Courtney Wusthoff, MD

All Publications

• 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 DOI 10.1542/peds.2018-0672

  View details for Web of Science ID 000445687600040

  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 DOI 10.1177/1833358318794501

  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 DOI 10.1055/s-0038-1646954

  View details for PubMedID 29702712

• 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 DOI 10.1001/jamapediatrics.2017.5211

  View details for Web of Science ID 000428909000013

  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 DOI 10.1371/journal.pone.0193599

  View details for Web of Science ID 000426902900027

  View details for PubMedID 29518120

  View details for PubMedCentralID PMC5843222

• 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 DOI 10.1038/jp.2017.153

  View details for Web of Science ID 000422835200010

  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 DOI 10.1111/epi.13937

  View details for Web of Science ID 000419173300010

  View details for PubMedID 29105055

  View details for PubMedCentralID PMC5863227

• 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 DOI 10.1001/jamapediatrics.2017.1743

  View details for Web of Science ID 000410140700013

  View details for PubMedID 28759667

  View details for PubMedCentralID PMC5710404

• 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

• 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 Web of Science ID 000378620800021

  View details for PubMedID 27106855

  View details for PubMedCentralID PMC4925241

• 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

• 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

• 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

• 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

• 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

• 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

  View details for DOI 10.1136/archdischild-2012-302569

  View details for Web of Science ID 000313717600002

  View details for PubMedID 23086597

• 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

• 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