., McCaffery, H., Li, Y., McCulloch, C. E., Shellhaas, R. A. 2023; 1 (3): 209-217

    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

  • Neonatal encephalopathy and hypoxic-ischemic encephalopathy: moving from controversy to consensus definitions and subclassification. Pediatric research Molloy, E. J., Branagan, A., Hurley, T., Quirke, F., Devane, D., Taneri, P. E., El-Dib, M., Bloomfield, F. H., Maeso, B., Pilon, B., Bonifacio, S. L., Wusthoff, C. J., Chalak, L., Bearer, C., Murray, D. M., Badawi, N., Campbell, S., Mulkey, S., Gressens, P., Ferriero, D. M., de Vries, L. S., Walker, K., Kay, S., Boylan, G., Gale, C., Robertson, N. J., D'Alton, M., Gunn, A., Nelson, K. B. 2023

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

    View details for PubMedID 37573378

    View details for PubMedCentralID 6477286

  • Can a smartphone jump start care for infantile spasms? The Journal of pediatrics Wusthoff, C. J., Shellhaas, R. A. 2023: 113442

    View details for DOI 10.1016/j.jpeds.2023.113442

    View details for PubMedID 37100196

  • Can electronic medical records predict neonatal seizures? The Lancet. Digital health Barsh, G. R., Wusthoff, C. J. 2023; 5 (4): e175-e176

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

    View details for PubMedID 36963906

  • Can electronic medical records predict neonatal seizures? LANCET DIGITAL HEALTH Barsh, G. R., Wusthoff, C. J. 2023; 5 (4): E175-E176
  • Continuous Electroencephalogram Use and Hospital Outcomes in Critically Ill Children. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society Oh, A., Wusthoff, C. J., Kim, H. 2023

    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

  • Antiseizure medication at discharge in infants with hypoxic-ischaemic encephalopathy: an observational study. Archives of disease in childhood. Fetal and neonatal edition Sewell, E. K., Shankaran, S., McDonald, S. A., Hamrick, S., Wusthoff, C. J., Adams-Chapman, I., Chalak, L. F., Davis, A. S., Van Meurs, K., Das, A., Maitre, N., Laptook, A., Patel, R. M., National Institute of Child Health and Human Development Neonatal Research Network 2023

    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

  • Neuromonitoring in neonatal critical care part I: neonatal encephalopathy and neonates with possible seizures. Pediatric research El-Dib, M., Abend, N. S., Austin, T., Boylan, G., Chock, V., Cilio, M. R., Greisen, G., Hellström-Westas, L., Lemmers, P., Pellicer, A., Pressler, R. M., Sansevere, A., Tsuchida, T., Vanhatalo, S., Wusthoff, C. J. 2022

    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

  • Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo. Pediatric research Glass, H. C., Wusthoff, C. J., Comstock, B. A., Numis, A. L., Gonzalez, F. F., Maitre, N., Massey, S. L., Mayock, D. E., Mietzsch, U., Natarajan, N., Sokol, G. M., Bonifacio, S. L., Van Meurs, K. P., Thomas, C., Ahmad, K. A., Heagerty, P. J., Juul, S. E., Wu, Y. W. 2022

    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

  • Neuromonitoring in neonatal critical care part II: extremely premature infants and critically ill neonates. Pediatric research El-Dib, M., Abend, N. S., Austin, T., Boylan, G., Chock, V., Cilio, M. R., Greisen, G., Hellstrom-Westas, L., Lemmers, P., Pellicer, A., Pressler, R. M., Sansevere, A., Szakmar, E., Tsuchida, T., Vanhatalo, S., Wusthoff, C. J., Newborn Brain Society Guidelines and Publications Committee, Bonifacio, S., Wintermark, P., Aly, H., Chang, T., Chau, V., Glass, H., Lemmon, M., Massaro, A., Wusthoff, C., deVeber, G., Pardo, A., McCaul, M. C. 2022

    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

  • Neuroprotective therapies in the NICU in term infants: present and future. Pediatric research Molloy, E. J., El-Dib, M., Juul, S. E., Benders, M., Gonzalez, F., Bearer, C., Wu, Y. W., Robertson, N. J., Hurley, T., Branagan, A., Michael Cotten, C., Tan, S., Laptook, A., Austin, T., Mohammad, K., Rogers, E., Luyt, K., Bonifacio, S., Soul, J. S., Gunn, A. J., Newborn Brain Society Guidelines and Publications Committee, Bonifacio, S., Wintermark, P., Aly, H., Chang, T., Chau, V., Glass, H., Lemmon, M., Massaro, A., Wusthoff, C., deVeber, G., Pardo, A., McCaul, M. C. 2022

    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

  • Seizure Burden, EEG, and Outcome in Neonates With Acute Intracranial Infections: A Prospective Multicenter Cohort Study. Pediatric neurology Mehta, N., Shellhaas, R. A., McCulloch, C. E., Chang, T., Wusthoff, C. J., Abend, N. S., Lemmon, M. E., Chu, C. J., Massey, S. L., Franck, L. S., Thomas, C., Soul, J. S., Rogers, E., Numis, A., Glass, H. C. 2022; 137: 54-61

    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

  • The Role of Electroencephalography in the Prognostication of Clinical Outcomes in Critically Ill Children: A Review. Children (Basel, Switzerland) Gilman, C. A., Wusthoff, C. J., Guerriero, R. M. 2022; 9 (9)

    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

  • Inequities in therapy for infantile spasms: a call to action. Annals of neurology Baumer, F. M., Mytinger, J. R., Neville, K., Briscoe Abath, C., Gutierrez, C. A., Numis, A. L., Harini, C., He, Z., Hussain, S. A., Berg, A. T., Chu, C. J., Gaillard, W. D., Loddenkemper, T., Pasupuleti, A., Samanata, D., Singh, R. K., Singhal, N. S., Wusthoff, C. J., Wirrell, E. C., Yozawitz, E., Knupp, K. G., Shellhaas, R. A., Grinspan, Z. M., Pediatric Epilepsy Research Consortium and National Infantile Spasms Consortium 2022

    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

  • Ultra-Rapid Nanopore Whole Genome Genetic Diagnosis of Dilated Cardiomyopathy in an Adolescent With Cardiogenic Shock. Circulation. Genomic and precision medicine Gorzynski, J. E., Goenka, S. D., Shafin, K., Jensen, T. D., Fisk, D. G., Grove, M. E., Spiteri, E., Pesout, T., Monlong, J., Bernstein, J. A., Ceresnak, S., Chang, P., Christle, J. W., Chubb, H., Dunn, K., Garalde, D. R., Guillory, J., Ruzhnikov, M. R., Wright, C., Wusthoff, C. J., Xiong, K., Hollander, S. A., Berry, G. J., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022: CIRCGEN121003591

    View details for DOI 10.1161/CIRCGEN.121.003591

    View details for PubMedID 35133172

  • Impact of COVID-19 Pandemic on Developmental Service Delivery in Children With a History of Neonatal Seizures. Pediatric neurology Peyton, C., Girvan, O., Shellhaas, R. A., Lemmon, M. E., Rogers, E. E., Soul, J. S., Chang, T., Hamlett, A., Wusthoff, C. J., Chu, C. J., Massey, S. L., Thomas, C., Guillet, R., Franck, L. S., Glass, H. C. 2022; 129: 14-18

    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

  • Epileptic high-frequency oscillations occur in neonates with a high risk for seizures. Frontiers in neurology Kuhnke, N., Wusthoff, C. J., Swarnalingam, E., Yanoussi, M., Jacobs, J. 2022; 13: 1048629

    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

  • Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting. The New England journal of medicine Gorzynski, J. E., Goenka, S. D., Shafin, K., Jensen, T. D., Fisk, D. G., Grove, M. E., Spiteri, E., Pesout, T., Monlong, J., Baid, G., Bernstein, J. A., Ceresnak, S., Chang, P. C., Christle, J. W., Chubb, H., Dalton, K. P., Dunn, K., Garalde, D. R., Guillory, J., Knowles, J. W., Kolesnikov, A., Ma, M., Moscarello, T., Nattestad, M., Perez, M., Ruzhnikov, M. R., Samadi, M., Setia, A., Wright, C., Wusthoff, C. J., Xiong, K., Zhu, T., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022

    View details for DOI 10.1056/NEJMc2112090

    View details for PubMedID 35020984

  • Parent Mental Health and Family Coping over Two Years after the Birth of a Child with Acute Neonatal Seizures. Children (Basel, Switzerland) Franck, L. S., Shellhaas, R. A., Lemmon, M. E., Sturza, J., Barnes, M., Brogi, T., Hill, E., Moline, K., Soul, J. S., Chang, T., Wusthoff, C. J., Chu, C. J., Massey, S. L., Abend, N. S., Thomas, C., Rogers, E. E., McCulloch, C. E., Glass, H. C. 1800; 9 (1)

    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

  • Characteristics of Neonates with Cardiopulmonary Disease Who Experience Seizures: A Multi-Center Study. The Journal of pediatrics Massey, S. L., Glass, H. C., Shellhaas, R. A., Bonifacio, S., Chang, T., Chu, C., Cilio, M. R., Lemmon, M. E., McCulloch, C. E., Soul, J. S., Thomas, C., Wusthoff, C. J., Xiao, R., Abend, N. S. 2021

    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

  • Management of seizures in neonates with neonatal encephalopathy treated with hypothermia. Seminars in fetal & neonatal medicine DeLaGarza-Pineda, O., Mailo, J. A., Boylan, G., Chau, V., Glass, H. C., Mathur, A. M., Shellhaas, R. A., Soul, J. S., Wusthoff, C. J., Chang, T., Newborn Brain Society Guidelines and Publications Committee 2021: 101279

    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

  • JCN Book Review. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society Wusthoff, C. J. 2021; 38 (5): e24

    View details for DOI 10.1097/WNP.0000000000000863

    View details for PubMedID 34491940

  • Neonatal encephalopathy: Etiologies other than hypoxic-ischemic encephalopathy. Seminars in fetal & neonatal medicine Sandoval Karamian, A. G., Mercimek-Andrews, S., Mohammad, K., Molloy, E. J., Chang, T., Chau, V., Murray, D. M., Wusthoff, C. J., Newborn Brain Society Guidelines and Publications Committee 2021: 101272

    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

  • Evaluation of Seizure Risk in Infants After Cardiopulmonary Bypass in the Absence of Deep Hypothermic Cardiac Arrest. Neurocritical care Levy, R. J., Mayne, E. W., Sandoval Karamian, A. G., Iqbal, M., Purington, N., Ryan, K. R., Wusthoff, C. J. 2021

    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

  • Comparative Effectiveness of Initial Treatment for Infantile Spasms in a Contemporary US Cohort. Neurology Grinspan, Z. M., Knupp, K. G., Patel, A. D., Yozawitz, E. G., Wusthoff, C. J., Wirrell, E., Valencia, I., Singhal, N. S., Nordli, D. R., Mytinger, J. R., Mitchell, W., Keator, C. G., Loddenkemper, T., Hussain, S. A., Harini, C., Gaillard, W. D., Fernandez, I. S., Coryell, J., Chu, C. J., Berg, A. T., Shellhaas, R. A. 2021

    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

  • Early-life epilepsy after acute symptomatic neonatal seizures: A prospective multicenter study. Epilepsia Shellhaas, R. A., Wusthoff, C. J., Numis, A. L., Chu, C. J., Massey, S. L., Abend, N. S., Soul, J. S., Chang, T., Lemmon, M. E., Thomas, C., McNamara, N. A., Guillet, R., Franck, L. S., Sturza, J., McCulloch, C. E., Glass, H. C. 2021

    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

  • Ethical considerations in the care of encephalopathic neonates treated with therapeutic hypothermia. Seminars in fetal & neonatal medicine Lemmon, M. E., Wusthoff, C. J., Boss, R. D., Rasmussen, L. A., Newborn Brain Society Guidelines and Publications Committee 2021: 101258

    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

  • Biomarkers in neonatal encephalopathy: new approaches and ongoing questions. Pediatric research Wusthoff, C. J. 2021

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

    View details for PubMedID 34103677

  • Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures. JAMA neurology Glass, H. C., Soul, J. S., Chang, T., Wusthoff, C. J., Chu, C. J., Massey, S. L., Abend, N. S., Lemmon, M., Thomas, C., Numis, A. L., Guillet, R., Sturza, J., McNamara, N. A., Rogers, E. E., Franck, L. S., McCulloch, C. E., Shellhaas, R. A. 2021

    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

  • Modifiable Risk Factors in Critically Ill Children: Moving Beyond Seizures. Neurology Scott, R. C., Wusthoff, C. J. 2021

    View details for DOI 10.1212/WNL.0000000000012026

    View details for PubMedID 33893199

  • Use of Continuous Electroencephalogram (cEEG) in Critically Ill Patients Oh, A., Wusthoff, C., Kim, H. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Clinical Manifestations of Neonatal Seizures. Pediatrics international : official journal of the Japan Pediatric Society Nguyen, T., Wusthoff, C. J. 2021

    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

  • American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2021 Version. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society Hirsch, L. J., Fong, M. W., Leitinger, M., LaRoche, S. M., Beniczky, S., Abend, N. S., Lee, J. W., Wusthoff, C. J., Hahn, C. D., Westover, M. B., Gerard, E. E., Herman, S. T., Haider, H. A., Osman, G., Rodriguez-Ruiz, A., Maciel, C. B., Gilmore, E. J., Fernandez, A., Rosenthal, E. S., Claassen, J., Husain, A. M., Yoo, J. Y., So, E. L., Kaplan, P. W., Nuwer, M. R., van Putten, M., Sutter, R., Drislane, F. W., Trinka, E., Gaspard, N. 2021; 38 (1): 1–29

    View details for DOI 10.1097/WNP.0000000000000806

    View details for PubMedID 33475321

  • Seizure Severity and Treatment Response in Newborn Infants with Seizures Attributed to Intracranial Hemorrhage. The Journal of pediatrics Herzberg, E. M., Machie, M., Glass, H. C., Shellhaas, R. A., Wusthoff, C. J., Chang, T., Abend, N. S., Chu, C. J., Cilio, M. R., Bonifacio, S. L., Massey, S. L., McCulloch, C. E., Soul, J. S. 2021

    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

  • Current and Future Uses of Continuous EEG in the NICU. Frontiers in pediatrics Sandoval Karamian, A. G., Wusthoff, C. J. 2021; 9: 768670

    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

  • Family-Centered Care for Children and Families Impacted by Neonatal Seizures: Advice From Parents. Pediatric neurology Lemmon, M. E., Glass, H. C., Shellhaas, R. A., Barks, M. C., Bansal, S., Annis, D., Guerriero, J. L., Pilon, B., Wusthoff, C. J., Chang, T., Soul, J. S., Chu, C. J., Thomas, C., Massey, S. L., Abend, N. S., Rau, S., Rogers, E. E., Franck, L. S. 2021; 124: 26-32

    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

  • Use of electronic medical record templates improves quality of care for patients with infantile spasms HEALTH INFORMATION MANAGEMENT JOURNAL Santoro, J. D., Sandoval Karamian, A. G., Ruzhnikov, M., Brimble, E., Chadwick, W., Wusthoff, C. J. 2021; 50 (1-2): 47–54
  • Barriers, access and management of paediatric epilepsy with telehealth. Journal of telemedicine and telecare Gali, K., Joshi, S., Hueneke, S., Katzenbach, A., Radecki, L., Calabrese, T., Fletcher, L., Trandafir, C., Wilson, C., Goyal, M., Wusthoff, C. J., Le Pichon, J., Corvalan, R., Golson, A., Hardy, J., Smith, M., Cook, E., Bonkowsky, J. L. 2020: 1357633X20969531

    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

  • Sarnat Grading Scale for Neonatal Encephalopathy after 45 Years: An Update Proposal. Pediatric neurology Sarnat, H. B., Flores-Sarnat, L., Fajardo, C., Leijser, L. M., Wusthoff, C., Mohammad, K. 2020; 113: 75–79
  • Parent experience of caring for neonates with seizures. Archives of disease in childhood. Fetal and neonatal edition Lemmon, M., Glass, H., Shellhaas, R. A., Barks, M. C., Bailey, B., Grant, K., Grossbauer, L., Pawlowski, K., Wusthoff, C. J., Chang, T., Soul, J., Chu, C. J., Thomas, C., Massey, S. L., Abend, N. S., Rogers, E. E., Franck, L. S., Neonatal Seizure Registry, Annis, D., Barako, T., Barnes, M., Brown, C., Contreras, K., Guerriero, J., Hill, L., Long, T., Ma, G. 2020

    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

  • Continuous EEG for Seizure Detection in Neonates after Cardiac Bypass without Deep Hypothermic Cardiac Arrest Levy, R., Karamian, A., Mayne, E., Iqbal, M., Purington, N., Ryan, K., Wusthoff, C. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Impact of recurrent seizures on white matter in non-structural neonatal epilepsy Karamian, A., Wusthoff, C., Yeom, K., Knowles, J. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • How Helpful Is aEEG? Context and User Experience Matter. American journal of perinatology Sandoval Karamian, A. G., Wusthoff, C. J. 2020

    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

  • Associations between Infant and Parent Characteristics and Measures of Family Well-Being in Neonates with Seizures: A Cohort Study. The Journal of pediatrics Franck, L. S., Shellhaas, R. A., Lemmon, M. n., Sturza, J. n., Soul, J. S., Chang, T. n., Wusthoff, C. J., Chu, C. J., Massey, S. L., Abend, N. S., Thomas, C. n., Rogers, E. E., McCulloch, C. E., Grant, K. n., Grossbauer, L. n., Pawlowski, K. n., Glass, H. C. 2020; 221: 64–71.e4

    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

  • The Sarnat score for neonatal encephalopathy: looking back and moving forward. Pediatric research Mrelashvili, A. n., Russ, J. B., Ferriero, D. M., Wusthoff, C. J. 2020

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

    View details for PubMedID 32916680

  • Characterization of Death in Infants With Neonatal Seizures. Pediatric neurology Lemmon, M. E., Bonifacio, S. L., Shellhaas, R. A., Wusthoff, C. J., Greenberg, R. G., Soul, J. S., Chang, T. n., Chu, C. J., Bates, S. n., Massey, S. L., Abend, N. S., Cilio, M. R., Glass, H. C. 2020; 113: 21–25

    Abstract

    Neonatal seizures are associated with death and neurological morbidity; however, little is known about how neonates with seizures die.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.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.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.

    View details for DOI 10.1016/j.pediatrneurol.2020.08.002

    View details for PubMedID 32980743

  • Integrative Medicine in Child Neurology: What Do Physicians Know and What Do They Want to Learn? Journal of child neurology Sandoval Karamian, A. G., Yeh, A. M., Wusthoff, C. J. 2020: 883073820925285

    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

  • Neonatal genetic epilepsies display convergent white matter microstructural abnormalities. Epilepsia Sandoval Karamian, A. G., Wusthoff, C. J., Boothroyd, D. n., Yeom, K. W., Knowles, J. K. 2020

    Abstract

    White matter undergoes rapid development in the neonatal period. Its structure during and after development is influenced by neuronal activity. Pathological neuronal activity, as in seizures, might alter white matter, which in turn may contribute to network dysfunction. Neonatal epilepsy presents an opportunity to investigate seizures and early white matter development. Our objective was to determine whether neonatal seizures in the absence of brain injury or congenital anomalies are associated with altered white matter microstructure. In this retrospective case-control study of term neonates, cases had confirmed or suspected genetic epilepsy and normal brain magnetic resonance imaging (MRI) and no other conditions independently impacting white matter. Controls were healthy neonates with normal MRI results. White matter microstructure was assessed via quantitative mean diffusivity (MD). In 22 cases, MD was significantly lower in the genu of the corpus callosum, compared to 22 controls, controlling for gestational age and postmenstrual age at MRI. This finding suggests convergent abnormal corpus callosum microstructure in neonatal epilepsies with diverse suspected genetic causes. Further study is needed to determine the specific nature, causes, and functional impact of seizure-associated abnormal white matter in neonates, a potential pathogenic mechanism.

    View details for DOI 10.1111/epi.16735

    View details for PubMedID 33098118

  • Immediate outcomes in early life epilepsy: A contemporary account. Epilepsy & behavior : E&B Berg, A. T., Wusthoff, C., Shellhaas, R. A., Loddenkemper, T., Grinspan, Z. M., Saneto, R. P., Knupp, K. G., Patel, A., Sullivan, J. E., Kossoff, E. H., Chu, C. J., Massey, S., Valencia, I., Keator, C., Wirrell, E. C., Coryell, J., Millichap, J. J., Gaillard, W. D. 2019; 97: 44–50

    Abstract

    RATIONALE: Early-life epilepsies (ELEs) include some of the most challenging forms of epilepsy to manage. Given recent diagnostic and therapeutic advances, a contemporary assessment of the immediate short-term outcomes can provide a valuable framework for identifying priorities and benchmarks for evaluating quality improvement efforts.METHODS: Children with newly diagnosed epilepsy and onset <3 years were prospectively recruited through 17 US hospitals, from 2012 to 2015 and followed for 1 year after diagnosis. Short-term outcome included mortality, drug resistance, evolution of nonsyndromic epilepsy to infantile spasms (IS) and from IS to other epilepsies, and developmental decline. Multivariable analyses assessed the risk of each outcome.RESULTS: Seven hundred seventy-five children were recruited, including 408 (53%) boys. Median age at onset was 7.5 months (interquartile range (IQR): 4.2-16.5), and 509 (66%) had onset in the first year of life. Of 22 deaths that occurred within one year of epilepsy diagnosis, 21 were children with epilepsy onset in infancy (<12 months). Of 680 children followed ≥6 months, 239 (35%) developed drug-resistant seizures; 34/227 (15%) infants with nonsyndromic epilepsy developed IS, and 48/210 (23%) initially presenting with IS developed additional seizure types. One hundred of 435 (23%) with initially typical development or only mild/equivocal delays at seizure onset, had clear developmental impairment within one year after initial diagnosis. Each outcome had a different set of predictors; however, younger age and impaired development at seizure onset were broadly indicative of poorer outcomes. Type of epilepsy and early identification of underlying cause were not reliable predictors of these outcomes.CONCLUSION: Early-life epilepsies carry a high risk of poor outcome which is evident shortly after epilepsy diagnosis. Onset in infancy and developmental delay is associated with an especially high risk, regardless of epilepsy type. The likelihood of poor outcomes is worrisome regardless of specific clinical profiles.

    View details for DOI 10.1016/j.yebeh.2019.05.011

    View details for PubMedID 31181428

  • Differences in patient characteristics and care practices between two trials of therapeutic hypothermia PEDIATRIC RESEARCH Bonifacio, S. L., McDonald, S. A., Chock, V. Y., Wusthoff, C. J., Hintz, S. R., Laptook, A. R., Shankara, S., Van Meurs, K. P. 2019; 85 (7): 1008–15
  • Differences in patient characteristics and care practices between two trials of therapeutic hypothermia. Pediatric research Bonifacio, S. L., McDonald, S. A., Chock, V. Y., Wusthoff, C. J., Hintz, S. R., Laptook, A. R., Shankara, S., Van Meurs, K. P. 2019

    Abstract

    BACKGROUND: The Induced Hypothermia (IH) and Optimizing Cooling (OC) trials for hypoxic-ischemic encephalopathy (HIE) had similar inclusion criteria. The rate of death/moderate-severe disability differed for the subgroups treated with therapeutic hypothermia (TH) at 33.5°C for 72h (44% vs. 29%, unadjusted p=0.03). We aimed to evaluate differences in patient characteristics and care practices between the trials.METHODS: We compared pre/post-randomization characteristics and care practices between IH and OC.RESULTS: There were 208 patients in the IH trial, 102 cooled, and 364 in the OC trial, 95 cooled to 33.5°C for 72h. In OC, neonates were less ill, fewer had severe HIE, and the majority were cooled prior to randomization. Differences between IH and OC were observed in the adjusted difference in the lowest PCO2 (+3.08mmHg, p=0.005) and highest PO2 (-82.7mmHg, p<0.001). In OC, compared to IH, the adjusted relative risk (RR) of exposure to anticonvulsant prior to randomization was decreased (RR 0.58, (0.40-0.85), p=0.005) and there was increased risk of exposure during cooling to sedatives/analgesia (RR 1.86 (1.21-2.86), p=0.005).CONCLUSION: Despite similar inclusion criteria, there were differences in patient characteristics and care practices between trials. Change in care practices over time should be considered when planning future neuroprotective trials.

    View details for PubMedID 30862961

  • Response to antiseizure medications in neonates with acute symptomatic seizures. Epilepsia Glass, H. C., Soul, J. S., Chu, C. J., Massey, S. L., Wusthoff, C. J., Chang, T., Cilio, M. R., Bonifacio, S. L., Abend, N. S., Thomas, C., Lemmon, M., McCulloch, C. E., Shellhaas, R. A., Neonatal Seizure Registry study group 2019

    Abstract

    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.

    View details for PubMedID 30790268

  • Breaking a Cycle of Dependence to Improve Neurology Education: A Qualitative Study Exploring Pediatric Residents' Perspectives. Clinical pediatrics Nguyen, T. n., Pavitt, S. n., Wusthoff, C. n., Rassbach, C. n. 2019: 9922819870557

    Abstract

    Objective. To understand pediatric residents' experiences and attitudes toward learning neurology; and to identify facilitators and barriers to learning neurology during residency. Study Design. Qualitative study using focus groups of pediatric residents at Stanford during November 2017. Focus groups were audio-recorded and transcribed verbatim. Investigators independently coded the transcripts and reconciled codes to develop themes using constant comparison associated with grounded theory. Results. Eighteen pediatric residents participated in 3 focus groups. Four themes emerged: (1) residents feel unprepared and uncomfortable; (2) intrinsic and extrinsic factors contribute to residents' dependence on neurologists; (3) residents desire more teaching; and (4) residents are motivated to overcome their dependence on neurologists and optimize their learning. Conclusion. Pediatric residents are motivated to acquire more skills to assess and manage patients with neurological conditions. They recognize key factors that contribute to a cycle of dependence that impedes their learning and offer strategies to overcome these barriers.

    View details for DOI 10.1177/0009922819870557

    View details for PubMedID 31455089

  • Neuroimaging of Early Life Epilepsy PEDIATRICS Coryell, J., Gaillard, W. D., Shellhaas, R. A., Grinspan, Z. M., Wirrell, E. C., Knupp, K. G., Wusthoff, C. J., Keator, C., Sullivan, J. E., Loddenkemper, T., Patel, A., Chu, C. J., Massey, S., Novotny, E. J., Saneto, R. P., Berg, A. T. 2018; 142 (3)

    Abstract

    We assessed the adherence to neuroimaging guidelines and the diagnostically relevant yield of neuroimaging in newly presenting early life epilepsy (ELE).There were 775 children with a new diagnosis of epilepsy (<3 years old at onset) who were recruited through the ELE study at 17 US pediatric epilepsy centers (2012-2015) and managed prospectively for 1 year. The data were analyzed to assess the proportion of children who underwent neuroimaging, the type of neuroimaging, and abnormalities.Of 725 children (93.5%) with neuroimaging, 714 had an MRI (87% with seizure protocols) and 11 had computed tomography or ultrasound only. Etiologically relevant abnormalities were present in 290 individuals (40%) and included: an acquired injury in 97 (13.4%), malformations of cortical development in 56 (7.7%), and other diffuse disorders of brain development in 51 (7.0%). Neuroimaging was abnormal in 160 of 262 (61%) children with abnormal development at diagnosis versus 113 of 463 (24%) children with typical development. Neuroimaging abnormalities were most common in association with focal seizure semiology (40%), spasms (47%), or unclear semiology (42%). In children without spasms or focal semiology with typical development, 29 of 185 (16%) had imaging abnormalities. Pathogenic genetic variants were identified in 53 of 121 (44%) children with abnormal neuroimaging in whom genetic testing was performed.Structural abnormalities occur commonly in ELE, and adherence to neuroimaging guidelines is high at US pediatric epilepsy centers. These data support the universal adoption of imaging guidelines because the yield is substantially high, even in the lowest risk group.

    View details for PubMedID 30089657

  • Use of electronic medical record templates improves quality of care for patients with infantile spasms. Health information management : journal of the Health Information Management Association of Australia Santoro, J. D., Sandoval, A., Ruzhnikov, M., Brimble, E., Chadwick, W., Wusthoff, C. J. 2018: 1833358318794501

    Abstract

    BACKGROUND: Infantile spasms (IS) is a neurologic disorder of childhood where time to treatment may affect long-term outcomes. Due to the clinical complexity of IS, care can be delayed.OBJECTIVE: To determine if the use of electronic medical record templates (EMRTs) improved care quality in patients treated for IS.METHOD: Records of patients newly diagnosed with IS were retrospectively reviewed both before and after creation of an EMRT for the workup and treatment of IS. Quality of care measures reviewed included delays in treatment plan, medication administration, obtaining neurodiagnostic studies and discharge. The need for repeat neurodiagnostic studies was also assessed. Resident physicians were surveyed regarding template ease of use and functionality.RESULTS: Of 17 patients with IS, 7 received template-based care and 10 did not. Patients in the non-template group had more delays in treatment ( p = 0.010), delay in medication administration ( p = 0.10), delay in diagnostic studies ( p = 0.01) and delay in discharge ( p = 0.39). Neurodiagnostic studies needed to be repeated in 5 out of 10 patients in the non-template group and none of the 7 patients in the template group ( p = 0.04). Surveyed resident physicians reported improved coordination in care, avoidance of delays in discharge and improved ability to predict side effects of treatment with template use.CONCLUSION: In a single centre, the use of protocolised EMRTs decreased treatment delays and the need for repeated invasive procedures in patients with newly diagnosed IS and was reported as easy to use by resident physicians.IMPLICATIONS: The use of protocolised EMRTs may improve the quality of patient care in IS and other rare diseases.

    View details for PubMedID 30124080

  • Development of a NeuroNICU with a Broader Focus on All Newborns at Risk of Brain Injury: The First 2 Years. American journal of perinatology Van Meurs, K. P., Yan, E. S., Randall, K. S., Chock, V. Y., Davis, A. S., Glennon, C. S., Clark, C. L., Wusthoff, C. J., Bonifacio, S. L. 2018

    Abstract

    OBJECTIVE: Many critically ill neonates have an existing brain injury or are at risk of neurologic injury. We developed a "NeuroNICU" (neurologic neonatal intensive care unit) to better provide neurologically focused intensive care.STUDY DESIGN: Demographic and clinical variables, services delivered, and patient outcomes were recorded in a prospective database for all neonates admitted to the NeuroNICU between April 23, 2013, and June 25, 2015.RESULTS: In total, 546 neonates were admitted to the NeuroNICU representing 32% of all NICU admissions. The most common admission diagnoses were congenital heart disease (30%), extreme prematurity (18%), seizures (10%), and hypoxic-ischemic encephalopathy (9%). Neuromonitoring was common, with near-infrared spectroscopy used in 69%, amplitude-integrated electroencephalography (EEG) in 45%, and continuous video EEG in 35%. Overall, 43% received neurology or neurosurgery consultation. Death prior to hospital discharge occurred in 11%. Among survivors, 87% were referred for developmental follow-up, and among those with a primary neurologic diagnosis 57% were referred for neurology or neurosurgical follow-up.CONCLUSION: The NeuroNICU-admitted newborns with or at risk of brain injury comprise a high percentage of NICU volume; 38% had primary neurologic diagnoses, whereas 62% had medical diagnoses. We found many opportunities to provide brain focused intensive care, impacting a substantial proportion of newborns in our NICU.

    View details for PubMedID 29702712

  • Integrative Medicine in Child Neurology: what do providers think and what do they need to learn? Karamian, A., Yeh, A., Wusthoff, C. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy JAMA PEDIATRICS Grinspan, Z. M., Shellhaas, R. A., Coryell, J., Sullivan, J. E., Wirrell, E. C., Mytinger, J. R., Gaillard, W. D., Kossoff, E. H., Valencia, I., Knupp, K. G., Wusthoff, C., Keator, C., Ryan, N., Loddenkemper, T., Chu, C. J., Novotny, E. J., Millichap, J., Berg, A. T. 2018; 172 (4): 352–60

    Abstract

    More than half of infants with new-onset epilepsy have electroencephalographic and clinical features that do not conform to known electroclinical syndromes (ie, nonsyndromic epilepsy). Levetiracetam and phenobarbital are the most commonly prescribed medications for epilepsy in infants, but their comparative effectiveness is unknown.To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy.The Early Life Epilepsy Study-a prospective, multicenter, observational cohort study conducted from March 1, 2012, to April 30, 2015, in 17 US medical centers-enrolled infants with nonsyndromic epilepsy and a first afebrile seizure between 1 month and 1 year of age.Use of levetiracetam or phenobarbital as initial monotherapy within 1 year of the first seizure.The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations.Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n = 117) were older at the time of the first seizure than those treated with phenobarbital (n = 38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P < .001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P = .01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]).Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

    View details for PubMedID 29435578

    View details for PubMedCentralID PMC5875334

  • Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms PLOS ONE Berg, A. T., Chakravorty, S., Koh, S., Grinspan, Z. M., Shellhaas, R. A., Saneto, R. P., Wirrell, E. C., Coryell, J., Chu, C. J., Mytinger, J. R., Gaillard, W. D., Valencia, I., Kriupp, K. G., Loddenkemper, T., Sullivan, J. E., Poduri, A., Millichap, J. J., Keator, C., Wusthoff, C., Ryan, N., Dobyns, W. B., Hegde, M. 2018; 13 (3): e0193599

    Abstract

    Infantile spasms are the defining seizures of West syndrome, a severe form of early life epilepsy with poorly-understood pathophysiology. We present a novel comparative analysis of infants with spasms versus other seizure-types and identify clinical, etiological, and molecular-genetic factors preferentially predisposing to spasms. We compared ages, clinical etiologies, and associated-genes between spasms and non-spasms groups in a multicenter cohort of 509 infants (<12months) with newly-diagnosed epilepsy. Gene ontology and pathway enrichment analysis of clinical laboratory-confirmed pathogenic variant-harboring genes was performed. Pathways, functions, and cellular compartments between spasms and non-spasms groups were compared. Spasms onset age was similar in infants initially presenting with spasms (6.1 months) versus developing spasms as a later seizure type (6.9 months) but lower in the non-spasms group (4.7 months, p<0.0001). This pattern held across most etiological categories. Gestational age negatively correlated with spasms onset-age (r = -0.29, p<0.0001) but not with non-spasm seizure age. Spasms were significantly preferentially associated with broad developmental and regulatory pathways, whereas motor functions and pathways including cellular response to stimuli, cell motility and ion transport were preferentially enriched in non-spasms. Neuronal cell-body organelles preferentially associated with spasms, while, axonal, dendritic, and synaptic regions preferentially associated with other seizures. Spasms are a clinically and biologically distinct infantile seizure type. Comparative clinical-epidemiological analyses identify the middle of the first year as the time of peak expression regardless of etiology. The inverse association with gestational age suggests the preterm brain must reach a certain post-conceptional, not just chronological, neurodevelopmental stage before spasms manifest. Clear differences exist between the biological pathways leading to spasms versus other seizure types and suggest that spasms result from dysregulation of multiple developmental pathways and involve different cellular components than other seizure types. This deeper level of understanding may guide investigations into pathways most critical to target in future precision medicine efforts.

    View details for PubMedID 29518120

  • Cooling in neonatal hypoxic-ischemic encephalopathy: practices and opinions on minimum standards in the state of California JOURNAL OF PERINATOLOGY Wusthoff, C. J., Clark, C. L., Glass, H. C., Shimotake, T. K., Schulman, J., Bonifacio, S. L. 2018; 38 (1): 54–58

    Abstract

    Although hospitals increasingly offer therapeutic hypothermia (TH), there is variable implementation of related services. We assessed current practices and opinions regarding what services should be required of centers providing TH in California.We surveyed neonatal intensive care unit physicians statewide regarding practices and opinions about services related to TH.Of the 50 participating centers (47% response rate), 66% offer TH. Most TH centers reported using: an evidence-based protocol (92%), neurology consultation (92%), amplitude-integrated electroencephalography (aEEG) or EEG (88%), magnetic resonance imagings (MRIs) interpreted by pediatric neuroradiologists (71%) and developmental follow-up (93%). TH centers reported treating a median of 11 patients annually (interquartile range (IQR) 4 to 24). Respondents considered it 'critical' that TH centers offer: aEEG monitoring (70%), MRI (69%), occupational and physical therapy (67%) and developmental follow-up (94%). Over 70% thought TH centers should treat a minimum volume annually (median=10, IQR 5 to 12).Physicians across practice settings in California endorsed minimum standards for TH centers to promote quality of care.

    View details for PubMedID 29048405

  • The impact of hypsarrhythmia on infantile spasms treatment response: Observational cohort study from the National Infantile Spasms Consortium EPILEPSIA Demarest, S. T., Shellhaas, R. A., Gaillard, W. D., Keator, C., Nickels, K. C., Hussain, S. A., Loddenkemper, T., Patel, A. D., Saneto, R. P., Wirrell, E., Fernandez, I., Chu, C. J., Grinspan, Z., Wusthoff, C. J., Joshi, S., Mohamed, I. S., Stafstrom, C. E., Stack, C. V., Yozawitz, E., Bluvstein, J. S., Singh, R. K., Knupp, K. G., Pediat Epilepsy Res Consortium 2017; 58 (12): 2098–2103

    Abstract

    The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia.Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation.Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) .First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.

    View details for PubMedID 29105055

    View details for PubMedCentralID PMC5863227

  • Initial Treatment for Nonsyndromic Early-Life Epilepsy: An Unexpected Consensus. Pediatric neurology Shellhaas, R. A., Berg, A. T., Grinspan, Z. M., Wusthoff, C. J., Millichap, J. J., Loddenkemper, T., Coryell, J., Saneto, R. P., Chu, C. J., Joshi, S. M., Sullivan, J. E., Knupp, K. G., Kossoff, E. H., Keator, C., Wirrell, E. C., Mytinger, J. R., Valencia, I., Massey, S., Gaillard, W. D. 2017; 75: 73-79

    Abstract

    There are no evidence-based guidelines on the preferred approach to treating early-life epilepsy. We examined initial therapy selection in a contemporary US cohort of children with newly diagnosed, nonsyndromic, early-life epilepsy (onset before age three years).Seventeen pediatric epilepsy centers participated in a prospective cohort study of children with newly diagnosed epilepsy with onset under 36 months of age. Details regarding demographics, seizure types, and initial medication selections were obtained from medical records.About half of the 495 enrolled children with new-onset, nonsyndromic epilepsy were less than 12 months old at the time of diagnosis (n = 263, 53%) and about half (n = 260, 52%) had epilepsy with focal features. Of 464 who were treated with monotherapy, 95% received one of five drugs: levetiracetam (n = 291, 63%), oxcarbazepine (n = 67, 14%), phenobarbital (n = 57, 12%), topiramate (n = 16, 3.4%), and zonisamide (n = 13, 2.8%). Phenobarbital was prescribed first for 50 of 163 (31%) infants less than six months old versus seven of 300 (2.3%) of children six months or older (P < 0.0001). Although the first treatment varied across study centers (P < 0.0001), levetiracetam was the most commonly prescribed medication regardless of epilepsy presentation (focal, generalized, mixed/uncertain). Between the first and second treatment choices, 367 (74%) of children received levetiracetam within the first year after diagnosis.Without any specific effort, the pediatric epilepsy community has developed an unexpectedly consistent approach to initial treatment selection for early-life epilepsy. This suggests that a standard practice is emerging and could be utilized as a widely acceptable basis of comparison in future drug studies.

    View details for DOI 10.1016/j.pediatrneurol.2017.06.011

    View details for PubMedID 28807611

    View details for PubMedCentralID PMC5863237

  • Early-Life Epilepsies and the Emerging Role of Genetic Testing JAMA PEDIATRICS Berg, A. T., Coryell, J., Saneto, R. P., Grinspan, Z. M., Alexander, J. J., Kekis, M., Sullivan, J. E., Wirrell, E. C., Shellhaas, R. A., Mytinger, J. R., Gaillard, W. D., Kossoff, E. H., Valencia, I., Knupp, K. G., Wusthoff, C., Keator, C., Dobyns, W. B., Ryan, N., Loddenkemper, T., Chu, C. J., Novotny, E. J., Koh, S. 2017; 171 (9): 863–71

    Abstract

    Early-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established.To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies.In this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined.Genetic diagnostic testing.Laboratory-confirmed pathogenic variant.Of the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P < .001) and whole exomes (5 of 18 [27.8%]; P = .02) than for chromosomal microarray (8 of 101 [7.9%]).Genetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.

    View details for PubMedID 28759667

    View details for PubMedCentralID PMC5710404

  • Profile of neonatal epilepsies: Characteristics of a prospective US cohort. Neurology Shellhaas, R. A., Wusthoff, C. J., Tsuchida, T. N., Glass, H. C., Chu, C. J., Massey, S. L., Soul, J. S., Wiwattanadittakun, N., Abend, N. S., Cilio, M. R. 2017; 89 (9): 893-899

    Abstract

    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.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.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).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.

    View details for DOI 10.1212/WNL.0000000000004284

    View details for PubMedID 28733343

    View details for PubMedCentralID PMC5577964

  • Seizures in Infants Born Preterm: Defining the Scale of the Problem. The Journal of pediatrics Wusthoff, C. J. 2017; 187: 7-8

    View details for DOI 10.1016/j.jpeds.2017.04.031

    View details for PubMedID 28499714

  • Seizures in Preterm Neonates: A Multicenter Observational Cohort Study. Pediatric neurology Glass, H. C., Shellhaas, R. A., Tsuchida, T. N., Chang, T., Wusthoff, C. J., Chu, C. J., Cilio, M. R., Bonifacio, S. L., Massey, S. L., Abend, N. S., Soul, J. S. 2017

    Abstract

    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.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.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%).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.

    View details for DOI 10.1016/j.pediatrneurol.2017.04.016

    View details for PubMedID 28558955

  • Improving the Identification of Neonatal Encephalopathy: Utility of a Web-Based Video Tool AMERICAN JOURNAL OF PERINATOLOGY Ivy, A. S., Clark, C. L., Bahm, S. M., Van Meurs, K. P., Wusthoff, C. J. 2017; 34 (5): 520-522

    Abstract

    Objective This study tested the effectiveness of a video teaching tool in improving identification and classification of encephalopathy in infants. Study Design We developed an innovative video teaching tool to help clinicians improve their skills in interpreting the neonatal neurological examination for grading encephalopathy. Pediatric residents were shown 1-minute video clips demonstrating exam findings in normal neonates and neonates with various degrees of encephalopathy. Findings from five domains were demonstrated: spontaneous activity, level of alertness, posture/tone, reflexes, and autonomic responses. After each clip, subjects were asked to identify whether the exam finding was normal or consistent with mild, moderate, or severe abnormality. Subjects were then directed to a web-based teaching toolkit, containing a compilation of videos demonstrating normal and abnormal findings on the neonatal neurological examination. Immediately after training, subjects underwent posttesting, again identifying exam findings as normal, mild, moderate, or severe abnormality. Results Residents improved in their overall ability to identify and classify neonatal encephalopathy after viewing the teaching tool. In particular, the identification of abnormal spontaneous activity, reflexes, and autonomic responses were most improved. Conclusion This pretest/posttest evaluation of an educational tool demonstrates that after viewing our toolkit, pediatric residents were able to improve their overall ability to detect neonatal encephalopathy.

    View details for DOI 10.1055/5-0036-1593846

    View details for Web of Science ID 000398011100015

  • Interrater agreement in the interpretation of neonatal electroencephalography in hypoxic-ischemic encephalopathy. Epilepsia Wusthoff, C. J., Sullivan, J., Glass, H. C., Shellhaas, R. A., Abend, N. S., Chang, T., Tsuchida, T. N. 2017; 58 (3): 429-435

    Abstract

    Research using neonatal electroencephalography (EEG) has been limited by a lack of a standardized classification system and interpretation terminology. In 2013, the American Clinical Neurophysiology Society (ACNS) published a guideline for standardized terminology and categorization in the description of continuous EEG in neonates. We sought to assess interrater agreement for this neonatal EEG categorization system as applied by a group of pediatric neurophysiologists.A total of 60 neonatal EEG studies were collected from three institutions. All EEG segments were from term neonates with hypoxic-ischemic encephalopathy. Three pediatric neurophysiologists independently reviewed each record using the ACNS standardized scoring system. Unweighted kappa values were calculated for interrater agreement of categorical data across multiple observers.Interrater agreement was very good for identification of seizures (κ = 0.93, p < 0.001), with perfect agreement in 95% of records (57 of 60). Interrater agreement was moderate for classifying records as normal or having any abnormality (κ = 0.49, p < 0.001), with perfect agreement in 78% of records (47 of 60). Interrater agreement was good in classifying EEG backgrounds on a 5-category scale (normal, excessively discontinuous, burst suppression, status epilepticus, or electrocerebral inactivity) (κ = 0.70, p < 0.001), with perfect agreement in 72% of records (43 of 60). Other specific background features had lower agreement, including voltage (κ = 0.41, p < 0.001), variability (κ = 0.35, p < 0.001), symmetry (κ = 0.18, p = 0.01), presence of abnormal sharp waves (κ < 0.20, p < 0.05), and presence of brief rhythmic discharges (κ < 0.20, p < 0.05).We found good or very good interrater agreement applying the ACNS system for identification of seizures and classification of EEG background. Other specific EEG features showed limited interrater agreement. Of importance to both clinicians and researchers, our findings support using the ACNS system in identifying seizures and classifying backgrounds of neonatal EEG recordings, but also suggest limited reproducibility for certain other EEG features.

    View details for DOI 10.1111/epi.13661

    View details for PubMedID 28166364

    View details for PubMedCentralID PMC5339031

  • Treatment Duration After Acute Symptomatic Seizures in Neonates: A Multicenter Cohort Study. journal of pediatrics Shellhaas, R., Chang, T., Wusthoff, C., Soul, J., Massey, S., Chu, C., Cilio, M. R., Bonifacio, S., Abend, N., Tsuchida, T., Glass, H. 2017; 181: 298-301 e1

    Abstract

    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.

    View details for DOI 10.1016/j.jpeds.2016.10.039

    View details for PubMedID 27829512

    View details for PubMedCentralID PMC5322461

  • MRI Patterns of brain injury and neurodevelopmental outcomes in neonates with severe anaemia at birth. Early human development Loureiro, B., Martinez-Biarge, M., Foti, F., Papadaki, M., Cowan, F. M., Wusthoff, C. J. 2017; 105: 17-22

    Abstract

    To define patterns of brain injury and associated neurodevelopmental outcomes in infants with severe neonatal anaemia.We studied 20 infants with severe anaemia at birth (haemoglobin<7g/dL). Clinical details were analysed for causes of anaemia and co-morbidities. All had early brain magnetic resonance imaging (MRI) scans, which were reviewed for injury pattern. Neurodevelopmental outcomes were assessed at a median age of 24months.The aetiology of the anaemia was feto-maternal haemorrhage in 17 and antepartum haemorrhage in 3 infants. The predominant site of injury was the white matter, which was affected in all infants, with differing grades of severity and with cystic evolution in 45%. Only one infant showed an injury pattern typical of an acute severe hypoxic-ischaemic insult. Outcomes correlated closely to the severity of MRI findings. Cerebral palsy was seen only with the most severe neuroimaging patterns (n=6). Global developmental delay, learning or behavioural problems and seizures were common with moderate injury. Visual impairment occurred, particularly with posterior injury. Microcephaly developed in 45%.Severe neonatal anaemia at birth was associated with a white matter predominant pattern of injury, the severity of which was related to neurodevelopmental outcomes. Early MRI and long-term follow-up are advisable following severe neonatal anaemia.

    View details for DOI 10.1016/j.earlhumdev.2017.01.001

    View details for PubMedID 28107673

  • Improving the Identification of Neonatal Encephalopathy: Utility of a Web-Based Video Tool. American journal of perinatology Ivy, A. S., Clark, C. L., Bahm, S. M., Meurs, K. P., Wusthoff, C. J. 2016: -?

    Abstract

    Objective This study tested the effectiveness of a video teaching tool in improving identification and classification of encephalopathy in infants. Study Design We developed an innovative video teaching tool to help clinicians improve their skills in interpreting the neonatal neurological examination for grading encephalopathy. Pediatric residents were shown 1-minute video clips demonstrating exam findings in normal neonates and neonates with various degrees of encephalopathy. Findings from five domains were demonstrated: spontaneous activity, level of alertness, posture/tone, reflexes, and autonomic responses. After each clip, subjects were asked to identify whether the exam finding was normal or consistent with mild, moderate, or severe abnormality. Subjects were then directed to a web-based teaching toolkit, containing a compilation of videos demonstrating normal and abnormal findings on the neonatal neurological examination. Immediately after training, subjects underwent posttesting, again identifying exam findings as normal, mild, moderate, or severe abnormality. Results Residents improved in their overall ability to identify and classify neonatal encephalopathy after viewing the teaching tool. In particular, the identification of abnormal spontaneous activity, reflexes, and autonomic responses were most improved. Conclusion This pretest/posttest evaluation of an educational tool demonstrates that after viewing our toolkit, pediatric residents were able to improve their overall ability to detect neonatal encephalopathy.

    View details for PubMedID 27788536

  • Neonatal EEG: An Update. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society Wusthoff, C. J. 2016; 33 (5): 375

    View details for DOI 10.1097/WNP.0000000000000298

    View details for PubMedID 27261643

  • Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study JOURNAL OF PEDIATRICS Glass, H. C., Shellhaas, R. A., Wusthoff, C. J., Chang, T., Abend, N. S., Chu, C. J., Cilio, M. R., Glidden, D. V., Bonifacio, S. L., Massey, S., Tsuchida, T. N., Silverstein, F. S., Soul, J. S. 2016; 174: 98-?

    Abstract

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

    View details for DOI 10.1016/j.jpeds.2016.03.035

    View details for PubMedID 27106855

  • Development and Feasibility Testing of a Critical Care EEG Monitoring Database for Standardized Clinical Reporting and Multicenter Collaborative Research JOURNAL OF CLINICAL NEUROPHYSIOLOGY Lee, J. W., LaRoche, S., Choi, H., Ruiz, A. A., Fertig, E., Politsky, J. M., Herman, S. T., Loddenkemper, T., Sansevere, A. J., Korb, P. J., Abend, N. S., Goldstein, J. L., Sinha, S. R., Dombrowski, K. E., Ritzl, E. K., Westover, M. B., Gavvala, J. R., Gerard, E. E., Schmitt, S. E., Szaflarski, J. P., Ding, K., Haas, K. F., Buchsbaum, R., Hirsch, L. J., Wusthoff, C. J., Hopp, J. L., Hahn, C. D. 2016; 33 (2): 133-140

    Abstract

    The rapid expansion of the use of continuous critical care electroencephalogram (cEEG) monitoring and resulting multicenter research studies through the Critical Care EEG Monitoring Research Consortium has created the need for a collaborative data sharing mechanism and repository. The authors describe the development of a research database incorporating the American Clinical Neurophysiology Society standardized terminology for critical care EEG monitoring. The database includes flexible report generation tools that allow for daily clinical use.Key clinical and research variables were incorporated into a Microsoft Access database. To assess its utility for multicenter research data collection, the authors performed a 21-center feasibility study in which each center entered data from 12 consecutive intensive care unit monitoring patients. To assess its utility as a clinical report generating tool, three large volume centers used it to generate daily clinical critical care EEG reports.A total of 280 subjects were enrolled in the multicenter feasibility study. The duration of recording (median, 25.5 hours) varied significantly between the centers. The incidence of seizure (17.6%), periodic/rhythmic discharges (35.7%), and interictal epileptiform discharges (11.8%) was similar to previous studies. The database was used as a clinical reporting tool by 3 centers that entered a total of 3,144 unique patients covering 6,665 recording days.The Critical Care EEG Monitoring Research Consortium database has been successfully developed and implemented with a dual role as a collaborative research platform and a clinical reporting tool. It is now available for public download to be used as a clinical data repository and report generating tool.

    View details for DOI 10.1097/WNP.0000000000000230

    View details for Web of Science ID 000373223500009

    View details for PubMedCentralID PMC4878836

  • Development and Feasibility Testing of a Critical Care EEG Monitoring Database for Standardized Clinical Reporting and Multicenter Collaborative Research. Journal of clinical neurophysiology Lee, J. W., LaRoche, S., Choi, H., Rodriguez Ruiz, A. A., Fertig, E., Politsky, J. M., Herman, S. T., Loddenkemper, T., Sansevere, A. J., Korb, P. J., Abend, N. S., Goldstein, J. L., Sinha, S. R., Dombrowski, K. E., Ritzl, E. K., Westover, M. B., Gavvala, J. R., Gerard, E. E., Schmitt, S. E., Szaflarski, J. P., Ding, K., Haas, K. F., Buchsbaum, R., Hirsch, L. J., Wusthoff, C. J., Hopp, J. L., Hahn, C. D. 2016; 33 (2): 133-140

    Abstract

    The rapid expansion of the use of continuous critical care electroencephalogram (cEEG) monitoring and resulting multicenter research studies through the Critical Care EEG Monitoring Research Consortium has created the need for a collaborative data sharing mechanism and repository. The authors describe the development of a research database incorporating the American Clinical Neurophysiology Society standardized terminology for critical care EEG monitoring. The database includes flexible report generation tools that allow for daily clinical use.Key clinical and research variables were incorporated into a Microsoft Access database. To assess its utility for multicenter research data collection, the authors performed a 21-center feasibility study in which each center entered data from 12 consecutive intensive care unit monitoring patients. To assess its utility as a clinical report generating tool, three large volume centers used it to generate daily clinical critical care EEG reports.A total of 280 subjects were enrolled in the multicenter feasibility study. The duration of recording (median, 25.5 hours) varied significantly between the centers. The incidence of seizure (17.6%), periodic/rhythmic discharges (35.7%), and interictal epileptiform discharges (11.8%) was similar to previous studies. The database was used as a clinical reporting tool by 3 centers that entered a total of 3,144 unique patients covering 6,665 recording days.The Critical Care EEG Monitoring Research Consortium database has been successfully developed and implemented with a dual role as a collaborative research platform and a clinical reporting tool. It is now available for public download to be used as a clinical data repository and report generating tool.

    View details for DOI 10.1097/WNP.0000000000000230

    View details for PubMedID 26943901

  • 50 Years Ago in The Journal of Pediatrics: Cerebrospinal Fluid Protein Values of Premature Infants. The Journal of pediatrics Wallenstein, M. B., Wusthoff, C. J. 2015; 166 (6): 1396

    View details for DOI 10.1016/j.jpeds.2014.12.042

    View details for PubMedID 26008171

  • How to use: amplitude-integrated EEG (aEEG) ARCHIVES OF DISEASE IN CHILDHOOD-EDUCATION AND PRACTICE EDITION Shah, N. A., Wusthoff, C. J. 2015; 100 (2): 75-81

    Abstract

    Amplitude-integrated electroencephalography (aEEG) is a method for continuous monitoring of brain activity that is increasingly used in the neonatal intensive care unit. In its simplest form, aEEG is a processed single-channel electroencephalogram that is filtered and time-compressed. Current evidence demonstrates that aEEG is useful to monitor cerebral background activity, diagnose and treat seizures and predict neurodevelopmental outcomes for preterm and term infants. This review aims to explain the fundamentals behind aEEG and its clinical applications.

    View details for DOI 10.1136/archdischild-2013-305676

    View details for Web of Science ID 000351216400004

    View details for PubMedID 25035312

  • Seizures and hypothermia: Importance of electroencephalographic monitoring and considerations for treatment SEMINARS IN FETAL & NEONATAL MEDICINE Boylan, G. B., Kharoshankaya, L., Wusthoff, C. J. 2015; 20 (2): 103-108

    Abstract

    Hypoxic-ischemic encephalopathy is a common cause of seizures in neonates. Despite the introduction of therapeutic hypothermia, seizure rates are similar to those reported in the pre-therapeutic hypothermia era. However, the seizure profile has been altered resulting in a lower overall seizure burden, shorter individual seizure durations, and seizures that are harder to detect. Electroencephalographic (EEG) monitoring is the gold standard for detecting all seizures in neonates and this is even more critical in neonates who are cooled, as they are often sedated, making seizures more difficult to detect. Several studies have shown that the majority of seizures in neonates undergoing therapeutic hypothermia remain subclinical, thus requiring EEG monitoring for diagnosis. Amplitude-integrated EEG monitoring is useful but shorter duration seizures are more likely to be missed. Evidence is emerging about the pharmacokinetic profile of routinely used antiepileptic drugs during therapeutic hypothermia and some modifications have been suggested, particularly for lidocaine use.

    View details for DOI 10.1016/j.siny.2015.01.001

    View details for Web of Science ID 000353075400007

    View details for PubMedID 25683598

  • Development and validation of a seizure prediction model in critically ill children. Seizure Yang, A., Arndt, D. H., Berg, R. A., Carpenter, J. L., Chapman, K. E., Dlugos, D. J., Gallentine, W. B., Giza, C. C., Goldstein, J. L., Hahn, C. D., Lerner, J. T., Loddenkemper, T., Matsumoto, J. H., Nash, K. B., Payne, E. T., Sánchez Fernández, I., Shults, J., Topjian, A. A., Williams, K., Wusthoff, C. J., Abend, N. S. 2015; 25: 104-111

    Abstract

    Electrographic seizures are common in encephalopathic critically ill children, but identification requires continuous EEG monitoring (CEEG). Development of a seizure prediction model would enable more efficient use of limited CEEG resources. We aimed to develop and validate a seizure prediction model for use among encephalopathic critically ill children.We developed a seizure prediction model using a retrospectively acquired multi-center database of children with acute encephalopathy without an epilepsy diagnosis, who underwent clinically indicated CEEG. We performed model validation using a separate prospectively acquired single center database. Predictor variables were chosen to be readily available to clinicians prior to the onset of CEEG and included: age, etiology category, clinical seizures prior to CEEG, initial EEG background category, and inter-ictal discharge category.The model has fair to good discrimination ability and overall performance. At the optimal cut-off point in the validation dataset, the model has a sensitivity of 59% and a specificity of 81%. Varied cut-off points could be chosen to optimize sensitivity or specificity depending on available CEEG resources.Despite inherent variability between centers, a model developed using multi-center CEEG data and few readily available variables could guide the use of limited CEEG resources when applied at a single center. Depending on CEEG resources, centers could choose lower cut-off points to maximize identification of all patients with seizures (but with more patients monitored) or higher cut-off points to reduce resource utilization by reducing monitoring of lower risk patients (but with failure to identify some patients with seizures).

    View details for DOI 10.1016/j.seizure.2014.09.013

    View details for PubMedID 25458097

    View details for PubMedCentralID PMC4315714

  • Impact of bilirubin-induced neurologic dysfunction on neurodevelopmental outcomes. Seminars in fetal & neonatal medicine Wusthoff, C. J., Loe, I. M. 2015; 20 (1): 52-57

    Abstract

    Bilirubin-induced neurologic dysfunction (BIND) is the constellation of neurologic sequelae following milder degrees of neonatal hyperbilirubinemia than are associated with kernicterus. Clinically, BIND may manifest after the neonatal period as developmental delay, cognitive impairment, disordered executive function, and behavioral and psychiatric disorders. However, there is controversy regarding the relative contribution of neonatal hyperbilirubinemia versus other risk factors to the development of later neurodevelopmental disorders in children with BIND. In this review, we focus on the empiric data from the past 25 years regarding neurodevelopmental outcomes and BIND, including specific effects on developmental delay, cognition, speech and language development, executive function, and the neurobehavioral disorders, such as attention deficit/hyperactivity disorder and autism.

    View details for DOI 10.1016/j.siny.2014.12.003

    View details for PubMedID 25585889

  • Development and validation of a seizure prediction model in critically ill children SEIZURE-EUROPEAN JOURNAL OF EPILEPSY Yang, A., Arndt, D. H., Berg, R. A., Carpenter, J. L., Chapman, K. E., Dlugos, D. J., Gallentine, W. B., Giza, C. C., Goldstein, J. L., Hahn, C. D., Lerner, J. T., Loddenkemper, T., Matsumoto, J. H., Nash, K. B., Payne, E. T., Fernandez, I. S., Shults, J., Topjian, A. A., Williams, K., Wusthoff, C. J., Abend, N. S. 2015; 25: 104-111

    Abstract

    Electrographic seizures are common in encephalopathic critically ill children, but identification requires continuous EEG monitoring (CEEG). Development of a seizure prediction model would enable more efficient use of limited CEEG resources. We aimed to develop and validate a seizure prediction model for use among encephalopathic critically ill children.We developed a seizure prediction model using a retrospectively acquired multi-center database of children with acute encephalopathy without an epilepsy diagnosis, who underwent clinically indicated CEEG. We performed model validation using a separate prospectively acquired single center database. Predictor variables were chosen to be readily available to clinicians prior to the onset of CEEG and included: age, etiology category, clinical seizures prior to CEEG, initial EEG background category, and inter-ictal discharge category.The model has fair to good discrimination ability and overall performance. At the optimal cut-off point in the validation dataset, the model has a sensitivity of 59% and a specificity of 81%. Varied cut-off points could be chosen to optimize sensitivity or specificity depending on available CEEG resources.Despite inherent variability between centers, a model developed using multi-center CEEG data and few readily available variables could guide the use of limited CEEG resources when applied at a single center. Depending on CEEG resources, centers could choose lower cut-off points to maximize identification of all patients with seizures (but with more patients monitored) or higher cut-off points to reduce resource utilization by reducing monitoring of lower risk patients (but with failure to identify some patients with seizures).

    View details for DOI 10.1016/j.seizure.2014.09.013

    View details for Web of Science ID 000349881100019

    View details for PubMedCentralID PMC4315714

  • Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION Shah, D. K., Wusthoff, C. J., Clarke, P., Wyatt, J. S., Ramaiah, S. M., Dias, R. J., Becher, J., Kapellou, O., Boardman, J. P. 2014; 99 (3): F219-F224

    Abstract

    Seizures are common among newborns with hypoxic-ischaemic encephalopathy (HIE) but the relationship between seizure burden and severity of brain injury among neonates receiving therapeutic hypothermia (TH) for HIE is unclear. We tested the hypothesis that seizure burden is associated with cerebral tissue injury independent of amplitude-integrated EEG (aEEG) background activity.Term neonates undergoing 72 h of TH at four centres were selected for study if they had continuous aEEG and MRI. The aEEG with corresponding 2-channel raw EEG (aEEG/EEG), was classified by severity of background and seizure burden; MR images were classified by the severity of tissue injury.Of 85 neonates, 52% had seizures on aEEG/EEG. Overall, 35% had high seizure burden, 49% had abnormal aEEG background in the first 24 h and 36% had severe injury on MRI. Seizures were most common on the first day, with significant recurrence during and after rewarming. Factors associated with severe injury on MRI were high seizure burden, poor aEEG background, 10 min Apgar and the need for more than one anticonvulsant. In multivariate logistic regression, high seizure burden was independently associated with greater injury on MRI (OR 5.00, 95% CI 1.47 to 17.05 p=0.01). Neither aEEG background, nor 10 min Apgar score were significant.Electrographic seizure burden is associated with severity of brain injury on MRI in newborns with HIE undergoing TH, independent of degree of abnormality on aEEG background. Seizures are common during cooling, particularly on day 1, with a significant rebound on day 4.

    View details for DOI 10.1136/archdischild-2013-305206

    View details for Web of Science ID 000334673600011

    View details for PubMedID 24443407

  • Risk factors for EEG seizures in neonates treated with hypothermia: A multicenter cohort study. Neurology Glass, H. C., Wusthoff, C. J., Shellhaas, R. A., Tsuchida, T. N., Bonifacio, S. L., Cordeiro, M., Sullivan, J., Abend, N. S., Chang, T. 2014; 82 (14): 1239-1244

    Abstract

    To assess the risk factors for electrographic seizures among neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE).Three-center observational cohort study of 90 term neonates treated with hypothermia, monitored with continuous video-EEG (cEEG) within the first day of life (median age at onset of recording 9.5 hours, interquartile range 6.3-14.5), and continued for >24 hours (total recording 93.3 hours, interquartile range 80.1-112.8 among survivors). A pediatric electroencephalographer at each site reviewed cEEGs for electrographic seizures and initial EEG background category.A total of 43 (48%) had electrographic seizures, including 9 (10%) with electrographic status epilepticus. Abnormal initial EEG background classification (excessively discontinuous, depressed and undifferentiated, burst suppression, or extremely low voltage), but not clinical variables (including pH <6.8, base excess ≤-20, or 10-minute Apgar ≤3), was strongly associated with seizures.Electrographic seizures are common among neonates with HIE undergoing hypothermia and are difficult to predict based on clinical features. These results justify the recommendation for cEEG monitoring in neonates treated with hypothermia.

    View details for DOI 10.1212/WNL.0000000000000282

    View details for PubMedID 24610326

  • Electrographic seizures and status epilepticus in critically ill children and neonates with encephalopathy LANCET NEUROLOGY Abend, N. S., Wusthoff, C. J., Goldberg, E. M., Dlugos, D. J. 2013; 12 (12): 1170-1179

    Abstract

    Electrographic seizures are seizures that are evident on EEG monitoring. They are common in critically ill children and neonates with acute encephalopathy. Most electrographic seizures have no associated clinical changes, and continuous EEG monitoring is necessary for identification. The effect of electrographic seizures on outcome is the focus of active investigation. Studies have shown that a high burden of electrographic seizures is associated with worsened clinical outcome after adjustment for cause and severity of brain injury, suggesting that a high burden of such seizures might independently contribute to secondary brain injury. Further research is needed to determine whether identification and management of electrographic seizures reduces secondary brain injury and improves outcome in critically ill children and neonates.

    View details for Web of Science ID 000327924100012

    View details for PubMedID 24229615

  • Amplitude-Integrated Electro-encephalography The Child Neurologist's Perspective JOURNAL OF CHILD NEUROLOGY Glass, H. C., Wusthoff, C. J., Shellhaas, R. A. 2013; 28 (10): 1342-1350

    Abstract

    Neurologists increasingly recognize that critically ill patients are at high risk for seizures, particularly nonconvulsive seizures, and that neuromonitoring is a useful tool for diagnosing seizures and assessing brain function in these patients. Amplitude-integrated electroencephalography (EEG) is a simplified bedside neurophysiology tool that has become widely used in neonates over the past decade. Despite widespread interest by both neurologists and neonatologists in continuous brain monitoring, amplitude-integrated EEG has been largely ignored by neurologists, forcing neonatologists to "go it alone" when interpreting data from this bedside tool. Although amplitude-integrated EEG cannot replace conventional EEG for background monitoring and detection of seizures, it remains a useful instrument that complements conventional EEG, is being widely adopted by neonatologists, and should be supported by neonatal neurologists.

    View details for DOI 10.1177/0883073813488663

    View details for Web of Science ID 000324399300025

    View details for PubMedID 23690296

  • Neurodevelopmental outcome in children with congenital heart disease SEMINARS IN FETAL & NEONATAL MEDICINE Martinez-Biarge, M., Jowett, V. C., Cowan, F. M., Wusthoff, C. J. 2013; 18 (5): 279-285

    Abstract

    Children with congenital heart disease (CHD) have multiple factors contributing toward their risk of later neurodevelopmental difficulties. With earlier diagnosis and improved survival rates, the management of CHD now includes the recognition of neurodevelopmental risks and optimisation of neurodevelopmental outcomes is emphasised. Neuroimaging studies have shown early differences in brain development for children with CHD, who then are vulnerable to additional brain injury in the perinatal period. For some children, complications and co-morbidities may further increase the risk of brain injury. Synthesis of multiple factors is necessary to estimate neurodevelopmental prognosis for an individual child. Long-term neurodevelopmental follow-up of children with CHD is warranted for early identification of and intervention for difficulties.

    View details for DOI 10.1016/j.siny.2013.04.006

    View details for Web of Science ID 000325905300007

    View details for PubMedID 23706956

  • How to use: the neonatal neurological examination. Archives of disease in childhood. Education and practice edition Wusthoff, C. J. 2013; 98 (4): 148-153

    Abstract

    The neurological exam can be a challenging part of a newborn's full evaluation. At the same time, the neonatal neurological exam is a useful tool in identifying babies needing closer evaluation for potential problems. The Dubowitz assessment is a standardised approach to the neonatal neurological exam designed for use by paediatricians in routine practice. Evidence has validated this technique and delineated its utility as a screening exam in various populations. This paper reviews clinical application of the Dubowitz assessment of the newborn.

    View details for DOI 10.1136/archdischild-2013-303640

    View details for PubMedID 23761325

  • Genetic testing in children with epilepsy. Continuum (Minneapolis, Minn.) Wusthoff, C. J., Olson, D. M. 2013; 19 (3 Epilepsy): 795-800

    Abstract

    Genetic testing is now available clinically for several epilepsies. Neurologists increasingly face decisions about diagnostic testing in affected patients and should carefully deliberate the ethical considerations associated with genetic testing. The merits of ordering a genetic test are largely based on the utility for guiding clinical care, providing a prognosis, estimating recurrence risk, and identifying comorbidities. At the same time, a decision to pursue any genetic testing also requires evaluation of associated ethical concerns. This case illustrates ethical challenges that arise when considering genetic testing for a pediatric patient with epilepsy.

    View details for DOI 10.1212/01.CON.0000431393.39099.89

    View details for PubMedID 23739111

  • Diagnosing Neonatal Seizures and Status Epilepticus JOURNAL OF CLINICAL NEUROPHYSIOLOGY Wusthoff, C. J. 2013; 30 (2): 115-121

    Abstract

    Continuous electroencephalographic (CEEG) monitoring is often applied in the Neonatal Intensive Care Unit to aid in the diagnosis and management of seizures. Neonatal seizures are particularly difficult to identify on the basis of clinical observation alone; diagnosis is greatly facilitated by CEEG monitoring. There is building evidence to suggest which neonates are at highest risk for seizures, and how CEEG can aid diagnosis. For the neurophysiologist, the unique features of neonatal seizures can distinguish them from nonictal patterns. These features include duration, location, morphology, and evolution. At the extreme, very frequent or prolonged neonatal seizures constitute status epilepticus. There is no consensus definition for neonatal status epilepticus, although the proposed criteria share some features. This article reviews available evidence to guide the application and interpretation of CEEG in the diagnosis of neonatal seizures and status epilepticus.

    View details for DOI 10.1097/WNP.0b013e3182872932

    View details for Web of Science ID 000316943400003

    View details for PubMedID 23545761

  • American Clinical Neurophysiology Society Standardized EEG Terminology and Categorization for the Description of Continuous EEG Monitoring in Neonates: Report of the American Clinical Neurophysiology Society Critical Care Monitoring Committee JOURNAL OF CLINICAL NEUROPHYSIOLOGY Tsuchida, T. N., Wusthoff, C. J., Shellhaas, R. A., Abend, N. S., Hahn, C. D., Sullivan, J. E., Nguyen, S., Weinstein, S., Scher, M. S., Riviello, J. J., Clancy, R. R. 2013; 30 (2): 161-173

    View details for DOI 10.1097/WNP.0b013e3182872b24

    View details for Web of Science ID 000316943400009

    View details for PubMedID 23545767

  • American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology: 2012 version JOURNAL OF CLINICAL NEUROPHYSIOLOGY Hirsch, L. J., LaRoche, S. M., Gaspard, N., Gerard, E., Svoronos, A., Herman, S. T., Mani, R., Arif, H., Jette, N., Minazad, Y., Kerrigan, J. F., Vespa, P., Hantus, S., Claassen, J., Young, G. B., So, E., Kaplan, P. W., Nuwer, M. R., Fountain, N. B., Drislane, F. W. 2013; 30 (1): 1-27

    View details for DOI 10.1097/WNP.0b013e3182784729

    View details for Web of Science ID 000314695400001

    View details for PubMedID 23377439

  • Hypoglycaemia and neonatal brain injury ARCHIVES OF DISEASE IN CHILDHOOD-EDUCATION AND PRACTICE EDITION Boardman, J. P., Wusthoff, C. J., Cowan, F. M. 2013; 98 (1): 2-6
  • White Matter and Cortical Injury in Hypoxic-Ischemic Encephalopathy: Antecedent Factors and 2-Year Outcome JOURNAL OF PEDIATRICS Martinez-Biarge, M., Bregant, T., Wusthoff, C. J., Chew, A. T., Diez-Sebastian, J., Rutherford, M. A., Cowan, F. M. 2012; 161 (5): 799-807

    Abstract

    To examine the spectrum of isolated white matter (WM)/cortical injury and its relation to outcomes in infants with hypoxic-ischemic encephalopathy (HIE) and normal appearing basal ganglia and thalami.From 1992-2007, 84 term infants with HIE and normal basal ganglia and thalami on neonatal magnetic resonance imaging were studied; WM/cortical lesions were classified by site and severity. Neurodevelopmental outcomes and head growth were documented at a median age of 2 years.The WM was normal or mildly abnormal in 33.5%, moderate in 40.5%, and severely abnormal in 26% of infants. Cortical involvement was not seen or was only mild in 75.5%, moderate in 13%, and severe in 12% of infants. WM and cortical injury severity were highly correlated (Spearman ρ = 0.74; P < .001). Infants with severe WM injury had more severe neonatal courses and a higher incidence of hypoglycemia. No infant died. Five infants (6%) developed cerebral palsy but all could walk independently. Cognitive, visual, language, behavioral, and seizure problems were highly prevalent and correlated significantly with the severity of WM injury and poor postnatal head growth.Infants with HIE and selective WM/cortical injury have a low prevalence of cerebral palsy but have a wide range of other problems, which occur more often with severe WM/cortical lesions.

    View details for DOI 10.1016/j.jpeds.2012.04.054

    View details for Web of Science ID 000310370600009

    View details for PubMedID 22682614

  • Feeding and communication impairments in infants with central grey matter lesions following perinatal hypoxic-ischaemic injury EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY Martinez-Biarge, M., Diez-Sebastian, J., Wusthoff, C. J., Lawrence, S., Aloysius, A., Rutherford, M. A., Cowan, F. M. 2012; 16 (6): 688-696

    Abstract

    Basal ganglia and thalamic (BGT) injury is common after acute perinatal hypoxia-ischaemia. Cerebral palsy is the most obvious consequence of BGT injury affecting 70-75% of survivors and is predictable from neonatal magnetic resonance imaging (MRI). However there is no equivalent predictive data for other specific outcomes. Feeding and communication impairments are also common in children following hypoxic-ischaemic encephalopathy (HIE) and BGT injury.To describe, in infants with HIE and BGT injury, the prevalence of feeding and communication impairments; and to evaluate the accuracy of early MRI for predicting these outcomes.175 term infants with HIE and BGT injury were studied. Brain lesions were classified by site and severity from the MRI scans. Motor, feeding and communication impairments were documented at 2 years.Feeding and communication impairments occurred in 65% and 82% of 126 survivors respectively and related strongly to the severity of motor impairment. Forty-one children had a gastrostomy or long-term nasogastric tube. Injury severity in all brain regions was significantly associated with feeding and communication impairment on univariate analysis. On logistic regression analysis BGT (OR 10.9) and mesencephalic lesions (OR 3.7) were independently associated with feeding impairment; BGT (OR 10.5) and pontine lesions (OR 3.8) were associated with gastrostomy; the severity of BGT lesions (OR 20.1) was related to the severity of communication impairment.Feeding and communication impairment are very common in children with BGT and brainstem injury of neonatal origin and can be well predicted from early MRI scans.

    View details for DOI 10.1016/j.ejpn.2012.05.001

    View details for Web of Science ID 000310862800019

    View details for PubMedID 22658307

  • Neonatal Seizures and Status Epilepticus JOURNAL OF CLINICAL NEUROPHYSIOLOGY Abend, N. S., Wusthoff, C. J. 2012; 29 (5): 441-448

    Abstract

    Neonatal seizures are common, often require EEG monitoring for diagnosis and management, may be associated with worse neurodevelopmental outcome, and can often be treated with existing anticonvulsants. A neonatal electrographic seizure is defined as a sudden, repetitive, evolving, and stereotyped event of abnormal electrographic pattern with amplitude of at least 2 μV and a minimum duration of 10 seconds. The diagnosis of neonatal seizures relies heavily on the neurophysiologist's interpretation of EEG. Consideration of specific criteria for the definition of a neonatal seizure, including seizure duration, location, morphology, evolution, semiology, and overall seizure burden, has utility for both the clinician and the researcher. The importance of EEG in the diagnosis and management of neonatal seizures, the electrographic characteristics of neonatal seizures, the impact of neonatal seizures on outcome, and tools to aid in the identification of neonatal seizures are reviewed.

    View details for DOI 10.1097/WNP.0b013e31826bd90d

    View details for Web of Science ID 000309547600012

    View details for PubMedID 23027101

  • Prediction of neurodevelopmental outcome after hypoxic-ischemic encephalopathy treated with hypothermia by diffusion tensor imaging analyzed using tract-based spatial statistics PEDIATRIC RESEARCH Tusor, N., Wusthoff, C., Smee, N., Merchant, N., Arichi, T., Allsop, J. M., Cowan, F. M., Azzopardi, D., Edwards, A. D., Counsell, S. J. 2012; 72 (1): 63-69

    Abstract

    Objective biomarkers are needed to assess neuroprotective therapies after perinatal hypoxic-ischemic encephalopathy (HIE). We tested the hypothesis that, in infants who underwent therapeutic hypothermia after perinatal HIE, neurodevelopmental performance was predicted by fractional anisotropy (FA) values in the white matter (WM) on early diffusion tensor imaging (DTI) as assessed by means of tract-based spatial statistics (TBSS).We studied 43 term infants with HIE. Developmental assessments were carried out at a median (range) age of 24 (12-28) mo.As compared with infants with favorable outcomes, those with unfavorable outcomes had significantly lower FA values (P < 0.05) in the centrum semiovale, corpus callosum (CC), anterior and posterior limbs of the internal capsule, external capsules, fornix, cingulum, cerebral peduncles, optic radiations, and inferior longitudinal fasciculus. In a second analysis in 32 assessable infants, the Griffiths Mental Development Scales (Revised) (GMDS-R) showed a significant linear correlation (P < 0.05) between FA values and developmental quotient (DQ) and all its component subscale scores.DTI analyzed by TBSS provides a qualified biomarker that can be used to assess the efficacy of additional neuroprotective therapies after HIE.

    View details for DOI 10.1038/pr.2012.40

    View details for Web of Science ID 000305440100010

    View details for PubMedID 22447318

  • Amplitude-integrated electroencephalography: a runaway horse? Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques Dysart, K. C., Kirpalani, H. M., Kirpalani, H. M., Wusthoff, C. J., Seshia, S. S. 2012; 39 (3): 267-268

    View details for PubMedID 22547504

  • Modified Pediatric ASPECTS Correlates with Infarct Volume in Childhood Arterial Ischemic Stroke. Frontiers in neurology Beslow, L. A., Vossough, A., Dahmoush, H. M., Kessler, S. K., Stainman, R., Favilla, C. G., Wusthoff, C. J., Zelonis, S., Licht, D. J., Ichord, R. N., Smith, S. E. 2012; 3: 122-?

    Abstract

    Background and Purpose: Larger infarct volume as a percent of supratentorial brain volume (SBV) predicts poor outcome and hemorrhagic transformation in childhood arterial ischemic stroke (AIS). In perinatal AIS, higher scores on a modified pediatric version of the Alberta Stroke Program Early CT Score using acute MRI (modASPECTS) predict later seizure occurrence. The objectives were to establish the relationship of modASPECTS to infarct volume in perinatal and childhood AIS and to establish the interrater reliability of the score. Methods: We performed a cross sectional study of 31 neonates and 40 children identified from a tertiary care center stroke registry with supratentorial AIS and acute MRI with diffusion weighted imaging (DWI) and T2 axial sequences. Infarct volume was expressed as a percent of SBV using computer-assisted manual segmentation tracings. ModASPECTS was performed on DWI by three independent raters. The modASPECTS were compared among raters and to infarct volume as a percent of SBV. Results: ModASPECTS correlated well with infarct volume. Spearman rank correlation coefficients (ρ) for the perinatal and childhood groups were 0.76, p < 0.001 and 0.69, p < 0.001, respectively. Excluding one perinatal and two childhood subjects with multifocal punctate ischemia without large or medium sized vessel stroke, ρ for the perinatal and childhood groups were 0.87, p < 0.001 and 0.80, p < 0.001, respectively. The intraclass correlation coefficients for the three raters for the neonates and children were 0.93 [95% confidence interval (CI) 0.89-0.97, p < 0.001] and 0.94 (95% CI 0.91-0.97, p < 0.001), respectively. Conclusion: The modified pediatric ASPECTS on acute MRI can be used to estimate infarct volume as a percent of SBV with a high degree of validity and interrater reliability.

    View details for PubMedID 23015799

  • The American Clinical Neurophysiology Society's Guideline on Continuous Electroencephalography Monitoring in Neonates JOURNAL OF CLINICAL NEUROPHYSIOLOGY Shellhaas, R. A., Chang, T., Tsuchida, T., Scher, M. S., Riviello, J. J., Abend, N. S., Sylvie Nguyen, S., Wusthoff, C. J., Clancy, R. R. 2011; 28 (6): 611-617

    View details for Web of Science ID 000298821700012

    View details for PubMedID 22146359

  • Risk of Later Seizure After Perinatal Arterial Ischemic Stroke: A Prospective Cohort Study PEDIATRICS Wusthoff, C. J., Kessler, S. K., Vossough, A., Ichord, R., Zelonis, S., Halperin, A., Gordon, D., Vargas, G., Licht, D. J., Smith, S. E. 2011; 127 (6): E1550-E1557

    Abstract

    Although acute seizures are common among neonates with arterial ischemic stroke (AIS), the incidence of subsequent seizures is unknown. The goals of this study were to determine the incidence of seizures following hospital discharge after perinatal acute AIS, and to assess lesion characteristics associated with later seizure occurrence.Neonates with confirmed acute AIS on MRI were identified through a prospective stroke registry. Clinic visits and telephone follow-up identified occurrence of seizures after hospital discharge. MRI scans were graded for size and characteristics of infarct, and associations with seizures after stroke were analyzed.At a mean (SD) follow-up of 31.3 (16.1) months, 11 of 46 (23.9%) patients with perinatal AIS had at least 1 seizure. Five patients had a single episode of seizure, and 6 developed epilepsy. The Kaplan-Meier probability of remaining seizure-free at 3 years was 73%. Stroke size on MRI was significantly associated with development of later seizures, with an incidence rate of later seizures 6.2 times higher among those with larger stroke size.Seizures occurred in <25% of patients during initial follow-up after perinatal AIS. Of those with seizures, nearly half had a single episode of seizure and not early epilepsy. Larger stroke size was associated with higher risk of seizure. These data suggest that prolonged treatment with anticonvulsant agents may not be indicated for seizure prophylaxis after perinatal AIS. These findings may help guide clinicians in counseling families and could form the basis for much-needed future research in this area.

    View details for DOI 10.1542/peds.2010-1577

    View details for Web of Science ID 000291146100024

    View details for PubMedID 21576305

  • Electrographic Seizures During Therapeutic Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy JOURNAL OF CHILD NEUROLOGY Wusthoff, C. J., Dlugos, D. J., Gutierrez-Colina, A., Wang, A., Cook, N., Donnelly, M., Clancy, R., Abend, N. S. 2011; 26 (6): 724-728

    Abstract

    Electrographic seizures are common in neonates with hypoxic-ischemic encephalopathy, but detailed data are not available regarding seizure incidence during therapeutic hypothermia. The objective of this prospective study was to determine the incidence and timing of electrographic seizures in term neonates undergoing whole-body therapeutic hypothermia for hypoxic-ischemic encephalopathy as detected by conventional full-array electroencephalography for 72 hours of therapeutic hypothermia and 24 hours of normothermia. Clinical and electroencephalography data were collected from 26 consecutive neonates. Electroencephalograms were reviewed by 2 pediatric neurophysiologists. Electrographic seizures occurred in 17 of 26 (65%) patients. Seizures were entirely nonconvulsive in 8 of 17 (47%), status epilepticus occurred in 4 of 17 (23%), and seizure onset was in the first 48 hours in 13 of 17 (76%) patients. Electrographic seizures were common, were often nonconvulsive, and had onset over a broad range of times in the first days of life.

    View details for DOI 10.1177/0883073810390036

    View details for Web of Science ID 000290961000009

    View details for PubMedID 21447810

  • The ketogenic diet in treatment of two adults with prolonged nonconvulsive status epilepticus EPILEPSIA Wusthoff, C. J., Kranick, S. M., Morley, J. F., Bergqvist, A. G. 2010; 51 (6): 1083-1085

    Abstract

    Prolonged status epilepticus (SE) can be refractory to conventional interventions, with high rates of subsequent morbidity and mortality. A high fat, low protein, low carbohydrate ketogenic diet (KD) has been used successfully to treat intractable epilepsy. However, its possible role in prolonged SE has not been well described. We report successful use of the KD in two adult patients with prolonged nonconvulsive SE (NCSE) refractory to multiple other interventions. Our observations suggest induction of ketosis may be a novel strategy to safely and effectively treat status in adults even after weeks to months of refractory seizures. Although there are few data regarding the use of the ketogenic diet in the treatment of adult epilepsy syndromes, it may be an option for the treatment of adults with refractory, prolonged SE.

    View details for DOI 10.1111/j.1528-1167.2009.02388.x

    View details for Web of Science ID 000278307900019

    View details for PubMedID 19845731

  • Interictal EEG spikes identify the region of electrographic seizure onset in some, but not all, pediatric epilepsy patients EPILEPSIA Marsh, E. D., Peltzer, B., Brown, M. W., Wusthoff, C., Storm, P. B., Litt, B., Porter, B. E. 2010; 51 (4): 592-601

    Abstract

    The role of sharps and spikes, interictal epileptiform discharges (IEDs), in guiding epilepsy surgery in children remains controversial, particularly with intracranial electroencephalography (IEEG). Although ictal recording is the mainstay of localizing epileptic networks for surgical resection, current practice dictates removing regions generating frequent IEDs if they are near the ictal onset zone. Indeed, past studies suggest an inconsistent relationship between IED and seizure-onset location, although these studies were based upon relatively short EEG epochs.We employ a previously validated, computerized spike detector to measure and localize IED activity over prolonged, representative segments of IEEG recorded from 19 children with intractable, mostly extratemporal lobe epilepsy. Approximately 8 h of IEEG, randomly selected 30-min segments of continuous interictal IEEG per patient, were analyzed over all intracranial electrode contacts.When spike frequency was averaged over the 16-time segments, electrodes with the highest mean spike frequency were found to be within the seizure-onset region in 11 of 19 patients. There was significant variability between individual 30-min segments in these patients, indicating that large statistical samples of interictal activity were required for improved localization. Low-voltage fast EEG at seizure onset was the only clinical factor predicting IED localization to the seizure-onset region.Our data suggest that automated IED detection over multiple representative samples of IEEG may be of utility in planning epilepsy surgery for children with intractable epilepsy. Further research is required to better determine which patients may benefit from this technique a priori.

    View details for DOI 10.1111/j.1528-1167.2009.02306.x

    View details for Web of Science ID 000276245600012

    View details for PubMedID 19780794

    View details for PubMedCentralID PMC2907216

  • Limitations of single-channel EEG on the forehead for neonatal seizure detection JOURNAL OF PERINATOLOGY Wusthoff, C. J., Shellhaas, R. A., Clancy, R. R. 2009; 29 (3): 237-242

    Abstract

    In amplitude-integrated EEG, lead placement across the forehead is convenient, but this location has unknown effects on neonatal seizure (NS) detection sensitivity. This study describes the limits of NS detection by a single forehead EEG channel.Records were taken from a digital library of conventional EEGs (CEEGs) with NS, previously characterized at a bicentral channel, C(3) --> C(4). We analyzed electrographic characteristics in a single forehead channel, Fp(3) --> Fp(4).A total of 330 seizures from 125 CEEGs were included. With Fp(3) --> Fp(4), at least one NS was detected in 66% of records vs 90% using C(3) --> C(4) (P<0.0001). Of 330 seizures, 46% appeared in Fp(3) --> Fp(4) vs 73% in C(3) --> C(4) (P<0.0001). Seizures appeared briefer in Fp(3) --> Fp(4) than C(3) --> C(4) (P<0.006) and CEEG (P<0.0001).NSs are significantly more difficult to detect with a single forehead channel than bicentrally or on CEEG. In Fp(3) --> Fp(4), a third of records with seizures were missed and over half of seizures were undetected.

    View details for DOI 10.1038/jp.2008.195

    View details for Web of Science ID 000263893500011

    View details for PubMedID 19052554

  • Hemosiderin-laden macrophages in the cerebrospinal fluid of a neonate after traumatic lumbar puncture PEDIATRIC INFECTIOUS DISEASE JOURNAL Wusthoff, C. J., Abend, N. S., Tennekoon, G. 2008; 27 (1): 83-84

    Abstract

    Macrophages in cerebrospinal fluid are described as indicators of pathology. We present findings from the lumbar puncture of a child without neurologic disease. Cerebrospinal fluid obtained after an initial, traumatic lumbar puncture attempt included a high proportion of macrophages, some containing erythrocyte fragments and hemosiderin. This suggests that although macrophages may indicate pathology, they can also accumulate after traumatic lumbar puncture.

    View details for DOI 10.1097/INF.0b013e3181506463

    View details for Web of Science ID 000252076200022

    View details for PubMedID 18162950

  • Management of common neurologic symptoms in pediatric palliative care: Seizures, agitation, and spasticity PEDIATRIC CLINICS OF NORTH AMERICA Wusthoff, C. J., Shellhaas, R. A., Licht, D. J. 2007; 54 (5): 709-?

    Abstract

    Palliative care for children is complex and focuses on patients' comfort. Some of the most troublesome symptoms as patients approach the end of life are seizures, agitation, and spasticity. Many doctors caring for children at the end of life are uncomfortable or untrained in managing these symptoms in children. Our goal is to help physicians recognize and treat these neurologic symptoms optimally.

    View details for DOI 10.1016/j.pcl.2007.06.004

    View details for Web of Science ID 000252210800008

    View details for PubMedID 17933619

  • Differences in pediatric oncologists' estimates of curability and treatment recommendations for patients with advanced cancer: Response PEDIATRIC BLOOD & CANCER Wusthoff, C. J., Ablin, A. R., McMillan, A. 2005; 45 (3): 358-358

    View details for DOI 10.1002/pbc.20410

    View details for Web of Science ID 000230740000025

  • Differences in pediatric oncologists' estimates of curability and treatment recommendations for patients with advanced cancer PEDIATRIC BLOOD & CANCER Wusthoff, C. J., McMillan, A., Ablin, A. R. 2005; 44 (2): 174-181

    Abstract

    When goals of therapy for children with advanced cancer are called into question, physician recommendations regarding treatment goals have been shown to be important for families. However, there has been no demonstration of the degree of variation between pediatric oncologists' recommendations in such situations.We provided 48 pediatric oncologists with two identical case histories and identical prognostic data from the literature. Individual interviews were then performed to assess variation in (1) recommended treatment goal, (2) perceived chances for cure, and (3) degree to which further curative intervention would be considered desirable for each patient.There was a large variability in each of the areas examined. For both patients, there was wide divergence (2:1 and 2:3) in whether to recommend cure as the goal of treatment. There were also differences in physician estimates for likelihood of cure for each patient. Finally, even among those with identical estimates for likelihood of cure, there were differences in the treatment goals physicians would recommend and how strongly they would counsel for them.This study demonstrates that even with identical clinical data and prognostic evidence from the literature, pediatric oncologists vary widely in their recommendations regarding goals of treatment for children with advanced cancer.

    View details for DOI 10.1002/pbc.20153

    View details for Web of Science ID 000225904600012

    View details for PubMedID 15390284

  • The dilemma of confidentiality in Huntington disease JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Wusthoff, C. 2003; 290 (9): 1219-1220

    View details for Web of Science ID 000185090400022

    View details for PubMedID 12953009

  • Medical mistakes and disclosure: The role of the medical student JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Wusthoff, C. J. 2001; 286 (9): 1080-1081

    View details for Web of Science ID 000170802500025

    View details for PubMedID 11559297

  • Numerical subtraction in the pigeon: Evidence for a linear subjective number scale PSYCHOLOGICAL SCIENCE Brannon, E. M., Wusthoff, C. J., Gallistel, C. R., Gibbon, J. 2001; 12 (3): 238-243

    Abstract

    When humans and animals compare two numbers, responding is faster and more accurate with increasing numerical disparity and decreasing numerical size. Researchers explaining these distance and size effects often, assume that the subjective number continuum is logarithmically compressed. An alternative hypothesis is that the subjective number continuum is linear, but positions farther along it are proportionately fuzzier, that is, less precisely located. These two hypotheses have been treated as functionally equivalent because of their similar empirical predictions. The current experiment sought to resolve this issue with a paradigm originally developed to address the subjective representation of time (time left). In our adaptation, pigeons were required to compare a constant number with the number remaining after a numerical subtraction. Our results indicate that subjective number is linearly, not logarithmically, related to objective number.

    View details for Web of Science ID 000169288000009

    View details for PubMedID 11437307